研究者情報

マスター

アカウント（マスター）

• 氏名

  吉川　雄朗(ヨシカワ　タケオ), ヨシカワ　タケオ

所属（マスター）

• 医学研究院　生理系部門　薬理学分野

所属（マスター）

• 医学研究院　生理系部門　薬理学分野

researchmap

プロフィール情報

所属

• 北海道大学, 大学院医学研究院　神経薬理学教室, 教授

学位

• 医学博士（2008年03月 東北大学）

プロフィール情報

• 姓

  吉川, ヨシカワ

• 名

  雄朗, タケオ

• ID各種

  201401073899761214

対象リソース

https://pharmacology1.med.hokudai.ac.jp/

所属

• 北海道大学, 大学院医学研究院　神経薬理学教室, 教授

業績リスト

研究分野

• ライフサイエンス / 薬理学

経歴

• 2023年10月 - 現在 北海道大学脳科学研究教育センター 教員
• 2023年05月 - 現在 北海道大学 大学院医学研究院 神経薬理学教室 教授
• 2016年04月 - 2023年04月 東北大学大学院医学系研究科 機能薬理学分野 准教授
• 2009年04月 - 2016年03月 東北大学大学院医学系研究科 機能薬理学分野 助教
• 2002年04月 - 2004年03月 福島県太田総合病院附属太田西ノ内病院 研修医

学歴

• 2004年04月 - 2008年03月   東北大学   医学系研究科博士課程
• 1996年04月 - 2002年03月   東北大学   医学部医学科

受賞

• 2022年06月 東北大学医学部教室員会 2021年度教室員会 The Best Teacher Awards
  
• 2021年06月 東北大学医学部教室員会 2020年度教室員会 The Best Teacher Awards
  
• 2020年06月 東北大学医学部教室員会 2019年度教室員会 The Best Teacher Awards
  
• 2016年01月 東北大学医学部 東北大学医学部奨学賞 銀賞
  
• 2015年05月 公益財団法人 艮陵医学振興会 平成27年度匂坂記念賞
  
• 2014年03月 東北大学大学院医学系研究科 平成25年度医学部・医学系研究科教育貢献賞
  
• 2012年10月 日本ヒスタミン学会 Young Investigator Award
  

論文

• Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy

  Fumito Naganuma, Birkan Girgin, Anne Bernadette S. Agu, Kyosuke Hirano, Tadaho Nakamura, Kazuhiko Yanai, Ramalingam Vetrivelan, Takatoshi Mochizuki, Masashi Yanagisawa, Takeo Yoshikawa

  Sleep 2024年10月 [査読有り][通常論文]
  
• MAST4 promotes primary ciliary resorption through phosphorylation of Tctex-1

  Kensuke Sakaji, Sara Ebrahimiazar, Yasuhiro Harigae, Kenichi Ishibashi, Takeya Sato, Takeo Yoshikawa, Gen-ichi Atsumi, Ching-Hwa Sung, Masaki Saito

  Life Science Alliance 6 11 e202301947 - e202301947 2023年09月19日 [査読有り][通常論文]
   

  The primary cilium undergoes cell cycle–dependent assembly and disassembly. Dysregulated ciliary dynamics are associated with several pathological conditions called ciliopathies. Previous studies showed that the localization of phosphorylated Tctex-1 at Thr94 (T94) at the ciliary base critically regulates ciliary resorption by accelerating actin remodeling and ciliary pocket membrane endocytosis. Here, we show that microtubule-associated serine/threonine kinase family member 4 (MAST4) is localized at the primary cilium. Suppressing MAST4 blocks serum-induced ciliary resorption, and overexpressing MAST4 accelerates ciliary resorption. Tctex-1 binds to the kinase domain of MAST4, in which the R503 and D504 residues are key to MAST4-mediated ciliary resorption. The ciliary resorption and the ciliary base localization of phospho-(T94)Tctex-1 are blocked by the knockdown of MAST4 or the expression of the catalytic-inactive site-directed MAST4 mutants. Moreover, MAST4 is required for Cdc42 activation and Rab5-mediated periciliary membrane endocytosis during ciliary resorption. These results support that MAST4 is a novel kinase that regulates ciliary resorption by modulating the ciliary base localization of phospho-(T94)Tctex-1. MAST4 is a potential new target for treating ciliopathies causally by ciliary resorption defects.
• Epitope Mapping of Anti-Mouse CCR3 Monoclonal Antibodies (C3Mab-6 and C3Mab-7).

  Nami Tateyama, Teizo Asano, Tomohiro Tanaka, Yu Isoda, Yuki Okada, Hiyori Kobayashi, Guanjie Li, Ren Nanamiya, Takeo Yoshikawa, Mika K Kaneko, Hiroyuki Suzuki, Yukinari Kato

  Monoclonal antibodies in immunodiagnosis and immunotherapy 42 2 68 - 72 2023年04月18日 

  One of G protein-coupled receptors, CC chemokine receptor 3 (CCR3), is expressed in eosinophils, basophils, a subset of Th2 lymphocytes, mast cells, and airway epithelial cells. CCR3 levels in the serum of colorectal cancer patients are significantly higher than in control groups. Moreover, CCR3 is essential for recruiting eosinophils into the lung. Therefore, CCR3 is considered both a therapeutic target for colorectal cancer and allergic diseases. Previously, we established anti-mouse CCR3 (mCCR3) monoclonal antibodies (mAbs), C3Mab-6 (rat IgG1, kappa) and C3Mab-7 (rat IgG1, kappa), by immunizing a rat with an N-terminal peptide of mCCR3. These mAbs can be used in flow cytometry and enzyme-linked immunosorbent assays. In this study, we performed the epitope mapping of C3Mab-6 and C3Mab-7 using alanine scanning. The reactivity between these mAbs and point mutants of mCCR3 were analyzed using flow cytometry. The results indicated that Phe3, Asn4, Thr5, Asp6, Glu7, Lys9, Thr10, and Glu13 of mCCR3 are essential for C3Mab-6 binding, whereas Phe15 and Glu16 are essential for C3Mab-7 binding.
• Epitope Mapping of the Novel Anti-Human CCR9 Monoclonal Antibody (C9Mab-11) by 2 × Alanine Scanning.

  Yu Isoda, Tomohiro Tanaka, Hiroyuki Suzuki, Teizo Asano, Kaishi Kitamura, Yuma Kudo, Ryo Ejima, Kazuki Ozawa, Takeo Yoshikawa, Mika K Kaneko, Yukinari Kato

  Monoclonal antibodies in immunodiagnosis and immunotherapy 42 2 73 - 76 2023年04月 

  We recently developed a novel anti-human C-C chemokine receptor 9 (hCCR9) monoclonal antibody (mAb), C9Mab-11, which is applicable to flow cytometry, western blotting, and enzyme-linked immunosorbent assay (ELISA). This study aims to identify the binding epitope of C9Mab-11 by using 1 × and 2 × alanine (or glycine) substituted-hCCR9 peptides (1 × and 2 × Ala-scan) by ELISA. According to the 1 × Ala-scan analysis, the response of C9Mab-11 was diminished against M13A of the hCCR9 peptide, but was not eliminated. In the 2 × Ala-scan analysis, the reactions were abolished in the substitution of P11A-N12A, N12A-M13A, and M13A-A14G of hCCR9 N-terminal peptides. The results indicate that the binding epitope of C9Mab-11 includes Pro11, Asn12, Met13, and Ala14 of hCCR9, with the region around Met13 being particularly important. The successful identification of the C9Mab-11 epitope might be useful for the future pathophysiological analysis of hCCR9.
• Epitope Mapping of an Anti-EpCAM Monoclonal Antibody (EpMab-37) Using the Alanine Scanning Method.

  Guanjie Li, Hiroyuki Suzuki, Tomohiro Tanaka, Teizo Asano, Takeo Yoshikawa, Mika K Kaneko, Yukinari Kato

  Monoclonal antibodies in immunodiagnosis and immunotherapy 42 1 41 - 47 2023年02月 

  The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein, and plays critical roles in cell adhesion, proliferation, and tumorigenesis. EpCAM has been considered as a promising target for tumor diagnosis and therapy. Anti-EpCAM monoclonal antibodies (mAbs) have been developed for EpCAM-overexpressed tumors, and several clinical trials have demonstrated promising outcomes. We previously established an anti-EpCAM mAb, EpMab-37 (mouse IgG1, kappa), using the Cell-Based Immunization and Screening method. EpMab-37 was revealed to recognize the conformational epitope of EpCAM. In this study, we determined the critical epitope of EpMab-37 by flow cytometry using the 1 × alanine scanning (1 × Ala-scan) and the 2 × alanine scanning (2 × Ala-scan) method. We first performed flow cytometry by 1 × Ala-scan using one alanine (or glycine)-substituted EpCAM mutants, which were expressed on Chinese hamster ovary-K1 cells, and found that the EpMab-37 did not recognize the R163A mutant of EpCAM. We next performed flow cytometry by 2 × Ala-scan using two alanine (or glycine) residues-substituted EpCAM mutants, and confirmed that EpMab-37 did not recognize R163A-including mutants of EpCAM. The results indicated that the critical binding epitope of EpMab-37 includes Arg163 of EpCAM.
• Antitumor activities of a defucosylated anti‑EpCAM monoclonal antibody in colorectal carcinoma xenograft models

  Guanjie Li, Hiroyuki Suzuki, Tomokazu Ohishi, Teizo Asano, Tomohiro Tanaka, Miyuki Yanaka, Takuro Nakamura, Takeo Yoshikawa, Manabu Kawada, Mika Kaneko, Yukinari Kato

  International Journal of Molecular Medicine 51 2 2023年01月18日 [査読有り]
  
• Establishment of a Sensitive Monoclonal Antibody Against Mouse CCR9 (C₉Mab-24) for Flow Cytometry

  Hiyori Kobayashi, Teizo Asano, Hiroyuki Suzuki, Tomohiro Tanaka, Takeo Yoshikawa, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 42 1 15 - 21 2022年12月13日 [査読有り][通常論文]
   

  The CC chemokine receptor 9 (CCR9), also known as CD199, is one of chemokine receptors. The CC chemokine ligand 25 (CCL25) is known to be the only ligand for CCR9. The CCR9-CCL25 interaction plays important roles in chemotaxis of lymphocytes and tumor cell migration. Therefore, CCR9-CCL25 axis is a promising target for tumor therapy and diagnosis. In this study, we established a sensitive and specific monoclonal antibody (mAb) against mouse CCR9 (mCCR9) using N-terminal peptide immunization method. The established anti-mCCR9 mAb, C9Mab-24 (rat immunoglobulin [IgG]2a, kappa), reacted with mCCR9-overexpressed Chinese hamster ovary-K1 (CHO/mCCR9) and mCCR9-endogenously expressed cell line, RL2, through flow cytometry. Kinetic analyses using flow cytometry showed that the dissociation constants (KD) of C9Mab-24 for CHO/mCCR9 and RL2 cell lines were 6.0 × 10-9 M and 4.7 × 10-10 M, respectively. Results indicated that C9Mab-24 is useful for detecting mCCR9 through flow cytometry, thereby providing a possibility for targeting mCCR9-expressing cells in vivo experiments.
• Epitope Mapping of Anti-Mouse CCR3 Monoclonal Antibodies Using Flow Cytometry

  Nami Tateyama, Teizo Asano, Hiroyuki Suzuki, Guanjie Li, Takeo Yoshikawa, Tomohiro Tanaka, Mika K. Kaneko, Yukinari Kato

  Antibodies 11 4 75 - 75 2022年12月02日 [査読有り][通常論文]
   

  The CC chemokine receptor 3 (CCR3) is a receptor for CC chemokines, including CCL5/RANTES, CCL7/MCP-3, and CCL11/eotaxin. CCR3 is expressed on the surface of eosinophils, basophils, a subset of Th2 lymphocytes, mast cells, and airway epithelial cells. CCR3 and its ligands are involved in airway hyperresponsiveness in allergic asthma, ocular allergies, and cancers. Therefore, CCR3 is an attractive target for those therapies. Previously, anti-mouse CCR3 (mCCR3) monoclonal antibodies (mAbs), C3Mab-3 (rat IgG2a, kappa), and C3Mab-4 (rat IgG2a, kappa) were developed using the Cell-Based Immunization and Screening (CBIS) method. In this study, the binding epitope of these mAbs was investigated using flow cytometry. A CCR3 extracellular domain-substituted mutant analysis showed that C3Mab-3, C3Mab-4, and a commercially available mAb (J073E5) recognized the N-terminal region (amino acids 1–38) of mCCR3. Next, alanine scanning was conducted in the N-terminal region. The results revealed that the Ala2, Phe3, Asn4, and Thr5 of mCCR3 are involved in C3Mab-3 binding, whereas Ala2, Phe3, and Thr5 are essential to C3Mab-4 binding, and Ala2 and Phe3 are crucial to J073E5 binding. These results reveal the involvement of the N-terminus of mCCR3 in the recognition of C3Mab-3, C3Mab-4, and J073E5.
• A Defucosylated Anti-EpCAM Monoclonal Antibody (EpMab-37-mG2a-f) Exerts Antitumor Activity in Xenograft Model

  Teizo Asano, Tomohiro Tanaka, Hiroyuki Suzuki, Guanjie Li, Tomokazu Ohishi, Manabu Kawada, Takeo Yoshikawa, Mika K. Kaneko, Yukinari Kato

  Antibodies 11 4 74 - 74 2022年11月24日 [査読有り][通常論文]
   

  The epithelial cell adhesion molecule (EpCAM) is a stem cell and carcinoma antigen, which mediates cellular adhesion and proliferative signaling by the proteolytic cleavage. In contrast to low expression in normal epithelium, EpCAM is frequently overexpressed in various carcinomas, which correlates with poor prognosis. Therefore, EpCAM has been considered as a promising target for tumor diagnosis and therapy. Using the Cell-Based Immunization and Screening (CBIS) method, we previously established an anti-EpCAM monoclonal antibody (EpMab-37; mouse IgG1, kappa). In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and an antitumor activity by a defucosylated mouse IgG2a-type of EpMab-37 (EpMab-37-mG2a-f) against a breast cancer cell line (BT-474) and a pancreatic cancer cell line (Capan-2), both of which express EpCAM. EpMab-37-mG2a-f recognized BT-474 and Capan-2 cells with a moderate binding-affinity [apparent dissociation constant (KD): 2.9 × 10−8 M and 1.8 × 10−8 M, respectively] by flow cytometry. EpMab-37-mG2a-f exhibited ADCC and CDC for both cells by murine splenocytes and complements, respectively. Furthermore, administration of EpMab-37-mG2a-f significantly suppressed the xenograft tumor development compared with the control mouse IgG. These results indicated that EpMab-37-mG2a-f exerts antitumor activities and could provide valuable therapeutic regimen for breast and pancreatic cancers.
• Defucosylated Mouse-Dog Chimeric Anti-Human Epidermal Growth Factor Receptor 2 Monoclonal Antibody (H77Bf) Exerts Antitumor Activities in Mouse Xenograft Models of Canine Osteosarcoma

  Ren Nanamiya, Tomokazu Ohishi, Hiroyuki Suzuki, Takuya Mizuno, Takeo Yoshikawa, Teizo Asano, Tomohiro Tanaka, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 42 1 27 - 33 2022年11月18日 [査読有り][通常論文]
   

  Human epidermal growth factor receptor 2 (HER2) has been studied in many human cancer types, and its overexpression and/or gene mutation contribute to the poor prognosis. Therefore, HER2 is an important therapeutic target in various cancer types, including breast and gastric cancers. We previously developed an anti-HER2 monoclonal antibody (mAb), H2Mab-77 (mouse IgG1, kappa), which detects HER2 and dog HER2 (dHER2) with high sensitivity and specificity. In this study, we produced a defucosylated mouse-dog chimeric anti-HER2 mAb (H77Bf), and investigated the reactivity against canine osteosarcoma D-17 cells by flow cytometry. Furthermore, we showed that H77Bf exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against D-17 cells in vitro and exhibited the potent antitumor activity in vivo. These results suggest that H77Bf exerts antitumor effects against dHER2-expressing canine tumors and could be valuable as part of an antibody treatment regimen for them.
• Antitumor Activity of an Anti-EGFR/HER2 Bispecific Antibody in a Mouse Xenograft Model of Canine Osteosarcoma

  Nami Tateyama, Hiroyuki Suzuki, Tomokazu Ohishi, Teizo Asano, Tomohiro Tanaka, Takuya Mizuno, Takeo Yoshikawa, Manabu Kawada, Mika K. Kaneko, Yukinari Kato

  Pharmaceutics 14 11 2494 - 2494 2022年11月17日 [査読有り][通常論文]
   

  The overexpression of epidermal growth factor receptors (EGFRs) has been reported in various human tumors, including breast, gastric, lung, colorectal, and pancreatic cancers. Humanized anti-EGFR and anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibodies (mAbs) have been shown to improve patients’ survival. Canine tumors resemble human tumors in the initiation and progression. We previously established a defucosylated mouse-dog chimeric anti-EGFR mAb (E134Bf) and a mouse-dog chimeric anti-HER2 mAb (H77Bf), which exerted antitumor activities in canine tumor xenograft models. Here, we produced E134Bf antibody fused to H77Bf single chain Fv at the light chains (E134Bf-H77scFv). The bispecific E134Bf-H77scFv recognized dog EGFR (dEGFR) and dog HER2 (dHER2)-overexpressed Chinese hamster ovary-K1 cells by flow cytometry. E134Bf-H77scFv also reacted with dEGFR/dHER2-positive canine osteosarcoma D-17 cells, and possesses a high binding-affinity (KD: 1.3 × 10−9 M). Furthermore, E134Bf-H77scFv exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against D-17 cells in the presence of canine mononuclear cells and complement, respectively. Moreover, administration of E134Bf-H77scFv suppressed the development of D-17 xenograft tumor in mice early compared with the control dog IgG, E134Bf and H77Bf alone. These results indicate that E134Bf-H77scFv exerts antitumor activities against dEGFR/dHER2-positive canine tumors, and could be a valuable treatment regimen for canine tumors.
• Development of a Novel Anti-Mouse CCR6 Monoclonal Antibody (C₆Mab-13) by N-Terminal Peptide Immunization

  Teizo Asano, Tomohiro Tanaka, Hiroyuki Suzuki, Guanjie Li, Ren Nanamiya, Nami Tateyama, Yu Isoda, Yuki Okada, Hiyori Kobayashi, Takeo Yoshikawa, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 41 6 343 - 349 2022年11月16日 [査読有り][通常論文]
   

  The CC chemokine receptor 6 (CCR6) is a G protein-coupled receptor family member that is highly expressed in B lymphocytes, certain subsets of effector and memory T cells, and immature dendritic cells. CCR6 has only one chemokine ligand, CCL20. The CCL20-CCR6 axis has been recognized as a therapeutic target for autoimmune diseases and tumor. This study developed specific monoclonal antibodies (mAbs) against mouse CCR6 (mCCR6) using the peptide immunization method. The established anti-mCCR6 mAb, C6Mab-13 (rat IgG1, kappa), reacted with mCCR6-overexpressed Chinese hamster ovary-K1 (CHO/mCCR6), and mCCR6-endogenously expressed P388 (mouse lymphoid neoplasma) and J774-1 (mouse macrophage-like) cells in flow cytometry. The dissociation constant (KD) of C6Mab-13 for CHO/mCCR6 cells was determined to be 2.8 × 10-9 M, indicating that C6Mab-13 binds to mCCR6 with high affinity. In summary, C6Mab-13 is useful for detecting mCCR6-expressing cells through flow cytometry.
• Antitumor Activities in Mouse Xenograft Models of Canine Fibroblastic Tumor by Defucosylated Mouse-Dog Chimeric Anti-HER2 Monoclonal Antibody (H77Bf)

  Hiroyuki Suzuki, Teizo Asano, Tomokazu Ohishi, Takeo Yoshikawa, Hiroyoshi Suzuki, Takuya Mizuno, Tomohiro Tanaka, Manabu Kawada, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 42 1 34 - 40 2022年11月16日 [査読有り][通常論文]
   

  Human epidermal growth factor receptor 2 (HER2) is a cell surface type I transmembrane glycoprotein that is overexpressed on a variety of solid tumors and transduces the oncogenic signaling upon homo- and heterodimerization with HER families. Anti-HER2 monoclonal antibodies (mAbs) including trastuzumab and its antibody-drug conjugate have been shown to improve patients' survival in HER2-positive breast, gastric, and lung cancers. Canine tumors have advantages as naturally occurring tumor models, and share biological and histological characteristics with human tumors. In this study, we generated a defucosylated version of mouse-dog chimeric anti-HER2 mAb (H77Bf) derived from H2Mab-77 (mouse IgG1, kappa). H77Bf possesses the high binding affinity (a dissociation constant: 8.7 × 10-10 M) for a dog HER2 (dHER2)-expressing canine fibroblastic tumor cell line (A-72). H77Bf exhibited antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity for A-72 cells. Moreover, intraperitoneal administration of H77Bf significantly suppressed the development of A-72 tumor compared with the control dog IgG in a mouse xenograft model. These results indicate that H77Bf exerts antitumor activities against dHER2-expressing canine cancers, which could provide a valuable information for canine cancer treatment.
• Development of a Sensitive Anti-Human CCR9 Monoclonal Antibody (C₉Mab-11) by N-Terminal Peptide Immunization

  Tomohiro Tanaka, Hiroyuki Suzuki, Yu Isoda, Teizo Asano, Takuro Nakamura, Miyuki Yanaka, Saori Handa, Nozomi Takahashi, Saori Okuno, Takeo Yoshikawa, Guanjie Li, Ren Nanamiya, Nohara Goto, Nami Tateyama, Yuki Okada, Hiyori Kobayashi, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 41 6 303 - 310 2022年11月16日 [査読有り][通常論文]
   

  The C-C chemokine receptor 9 (CCR9) belongs to the G-protein-coupled receptor superfamily, and is highly expressed on the T cells and intestinal cells. CCR9 regulates various immune responses by binding to the C-C chemokine ligand, CCL25, and is involved in inflammatory diseases and tumors. Therefore, the development of sensitive monoclonal antibodies (mAbs) for CCR9 is necessary for treatment and diagnosis. In this study, we established a specific anti-human CCR9 (hCCR9) mAb; C9Mab-11 (mouse IgG2a, kappa), using the synthetic peptide immunization method. C9Mab-11 reacted with hCCR9-overexpressed Chinese hamster ovary-K1 (CHO/hCCR9) and hCCR9-endogenously expressed MOLT-4 (human T-lymphoblastic leukemia) cells in flow cytometry. The dissociation constant (KD) of C9Mab-11 for CHO/hCCR9 and MOLT-4 cells were determined to be 1.2 × 10-9 M and 4.9 × 10-10 M, respectively, indicating that C9Mab-11 possesses a high affinity for both exogenously and endogenously hCCR9-expressing cells. Furthermore, C9Mab-11 clearly detected hCCR9 protein in CHO/hCCR9 cells using western blot analysis. In summary, C9Mab-11 can be a useful tool for analyzing hCCR9-related biological responses.
• Epitope Mapping Using the Cell-Based 2 × Alanine Substitution Method About the Anti-mouse CXCR6 Monoclonal Antibody, Cx₆Mab-1

  Yu Isoda, Tomohiro Tanaka, Hiroyuki Suzuki, Teizo Asano, Takeo Yoshikawa, Kaishi Kitamura, Yuma Kudo, Ryo Ejima, Kazuki Ozawa, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 42 1 22 - 26 2022年11月16日 [査読有り][通常論文]
   

  An anti-mouse CXC chemokine receptor 6 (mCXCR6) monoclonal antibody (mAb), Cx6Mab-1, was developed recently. Cx6Mab-1 is applicable for flow cytometry, Western blotting, and enzyme-linked immunosorbent assay. The purpose of this study is to determine the binding epitope of Cx6Mab-1 using 2 × alanine mutated mCXCR6. Analysis of flow cytometry revealed that Cx6Mab-1 did not recognize S8A-A9G, L10A-Y11A, D12A-G13A, and H14A-Y15A mutants of mCXCR6. The results clearly indicate that the binding epitope of Cx6Mab-1 includes Ser8, Ala9, Leu10, Tyr11, Asp12, Gly13, His14, and Tyr15 of mCXCR6. The successful determination of the Cx6Mab-1 epitope might contribute to the pathophysiological investigation of mCXCR6.
• Epitope Mapping of an Anti-Mouse CCR2 Monoclonal Antibody (C₂Mab-6) Using Enzyme-Linked Immunosorbent Assay

  Tomohiro Tanaka, Hiroyuki Suzuki, Teizo Asano, Guanjie Li, Ren Nanamiya, Nami Tateyama, Yu Isoda, Yuki Okada, Hiyori Kobayashi, Takeo Yoshikawa, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 41 6 339 - 342 2022年11月07日 [査読有り][通常論文]
   

  CC chemokine receptor type-2 (CCR2) is a member of the G protein-coupled receptors, and is mainly expressed on cell surface of immune cells. CCR2 binds to its ligand, C-C motif chemokine 2 (also named as monocyte chemoattractant protein-1), which involves in the tumor progression by modulating the tumor microenvironment. Therefore, the monoclonal antibody (mAb) targeting CCR2 could be one of the strategies for cancer treatment. In this study, we investigated the critical epitope of C2Mab-6, an anti-mouse CCR2 (mCCR2) mAb developed by N-terminal peptides immunization. We first performed enzyme-linked immunosorbent assay (ELISA) using N-terminal peptides of mCCR2 and demonstrated that C2Mab-6 recognizes 1-19 amino acids of mCCR2. We further performed ELISA using 20 alanine-substituted peptides of mCCR2. C2Mab-6 lost the reaction to the alanine-substituted peptides of D3A, N4A, M6A, P8A, Q9A, and F10A. These results indicate that the binding epitope of C2Mab-6 includes Asp3, Asn4, Met6, Pro8, Gln9, and Phe10 of mCCR2.
• KLMab-1: An Anti-human KLRG1 Monoclonal Antibody for Immunocytochemistry

  Masaki Saito, Hiroyuki Suzuki, Teizo Asano, Tomohiro Tanaka, Takeo Yoshikawa, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 41 5 279 - 284 2022年10月28日 [査読有り][通常論文]
   

  Immune checkpoint molecules have received attention as targets of cancer immunotherapy. Killer cell lectin-like receptor subfamily G member 1 (KLRG1) is one of the immune checkpoint molecules expressed in CD4+ T, CD8+ T, and natural killer (NK) cells. KLRG1 exhibits antiviral and antitumor immunity, and its expression in T and NK cells is upregulated by viral infectious diseases and some tumors. Thus, monoclonal antibodies (mAbs) for KLRG1 would be useful tools for the diagnosis and immunotherapy against viral infectious diseases and cancers. We have developed anti-human KLRG1 (hKLRG1) mAb (clone KLMab-1, mouse IgG1, kappa) by the Cell-Based Immunization and Screening method. We have also demonstrated that KLMab-1 recognizes both exogenous and endogenous hKLRG1 in flow cytometry. In this study, we first showed that KLMab-1 and its recombinant mAb (recKLMab-1) bound to exogenous hKLRG1 overexpressed in Chinese hamster ovary (CHO)-K1 cells, but not in parental CHO-K1 cells, in immunocytochemistry. We next showed that both mAbs detected endogenous hKLRG1 expressed in human NK cells. These results demonstrate that KLMab-1 and recKLMab-1 are available for immunocytochemistry.
• Epitope Mapping of an Anti-Mouse CXCR6 Monoclonal Antibody (Cx₆Mab-1) Using the 2 × Alanine Scanning Method

  Yu Isoda, Tomohiro Tanaka, Hiroyuki Suzuki, Teizo Asano, Takuro Nakamura, Miyuki Yanaka, Saori Handa, Yu Komatsu, Saori Okuno, Nozomi Takahashi, Yuki Okada, Hiyori Kobayashi, Guanjie Li, Ren Nanamiya, Nohara Goto, Nami Tateyama, Takeo Yoshikawa, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 41 5 275 - 278 2022年10月25日 [査読有り][通常論文]
   

  The CXC chemokine receptor 6 (CXCR6) is a member of the G protein-coupled receptor family that is highly expressed in helper T type 1 cells, cytotoxic T lymphocytes (CTLs), and natural killer cells. CXCR6 plays critical roles in local expansion of effector-like CTLs in tumor microenvironment to potentiate the antitumor response. Therefore, the development of anti-CXCR6 monoclonal antibodies (mAbs) is essential to evaluate the immune microenvironment of tumors. Using N-terminal peptide immunization, we previously developed an anti-mouse CXCR6 (mCXCR6) mAb, Cx6Mab-1 (rat IgG1, kappa) , which is useful for flow cytometry and western blotting. In this study, we determined the critical epitope of Cx6Mab-1 by enzyme-linked immunosorbent assay (ELISA) using the 1 × alanine scanning (1 × Ala-scan) method or the 2 × alanine scanning (2 × Ala-scan) method. Although we first performed ELISA by 1 × Ala-scan using one alanine-substituted peptides of mCXCR6 N-terminal domain (amino acids 1-20), we could not identify the Cx6Mab-1 epitope. We next performed ELISA by 2 × Ala-scan using two alanine (or glycine) residues-substituted peptides of mCXCR6 N-terminal domain, and found that Cx6Mab-1 did not recognize S8A-A9G, A9G-L10A, L10A-Y11A, and G13A-H14A of the mCXCR6 N-terminal peptide. The results indicate that the binding epitope of Cx6Mab-1 includes Ser8, Ala9, Leu10, Tyr11, Gly13, and His14 of mCXCR6. Therefore, we could demonstrate that the 2 × Ala scan method is useful for determining the critical epitope of mAbs.
• Epitope Mapping of the Anti-Human CC Chemokine Receptor Type-2 Monoclonal Antibody (K036C2)

  Tomohiro Tanaka, Hiroyuki Suzuki, Guanjie Li, Ren Nanamiya, Yu Isoda, Yuki Okada, Hiyori Kobayashi, Takeo Yoshikawa, Mika K. Kaneko, Yukinari Kato

  Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 41 5 285 - 289 2022年10月25日 [査読有り][通常論文]
   

  CC chemokine receptor type-2 (CCR2) belongs to the G protein-coupled receptors superfamily, and is localized on cell surface of tumor cells and some immune cells, including monocytes and macrophages. CCR2 is a receptor for monocyte chemoattractant protein-1/C-C motif chemokine 2, and is involved in the progression of various diseases such as cancers. Therefore, the development of CCR2-targeted monoclonal antibody (mAb) is desired. Its characterization, including epitope of mAb, is very important for antibody applications. In this study, we investigated the critical epitope of K036C2, which is a commercially available anti-human CCR2 (hCCR2) mAb. We conducted enzyme-linked immunosorbent assay (ELISA) using three N-terminal peptides of hCCR2 and demonstrated that K036C2 recognizes 11-29 and 21-39 amino acids of hCCR2. We further performed ELISA using 20 peptides, which include alanine substitution of hCCR2. K036C2 lost the reaction to the alanine-substituted peptides of D25A, Y26A, D27A, G29A, and A30G. These results indicate that the critical binding epitope of K036C2 includes Asp25, Tyr26, Asp27, Gly29, and Ala30 of hCCR2.
• Defucosylated mouse‑dog chimeric anti‑HER2 monoclonal antibody exerts antitumor activities in mouse xenograft models of canine tumors

  Hiroyuki Suzuki, Tomokazu Ohishi, Teizo Asano, Tomohiro Tanaka, Masaki Saito, Takuya Mizuno, Takeo Yoshikawa, Manabu Kawada, Mika Kaneko, Yukinari Kato

  Oncology Reports 48 3 2022年07月15日
• Oral histidine intake improves working memory through the activation of histaminergic nervous system in mice

  Tadaho Nakamura, Fumito Naganuma, Uta Kudomi, Sueji Roh, Kazuhiko Yanai, Takeo Yoshikawa

  Biochemical and Biophysical Research Communications 609 141 - 148 2022年06月 [査読有り][通常論文]
   

  Histamine is synthesised from l-histidine through the catalysis of histidine decarboxylase (HDC). In the central nervous system (CNS), histamine is exclusively produced in histaminergic neurons located in the posterior hypothalamus and controls various CNS functions. Although histidine was known as a precursor of histamine, the impact of oral histidine intake on brain histamine concentration and brain function has not been fully elucidated. In the present study, we aimed to elucidate the importance of oral histidine supplementation in the histaminergic nervous system and working memory in stressful conditions. First, we confirmed that sleep deprivation by water-floor stress in male mice increased histamine consumption and resulted in histamine reduction and impaired working memory in the Y-maze test. This memory impairment was rescued by intracerebroventricular injection of histamine and histidine, indicating that oral histidine intake could also improve memory function. Next, we examined the impact of histidine intake on brain histamine concentration and neuronal activity. Histidine intake increased extracellular histamine concentration around the prefrontal cortex (PFC) and the basal forebrain (BF), leading to a robust increase in the number of c-fos-positive cells around these areas. Finally, we investigated the beneficial effects of histidine intake on working memory. Histidine supplementation alleviated impaired memory function induced by sleep deprivation. This beneficial effect of histidine on memory was cancelled by intracerebroventricular injection of the HDC inhibitor α-fluoromethylhistidine. These results demonstrate that oral histidine intake replenishes brain histamine and leads to the recovery of impaired working memory induced by sleep deprivation through histaminergic activation.
• Histamine and Microglia.

  Tomomitsu Iida, Kazuhiko Yanai, Takeo Yoshikawa

  Current topics in behavioral neurosciences 59 241 - 259 2022年05月11日 [査読有り]
   

  Microglia, a category of glial cells in the central nervous system (CNS), have attracted much attention because of their important role in neuroinflammation. Many translational studies are currently ongoing to discover novel drugs targeting microglia for the treatment of various CNS disorders, such as Alzheimer's disease, Parkinson's disease (PD), and depression. Recent studies have shown that brain histamine, a neurotransmitter essential for the regulation of diverse brain functions, controls glial cells and neurons. In vitro studies using primary microglia and microglial cell lines have reported that histamine receptors are expressed in microglia and control microglial functions, including chemotaxis, migration, cytokine secretion, and autophagy. In vivo studies have demonstrated that histamine-related reagents could ameliorate abnormal symptoms in animal models of human diseases, such as amyotrophic lateral sclerosis (ALS), PD, and brain ischemia. Several human studies have revealed alterations in histamine receptor levels in ALS and PD, emphasizing the importance of the CNS histamine system, including histamine-dependent microglial modulation, as a therapeutic target for these disorders. In this review article, we summarize histamine-related research focusing on microglial functions.
• Contribution of astrocytic histamine N-methyltransferase to histamine clearance and brain function in mice.

  Rina Otsuka, Fumito Naganuma, Tadaho Nakamura, Hideki Miwa, Rumi Nakayama-Naono, Takuro Matsuzawa, Yurika Komatsu, Yuki Sato, Yuna Takahashi, Haruna Tatsuoka-Kitano, Kazuhiko Yanai, Takeo Yoshikawa

  Neuropharmacology 212 109065 - 109065 2022年04月26日 [査読有り]
   

  Brain histamine acts as a neurotransmitter in the regulation of various brain activities. Previous studies have shown that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, controls brain histamine concentration and brain function. However, the relative contribution of astrocytic or neuronal HNMT to the regulation of the histaminergic system is still inconclusive. Here, we phenotyped astrocytes-specific HNMT knockout (cKO) mice to clarify the involvement of astrocytic HNMT in histamine clearance and brain function. First, we performed histological examinations using HNMT reporter mice and showed a wide distribution of HNMT in the brain and astrocytic HNMT expression. Then, we created cKO mice by Cre-loxP system and confirmed that HNMT expression in cKO primary astrocytes was robustly decreased. Although total HNMT level in the cortex was not substantially different between control and cKO brains, histamine concentration after histamine release was elevated in cKO cortex. In behavioral tests, impaired motor coordination and lower locomotor activity were observed in the cKO mice. However, anxiety-like behaviors, depression-like behaviors, and memory functions were not altered by astrocytic HNMT disruption. Although sleep analysis demonstrated that the quantity of wakefulness and sleep did not change, the increased power density of delta frequency during wakefulness indicated lower cortical activation in cKO mice. These results demonstrate that astrocytic HNMT contributes to histamine clearance after histamine release in the cortex and plays a role in the regulation of motor coordination, locomotor activity, and vigilance state.
• 【With/afterコロナ時代の新たな薬理学教育I:遠隔教育の実践と課題】オンライン薬理学ロールプレイの実践と課題

  中村 正帆, 吉川 雄朗, 柳田 俊彦, 岡村 信行, 谷内 一彦

  日本薬理学雑誌 156 6 338 - 344 (公社)日本薬理学会 2021年11月 

  薬理学ロールプレイは,適切な処方や調剤を実践するために必要なコミュニケーションや職種間連携,問題対応などのコンピテンシーを習得することを目的に,学生が医療者役や患者家族役に扮して模擬診療を行う実践的演習である.この演習の主体は,模擬診療での対話であるため,これまでは対面型と親和性が高い授業であると考えられてきたが,コロナ禍に伴い実施されたオンライン型でも対面型と同等の学習効果が得られることが明らかになった.また,演者の大幅な増加や遠隔地間での開催など,空間的な制約がないオンライン授業の利点を活かした薬理学ロールプレイも実践されている.本稿ではまず,オンライン薬理学ロールプレイの実施に必要な,授業の設計や準備,実際の運用について具体的な事例を元に説明する.次に,オンライン薬理学ロールプレイが対面型と比べて優れている点について解説すると共に,オンライン型特有の問題について取り上げる.最後に,オンライン薬理学ロールプレイそのものが,あるいはそれを組み込んだ学習システムが,理解の深化や動機付けの向上だけでなく,メタ認知を促す可能性があることについて考察する.オンライン薬理学ロールプレイは,対面型の代替に留まらず,薬理学や臨床薬理学,薬物治療学教育においてコアをなす授業形態の一つとして,今後発展する可能性がある.(著者抄録)
• Efficacy and Safety of Non-brain Penetrating H1-Antihistamines for the Treatment of Allergic Diseases.

  Kazuhiko Yanai, Takeo Yoshikawa, Martin K Church

  Current topics in behavioral neurosciences 59 193 - 214 2021年10月08日 

  H1 receptor antagonists, known as H1-antihistamines (AHs), inactivate the histamine H1-receptor thereby preventing histamine causing the primary symptoms of allergic diseases, such as atopic dermatitis, pollinosis, food allergies, and urticaria. AHs, which are classified into first-generation (fgAHs) and second-generation (sgAHs) antihistamines, are the first line of treatment for allergic diseases. Although fgAHs are effective, they cause adverse reactions such as potent sedating effects, including drowsiness, lassitude, and cognitive impairment; anticholinergic effects, including thirst and tachycardia. Consequently, the use of fgAHs is not recommended for allergic diseases. Today, sgAHs, which are minimally sedating and, therefore, may be used at more effective doses, are the first-line treatment for alleviating the symptoms of allergic diseases. Pharmacologically, the use of sedating fgAHs is limited to antiemetics, anti-motion sickness drugs, and antivertigo drugs. The use of histamine H1-receptor occupancy (H1RO) based on positron emission tomography (PET) has been developed for the evaluation of brain penetrability. Based on the results of the H1RO-PET studies, non-brain-penetrating AHs (nbpAHs) have recently been reclassified among sgAHs. The nbpAHs are rapidly acting and exhibit minimal adverse reactions and, thus, are considered first-line drugs for allergic diseases. In this review, we will introduce recent topics on the pharmacodynamics and pharmacokinetics of AHs and make recommendations for the use of nbpAHs as first-line treatment options for allergic diseases.
• Chemogenetic modulation of histaminergic neurons in the tuberomamillary nucleus alters territorial aggression and wakefulness.

  Fumito Naganuma, Tadaho Nakamura, Hiroshi Kuroyanagi, Masato Tanaka, Takeo Yoshikawa, Kazuhiko Yanai, Nobuyuki Okamura

  Scientific reports 11 1 17935 - 17935 2021年09月09日 

  Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomamillary nucleus (HATMN neurons) has produced inconsistent effects on the sleep-wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HATMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep-wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HATMN moderately enhanced locomotor activity in a novel open field. Activation of HATMN neurons significantly enhanced aggressive behaviour in the resident-intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HATMN chemoactivation. Conversely HATMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 h. These changes in wakefulness induced by HATMN modulation were related to the maintenance of vigilance state. These results indicate the influences of HATMN neurons on exploratory activity, territorial aggression, and wake maintenance.
• Heparan sulfate promotes differentiation of white adipocytes to maintain insulin sensitivity and glucose homeostasis.

  Takuro Matsuzawa, Masanobu Morita, Ai Shimane, Rina Otsuka, Yu Mei, Fumitoshi Irie, Yu Yamaguchi, Kazuhiko Yanai, Takeo Yoshikawa

  The Journal of biological chemistry 297 3 101006 - 101006 2021年07月23日 [査読有り][通常論文]
   

  Heparan sulfate (HS), a highly sulfated linear polysaccharide, is involved in diverse biological functions in various tissues. Although previous studies have suggested a possible contribution of HS to the differentiation of white adipocytes, there has been no direct evidence supporting this. Here, we inhibited the synthesis of HS chains in 3T3-L1 cells using CRISPR/Cas9 technology, resulting in impaired differentiation of adipocytes with attenuated BMP4 (bone morphogenetic protein 4)/FGF1 (fibroblast growth factor 1) signaling pathways. HS reduction resulted in reduced glucose uptake and decreased insulin-dependent intracellular signaling. We then made heterozygous mutant mice for the Ext1 gene, which encodes an enzyme essential for the HS biosynthesis, specifically in the visceral white adipose tissue (Fabp4-Cre+::Ext1flox/WT mice, hereafter called Ext1Δ/WT) to confirm the importance of HS in vivo. The expression levels of transcription factors that control adipocyte differentiation, such as peroxisome proliferator-activated receptor gamma, were reduced in Ext1Δ/WT adipocytes, which contained smaller, unilocular lipid droplets, reduced levels of enzymes involved in lipid synthesis, and altered expression of BMP4/FGF1 signaling molecules. Further, we examined the impact of HS reduction in visceral white adipose tissue on systemic glucose homeostasis. We observed that Ext1Δ/WT mice showed glucose intolerance due to insulin resistance. Our results demonstrate that HS plays a crucial role in the differentiation of white adipocytes through BMP4/FGF1 signaling pathways, thereby contributing to insulin sensitivity and glucose homeostasis.
• 臨床化学に寄与する糖鎖科学の進展 ブドウ糖代謝におけるヘパラン硫酸の重要性について

  松澤 拓郎, 谷内 一彦, 吉川 雄朗

  日本臨床検査医学会誌 69 6 451 - 457 (一社)日本臨床検査医学会 2021年06月
• 膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

  横山 敦, 野呂 英理香, 岡本 好司, 松澤 拓郎, 吉川 雄朗, 島 弘季, 五十嵐 和彦, 菅原 明

  日本内分泌学会雑誌 97 1 319 - 319 (一社)日本内分泌学会 2021年04月
• Organic Cation Transporters in Brain Histamine Clearance: Physiological and Psychiatric Implications.

  Fumito Naganuma, Takeo Yoshikawa

  Handbook of experimental pharmacology 266 169 - 185 2021年02月28日 

  Histamine acts as a neurotransmitter in the central nervous system and is involved in numerous physiological functions. Recent studies have identified the causative role of decreased histaminergic systems in various neurological disorders. Thus, the brain histamine system has attracted attention as a therapeutic target to improve brain function. Neurotransmitter clearance is one of the most important processes for the regulation of neuronal activity and is an essential target for diverse drugs. Our previous study has shown the importance of histamine N-methyltransferase for the inactivation of brain histamine and the intracellular localization of this enzyme; the study indicated that the transport system for the movement of positively charged histamine from the extracellular to intracellular space is a prerequisite for histamine inactivation. Several studies on in vitro astrocytic histamine transport have indicated the contribution of organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) in histamine uptake, although the importance of these transporters in in vivo histamine clearance remains unknown. Immunohistochemical analyses have revealed the expression of OCT3 and PMAT on neurons, emphasizing the importance of investigating neuronal histamine uptake. Further studies using knockout mice or fast-scan cyclic voltammetry will accelerate the research on histamine transporters. In this review article, we summarize histamine transport assays and describe the candidate transporters responsible for histamine transport in the brain.
• Histaminergic neurons in the tuberomammillary nucleus as a control centre for wakefulness

  Takeo Yoshikawa, Tadaho Nakamura, Kazuhiko Yanai

  British Journal of Pharmacology 178 4 750 - 769 2021年02月 

  Histamine plays pleiotropic roles as a neurotransmitter in the physiology of brain function, this includes the maintenance of wakefulness, appetite regulation and memory retrieval. Since numerous studies have revealed an association between histaminergic dysfunction and diverse neuropsychiatric disorders, such as Alzheimer's disease and schizophrenia, a large number of compounds acting on the brain histamine system have been developed to treat neurological disorders. In 2016, pitolisant, which was developed as a histamine H3 receptor inverse agonist by Schwartz and colleagues, was launched for the treatment of narcolepsy, emphasising the prominent role of brain histamine on wakefulness. Recent advances in neuroscientific techniques such as chemogenetic and optogenetic approaches have led to remarkable progress in the understanding of histaminergic neural circuits essential for the control of wakefulness. In this review article, we summarise the basic knowledge about the histaminergic nervous system and the mechanisms underlying sleep/wake regulation that are controlled by the brain histamine system. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.
• The development of online role-play for pharmacological education

  Tadaho Nakamura, Takeo Yoshikawa, Toshihiko Yanagita, Nobuyuki Okamura, Kazuhiko Yanai

  Folia Pharmacologica Japonica 156 6 338 - 344 2021年 

  The role-play for pharmacological education has been developed by Yanagita et al. since 2010 and incorporated into the curriculum of more than 20 medical or pharmaceutical universities in Japan. This case and communication based active learning course provides the practice to acqire fundamental competences for drug therapy, through role playing of medical professionals and patients in simulated clinical settings. The online pharmacological role-play for the first time was performed at Tohoku Medical and Pharmaceutical University Faculty of Medicine during the state of emergency in Japan. We found that the online role-play was as useful as face-to-face role-plays to train appropriate drug prescriptions and communication skills in medical students. In this review, we described the course design, preparation, and operation of online role-play for pharmacological education. We also explained the differences, advantages, and disadvantages between online and face-to-face setting. Finally, we gave examples on-going challenges to the effective use of the online role-play as a core curricular model of pharmacological and pharmacotherapeutic education.
• 【COVID-19パンデミック下での薬学教育〜レジリエントな教育システム構築に向けて〜】医学・薬学・歯学教育におけるオンラインロールプレイを活用した実践的薬物治療教育の試み

  柳田 俊彦, 中村 正帆, 吉川 雄朗, 石塚 洋一, 近藤 悠希, 高橋 富美, 藤田 朋恵, 有賀 純, 近藤 一直, 岡田 尚志郎, 竹内 弘, 岡村 信行, 谷内 一彦

  薬学教育 5 別刷 97 - 102 日本薬学教育学会 2021年
• Chronic brain histamine depletion in adult mice induced depression-like behaviours and impaired sleep-wake cycle.

  Yo Yamada, Takeo Yoshikawa, Fumito Naganuma, Takako Kikkawa, Noriko Osumi, Kazuhiko Yanai

  Neuropharmacology 175 108179 - 108179 2020年09月15日 [査読有り][通常論文]
   

  Histamine acts as a neurotransmitter to regulate various physiological processes. Brain histamine is synthesized from an essential amino acid histidine in a reaction catalysed by histidine decarboxylase (Hdc). Hdc-positive neurons exist mainly in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and project their axons to the entire brain. Recent studies have reported that a chronic decrease in histamine levels in the adult human brain was observed in several neurological disorders. However, it is poorly understood whether lower histamine levels play a causative role in those disorders. In the present study, we induced chronic histamine deficiency in the brains of adult mice to allow direct interpretation of the relationship between an impaired histaminergic nervous system and the resultant phenotype. To induce chronic brain histamine deficiency starting in adulthood, adeno-associated virus expressing Cre recombinase was microinjected into the TMN of Hdc flox mice (cKO mice) at the age of 8 weeks. Immunohistochemical analysis showed expression of Cre recombinase in the TMN of cKO mice. The reduction of histamine contents with the decreased Hdc expression in cKO brain was also confirmed. Behavioural studies revealed that chronic histamine depletion in cKO mice induced depression-like behaviour, decreased locomotor activity in the home cage, and impaired aversive memory. Sleep analysis showed that cKO mice exhibited a decrease in wakefulness and increase in non-rapid eye movement sleep throughout the day. Taken together, this study clearly demonstrates that chronic histamine depletion in the adult mouse brain plays a causative role in brain dysfunction.
• Heparan sulfate controls skeletal muscle differentiation and motor functions.

  Mariko Yokoyama, Takuro Matsuzawa, Takeo Yoshikawa, Aki Nunomiya, Yu Yamaguchi, Kazuhiko Yanai

  Biochimica et biophysica acta. General subjects 1864 12 129707 - 129707 2020年08月15日 [査読有り][通常論文]
   

  BACKGROUND: Heparan sulfate (HS) is a sulfated linear polysaccharide on cell surfaces that plays an important role in physiological processes. HS is present in skeletal muscles but its detailed role in this tissue remains unclear. METHODS: We examined the role of HS in the differentiation of C2C12 cells, a mouse myoblast cell line. We also phenotyped the impact of HS deletion in mouse skeletal muscles on their functions by using Cre-loxP system. RESULTS: CRISPR-Cas9-dependent HS deletion or pharmacological removal of HS dramatically impaired myoblast differentiation of C2C12 cells. To confirm the importance of HS in vivo, we deleted Ext1, which encodes an enzyme essential for HS biosynthesis, specifically in the mouse skeletal muscles (referred to as mExt1CKO mice). Treadmill and wire hang tests demonstrated that mExt1CKO mice exhibited muscle weakness. The contraction of isolated soleus muscles from mExt1CKO mice was also impaired. Morphological examination of mExt1CKO muscle tissue under light and electron microscopes revealed smaller cross sectional areas and thinner myofibrils. Finally, a model of muscle regeneration following BaCl2 injection into the tibialis anterior muscle of mice demonstrated that mExt1CKO mice had reduced expression of myosin heavy chain and an increased number of centronucleated cells. This indicates that muscle regeneration after injury was attenuated in the absence of HS expression in muscle cells. SIGNIFICANCE: These results demonstrate that HS plays an important role in skeletal muscle function by promoting differentiation.
• Histamine H1 receptor on astrocytes and neurons controls distinct aspects of mouse behaviour.

  Kárpáti A, Yoshikawa T, Naganuma F, Matsuzawa T, Kitano H, Yamada Y, Yokoyama M, Futatsugi A, Mikoshiba K, Yanai K

  Scientific Reports 9 1 16451 - 16451 2019年11月 [査読有り][通常論文]
   

  Histamine is an important neurotransmitter that contributes to various processes, including the sleep-wake cycle, learning, memory, and stress responses. Its actions are mediated through histamine H1-H4 receptors. Gene knockout and pharmacological studies have revealed the importance of H1 receptors in learning and memory, regulation of aggression, and wakefulness. H1 receptors are abundantly expressed on neurons and astrocytes. However, to date, studies selectively investigating the roles of neuronal and astrocytic H1 receptors in behaviour are lacking. We generated novel astrocyte- and neuron-specific conditional knockout (cKO) mice to address this gap in knowledge. cKO mice showed cell-specific reduction of H1 receptor gene expression. Behavioural assessment revealed significant changes and highlighted the importance of H1 receptors on both astrocytes and neurons. H1 receptors on both cell types played a significant role in anxiety. Astrocytic H1 receptors were involved in regulating aggressive behaviour, circadian rhythms, and quality of wakefulness, but not sleep behaviour. Our results emphasise the roles of neuronal H1 receptors in recognition memory. In conclusion, this study highlights the novel roles of H1 receptors on astrocytes and neurons in various brain functions.
• Brain histamine H1 receptor occupancy after oral administration of desloratadine and loratadine.

  Tadaho Nakamura, Kotaro Hiraoka, Ryuichi Harada, Takuro Matsuzawa, Yoichi Ishikawa, Yoshihito Funaki, Takeo Yoshikawa, Manabu Tashiro, Kazuhiko Yanai, Nobuyuki Okamura

  Pharmacology research & perspectives 7 4 e00499  2019年08月 [査読有り][通常論文]
   

  Some histamine H1 receptor (H1R) antagonists induce adverse sedative reactions caused by blockade of histamine transmission in the brain. Desloratadine is a second-generation antihistamine for treatment of allergic disorders. Its binding to brain H1Rs, which is the basis of sedative property of antihistamines, has not been examined previously in the human brain by positron emission tomography (PET). We examined brain H1R binding potential ratio (BPR), H1R occupancy (H1RO), and subjective sleepiness after oral desloratadine administration in comparison to loratadine. Eight healthy male volunteers underwent PET imaging with [11C]-doxepin, a PET tracer for H1Rs, after a single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double-blind crossover study. BPR and H1RO in the cerebral cortex were calculated, and plasma concentrations of loratadine and desloratadine were measured. Subjective sleepiness was quantified by the Line Analogue Rating Scale (LARS) and the Stanford Sleepiness Scale (SSS). BPR was significantly lower after loratadine administration than after placebo (0.504 ± 0.074 vs 0.584 ± 0.059 [mean ± SD], P < 0.05), but BPR after desloratadine administration was not significantly different from BPR after placebo (0.546 ± 0.084 vs 0.584 ± 0.059, P = 0.250). The plasma concentration of loratadine was negatively correlated with BPR in subjects receiving loratadine, but that of desloratadine was not correlated with BPR. Brain H1ROs after desloratadine and loratadine administration were 6.47 ± 10.5% and 13.8 ± 7.00%, respectively (P = 0.103). Subjective sleepiness did not significantly differ among subjects receiving the two antihistamines and placebo. At therapeutic doses, desloratadine did not bind significantly to brain H1Rs and did not induce any significant sedation.
• Site-Specific Labeling of F-18 Proteins Using a Supplemented Cell-Free Protein Synthesis System and O-2-[¹⁸F]Fluoroethyl-L-Tyrosine: [¹⁸F]FET-HER2 Affibody Molecule.

  Yanai A, Harada R, Iwata R, Yoshikawa T, Ishikawa Y, Furumoto S, Ishida T, Yanai K

  Molecular imaging and biology 21 3 529 - 537 2019年06月 [査読有り][通常論文]
   

  PURPOSE: Although a preparation method for F-18-labeled proteins that used a cell-free translation system and 4-[18F]fluoro-L-proline instead of L-proline has been reported, its introduction depends on amino acid sequences of target proteins. The purpose of the study was to propose site-specific labeling method of F-18 by using cell-free translation systems supplemented with an engineered orthogonal aminoacyl-tRNA synthetase derived from Methanocaldococcus jannaschii (pCNF-RS)/suppressor tRNA (tRNACUAopt) pair, O-2-[18F]fluoroethyl-L-tyrosine ([18F]FET), and template DNA inserted with an amber codon. PROCEDURES: [18F]FET was prepared from the corresponding precursor and determined whether [18F]FET could be incorporated into an affibody molecule for human epidermal growth factor receptor type 2 (HER2; ZHER2:342) as the 21st amino acid used with the pCNF-RS-tRNACUAopt pair and template DNA inserted with an amber codon in a cell-free translation system. Using SKOV-3 cells, we performed an in vitro binding assay of [18F]FET-ZHER2:342. Furthermore, in vivo positron emission tomography (PET) imaging in SKOV-3 xenograft-bearing mice was performed after the intravenous administration of [18F]FET-ZHER2:342. RESULTS: [18F]FET was successfully incorporated into proteins by using commercially available cell-free protein synthesis reagents with a pCNF-RS-tRNACUAopt pair and template DNA of the desired proteins inserted with an amber codon. The mean radiochemical yield (non-decay-corrected) of [18F]FET-ZHER2:342 was 6.5 ± 4.1 %. An in vitro cell binding assay revealed that SKOV-3 cells-bound [18F]FET-ZHER2:342 expressed HER2. The in vivo PET imaging in SKOV-3 xenograft-bearing mice revealed that [18F]FET-ZHER2:342 accumulated in SKOV-3 xenografts. CONCLUSION: The method proposed in this study might be useful for preparing proteins with F-18 and molecular imaging in the preclinical development.
• Histamine N-Methyltransferase in the Brain.

  Yoshikawa T, Nakamura T, Yanai K

  International journal of molecular sciences 20 3 737 - 737 2019年02月 [査読有り][通常論文]
   

  Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain functions, HNMT inhibitors with high specificity and sufficient blood–brain barrier permeability have not been available until now. Recently, we have phenotyped Hnmt-deficient mice to elucidate the importance of HNMT in the central nervous system. Hnmt disruption resulted in a robust increase in brain histamine concentration, demonstrating the essential role of HNMT in the brain histamine system. Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson’s disease and attention deficit hyperactivity disorder. Postmortem studies also have indicated that HNMT expression is altered in human brain diseases. These findings emphasise that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.
• Optically active iodohelicene derivatives exhibit histamine N-methyl transferase inhibitory activity

  Ichinose, W., Sawato, T., Kitano, H., Shinozaki, Y., Arisawa, M., Saito, N., Yoshikawa, T., Yamaguchi, M.

  Journal of Antibiotics 72 6 2019年 [査読有り][通常論文]
  
• Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia - Crucial roles of endothelial nitric oxide synthase.

  Eguchi K, Shindo T, Ito K, Ogata T, Kurosawa R, Kagaya Y, Monma Y, Ichijo S, Kasukabe S, Miyata S, Yoshikawa T, Yanai K, Taki H, Kanai H, Osumi N, Shimokawa H

  Brain stimulation 11 5 959 - 973 2018年09月 [査読有り][通常論文]
   

  © 2018 The Authors Background: Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved. Methods: We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain. Results: In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice. Conclusions: These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism.
• 【遺伝子改変マウスを用いた新しい創薬・薬理学研究の展開】新規遺伝子ノックアウトマウスを用いた脳内ヒスタミンクリアランス系の解明

  吉川 雄朗, 中村 正帆, 谷内 一彦

  日本薬理学雑誌 152 1 16 - 20 (公社)日本薬理学会 2018年07月 

  ヒスタミンは脳内では神経伝達物質として機能している。ヒスタミン神経は視床下部後部に位置する結節乳頭核に細胞体を有し、その神経線維を脳全体に投射する。これまでの研究により、ヒスタミン神経系の機能低下が様々な神経疾患と関連している可能性が示された。我々はシナプス間隙に放出されたヒスタミンの除去機構を抑制することで、ヒスタミン神経系を活性化し神経疾患の治療へと結びつけたいと考え、未解明の課題であったヒスタミンのクリアランス機構の解明に着手した。まず初代培養ヒトアストロサイトを用いた研究を行い、細胞外のヒスタミンがorganic cation transporter(OCT)3およびplasma membrane monoamine transporter(PMAT)によって細胞内へと輸送され、その後histamine N-methyltransferase(HNMT)によって不活化される、という分子機構を明らかにした。次にHNMTの生体における役割を明らかにするため、HNMT欠損マウスを新規に作製し、表現型を解析した。その結果、HNMTが脳内ヒスタミン濃度制御において中心的な役割を担っていることが示された。またHNMT欠損によりヒスタミンが異常高値となると、ヒスタミンH2受容体を介して高い攻撃性が惹起されること、H1受容体を介して睡眠覚醒サイクルに異常を来すことも明らかとなった。OCT3とPMATの脳内における役割については、セロトニン神経系やドパミン神経系との関連は報告されているものの、ヒスタミン神経系におけるこれらのトランスポーターの役割については不明な点が多い。現在我々はPMAT欠損マウスの表現型解析、およびHNMT阻害薬探索研究を行っている。今後トランスポーターとヒスタミン神経系との関連を解明することや中枢ヒスタミン系を標的とした創薬に尽力していきたいと考えている。(著者抄録)
• Heparan sulfate in pancreatic β-cells contributes to normal glucose homeostasis by regulating insulin secretion.

  Matsuzawa T, Yoshikawa T, Iida T, Kárpáti A, Kitano H, Harada R, Nakamura T, Sugawara A, Yamaguchi Y, Yanai K

  Biochemical and biophysical research communications 499 3 688 - 695 2018年05月15日 [査読有り][通常論文]
   

  Heparan sulfate (HS), a linear polysaccharide, is involved in diverse biological functions of various tissues. HS is expressed in pancreatic β-cells and may be involved in β-cell functions. However, the importance of HS for β-cell function remains unknown. Here, we generated mice with β-cell-specific deletion of Ext1 (βExt1CKO), which encodes an enzyme essential for HS synthesis, to investigate the detailed roles of HS in β-cell function. βExt1CKO mice decreased body weights compared with control mice, despite increased food intake. Additionally, βExt1CKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge. Glucose-induced insulin secretion (GIIS) from isolated βExt1CKO islets was also significantly reduced, highlighting the contribution of HS to insulin secretion and glucose homeostasis. The gene expression essential for GIIS was decreased in βExt1CKO islets. Pdx1 and MafA were downregulated in βExt1CKO islets, indicating that HS promoted β-cell development and maturation. BrdU- or Ki67-positive β-cells were reduced in βExt1CKO pancreatic sections, suggesting the involvement of HS in the proliferation of β-cells. Moreover, insufficient vascularization in βExt1CKO islets may contribute to central distribution of α-cells. These data demonstrate HS plays diverse roles in β-cells, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis.
• Correlations of 18F-THK5351 PET with Postmortem Burden of Tau and Astrogliosis in Alzheimer Disease.

  Ryuichi Harada, Aiko Ishiki, Hideaki Kai, Naomi Sato, Katsutoshi Furukawa, Shozo Furumoto, Tetsuro Tago, Naoki Tomita, Shoichi Watanuki, Kotaro Hiraoka, Yoichi Ishikawa, Yoshihito Funaki, Tadaho Nakamura, Takeo Yoshikawa, Ren Iwata, Manabu Tashiro, Hironobu Sasano, Tetsuyuki Kitamoto, Kazuhiko Yanai, Hiroyuki Arai, Yukitsuka Kudo, Nobuyuki Okamura

  Journal of nuclear medicine : official publication, Society of Nuclear Medicine 59 4 671 - 674 2018年04月 [査読有り][通常論文]
   

  Clinical PET studies using 18F-THK5351 have demonstrated significant tracer retention in sites susceptible to tau burden in Alzheimer disease (AD). However, the in vivo PET signal to reflect tau aggregates remains controversial. Methods: We examined the spatial pattern of tracer binding, amyloid-β, tau, and gliosis in an autopsy-confirmed AD patient who underwent 18F-THK5351 and 11C-Pittsburgh compound B PET before death. Results: Regional in vivo 18F-THK5351 retention was significantly correlated with the density of tau aggregates in the neocortex and monoamine oxidase-B in the whole brain, but not correlated with that of insoluble amyloid-β. Furthermore, significant association was observed between the density of tau aggregates, monoamine oxidase-B, and glial fibrillary acidic protein, suggesting that neocortical tau would strongly influence the formation of reactive astrocytes. Conclusion:18F-THK5351 PET may have limited utility as a biomarker of tau pathology in AD; however, it could be used to monitor the neuroinflammatory processes in the living brain.
• Histamine elicits glutamate release from cultured astrocytes

  Anikó Kárpáti, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Takuro Matsuzawa, Haruna Kitano, Ryuichi Harada, Kazuhiko Yanai

  Journal of Pharmacological Sciences 137 2 122 - 128 2018年 [査読有り][通常論文]
   

  Astrocytes play key roles in regulating brain homeostasis and neuronal activity. This is, in part, accomplished by the ability of neurotransmitters in the synaptic cleft to bind astrocyte membrane receptors, activating signalling cascades that regulate concentration of intracellular Ca2+ ([Ca2+]i) and gliotransmitter release, including ATP and glutamate. Gliotransmitters contribute to dendrite formation and synaptic plasticity, and in some cases, exacerbate neurodegeneration. The neurotransmitter histamine participates in several physiological processes, such as the sleep-wake cycle and learning and memory. Previous studies have demonstrated the expression of histamine receptors on astrocytes, but until now, only a few studies have examined the effects of histamine on astrocyte intracellular signalling and gliotransmitter release. Here, we used the human astrocytoma cell line 1321N1 to study the role of histamine in astrocyte intracellular signalling and gliotransmitter release. We found that histamine activated astrocyte signalling through histamine H1 and H2 receptors, leading to distinct cellular responses. Activation of histamine H1 receptors caused concentration-dependent release of [Ca2+]i from internal stores and concentration-dependent increase in glutamate release. Histamine H2 receptor activation increased cyclic adenosine monophosphate (cAMP) levels and phosphorylation of transcription factor cAMP response-element binding protein. Taken together, these data emphasize a role for histamine in neuron-glia communication.
• [Analysis of brain histamine clearance using genetically engineered mice].

  Yoshikawa T, Nakamura T, Yanai K

  Nihon yakurigaku zasshi. Folia pharmacologica Japonica 152 1 16 - 20 2018年 [査読有り][通常論文]
  
• The reduction of heparan sulphate in the glomerular basement membrane does not augment urinary albumin excretion

  Satoshi Aoki, Akiko Saito-Hakoda, Takeo Yoshikawa, Kyoko Shimizu, Kiyomi Kisu, Susumu Suzuki, Kiyoshi Takagi, Shuji Mizumoto, Shuhei Yamada, Toin H. Van Kuppevelt, Atsushi Yokoyama, Taiji Matsusaka, Hiroshi Sato, Sadayoshi Ito, Akira Sugawara

  Nephrology Dialysis Transplantation 33 1 26 - 33 2018年01月01日 [査読有り][通常論文]
   

  Background. Heparan sulphate proteoglycan (HSPG) is present in the glomerular basement membrane (GBM) and is thought to play a major role in the glomerular charge barrier. Reductions and structural alterations of HSPG are observed in different types of kidney diseases accompanied by proteinuria. However, their causal relations remain unknown. Methods. We generated podocyte-specific exostosin-like 3 gene (Extl3) knockout mice (Extl3KO) using a Cre-loxP recombination approach. A reduction of HSPG was expected in the GBM of these mice, because EXTL3 is involved in its synthesis. Mice were separated into three groups, according to the loads on the glomeruli: a high-protein diet group, a high-protein and highsodium diet group and a hyperglycaemic group induced by streptozotocin treatment in addition to maintenance on a highprotein and high-sodium diet. The urinary albumin:creatinine ratio was measured at 7, 11, 15 and 19 weeks of age. Renal histology was also investigated. Results. Podocyte-specific expression of Cre recombinase was detected by immunohistochemistry. Moreover, immunofluorescent staining demonstrated a significant reduction of HSPG in the GBM. Electron microscopy showed irregularities in the GBM and effacement of the foot processes in Extl3KO. The values of the urinary albumin:creatinine ratio were within the range of microalbuminuria in all groups and did not significantly differ between the control mice and Extl3KO. Conclusions. The reduction of HSPG in the GBM did not augment urinary albumin excretion. HSPG's anionic charge appears to contribute little to the glomerular charge barrier.
• Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice.

  Shin-Ichi Inoue, Shingo Takahara, Takeo Yoshikawa, Tetsuya Niihori, Kazuhiko Yanai, Yoichi Matsubara, Yoko Aoki

  Human molecular genetics 26 23 4715 - 4727 2017年12月01日 [査読有り][通常論文]
   

  Germline mutations in BRAF are a major cause of cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, characteristic craniofacial dysmorphology and dermatologic abnormalities. Patients with CFC syndrome also commonly show gastrointestinal dysfunction, including feeding and swallowing difficulties and gastroesophageal reflux. We have previously found that knock-in mice expressing a Braf Q241R mutation exhibit CFC syndrome-related phenotypes, such as growth retardation, craniofacial dysmorphisms, congenital heart defects and learning deficits. However, it remains unclear whether BrafQ241R/+ mice exhibit gastrointestinal dysfunction. Here, we report that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the BrafQ241R/+ mice showed hyperkeratosis and a thickened muscle layer in the forestomach. Treatment with MEK inhibitors ameliorated the growth retardation, esophageal dilation, hyperkeratosis and thickened muscle layer in the forestomach in BrafQ241R/+ mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in BrafQ241R/+ mice were recovered after treatment with the histone H3K27 demethylase inhibitor GSK-J4. Our results provide clues to elucidate the pathogenesis and possible treatment of gastrointestinal dysfunction and failure to thrive in patients with CFC syndrome.
• Histamine N-methyltransferase regulates aggression and the sleep-wake cycle

  Fumito Naganuma, Tadaho Nakamura, Takeo Yoshikawa, Tomomitsu Iida, Yamato Miura, Aniko Karpati, Takuro Matsuzawa, Atushi Yanai, Asuka Mogi, Takatoshi Mochizuki, Nobuyuki Okamura, Kazuhiko Yanai

  SCIENTIFIC REPORTS 7 1 15899  2017年11月 [査読有り][通常論文]
   

  Histamine is a neurotransmitter that regulates diverse physiological functions including the sleep-wake cycle. Recent studies have reported that histaminergic dysfunction in the brain is associated with neuropsychiatric disorders. Histamine N-methyltransferase (HNMT) is an enzyme expressed in the central nervous system that specifically metabolises histamine; yet, the exact physiological roles of HNMT are unknown. Accordingly, we phenotyped Hnmt knockout mice (KO) to determine the relevance of HNMT to various brain functions. First, we showed that HNMT deficiency enhanced brain histamine concentrations, confirming a role for HNMT in histamine inactivation. Next, we performed comprehensive behavioural testing and determined that KO mice exhibited high aggressive behaviours in the resident-intruder and aggressive biting behaviour tests. High aggression in KO mice was suppressed by treatment with zolantidine, a histamine H2 receptor (H2R) antagonist, indicating that abnormal H2R activation promoted aggression in KO mice. A sleep analysis revealed that KO mice exhibited prolonged bouts of awakening during the light (inactive) period and compensatory sleep during the dark (active) period. Abnormal sleep behaviour was suppressed by treatment with pyrilamine, a H1R antagonist, prior to light period, suggesting that excessive H1R activation led to the dysregulation of sleep-wake cycles in KO mice. These observations inform the physiological roles of HNMT.
• Induced histamine regulates Ni elution from an implanted Ni wire in mice by downregulating neutrophil migration

  Yu Kishimoto, Sanki Asakawa, Taiki Sato, Takayuki Takano, Takahisa Nakajyo, Natsumi Mizuno, Ryosuke Segawa, Takeo Yoshikawa, Masahiro Hiratsuka, Kazuhiko Yanai, Hiroshi Ohtsu, Noriyasu Hirasawa

  EXPERIMENTAL DERMATOLOGY 26 10 868 - 874 2017年10月 [査読有り][通常論文]
   

  Histamine regulates various inflammatory reactions. We have reported that the expression of histidine decarboxylase (HDC) was induced by subcutaneous implantation of nickel (Ni) wire. However, the source and functions of histamine in Ni elution and Ni wire-induced inflammation have not been completely studied. We aimed to elucidate the effects of de novo synthesized histamine on leucocyte infiltration and Ni elution. Implantation of Ni wire induced an increase in the Ni ion content of the surrounding tissues and serum and in the mRNA levels of HDC, a histamine-producing enzyme, macrophage inflammatory protein-2 (MIP-2), a chemoattractant for neutrophils, and monocyte chemoattractant protein-1 (MCP-1), a chemoattractant for monocytes. The Ni wire induced HDC expression even in mast cell-deficient WBB6F1-W/W-V mice. In HDC knockout (HDC KO) mice, the Ni wire-induced increase in MIP-2 mRNA expression was significantly higher than that in wild-type mice but not MCP-1. MIP-2 expression was enhanced in histamine H2 receptor knockout (H2R KO) mice but not in WBB6F1-W/W-V mice. Histamine inhibited NiCl2-induced MIP-2 mRNA expression in mouse bone marrow-derived macrophages (BMDMs) obtained from wild-type mice; this inhibition was not observed in BMDMs from H2R KO mice. Ni elution increased in HDC KO mice, in which leucocyte infiltration also increased, and was suppressed in mice treated with neutrophil-specific antibody. These results suggest that the Ni wire induced HDC expression in non-mast cells and that, in the chronic phase of inflammation, endogenous histamine reduced Ni elution, probably through regulation of MIP-2 expression and neutrophil migration.
• The clinical pharmacology of non-sedating antihistamines

  Kazuhiko Yanai, Takeo Yoshikawa, Ai Yanai, Tadaho Nakamura, Tomomitsu Iida, Rob Leurs, Manabu Tashiro

  PHARMACOLOGY & THERAPEUTICS 178 148 - 156 2017年10月 [査読有り][通常論文]
   

  We previously reported on brain Hi receptor occupancy measurements of antihistamines in human brain using [C-11]doxepin and positron emission tomography (PET). We proposed the use of brain H-1 receptor occupancy to classify antihistamines objectively into three categories of sedating, less-sedating, and non-sedating antihistamines according to their sedative effects. Non-sedating antihistamines are recommended for the treatment of allergies such as pollinosis and atopic dermatitis because of their low penetration into the central nervous system. Physicians and pharmacists are responsible for fully educating patients about the risks of sedating antihistamines from pharmacological points of view. If a sedating antihistamine must be prescribed, its sedative effects should be thoroughly considered before choosing the drug. Non-sedating antihistamines should be preferentially used whenever possible as most antihistamines are equally efficacious, while adverse effects of sedating antihistamines can be serious. This review summarizes the pharmacological properties of clinically useful non-sedating antihistamines from the perspective of histamine function in the CNS. (C) 2017 Elsevier Inc. All rights reserved.
• JNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice

  Tomomitsu Iida, Takeo Yoshikawa, Aniko Karpati, Takuro Matsuzawa, Haruna Kitano, Asuka Mogi, Ryuichi Harada, Fumito Naganuma, Tadaho Nakamura, Kazuhiko Yanai

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 488 3 534 - 540 2017年07月 [査読有り][通常論文]
   

  Brain histamine acts as a neurotransmitter and regulates various physiological functions, such as learning and memory, sleep-wake cycles, and appetite regulation. We have recently shown that histamine H3 receptor (H3R) is expressed in primary mouse microglia and has a strong influence on critical functions in microglia, including chemotaxis, phagocytosis, and cytokine secretion in vitro. However, the importance of H3R in microglial activity in vivo remains unknown. Here, we examined the effects of JNJ10181457 (JNJ), a selective and potent H3R inverse agonist, on microglial functions ex vivo and in vivo. First, we injected ATP, which is a typical chemoattractant, into hippocampal slices to investigate the effect of JNJ on chemotaxis. ATP-induced microglial migration toward the injected site was significantly suppressed by JNJ treatment. Next, we examined whether JNJ affected microglial phagocytosis in hippocampal slices and in the prefrontal cortex. Microglial engulfment of dead neurons induced by N-methyl-(D)-aspartate was inhibited in the presence of JNJ. The increase in zymosan particle uptake by activated microglia in the prefrontal cortex was prevented by JNJ administration. Finally, we determined the importance of JNJ in a lipopolysaccharide (LPS)-induced depression model. JNJ reduced the LPS-induced upregulation of microglial pro-inflammatory cytokines and improved depression-like behaviour in the tail-suspension test. These results demonstrate the inhibitory effects of JNJ on chemotaxis, phagocytosis, and cytokine production in microglia inside the brain, and highlight the importance of microglial H3R for brain homeostasis. (C) 2017 Elsevier Inc. All rights reserved.
• Characterization of murine polyspecific monoamine transporters

  Yamato Miura, Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Tomomitsu Iida, Aniko Karpati, Takuro Matsuzawa, Asuka Mogi, Ryuichi Harada, Kazuhiko Yanai

  FEBS OPEN BIO 7 2 237 - 248 2017年02月 [査読有り][通常論文]
   

  The dysregulation of monoamine clearance in the central nervous system occurs in various neuropsychiatric disorders, and the role of polyspecific monoamine transporters in monoamine clearance is increasingly highlighted in recent studies. However, no study to date has properly characterized polyspecific monoamine transporters in the mouse brain. In the present study, we examined the kinetic properties of three mouse polyspecific monoamine transporters [organic cation transporter 2 (Oct2), Oct3, and plasma membrane monoamine transporter (Pmat)] and compared the absolute mRNA expression levels of these transporters in various brain areas. First, we evaluated the affinities of each transporter for noradrenaline, dopamine, serotonin, and histamine, and found that mouse ortholog substrate affinities were similar to those of human orthologs. Next, we performed drug inhibition assays and identified interspecies differences in the pharmacological properties of polyspecific monoamine transporters; in particular, corticosterone and decynium-22, which are widely recognized as typical inhibitors of human OCT3, enhanced the transport activity of mouse Oct3. Finally, we quantified absolute mRNA expression levels of each transporter in various regions of the mouse brain and found that while all three transporters were ubiquitously expressed, Pmat was the most highly expressed transporter. These results provide an important foundation for future translational research investigating the roles of polyspecific monoamine transporters in neurological and neuropsychiatric disease.
• Histamine clearance through polyspecific transporters in the brain

  Yoshikawa, T., Yanai, K.

  Handbook of Experimental Pharmacology 241 173 - 187 2017年 [査読有り][通常論文]
  
• Synthesis and Characterization of ¹⁸F-Interleukin-8 Using a Cell-Free Translation System and 4-¹⁸F-Fluoro-L-Proline.

  Harada R, Furumoto S, Yoshikawa T, Ishikawa Y, Shibuya K, Okamura N, Ishiwata K, Iwata R, Yanai K

  Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57 4 634 - 639 2016年04月 [査読有り][通常論文]
   

  Macromolecules such as proteins are attracting increasing interest for molecular imaging. We previously proposed a novel strategy for preparing macromolecules labeled with a PET radionuclide, C-11, using a cell-free translation system with C-11-methionine. However, macromolecules tend to exhibit slower kinetics, thus requiring a longer scanning time. Here, we expand our strategy using F-18, which has a longer half-life, with the cell-free translation system with 4-F-18-fluoro-L-proline (F-18-FPro). We evaluated F-18-interleukin-8 (F-18-IL-8) produced by this method in vitro and in vivo to provide a proof of concept of our strategy. Methods: We tested some fluorinated amino acids to be incorporated into a protein. Trans-F-18-FPro was radiolabeled from the corresponding precursor. F-18-IL-8 was produced using the cell-free translation system with trans-F-18-FPro instead of natural L-proline with incubation at 37 degrees C for 120 min. An in vitro binding assay of F-18-IL-8 was performed using IL-8 receptor-expressing cells. After intravenous administration of F-18-IL-8, in vivo PET imaging of IL-8 receptor-expressing xenograft-bearing mice was performed using a small-animal PET system. Results: FPro was identified as an amino acid incorporated into the protein. F-18-IL-8 was successfully prepared using the cell-free translation system and trans-F-18-FPro with the radiochemical yield of 1.5% (decay-corrected) based on trans-F-18-FPro. In vitro binding assays of F-18-IL-8 demonstrated its binding to IL-8 receptor. In vivo PET imaging demonstrated that F-18-IL-8 clearly accumulated in IL-8 receptor-expressing xenografts in mice, unlike trans-F-18-FPro. Conclusion: F-18-IL-8 produced by this method binds to IL-8 receptors in vitro, and F-18-IL-8 PET clearly visualizes its target receptor-expressing xenograft in vivo. Therefore, this technique might be useful for labeling macromolecules and performing preclinical evaluations of proteins of interest in vitro and in vivo.
• F-18-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Katsutoshi Furukawa, Aiko Ishiki, Naoki Tomita, Tetsuro Tago, Kotaro Hiraoka, Shoichi Watanuki, Miho Shidahara, Masayasu Miyake, Yoichi Ishikawa, Rin Matsuda, Akie Inami, Takeo Yoshikawa, Yoshihito Funaki, Ren Iwata, Manabu Tashiro, Kazuhiko Yanai, Hiroyuki Arai, Yukitsuka Kudo

  JOURNAL OF NUCLEAR MEDICINE 57 2 208 - 214 2016年02月 [査読有り][通常論文]
   

  Imaging of neurofibrillary pathology in the brain helps in diagnosing dementia, tracking disease progression, and evaluating the therapeutic efficacy of antidementia drugs. The radiotracers used in this imaging must be highly sensitive and specific for tau protein fibrils in the human brain. We developed a novel-tau PET tracer, F-18-THK5351, through compound optimization of arylquinoline derivatives. Methods: The in vitro binding properties, pharmacokinetics, and safety of F-18-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed. Results: F-18-THK5351 demonstrated higher binding affinity for hippocampal homogenates from AD brains and faster dissociation from white matter tissue than did F-18-THK5117. The THK5351 binding amount correlated with the amount of tau deposits in human brain samples. Autoradiography of brain sections revealed that THK5351 bound to neurofibrillary tangles selectively and with a higher signal-to background ratio than did THK5117. THK5351 exhibited favorable pharmacokinetics and no defluorination in mice. In first-in-human PET studies in AD patients, F-18-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than F-18-THK5117. Conclusion: F-18-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.
• Histamine H1 Receptor Occupancy in the Human Brain Measured by Positron Emission Tomography

  Kazuhiko Yanai, Kotaro Hiraoka, Anikó Kárpáti, Fumito Naganuma, Nobuyuki Okamura, Manabu Tashiro, Tadaho Nakamura, Takeo Yoshikawa

  Histamine Receptors 311 - 325 2016年
• Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression

  Akiko Saito-Hakoda, Akira Uruno, Atsushi Yokoyama, Kyoko Shimizu, Rehana Parvin, Masataka Kudo, Takako Saito-Ito, Ikuko Sato, Naotaka Kogure, Dai Suzuki, Hiroki Shimada, Takeo Yoshikawa, Ikuma Fujiwara, Hiroyuki Kagechika, Yasumasa Iwasaki, Shigeo Kure, Sadayoshi Ito, Akira Sugawara

  PLOS ONE 10 12 e0141960  2015年12月 [査読有り][通常論文]
   

  Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing's disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we examined the effects of synthetic RXR pan-agonists HX630 and PA024 on the proliferation, apoptosis, ACTH secretion, and pro-opiomelanocortin (Pomc) gene expression of murine pituitary corticotroph tumor AtT20 cells. We demonstrated that both RXR agonists induced apoptosis dose-dependently in AtT20 cells, and inhibited their proliferation at their higher doses. Microarray analysis identified a significant gene network associated with caspase 3 induced by high dose HX630. On the other hand, HX630, but not PA024, inhibited Pomc transcription, Pomc mRNA expression, and ACTH secretion dose-dependently. Furthermore, we provide new evidence that HX630 negatively regulates the Pomc promoter activity at the transcriptional level due to the suppression of the transcription factor Nur77 and Nurr1 mRNA expression and the reduction of Nur77/Nurr1 heterodimer recruiting to the Pomc promoter region. We also demonstrated that the HX630-mediated suppression of the Pomc gene expression was exerted via RXR alpha. Furthermore, HX630 inhibited tumor growth and decreased Pomc mRNA expression in corticotroph tumor cells in female nude mice in vivo. Thus, these results indicate that RXR agonists, especially HX630, could be a new therapeutic candidate for Cushing's disease.
• Histamine H-1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers

  Hirotoshi Sato, Chihiro Ito, Kotaro Hiraoka, Manabu Tashiro, Katsuhiko Shibuya, Yoshihito Funaki, Takeo Yoshikawa, Ren Iwata, Hiroo Matsuoka, Kazuhiko Yanai

  PSYCHOPHARMACOLOGY 232 19 3497 - 3505 2015年10月 [査読有り][通常論文]
   

  Rationale Histamine H-1 antagonists have hypnotic, appetite-promoting, and sedative side effects. Most second-generation antipsychotics have potent antagonistic effects on histamine H-1 receptor (H1R). Positron emission tomography (PET) can measure the H1R occupancy (H1RO) in vivo, although there are no reports regarding antipsychotics. Objectives We studied the H1RO of olanzapine and quetiapine in vivo with respect to their plasma concentrations and subjective drowsiness by performing human PET imaging studies with [C-11]doxepin, a potent PET ligand of H1R. Methods Six healthy Japanese male volunteers were enrolled. Cross-randomized PET imaging was performed after a single oral administration of olanzapine (2.5 mg), quetiapine (25mg), or placebo. PET data were analyzed by region of interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations by liquid chromatography/tandem mass spectrometry and evaluated subjective sleepiness. Results The binding potential ratios of olanzapine and quetiapine in the cerebral cortex were significantly lower than that of the placebo. The H1RO values of olanzapine and quetiapine in the cortex were approximately 61-80 and 56-81 %, respectively. The binding potential ratios of the drugs were significantly lower than that of the placebo in the dorsolateral prefrontal and lateral temporal cortices, and anterior and posterior cingulate gyri. The H1RO values in the cortex were significantly correlated with subjective sleepiness but not plasma drug concentrations. Conclusions Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.
• Histamine H-3 Receptor in Primary Mouse Microglia Inhibits Chemotaxis, Phagocytosis, and Cytokine Secretion

  Tomomitsu Iida, Takeo Yoshikawa, Takuro Matsuzawa, Fumito Naganuma, Tadaho Nakamura, Yamato Miura, Attayeb S. Mohsen, Ryuichi Harada, Ren Iwata, Kazuhiko Yanai

  GLIA 63 7 1213 - 1225 2015年07月 [査読有り][通常論文]
   

  Histamine is a physiological amine which initiates a multitude of physiological responses by binding to four known G-protein coupled histamine receptor subtypes as follows: histamine H-1 receptor (H1R), H2R, H3R, and H4R. Brain histamine elicits neuronal excitation and regulates a variety of physiological processes such as learning and memory, sleep-awake cycle and appetite regulation. Microglia, the resident macrophages in the brain, express histamine receptors; however, the effects of histamine on critical microglial functions such as chemotaxis, phagocytosis, and cytokine secretion have not been examined in primary cells. We demonstrated that mouse primary microglia express H2R, H3R, histidine decarboxylase, a histamine synthase, and histamine N-methyltransferase, a histamine metabolizing enzyme. Both forskolin-induced cAMP accumulation and ATP-induced intracellular Ca2+ transients were reduced by the H3R agonist imetit but not the H2R agonist amthamine. H3R activation on two ubiquitous second messenger signalling pathways suggests that H3R can regulate various microglial functions. In fact, histamine and imetit dose-dependently inhibited microglial chemotaxis, phagocytosis, and lipopolysaccharide (LPS)-induced cytokine production. Furthermore, we confirmed that microglia produced histamine in the presence of LPS, suggesting that H3R activation regulate microglial function by autocrine and/or paracrine signalling. In conclusion, we demonstrate the involvement of histamine in primary microglial functions, providing the novel insight into physiological roles of brain histamine. GLIA 2015;63:1213-1225
• [F-18]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer's disease

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Katsutoshi Furukawa, Aiko Ishiki, Naoki Tomita, Kotaro Hiraoka, Shoichi Watanuki, Miho Shidahara, Masayasu Miyake, Yoichi Ishikawa, Rin Matsuda, Akie Inami, Takeo Yoshikawa, Tetsuro Tago, Yoshihito Funaki, Ren Iwata, Manabu Tashiro, Kazuhiko Yanai, Hiroyuki Arai, Yukitsuka Kudo

  EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 42 7 1052 - 1061 2015年06月 [査読有り][通常論文]
   

  Purpose Visualization of the spatial distribution of neurofibrillary tangles would help in the diagnosis, prevention and treatment of dementia. The purpose of the study was to evaluate the clinical utility of [F-18]THK-5117 as a highly selective tau imaging radiotracer. Methods We initially evaluated in vitro binding of [H-3]THK-5117 in post-mortem brain tissues from patients with Alzheimer's disease (AD). In clinical PET studies, [F-18]THK-5117 retention in eight patients with AD was compared with that in six healthy elderly controls. Ten subjects underwent an additional [C-11]PiB PET scan within 2 weeks. Results In post-mortem brain samples, THK-5117 bound selectively to neurofibrillary deposits, which differed from the binding target of PiB. In clinical PET studies, [F-18]THK-5117 binding in the temporal lobe clearly distinguished patients with AD from healthy elderly subjects. Compared with [C-11]PiB, [F-18]THK-5117 retention was higher in the medial temporal cortex. Conclusion These findings suggest that [F-18]THK-5117 provides regional information on neurofibrillary pathology in living subjects.
• G-cell hyperplasia of the stomach induces ECL-cell proliferation in the pyloric glands in a paracrinal manner

  Atsuko Kasajima, Fumiyoshi Fujishima, Takanori Morikawa, Shuhei Kawasaki, Sachiko Konosu-Fukaya, Yukiko Shibahara, Tadaho Nakamura, Takeo Yoshikawa, Katsunori Iijima, Tomoyuki Koike, Mika Watanabe, Chikashi Shibata, Hironobu Sasano

  PATHOLOGY INTERNATIONAL 65 5 259 - 263 2015年05月 [査読有り][通常論文]
   

  An inhibitory mechanism toward gastrin hypersecretion is significantly different between G-cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G-cell, d-cell and ECL-cell density in a case of G-cell hyperplasia. The 70-year-old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G-cells in the pyloric glands was quantified on the surgical specimens and G-cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL-cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G-cell density. Somatostatin immunoreactive cells (d-cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G-cell hyperplasia could induce ECL-cell proliferation in a paracrinal manner. In addition, relatively non-prominent endocrinological features in the G-cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL-cells in the pyloric glands.
• Involvement of the histamine H1 receptor in the regulation of sympathetic nerve activity

  Manabu Murakami, Takeo Yoshikawa, Tadaho Nakamura, Takayoshi Ohba, Yasushi Matsuzaki, Daisuke Sawamura, Kenji Kuwasako, Teruyuki Yanagisawa, Kyouichi Ono, Shigeyuki Nakaji, Kazuhiko Yanai

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 458 3 584 - 589 2015年03月 [査読有り][通常論文]
   

  The histamine system is involved in the regulation of the autonomic nervous system. We used gene-targeted mice to investigate the role of histamine receptors in the regulation of the sympathetic nervous system. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed histamine H1, H2, and H3 receptor expression in the superior cervical ganglion, which contains sympathetic nerve cell bodies. We measured the heart rate variability (HRV), the changes in the beat-to-beat heart rate, which is widely used to assess autonomic activity in the heart. H1 blockade attenuated the baroreflex-mediated changes in heart rate in wild-type (WT) mice, whereas the heart rate response to H2- and H3-specific blockers was unaffected. L-Histidine decarboxylase (HDC) expression in the superior cervical ganglion of H1R-null mice was higher than that in WT controls, whereas the enzyme levels in H2R- and H3R-null mice were not significantly different from those in the WT. All mutant mice (H1R-, H2R-, and H3R-null mice) showed normal electrocardiogram (ECG) patterns with little modification in ECG parameters and the expected response to the beta-adrenergic blocker propranolol. Similar to our findings in WT mice, H1 blockade attenuated the baroreflex-mediated heart rate change in H1R-null mice, whereas the heart rate response was unaffected in H2R- and H3R-null mice. The HRV analysis revealed relatively unstable RR intervals, an increased standard deviation of the interbeat interval (SDNN), and low-frequency (LF) component in H1R-null mice compared with the other groups, suggesting that sympathetic nerve activity was altered in H1R-null mice. Taken together, our findings indicate that H1 receptors play a major role in the regulation of sympathetic nerve activity. (C) 2015 Elsevier Inc. All rights reserved.
• Role of histamine H-3 receptor in glucagon-secreting alpha TC1.6 cells

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Attayeb Mohsen, Tomomitsu Iida, Yamato Miura, Akira Sugawara, Kazuhiko Yanai

  FEBS OPEN BIO 5 36 - 41 2015年 [査読有り][通常論文]
   

  Pancreatic alpha-cells secrete glucagon to maintain energy homeostasis. Although histamine has an important role in energy homeostasis, the expression and function of histamine receptors in pancreatic alpha-cells remains unknown. We found that the histamine H-3 receptor (H3R) was expressed in mouse pancreatic alpha-cells and alpha TC1.6 cells, a mouse pancreatic alpha-cell line. H3R inhibited glucagon secretion from alpha TC1.6 cells by inhibiting an increase in intracellular Ca2+ concentration. We also found that immepip, a selective H3R agonist, decreased serum glucagon concentration in rats. These results suggest that H3R modulates glucagon secretion from pancreatic alpha-cells. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. This
• Structural abnormality of the hippocampus associated with depressive symptoms in heart failure rats

  Hideaki Suzuki, Akira Sumiyoshi, Yasuharu Matsumoto, Ben A. Duffy, Takeo Yoshikawa, Mark F. Lythgoe, Kazuhiko Yanai, Yasuyuki Taki, Ryuta Kawashima, Hiroaki Shimokawa

  NEUROIMAGE 105 84 - 92 2015年01月 [査読有り][通常論文]
   

  Heart failure (HF) is characterized by a blood supply which is insufficient to meet the body's demand. HF can potentially affect the brain and is associated with a high prevalence of depression. However, the mechanisms by which the two are related remain largely unclear. Structural abnormalities of the ventral hippocampus have been observed in depression but have never been reported in HF. In this study, we thus investigated structural brain abnormality in HF using voxel-based morphometry (VBM) and histological analysis in a rat model of HF. T2-weighted images were obtained in rats with HF (n = 20) and sham rats (n = 17) and VBM was used to produce gray matter concentration (GMC) maps. Twenty-four hour locomotor activity was used as a sign of depressive behavior. Brains of HF and sham rats (n = 8, each) were fixed and histologically analyzed for the measurement of neurogenesis, the number of astrocytes and neurite outgrowth in the ventral hippocampus. VBM demonstrated significant GMC decrease in the hippocampus, which was restricted to the ventral segment. Similarly, neurogenesis and neurite outgrowth were significantly decreased and the number of astrocytes was significantly increased in HF rats as compared with sham rats in the ventral hippocampus. GMC values in the ventral hippocampus were significantly and negatively correlated with 24 hour locomotor activity in HF rats. In conclusion, the present study has demonstrated for the first time that the structural abnormality of the ventral hippocampus is associated with depressive symptoms in HF rats. (C) 2014 Elsevier Inc. All rights reserved.
• Insufficient Intake of L-Histidine Reduces Brain Histamine and Causes Anxiety-Like Behaviors in Male Mice

  Takeo Yoshikawa, Tadaho Nakamura, Tetsuro Shibakusa, Mayu Sugita, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Attayeb Mohsen, Ryuichi Harada, Kazuhiko Yanai

  JOURNAL OF NUTRITION 144 10 1637 - 1641 2014年10月 [査読有り][通常論文]
   

  L-histidine is one of the essential amino acids for humans, and it plays a critical role as a component of proteins. L-histidine is also important as a precursor of histamine. Brain histamine is synthesized from L-histidine in the presence of histidine decarboxylase, which is expressed in histamine neurons. In the present study, we aimed to elucidate the importance of dietary L-histidine as a precursor of brain histamine and the histaminergic nervous system. C57BL/6J male mice at 8 wk of age were assigned to 2 different diets for at least 2 wk: the control (Con) diet (5.08 g L-histidine/kg diet) or the low L-histidine diet (LHD) (1.28 g L-histidine/kg diet). We measured the histamine concentration in the brain areas of Con diet fed mice (Con group) and LHD-fed mice (LHD group). The histamine concentration was significantly lower in the LHD group [Con group vs. LHD group, histamine in cortex (means +/- SEs): 13.9 +/- 1.25 vs. 9.36 +/- 0.549 ng/g tissue; P = 0.002]. Our in vivo microdialysis assays revealed that histamine release stimulated by high K from the hypothalamus in the LHD group was 60% of that in the Con group (P = 0.012). However, the concentrations of other monoamines and their metabolites were not changed by the LH D. The open-field tests showed that the LH D group spent a shorter amount of time in the central zone (87.6 +/- 14.1 vs. 50.0 +/- 6.03 s/10 min; P = 0.019), and the light/dark box tests demonstrated that the LHD group spent a shorter amount of time in the light box (198 +/- 8.19 vs. 162 +/- 14.1 s/10 min; P=0.048), suggesting that the LHD induced anxiety-like behaviors. However, locomotor activity, memory functions, and social interaction did not differ between the 2 groups. The results of the present study demonstrated that insufficient intake of histidine reduced the brain histamine content, leading to anxiety-like behaviors in the mice.
• Generation of a Stable H295R Cell Line Expressing 11beta-Hydroxylase Gene Promoter and the Effect of High-Glucose on Its Expression

  Sugawara Kaori, Matsuda Ken, Kogure Naotaka, Uruno Akira, Sato Ikuko, Shimizu Kyoko, Parvin Rehana, Yoshikawa Takeo, Kudo Masataka, Saito-Hakoda Akiko, Ito Ryo, Yokoyama Atsushi, Ito Sadayoshi, Sugawara Akira

  ENDOCRINE REVIEWS 35 3 2014年06月 [査読有り][通常論文]
  
• Mechanism of the histamine H-3 receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice

  Attayeb Mohsen, Takeo Yoshikawa, Yamato Miura, Tadaho Nakamura, Fumito Naganuma, Katsuhiko Shibuya, Tomomitsu Iida, Ryuichi Harada, Nobuyuki Okamura, Takehiko Watanabe, Kazuhiko Yanai

  NEUROPHARMACOLOGY 81 188 - 194 2014年06月 [査読有り][通常論文]
   

  Histaminergic neurons are activated by histamine H-3 receptor (H3R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H3R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H3R-mediated behavioural changes using a specific H3R antagonist, JNJ-10181457 (JNJ). First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased N-J-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines. Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by a-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H3R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H1R gene knockout mice but not in histamine H-2 receptor (H2R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an HiR antagonist, and dominantly by zolantidine, an H2R antagonist. These results suggest that H3R blockade induces histamine release, activates H2R and elicits exploratory locomotor activity and anxiety-like behaviours. (c) 2014 Elsevier Ltd. All rights reserved.
• Predominant role of plasma membrane monoamine transporters in monoamine transport in 1321N1, a human astrocytoma-derived cell line

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Ryuichi Harada, Attayeb S. Mohsen, Yamato Miura, Kazuhiko Yanai

  JOURNAL OF NEUROCHEMISTRY 129 4 591 - 601 2014年05月 [査読有り][通常論文]
   

  Monoamine neurotransmitters should be immediately removed from the synaptic cleft to avoid excessive neuronal activity. Recent studies have shown that astrocytes and neurons are involved in monoamine removal. We aimed to elucidate the transporters responsible for monoamine transport by astrocytes in 1321N1, a human astrocytoma-derived cell line. Kinetics analysis suggested the involvement of low-affinity monoamine transporters, e.g., organic cation transporter (OCT) 2 and 3 and plasma membrane monoamine transporter (PMAT). Our results indicate that PMAT and OCT3 in human astrocytes are involved in monoamine clearance.
• Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells

  Ken Matsuda, Akira Uruno, Naotaka Kogure, Kaori Sugawara, Hiroki Shimada, Masahiro Nezu, Takako Saito-Ito, Yuko Iki, Masataka Kudo, Kyoko Shimizu, Ikuko Sato, Takeo Yoshikawa, Fumitoshi Satoh, Ryo Ito, Atsushi Yokoyama, William E. Rainey, Akiko Saito-Hakoda, Sadayoshi Ito, Akira Sugawara

  MOLECULAR AND CELLULAR ENDOCRINOLOGY 383 1-2 60 - 68 2014年03月 [査読有り][通常論文]
   

  We generated a stable H295R cell line expressing aldosterone synthase gene (CYP11B2) promoter/luciferase chimeric reporter construct that is highly sensitive to angiotensin II (All) and potassium, and defined All receptor blocker (ARB) effects. In the presence of All, all ARBs suppressed All-induced CYP11B2 transcription. However, telmisartan alone increased CYP11B2 transcription in the absence of All. Telmisartan dose-dependently increased CYP11B2 transcription/mRNA expression and aldosterone secretion. Experiments using CYP11B2 promoter mutants indicated that the Ad5 element was responsible. Among transcription factors involved in the element, telmisartan significantly induced NGFIB/NURRI expression. KN-93, a CaMK inhibitor, abrogated the telmisartan-mediated increase of CYP11B2 transcription/mRNA expression and NURR1 mRNA expression, but not NGFIB mRNA expression. NURRI over-expression significantly augmented the telmisartan-mediated CYP11B2 transcription, while high-dose olmesartan did not affect it. Taken together, telmisartan may stimulate CYP11B2 transcription via NGFIB and the CaMK-mediated induction of NURR1 that activates the Ad5 element, independent of All type 1 receptor. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
• Use of a Benzimidazole Derivative BF-188 in Fluorescence Multispectral Imaging for Selective Visualization of Tau Protein Fibrils in the Alzheimer's Disease Brain

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Takeo Yoshikawa, Hiroyuki Arai, Kazuhiko Yanai, Yukitsuka Kudo

  MOLECULAR IMAGING AND BIOLOGY 16 1 19 - 27 2014年02月 [査読有り][通常論文]
   

  Selective visualization of amyloid-beta and tau protein deposits will help to understand the pathophysiology of Alzheimer's disease (AD). Here, we introduce a novel fluorescent probe that can distinguish between these two deposits by multispectral fluorescence imaging technique. Fluorescence spectral analysis was performed using AD brain sections stained with novel fluorescence compounds. Competitive binding assay using [H-3]-PiB was performed to evaluate the binding affinity of BF-188 for synthetic amyloid-beta (A beta) and tau fibrils. In AD brain sections, BF-188 clearly stained A beta and tau protein deposits with different fluorescence spectra. In vitro binding assays indicated that BF-188 bound to both amyloid-beta and tau fibrils with high affinity (K (i) < 10 nM). In addition, BF-188 showed an excellent blood-brain barrier permeability in mice. Multispectral imaging with BF-188 could potentially be used for selective in vivo imaging of tau deposits as well as amyloid-beta in the brain.
• Coffee treatment prevents the progression of sarcopenia in aged mice in vivo and in vitro

  Yinting Guo, Kaijun Niu, Tatsuma Okazaki, Hongmei Wu, Takeo Yoshikawa, Takashi Ohrui, Katsutoshi Furukawa, Masakazu Ichinose, Kazuhiko Yanai, Hiroyuki Arai, Guowei Huang, Ryoichi Nagatomi

  EXPERIMENTAL GERONTOLOGY 50 1 - 8 2014年02月 [査読有り][通常論文]
   

  Sarcopenia is characterized by the age-related loss of muscle mass and strength, which results in higher mortality in aged people. One of the mechanisms of the sarcopenia is the loss in the function and number of muscle satellite cells. Chronic low-grade inflammation plays a central role in the pathogenesis of age-related sarcopenia. Accumulating evidence suggests that coffee, one of the most widely consumed beverages in the world, has potential pharmacological benefits such as anti-inflammatory and anti-oxidant effects. Since these effects may improve sarcopenia and the functions of satellite cells, we examined the effects of coffee on the skeletal muscles in an animal model using aged mice. In vivo, coffee treatment attenuated the decrease in the muscle weight and grip strength, increased the regenerating capacity of injured muscles, and decreased the serumpro-inflammatory mediator levels compared to controls. In vitro, using satellite cells isolated from aged mice, coffee treatment increased the cell proliferation rate, augmented the cell cycle, and increased the activation level of Akt intracellular signaling pathway compared to controls. These findings suggest that the coffee treatment had a beneficial effect on age-related sarcopenia. (C) 2013 Elsevier Inc. All rights reserved.
• ARB affects nicotine-induced gene expression profile in human coronary artery endothelial cells

  Kudo M, Matsuda K, Sugawara K, Iki Y, Kogure N, Saito-Ito T, Shimizu K, Sato I, Yoshikawa T, Uruno A, Ito R, Yokoyama A, Saito-Hakoda A, Ito S, Sugawara A

  World J Hypertens 4 1 7 - 14 2014年 [査読有り][通常論文]
  
• The expression and function of histamine H-3 receptors in pancreatic beta cells

  T. Nakamura, T. Yoshikawa, N. Noguchi, A. Sugawara, A. Kasajima, H. Sasano, K. Yanai

  BRITISH JOURNAL OF PHARMACOLOGY 171 1 171 - 185 2014年01月 [査読有り][通常論文]
   

  Background and PurposeHistamine and its receptors in the CNS play important roles in energy homeostasis. Here, we have investigated the expression and role of histamine receptors in pancreatic beta cells, which secrete insulin. Experimental ApproachThe expression of histamine receptors in pancreatic beta cells was examined by RT-PCR, Western blotting and immunostaining. Insulin secretion assay, ATP measurement and calcium imaging studies were performed to determine the function and signalling pathway of histamine H-3 receptors in glucose-induced insulin secretion (GIIS) from MIN6 cells, a mouse pancreatic beta cell line. The function and signalling pathway of H-3 receptors in MIN6 cell proliferation were examined using pharmacological assay and Western blotting. Key ResultsHistamine H-3 receptors were expressed in pancreatic beta cells. A selective H-3 receptor agonist, imetit, and a selective inverse H-3 receptor agonist, JNJ-5207852, had inhibitory and facilitatory effects, respectively, on GIIS in MIN6 cells. Neither imetit nor JNJ-5207852 altered intracellular ATP concentration, or intracellular calcium concentration stimulated by glucose and KCl, indicating that GIIS signalling was affected by H-3 receptor signalling downstream of the increase in intracellular calcium concentration. Moreover, imetit attenuated bromodeoxyuridine incorporation in MIN6 cells. The phosphorylation of cAMP response element-binding protein (CREB), which facilitated beta cell proliferation, was inhibited, though not significantly, by imetit, indicating that activated H-3 receptors inhibited MIN6 cell proliferation, possibly by decreasing CREB phosphorylation. Conclusions and ImplicationsHistamine H-3 receptors were expressed in mouse beta cells and could play a role in insulin secretion and, possibly, beta cell proliferation.
• Is Heparan Sulfate in the Glomerular Basement Membrane Necessary for the Etiology of Diabetic Nephropathy?

  Akiko Saito-Hakoda, Naotaka Kogure, Takeo Yoshikawa, Kyoko Shimizu, Yuko Iki, Ikuko Sato, Masataka Kudo, Akira Uruno, Ken Matsuda, Rehana Parvin, Kaori Sugawara, Atushi Yokoyama, Sadayoshi Ito, Akira Sugawara

  J Biomol Res Ther 3 2 1000e127  2014年01月 [査読有り][通常論文]
  
• Retinoic acid receptor-α up-regulates proopiomelanocortin gene expression in AtT20 corticotroph cells

  Akira Uruno, Akiko Saito-Hakoda, Atsushi Yokoyama, Naotaka Kogure, Ken Matsuda, Rehana Parvin, Kyoko Shimizu, Ikuko Sato, Masataka Kudo, Takeo Yoshikawa, Hiroyuki Kagechika, Yasumasa Iwasaki, Sadayoshi Ito, Akira Sugawara

  Endocrine Journal 61 11 1105 - 1114 2014年 [査読有り][通常論文]
   

  Cushing’s disease is a disorder caused by excessive ACTH secretion from a corticotroph tumor of the pituitary gland. Although its standard therapy is a transsphenoidal surgery, innovation of novel medical treatments for the disease is urgently necessary. Retinoic acid (RA) has been reported to suppress adrenocorticotropic hormone (ACTH) secretion in Cushing’s disease. However, the role of RA receptor (RAR) in proopiomelanocortin (Pomc) gene expression remains uncertain. We here examined the involvement of RARα in Pomc regulation using AtT20 corticotroph cells. Surprisingly, a synthetic RARα agonist Am80 increased Pomc mRNA expression, CRH-induced ACTH secretion, and Pomc promoter activity. Small interfering RNA-mediated RARα-knockdown suppressed both basal and Am80-induced Pomc promoter activity. RARα-overexpression dose-dependently increased Pomc promoter activity. Pomc promoter mutation analysis revealed that both Tpit and NeuroD1 binding elements were responsible for the Am80-mediated effect. Am80 increased Tpit expression while RAR antagonist LE540 suppressed the increase. Tpit-overexpression increased Pomc promoter activity. Mammalian two-hybrid assay revealed that Am80 induced NeuroD1-RARα interaction. NeuroD1-overexpression enhanced the Am80-induced Pomc promoter activity, which was suppressed by NeuroD1 truncated mutant-overexpression. RARα thus positively regulates ACTH secretion/Pomc gene expression through interaction with NeuroD1 and Tpit expression increase. The present observation will be useful for the future development of the RA/retinoid-derived therapeutics of the disease.
• Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease.

  Nobuyuki Okamura, Shozo Furumoto, Ryuichi Harada, Tetsuro Tago, Takeo Yoshikawa, Michelle Fodero-Tavoletti, Rachel S Mulligan, Victor L Villemagne, Hiroyasu Akatsu, Takayuki Yamamoto, Hiroyuki Arai, Ren Iwata, Kazuhiko Yanai, Yukitsuka Kudo

  Journal of nuclear medicine : official publication, Society of Nuclear Medicine 54 8 1420 - 7 2013年08月 [査読有り][通常論文]
   

  UNLABELLED: Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported (18)F-labeled THK-523 ((18)F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel (18)F-labeled arylquinoline derivatives, (18)F-THK-5105 and (18)F-THK-5117, for use as tau imaging PET tracers. METHODS: (18)F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice. RESULTS: In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of (11)C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than (18)F-THK-523 and other reported (18)F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-μM concentrations. CONCLUSION: (18)F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.
• Molecular mechanism of histamine clearance by primary human astrocytes

  Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Tadaho Nakamura, Ryuichi Harada, Attayeb S. Mohsen, Atsuko Kasajima, Hironobu Sasano, Kazuhiko Yanai

  GLIA 61 6 905 - 916 2013年06月 [査読有り][通常論文]
   

  Histamine clearance is an essential process for avoiding excessive histaminergic neuronal activity. Previous studies using rodents revealed the predominant role of astrocytes in brain histamine clearance. However, the molecular mechanism of histamine clearance has remained unclear. We detected histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, in primary human astrocytes and the astrocytes of human brain specimens. Immunocytochemical analysis and subcellular fractionation assays revealed that active HNMT localized to the cytosol, suggesting that histamine transport into the cytosol is crucial for histamine inactivation. We showed that primary human astrocytes transported histamine in a time-dependent manner. Kinetics analysis showed that two low-affinity transporters were involved in histamine transport. Histamine uptake by primary human astrocytes was not dependent on the extracellular Na+/Cl- concentration. Histamine is reported to be a substrate for three low-affinity and Na+/Cl--independent transporters: organic cation transporter 2 (OCT2), OCT3, and plasma membrane monoamine transporter (PMAT). RT-PCR analysis revealed that OCT3 and PMAT were expressed in primary human astrocytes. Immunohistochemistry confirmed OCT3 and PMAT expression in the astrocytes of human brain specimens. Drug inhibition assays and gene knockdown assays revealed the major contribution of PMAT and the minor contribution of OCT3 to histamine transport. The present study demonstrates for the first time that the molecular mechanism of histamine clearance is by primary human astrocytes. These findings might indicate that PMAT, OCT3 and HNMT in human astrocytes play a role in the regulation of extraneuronal histamine concentration and the activities of histaminergic neurons. © 2013 Wiley Periodicals, Inc.
• 高血糖刺激は副腎アルドステロン合成酵素の発現をT型Caチャネルの発現増加を介して誘導する

  小暮 直敬, 伊藤 貴子, 菅原 香織, 松田 謙, 壹岐 裕子, 佐藤 郁子, 皆川 敬治, 勝木 将人, 清水 恭子, 吉川 雄朗, 工藤 正孝, 宇留野 晃, 箱田 明子, 伊藤 貞嘉, 菅原 明

  日本内分泌学会雑誌 89 1 278 - 278 (一社)日本内分泌学会 2013年04月
• ニコチンのヒト冠動脈血管内皮細胞の遺伝子発現に及ぼす影響ならびにそれに対するARBの効果

  壹岐 裕子, 工藤 正孝, 伊藤 貴子, 菅原 香織, 松田 謙, 小暮 直敬, 皆川 敬治, 勝木 将人, 佐藤 郁子, 宇留野 晃, 清水 恭子, 吉川 雄朗, 箱田 明子, 伊藤 貞嘉, 菅原 明

  日本内分泌学会雑誌 89 1 313 - 313 (一社)日本内分泌学会 2013年04月
• Comparison of the binding characteristics of [F-18]THK-523 and other amyloid imaging tracers to Alzheimer's disease pathology

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Tetsuro Tago, Masahiro Maruyama, Makoto Higuchi, Takeo Yoshikawa, Hiroyuki Arai, Ren Iwata, Yukitsuka Kudo, Kazuhiko Yanai

  EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 40 1 125 - 132 2013年01月 [査読有り][通常論文]
   

  Extensive deposition of senile plaques and neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer's disease (AD). Although several PET imaging agents have been developed for in vivo detection of senile plaques, no PET probe is currently available for selective detection of neurofibrillary tangles in the living human brain. Recently, [F-18]THK-523 was developed as a potential in vivo imaging probe for tau pathology. The purpose of this study was to compare the binding properties of [F-18]THK-523 and other amyloid imaging agents, including PiB, BF-227 and FDDNP, to synthetic protein fibrils and human brain tissue. In vitro radioligand binding assays were conducted using synthetic amyloid beta(42) and K18 Delta K280-tau fibrils. Nonspecific binding was determined by the addition of unlabelled compounds at a concentration of 2 mu M. To examine radioligand binding to neuropathological lesions, in vitro autoradiography was conducted using sections of AD brain. [F-18]THK-523 showed higher affinity for tau fibrils than for A beta fibrils, whereas the other probes showed a higher affinity for A beta fibrils. The autoradiographic analysis indicated that [F-18]THK-523 accumulated in the regions containing a high density of tau protein deposits. Conversely, PiB and BF-227 accumulated in the regions containing a high density of A beta plaques. These findings suggest that the unique binding profile of [F-18]THK-523 can be used to identify tau deposits in AD brain.
• Identification of a major enzyme for the synthesis and hydrolysis of cyclic ADP-ribose in amphibian cells and evolutional conservation of the enzyme from human to invertebrate

  Takayuki Ikeda, Shin Takasawa, Naoya Noguchi, Koji Nata, Akiyo Yamauchi, Iwao Takahashi, Takeo Yoshikawa, Akira Sugawara, Hideto Yonekura, Hiroshi Okamoto

  MOLECULAR AND CELLULAR BIOCHEMISTRY 366 1-2 69 - 80 2012年07月 [査読有り][通常論文]
   

  Cyclic ADP-ribose (cADPR), a metabolite of NAD(+), is known to function as a second messenger for intracellular Ca2+ mobilization in various vertebrate and invertebrate tissues. In this study, we isolated two Xenopus laevis cDNAs (frog cd38 and cd157 cDNAs) homologous to the one encoding the human cADPR-metabolizing enzyme CD38. Frog CD38 and CD157 are 298-amino acid proteins with 35.9 and 27.2 % identity to human CD38 and CD157, respectively. Transfection of expression vectors for frog CD38 and CD157 into COS-7 cells revealed that frog CD38 had NAD(+) glycohydrolase, ADP-ribosyl cyclase (ARC), and cADPR hydrolase activities, and that frog CD157 had no enzymatic activity under physiological conditions. In addition, when recombinant CD38 and frog brain homogenate were electrophoresed on an SDS-polyacrylamide gel, ARC of the brain homogenate migrated to the same position in the gel as that of frog CD38, suggesting that frog CD38 is the major enzyme responsible for cADPR metabolism in amphibian cells. The frog cd38 gene consists of eight exons and is ubiquitously expressed in various tissues. These findings provide evidence for the existence of the CD38-cADPR signaling system in frog cells and suggest that the CD38-cADPR signaling system is conserved during vertebrate evolution.
• [ 11C]doxepin binding to histamine H1 receptors in living human brain: Reproducibility during attentive waking and circadian rhythm

  Katsuhiko Shibuya, Yoshihito Funaki, Kotaro Hiraoka, Takeo Yoshikawa, Fumito Naganuma, Masayasu Miyake, Shoichi Watanuki, Hirotoshi Sato, Manabu Tashiro, Kazuhiko Yanai

  Frontiers in Systems Neuroscience 6 2012 45 - 45 2012年06月11日 [査読有り][通常論文]
   

  Molecular imaging in neuroscience is a new research field that enables visualization of the impact of molecular events on brain structure and function in humans. While magnetic resonance-based imaging techniques can provide complex information at the level of system, positron emission tomography (PET) enables determination of the distribution and density of receptor and enzyme in the human brain. Previous studies using [ 11C]raclopride and [ 11C]FLB457 revealed that the release of neuronal dopamine was increased in human brain by psychostimulants or reward stimuli. Following on from these previous [ 11C]raclopride studies, we examined whether the levels of neuronal release of histamine might change [ 11C]doxepin binding to the H1 receptors under the influence of physiological stimuli. The purpose of the present study was to evaluate the test-retest reliability of quantitative measurement of [ 11C]doxepin binding between morning and afternoon and between resting and attentive waking conditions in healthy human subjects. There was a trend for a decrease in [ 11C]doxepin binding during attentive calculation tasks compared with that in resting conditions, but the difference (less than 10%) was not significant. Similarly, the binding potential of [ 11C]doxepin in the cerebral cortex was slightly higher in the morning than that in the afternoon, but it was also insignificant. These data suggest that higher histamine release during wakefulness could not decrease the [ 11C]doxepin binding in the brain. This study confirmed the reproducibility and reliability of [ 11C]doxepin in the previous imaging studies to measure the H1 receptor. © 2012 Shibuya,Funaki, Hiraoka, Yoshikawa, Naganuma, Miyake, Watanuki, Sato, Tashiroand Yanai.
• Synthesis of [C-11]interleukin 8 using a cell-free translation system and L-[C-11]methionine

  Ryuichi Harada, Shozo Furumoto, Takeo Yoshikawa, Yoichi Ishikawa, Katsuhiko Shibuya, Nobuyuki Okamura, Ren Iwata, Kazuhiko Yanai

  NUCLEAR MEDICINE AND BIOLOGY 39 1 155 - 160 2012年01月 [査読有り][通常論文]
   

  Positron emission tomography (PET), which requires a compound labeled with a positron emitter radioisotope as an imaging probe, is one of the most useful and valuable imaging modalities in molecular imaging. It has several advantages over other imaging modalities, particularly in sensitive and quantitative investigations of molecular functions and processes in vivo. Recent advances in biopharmaceuticals development have increased interest in practical methods for proteins and peptides labeling with positron emitter radioisotope for PET molecular imaging. Here, we propose a novel approach for preparing positron emitter-labeled proteins and peptides based on biochemical synthesis using a reconstituted cell-free translation system. In this study, [C-11]interleukin 8 (IL-8; MW 9.2 kDa) was successfully synthesized by the cell-Free system in combination with L-[C-11]methionine. The in vitro biochemical reaction proceeded smoothly and gave maximum radioactivity of [C-11]IL-8 at 20 min with a radiochemical yield of 63%. Purification of [C-11]IL-8 was achieved by conventional cation exchange and ultrafiltration methods, resulting in enough amount of radioactivity with excellent radiochemical purity (>95%) for small-animal imaging. This study clearly demonstrates that cell-free protein production system combined with positron emitter-labeled amino acid holds great promise as a novel approach to prepare radiolabeled proteins and peptides for PET imaging. (C) 2012 Elsevier Inc. All rights reserved.
• All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells: possible involvement of protein kinase C-delta

  Akira Uruno, Naoya Noguchi, Ken Matsuda, Koji Nata, Takeo Yoshikawa, Youichiro Chikamatsu, Hiroyuki Kagechika, Hideo Harigae, Sadayoshi Ito, Hiroshi Okamoto, Akira Sugawara

  JOURNAL OF LEUKOCYTE BIOLOGY 90 2 235 - 247 2011年08月 [査読有り][通常論文]
   

  ATRA and a synthetic RAR agonist tamibarotene (Am80) induce granulocytic differentiation of human acute leukemia HL-60 cells and have been used in antineoplastic therapy. ATRA induces CD38 antigen during HL-60 cell differentiation, which interacts with CD31 antigen on the vascular EC surface and may induce disadvantages in the therapy. We here examined the mechanisms of the ATRA-mediated CD38 induction and compared the difference between ATRA-and tamibarotene-mediated induction. Tamibarotene-induced HL-60 cell adhesion to ECs was 38% lower than ATRA, and NB4 cell adhesion to ECs by tamibarotene was equivalent to ATRA, which induced CD38 gene transcription biphasically in HL-60 cells, the early-phase induction via DR-RARE containing intron 1, and the delayed-phase induction via RARE lacking the 5'-flanking region. In contrast to ATRA, tamibarotene induced only the early-phase induction, resulting in its lower CD38 induction than ATRA. A PKC delta inhibitor, rottlerin, and siRNA-mediated PKC delta knockdown suppressed the ATRA-induced CD38 promoter activity of the 5'-flanking region, whereas a RAR antagonist, LE540, or RAR knockdown did not affect it. Cycloheximide and rottlerin suppressed the delayed-phase induction of CD38 expression by ATRA but did not affect the early-phase induction. Moreover, ATRA, but not tamibarotene, induced PKC delta expression without affecting its mRNA stability. The diminished effect of tamibarotene on CD38-mediated HL-60 cell adhesion to ECs compared with ATRA is likely a result of the lack of its delayed-phase induction of CD38 expression, which may be advantageous in antineoplastic therapy. J. Leukoc. Biol. 90: 235-247; 2011.
• Positron emission tomography evaluation of sedative properties of antihistamines

  Kazuhiko Yanai, Dongying Zhang, Manabu Tashiro, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Tadaho Nakamura, Katsuhiko Shibuya, Nobuyuki Okamura

  EXPERT OPINION ON DRUG SAFETY 10 4 613 - 622 2011年07月 [査読有り][通常論文]
   

  Introduction: H-1 antihistamines are often used in the medication for allergic diseases, coughs and colds, and insomnia, with or without prescription, even though their sedative properties are a potentially dangerous unwanted side effect that is not properly recognized. These sedative properties have been evaluated using the incidence of subjective sleepiness, objective cognitive and psychomotor functions, and positron emission tomography (PET) measurement of H-1 receptor occupancy. Areas covered: This article reviews the current updated literature on the sedative properties of antihistamines examined by PET measurement of H-1 receptor occupancy. Expert opinion: The use of PET to examine antihistamine penetration in the human brain in relation to psychometric and other functional measures of CNS effects is a major breakthrough and provides a new standard by which the functional CNS effects of antihistamines can be related directly to H-1 receptor occupancy. Therapy with antihistamines can be better guided by considering histamine H-1 receptor occupancy from the view of their sedative properties.
• Peroxisome proliferator-activated receptor-gamma suppresses CYP11B2 expression and aldosterone production

  Akira Uruno, Ken Matsuda, Naoya Noguchi, Takeo Yoshikawa, Masataka Kudo, Fumitoshi Satoh, William E. Rainey, Xiao-Gang Hui, Jun-ichi Akahira, Yasuhiro Nakamura, Hironobu Sasano, Hiroshi Okamoto, Sadayoshi Ito, Akira Sugawara

  JOURNAL OF MOLECULAR ENDOCRINOLOGY 46 1 37 - 49 2011年02月 [査読有り][通常論文]
   

  Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear receptor for the antidiabetic agent thiazolidinedione, which exerts various physiological activities, independent of lowering blood glucose. However, the role of PPAR gamma in aldosterone production has not been clarified. The objective of this study was to investigate the effect of PPAR gamma on aldosterone synthase gene (CYP11B2) expression and aldosterone production. Localization of PPAR gamma expression in normal adrenal cortex was determined by immunohistochemistry. Aldosterone production and CYP11B2 expression levels were determined using human adrenocortical carcinoma H295R cells. Pioglitazone suppressed angiotensin II-induced aldosterone secretion and CYP11B2 expression. PPAR gamma was expressed in zona glomerulosa in human normal adrenal gland. PPAR gamma overexpression enhanced pioglitazone-mediated CYP11B2 transrepression. The pioglitazone-mediated suppression of aldosterone secretion and CYP11B2 expression were canceled by PPARg L466A/E469A mutant. Pioglitazone also suppressed potassium-mediated CYP11B2 induction, but not N6-2'-O-dibutyladenosine- 3',5'-cyclic monophosphate stimulation. Rosiglitazone and GW1929 also suppressed CYP11B2 transactivation. Mutation analysis revealed that the Ad1/CRE element in CYP11B2 5'-flanking region was responsible for the pioglitazone-mediated transrepression. Pioglitazone suppressed ionomycin and a truncated constitutively active form Ca(2+)/calmodulin-dependent kinase I (CaMKI)-mediated CYP11B2 transcriptional activation. A CaMK inhibitor KN-93 attenuated pioglitazone-mediated CYP11B2 transrepression. PPAR gamma suppresses CYP11B2 expression and aldosterone secretion.
• In vivo Detection of Amyloid Plaques in the Mouse Brain using the Near-Infrared Fluorescence Probe THK-265

  Nobuyuki Okamura, Masanori Mori, Shozo Furumoto, Takeo Yoshikawa, Ryuichi Harada, Satoshi Ito, Yosuke Fujikawa, Hiroyuki Arai, Kazuhiko Yanai, Yukitsuka Kudo

  JOURNAL OF ALZHEIMERS DISEASE 23 1 37 - 48 2011年 [査読有り][通常論文]
   

  Noninvasive detection of amyloid-beta (A beta) deposits in the brain would be beneficial for an early and presymptomatic diagnosis of Alzheimer's disease (AD). We developed THK-265 as a candidate near-infrared fluorescence (NIRF) probe for the in vivo detection of amyloid deposits in the brain. The maximal emission wavelength of THK-265 was greater than 650 nm and it showed high quantum yield and molar absorption coefficients. A fluorescence binding assay showed its high binding affinity to A beta fibrils (Kd = 97 nM). THK-265 clearly stained amyloid plaques in AD neocortical brain sections and showed a moderate log p value (1.8). After intravenous administration of THK-265 in amyloid-beta protein precursor (A beta PP) transgenic mice, amyloid deposits in the brain were clearly labeled with THK-265. Furthermore, in vivo NIRF imaging demonstrated significantly higher fluorescence intensity in the brains of A beta PP transgenic mice than in those of wild-type mice. As THK-265 showed profound hyperchromic effect upon binding to A beta fibrils, good discrimination between A beta PP transgenic and wild-type mice was demonstrated even early after THK-265 administration. Furthermore, the fluorescence intensity of THK-265 correlated with amyloid plaque burden in the brains of A beta PP transgenic mice. These findings strongly support the usefulness of THK-265 as an NIRF imaging probe for the noninvasive measurement of brain amyloid load.
• Roles of Hypothalamic Subgroup Histamine and Orexin Neurons on Behavioral Responses to Sleep Deprivation Induced by the Treadmill Method in Adolescent Rats

  Ajing Xu, Eilko Sakurai, Atsuo Kuramasu, Jian Zhang, Jiyu Li, Nobuyuki Okamura, Dongying Zhang, Takeo Yoshikawa, Takehiko Watanabe, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 114 4 444 - 453 2010年12月 [査読有り][通常論文]
   

  Sleep deprivation induces several negative effects on behavior, emotion, attention, and learning ability Sleep appears to be particularly important during adolescent brain development In the present study, we examined the effects of sleep deprivation on behavior and hypothalamic neurotransmission including histamine and orexin neurons in adolescent rats using the treadmill method Adolescent male rats were divided into three groups treadmill sleep-deprived, treadmill control, and cage control groups Energy expenditure, anxiety-like behavior, and locomotor activity were examined among the three groups Histamine concentration in the cortex and diencephalon and the number of c-Fos-positive neurons in the hypothalamus were also examined In addition, histamine and orexin neurons in the hypothalamus were simultaneously identified using rat histidine decarboxylase and orexin-A immunohistochemistry, respectively Both energy expenditure and anxiety-related behavior significantly increased by the experimental 3-day sleep deprivation, while exploratory locomotor activity significantly decreased Histamine contents did not change in the cortex, but significantly decreased in the diencephalon of sleep-deprived rats Increased expression of c-Fos-positive neurons, including subgroup histamine and orexin neurons, was observed in the hypothalamus These findings indicate that sleep deprivation increases energy expenditure and anxiety in adolescent rats and provide evidence for the pivotal role of hypothalamus subgroup histamine and orexin neurons in the behavioral response to sleep deprivation
• Next-Day Residual Sedative Effect After Nighttime Administration of an Over-the-Counter Antihistamine Sleep Aid, Diphenhydramine, Measured by Positron Emission Tomography

  Dongying Zhang, Manabu Tashiro, Katsuhiko Shibuya, Nobuyuki Okamura, Yoshihito Funaki, Takeo Yoshikawa, Masato Kato, Kazuhiko Yanai

  JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 30 6 694 - 701 2010年12月 [査読有り][通常論文]
   

  Antihistamines often are self-administered at night as over-the-counter (OTC) sleep aids, but their next-day residual sedative effect has never been evaluated using a reliable quantitative method such as positron emission tomography (PET). We performed a double-blind, placebo-controlled, crossover study in which we evaluated the residual effect the next day after nighttime administration of diphenhydramine, a commonly used OTC sleep aid, in terms of brain H-1 receptor occupancy (H1RO) measured using C-11-doxepin-PET. We also compared the results of diphenhydramine with those of bepotastine, a second-generation antihistamine. Eight healthy adult male subjects underwent PET measurement the morning (11:00) after random oral administration of diphenhydramine (50 mg), bepotastine (10 mg), or placebo the night before (23:00). Binding potential ratios and H1ROs were calculated in different brain regions of interest such as the cingulate gyrus, frontotemporal cortex, and cerebellum. Subjective sleepiness and plasma drug concentration also were measured. Calculation of binding potential ratios revealed significantly lower values for diphenhydramine than for bepotastine or placebo in all regions of interest (P < 0.01). Cortical mean H1RO after diphenhydramine treatment was 44.7% compared with 16.6% for bepotastine treatment (P < 0.01). Subjective sleepiness was not significantly different among the subjects treated with each test drug or the placebo. In conclusion, the next-day residual sedative effect after nighttime administration of the OTC sleep aid diphenhydramine was verified for the first time by direct PET measurement of H1RO. Taking into account the possible hangover effect of OTC antihistamine sleep aids, care needs to be taken during their administration.
• Upregulation of REG I alpha accelerates tumor progression in pancreatic cancer with diabetes

  Lin Zhou, Ruifeng Zhang, Lishun Wang, Shaoming Shen, Hiroshi Okamoto, Akira Sugawara, Li Xia, Xiaoling Wang, Naoya Noguchi, Takeo Yoshikawa, Akira Uruno, Weiyan Yao, Yaozong Yuan

  INTERNATIONAL JOURNAL OF CANCER 127 8 1795 - 1803 2010年10月 [査読有り][通常論文]
   

  Diabetes is now generally accepted as a crucial event in the process of pancreatic cancer (PaC). However, molecular mechanisms underlying the relationship between diabetes and PaC are not fully understood. Regenerating gene (REG) I alpha is a growth factor affecting pancreatic islet beta cells, and it has been shown to be involved in the carcinogenesis in gastrointestinal tract. It is rational to speculate that REG I alpha plays a potential role in the pathogenesis of PaC with diabetes. The aim of this study was to evaluate the REG I alpha protein expression profile in PaC with and without diabetes, and define the contribution of REG I alpha on PaC development. We found that REG I alpha protein preferentially expressed in cancerous tissues of PaC patients with diabetes by Western blot. REG I alpha positive cancer cells in PaC with diabetes (n = 38) was significantly higher than that in subjects without diabetes (n = 42, p < 0.05) by immunohistochemical analysis. Furthermore, we found that overexpression of REG I alpha protein in PaC cell lines resulted in accelerated cell proliferation and consequently tumor growth, both in vitro and in vivo. The findings suggest that REG I alpha may act as one of the tumor promoter and contribute to the aggressive nature of PaC, especially in the subpopulation with diabetes. This study would shed new insights for understanding the molecular mechanisms underlying the link between diabetes and PaC.
• A novel ryanodine receptor expressed in pancreatic islets by alternative splicing from type 2 ryanodine receptor gene

  Shin Takasawa, Michio Kuroki, Koji Nata, Naoya Noguchi, Takayuki Ikeda, Akiyo Yamauchi, Hiroyo Ota, Asako Itaya-Hironaka, Sumiyo Sakuramoto-Tsuchida, Iwao Takahashi, Takeo Yoshikawa, Tooru Shimosegawa, Hiroshi Okamoto

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 397 2 140 - 145 2010年06月 [査読有り][通常論文]
   

  Cyclic ADP-ribose (cADPR), a potent Ca(2+) mobilizing intracellular messenger synthesized by CD38, regulates the opening of ryanodine receptors (RyRs). Increases in intracellular Ca(2+) concentrations in pancreatic islets, resulting from Ca(2+) mobilization from RyRs as well as Ca(2+) influx from extracellular sources, are important in insulin secretion by glucose. In the present study, by screening a rat islet cDNA library, we isolated a novel RyR cDNA (the islet-type RyR), which is generated from the RyR2 gene by alternative splicing of exons 4 and 75. When the expression vectors for the islet-type and the authentic RyRs were transfected into HEK293 cells, the islet-type RyR2 as well as the authentic one showed high affinity [(3)H]ryanodine binding. Intracellular Ca(2+) release in the islet-type RyR2-transfected cells was enhanced in the presence of cADPR but not in the authentic RyR2-transfected cells. The islet-type RyR2 mRNA was expressed in a variety of tissues such as in pancreatic islets, cerebrum, and cerebellum, whereas the authentic RyR2 mRNA was predominantly expressed in heart and aorta. These results suggest that the islet-type RyR2 may be an intracellular target for cADPR signaling. (C) 2010 Elsevier Inc. All rights reserved.
• Methamphetamine- and 3,4-Methylenedioxymethamphetamine-Induced Behavioral Changes in Histamine H-3-Receptor Knockout Mice

  Tomohiro Okuda, Dongying Zhang, He Shao, Nobuyuki Okamura, Naoko Takino, Tatsunori Iwamura, Eiko Sakurai, Takeo Yoshikawa, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 111 2 167 - 174 2009年10月 [査読有り][通常論文]
   

  Histamine H-3 receptors inhibit the release of not only histamine itself, but also other neurotransmitters including dopamine. Previous papers have reported that histaminergic neurons inhibit psychostimulant-induced behavioral changes. To examine whether deficiency in histamine H-3 receptors influences psychostimulant-induced behavioral sensitization and reward, we examined locomotor activity, conditioned place preference (CPP), and c-Fos expression in histamine H3 receptor-gene knockout mice (H3KO) and their wild-type (WT) counterparts before and after treatment with methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA). The increase in locomotion induced by treatment with METH or MDMA was lower in histamine H3KO mice than in WT mice, while the locomotor sensitization was developed by METH or MDMA in both strains. However, no significant difference in METH- and MDMA-induced preference scores of CPP between histamine H3KO mice and WT mice was observed. Following treatment with METH, the number of c-Fos-positive neurons in the the caudate-putamen of histamine H3KO mice was lower than that in the caudate-putamen of WT mice. In contrast, there was no significant difference in the number of the psychostimulant-induced c-Fos-positive cells in the nucleus accumbens between the two strains of mice. These findings suggest that deficiency in histamine H-3 receptors may have inhibitory effects on psychostimulant-induced increase in locomotion, but insignificant effects on the reward.
• FKBP12.6ノックアウトマウスではブドウ糖刺激インスリン分泌が低下する

  吉川雄朗

  東北医学雑誌 121 1 84 - 87 2009年06月 [査読無し][招待有り]
  
• Important role of heparan sulfate in postnatal islet growth and insulin secretion

  Iwao Takahashi, Naoya Noguchi, Koji Nata, Shuhei Yamada, Tomoyuki Kaneiwa, Shuji Mizumoto, Takayuki Ikeda, Kazushi Sugihara, Masahide Asano, Takeo Yoshikawa, Akiyo Yamauchi, Nausheen Jamal Shervani, Akira Uruno, Ichiro Kato, Michiaki Unno, Kazuyuki Sugahara, Shin Takasawa, Hiroshi Okamoto, Akira Sugawara

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 383 1 113 - 118 2009年05月 [査読有り][通常論文]
   

  Heparan sulfate (HS) binds with several signaling molecules and regulates ligand-receptor interactions, playing an essential role in embryonic development. Here we showed that HS was intensively expressed in pancreatic islet beta-cells after I week of age in mice. The enzymatic removal of HS in isolated islets resulted in attenuated glucose-induced insulin secretion with a concomitant reduction in gene expression of several key components in the insulin secretion machinery. We further depleted islet HS by inactivating the exostosin tumor-like 3 gene specifically in beta-cells. These truce exhibited abnormal islet morphology with reduced beta-cell proliferation after 1 week of age and glucose intolerance due to defective insulin secretion. These results demonstrate that islet HS is involved in the regulation of postnatal islet maturation and required to ensure normal insulin secretion. (C) 2009 Elsevier Inc. All rights reserved.
• Thiazolidinediones inhibit REG I alpha gene transcription in gastrointestinal cancer cells

  Akiyo Yamauchi, Iwao Takahashi, Shin Takasawa, Koji Nata, Naoya Noguchi, Takayuki Ikeda, Takeo Yoshikawa, Nausheen J. Shervani, Iwao Suzuki, Akira Uruno, Michiaki Unno, Hiroshi Okamoto, Akira Sugawara

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 379 3 743 - 748 2009年02月 [査読有り][通常論文]
   

  REG (Regenerating gene) lot protein functions as a growth factor for gastrointestinal cancer cells, and its mRNA expression is strongly associated with a poor prognosis in gastrointestinal cancer patients. We here demonstrated that PPAR gamma-agonist thiazolidinediones (TZDs) inhibited cell proliferation and REG I alpha protein/mRNA expression in gastrointestinal cancer cells. TZDs inhibited the REG]a gene promoter activity, via its cis-acting element which lacked PPAR response element and could not bind to PPAR,1, in PPAR gamma-expressing gastrointestinal cancer cells. The inhibition was reversed by co-treatment with a specific PPAR gamma-antagonist GW9662. Although TZDs did not inhibit the REG la gene promoter activity in PPAR gamma-non-expressing cells, PPAR gamma overexpression in the cells recovered their inhibitory effect. Taken together, TZDs inhibit REG la gene transcription through a PPAR gamma-dependent pathway. The TZD-induced REG lot mRNA reduction was abolished by cycloheximide, indicating the necessity of novel protein(s) synthesis. TZDs may therefore be a candidate for novel anti-cancer drugs for patients with gastrointestinal cancer expressing both REG I alpha and PPAR gamma. (C) 2008 Elsevier Inc. All rights reserved.
• FKBP12.6 disruption impairs glucose-induced insulin secretion

  Naoya Noguchi, Takeo Yoshikawa, Takayuki Ikeda, Iwao Takahashi, Nausheen Jamal Shervani, Akira Uruno, Akiyo Yamauchi, Koji Nata, Shin Takasawa, Hiroshi Okamoto, Akira Sugawara

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 371 4 735 - 740 2008年07月 [査読有り][通常論文]
   

  Cyclic ADP-ribose (cADPR), accumulated in pancreatic P-cells in response to elevated ATP levels after glucose stimulation, mobilizes Ca2+ from the endoplasmic reticulum through the ryanodine receptor (RyR) and thereby induces insulin secretion. We have recently demonstrated in an in vitro study that cADPR activates RyR through binding to FK506-binding protein 12.6 (FKBP12.6), an accessory protein of RyR. Here we generated FKBP12.6-deficient (FKBP12.6(-/-)) mice by homologous recombination. FKBP12.6(-/-) mice showed glucose intolerance coupled to insufficient insulin secretion upon a glucose challenge. Insulin secretion in response to glucose was markedly impaired in FKP12.6(-/-) islets, while sulfonylurea- or KCl-incluced insulin secretion was unaffected. No difference was found in the glucose oxidation rate between FKBP12.6(-/-) and wild-type islets. These results indicate that FKBP12.6 plays a role in glucose-induced insulin secretion downstream of ATP production, independently of ATP-sensitive K+ channels, in pancreatic beta-cells. (c) 2008 Elsevier Inc. All rights reserved.
• Genomic organization, chromosomal localization, and promoter of human gene for FK506-binding protein 12.6

  T Nakazawa, S Takasawa, N Noguchi, K Nata, A Tohgo, M Mori, K Nakagawara, T Akiyama, T Ikeda, A Yamauchi, Takahashi, I, T Yoshikawa, H Okamoto

  GENE 360 1 55 - 64 2005年10月 [査読有り][通常論文]
   

  Cyclic ADP-ribose (cADPR) induces the release of Ca2+ from microsomes of pancreatic islets for insulin secretion. It has been demonstrated that cADPR binds to FK506-binding protein 12.6 (FKBP 12.6) on rat islet ryanodine receptor and that the binding of cADPR to FKBP 12.6 frees the ryanodine receptor from FKBP 12.6, causing it to release Ca2+ [Noguchi, N., Takasawa, S., Nata, K., Tohgo, A., Kato, I, Ikehata, F., Yonekura, H., Okamoto, H., 1997. Cyclic ADP-ribose binds to FK506-binding protein to release Ca2+ from islet microsomes. J. Biol. Chem. 272,3133 -3136.]. In this study, we cloned, characterized the structural organization of the human FKBP12.6, which is highly homologous to human FKBP12, and analyzed the promoters for FKBP12.6 and FKBP12. Human FKBP12.6 gene spanned about 16 kb in length and consisted of four exons and three introns. The positions of exon-intronjunction of the FYBP12.6 gene were perfectly matched with those of FKBP12 gene except that FKBP12 has an additional exon, exon V, to code exclusively for 3'-UTR. Fluorescence in situ hybridization revealed that the FKBP12.6 gene was located on chromosome 2 p21-23, which is different from the locus (chromosome 20 p13) of the FKBP12 gene. Reporter gene analyses revealed that the regions of - 58 similar to - 24 of FKBP12.6 and - 106 similar to - 79 of FKBP12 are important for promoter activities. The promoters contain a consensus transcription factor binding sequence for Sp family in FKBP12.6 and Ets-1 in FK-BP12. Electrophoretic mobility shift assays showed that nuclear proteins bind to the promoters. The DNA/protein complex on FKBP12.6 promoter was competed out by Sp1 consensus probe and the complex was supershifted by anti-Sp3 antibodies. On the other hand, the DNA/protein complex on FKBP12 promoter was competed out by Ets-1 consensus probe but not by its mutant probe, indicating that Sp3 and Ets-1 play an essential role in transcription of FKBP12.6 and FKBP12, respectively. (c) 2005 Elsevier B.V. All rights reserved.
• An Anti-EpCAM Monoclonal Antibody (EpMab-37-mG2a-f) Exerts Antitumor Activity against Breast Cancer in Mouse Xenograft Model

  Takeo Yoshikawa

MISC

• 扁桃体中心核ニューロテンシン神経細胞の睡眠覚醒サイクルにおける役割の検討

  中村 正帆, 長沼 史登, 田中 聖人, 井上 まり絵, 直野 留美, 吉川 雄朗, 岡村 信行 応用薬理 102 (5-6) 128 -128 2022年08月
• ブドウ糖代謝におけるヘパラン硫酸の役割について

  吉川 雄朗, 松澤 拓郎, 谷内 一彦, 山口 祐 糖尿病 65 (Suppl.1) S -282 2022年04月
• 【皮膚科医が学ぶ睡眠医学-皮膚科診療に活かそう!】(Part1.)皮膚科医が知っておくべき睡眠の科学(総説7) ヒスタミンH1受容体拮抗薬による眠気と鎮静作用発生メカニズム

  谷内 一彦, 吉川 雄朗 Visual Dermatology 21 (3) 262 -265 2022年02月
• 成体マウス脳内のヒスタミン減少により,うつ様行動の増加,記憶能の低下,自発行動量の減少が惹起される

  吉川雄朗, 長沼史登, 長沼史登, 山田瑶, 吉川貴子, 大隅典子, 谷内一彦 日本神経精神薬理学会プログラム・抄録集 50th 179 -179 2020年
• 膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

  横山 敦, 野呂 英理香, 松澤 拓郎, 吉川 雄朗, 島 弘季, 五十嵐 和彦, 菅原 明 日本生化学会大会プログラム・講演要旨集 92回 [3T15m -04] 2019年09月 [査読無し][通常論文]
  
• Histamine H1 receptor occupancy measured by PET in the human brain after oral administration of desloratadine

  Tadaho Nakamura, Takeo Yoshikawa, Manabu Tashiro, Nobuyuki Okamura, Kazuhiko Yanai Inflammation Research 68 (S1) S14 -S15 2019年07月 [査読無し][通常論文]
  
• 無細胞蛋白合成系を用いたタンパク質の部位特異的フッ素18標識法

  谷内 一彦, 原田 龍一, 谷内 亜衣, 吉川 雄朗, 古本 祥三, 岩田 錬 JSMI Report 12 (2) 97 -97 2019年05月 [査読無し][通常論文]
  
• 白色脂肪細胞におけるヘパラン硫酸は糖の恒常性の維持に重要である

  松澤 拓郎, 吉川 雄朗, 谷内 一彦 糖尿病 62 (Suppl.1) S -179 2019年04月 [査読無し][通常論文]
  
• Affibodyの新規18F標識法によるHER2、PD-L1発現腫瘍の分子イメージング

  谷内 亜衣, 原田 龍一, 岩田 錬, 吉川 雄朗, 古本 祥三, 谷内 一彦, 内藤 剛, 海野 倫明, 亀井 尚, 石田 孝宜 日本外科学会定期学術集会抄録集 119回 PS -110 2019年04月 [査読無し][通常論文]
  
• ヒスチジンの疲労感低減機能に関する研究

  笹原 育子, 安居 昌子, 杉田 麻友, 柴草 哲郎, 藤村 尚子, 野沢 与志津, 吉川 雄朗, 谷内 一彦 アミノ酸研究 12 (1) 58 -58 2019年02月 [査読無し][通常論文]
  
• デスロラタジンおよびロラタジン経口投与後の陽電子放出断層撮影による脳内ヒスタミン１型受容体占拠率測定

  中村 正帆, 平岡 宏太良, 原田 龍一, 松澤 拓郎, 吉川 雄朗, 田代 学, 谷内 一彦, 岡村 信行 日本薬理学会年会要旨集 92 (0) 3 -O-25 2019年 

  Objective: Some histamine H₁ receptor (H₁R) antagonists have sedative effects, caused by the blockade of histamine neural transmission. Desloratadine is a newly-marked antihistamine, but its sedative properties have not been examined by positron emission tomography (PET). We examined the brain H₁R binding potential ratio (BPR), H₁R occupancy (H₁RO) and the subjective sleepiness after oral administration of desloratadine and loratadine, the prodrug of desloratadine.

  Methods: Eight healthy male volunteers underwent PET imaging with [¹¹C]doxepin after single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double-blind crossover study. BPRs and H₁ROs in the cerebral cortices were calculated. Subjective sleepiness was quantified by the LARS and the SSS.

  Results: BPR after loratadine administration was significantly lower than placebo (p<0.05), but BPR after desloratadine was not significant. There was no significant difference, however, between H₁RO after desloratadine and loratadine administration. The subjective sleepiness was not significantly different among the two antihistamines and placebo.

  Conclusion: At therapeutic dose, desloratadine did not bind significantly to brain H₁Rs and did not cause significant sedation.

• 脳内ヒスタミン除去機構を標的とした創薬研究 ヒスタミン代謝酵素HNMTの機能解明と阻害剤探索

  吉川 雄朗, 北野 陽菜, 谷内 一彦 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集 28回・48回 221 -221 2018年11月 [査読無し][通常論文]
  
• 【神経系のトランスポーター-Up to date】トランスポーターの基礎 モノアミントランスポーター

  吉川 雄朗, 北野 陽菜, 谷内 一彦 Clinical Neuroscience 36 (6) 652 -655 2018年06月
• Affibodyの新規18F標識法によるHER2発現乳癌の分子イメージング

  谷内 亜衣, 原田 龍一, 岩田 錬, 吉川 雄朗, 古本 祥三, 谷内 一彦, 石田 孝宣 日本乳癌学会総会プログラム抄録集 26回 431 -431 2018年05月 [査読無し][通常論文]
  
• Affibodyの新規18F標識法によるHER2発現乳癌の分子イメージング

  谷内 亜衣, 原田 龍一, 岩田 錬, 吉川 雄朗, 古本 祥三, 谷内 一彦, 石田 孝宣 日本乳癌学会総会プログラム抄録集 26回 431 -431 2018年05月
• 脂肪組織におけるヘパラン硫酸の役割について

  松澤 拓郎, 吉川 雄朗, 谷内 一彦 糖尿病 61 (Suppl.1) S -320 2018年04月
• がん原遺伝子Brafの活性化はマウス食道の拡張と前胃上皮の過増殖をもたらす

  井上 晋一, 高原 真吾, 吉川 雄朗, 新堀 哲也, 谷内 一彦, 松原 洋一, 青木 洋子 生命科学系学会合同年次大会 2017年度 [1LBA -090] 2017年12月 [査読無し][通常論文]
  
• 膵β細胞におけるヘパラン硫酸はインスリン分泌及び糖の恒常性維持に重要である

  松澤 拓郎, 吉川 雄朗, 中村 正帆, 谷内 一彦 生命科学系学会合同年次大会 2017年度 [1AT26 -0059)] 2017年12月
• Low intensity Pulsed Ultrasound Ameliorates Cognitive Impairment in a Mouse Model of Vascular Dementia

  Kumiko Eguchi, Kenta Ito, Tomohiko Shindo, Ryo Kurosawa, Yuta Kagaya, Yuto Monma, Sadamitsu Ichijyo, Satoshi Miyata, Takeo Yoshikawa, Kazuhiko Yanai, Hirofumi Taki, Hiroshi Kanai, Noriko Osumi, Hiroaki Shimokawa CIRCULATION 136 2017年11月 

  0
• ヒスタミン3型受容体インバースアゴニストによるミクログリア機能抑制について(Suppression of microglial functions by an H3R inverse agonist)

  飯田 智光, 吉川 雄朗, 谷内 一彦 日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集 39回・47回 202 -202 2017年09月 [査読無し][通常論文]
  
• 脳内ヒスタミン神経系の過剰な興奮はH2受容体を介してマウスの攻撃性を増加させる

  吉川 雄朗, 飯田 智光, 長沼 史登, 中村 正帆, 岡村 信行, 谷内 一彦 日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集 39回・47回 151 -151 2017年09月
• The effect of H3 receptor antagonism on rat neuropathic nociception

  Tadaho Nakamura, Takuro Matsuzawa, Maria Mogilevskaya, Takeo Yoshikawa, Fumito Naganuma, Nobuyuki Okamura, Kazuhiko Yanai Inflammation Research 66 (S1) S22 -SS22 2017年07月 [査読無し][通常論文]
  
• Development of a lanthanide complex labeled beta-sheet ligand for high-throughput screening using time-resolved fluorescence method

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Takeo Yoshikawa, Yukitsuka Kudo, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 133 (3) S131 -S131 2017年03月
• CHARACTERIZATION OF F-18-BF227 IN A MOUSE MODEL OF STEREOTAXIC alpha-SYNUCLEIN AGGREGATE INJECTIONS

  Michael Elmer Jan Stouthandel, Ryuichi Harada, Yoshimi Hayakawa, Takeo Yoshikawa, Shozo Furumoto, Yukitsuka Kudo, Nobuyuki Okamura, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 133 (3) S236 -S236 2017年03月
• Histamine induced gliotransmitter release from cortical rat astrocytes

  Aniko Karpati, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 133 (3) S89 -S89 2017年03月
• Role of histamine receptors in desflurane anesthesia

  Toru Tamii, Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Takuro Matsuzawa, Haruna Kitano, Nobuyuki Okamura, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 133 (3) S171 -S171 2017年03月
• 【蕁麻疹の原因と最新治療】 臨床薬理学からみた非鎮静性抗ヒスタミン薬

  谷内 一彦, 谷内 亜衣, 中村 正帆, 吉川 雄朗 アレルギーの臨床 37 (1) 35 -39 2017年01月 [査読無し][通常論文]
   

  1936年にノーベル生理学・医学賞を受賞したSir Henry Daleによりヒスタミンの作用が見出されて以来、現在までその生理的および病態的作用について多くの研究が行われている。さらにH1、H2受容体拮抗薬を開発したDaniel Bovet、Sir James W.Blackが、それぞれ1957年、1988年にノーベル医学生理学賞を受賞し、人類に多大な貢献をしている。近年、遺伝子ノックアウトマウスがH1〜H4受容体、ヒスチジン脱炭酸酵素(HDC)、ヒスタミンN-メチル転移酵素(HNMT)で作成されており、さらにH1受容体のX線解析も報告されている。ヒスタミンはアレルギーの起因物質として考えると「悪玉」と考えられていたが、最近の研究からヒスタミンの生理作用は生体にとって有益であることが多い。花粉症やアトピー性皮膚炎などのアレルギー性疾患ガイドラインで中枢移行性の少ない非鎮静性抗ヒスタミン薬が推奨されている。本稿では臨床薬理学からみた非鎮静性抗ヒスタミン薬の特徴について紹介する。(著者抄録)
• 吸入麻酔薬の意識消失作用におけるヒスタミン受容体の役割

  民井亨, 民井亨, 中村正帆, 吉川雄朗, 長沼史登, 飯田智光, KARPATI Aniko, 松澤拓郎, 北野陽菜, 山内正憲, 岡村信行, 谷内一彦 日本薬理学会北部会プログラム・抄録集 68th 2017年
• 骨格筋におけるヘパラン硫酸の重要性について

  松澤 拓郎, 吉川 雄朗, 三浦 大和, 谷内 一彦 日本生化学会大会プログラム・講演要旨集 89回 [3P -372] 2016年09月
• Electroencephalogram of H1KO mice under isoflurane anesthesia

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Toru Tamii, Nobuyuki Okamura, Kazuhiko Yanai Inflammation Research 65 (S1) S26 -S26 2016年07月 [査読無し][通常論文]
  
• Role of brain histamine in glutamate release from cultured astrocytes

  Aniko Karpati, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S83 -S83 2016年03月
• Histamine N-methyltransferase deficiency causes abnormal sleep-wake cycles and aggressive behaviors

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Ai Horigome, Yamato Miura, Atsushi Yanai, Takatoshi Mochizuki, Kazuhiku Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S112 -S112 2016年03月
• Interactions between histaminergic neuronal system and isoflurane anesthesia in mice

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Aniko Karpati, Takatoshi Mochizuki, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S98 -S98 2016年03月
• ニューロン新生マーカー・BrdUの脳内分布における拡散型ヌクレオシドトランスポーター1の役割の解明

  木村隼也, 吉田寛伸, 竹生田淳, BASTOS Gilmara, 鈴木登紀子, 吉川雄朗, 根本亙, 中川西修, 丹野孝一, 谷内一彦, 平澤典保, 守屋孝洋 日本薬理学会北部会プログラム・抄録集 67th 2016年
• ヒスタミンによるミクログリア機能制御について

  吉川 雄朗, 飯田 智光, 松澤 拓郎, 中村 正帆, 谷内 一彦 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 88回・38回 [1LBA126] -[1LBA126] 2015年12月
• H1-knocked out mouse has high sensitivity to isoflurane-induced anesthesia

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai Inflammation Research 64 (S1) S22 -S22 2015年07月 [査読無し][通常論文]
  
• Analysis of skeletal muscle-specific Ext1 lacking mice

  Yamato Miura, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 128 (3) S94 -S94 2015年07月
• Analysis of Histamine N-methyltransferase deficitent mice

  Fumito Naganuma, Takeo Yoshikawa, Yamato Miura, Ayano Yagyuu, Tadaho Nakamura, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 128 (3) S87 -S87 2015年07月
• Role of neuronal histamine and histamine H-1 receptor in isoflurane anesthesia

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 128 (3) S189 -S189 2015年07月
• 種々のレチノイドX受容体アゴニストは、AtT20細胞の増殖・アポトーシス・Pomc発現・ACTH分泌に異なる影響を及ぼす

  箱田 明子, 宇留野 晃, 清水 恭子, パービン・レハナ, 横山 敦, 吉川 雄朗, 工藤 正孝, 影近 弘之, 岩崎 泰正, 伊藤 貞嘉, 菅原 明 日本内分泌学会雑誌 91 (1) 269 -269 2015年04月
• ヒスタミン神経系におけるイソフルランの作用

  中村正帆, 吉川雄朗, 長沼史登, 三浦大和, 飯田智光, 松澤拓郎, 堀米愛, KARPATI Aniko, 谷内一彦 日本ヒスタミン学会プログラム・講演要旨集 19th 2015年
• 生体内ミクログリアにおける中枢ヒスタミン系の役割

  飯田智光, 吉川雄朗, 松澤拓郎, 長沼史登, 中村正帆, 三浦大和, 谷内一彦 日本薬理学会北部会プログラム・抄録集 66th 2015年
• イソフルランの麻酔作用におけるヒスタミン神経系の役割

  中村正帆, 吉川雄朗, 長沼史登, 三浦大和, 飯田智光, 松澤拓郎, 堀米愛, ANIKO Karpati, 谷内一彦 日本薬理学会北部会プログラム・抄録集 66th 2015年
• Histamine N-methyltransferaseの欠損はマウスにおいて攻撃性を高め,睡眠サイクルの異常を引き起こす

  長沼史登, 吉川雄朗, 堀米愛, 三浦大和, 中村正帆, 矢内敦, 矢内敦, 望月貴年, 谷内一彦 日本神経精神薬理学会プログラム・抄録集 45th 2015年
• Histamine N-methyltransferaseの欠損はマウスにおいて睡眠覚醒サイクルの異常を引き起こす

  長沼史登, 吉川雄朗, 中村正帆, 堀米愛, 三浦大和, 矢内敦, 矢内敦, 望月貴年, 谷内一彦, 矢内敦, 望月貴年 日本ヒスタミン学会プログラム・講演要旨集 19th 2015年
• Development of 18F-labeling Method for Proteins Using a Cell-free Translation System and 18F-fluoro-L-proline

  Harada R., Furumoto S., Yoshikawa T., Ishikawa Y., Iwata R., Yanai K. CYRIC annual report 2014 69 -72 2015年
• 高血糖刺激による副腎アルドステロン合成酵素遺伝子(CYP11B2)発現亢進の分子機構

  小暮 直敬, 菅原 香織, 松田 謙, 宇留野 晃, 佐藤 郁子, 清水 恭子, レハナ・パービン, 島田 洋樹, 吉川 雄朗, 工藤 正孝, 箱田 明子, 伊藤 亮, 横山 敦, 伊藤 貞嘉, 菅原 明 日本高血圧学会総会プログラム・抄録集 37回 333 -333 2014年10月
• 高血糖刺激は副腎11β-水酸化酵素遺伝子(CYP11B1)の発現を誘導する

  菅原 香織, 小暮 直敬, 松田 謙, 宇留野 晃, 佐藤 郁子, 清水 恭子, レハナ・パービン, 島田 洋樹, 吉川 雄朗, 工藤 正孝, 箱田 明子, 伊藤 亮, 横山 敦, 伊藤 貞嘉, 菅原 明 日本高血圧学会総会プログラム・抄録集 37回 399 -399 2014年10月
• Expression and function of histamine H3 receptor in pancreatic islets

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Attayb Mohsen, Kazuhiko Yanai Basic & Clinical Pharmacology & Toxicology 115 S241 -S241 2014年07月 [査読無し][通常論文]
  
• タウイメージングトレーサー18F-THK5117の結合メカニズムの検討

  原田 龍一, 岡村 信行, 古本 祥三, 多胡 哲郎, 吉川 雄朗, 荒井 啓行, 谷内 一彦, 工藤 幸司 JSMI Report 7 (2) 108 -108 2014年05月
• ヒスタミン代謝酵素欠損マウスの解析

  吉川雄朗, 長沼史登, 三浦大和, 柳生彩乃, 谷内一彦 日本薬理学会北部会プログラム・抄録集 65th 2014年
• 睡眠剥奪ストレスに惹起される不安様行動は、ヒスタミン摂取により低減される

  長沼 史登, Mohsen Attayeb, 吉川 雄朗, 谷内 一彦 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集 23回・43回 248 -248 2013年10月 [査読無し][通常論文]
  
• ヒトアストロサイトーマ由来細胞株1321N1はPMATを介してモノアミンを取り込む

  長沼 史登, 吉川 雄朗, 飯田 智光, 谷内 一彦 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集 23回・43回 193 -193 2013年10月 [査読無し][通常論文]
  
• タウイメージング用トレーサー[18F]THK-5117の前臨床評価

  原田 龍一, 岡村 信行, 古本 祥三, 多胡 哲郎, 吉川 雄朗, 荒井 啓行, 岩田 錬, 谷内 一彦, 工藤 幸司 Dementia Japan 27 (4) 505 -505 2013年10月
• The role of histamine receptors on glucagon secretion in atc1.6 cell

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Attayb Mohsen, Kazuhiko Yanai Inflammation Research 62 (S1) S40 -S40 2013年07月 [査読無し][通常論文]
  
• Histamine transport by mouse plasma membrane monoamine transporter and mouse organic cation transporter 3

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Ryuichi Harada, Attayb Mohsen, Kazuhiko Yanai Inflammation Research 62 (S1) S32 -S32 2013年07月 [査読無し][通常論文]
  
• 脳・心臓 タウイメージング用トレーサー[18F]THK-5117の結合性評価

  原田 龍一, 岡村 信行, 古本 祥三, 多胡 哲朗, 吉川 雄朗, 荒井 啓行, 谷内 一彦, 工藤 幸司 JSMI Report 6 (2) 71 -71 2013年05月
• タウイメージング用トレーサー[18]THK-5117の結合性評価

  原田 龍一, 岡村 信行, 古本 祥三, 多胡 哲朗, 吉川 雄朗, 荒井 啓行, 谷内 一彦, 工藤 幸司 JSMI Report 6 (2) 100 -100 2013年05月
• 非鎮静性抗ヒスタミン薬の薬理学的特徴

  中村正帆, 長沼史登, 谷内一彦, 吉川雄朗 アレルギーの臨床 33 (439) 22 -26 2013年01月20日 [査読無し][通常論文]
  
• ヒトアストロサイトーマ由来細胞株1321N1細胞におけるセロトニン取り込み機構の解明

  長沼 史登, 吉川 雄朗, 飯田 智光, 谷内 一彦 日本薬理学雑誌 141 (1) 2P -2P 2013年01月 [査読無し][通常論文]
  
• 小動物PET/CTを用いた抗ヒスタミン薬レボセチリジンの鎮静性評価

  飯田 智光, 船木 善仁, 石渡 喜一, 長沼 史登, 原田 龍一, 吉川 雄朗, 古本 祥三, 岩田 錬, 谷内 一彦 日本薬理学雑誌 141 (1) 3P -3P 2013年01月 [査読無し][通常論文]
  
• Development of a novel near-infrared fluorescence probe X65 for in vivo detection of amyloid fibrils

  Nobuyuki Okamura, Ryuichi Harada, Shozo Furumoto, Takeo Yoshikawa, Yukitsuka Kudo, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 121 220P -220P 2013年
• 低親和性モノアミントランスポーターの機能解析

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, 飯田智光, 谷内一彦 日本薬理学会北部会プログラム・抄録集 64th 2013年
• ヒスタミンはヒスタミンH3受容体を介してミクログリアの機能を抑制する

  飯田智光, 飯田智光, 吉川雄朗, 根東明広, 長沼史登, 中村正帆, 三浦大和, 岩田錬, 谷内一彦, 谷内一彦 日本薬理学会北部会プログラム・抄録集 64th 2013年
• 抗ヒスタミン薬~新たな地平~1 ヒスタミンの生理作用:“善玉”としてのヒスタミン

  飯田智光, 三浦大和, 長沼史登, 中村正帆, 吉川雄朗, 谷内一彦 皮膚アレルギーフロンティア 11 (2) 2013年
• アレルギー疾患と睡眠 6.ヒスタミンと睡眠との関わり:ヒスタミン神経系の覚醒と睡眠

  三浦大和, 飯田智光, 長沼史登, 中村正帆, 吉川雄朗, 谷内一彦 Progress in Medicine 33 (12) 2013年
• Histamine stimulated phagocytosis of the primary rat microglia

  Tomomitsu Iida, Takeo Yoshikawa, Akihiro Kondo, Tadaho Nakamura, Fumito Naganuma, Ryuichi Harada, Ren Iwata, Kazuhiko Yanai JOURNAL OF PHARMACOLOGICAL SCIENCES 121 217P -217P 2013年
• Comparison of the Binding Properties of Tau PET Radiotracer 18F-THK523 and Other Amyloid PET Tracers to Alzheimer's Disease Pathology

  Harada R., Okamura N., Furumoto S., Tago T., Yoshikawa T., Arai H., Iwata R., Yanai K., Kudo Y. CYRIC annual report 2012 132 -135 2013年
• ヒトアストロサイトーマ由来細胞株1321N1におけるセロトニン取り込み機構について

  長沼 史登, 吉川 雄朗, 飯田 智光, 谷内 一彦 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集 22回・42回 165 -165 2012年10月 [査読無し][通常論文]
  
• HISTAMINE H-3 RECEPTOR REGULATES THE FUNCTIONS OF THE PANCREATIC beta-CELL

  T. Nakamura, T. Yoshikawa, N. Noguchi, F. Naganuma, R. Harada, A. Mohsen, K. Yanai INFLAMMATION RESEARCH 61 S83 -S83 2012年09月 [査読無し][通常論文]
  
• レチノイン酸／レチノイドの抗動脈硬化作用

  菅原明, 宇留野晃, 箱田明子, 清水恭子, 佐藤郁子, 松田謙, 壱岐裕子, 吉川雄朗, 工藤正孝, 伊藤貴子, 伊藤貞嘉 東北大学医学部保健学科紀要 21 (2) 61 -63 2012年07月 [査読無し][通常論文]
  
• 脳 アルツハイマー病病理像を生体画像化するための光イメージングプローブの開発

  原田 龍一, 岡村 信行, 古本 祥三, 吉川 雄朗, 谷内 一彦, 工藤 幸司 JSMI Report 5 (2) 35 -35 2012年05月
• 波長依存性蛍光プローブによるアミロイド・タウの選択的検出

  原田 龍一, 岡村 信行, 古本 祥三, 吉川 雄朗, 谷内 一彦, 工藤 幸司 JSMI Report 5 (2) 142 -142 2012年05月
• 種々のレチノイドX受容体(RXR)アゴニストは、AtT20細胞の増殖・アポトーシス・POMC発現・ACTH分泌に異なる影響を及ぼす

  箱田明子, 宇留野晃, 清水恭子, 伊藤貴子, 吉川雄朗, 藤原幾磨, 松田謙, 工藤正孝, 影近弘之, 岩崎泰正, 伊藤貞嘉, 菅原明 ACTH RELATED PEPTIDES 23 15 -16 2012年03月 [査読有り][通常論文]
  
• ヒトアストロサイトによるヒスタミン取り込み機構

  長沼 史登, 吉川 雄朗, 中村 正帆, 井筒 敏恵, 谷内 一彦 日本薬理学雑誌 139 (1) 6P -6P 2012年01月 [査読無し][通常論文]
  
• 膵β細胞におけるヒスタミン3型受容体の発現とインスリン分泌での役割

  中村 正帆, 大杉 真也, 吉川 雄朗, 谷内 一彦 日本薬理学雑誌 139 (1) 10P -10P 2012年01月 [査読無し][通常論文]
  
• PPARγと高血圧・動脈硬化

  菅原明, 宇留野晃, 工藤正孝, 松田謙, 清水恭子, 吉川雄朗, 伊藤貴子, 箱田明子, 伊藤貞嘉 東北大学医学部保健学科紀要 21 (1) 1 -5 2012年01月 [査読無し][通常論文]
  
• 臨床に役立つ神経薬理・化学 ヒスタミンと神経系 睡眠と覚醒

  吉川 雄朗, 谷内 一彦 Clinical Neuroscience 30 (1) 8 -9 2012年01月 [査読無し][通常論文]
  
• THE ROLE OF HISTAMINE RECEPTOR H3 IN PANCREATIC b-CELLS

  T. Nakamura, T. Yoshikawa, N. Noguchi, M. Ohsugi, K. Yanai Inflammation Research 60 (S2) S336 -S336 2011年09月 [査読無し][通常論文]
  
• ヒトアストロサイトによるヒスタミン取り込み機構について(Important role of plasma membrane monoamine transporters in histamine uptake by human astrocytes)

  長沼 史登, 吉川 雄朗, 中村 正帆, 井筒 敏恵, 谷内 一彦 神経化学 50 (2-3) 174 -174 2011年09月 [査読無し][通常論文]
  
• 膵β細胞に発現しているヒスタミン3型受容体はブドウ糖刺激インスリン分泌を抑制する

  中村 正帆, 吉川 雄朗, 大杉 真也, 長沼 史登, 野口 直哉, 谷内 一彦 日本生化学会大会プログラム・講演要旨集 84回 4T15p -15 2011年09月 [査読無し][通常論文]
  
• Histamine Receptor H3 Regulates the Functions of Pancreatic [beta]-Cells

  Tadaho Nakamura, Takeo Yoshikawa, Naoya Noguchi, Hiroshi Okamoto, Akira Sugawara, Kazuhiko Yanai Diabetes 60 (Supplement_1) A539 -A540 2011年07月01日 [査読無し][通常論文]
  
• Positron emission tomography evaluation of sedative properties of antihistamines

  Kazuhiko Yanai, Dongying Zhang, Manabu Tashiro, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Tadaho Nakamura, Katsuhiko Shibuya, Nobuyuki Okamura EXPERT OPINION ON DRUG SAFETY 10 (4) 613 -622 2011年07月 [査読無し][通常論文]
   

  Introduction: H-1 antihistamines are often used in the medication for allergic diseases, coughs and colds, and insomnia, with or without prescription, even though their sedative properties are a potentially dangerous unwanted side effect that is not properly recognized. These sedative properties have been evaluated using the incidence of subjective sleepiness, objective cognitive and psychomotor functions, and positron emission tomography (PET) measurement of H-1 receptor occupancy. Areas covered: This article reviews the current updated literature on the sedative properties of antihistamines examined by PET measurement of H-1 receptor occupancy. Expert opinion: The use of PET to examine antihistamine penetration in the human brain in relation to psychometric and other functional measures of CNS effects is a major breakthrough and provides a new standard by which the functional CNS effects of antihistamines can be related directly to H-1 receptor occupancy. Therapy with antihistamines can be better guided by considering histamine H-1 receptor occupancy from the view of their sedative properties.
• 「ヒスタミン受容体」を理解する (Dermatology Today)

  谷内一彦, 長沼史登, 中村正帆, 吉川雄朗 Dermatology Today 4 (4) 4 -12 2011年04月15日 [査読無し][通常論文]
  
• 薬物脳内移行性のPETによる測定 抗ヒスタミン薬を例に

  谷内 一彦, 張 冬穎, 原田 龍一, 中村 正帆, 吉川 雄朗, 船木 善仁, 渋谷 勝彦, 古本 祥三, 田代 学, 岩田 錬, 岡村 信行 ナノ医工学年報 4 (1) 119 -122 2011年03月 [査読無し][通常論文]
  
• ヒスタミンＨ１受容体占拠率による脳内移行性評価

  谷内一彦, 田代 学, 古本祥三, 吉川雄朗, 岡村信行 創薬技術の革新 マイクロドーズからPET分子イメージングへの新展開 147 -152 2011年 [査読無し][通常論文]
   

  編集者 杉山雄一、山下伸二、栗原千絵子 メディカルドゥ社
• 【創薬研究への分子イメージング応用】 PET・PECT分子イメージングと医薬品開発 画像バイオマーカーとしての分子イメージングの利用 分子イメージングによる受容体占拠率の解析 (遺伝子医学MOOK)

  谷内一彦, 吉川雄朗, 古本祥三 遺伝子医学MOOK (18) 133 -139 2010年12月 [査読無し][通常論文]
  
• 【創薬技術の革新 マイクロドーズからPET分子イメージングへの新展開】PET分子イメージング マイクロドーズからバイオマーカー開発へ PETが着目する課題(個別課題) ヒスタミンH1受容体占拠率による脳内移行性評価

  谷内 一彦, 田代 学, 古本 祥三, 吉川 雄朗, 岡村 信行 遺伝子医学MOOK 別冊 (創薬技術の革新 マイクロドーズからPET分子イメージングへの新展開) 147 -152 2010年10月 [査読無し][通常論文]
   

  PETは疾患の臨床診断のみならず,創薬・育薬に関連した分子イメージング研究に活発に利用されている。抗ヒスタミン薬はアレルギー症状緩和のために主に使用されるが,脳内移行性が高い場合には強力な鎮静作用を引き起こす。脳移行性が低い第二世代抗ヒスタミン薬が開発されているが,その鎮静作用の差異を主観的眠気や認知機能試験のみで比較するのは困難である。われわれはヒスタミンH1受容体の分子イメージング法を開発して,脳内H1受容体占拠率を鎮静作用の客観的な指標として活用することを提案している。(著者抄録)
• 【脳とアレルギー】 脳機能を標的とした新しい痒み治療戦略 痒みイメージング研究の視点から (アレルギー・免疫)

  中村正帆, 吉川雄朗, 谷内一彦 アレルギー・免疫 17 (11) 1868 -1873 2010年10月 [査読無し][通常論文]
  
• ヒスタミン受容体とストレス脆弱性(Histamine receptors and stress vulnerability)

  谷内 一彦, 吉川 雄朗, 櫻井 映子, 及川 綾子, 長沼 史登, 岡村 信行 神経化学 49 (2-3) 737 -737 2010年08月 [査読無し][通常論文]
  
• 内標準法によるヒスタミンと1-メチルヒスタミンの同時測定

  長沼史登, 井筒敏恵, 張冬頴, 中村正帆, 原田龍一, 吉川雄朗, 岡村信行, 谷内一彦 日本薬理学会北部会プログラム・抄録集 61st 2010年
• 【花粉症の理想的治療法】 薬理学からみた理想的な抗ヒスタミン薬 (臨床免疫・アレルギー科)

  吉川雄朗, 田代学, 岡村信行, 谷内一彦 臨床免疫・アレルギー科 52 (6) 623 -628 2009年12月 [査読無し][通常論文]
  
• 最近の話題 抗ヒスタミン薬と認知機能 dimebonはアルツハイマー病の認知機能を改善する (日本薬理学雑誌)

  谷内一彦, 吉川雄朗 日本薬理学雑誌 134 (4) 235 -235 2009年10月 [査読無し][通常論文]
  
• ２型リアノジン受容体遺伝子にはGG-AG配列で切断されるイントロンが存在する

  池田崇之, 野口直哉, 吉川雄朗, 宇留野 晃, 那谷耕司, 高沢 伸, 岡本 宏, 米倉秀人, 菅原 明 第82回日本生化学会大会プログラム・要旨集 3T18a-6 2009年 [査読無し][通常論文]
  
• FK506結合蛋白質ノックアウトマウスにおけるブドウ糖刺激インスリン分泌の低下

  吉川雄朗 東北医学雑誌 120 (1) 118 -121 2008年06月 [査読無し][招待有り]
  
• 消化管がん細胞におけるチアゾリジン誘導体のREG遺伝子転写抑制および細胞増殖抑制効果

  山内晶世, 高橋巌, 桑名文二, 那谷耕司, 野口直哉, 池田崇之, 吉川雄朗, 小野川徹, 鈴木巌, 高沢伸, 岡本宏 日本薬学会126年会講演要旨集 (2) 99 -99 2006年 [査読無し][通常論文]
  
• 消化管がん細胞におけるREG (Regenerating gene)遺伝子の発現

  高沢 伸, 山内晶世, 高橋 巌, 小野川 徹, 池田崇之, 秋山貴子, 野口直哉, 那谷耕司, 吉川雄朗, 岡本 宏 Cancer Science 95 429-429 -429 2004年 [査読無し][通常論文]
  

書籍等出版物

• 創薬技術の革新 マイクロドーズからPET分子イメージングへの新展開

  杉山雄一, 山下伸二, 栗原千絵子, d, 谷内一彦, 田代学, 古本祥三, 吉川雄朗, 岡村信行 (担当:共著範囲:ヒスタミンＨ１受容体占拠率による脳内移行性評価, 147-152)
  メディカルドゥ 2010年10月

講演・口頭発表等

• 視床下部外側ニューロテンシン神経の覚醒調節における重要性の検討

  長沼史登, 平野匡佑, 中村正帆, Ramalingam Vetrivelan, 吉川雄朗

  第75回日本薬理学会北部会 2024年09月
• 過眠症治療におけるヒスタミン代謝酵素阻害薬の有効性評価  [通常講演]

  吉川雄朗, Girgin Birkan、Agu Anne, 平野匡佑, 長澤翔太, 岩渕好治, 中村正帆, 谷内一彦, 望月貴年, 柳沢正史, 長沼史登

  第75回日本薬理学会北部会 2024年09月 口頭発表（一般）
• Evaluation of histamine N-methyltransferase inhibition on sleep- wake behavior in wild-type and narcolepsy model mice

  Anne Bernadette Agu, Fumito Naganuma, Birkan Girgin, Kyosuke Hirano, Takatoshi Mochizuki, Masashi Yanagisawa, Takeo Yoshikawa

  第37回北海道薬物作用談話会 2024年08月 口頭発表（一般）
• Evaluation of Therapeutic Potential for Histamine N-methyltransferase Inhibitior in Narcolepsy  [通常講演]

  Birkan Girgin, Fumito Naganuma, Anne Bernadette Agu, Tadaho Nakamura, Takatoshi Mochizuki, Takeo Yoshikawa

  Neuro2024 2024年07月 ポスター発表
• Inhibition of histamine metabolizing enzyme in the brain reduces cataplexy in narcolepsy model mice  [通常講演]

  Takeo Yoshikawa, Birkan Girgin, Anne Bernadette Agu, Tadaho Nakamura, Kazuhiko Yanai, Takatoshi Mochizuki, Shota Nagasawa, Yoshiharu Iwabuchi, Fumito Naganuma

  35th World Congress Collegium Internationale Neuro-Psychopharmacologicum 2024年05月 ポスター発表
• ヒスタミン代謝酵素阻害薬の薬理作用について  [通常講演]

  吉川雄朗, Birkan Girgin, Anne Bernadette Agu, 谷内一彦, 中村正帆, 長沼史登

  第24回日本ヒスタミン学会 2024年02月 口頭発表（一般）
• ナルコレプシーに対する創薬を目指して  [招待講演]

  吉川雄朗

  蔵王カンファレンス 2024年01月 口頭発表（基調）
• ヒスタミン代謝酵素阻害薬のナルコレプシー治療に対する有用性の検討

  長沼史登, Birkan Girgin, Anne Bernadette S. Agu, 中村正帆, 谷内一彦, 吉川雄朗

  第30回日本時間生物学会学術大会 2023年09月 ポスター発表
• ナルコレプシー治療におけるヒスタミン 代謝酵素阻害薬の重要性について

  吉川雄朗, 長沼史登, Girgin Birkan, 谷内一彦, 中村正帆

  第7回黒潮カンファレンス 2023年07月 口頭発表（一般）
• 炎症シグナルによるグルコース応答性転写因子ChREBPの機能制御メカニズムの解明

  横山 敦, 野呂 英理香, 岡本 好司, 吉川 雄朗, 島 弘季, 五十嵐 和彦, 菅原 明

  内分泌代謝学サマーセミナー 2023年07月
• 薬理学ロールプレイの学習目標到達度：ルーブリック自己評価を用いた検討  [通常講演]

  中村正帆, 木村武司, 長沼史登, 吉川雄朗, 岡村信行, 柳田俊彦

  第96回日本薬理学会年会 2022年12月
• 視床下部外側ニューロテンシン神経は睡眠覚醒サイクルに重要である  [通常講演]

  長沼史登, 中村正帆, ベトリベラン・ラマリンガム, 吉川雄朗, 岡村信行

  第96回日本薬理学会年会 2022年12月
• ヒスタミン代謝酵素阻害剤メトプリンの行動薬理学的検討

  吉川雄朗, 長沼史登, 長谷茜音, 谷内一彦, 中村正帆

  第73回日本薬理学会北部会 2022年09月 口頭発表（一般）
• 脳内ヒスタミン濃度と脳機能との関連について

  吉川雄朗

  第23回応用薬理シンポジウム 2022年09月 シンポジウム・ワークショップパネル（指名）
• 扁桃体中心核ニューロテンシン神経細胞の睡眠覚醒サイクルにおける役割の検討

  中村 正帆, 長沼 史登, 田中 聖人, 井上 まり絵, 直野 留美, 吉川 雄朗, 岡村 信行

  応用薬理 2022年08月 応用薬理研究会
  
• ブドウ糖代謝におけるヘパラン硫酸の役割について

  吉川 雄朗, 松澤 拓郎, 谷内 一彦, 山口 祐

  糖尿病 2022年04月 (一社)日本糖尿病学会
  
• 神経細胞に発現するヒスタミン代謝酵素の重要性について

  吉川雄朗, 小松由梨香, 松澤健介, 大塚里奈, 長沼史登, 中村正帆, 谷内一彦

  第95回日本薬理学会年会 2022年03月
• ヒスタミン3型受容体は膵β細胞機能を抑制している

  久冨宇太, 松澤拓郎, 中村正帆, 谷内一彦, 吉川雄朗

  第95回日本薬理学会年会 2022年03月
• 肝細胞特異的ヘパラン硫酸欠損マウスはインスリン感受性が亢進する

  松澤拓郎, 小玉菜穂, 久冨宇太, 谷内一彦, 吉川雄朗

  第95回日本薬理学会年会 2022年03月
• 経口ヒスチジン摂取は脳内ヒスタミン神経系を活性化させることで記憶能を向上させる

  盧優慈, 中村正帆, 長沼史登, 谷内一彦, 吉川雄朗

  第95回日本薬理学会年会 2022年03月
• 脳内ヒスタミン代謝酵素の機能解析

  吉川雄朗, 小松由梨香, 松澤健介, 大塚里奈, 長沼史登, 中村正帆, 谷内一彦

  第23回日本ヒスタミン学会 2022年01月
• 膵臓β細胞特異的ヒスタミン3型受容体欠損マウスの解析

  久冨宇太, 松澤拓郎, 中村正帆, 谷内一彦, 吉川雄朗

  第23回日本ヒスタミン学会 2022年01月
• ヒスタミン神経細胞特異的な活性変化が攻撃行動と睡眠覚醒サイクルに及ぼす影響

  中村正帆, 長沼史登, 黒柳浩志, 田中聖人, 吉川雄朗, 谷内一彦, 岡村信行

  日本ヒスタミン学会プログラム・講演要旨集 2022年
• 中脳水道周辺灰白質へ投射するヒスタミン神経は神経因性疼痛を緩和する

  長沼史登, 長沼史登, 梅ゆう, 松澤拓郎, 中村正帆, 中村正帆, 岡村信行, 岡村信行, 谷内一彦, 吉川雄朗

  日本ヒスタミン学会プログラム・講演要旨集 2022年
• 白色脂肪細胞機能におけるヘパラン硫酸の重要性について

  松澤 拓郎, 守田 匡伸, 谷内 一彦, 吉川 雄朗

  日本生化学会大会プログラム・講演要旨集 2021年11月 (公社)日本生化学会
  
• ブドウ糖代謝組織におけるヘパラン硫酸の役割について

  松澤拓郎, 横山眞理子, 谷内一彦, 吉川雄朗

  第40回日本糖質学会年会 2021年10月
• ヘパラン硫酸は白色脂肪細胞の分化を促進し、インスリン感受性を高める

  松澤拓郎, 守田匡伸, 入江史敏, 山口祐, 谷内一彦, 吉川雄朗

  第15回東北糖鎖研究会 2021年09月
• 白色脂肪細胞におけるヘパラン硫酸はインスリン感受性を亢進することで糖恒常性維持に寄与している  [通常講演]

  松澤拓郎, 守田匡伸, 谷内一彦, 吉川雄郎

  第87回日本生化学会 東北支部会 2021年05月
• 膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

  横山 敦, 野呂 英理香, 岡本 好司, 松澤 拓郎, 吉川 雄朗, 島 弘季, 五十嵐 和彦, 菅原 明

  日本内分泌学会雑誌 2021年04月 (一社)日本内分泌学会
  
• 四塩化炭素誘発性肝細胞障害に対するヘパラン硫酸の保護的効果について

  松澤 拓郎, 島根 彩衣, 谷内 一彦, 吉川 雄朗

  第94回日本薬理学会年会 2021年03月
• ワイヤレス給電を用いた集団飼育マウスの長期自発行動および体温測定機器開発

  谷内 一彦, 吉川 雄朗, 相良 健一, 佐々木 秀

  第94回日本薬理学会年会 2021年03月
• ヒスタミン代謝酵素阻害剤の探索研究  [通常講演]

  吉川 雄朗, 大塚 里奈, 佐藤 夕季, 谷内 一彦

  第94回日本薬理学会年会 2021年03月
• アストロサイトに発現するヒスタミン代謝酵素は自発行動量と覚醒状態を制御する  [通常講演]

  大塚 里奈, 長沼 史登, 佐藤 夕季, 高橋 佑奈, 谷内 一彦, 吉川 雄朗

  第94回日本薬理学会年会 2021年03月
• Histamine activation of periaqueductal grey matter and somatosensory cortex exerts an antinociceptive effect in mechanical allodynia  [通常講演]

  梅 煜, 吉川 雄朗, 長沼 史登, 谷内 一彦

  第94回日本薬理学会年会 2021年03月
• 薬理学的知識に基づいた抗ヒスタミン薬の選び方〜効き目を科学し、理解し、伝えましょう〜  [招待講演]

  吉川雄朗

  看護薬理学カンファレンス 2021年03月 口頭発表（招待・特別）
• ブドウ糖代謝におけるヘパラン硫酸の重要性について  [招待講演]

  吉川雄朗

  第67回日本臨床検査医学会学術集会 シンポジウム・ワークショップパネル（指名）
• アストロサイトによる脳内ヒスタミン系制御の重要性について  [通常講演]

  大塚里奈, 吉川雄朗, 長沼史登, 佐藤夕季, 高橋佑奈, 谷内一彦

  第71回日本薬理学会北部会 2020年09月 口頭発表（一般）
• Histaminergic activation of periaqueductal grey matter and somatosensory cortex relieves mechanical allodynia in nerve-injury model mice.  [通常講演]

  Mei Yu, Takeo Yoshikawa, Fumito Naganuma, Kazuhiko Yanai

  第71回日本薬理学会北部会 2020年09月 口頭発表（一般）
• 成体マウス脳内のヒスタミン減少により、うつ様行動の増加、記憶能の低下、自発行 動量の減少が惹起される  [通常講演]

  吉川雄朗, 長沼史登, 山田瑶, 吉川貴子, 大隅典子, 谷内一彦

  NPBPPP2020合同年会 口頭発表（一般）
• 成体マウス脳内のヒスタミン減少により、うつ様行動の増加、記憶能の低下、自発行動量の減少が惹起される

  吉川 雄朗, 長沼 史登, 山田 瑶, 吉川 貴子, 大隅 典子, 谷内 一彦

  日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集 2020年08月 日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会
  
• 医学部学生に対してイオントラップの概念を理解するためのアスピリンを用いた薬物動態学実習  [通常講演]

  佐藤岳哉、斎藤将樹、吉川雄朗、長沼史登、中村正帆、岡村信行、柳澤輝行、谷内一彦

  第93回日本薬理学会年会 2020年03月 シンポジウム・ワークショップパネル（指名）
• 高血糖状態におけるミクログリア機能異常

  大塚 里奈、飯田 智光、吉川 雄朗、谷内 一彦

  第93回日本薬理学会年会 2020年03月 ポスター発表
• へパラン硫酸による筋分化促進作用は、骨格筋機能維持に必須である。

  横山 眞理子、吉川 雄朗、松澤 拓郎、山口 祐、谷内 一彦

  第93回日本薬理学会年会 2020年03月 口頭発表（一般）
• ヒスタミンH3受容体逆作動薬は中脳水道周辺灰白質のヒスタミンH1受容体とH2受容体を活性化して、神経因性疼痛の症状を緩和する  [通常講演]

  梅 煜、吉川 雄朗、松澤 拓郎、齊藤 秀俊、谷内 一彦

  第93回日本薬理学会年会 2020年03月 ポスター発表
• 神経細胞およびアストロサイト特異的ヒスタミンH1受容体欠損マウスの解析  [通常講演]

  吉川 雄朗、Karpati Aniko、長沼 史登、松澤 拓郎、谷内 一彦

  第93回日本薬理学会年会 2020年03月 口頭発表（一般）
• 成熟マウスにおける慢性ヒスタミン減少はうつ様行動と睡眠障害を惹起する

  山田 瑶、吉川 雄朗、長沼 史登、谷内 一彦

  第93回日本薬理学会年会 2020年03月 口頭発表（一般）
• ワイヤレス給電と体内埋め込み型センサーを用いた新しい動物行動薬理学

  谷内 一彦、吉川 雄朗、相良 健一、佐々木 秀

  第93回日本薬理学会年会 2020年03月 ポスター発表
• アストロサイトに発現するヒスタミン代謝酵素の役割について  [通常講演]

  高橋 佑奈、吉川 雄朗、大塚 里奈、谷内 一彦

  第93回日本薬理学会年会 2020年03月 ポスター発表
• ヒスタミン神経細胞の薬理遺伝学的活性化が睡眠覚醒に及ぼす影響

  中村正帆、長沼史登、黒柳浩志、田中聖人、吉川雄朗、谷内一彦、 岡村信行

  第22回日本ヒスタミン学会 2020年02月 口頭発表（一般）
• 成体マウス脳内の慢性的ヒスタミン減少は、うつ様行動の増加及び 自発行動量の減少を惹起する

  山田瑶、吉川雄朗、長沼史登、谷内一彦

  第22回日本ヒスタミン学会 2020年02月 口頭発表（一般）
• アストロサイト特異的ヒスタミン代謝酵素欠損マウスの表現型解析

  高橋佑奈、吉川雄朗、谷内一彦

  第22回日本ヒスタミン学会 2020年02月 口頭発表（一般）
• 経口デスロラタジンの脳内ヒスタミンH1受容体結合 陽電子放出断層撮影を用いたin vivoランダム割付二重盲検クロスオーバー臨床試験  [通常講演]

  中村 正帆, 平岡 宏太良, 原田 龍一, 松澤 拓郎, 吉川 雄朗, 長沼 史登, 田代 学, 谷内 一彦, 岡村 信行

  臨床薬理 2019年11月 (一社)日本臨床薬理学会
  
• Histamine H3 Receptor Antagonist Enhances Histamine Levels in Periaqueductal Grey Matter and Ameliorates Mechanical Allodynia via Histamine H1 and H2 Receptors  [通常講演]

  Takeo Yoshikawa, Yu Mei, Takuro Matsuzawa, Hidetoshi Tozaki-Saitoh, Kazuhiko Yanai

  6th Congress of Asian College of Neuropyschopharmacology 2019年10月 ポスター発表
• ヘパラン硫酸による糖代謝制御機構の解明  [通常講演]

  松澤拓郎, 吉川雄朗, 谷内一彦

  第70回日本薬理学会北部会 2019年09月 口頭発表（招待・特別）
• 脳内ヒスタミン減少による成熟マウスでの行動変化について  [通常講演]

  山田瑶, 吉川雄朗, 長沼史登, 谷内一彦

  第70回日本薬理学会北部会 2019年09月 口頭発表（一般）
• 骨格筋におけるヘパラン硫酸の機能解明  [通常講演]

  横山眞理子, 吉川雄朗, 松澤拓郎, 山口祐, 谷内一彦

  第13回東北糖鎖研究会 2019年09月 ポスター発表
• 糖代謝関連臓器におけるヘパラン硫酸の役割について  [通常講演]

  吉川雄朗, 松澤拓郎, 横山眞理子, 菅原明, 山口祐, 谷内一彦

  第13回東北糖鎖研究会 2019年09月 口頭発表（一般）
• 膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

  横山 敦, 野呂 英理香, 松澤 拓郎, 吉川 雄朗, 島 弘季, 五十嵐 和彦, 菅原 明

  日本生化学会大会プログラム・講演要旨集 2019年09月 (公社)日本生化学会
  
• Histamine H1 receptors on astrocytes regulate aggressive behaviour, circadian rhythm, and wakefulness in mice  [通常講演]

  Aniko Karpati, Takeo Yoshikawa, Fumito Naganuma, Kazuhiko Yanai

  Neuro2019 2019年07月 ポスター発表
• Involvement of Astrocyte Histamine H1 Receptors in the Regulation of Behavior  [通常講演]

  Karpati A, Yoshikawa T, Yanai K

  XIV European Meeting on Glial Cells in Health and Disease, GLIA 2019 2019年07月 ポスター発表
• 肥満細胞は脳内ヒスタミン量を調節して覚醒を引き起こす  [通常講演]

  酒井 紀彰, 八木 櫻子, 吉川 雄朗, 小野 太輔, 西紋 昌平, 久保 允人, 谷内 一彦, 西野 精治

  日本睡眠学会定期学術集会プログラム・抄録集 2019年06月 (一社)日本睡眠学会
  
• Histamine H1 receptor occupancy measured by PET in the human brain after oral administration of desloratadine  [通常講演]

  Nakamura T, Yoshikawa T, Tashiro M, Okamura N, Yanai K

  48th meeding of the European Histamine Research Society 2019年05月 ポスター発表
• Histamine N-Methyltransferase in the Brain  [招待講演]

  Yoshikawa T, Nakamura T, Yanai K

  48th Meeting of the European Histamine Research Society 2019年05月 口頭発表（招待・特別）
• 無細胞蛋白合成系を用いたタンパク質の部位特異的フッ素18標識法  [通常講演]

  谷内 一彦, 原田 龍一, 谷内 亜衣, 吉川 雄朗, 古本 祥三, 岩田 錬

  JSMI Report 2019年05月 日本分子イメージング学会
  
• 無細胞蛋白合成系を用いたタンパク質の部位特異的フッ素18標識法  [通常講演]

  谷内 一彦, 原田 龍一, 谷内 亜衣, 吉川 雄朗, 古本 祥三, 岩田 錬

  JSMI Report 2019年05月 日本分子イメージング学会
  
• 白色脂肪細胞におけるヘパラン硫酸は糖の恒常性の維持に重要である  [通常講演]

  松澤 拓郎, 吉川 雄朗, 谷内 一彦

  糖尿病 2019年04月 (一社)日本糖尿病学会
  
• Affibodyの新規18F標識法によるHER2、PD-L1発現腫瘍の分子イメージング  [通常講演]

  谷内 亜衣, 原田 龍一, 岩田 錬, 吉川 雄朗, 古本 祥三, 谷内 一彦, 内藤 剛, 海野 倫明, 亀井 尚, 石田 孝宜

  日本外科学会定期学術集会抄録集 2019年04月 (一社)日本外科学会
  
• 白色脂肪細胞におけるヘパラン硫酸は糖の恒常性の維持に重要である  [通常講演]

  松澤 拓郎, 吉川 雄朗, 谷内 一彦

  糖尿病 2019年04月 (一社)日本糖尿病学会
  
• Affibodyの新規18F標識法によるHER2、PD-L1発現腫瘍の分子イメージング  [通常講演]

  谷内 亜衣, 原田 龍一, 岩田 錬, 吉川 雄朗, 古本 祥三, 谷内 一彦, 内藤 剛, 海野 倫明, 亀井 尚, 石田 孝宜

  日本外科学会定期学術集会抄録集 2019年04月 (一社)日本外科学会
  
• 骨格筋分化におけるヘパラン硫酸の機能解明  [通常講演]

  吉川雄朗, 横山眞理子, 松澤拓郎, 谷内一彦

  第９２回日本薬理学会年会 2019年03月 口頭発表（一般）
• マウス線維芽細胞3T3-L1および白色脂肪細胞におけるヘパラン硫酸の重要性について  [通常講演]

  松澤拓郎, 吉川雄朗, 谷内一彦

  第９２回日本薬理学会年会 2019年03月 ポスター発表
• アデノ随伴ウイルスを用いた脳内ヒスタミン合成酵素の機能解析  [通常講演]

  山田瑶, 吉川雄朗, 長沼史登, 谷内一彦

  第９２回日本薬理学会年会 2019年03月 ポスター発表
• ハイスループットスクリーニング系を用いたHNMT特異的阻害剤の探索  [通常講演]

  北野陽菜, 吉川雄朗, 谷内一彦

  第９２回日本薬理学会年会 2019年03月 ポスター発表
• ヒスチジンの疲労感低減機能に関する研究  [通常講演]

  笹原 育子, 安居 昌子, 杉田 麻友, 柴草 哲郎, 藤村 尚子, 野沢 与志津, 吉川 雄朗, 谷内 一彦

  アミノ酸研究 2019年02月 日本アミノ酸学会
  
• デスロラタジンおよびロラタジン経口投与後の陽電子放出断層撮影による脳内ヒスタミン１型受容体占拠率測定

  中村 正帆, 平岡 宏太良, 原田 龍一, 松澤 拓郎, 吉川 雄朗, 田代 学, 谷内 一彦, 岡村 信行

  日本薬理学会年会要旨集 2019年 公益社団法人 日本薬理学会
   

  Objective: Some histamine H₁ receptor (H₁R) antagonists have sedative effects, caused by the blockade of histamine neural transmission. Desloratadine is a newly-marked antihistamine, but its sedative properties have not been examined by positron emission tomography (PET). We examined the brain H₁R binding potential ratio (BPR), H₁R occupancy (H₁RO) and the subjective sleepiness after oral administration of desloratadine and loratadine, the prodrug of desloratadine.

  Methods: Eight healthy male volunteers underwent PET imaging with [¹¹C]doxepin after single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double-blind crossover study. BPRs and H₁ROs in the cerebral cortices were calculated. Subjective sleepiness was quantified by the LARS and the SSS.

  Results: BPR after loratadine administration was significantly lower than placebo (p<0.05), but BPR after desloratadine was not significant. There was no significant difference, however, between H₁RO after desloratadine and loratadine administration. The subjective sleepiness was not significantly different among the two antihistamines and placebo.

  Conclusion: At therapeutic dose, desloratadine did not bind significantly to brain H₁Rs and did not cause significant sedation.

• Important role fo heparan sulfate in skeletal muscles  [通常講演]

  Takeo Yoshikawa, Mariko Yokoyama, Takuro Matsuzawa, Kazuhiko Yanai

  American society of cell biology 2018 meeting 2018年12月 ポスター発表
• 脳内ヒスタミン除去機構を標的とした創薬研究：ヒスタミン代謝酵素HNMTの機能解明と阻害剤探索  [通常講演]

  吉川雄朗, 北野陽菜, 谷内一彦

  第48回日本神経精神薬理学会 2018年11月 ポスター発表
• アンバーコドンを用いた無細胞蛋白質合成法による新規18F標識法タンパク質合成法の開発  [通常講演]

  原田 龍一, 谷内 亜衣, 岩田 錬, 吉川 雄朗, 石川 洋一, 古本 祥三, 谷内 一彦

  核医学 2018年11月 (一社)日本核医学会
  
• 脳内ヒスタミン除去機構を標的とした創薬研究 ヒスタミン代謝酵素HNMTの機能解明と阻害剤探索  [通常講演]

  吉川 雄朗, 北野 陽菜, 谷内 一彦

  日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集 2018年11月 日本臨床精神神経薬理学会・日本神経精神薬理学会
  
• 脳内ヒスタミン系を標的とした創薬研究について  [招待講演]

  吉川 雄朗, 谷内 一彦

  第3回黒潮カンファレンス 2018年10月 シンポジウム・ワークショップパネル（指名）
• Cardio-facio-cutaneous症候群における成長障害の研究 -疾患モデルマウスによる胃・食道病変の解析-  [通常講演]

  井上晋一, 高原真吾, 吉川雄朗, 新堀哲也, 谷内一彦, 松原洋一, 青木洋子

  日本人類遺伝学会 第63回大会 2018年10月 口頭発表（一般）
• 糖尿病モデルマウスにおけるミクログリア機能解析  [通常講演]

  大塚里奈, 飯田智光, 吉川雄朗, 谷内一彦

  第69回日本薬理学会北部会 2018年09月 口頭発表（一般）
• 糖代謝におけるヘパラン硫酸の役割について  [通常講演]

  吉川 雄朗, 松澤 拓郎, 谷内 一彦

  第69回日本薬理学会北部会 2018年09月 シンポジウム・ワークショップパネル（公募）
• 骨格筋組織におけるヘパラン硫酸の機能解析  [通常講演]

  吉川雄朗, 横山眞理子, 松澤拓郎, 谷内一彦

  第37回日本糖質学会 2018年08月 ポスター発表
• Histamine clearance through polyspecific transporters and histamine N-methyltransferase in the brain  [招待講演]

  Tadaho Nakamura, Takeo Yoshikawa, Kazuhiko Yanai

  World Histamine Symposium (WHS2018) 2018年07月 シンポジウム・ワークショップパネル（指名）
• IMPORTANCE OF H1 AND H2 RECEPTORS IN PERIAQUEDUCTAL GRAY FOR JNJ10181457-INDUCED PAIN RELIEF  [通常講演]

  Takuro Matsuzawa, Takeo Yoshikawa, Maria Mogilevskaya, Kazuhiko Yanai

  World Histamine Symposium (WHS2018) 2018年07月 ポスター発表
• 【遺伝子改変マウスを用いた新しい創薬・薬理学研究の展開】新規遺伝子ノックアウトマウスを用いた脳内ヒスタミンクリアランス系の解明  [通常講演]

  吉川 雄朗, 中村 正帆, 谷内 一彦

  日本薬理学雑誌 2018年07月 (公社)日本薬理学会
   

  ヒスタミンは脳内では神経伝達物質として機能している。ヒスタミン神経は視床下部後部に位置する結節乳頭核に細胞体を有し、その神経線維を脳全体に投射する。これまでの研究により、ヒスタミン神経系の機能低下が様々な神経疾患と関連している可能性が示された。我々はシナプス間隙に放出されたヒスタミンの除去機構を抑制することで、ヒスタミン神経系を活性化し神経疾患の治療へと結びつけたいと考え、未解明の課題であったヒスタミンのクリアランス機構の解明に着手した。まず初代培養ヒトアストロサイトを用いた研究を行い、細胞外のヒスタミンがorganic cation transporter(OCT)3およびplasma membrane monoamine transporter(PMAT)によって細胞内へと輸送され、その後histamine N-methyltransferase(HNMT)によって不活化される、という分子機構を明らかにした。次にHNMTの生体における役割を明らかにするため、HNMT欠損マウスを新規に作製し、表現型を解析した。その結果、HNMTが脳内ヒスタミン濃度制御において中心的な役割を担っていることが示された。またHNMT欠損によりヒスタミンが異常高値となると、ヒスタミンH2受容体を介して高い攻撃性が惹起されること、H1受容体を介して睡眠覚醒サイクルに異常を来すことも明らかとなった。OCT3とPMATの脳内における役割については、セロトニン神経系やドパミン神経系との関連は報告されているものの、ヒスタミン神経系におけるこれらのトランスポーターの役割については不明な点が多い。現在我々はPMAT欠損マウスの表現型解析、およびHNMT阻害薬探索研究を行っている。今後トランスポーターとヒスタミン神経系との関連を解明することや中枢ヒスタミン系を標的とした創薬に尽力していきたいと考えている。(著者抄録)
• Importance of heparan sulfate in adipose tissue  [通常講演]

  Matsuzawa T, Yoshikawa T, Yanai K

  18th world congress of basic and clinical pharmacology 2018年07月 ポスター発表
• Important Role of Heparan Sulfate in Skeletal Mscules  [通常講演]

  Yoshikawa T, Mogi A, Miura Y, Matsuzawa T, Yanai K

  18th world congress of basic and clinical pharmacology 2018年07月 ポスター発表
• Heparan sulfate in beta-cells regulates insulin secretion and contributes to normal glucose homeostasis  [通常講演]

  Matsuzawa T, Yoshikawa T, Sugawara A, Yanai K

  American Diabetes Association, 78th scientific sessions 2018年06月 ポスター発表
• 【神経系のトランスポーター-Up to date】トランスポーターの基礎 モノアミントランスポーター  [通常講演]

  吉川 雄朗, 北野 陽菜, 谷内 一彦

  Clinical Neuroscience 2018年06月 (株)中外医学社
  
• Inhibitory effects of H3R inverse agonist/antagonist on microglial functions  [通常講演]

  Iida T, Yoshikawa T, Yanai K

  European Histamine Research Society 47the Annual Meeting 2018年05月 口頭発表（一般）
• 脂肪組織におけるヘパラン硫酸の役割について  [通常講演]

  松澤拓郎, 吉川雄朗, 谷内一彦

  第61回日本糖尿病学会年次学術集会 2018年05月 ポスター発表
• 筋芽細胞株C2C12および筋組織におけるヘパラン硫酸の役割  [通常講演]

  横山眞理子, 吉川雄朗, 松澤拓郎, 谷内一彦

  日本生化学会東北支部第84回例会 2018年05月 ポスター発表
• 白色脂肪細胞におけるヘパラン硫酸は糖の恒常性維持に重要である  [通常講演]

  松澤拓郎, 吉川雄朗, 谷内一彦

  日本生化学会東北支部第84会例会 2018年05月 ポスター発表
• Affibodyの新規18F標識法によるHER2発現乳癌の分子イメージング  [通常講演]

  谷内 亜衣, 原田 龍一, 岩田 錬, 吉川 雄朗, 古本 祥三, 谷内 一彦, 石田 孝宣

  日本乳癌学会総会プログラム抄録集 2018年05月 (一社)日本乳癌学会
  
• 脂肪組織におけるヘパラン硫酸の役割について  [通常講演]

  松澤 拓郎, 吉川 雄朗, 谷内 一彦

  糖尿病 2018年04月 (一社)日本糖尿病学会
  
• 低出力パルス波超音波の全脳照射はマウスの認知症モデルにおいて認知機能障害を改善する-内皮型NO合成酵素の重要性-

  江口久美子, 伊藤健太, 進藤智彦, 尾形剛, 加賀谷裕太, 黒澤亮, 門間雄斗, 一條貞満, 吉川雄朗, 谷内一彦, 瀧宏文, 金井浩, 大隅典子, 下川宏明

  日本酸化ストレス学会学術集会プログラム・抄録集 2018年
• ヒスタミン3型受容体インバースアゴニストはミクログリア機能を抑制しうつ様行動を改善する  [通常講演]

  飯田智光, 吉川雄朗, 谷内一彦

  2017年12月 口頭発表（一般）
• がん原遺伝子Brafの活性化はマウス食道の拡張と前胃上皮の過増殖をもたらす  [通常講演]

  井上 晋一, 高原 真吾, 吉川 雄朗, 新堀 哲也, 谷内 一彦, 松原 洋一, 青木 洋子

  生命科学系学会合同年次大会 2017年12月 生命科学系学会合同年次大会運営事務局
  
• 膵β細胞におけるヘパラン硫酸はインスリン分泌及び糖の恒常性維持に重要である  [通常講演]

  松澤 拓郎, 吉川 雄朗, 中村 正帆, 谷内 一彦

  生命科学系学会合同年次大会 2017年12月 生命科学系学会合同年次大会運営事務局
  
• ヒスタミン3型受容体インバースアゴニストによるミクログリア機能抑制について  [通常講演]

  飯田智光, 吉川雄朗, 谷内一彦

  2017年09月 ポスター発表
• 脳内ヒスタミン神経系の過剰な興奮はH2受容体を介してマウスの攻撃性を増加させる  [通常講演]

  吉川雄朗, 飯田智光, 長沼史登, 中村正帆, 岡村信行, 谷内一彦

  第39回日本生物学的精神医学会・第47回日本神経精神薬理学会合同年会 2017年09月 口頭発表（一般） 札幌
• フェルラ酸のαシヌクレインの凝集・線維化に対する阻害効果の検討  [通常講演]

  陳梦格, 原田龍一, 吉川雄朗, 工藤幸司, 岡村信行, 谷内一彦

  第68回日本薬理学会北部会 2017年09月 口頭発表（一般）
• 吸入麻酔薬の意識消失作用におけるヒスタミン受容体の役割  [通常講演]

  民井亨, 中村正帆, 吉川雄朗, 長沼史登, 飯田智光, Karpati Aniko, 松澤拓郎, 北野陽菜, 山内正憲, 岡村信行, 谷内一彦

  第68回日本薬理学会北部会 2017年09月 口頭発表（一般）
• ヒスタミン-N-メチルトランスフェラーゼのin vivo機能解析  [通常講演]

  中村 正帆, 吉川 雄朗, 岡村 信行

  第68回日本薬理学会北部会 2017年09月 口頭発表（一般）
• Neurotransmitter histamine positively affects astrocyte signaling and gliotransmitter release  [通常講演]

  Karpati Aniko, 飯田 智光, 吉川 雄朗

  第68回日本薬理学会北部会 2017年09月 口頭発表（一般）
• 骨格筋におけるヘパラン硫酸の役割について  [通常講演]

  吉川雄朗, 茂木明日香, 松澤拓郎, 三浦大和, 中村正帆, 谷内一彦

  第68回日本薬理学会北部会 2017年09月 口頭発表（一般） 山形
• 脳に効くヒスチジン摂取  [通常講演]

  吉川雄朗

  第60回日本神経化学学会 2017年09月 口頭発表（招待・特別） 仙台
• ヒスタミン3型受容体インバースアゴニストによるミクログリア機能抑制について(Suppression of microglial functions by an H3R inverse agonist)  [通常講演]

  飯田 智光, 吉川 雄朗, 谷内 一彦

  日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集 2017年09月 日本生物学的精神医学会・日本神経精神薬理学会
  
• ミクログリア機能におけるヒスタミンの重要性  [通常講演]

  飯田智光, 吉川雄朗, 中村正帆, 谷内一彦

  第40回日本神経科学大会 2017年07月 口頭発表（一般） 千葉
• マウスOCT2、OCT3、PMATの機能解析  [通常講演]

  吉川雄朗, 三浦大和, 茂木明日香, 谷内一彦

  第12回トランスポーター研究年会 2017年07月 ポスター発表 仙台
• THE EFFECT OF H3 RECEPTOR ANTAGONIST ON NEUROPATHIC PAIN  [通常講演]

  T Nakamura, T Matsuzawa, M Mogilevskaya, A Mogi, T Yoshikawa, F Naganuma, N Okamura, K Yanai

  Histamine 2017 2017年05月 ポスター発表 オランダ アムステルダム
• 糸球体足細胞特異的Extl3欠損マウスを用いた糸球体チャージバリアの検討  [通常講演]

  青木聡, 箱田明子, 吉川雄朗, 松阪泰二, 佐藤博, 伊藤貞嘉, 菅原明

  日本腎臓学会誌 2017年04月
• 新規遺伝子ノックアウトマウスを用いた脳内ヒスタミンクリアランス系の解明  [通常講演]

  吉川雄朗, 谷内一彦

  第90回日本薬理学会年会 2017年03月 シンポジウム・ワークショップパネル（公募） 日本国 長崎
• Histamine induced gliotransmitter release from cortical rat astrocytes  [通常講演]

  Aniko Karpati, 吉川雄朗, 中村正帆, 長沼史登, 飯田智光, 谷内一彦

  第90回日本薬理学会年会 2017年03月 口頭発表（一般） 日本国 長崎
• 膵β細胞におけるヘパラン硫酸はインスリン分泌や籐の恒常性維持に重要である  [通常講演]

  松澤拓郎, 吉川雄朗, 中村正帆, 谷内一彦

  第90回日本薬理学会年会 2017年03月 口頭発表（一般） 日本国 長崎
• 時間分解蛍光法ランタニド錯体標識βシートリガンドの開発  [通常講演]

  原田龍一, 岡村信行, 古本祥三, 吉川雄朗, 工藤幸司, 谷内一彦

  第90回日本薬理学会年会 2017年03月 口頭発表（一般） 日本国 長崎
• ヒスタミンH3受容体によるミクログリア機能の重要性  [通常講演]

  飯田智光, 吉川雄朗, 谷内一彦

  第90回日本薬理学会年会 2017年03月 口頭発表（一般） 日本国 長崎
• デスフルラン麻酔におけるヒスタミン受容体の役割  [通常講演]

  民井亨, 中村正帆, 吉川雄朗, 長沼史登, 飯田智光, Karpati Aniko, 松澤拓郎, 北野陽奈, 岡村信行, 谷内一彦

  第90回日本薬理学会年会 2017年03月 ポスター発表 日本国 長崎
• 神経障害性疼痛に対するヒスタミンH3受容体拮抗薬の効果  [通常講演]

  吉川雄朗, 松澤拓郎, 茂木明日香, Maria Mogilevskaya, 中村正帆, 谷内一彦

  第90回日本薬理学会年会 2017年03月 ポスター発表 日本国 長崎
• 骨格筋におけるヘパラン硫酸欠損による筋力や運動能の低下  [通常講演]

  茂木明日香, 吉川雄朗, 三浦大和, 松澤拓郎, 谷内一彦

  第90回日本薬理学会年会 2017年03月 ポスター発表 日本国 長崎
• 神経障害性疼痛におけるヒスタミンH3受容体（H3R）拮抗薬の作用について  [通常講演]

  松澤拓郎, Mogilevskaya Maria, 吉川雄朗, 中村正帆, 谷内一彦

  第20回日本ヒスタミン学会 2016年11月 口頭発表（一般） 日本国 倉敷
• Histamine promotes gliotransmitter release from astrocytes  [通常講演]

  Karpati A, Yoshikawa T, Nakamura T, Naganuma F, Iida T, Yanai K

  Society for Neuroscience 2016年11月 ポスター発表
• Importance of Histamine Clearance for Brain Functions  [通常講演]

  Yoshikawa T, Naganuma F, Nakamura T, Iida T, Karpati A, Mochizuki T, Yanai K

  Society for Neuroscience 2016年11月 ポスター発表
• 神経障害性疼痛におけるヒスタミン3型受容体の役割について  [通常講演]

  松澤拓郎, Mogilevskaya Maria, 吉川雄朗, 中村正帆, 谷内一彦

  第67回日本薬理学会北部会 2016年09月 口頭発表（一般） 札幌
• 膵β細胞特異的Ｅｘｔ１ノックアウトマウスの解析  [通常講演]

  松澤拓郎, 吉川雄朗, 中村正帆, 谷内一彦

  第67回日本薬理学会北部会 2016年09月 口頭発表（一般） 札幌
• ニューロン新生マーカー・BrdUの脳内分布における拡散型ヌクレオシドトランスポーター1の役割の解明  [通常講演]

  木村隼也, 吉田寛伸, 竹生田淳, Bastos Gilmara, 鈴木登紀子, 吉川雄朗, 根元瓦, 中川西修, 丹野孝一, 谷内一彦, 平澤典保健, 守屋孝洋

  第67回日本薬理学会北部会 2016年09月 口頭発表（一般） 札幌
• Role of histamine neurons in isoflurane anesthesia.  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Toru Tamii, Nobuyuki Okamura, Kazuiko Yanai

  第39回日本神経科学大会 2016年07月 ポスター発表 横浜
• Importance of histamine N-methyltransferase in brain functions  [通常講演]

  Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Takatoshi Mochizuki, Tomomitsu Iida, Aniko Karpati, Takuro Matsuzawa, Kazuhiko Yanai

  第39回日本神経科学大会 2016年07月 ポスター発表 横浜
• Astrocytes elevate glutamate release in response to histamine  [通常講演]

  Anikó Kárpáti, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai

  第39回日本神経科学大会 2016年07月 ポスター発表 横浜
• Histamine N-methyltransferase is important for the normal sleep-wake cycles and aggression through the regulation of brain histamine concentration.  [通常講演]

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Kazuhiko Yanai

  30th CINP world congress of neuropsychopharmacology 2016年07月 ポスター発表 韓国 ソウル
• Interactions between histaminergic neuronal system and isoflurane anesthesia in mice  [通常講演]

  Toru Tamii, Tadaho Nakamura, Takeo Yoshikawa, Osamu Kobayashi, Masanori Yamauchi, Kazuiko Yanai

  日本麻酔科学会第63回学術集会 2016年05月 ポスター発表 福岡
• Electroencephalogram of H1KO mice under isoflurane anesthesia.  [通常講演]

  Tadaho, Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Toru Tamii, Nobuyuki Okamura, Kazuiko Yanai

  European Histamine Research Society 45th annual meeting 2016年05月 ポスター発表 イタリア Florence
• Role of brain histamine in glutamate release from cultured astrocytes  [通常講演]

  Aniko Karpati, 吉川雄朗, 中村正帆, 長沼史登, 飯田智光, 三浦大和, 谷内一彦

  第89回日本薬理学会年会 2016年03月 口頭発表（一般） 横浜
• マウスにおけるヒスタミン神経系とイソフルラン麻酔の相互作用について  [通常講演]

  中村正帆, 吉川雄朗, 長沼史登, 飯田智光, 三浦大和, Aniko Karpati, 望月貴年, 谷内一彦

  第89回日本薬理学会年会 2016年03月 口頭発表（一般） 横浜
• Histamine N-methyltransferaseの欠損はマウスにおいて睡眠覚醒サイクル異常と高い攻撃性を引き起こす  [通常講演]

  長沼史登, 吉川雄朗, 中村正帆, 堀米愛, 三浦大和, 矢内敦, 望月貴年, 谷内一彦

  第89回日本薬理学会年会 2016年03月 口頭発表（一般） 横浜
• 膵β細胞におけるヘパラン硫酸の重要性  [通常講演]

  松澤拓郎, 吉川雄朗, 中村正帆, 谷内一彦

  第89回日本薬理学会年会 2016年03月 ポスター発表 横浜
• ヒスタミンによるミクログリア機能制御について  [通常講演]

  吉川雄朗, 飯田智光, 松澤拓郎, 中村正帆, 谷内一彦

  第38回日本分子生物学会年会第88回日本生化学会合同大会 2015年12月 ポスター発表 神戸
• Role of histaminergic neuronal system in isoflurane anesthesia  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Osamu Kobayashi, Miho Kaneko, Masanori Yamauchi, Kazuhiko Yanai

  Anesthesiology 2015 2015年10月 ポスター発表 アメリカ合衆国 San Diego
• Histamine N-methyltransferseノ欠損はマウスにおいて攻撃性を高め、睡眠サイクル異常を引き起こす  [通常講演]

  長沼史登, 吉川雄朗, 堀米愛, 三浦大和, 中村正帆, 矢内敦, 望月貴年, 谷内一彦

  第37回日本生物学的精神医学会第45回日本精神神経薬理学会 2015年09月 口頭発表（一般） 東京
• 生体内ミクログリアにおける中枢ヒスタミン系の役割  [通常講演]

  飯田智光, 吉川雄朗, 松澤拓郎, 長沼史登, 中村正帆, 三浦大和, 谷内一彦

  第66回日本薬理学会北部会 2015年09月 口頭発表（一般） 富山
• イソフルランの麻酔作用におけるヒスタミン神経系の役割  [通常講演]

  中村正帆, 吉川雄朗, 長沼史登, 三浦大和, 飯田智光, 松澤拓郎, 堀米愛, Karpati Aniko, 谷内一彦

  第66回日本薬理学会北部会 2015年09月 口頭発表（一般） 富山
• Histamine N-methyltransferase deficiency induced the abnormal sleep-awake cycles and aggressive behavior in mice  [通常講演]

  長沼史登, 吉川雄朗, 矢内敦, 堀米愛, 三浦大和, 中村正帆, 望月貴年, 谷内一彦

  第58回日本神経化学大会 2015年09月 口頭発表（一般） 大宮
• ヒスタミン研究に残された解決されるべき課題：脳内ヒスタミンの分解系を中心に  [通常講演]

  谷内一彦, 長沼史登, 中村正帆, 岡村信行, 吉川雄朗

  第19回活性アミンに関するワークショップ 2015年08月 口頭発表（招待・特別） いわき
• マウス多基質性トランスポーターによるモノアミン輸送能の検討  [通常講演]

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, 飯田智光, 谷内一彦

  第19回活性アミンに関するワークショップ 2015年08月 口頭発表（一般） いわき
• Mechanism of brain histamine clearance  [通常講演]

  吉川雄朗, 長沼史登, 三浦大和, 矢内敦, 堀米愛, 中村正帆, 望月貴年, 谷内一彦

  第38回日本神経科学大会 2015年07月 ポスター発表 神戸
• Role of histamine in gliotransmitter release from astrocytes  [通常講演]

  Aniko Karpati, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai

  第38回日本神経科学大会 2015年07月 ポスター発表 神戸
• 無細胞蛋白質合成法を用いたIL8受容体のPETイメージング  [通常講演]

  吉川雄朗, 原田龍一, 古本祥三, 渋谷勝彦, 岩田錬, 谷内一彦

  日本生化学会東北支部第81回例会 2015年05月 ポスター発表 仙台
• 脳内ヒスタミンのクリアランス機構について  [通常講演]

  吉川雄朗, 長沼史登, 三浦大和, 矢内敦, 堀米愛, 中村正帆, 望月貴年, 谷内一彦

  日本生化学会東北支部第81回例会 2015年05月 口頭発表（一般） 仙台
• Analysis of histamine N-methyltransferase deficient mice  [通常講演]

  Naganuma F, Yoshikawa T, Nakamura T, Miura Y, Matsuzawa T, Yanai K

  European Histamine Research Society 44th annual meeting 2015年05月 口頭発表（一般） スペイン Malaga
• H1-knocked out mouse had high sensitivity to isoflurane anesthesia  [通常講演]

  Nakamura T, Yoshikawa T, Naganuma F, iida T, Miura Y, Yanai K

  European Histamine Research Society 44th annual meeting 2015年05月 ポスター発表 スペイン Malaga
• 種々のレチノイドX受容体アゴニストは、AtT20細胞の増殖・アポトーシス・Pomc発現・ACTH分泌に異なる影響を及ぼす  [通常講演]

  箱田明子, 宇留野晃, 清水恭子, レハナ・パービン, 横山敦, 吉川雄朗, 工藤正孝, 影近弘之, 岩崎泰正, 伊藤貞嘉, 菅原 明

  第88回日本内分泌学会学術総会 2015年04月 ポスター発表 東京
• Histamine N-methyltransferase ノックアウトマウスの解析  [通常講演]

  長沼史登, 吉川雄朗, 三浦大和, 柳生彩乃, 中村正帆, 谷内一彦

  第88回日本薬理学年会 2015年03月 口頭発表（一般） 名古屋
• イソフルラン麻酔における神経ヒスタミンとヒスタミンH1受容体の役割  [通常講演]

  中村正帆, 吉川雄朗, 長沼史登, 飯田智光, 三浦大和, 谷内一彦

  第88回日本薬理学年会 2015年03月 ポスター発表 名古屋
• 骨格筋特異的Ext1欠損マウスの解析  [通常講演]

  三浦大和, 吉川雄朗, 中村正帆, 長沼史登, 飯田智光, 谷内一彦

  第88回日本薬理学年会 2015年03月 口頭発表（一般） 名古屋
• Histamine N-methyltransferaseノックアウトマウスの行動解析  [通常講演]

  長沼史登, 吉川雄朗, 中村正帆, 三浦大和, 堀米愛, 谷内一彦

  第24回神経行動薬理若手研究者の集い 2015年03月 口頭発表（一般） 名古屋
• 脳内ヒスタミン研究におけるマイクロダイアリシスの使用について  [通常講演]

  吉川雄朗, 中村正帆, 長沼史登, 三浦大和, 谷内一彦

  第２５回マイクロダイアリシス研究会 2014年12月 口頭発表（招待・特別） 東京
• グリア細胞とヒスタミンとの関連について  [通常講演]

  吉川雄朗

  2014年度包括脳ネットワーク冬のシンポジウム 2014年12月 ポスター発表 東京
• 高血糖刺激は副腎11β-水酸化酵素遺伝子（CYP11B1）の発現を誘導する  [通常講演]

  菅原香織, 小暮直敬, 松田 謙, 宇留野晃, 佐藤郁子, 清水恭子, レハナ・パービン, 島田洋樹, 吉川雄朗, 工藤正孝, 箱田明子, 伊藤 亮, 横山 敦, 伊藤貞嘉, 菅原 明

  第37回日本高血圧学会総会 2014年10月 ポスター発表 横浜
• 高血糖刺激による副腎アルドステロン合成酵素遺伝子（CYP11B2）発現亢進の分子機構  [通常講演]

  小暮直敬, 菅原香織, 松田 謙, 宇留野晃, 佐藤郁子, 清水恭子, レハナ・パービン, 島田洋樹, 吉川雄朗, 工藤正孝, 箱田明子, 伊藤 亮, 横山 敦, 伊藤貞嘉, 菅原 明

  第37回日本高血圧学会総会 2014年10月 ポスター発表 横浜
• マウスにおける低親和性トランスポーターの輸送能解析  [通常講演]

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, 谷内一彦

  第18回日本ヒスタミン学会 2014年10月 口頭発表（一般） 尼崎
• Histamine N-methyl transferaseノックアウトマウスの解析  [通常講演]

  長沼史登, 吉川雄朗, 三浦大和, 中村正帆, 谷内一彦

  第18回日本ヒスタミン学会 2014年10月 口頭発表（一般） 尼崎
• 低ヒスチジン食によりマウス脳内ヒスタミン含量が減少し、不安様行動が惹起される  [通常講演]

  吉川雄朗, 中村正帆, 柴草哲朗, 杉田麻友, 長沼史登, 飯田智光, 三浦大和, モフセンアタイエブ, 原田龍一, 谷内一彦

  第18回日本ヒスタミン学会 2014年10月 口頭発表（一般） 尼崎
• 無細胞蛋白質合成法を用いたPETイメージングプローブ作製  [通常講演]

  吉川雄朗, 原田龍一, 古本祥三, 渋谷勝彦, 岩田錬, 谷内一彦

  第65回日本薬理学会北部会 2014年09月 口頭発表（一般） 福島
• ヒスタミン代謝酵素欠損マウスの解析  [通常講演]

  吉川雄朗, 長沼史登, 三浦大和, 柳生彩乃, 谷内一彦

  第65回日本薬理学会北部会 2014年09月 口頭発表（一般） 福島
• Expression and Function of Histamine H3 receptor in Pancreatic Islets  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Kazuhiko Yanai

  17th world congress of basic & clinical pharmacology 2014年07月 ポスター発表 南アフリカ Cape Town
• The mechanism of monoamine transport by human astrocytes  [通常講演]

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai

  17th world congress of basic & clinical pharmacology 2014年07月 ポスター発表 南アフリカ Cape Town
• Generation of a stable H295R cell line expressing 11β-hydroxylase gene promoter and the effect of high-glucose on its expression  [通常講演]

  Kaori Sugawara, Ken Matsuda, Naotaka Kogure, Akira Uruno, Ikuko Sato, Kyoko Shimizu, Rehana Parvin, Takeo Yoshikawa, Masataka Kudo, Akiko Saito-Hakoda, Ryo Ito, Atsushi Yokoyama, Sadayoshi Ito, Akira Sugawara

  16th international congress of endocrinology 2014年06月 口頭発表（一般） アメリカ合衆国 Chicago
• High-glucose stimulates aldosterone synthase gene (CYP11B2) expression via the induction of T-type calcium channels in H295R cells  [通常講演]

  Naotaka Kogure, Ken Matsuda, Akira Uruno, Kaori Sugawara, Ikuko Sato, Kyoko Shimizu, Rehana Parvin, Takeo Yoshikawa, Masataka Kudo, Akiko Saito-Hakoda, Ryo Ito, Atsushi Yokoyama, Sadayoshi Ito, Akira Sugawara

  16th international congress of endocrinology 2014年06月 口頭発表（一般） アメリカ合衆国 Chicago
• Generation of a Stable H295R Cell Line Expressing 11beta-Hydroxylase Gene Promoter and the Effect of High-Glucose on Its Expression  [通常講演]

  Sugawara Kaori, Matsuda Ken, Kogure Naotaka, Uruno Akira, Sato Ikuko, Shimizu Kyoko, Parvin Rehana, Yoshikawa Takeo, Kudo Masataka, Saito-Hakoda Akiko, Ito Ryo, Yokoyama Atsushi, Ito Sadayoshi, Sugawara Akira

  ENDOCRINE REVIEWS 2014年06月
• High-Glucose Stimulates Aldosterone Synthase Gene (CYP11B2) Expression Via the Induction of T-Type Calcium Channels in H295R Cells  [通常講演]

  Naotaka Kogure, Ken Matsuda, Akira Uruno, Kaori Sugawara, Ikuko Sato, Kyoko Shimizu, Rehana Parvin, Takeo Yoshikawa, Masataka Kudo, Akiko Saito-Hakoda, Ryo Ito, Atsushi Yokoyama, Sadayoshi Ito, Akira Sugawara

  ENDOCRINE REVIEWS 2014年06月 ENDOCRINE SOC
  
• The inhibitory effect of histamine in mouse primary microglia  [通常講演]

  Iida T, Yoshikawa T, Asami Y, Naganuma F, Miura Y, Nakamura T, Mohsen A, Iwata R, Yanai K

  European histamine research society 43rd annual meeting 2014年05月 口頭発表（一般） フランス Lyon
• Analysis of mouse polyspecific transporters  [通常講演]

  Miura Y, Yoshikawa T, Naganuma F, Nakamura T, Iida T, Harada R, Mohsen A, Yanai K

  European histamine research society 43rd annual meeting 2014年05月 ポスター発表 フランス Lyon
• Importance of histidine intake for histaminergic nervous system  [通常講演]

  Miura Y, Yoshikawa T, Shibakusa T, Sugita M, Yanai K

  European histamine research society 43rd annual meeting 2014年05月 口頭発表（一般） フランス Lyon
• マウス初代培養ミクログリアにおけるヒスタミンの役割  [通常講演]

  飯田智光, 吉川雄朗, 浅見雄太, 中村正帆, 長沼史登, 原田龍一, 岩田錬, 谷内一彦

  第87回日本薬理学会年会 2014年03月 口頭発表（一般） 仙台
• 膵ランゲルハンス島アルファ細胞におけるヒスタミンH3受容体の役割  [通常講演]

  中村正帆, 吉川雄朗, 長沼史登, 飯田智光, 三浦大和, 谷内一彦

  第87回日本薬理学会年会 2014年03月 口頭発表（一般） 仙台
• ヒトアストロサイトにおけるモノアミン取り込み機構の解明  [通常講演]

  長沼史登, 吉川雄朗, 中村正帆, 飯田智光, 三浦大和, 谷内一彦

  第87回日本薬理学会年会 2014年03月 口頭発表（一般） 仙台
• 食餌中に含まれるヒスチジンはヒスタミン神経系に必須である  [通常講演]

  吉川雄朗, 柴草哲朗, 杉田麻友, モフセン・アタイエブ, 長沼史登, 谷内一彦

  第87回日本薬理学会年会 2014年03月 ポスター発表 仙台
• マウス多特異性トランスポーターの機能解析  [通常講演]

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, モフセン・アタイエブ, 飯田智光, 谷内一彦

  第87回日本薬理学会年会 2014年03月 ポスター発表 仙台
• 低親和性モノアミントランスポーターの機能解析  [通常講演]

  三浦大和, 吉川雄朗, 谷内一彦

  第7回リトリート大学院生研究発表会 2014年01月 ポスター発表 仙台
• ヒトアストロサイトによるモノアミン取り込み機構  [通常講演]

  長沼史登, 吉川雄朗, 飯田智光, 三浦大和, 谷内一彦

  第7回リトリート大学院生研究発表会 2014年01月 ポスター発表 仙台
• マウス初代培養ミクログリアにおけるヒスタミンの役割  [通常講演]

  飯田智光, 吉川雄朗, 谷内一彦

  第7回リトリート大学院生研究発表会 2014年01月 ポスター発表 仙台
• マウス初代培養ミクログリアにおけるヒスタミンの役割について  [通常講演]

  飯田智光, 吉川雄朗, 長沼史登, 中村正帆, 三浦大和, 岩田錬, 谷内一彦

  第17回日本ヒスタミン学会 2013年11月 口頭発表（一般） 松江
• Plasma membrane monoamine transporter is important for monoamine uptake in a human astrocytoma-derived cell line, 1321N1 cells  [通常講演]

  Naganuma F, Yoshikawa T, Nakamura T, Yanai K

  7th east asian consortium on biomedical engineering 2013年11月 口頭発表（一般） 台湾 台北
• The role of histamine receptors in pancreatic alpha-cells  [通常講演]

  Nakamura T, Yoshikawa T, Naganuma F, Harada R, Yanai K

  7th east asian consortium on biomedical engineering 2013年11月 口頭発表（一般） 台湾 台北
• ヒトアストロサイトーマ由来細胞株1321N1はPMATを介してモノアミンを取り込む  [通常講演]

  長沼史登, 吉川雄朗, 谷内一彦

  第23回日本臨床精神神経薬理学会・第43回日本神経精神薬理学会 合同大会 2013年10月 口頭発表（一般） 沖縄
• 睡眠剥奪ストレスに惹起される不安様行動は、ヒスタミン摂取により低減される  [通常講演]

  長沼史登, Attayeb Mohsen, 吉川雄朗, 谷内一彦

  第23回日本臨床精神神経薬理学会・第43回日本神経精神薬理学会 合同大会 2013年10月 口頭発表（一般） 沖縄
• ヒスタミンはヒスタミンH3受容体を介してミクログリアの機能を抑制する  [通常講演]

  飯田智光, 吉川雄朗, 根東明広, 長沼史登, 中村正帆, 三浦大和, 岩田錬, 谷内一彦

  第64回日本薬理学会北部会 2013年09月 口頭発表（一般） 旭川
• 低親和性モノアミントランスポーターの機能解析  [通常講演]

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, 飯田智光, 谷内一彦

  第64回日本薬理学会北部会 2013年09月 口頭発表（一般） 旭川
• RXRアゴニストHX630のCushing病新規治療薬としての可能性  [通常講演]

  小暮直敬, 箱田明子, 宇留野晃, 清水恭子, 菅原香織, 壹岐裕子, 吉川雄朗, 松田謙, 工藤正孝, 影近弘之, 岩崎泰正, 伊藤貞嘉, 菅原明

  第49回高血圧関連疾患モデル学会学術総会 2013年09月 口頭発表（一般） 東京
• グリア細胞とヒスタミン  [通常講演]

  吉川雄朗

  2013年度 包括脳ネットワーク夏のワークショップ 2013年08月 シンポジウム・ワークショップパネル（指名） 名古屋
• Low histamine diet increases anxiogenic like behavior in chronic sleep deprived mice  [通常講演]

  Attayeb Mohsen, Takeo Yoshikawa, Kazuhiko Yanai

  Neuro2013 2013年06月 口頭発表（一般） 京都
• Development of PET imaging tracer for in vivo detection of Tau pathology in Alzheimer's disease  [通常講演]

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Teturo Tago, Takeo Yoshikawa, Hiroyuki Arai, Ren Iwata, Yukitsuk kudo, Kazuhiko Yanai

  NIH Tohoku University JSPS symposium 2013年05月 ポスター発表 日本国 仙台
• Dietary histamine is functioning against stress vulnerability induced by chronic sleep deprivation  [通常講演]

  Attayeb Mohsen, Takeo Yoshikawa, Kazuhiko Yanai

  NIH Tohoku University JSPS symposium 2013年05月 ポスター発表 日本国 仙台
• Histamine inhibits phagocytosis and morphological change in mouse primary microglia  [通常講演]

  Tomomitsu Iida, Takeo Yoshikawa, Akihiro Kondo, Fumito Naganuma, Tadaho Nakamura, Ren Iwata, Kazuhiko Yanai

  NIH Tohoku University JSPS symposium 2013年05月 ポスター発表 日本国 仙台
• The role of histamine receptors on glucagon secretion in αTC1.6 cell  [通常講演]

  T Nakamura, T, Yoshikawa, F Naganuma, R Harada, A Mohsen,K Yanai

  42nd European Histamine Research Society Annual Meeting 2013年05月 口頭発表（一般） ポーランド Lodz
• Histamine transport by mouse plasma membrane monoamine transporter and mouse organic cation transporter 3  [通常講演]

  F Naganuma,T, Yoshikawa, T, Nakamura, T Iida, R Harada,A Mohsen, K Yanai

  42nd European Histamine Research Society Annual Meeting 2013年05月 口頭発表（一般） ポーランド Lodz
• High-glucose stimulates aldosterone synthase gene (CYP11B2) expression via T-type calcium channel in human adrenal H295R cells  [通常講演]

  Akira Sugawara, Takako Saito-Ito, Naotaka Kogure, Kaori Sugawara, Ken Matsuda, Akira Uruno, Ikuko Sato, Kyoko Shimizu, Yuko Iki, Takeo Yoshikawa, Masataka Kudo, Akiko Saito-Hakoda, Sadayoshi Ito

  The 6th international aldosterone forum in Japan 2013年04月 ポスター発表 日本国
• Histamine Inhibited Phagocytosis of the Primary Mouse Microglia  [通常講演]

  Tomomitsu Iida, Takeo Yoshikawa, Akihiro Kondo, FUmito Naganuma, Tadaho Nakamura, Attayeb Mohsen, Ren Iwata, Kazuhiko Yanai

  6th East Asian Pacific Student Workshop on Nano-Biomedical Engineering 2013年03月 口頭発表（一般） シンガポール
• CHronic Sleep Deprivation Impacts on Behaviors in Mice  [通常講演]

  Attayeb Mohsen, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Kazuhiko Yanai

  6th East Asian Pacific Student Workshop on Nano-Biomedical Engineering 2013年03月 口頭発表（一般） シンガポール
• アストロサイトにおけるモノアミン取り込みにはPMATが重要な役割を果たしている  [通常講演]

  長沼史登, 吉川雄朗, 飯田智光, 谷内一彦

  第86回日本薬理学会年会 2013年03月 口頭発表（一般） 福岡
• マウス自発行動及び不安様行動における睡眠剥奪ストレスとヒスタミンの効果について  [通常講演]

  Mohsen Attayeb, 吉川雄朗, 谷内一彦

  第86回日本薬理学会年会 2013年03月 口頭発表（一般） 福岡
• タウイメージングプローブ候補化合物18F標識アリールキノリン誘導体の前臨床評価  [通常講演]

  原田龍一, 岡村信行, 古本祥三, 多胡哲郎, 吉川雄朗, 荒井啓行, 岩田錬, 谷内一彦, 工藤幸司

  第86回日本薬理学会年会 2013年03月 口頭発表（一般） 福岡
• ヒトアストロサイトによるヒスタミン除去メカニズムの解明  [通常講演]

  吉川雄朗, 長沼史登, 飯田智光, 中村正帆, 笠島敦子, 笹野公伸, 谷内一彦

  第86回日本薬理学会年会 2013年03月 ポスター発表 福岡
• グルカゴン産生α細胞株TC1.6におけるヒスタミンの役割  [通常講演]

  中村正帆, 吉川雄朗, 谷内一彦

  第86回日本薬理学会年会 2013年03月 ポスター発表 福岡
• Plasma membrane monoamine transporter (PMAT) is important for monoamine clearance by human astrocytoma-derived cell line.,1321N1 cells  [通常講演]

  Fumito Naganuma, Takeo Yoshikawa, Tomomitsu Iida, kazuhiko Yanai

  The 21st Korea-Japan joint seminar on pharmacology 2012年10月 ポスター発表 韓国 Jeju
• ヒトアストロサイトによるヒスタミン除去機構について  [通常講演]

  吉川雄朗, 長沼史登, 飯田智光, 中村正帆, 笠島敦子, 笹野公伸, 谷内一彦

  第16回日本ヒスタミン学会 2012年10月 口頭発表（一般） 日本国 岡山
• ヒトアストロサイトーマ由来細胞株1321N1におけるセロトニン取り込み機構について  [通常講演]

  長沼史登, 吉川雄朗, 飯田智光, 谷内一彦

  第22回日本臨床精神神経薬理学会第42回日本神経精神薬理学会合同大会 2012年10月 口頭発表（一般） 日本国 宇都宮
• 高血糖刺激はアルドステロン合成酵素遺伝子（CYP11B2）の発現を増強する  [通常講演]

  伊藤貴子, 松田謙, 宇留野晃, 佐藤郁子, 清水恭子, 壱岐裕子, 吉川雄朗, 工藤正孝, 箱田明子, 伊藤貞嘉, 菅原晃

  第16回日本内分泌病理学会 2012年10月 口頭発表（一般） 日本国
• 種々のRXRアゴニストがAtT20細胞増殖・アポトーシス・POMC発現・ACTH分泌に及ぼす影響  [通常講演]

  箱田明子, 宇留野晃, 清水恭子, 伊藤貴子, 吉川雄朗, 藤原幾磨, 松田謙, 佐藤郁子, 壱岐裕子, 工藤正孝, 影近弘之, 岩崎泰正, 伊藤貞嘉, 菅原明

  第16回日本内分泌病理学会 2012年10月 口頭発表（一般） 日本国 仙台
• ニコチンがヒト冠動脈血管内皮細胞の遺伝子発現に及ぼす影響ならびにそれに対するACE阻害薬・ＡＲＢの効果  [通常講演]

  工藤正孝, 松田謙, 伊藤貴子, 宇留野晃, 清水恭子, 吉川雄朗, 箱田明子, 伊藤貞嘉, 菅原明

  第35回日本高血圧学会総会 2012年09月 ポスター発表 日本国 名古屋
• 高血糖刺激はヒト副腎H295R細胞におけるアルドステロン合成酵素遺伝子の発現を増強する  [通常講演]

  伊藤貴子, 松田謙, 宇留野晃, 清水恭子, 吉川雄朗, 工藤正孝, 箱田明子, 伊藤貞嘉, 菅原明

  第35回日本高血圧学会総会 2012年09月 ポスター発表 日本国 名古屋
• Plasma membrane monoamine transporterはヒトアストロサイトにおけるドパミン不活化に重要である  [通常講演]

  長沼史登, 吉川雄朗, 飯田智光, 中村正帆, 谷内一彦

  第35回日本神経科学大会 2012年09月 口頭発表（一般） 日本国 名古屋
• 小動物PET/CTを用いた抗ヒスタミン薬レボセチリジンの鎮静性評価  [通常講演]

  飯田智光, 船木善仁, 石渡喜一, 長沼史登, 原田龍一, 吉川雄朗, 古本祥三, 岩田錬, 谷内一彦

  第63回日本薬理学会北部会 2012年09月 口頭発表（一般） 日本国 新潟
• ヒトアストロサイトーマ由来細胞株1321N1細胞におけるセロトニン取り込み機構の解明  [通常講演]

  長沼史登, 吉川雄朗, 飯田智光, 谷内一彦

  第63回日本薬理学会北部会 2012年09月 口頭発表（一般） 日本国 新潟
• Mechanism of histamine clearance by primary human astrocytes  [通常講演]

  T Yoshikawa, F Naganuma, T Iida, T Nakamura, K Yanai

  包括型脳科学研究推進支援ネットワーク 夏のワークショップ 2012年07月 ポスター発表 日本国 仙台
• ヒトアストロサイトによるヒスタミン不活化機構の解明  [通常講演]

  長沼史登, 吉川雄朗, 中村正帆, 飯田智光, 谷内一彦

  第7回トランスポーター研究会年会 2012年06月 ポスター発表 日本国 京都
• Human Astrocytes transport histamine through plasma membrane monoamine transporter  [通常講演]

  T Yoshikawa, F Naganuma, T Nakamura, T Iida, R harada, A Mohsen, K Yanai

  41st Annual Meeting of the European Histamine Research Society 2012年05月 口頭発表（一般） Belfast
• Histamine H3 receptor regulates the functions of pancreatic ß-cells  [通常講演]

  T Nakamura, T Yoshikawa, N Noguchi, F Naganuma, R Harada, A Mohsen, K Yanai

  41st Annual Meeting of the European Histamine Research Society. 2012年05月 口頭発表（一般） Belfast
• 高血糖刺激によるアルドステロン合成酵素（CYP11B2）の発現増強効果  [通常講演]

  松田 謙, 伊藤貴子, 宇留野晃, 中村美輝, 高橋 朗, 吉川雄朗, 清水恭子, 箱田明子, 工藤正孝, 伊藤貞嘉, 菅原 明

  第85回日本内分泌学会学術総会 2012年04月 口頭発表（一般） 日本国 名古屋
• 高血糖刺激はアルドステロン合成酵素遺伝子（CYP11B2)の発現を増強する  [通常講演]

  伊藤貴子, 松田謙, 宇留野晃, 清水恭子, 吉川雄朗, 工藤正孝, 箱田明子, 伊藤貞嘉, 菅原明

  第23回間脳・下垂体・副腎系研究会 2012年03月 口頭発表（一般） 日本国
• 各アンジオテンシンII受容体拮抗薬（ARB）はアルドステロン合成酵素遺伝子（CYP11B2）発現に異なる影響を及ぼすに  [通常講演]

  松田謙, 宇留野晃, 伊藤貴子, 清水恭子, 吉川雄朗, 工藤正孝, 佐藤文俊, 箱田明子, 伊藤貞嘉, 菅原明

  第23回間脳・下垂体・副腎系研究会 2012年03月 口頭発表（一般） 日本国
• 種々のレチノイドX受容体（RXR）アゴニストは、AtT20細胞の増殖・アポトーシス・POMC発現・ACTH分泌に異なる影響を及ぼす  [通常講演]

  箱田明子, 宇留野晃, 清水恭子, 伊藤貴子, 吉川雄朗, 藤原幾磨, 松田謙, 工藤正孝, 影近弘之, 岩崎泰正, 伊藤貞嘉, 菅原明

  第23回間脳・下垂体・副腎系研究会 2012年03月 口頭発表（一般） 日本国
• [18F]THK-523によるin vivoタウイメージング  [通常講演]

  原田龍一, 岡村信行, 古本祥三, 吉川雄朗, 荒井啓行, 谷内一彦, 工藤幸司

  第85回日本薬理学会年会 2012年03月 口頭発表（一般） 日本国 京都
• ヒスタミン3型受容体による膵ß細胞機能の制御  [通常講演]

  中村正帆, 吉川雄朗, 野口直哉, 長沼史登, 原田龍一, Attayeb Mohsen, 飯田智光, 笠島敦子, 笹野公伸, 谷内一彦

  第85回日本薬理学会年会 2012年03月 口頭発表（一般） 日本国 京都
• 正常ヒトアストロサイトによるヒスタミン取込はPMATを介して行われる  [通常講演]

  吉川雄朗, 長沼史登, 中村正帆, 飯田智光, 谷内一彦

  第85回日本薬理学会年会 2012年03月 口頭発表（一般） 日本国 京都
• ヒトアストロサイトーマ由来細胞株はPMATを介してドパミンを取り込む  [通常講演]

  長沼史登, 吉川雄朗, 中村正帆, 飯田智光, 谷内一彦

  第85回日本薬理学会年会 2012年03月 ポスター発表 日本国 京都
• H3 receptor blockade increases locomotor activity in sleep-deprived wild type and H1 receptor knockout mice  [通常講演]

  Attayeb Mohsen, 長沼史登, 渋谷勝彦, 中村正帆, 吉川雄朗, 岡村信行, 谷内一彦

  第85回日本薬理学会年会 2012年03月 ポスター発表 日本国 京都
• Selective detection of tau neuropathology with novel fluorescent probes  [通常講演]

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Takeo Yoshikawa, Yukitsuka Kudo, Kazuhiko Yanai

  第18回GCOE国際シンポジウム 2012年03月 ポスター発表 仙台
• The expression and functions of histamine H3 receptor in pancreatic ß-cells  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Kazuhiko Yanai

  第18回GCOE国際シンポジウム 2012年03月 ポスター発表 仙台
• Wavelength-dependent detection of senile plaques and nuerofibrillary tangles with novel fluorescent probes  [通常講演]

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Takeo Yoshikawa, Yukitsuka Kudo, Kazuhiko Yanai

  NRF-JSPS Asian Science Seminar 2012年02月 ポスター発表 ソウル
• Histamine H3 recptor regulates the functions of pancreatic ß-cells  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Attayeb Mohsen, Masashi Saito, Kazuhiko Yanai

  NRF-JSPS Asian Science Seminar 2012年02月 ポスター発表 ソウル
• 18F標識アミノ酸と無細胞蛋白質合成系を用いたポジトロン標識蛋白質の合成法の開発  [通常講演]

  原田龍一, 古本祥三, 吉川雄朗, 石渡喜一, 岩田錬, 谷内一彦

  第5回リトリート研究発表会 2012年01月 口頭発表（一般） 日本国 仙台
• 膵β細胞におけるヒスタミン3型受容体の発現とインスリン分泌での役割  [通常講演]

  中村 正帆, 大杉 真也, 吉川 雄朗, 谷内 一彦

  日本薬理学雑誌 2012年01月 (公社)日本薬理学会
  
• ヒトアストロサイトによるヒスタミン取り込み機構  [通常講演]

  長沼 史登, 吉川 雄朗, 中村 正帆, 井筒 敏恵, 谷内 一彦

  日本薬理学雑誌 2012年01月 (公社)日本薬理学会
  
• Predominant role of PMAT in histamine uptake by normal human astrocytes  [通常講演]

  Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Tomomitsu Iida, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 2012年 JAPANESE PHARMACOLOGICAL SOC
  
• A human astrocytoma-derived cell line transports dopamine through PMAT  [通常講演]

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 2012年 JAPANESE PHARMACOLOGICAL SOC
  
• The expression and functions of histamine H3 receptor in pacreatic ß-cells  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Kazuhiko Yanai

  5th east asian pacific student workshop on nano-biomedical engineering 2011年12月 ポスター発表
• in vitro binding analysis of THK523 to Aß and tau protein fibirils  [通常講演]

  R Harada, N Okamura, S Furumoto, T Yoshikawa, H Arai, Y Kudo, k Yanai

  Neuroscience 2011 2011年11月 ポスター発表 ワシントンDC
• インスリン分泌膵ß細胞におけるヒスタミン3型受容体の発現と機能  [通常講演]

  中村正帆, 吉川雄朗, 野口直哉, 大杉真也, 笠島敦子, 笹野公伸, 谷内一彦

  第15回日本ヒスタミン学会 2011年10月 口頭発表（一般） 日本国 盛岡
• 正常ヒトアストロサイトによるヒスタミン取り込み機構の解明  [通常講演]

  長沼史登, 吉川雄朗, 中村正帆, 井筒敏恵, 谷内一彦

  第15回日本ヒスタミン学会 2011年10月 口頭発表（一般） 日本国 盛岡
• Locomotor activity and antigenic-like behaviors are increased by histamine H3 receptors antagonist  [通常講演]

  Attayeb, Mohsen, FUmito Naganuma, Tadaho Nakamura, Katsuhiko Shibuya, Takeo Yoshikawa, Nobuyuki Okamura, Kazuhiko Yanai

  第15回日本ヒスタミン学会 2011年10月 口頭発表（一般） 日本国 盛岡
• 膵ß細胞におけるヒスタミン3型受容体の発現とインスリン分泌  [通常講演]

  中村正帆, 大杉真也, 吉川雄朗, 谷内一彦

  第62回日本薬理学会北部会 2011年09月 口頭発表（一般） 日本国 仙台
• ヒトアストロサイトによるヒスタミン取り込み機構  [通常講演]

  長沼史登, 吉川雄朗, 中村正帆, 井筒敏恵, 谷内一彦

  第62回日本薬理学会北部会 2011年09月 口頭発表（一般） 日本国 仙台
• Histamine H3 receptors antagonists increase anziogenic-like behaviors and locomotor activity  [通常講演]

  A Mohsen, F Naganuma, T Nakamura, T Yoshikawa, N Okamura, K Yanai

  第62回日本薬理学会北部会 2011年09月 口頭発表（一般） 日本国 仙台
• Important role of plasma membrane monoamine transporters in histamine uptake by human astrocytes  [通常講演]

  F Naganuma, T Yoshikawa, T Nakamura, T Idutsu, K Yanai

  第54回日本神経化学学会 2011年09月 口頭発表（一般） 日本国 金沢
• 膵ß細胞に発現しているヒスタミン3型受容体はブドウ糖刺激インスリン分泌を抑制する  [通常講演]

  中村正帆, 吉川雄朗, 大杉真也, 長沼史登, 野口直哉, 谷内一彦

  第84回日本生化学会大会 2011年09月 口頭発表（一般） 日本国 京都
• in vitro comparative binding studies: amyloid and tau imaging probes  [通常講演]

  原田龍一, 岡村信行, 古本祥三, 吉川雄朗, 荒井啓行, 工藤幸司, 谷内一彦

  第34回日本神経科学会年回 2011年09月 口頭発表（一般） 日本国 横浜
• The mechanism of histamine uptake by human astrocytoma-derived cell line  [通常講演]

  F Naganuma, T Yoshikawa, T Nakamura, T Idutsu, K Yanai

  第34回日本神経科学会年会 2011年09月 口頭発表（一般） 日本国 横浜
• 膵β細胞に発現しているヒスタミン3型受容体はブドウ糖刺激インスリン分泌を抑制する  [通常講演]

  中村 正帆, 吉川 雄朗, 大杉 真也, 長沼 史登, 野口 直哉, 谷内 一彦

  日本生化学会大会プログラム・講演要旨集 2011年09月 (公社)日本生化学会
  
• ヒトアストロサイトによるヒスタミン取り込み機構について(Important role of plasma membrane monoamine transporters in histamine uptake by human astrocytes)  [通常講演]

  長沼 史登, 吉川 雄朗, 中村 正帆, 井筒 敏恵, 谷内 一彦

  神経化学 2011年09月 日本神経化学会
  
• Histamine receptor H3 regulates the functions of pancreatic ß-cells  [通常講演]

  T Nakamura, T Yoshikawa, N Noguchi, H Okamoto, A Sugawara, K Yanai

  America Diabetes Association, 71th sicentific sessions 2011年06月 ポスター発表 サンディエゴ
• The role of histamine receptro H3 in pancreatic ß-cells  [通常講演]

  T Nakamura, T Yoshikawa, N Noguchi, M Ohsugi, K Yanai

  The 40th anniversary European Histamine Resarch Society meeting 2011年05月 口頭発表（一般） ソチ
• ヒスタミン3型受容体による膵β細胞機能の制御  [通常講演]

  中村正帆, 吉川雄朗, 野口直哉, 大杉真也, 谷内一彦

  糖尿病 2011年04月
• The role of histamine H3 receptor in pancreatic β-cells  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Naoya Noguchi, Kazuhiko Yanai

  第８４回日本薬理学会年会 2011年03月 口頭発表（一般） 日本国 横浜
• Repeated exposeres to the elevated zero maze increase anxiety in mice: gender difference  [通常講演]

  Attayeb Mofsen, Tadaho Nakamura, Fumito Naganuma, Takeo Yoshikawa, Zhang Dongying, Nobuyuki Okamura, Kazuhiko Yanai

  第８４回日本薬理学会年会 2011年03月 ポスター発表 日本国 横浜
• Potential ce3ntral sedative effect of antihistamine eye-drops: histamine H1 receptor occupancy measured by positron emission tomography  [通常講演]

  Dongying Zhang, Katsuhiko Shibuya, manabu Tashiro, Ryuichi Harada, Takeo Yoshikawa, Nobuyuki Okamura, Kazuhiko Yanai

  第８４回日本薬理学会年会 2011年03月 ポスター発表 日本国 横浜
• The deficiency of histamine h3 receptor increases the sensitiviy of morphine-induced hyperlocomotion without affecting the reward in mice  [通常講演]

  Dongying Zhang, Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Attayeb Mofsen, Kazuhiko Yanai

  第８４回日本薬理学会年会 2011年03月 ポスター発表 日本国 横浜
• ヒトアストロサイトーマ由来細胞株におけるヒスタミン取り込み機構  [通常講演]

  長沼史登, 吉川雄朗, 井筒敏恵, 中村正帆, 谷内一彦

  第８４回日本薬理学会年会 2011年03月 ポスター発表 日本国 横浜
• 膵β細胞機能におけるヒスタミン３型受容体の機能解析  [通常講演]

  中村正帆, 吉川雄朗, 谷内一彦

  第４回リトリート大学院生研究発表会 2011年01月 ポスター発表 日本国 仙台
• アストロサイトによるヒスタミン取り込み機構の解明  [通常講演]

  長沼史登, 吉川雄朗, 中村正帆, 井筒敏恵, 谷内一彦

  第４回リトリート大学院生研究発表会 2011年01月 ポスター発表 日本国 仙台
• In vitro comparative binding studies: Amyloid and tau imaging probes  [通常講演]

  Ryuichi Harada, Nobuyuki Okamura, Shozo Furumoto, Takeo Yoshikawa, Hiroyuki Arai, Yukitsuka Kudo, Kazuhiko Yanai

  NEUROSCIENCE RESEARCH 2011年 ELSEVIER IRELAND LTD
  
• Potential central sedative effect of antihistamine eye-drops: histamine H-1 receptor occupancy measured by positron emission tomography  [通常講演]

  Dongying Zhang, Katsuhiko Shibuya, Manabu Tashiro, Ryuichi Harada, Nobuyuki Okamura, Takeo Yoshikawa, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 2011年 JAPANESE PHARMACOLOGICAL SOC
  
• Repeated exposures to the elevated zero maze increase anxiety in mice: gender difference  [通常講演]

  Attayeb Mohsen, Tadaho Nakamura, Fumito Naganuma, Takeo Yoshikawa, Dongying Zhang, Nobuyuki Okamura, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 2011年 JAPANESE PHARMACOLOGICAL SOC
  
• The molecular mechanism of histamine uptake by human astrocytoma-derived cell line  [通常講演]

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Toshie Idutsu, Kazuhiko Yanai

  NEUROSCIENCE RESEARCH 2011年 ELSEVIER IRELAND LTD
  
• The deficiency of histamine H3 receptor increases the sensitivity of morphine-induced hyperlocomotion without affecting the reward in mice  [通常講演]

  Dongying Zhang, Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Attayeb Mohsen, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 2011年 JAPANESE PHARMACOLOGICAL SOC
  
• Histamine clearance in human astrocytoma derived cell lines  [通常講演]

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Toshie Idutsu, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 2011年 JAPANESE PHARMACOLOGICAL SOC
  
• The role of histamine H3 receptor in pancreatic beta-cells  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Naoya Noguchi, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 2011年 JAPANESE PHARMACOLOGICAL SOC
  
• Histamine receptor H3 regulates insulin secretion in mouse pancreatic β-cell line MIN6 cells  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Junya Fukuda, Naoya Noguchi, Kazuhiko Yanai

  4th east asian pacific student workshop on nano-biomedical engineering 2010年12月 ポスター発表 シンガポール Singapore
• The role of histamine H3 receptro in the functions of pancreatic β-cells  [通常講演]

  中村正帆, 吉川雄朗, 野口直哉, 谷内一彦

  第３３回日本分子生物学会・第８３回日本生化学会大会 合同大会 2010年12月 ポスター発表 日本国 神戸
• Histamine-H3R-deficiency increased the sensitivity of morphine-induced hyperactivity but unaffected the rewarding response in in mice  [通常講演]

  張冬穎, 吉川雄朗, 長沼史登, 中村正帆, 岡村信行, 加藤正人, 谷内一彦

  第61回日本薬理学会北部会 2010年09月 口頭発表（一般） 日本国 札幌
• 内標準法によるヒスタミンと1-メチルヒスタミンの同時測定  [通常講演]

  長沼史登, 井筒敏恵, 張冬穎, 中村正帆, 原田龍一, 吉川雄朗, 岡村信行, 谷内一彦

  第61回日本薬理学会北部会 2010年09月 口頭発表（一般） 日本国 札幌
• Histamine receptors and stress vulnerability  [通常講演]

  谷内一彦, 吉川雄朗, 櫻井映子, 及川綾子, 長沼史登, 岡村信行

  第33回日本神経化学大会 2010年09月 ポスター発表 日本国 神戸
• Histamine Receptor H3 Regulates Insulin Secretion in Mouse Pancreatic β-cell Line MIN6 cells  [通常講演]

  Tadaho Nakamura, Takeo Yoshikawa, Junya Fukuda, Naoya Noguchi, Kazuhiko Yanai

  KIST-Tohoku Joint Symposium on Nanobiomedical Engineering 2010年08月 ポスター発表 韓国 ソウル
• ole of heparan sulfate in glucose-induced insulin secretion in mouse pancreatic β-cell line MIN6 cells  [通常講演]

  Takeo Yoshikawa, S Takayanagi, N Noguchi, D Zhang, Y Ariyama, A Uruno, H Okamoto, A Sugawara, K Yanai

  16th world congress of basic and clinical pharmacology 2010年07月 ポスター発表 デンマーク コペンハーゲン
• Molecular imaging in Alzheimer's disease: from basic to clinical  [通常講演]

  K Yanai, S Furumoto, T Yoshikawa, R Iwata, M Tashiro, N Okamura

  16th world congress on basic and clinical pharmacology 2010年07月 口頭発表（一般） デンマーク コペンハーゲン
• Role of Heparan Sulfate in Glucose-Induced Insulin Secretion in MIN6 Cells  [通常講演]

  Takeo Yoshikawa, Shiori Takayanagi, Naoya Noguchi, Akira Uruno, Hiroshi, Okamoto, Akira Sugawara, Kazuhiko Yanai

  the American Diabetes Association's 70th Scientific Sessions. 2010年06月 ポスター発表 アメリカ合衆国 Orland, FL
• PPARgamma down-regulates CYP11B2 expression and aldosterone production in adrenocortical carcinoma H295R cells by suppression of Ca2+-CaMK signals  [通常講演]

  Akira Uruno, Ken Matsuda, Naoya Noguchi, Takeo Yoshikawa, Masataka Kudo, Fumitoshi Satoh, William E. Rainey, Hiroshi Okamoto, Sadayoshi Ito, Akira Sugawara

  International symposium for aldosterone and related substances in hypertension 2010年03月 口頭発表（一般） 日本国 仙台
• 新規開発HPLC法を用いたヒスタミン代謝についての検討  [通常講演]

  井筒敏恵, 櫻井映子, 及川綾子, 高柳詩織, 吉川雄朗, 谷内一彦

  第53回日本薬理学会年会 2010年03月 ポスター発表 日本国 大阪
• ストレス条件下でのヒスタミン受容体の応答と役割ーヒスタミン受容体欠損マウスをもちいて  [通常講演]

  及川綾子, 櫻井映子, 井筒敏恵, 張冬穎, 助川淳, 吉川雄朗, 谷内一彦

  第39回日本精神神経薬理学会年会 2009年11月 ポスター発表 日本国
• PPARgammaはCaＭＫ-ATF-2のシグナル伝達を抑制し、アンジオテンシン？/カリウム応答性アルドステロン分泌を抑制する  [通常講演]

  宇留野晃, 松田謙, 野口直哉, 工藤正孝, 佐藤文俊, 伊藤貞嘉, 岡本宏, 菅原明

  第13回日本心血管内分泌代謝学会学術総会 2009年10月 ポスター発表 日本国 大宮
• 2型リアノジン受容体遺伝子にはGG-AG配列で切断されるイントロンが存在する  [通常講演]

  池田崇之, 野口直哉, 吉川雄朗, 宇留野晃, 那谷耕司, 高沢伸, 岡本宏, 米倉秀人, 菅原明

  第82回日本生化学会大会 2009年10月 口頭発表（一般） 日本国 神戸
• Sera from Japanese diabetes patients show autoimmunity to REG family antigens  [通常講演]

  NJ. Shervani, K. Nata, N. Noguchi, I. Takahashi, T. Ikeda, K. Ohashi, T. Yoshikawa, A. Uruno, S. Takasawa, H. Okamoto, A. Sugawara

  第82回日本生化学会大会 2009年10月 ポスター発表 日本国 神戸
• ブドウ糖刺激インスリン分泌におけるFKBP12.6結合たんぱく質12.6の関与  [通常講演]

  吉川雄朗, 野口直哉, 高柳詩織, 張冬頴, 有山雄太, 宇留野晃, 菅原明, 谷内一彦

  第37回薬物活性シンポジウム 2009年10月 口頭発表（一般） 日本国 仙台
• ストレス反応に対するヒスタミン受容体の応答変化  [通常講演]

  及川綾子, 櫻井映子, 井筒敏恵, 張冬穎娃, 助川淳, 吉川雄朗, 谷内一彦

  第13回日本ヒスタミン学会 2009年10月 口頭発表（一般） 日本国 仙台
• Autoantibodies to REG family proteins in Japanese diabetes patients  [通常講演]

  NJ. Shervani, N. Noguchi, T. Ikeda, I. Takahashi, T. Yoshikawa, A. Yamauchi, A. Uruno, K. Nata, S. Takasawa, H. Okamoto, A. Sugawara

  European Association for the Study of Diabetes 2009年09月 ポスター発表 オーストリア Vienna
• FK506結合蛋白質12.6ノックアウトマウスではブドウ糖刺激インスリン分泌が低下する  [通常講演]

  吉川雄朗, 野口直哉, 高柳詩織, 宇留野晃, 菅原明, 谷内一彦

  第60回日本薬理学会北部会 2009年09月 口頭発表（一般） 日本国 富山
• ヒスタミン代謝物とヒスタミンの同時測定：培養細胞への応用  [通常講演]

  井筒敏恵, 櫻井映子, 及川綾子, 吉川雄朗, 谷内一彦

  第60回日本薬理学会北部会 2009年09月 口頭発表（一般） 日本国 富山
• PPARgamma suppresses antiotensin II- and potassium-induced CYP11B2 expression and aldosterone pruduction in adrenocortical carcinoma H295 cells  [通常講演]

  A. Uruno, K. Matsuda, N. Noguchi, T. Yoshikawa, M. Kudo, F. Satoh, WE. Rainey, S. Ito, H. Okamoto, A. Sugawara

  35th meeting of the International Aldosterone Conference 2009年06月 ポスター発表 アメリカ合衆国 Washington
• マウス膵β細胞におけるヘパラン硫酸とインスリン分泌の維持  [通常講演]

  野口直哉, 高橋巌, 吉川雄朗, NJ Shervani, 宇留野晃, 海野倫明, 岡本宏, 菅原明

  第52回日本糖尿病学会年次学術集会 2009年05月 ポスター発表 日本国 大阪
• Predominant role of REGIα among the REG gene family in the proliferation of human colorectal adenocarcinoma  [通常講演]

  T. Yoshikawa, T. Ikeda, K. Sakai, N. Noguchi, I. Takahashi, NJ. Shervani, A Uruno, A. Yamauchi, E. Sakai, T. Onogawa, M. Okabe, T. Ando, M. Kinouchi, K. Miura, M. Unno, T. Emura, M. Fujiwara, S. Takasawa, H. Okamoto, A. Sugawara

  American Association for Cancer Research 2009年04月 ポスター発表 アメリカ合衆国 デンバー
• 消化器癌における全REG遺伝子の発現解析および増殖効果の検討  [通常講演]

  吉川雄朗, 池田崇之, 坂井和子, 野口直哉, 高橋巌, NJ Shervani, 宇留野晃, 山内晶世, 酒井栄一, 小野川徹, 渋谷恵美子, 岡部光規, 安藤敏典, 木内誠, 三浦康, 海野倫明, 江村智博

  第31回日本分子生物学会年会・第81回日本生化学会大会合同大会 2008年12月 ポスター発表 日本国 神戸
• Reduced beta cell proliferation and impaired glucose tolerance in pancreatic betra cell specific Extl3 knockout mice  [通常講演]

  I. Takahashi, K. Nata, N. Noguchi, T. Ikeda, K. Sugihara, M. Asano, T. Yoshikawa, NJ. Shervani, A. Uruno, M. Unno, S. Takasawa, H. Okamoto, A. Sugawara

  The 44th European Association for the Study of Diabetes 2008年09月 ポスター発表 イタリア Roma
• Impaired glucose-induced insulin secretion in FK506-binding protein 12.6-deficient mice  [通常講演]

  T. Yoshikawa, N. Noguchi, T. Ikeda, I. Takahashi, NJ. Shervani, A. Uruno, Y. Yamauchi, K. Nata, S. Takasawa, H. Okamoto, A. Sugawara

  American Diabetes Association's 68th Scientific Sessions 2008年06月 口頭発表（一般） アメリカ合衆国 San Francisco
• FK506結合蛋白質１２．６ノックアウトマウスにおけるグルコース刺激インスリン分泌の低下  [通常講演]

  吉川雄朗, 野口直哉, 池田崇之, 高橋巌, NJ Shervani, 宇留野晃, 山内晶世, 那谷耕司, 高沢伸, 岡本宏, 菅原明

  第51回日本糖尿病学会年次学術集会 2008年05月 口頭発表（一般） 日本国 東京
• 膵β細胞特異的糖転移酵素EXTL３欠損マウスはβ細胞増殖能低下と耐糖能異常を生じる  [通常講演]

  高橋巌, 那谷耕司, 野口直哉, 池田崇之, 吉川雄朗, 山内晶世, NJ Shervani, 宇留野晃, 杉原一司, 浅野雅秀, 海野倫明, 高沢伸, 岡本宏, 菅原明

  第51回日本糖尿病学会年次学術集会 2008年05月 口頭発表（一般） 日本国 東京

所属学協会

• 日本糖尿病学会   日本生化学会   日本神経科学学会   日本薬理学会   米国神経科学会   日本臨床薬理学会   日本糖質学会   

共同研究・競争的資金等の研究課題

• 中枢神経系脆弱性と全身麻酔に関連した周術期認知機能障害の神経病理解析

  日本学術振興会：科学研究費助成事業

  研究期間 : 2023年04月 -2027年03月 

  代表者 : 中村 正帆, 吉川 雄朗, 長沼 史登
• ヒスタミン系薬理学研究に残された解決すべき重要な研究課題の解明

  日本学術振興会：科学研究費助成事業

  研究期間 : 2022年04月 -2025年03月 

  代表者 : 谷内 一彦, 吉川 雄朗, 中村 正帆
• 骨格筋におけるヘパラン硫酸代謝酵素の機能解明と阻害剤探索

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2021年04月 -2024年03月 

  代表者 : 吉川 雄朗, 有澤 美枝子

   

  ヘパラン硫酸は細胞外に豊富に存在する直鎖状糖鎖の一つである。これまでに我々が実施した研究によりヘパラン硫酸は骨格筋に発現していること、骨格筋でヘパラン硫酸を欠損させると、正常な筋分化が阻害され、運動機能が低下することが示されている。そこで骨格筋においてヘパラン硫酸を増加させることは、筋分化を促進し、運動機能を改善する可能性が考えられた。そこで骨格筋に限定してヘパラン硫酸を増加させた場合に、骨格筋機能にどのような変化が生じるかを検討することとした。ヘパラン硫酸を増加させるために、まずヘパラン硫酸分解酵素に着目した。ヘパラン硫酸分解酵素（heparan sulfate endoglycosidase、HPSE）を抑制することで、ヘパラン硫酸量が増加すると考えられるため、ヘパラン硫酸分解酵素のfloxマウス（HPSE floxマウス）を新規に導入した。また骨格筋特異的にHPSE機能を欠損させるため、HPSE floxマウスと骨格筋特異的にCre recombinaseを発現するCKMM-Creマウスとを交配させ、これまでにヘテロ欠損マウスを得ている。今後骨格筋特異的にHPSEをホモ欠損したマウスを得て、表現型解析を実施する。また阻害剤の探索研究に必要なHPSEを得るために、293細胞にHPSEを安定発現させた細胞株を樹立した。HPSEにはタグを付与しており、このタグを用いることで純度の高いHPSEを得る。その後精製したHPSEを用いて酵素活性確認とハイスループットスクリーニング系の構築を実施する。
• 吸入麻酔薬の意識消失作用におけるニューロテンシン神経系の役割

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2020年04月 -2023年03月 

  代表者 : 中村 正帆, 吉川 雄朗, 長沼 史登

   

  睡眠から覚醒への移行に関わる覚醒系神経回路は、ヒスタミン神経細胞などのモノアミン神経系とそれを制御するオレキシン神経細胞などの神経ペプチド系により構成されている。これらの神経細胞が活性化することが、覚醒への移行と維持に重要であると考えられている。吸入麻酔薬の意識消失作用は、これらの神経細胞や神経回路を抑制することで発揮されると仮説し、以下の実験を行い（あるいは現在行っている）、以下の結果が得られた（あるいはデータ取得の途中である）。 １）神経ペプチド系のニューロテンシン神経細胞とモノアミン神経系のヒスタミン神経細胞の活性化が、吸入麻酔薬によってどのように変化するかを、生体内の神経細胞活動を測定するファイバーフォトメトリーを用いて検討した。原則として吸入麻酔薬はニューロテンシン神経細胞とヒスタミン神経細胞の細胞活性を抑制した（する傾向を示した）が、吸入麻酔薬の種類や濃度によって一様に抑制されるわけではないことが明らかになった。対象神経細胞の局在によって細胞活性の反応が異なる場合と、同じ局在の神経細胞でも反応が異なる場合があり、局在と神経細胞のサブポピュレーションについて精査する必要がある。２）薬理遺伝学的手法を用いて対象神経細胞を特異的に活性化あるいは不活性化した時に、吸入麻酔薬の意識消失作用がどのように変化するかを検討した。対象神経細胞を特異的に活性化すると吸入麻酔薬が作用しづらくなり（用量反応曲線が右方にシフトする）、不活性化した場合は左方にシフトする傾向を示した。
• 18F標識カチオン型心筋血流薬剤のトレンスレーショナル研究

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  研究期間 : 2019年04月 -2022年03月 

  代表者 : 古本 祥三, 吉川 雄朗, 高浪 健太郎

   

  本研究は、これまでに取り組んできた１８Ｆ－カチオン型トレーサー開発の継続的な発展課題であり、将来的に本格的な臨床研究の展開を見据えて行う新規ＰＥＴ薬剤のトランスレーショナル（橋渡し）研究である。この研究ビジョンの実現に向けて本年度は次の課題に取り組んだ。まず臨床用ＰＥＴ薬剤の製造法確立と安全性評価を目的として、これまでに確立した合成方法に従って合成を行い、目標とする１ｇ以上の標識前駆体化合物を合成した。さらに、自動合成装置でのワンポット合成に利用できる新しい構造の標識前駆体を開発した。基礎実験においてその新規前駆体を用いても従来の前駆体と同等以上の収率で標識化合物を合成することができた。そこで臨床用途に適したカセット式標識合成装置であるＦＡＳＴｌａｂ－Ｄｅｖｅｌｏｐｅｒを用いて新規前駆体から１８Ｆ－ＴＡＰ－Ｘを製造する合成反応条件、精製条件、シークエンス等の検討を行った。その結果、高速液体クロマトグラフィーを利用せずに固相抽出カートリッジの利用だけで非常に高い放射化学的純度の目的標識体を自動合成することに成功した。つづいて心筋血流イメージング剤としての性能の評価を目的として、ＳＰＥＣＴの標準的な薬剤である９９ｍＴｃ－ＭＩＢＩ と１８Ｆ－ＴＡＰ－Ｘの動態をラットの体内分布法により比較評価した。その結果、１８Ｆ－ＴＡＰ－Ｘの心臓集積率は９９ｍＴｃ－ＭＩＢＩよりも２倍以上高い値を示し、心筋イメージング剤としての優位性が示唆された。
• ヒスタミン神経系による攻撃性制御機構の解明

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2018年04月 -2021年03月 

  代表者 : 吉川 雄朗

   

  ヒスタミンはアレルギーや胃酸分泌に関わる活性アミンですが、脳内では神経伝達物質として機能しています。我々はヒスタミンを分解する酵素を欠損させたマウスを解析した結果から、ヒスタミンが脳内で攻撃性にも関わる事を明らかに致しました。しかし、どのような機構でヒスタミンが攻撃性を制御しているのかについては不明のままでした。平成30年度に見いだした結果として、アストロサイトに発現するヒスタミンH1受容体が攻撃性を減弱させる機能を有していることが上げられます。この成果をまとめ、Scientific Reports誌に論文発表を行いました。以前の研究成果により、ヒスタミン代謝酵素であるhistamine N-methyltransferase（HNMT）を欠損させたマウスでは高い攻撃性が認められることが明らかとなっていました。本年度はアストロサイト特異的に欠損したマウスを作製し、このマウスの攻撃性についてresident-intruderテストを用いて評価を行いました。このマウスでは攻撃性の増加は認められず、アストロサイトに発現するHNMTは攻撃性の制御には関わっていないと考えられました。またヒスタミン神経系の投射先について遺伝子組み換え技術を用いて検討を行いました。視床下部後部に位置する結節乳頭核を起始とするヒスタミン神経線維は、視索前野（preoptic area, POA）、外側視床下部（lateral hypothalamus, LH）、腹外側中脳水道周辺灰白質（ventrolateral periaqueductal gray matter ,vlPAG）や扁桃体などに数多くの神経線維を投射していることが明らかとなりました。
• F-18標識アミノ酸と無細胞蛋白質合成による新規Affibody標識法の開発

  日本学術振興会：科学研究費助成事業 挑戦的萌芽研究

  研究期間 : 2016年04月 -2018年03月 

  代表者 : 谷内 一彦, 吉川 雄朗, 原田 龍一

   

  本研究では直交系のアミノアシル合成酵素-tRNAペア、アンバーコドンに着目し、無細胞タンパク質合成試薬を用いタンパク質のアミノ酸に依存しない新規ポジトロン標識タンパク質合成の開発を検討した。18F-フルオロエチルチロシンと直交系のアミノアシル合成酵素-tRNAペア、アンバーコドンを用いること18F標識タンパク質の合成に成功した。HER2に対するaffibodyでHER2高発現のSKOV-3をヌードマウスに植えた担癌マウスにおけるPETイメージングを検討したところ、コントラストに優れた画像を得ることに成功した。
• 中枢神経疾患におけるヒスタミン代謝酵素の機能解明と阻害剤開発

  日本学術振興会：科学研究費助成事業 若手研究(B)

  研究期間 : 2016年04月 -2018年03月 

  代表者 : 吉川 雄朗

   

  ヒスタミンは脳内で神経伝達物質として様々な脳機能に関わることが知られています。私は脳内にあるヒスタミン代謝酵素の役割について実験を行い、この酵素がヒスタミン濃度調節に非常に重要であること、また脳機能の維持にも関わっていることを明らかにしました。また多くの神経疾患でヒスタミン濃度が減少していることから、ヒスタミン代謝酵素の作用を阻害すれば、ヒスタミン濃度が上昇し、神経疾患治療に用いられる可能性が考えられます。そこで新たな阻害剤を見出すべく実験を行い、いくつかの候補化合物を得ました。これらの化合物から優れた薬剤が得られることを期待して、更に研究を進めたいと考えています。
• 分子イメージングと新規KOマウスによる"善玉”としてのヒスタミン系の機能研究

  日本学術振興会：科学研究費助成事業 基盤研究(A)

  研究期間 : 2014年06月 -2018年03月 

  代表者 : 谷内 一彦, 吉川 雄朗, 中村 正帆, 渋谷 勝彦

   

  脳内のヒスタミンの役割について検討を行った。まず、histamine N-methyltransferase（HNMT）というヒスタミンを不活化する酵素に着目し、この機能を解析した。その結果、HNMTは脳内ヒスタミン濃度を正常に保つだけでなく、攻撃性や睡眠にも関係していることが示された。またアストロサイトやミクログリアといった、脳内に存在するグリア細胞の機能にもヒスタミンが関わっていることが明らかとなった。これらの結果は、ヒスタミン除去機構が脳機能に極めて重要であること、またヒスタミンがグリア細胞機能調節にも寄与していることを明らかにしたものである。
• モノアミントランスポーターPMATの機能解析と阻害剤開発

  日本学術振興会：科学研究費助成事業 若手研究(B)

  研究期間 : 2014年04月 -2016年03月 

  代表者 : 吉川 雄朗

   

  plasma membrane monoamine transporter（PMAT）は脳内に存在するモノアミン輸送体の一つである。しかしモノアミン濃度調節におけるPMATの役割は未だに不明のままであったため、PMAT遺伝子を欠損したマウスの作製により、PMATの機能を明らかにしようと考えた。本研究によりPMAT遺伝子を欠損したマウスの作製を終えることが出来たが、未だに十分な匹数が確保できておらず、今後PMAT欠損による影響を検討していく。またPMAT阻害剤の開発にも着手し、いくつかの候補化合物を得ることが出来た。
• ヒスタミンの分解と再取込み系に関する新規作成KOマウスによる機能研究

  日本学術振興会：科学研究費助成事業 挑戦的萌芽研究

  研究期間 : 2014年04月 -2015年03月 

  代表者 : 谷内 一彦, 渡邉 建彦, 吉川 雄朗

   

  ヒスタミンは脳内で神経伝達物質として機能しており、睡眠やストレス応答などにおいて重要な役割を担っている。我々は神経細胞から放出されたヒスタミンがどのように除去されるかというヒスタミンクリアランス機構について研究を行った。その結果、ヒスタミンを不活化するhistamine N-methyltransferase分子がヒスタミンクリアランスに重要であることを明らかにした。
• 小型霊長類マーモセットを用いた分子イメージング薬理学の創生

  日本学術振興会：科学研究費助成事業 挑戦的萌芽研究

  研究期間 : 2012年04月 -2014年03月 

  代表者 : 谷内 一彦, 吉川 雄朗, 渋谷 勝彦

   

  マーモセットを飼育してPET研究を行っている施設見学や東北大学内の規定・法規制等を調べる調査研究を行った。現状では炭素11やフッ素18標識薬剤を投与した動物は1週間以上RI施設内に飼育する必要がある。併行して小動物PET/CTを用いた分子イメージング研究を行った。東北大学で開発している分子イメージング・プローブを用いて、マウス・ラットの齧歯類において体内動態を測定して体内動態データから被ばく量を計算することを行った。分子イメージングにより使用する動物を減らしてデータを得ることができる点が良い点である。
• 最新技術による分子・個体レベルの統合的ヒスタミン研究と神経変性疾患への応用

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  研究期間 : 2009年 -2011年 

  代表者 : 谷内 一彦, 渡邉 建彦, 吉川 雄朗, 倉増 敦朗, 櫻井 映子, 岡村 信行

   

  本研究は十分に明らかにされていない中枢におけるヒスタミン系の役割を、最新技術による分子・細胞・動物個体レベルの研究を統合して研究した。明らかにした研究内容は以下の通り:1)H3受容体のシグナル伝達におけるC末の役割、2)膵β細胞におけるH3受容体、3)非特異的トランスポーターPMAT (plasma membrane monoamine transporter)によるヒスタミン取り込み機構、4)ヒスタミンH1～H3受容体遺伝子ノックアウトマウスを用いた痛み受容、ストレス脆弱性、睡眠除去におけるヒスタミン受容体の役割、5)臨床用PETと小動物用PET/CTを用いたヒスタミンH1受容体アンタゴニストの脳内動態。

その他

• 2015年04月 - 2015年04月  神経障害性疼痛バイオマーカーの探索とP2X4受容体マーカーの開発 

  神経障害性疼痛バイオマーカーの探索とP2X4受容体マーカーの開発
• 2012年01月 - 2012年01月  ミクログリアにおけるヒスタミン系の機能解析と分子イメージング 

  ミクログリアにおけるヒスタミン系の機能解析と分子イメージング
• 2011年10月 - 2011年10月  ヒスタミンと中枢神経系の関係する薬理学的研究 

  ヒスタミンと中枢神経系の関係する薬理学的研究