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Affiliation |
Faculty of Pharmaceutical Sciences Department of Pharmaceutical Sciences |
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Associate Professor |
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External Link |
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MOTEKI Hajime
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From School 【 display / non-display 】
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Josai University Faculty of Pharmaceutical Science Graduated
2001.04 - 2005.03
Country：Japan
From Graduate School 【 display / non-display 】
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Josai University Graduate School, Division of Pharmaceutical Sciences Master's Course Completed
2005.04 - 2007.03
Country：Japan
Employment Record in Research 【 display / non-display 】
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Josai University Faculty of Pharmaceutical Sciences Department of Pharmaceutical Sciences Associate Professor
2024.04
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Josai University Faculty of Pharmaceutical Sciences Department of Pharmaceutical Sciences Assistant Professor
2018.04 - 2024.03
Professional Memberships 【 display / non-display 】
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日本薬理学会
2011.04
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日本薬学会
2010.04
Research Career 【 display / non-display 】
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初代培養肝実質細胞の増殖に影響を及ぼす因子の探索およびその作用メカニズムの検討
Project Year： 2010.04 -
成熟ラット初代培養肝実質細胞系および部分肝切除動物を用いて、肝細胞の増殖促進や抑制に及ぼす増殖因子やサイトカイン、ホルモン、アミノ酸、ビタミンなどの細胞内シグナル伝達機構の検討および肝再生促進作用を示す新薬候補物質の探索や作用メカニズムの検討を行っている。
Papers 【 display / non-display 】
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Phenylephrine Enhances the Mitogenic Effect of S-Allyl-L-cysteine on Primary Cultured Hepatocytes through Protein Kinase C-Induced B-Raf Phosphorylation Reviewed International journal
Hajime Moteki, Masahiko Ogihara, Mitsutoshi Kimura
Biological and Pharmaceutical Bulletin 47 ( 9 ) 1565 - 1574 2024.09
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
The co-mitogenic effects of the α1-adrenoceptor agonist phenylephrine on S-allyl-L-cysteine (SAC)-induced hepatocyte proliferation were examined in primary cultures of adult rat hepatocytes. The combination of phenylephrine (10−10–10−6 M) and SAC (10−6 M) exhibited a significant dose-dependent increase in the number of hepatocyte nuclei and viable cells compared to SAC alone. This combination also increased the progression of hepatocyte nuclei into the S-phase. The potentiating effect of phenylephrine on SAC-induced cell proliferation was counteracted by prazosin (an α1-adrenergic receptor antagonist) and GF109203X (selective protein kinase C (PKC) inhibitor). In addition, PMA (direct PKC activator) potentiated the proliferative effects of SAC similarly to phenylephrine. In essence, these findings suggest that PKC activity plays a crucial role in enhancing SAC-induced cell proliferation. Moreover, the effects of phenylephrine on SAC-induced Ras activity, Raf phosphorylation, and extracellular signal-regulated kinase 2 (ERK2) phosphorylation were investigated. Phenylephrine (or PMA) in combination with SAC did not augment Ras activity, but further increased ERK2 phosphorylation and its upstream B-Raf phosphorylation. These results indicate that PKC activation, triggered by stimulating adrenergic α1 receptors, further amplifies SAC-induced cell proliferation through enhanced ERK2 phosphorylation via increased B-Raf-specific phosphorylation in primary cultured hepatocytes.
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Preparation,solubility,and anti-inflammatory effects of a complex of diphenylcyclopropenone/β-cyclodextrin derivatives as the treatment of alopecia areata Reviewed International journal
Inoue, Yutaka / Yoshino, Kaede / Kudo, Suzu / Kodama, Nao / Moteki, Hajime / Kimura, Mitsutoshi
Journal of Pharmacy and Phamaceutical Sciences 27 1 - 15 2024.08
Language：English
Purpose: To investigate the preparation of inclusion complexes of diphenylcyclopropenone (DPCP)/β-cyclodextrin (β-CD) derivatives using a three-dimensional (3D) ball mill, and verify the inclusion behavior of the solid dispersion. Additionally, we aimed to investigate the effect of DPCP/β-CDs complex formation on the spleens of male C57BL/6 mice in terms of anti-inflammatory effects. Methods: The inclusion complexes of DPCP with β-CD and hydroxypropyl-β-cyclodextrin (HPβCD) were prepared using a 3D ball mill. Powder X-ray diffraction (PXRD) and Fourier-transform infrared spectroscopy (FT-IR) were used to evaluate the solid-state properties. The solubility of the prepared DPCP/β-CD and HPβCD complexes and the intermolecular interaction between DPCP and β-CD derivatives in solution were assessed using 1H nuclear magnetic resonance (NMR). Furthermore, the anti-inflammatory effects of DPCPs in the prepared DPCP/CD complexes were investigated using spleens from male C57BL/6 mice, with measurement of interferon gamma (IFN-γ) secretion as an endpoint. Additionally, the protective effects of each drug on NIH-3T3 cells exposed to ultraviolet (UV) irradiation were examined. Results: Solid-state characterization confirmed the formation of inclusion complexes in the 3D ground mixture (3DGM) (DPCP/β-CD = 1/1) and 3DGM (DPCP/HPβCD = 1/1) complexes through PXRD and IR analysis. The solubility of 3DGM (DPCP/β-CD = 1/1) and 3DGM (DPCP/HPβCD = 1/1) was 17.5 μg/mL and 58.4 μg/mL, respectively, indicating higher solubility than that of DPCP alone. NMR analysis of 3DGM samples suggested that DPCP/β-CD and DPCP/HPβCD form inclusion complexes at a molar ratio of 1/1 but with different inclusion modes. Regarding the anti-inflammatory activity of DPCP, 3DGM (DPCP/HPβ-CD) showed anti-inflammatory effects at lower doses compared to 3DGM (DPCP/β-CD) in terms of IFN-γ and NIH-3T3 cells injured by UV irradiation. Conclusion: We successfully formed inclusion complexes of DPCP/β-CD and DPCP/HPβCD using the 3D ground mixture method. NMR analysis suggested that DPCP/β-CD and DPCP/HPβCD form inclusion complexes at a molar ratio of 1/1 but with different inclusion modes. The anti-inflammatory activity of DPCP was more pronounced in 3DGM (DPCP/HPβCD) at lower doses compared to that in 3DGM (DPCP/β-CD), indicating that the HPβCD derivatives were more effective in enhancing the anti-inflammatory properties of DPCP.
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Role of Hepatocyte Growth Regulators in Liver Regeneration Invited Reviewed
Kimura M, Moteki H, Ogihara M.
cells 12 ( 208 ) 2023.01
Authorship：Second author Language：English Publishing type：Research paper (scientific journal)
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Preparation, Characterization, and In Vitro Evaluation of Inclusion Complexes Formed between S-Allylcysteine and Cyclodextrins Reviewed
Tachikawa R, Saito H, Moteki H, Kimura M, Kitagishi H, Arce F Jr, See GL, Tanikawa T, Inoue Y.
OCS Omega 7 ( 35 ) 31233 - 31245 2022.08
Authorship：Second author Language：English Publishing type：Research paper (scientific journal)
The present study prepared inclusion complexes of S-allylcysteine (SAC) and cyclodextrin (α, β, γ) by the freeze-drying (FD) method and verified the inclusion behavior of the solid dispersion. Also, the study investigated the effect of SAC/CD complex formation on liver tumor cells. Isothermal titration calorimetry (ITC) measurements confirmed the exothermic titration curve for SAC/αCD, suggesting a molar ratio of SAC/αCD = 1/1, but no exothermic/endothermic reaction was obtained for the SAC/βCD and SAC/γCD system. Powder X-ray diffraction (PXRD) results showed that the characteristic diffraction peaks of SAC and CDs disappeared in FD (SAC/αCD) and FD (SAC/γCD), indicated by a halo pattern. On the other hand, diffraction peaks originating from SAC and βCDs were observed in FD (SAC/βCD). Near-infrared (NIR) absorption spectroscopy results showed that CH and OH groups derived from SAC and OH groups derived from αCD and γCD cavity were shifted, suggesting complex formation due to intermolecular interactions occurring in SAC/αCD and SAC/γCD. Stability test results showed that the stability was maintained with FD (SAC/αCD) over FD (SAC/βCD) and FD (SAC/γCD). In 1H–1H of NOESY NMR measurement, FD (SAC/αCD) was confirmed to have a cross peak at the CH group of the alkene of SAC and the proton (H-3, -5, -6) in the αCD cavity. In FD (SAC/γCD), a cross peak was confirmed at the alkyl group on the carbonyl group side of SAC and the proton (H-3) in the cavity of γCD. From the above, it was suggested that the inclusion mode of SAC is different on FD (SAC/CDs). The results of the hepatocyte proliferation inhibition test using HepG2 cells showed that FD (SAC/βCD) inhibited cell proliferation. On the other hand, FD (SAC/αCD) and FD (SAC/γCD) did not show a significant decrease in the number of viable cells. These results suggest that the difference in the inclusion mode may contribute to the stability and cell proliferation inhibition.
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Cell proliferation effects of S-allyl-L-cysteine are associated with phosphorylation of janus kinase 2, insulin-like growth factor type-I receptor tyrosine kinase, and extracellular signal-regulated kinase 2 in primary cultures of adult rat hepatocytes Reviewed International journal
Hajime Moteki, Masahiko Ogihara, Mitsutoshi Kimura
European Journal of Pharmacology 927 175067 2022.05
Authorship：Lead author, Last author Language：English Publishing type：Research paper (scientific journal)
The cell proliferation effect of S-allyl-L-cysteine (SAC) and its mechanisms were examined in primary cultures of adult rat hepatocytes. In serum-free cultivation, SAC (10−6 M)-stimulated hepatocytes showed significant proliferation compared to control at 5-h culture; the effect was dependent on the culture time and the dose of SAC (EC50 value 8.58 × 10−8 M). In addition, SAC-stimulated hepatocytes significantly increased mRNA expression levels of c-Myc and c-Fos at 1 h and cyclin B1 at 3.5 and 4 h, respectively. In contrast, alliin and allicin, structural analogs of SAC, did not show these effects observed with SAC. The SAC-induced hepatocyte proliferation effects were completely suppressed by monoclonal antibodies against growth hormone receptor and insulin-like growth factor type-I (IGF-I) receptor, respectively. Furthermore, the Janus kinase 2 (JAK2) inhibitor TG101209, phospholipase C (PLC) inhibitor U-73122, IGF-I receptor tyrosine kinase (RTK) inhibitor AG538, PI3 kinase inhibitor LY294002, MEK inhibitor PD98059, and mTOR inhibitor rapamycin completely suppressed the SAC-induced hepatocyte proliferation. JAK2 (p125 kDa) phosphorylation in cultured hepatocytes peaked 5 min after SAC stimulation. SAC-induced IGF-I RTK (p95 kDa) and ERK2 (p42 kDa) phosphorylation had slower rises than JAK2, peaking at 20 and 30 min, respectively. These results indicate that SAC promoted cell proliferation by growth hormone receptor/JAK2/PLC pathway activation followed by activation of the IGF-I RTK/PI3K/ERK2/mTOR pathway in primary cultures of adult rat hepatocytes.
Presentations 【 display / non-display 】
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Proliferative effects of thyroid hormones on primary cultured of adult rat hepatic parenchymal cells
Hajime Moteki, Miho Akimoto, Masahiko Ogihara, Mitsutoshi Kimura
2024.03
Event date： 2024.03
Language：Japanese Presentation type：Poster presentation
Country：Japan
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Proliferative effects of erythropoietin in primary cultures of adult rat hepatocytes.
Yuka Kano, Rina Ueki, Harua Nonaka, Hajime Moteki, Masahiko Ogihara, Mitsutoshi Kimura
2024.03
Event date： 2024.03
Language：Japanese Presentation type：Poster presentation
Country：Japan
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Effects of S-allyl-L-cysteine on binding to growth hormone receptors in primary cultures of adult rat hepatocytes.
Hajime Moteki, Masahiko Ogihara and Mitsutoshi Kimura
2023.12
Event date： 2023.12
Language：Japanese Presentation type：Poster presentation
Country：Japan
We previously reported that S-allyl-L-cysteine (SAC)-induced cell proliferation was involved in intracellular insulin-like growth factor (IGF)-I secretion via the Janus kinase 2 (JAK2) / phospholipase C (PLC) pathway in primary cultures of adult rat hepatocytes. Furthermore, we demonstrated that growth hormone (GH) stimulates the GH receptors in cultured hepatocytes to promote IGF-I secretion through the JAK2/PLC pathway. In this study, we investigated whether SAC binds to GH receptors by examining the affinity between the anti-GH receptor monoclonal antibody (anti-GHR mAb) and GH receptors in the presence of SAC or GH using a GH receptor immunofluorescence technique (GH receptor imaging). The GHR in hepatocytes emitted a fluorescent signal when labeled with a fluorescent dye-coupled anti-GHR mAb. Interestingly, SAC-treated fluorescent signals tended to decrease compared to the absence of SAC, and this effect was dependent on SAC doses. A similar trend was observed in GH treatment. In contrast, S-methyl-L-cysteine, which is a structural analog of SAC and has no hepatocyte proliferation capacity, did not show any decrease in fluorescence intensity. These results indicate that SAC shares the same binding site as GH for the GH receptor. In other words, SAC induces JAK2 phosphorylation by binding to GH receptors expressed on the hepatocyte membrane.
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Potentiating effects of α1-adrenoceptor agonists on S-allyl-L-cysteine-included ERK2 phosphorylation in primary cultures of adult rat hepatocytes.
Hajime Moteki, Masahiko Ogihara, Mitsutoshi Kimura
2023.03
Event date： 2023.03
Language：Japanese Presentation type：Poster presentation
Country：Japan
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Effects of S-allyl-L-cysteine on phosphorylation of insulin-like growth factor type-I receptor tyrosine kinase in primary cultures of adult rat hepatocytes.
Hajime Moteki, Masahiko Ogihara, Mitsutoshi Kimura
2022.12
Event date： 2022.11 - 2022.12
Language：Japanese Presentation type：Poster presentation
Country：Japan
We previously reported that S-allyl-L-cysteine (SAC)-induced cell proliferation was involved in intracellular IGF-I secretion via Janus kinase 2 (JAK2) / phospholipase C (PLC) pathway in primary cultures of adult rat hepatocytes. In this study, we investigated the involvement of IGF-I receptor tyrosine kinase (RTK) in the SAC-induced hepatocyte proliferation by using Western blot analysis. IGF-I RTK (p95 kDa) phosphorylation in cultured hepatocytes peaked 20 min after SAC stimulation. SAC-induced IGF-I RTK phosphorylation was suppressed not only by the IGF-I RTK inhibitor AG538 but also by the JAK2 inhibitor TG101209 and the PLC inhibitor U-73122. Furthermore, the SAC-induced cell proliferation was significantly suppressed by PI3 kinase inhibitor LY294002, MEK inhibitor PD98059, and mTOR inhibitor rapamycin. These results suggested that the SAC-induced IGF-I RTK phosphorylation is mediated by JAK2/PLC phosphorylation and subsequently released IGF-I phosphorylates IGF-I RTK. Then hepatocyte proliferation may be induced via IGF-I RTK / PI3 kinase / MEK / mTOR pathway.
Scientific Research Funds Acquisition Results 【 display / non-display 】
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生体肝移植後の肝再生現象に対する甲状腺ホルモンの作用の検討とその分子機構の解明
Grant number：23K08036 2023.04 - 2026.03
学術振興会 科学研究費助成事業 基盤研究C
木村 光利
Authorship：Coinvestigator(s) Grant type：Competitive
Grant amount：\4680000
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初代培養肝実質細胞の増殖に対するS-アリル-L-システインの効果に関する研究
Grant number：20K16011 2021.04 - 2023.03
独立行政法人日本学術振興会 科学研究費助成事業 若手研究
茂木 肇
Authorship：Principal investigator Grant type：Competitive
Grant amount：\4030000 （ Direct Cost: \3100000 、 Indirect Cost：\930000 ）
私は、これまで、肝再生の分子機構の解明の一端として、初代培養肝実質細胞（in vitro実験系）および部分肝切除動物（in vivo実験系）を用いて、肝再生促進薬の探索、候補薬の細胞増殖作用機構およびアドレナリン作動性調節機構との関連性について検討してきた。一連の研究の中で、熟成ニンニクに含まれるS-allyl-L-cysteine（SAC）が、部分肝切除ラットの肝再生を促進させることを見出した。これを応用すれば生体肝移植後の肝再生を促進させる新薬として患者のQOLを大きく向上させる期待できる。しかし、SACがどのような細胞内シグナル伝達機構により細胞増殖促進作用を促進させているのかは不明である。本研究では、成熟ラット初代培養肝実質細胞におけるSACの細胞増殖促進作用機構およびアドレナリン作動性調節機構との関連性について薬理学的手法（DNA合成能解析）、生化学的手法（western blot解析法）および分子生物学的手法（リアルタイム-PCR解析法）により検討する。
Teaching Experience 【 display / non-display 】
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IPW実習
2019.04 Institution：Saitama Prefectural University
Social Activities 【 display / non-display 】
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2021年度 ひらめき☆ときめきサイエンス 「初代培養肝実質細胞の増殖に影響を及ぼすくすりの効果を観察しよう！」
Role(s)： Lecturer, Organizing member
2021.08
Audience： High school students
Type：Seminar, workshop
2021年8月10日（火）、12日（木）、14日（土）の3日間、城西大学薬学部において、2021年度ひらめき☆ときめきサイエンス～ようこそ大学の研究室へ～KAKENHI「初代培養肝実質細胞の増殖に影響を及ぼすくすりの効果を観察しよう！」が開催され、応募のありました高等学校（1～3年生）の中で、抽選で選ばれた生徒さん合計9名とその保護者2名が講義と実習を体験しました。
本学薬学部は、独立行政法人日本学術振興会の採択を受けて3年ぶりに本プログラムを実施致しました。今年度は、研究代表者の木村 光利教授の研究グループが中心となって、コロナ感染症拡大防止の観点と生徒さんの理解度並びに使用する機器やスペースを考慮して、同一プログラムを3日間行い、ほぼマンツーマンで対応することにしました。
各日、生徒さんたちは、事前10日前からの健康チェックシートと交換に、薬学部棟21号館1階にて、薬学部長若しくは薬学科主任の開会の挨拶の後、科研費の説明および研究テーマと実験プログラムに関連する講義を受け、午後には6階の臨床薬理学講座で主に体験実習に参加しました。 -
平成27年度「スーパーサイエンスハイスクール」－城西大学薬学部で学ぶ「生命と薬」－
Role(s)： Lecturer, Organizing member
城西大学薬学部 2015.10
Audience： High school students
Type：Seminar, workshop
熊谷女子高等学校の1,2年生を対象に、くすりに関するテーマで体験実習を行った。平成27年度は「薬物の吸収過程と腸管の運動に影響を及ぼすくすりの効果を観察しよう」をテーマに、体験実習を行った。参加者は、マウスに、予め腸管の動きをコントロールする薬物(副交感神経作動
薬と遮断薬)をそれぞれ投与し、そのマウスに目的となる色のついた懸
濁薬液を飲ませ、麻酔下で開腹して、それらの消化管内の移動状態を
観察し、消化管の運動を調節する薬と薬物の吸収過程について学習し
てもらった。また、消化管の摘出操作（解剖）を通して、マウスの内臓
の構造やはたらき及び生命倫理について学習してもらった。 -
平成27年度「ひらめき☆ときめきサイエンス」－ようこそ大学の研究室へー
Role(s)： Lecturer, Organizing member
2015.07
Type：Seminar, workshop
独立行政法人、日本学術振興会の委託を受けて、首都圏の高等学校から応募のあった高校生を対象に、「腸管の運動に影響を及ぼすくすりの効果を観察しよう！」をテーマに体験実習を行った。体験実習の参加者には、マウスの腸管平滑筋を生体の体内と同様の環境を人工的に作った装置の中で生かした条件下で、色々な薬物、特に自律神経系に作用する薬物を添加して、小腸の応答性を観察し、これらの運動が自律神経系によって調節されていることを学習してもらった。この体験実習を通して、実験動物に対する感謝を含む生命倫理について学習してもらった。
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平成26年度「スーパーサイエンスハイスクール」－城西大学薬学部で学ぶ「生命と薬」－
Role(s)： Lecturer, Organizing member
2014.10
Type：Seminar, workshop
熊谷女子高等学校の1,2年生を対象に、くすりに関するテーマで体験実習を行った。平成26年度は「血液中のブドウ糖濃度をコントロールしよう！」をテーマに、体験実習を行った。参加者は、糖尿病誘発マウスにアドレナリンやインスリンを投与して、それぞれのマウスの血糖値を測定することにより、血糖値の調節に関係しているホルモンの作用について学習してもらった。さらに、参加者には、実験動物に対する感謝を含む生命倫理についても学習してもらった。
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平成26年度「ひらめき☆ときめきサイエンス」－ようこそ大学の研究室へ－
Role(s)： Lecturer, Organizing member
2014.08
Type：Seminar, workshop
独立行政法人、日本学術振興会の委託を受けて、首都圏の高等学校から応募のあった高校生を対象に、「麻酔薬の効果と薬物相互作用を観察しようⅡ」をテーマに体験実習を行った。体験実習の参加者には、マウスに様々の用量の全身麻酔薬を投与し、その効果（睡眠に至るまでの時間など）について観察してもらった。また、この体験実習を通して、実験動物に対する感謝を含む生命倫理について学習してもらった。