菊地　晴久 （ キクチ　ハルヒサ ）

Kikuchi, Haruhisa

写真a

所属（所属キャンパス）

薬学部 薬学科 天然医薬資源学講座 （ 芝共立 ）

職名

教授

外部リンク
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経歴 【 表示 ／ 非表示 】

  • 1998年05月
    -
    1999年03月

    東北大学, 薬学部, 助手

  • 1999年04月
    -
    2007年03月

    東北大学, 大学院薬学研究科, 助手

  • 2007年04月
    -
    2009年03月

    東北大学, 大学院薬学研究科, 助教

  • 2009年04月
    -
    2021年03月

    東北大学, 大学院薬学研究科, 准教授

  • 2021年04月
    -
    継続中

    慶應義塾大学, 薬学部, 教授

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 環境、天然医薬資源学 （天然物化学）

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著書 【 表示 ／ 非表示 】

  • 細胞性粘菌：研究の新展開〜モデル生物，創薬資源，バイオ〜

    菊地晴久, 久保原禅, アイピーシー出版, 2012年

    担当範囲: 第１０章 創薬資源としての細胞性粘菌

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論文 【 表示 ／ 非表示 】

  • Analysis of compound–compound interactions between berberine and baicalin derivatives

    Takehiro Nishimura, Chihiro Iida, Haruhisa Kikuchi

    Journal of Natural Medicines （Springer Science and Business Media LLC）  2025年11月

    最終著者, 責任著者, 査読有り,  ISSN  1340-3443

    　概要を見る

    In multicomponent drugs, such as Kampo (traditional Japanese medicine) medicines, compound–compound interactions, including synergistic effects, inhibitory effects, and complex formations, should be considered. Orengedokuto is a Kampo formula, which is used for the treatment of various diseases, including inflammation, hypertension, gastrointestinal disorders, and liver and cerebrovascular diseases. During the decoction process in the production of Orengedokuto, yellow precipitates are obtained from berberine–baicalin complexation; these precipitates enhance the in vivo coprecipitation and coabsorption of both compounds. Scutellaria root contains various baicalin analogs, such as wogonoside, oroxyloside, and scutellarin; however, the compound–compound interactions between berberine and flavonoid glycosides have not been investigated. Herein, we performed precipitation assays for berberine and the crude extract of Scutellaria root to detect and quantify compounds that interact with berberine by HPLC analysis. Furthermore, we performed precipitation assays and NMR experiments to identify chemical structures that affect the formation of precipitates; specifically, we analyzed all combinations of berberine and identified flavonoids to provide insights into associated compound–compound interactions. The NMR experiments indicated that C-8 modification affected the pi–pi interaction between berberine and flavonoids. This information enables the synthesis of more effective molecules and provides insights into their functions, such as drug delivery. The investigation of the interaction mechanisms of berberine and baicalin analogs in Kampo medicines can provide comprehensive insights regarding multicomponent drugs.

  • Inhibition kinetics of citrus jabara juice and its components on CYP2C9 activity

    Kana Koinuma, Tokio Morita, Yoshinori Uekusa, Haruhisa Kikuchi, Ayuko Imaoka, Takeshi Akiyoshi, Hisakazu Ohtani

    Journal of Pharmaceutical Sciences （Elsevier BV）  114 （ 11 ） 103983 - 103983 2025年11月

    査読有り,  ISSN  0022-3549

    　概要を見る

    Our previous studies demonstrated that the ethyl acetate extract of the juice of jabara (JEx), a Japanese citrus fruit, inhibited cytochrome P450 (CYP) 3A4 activity in a time-dependent manner, but does not inhibit CYP2C19 activity. Its components, 3,3′,4′,5,6,7,8-heptamethoxyflavone (HpMF) and 3,3′,4′,5,6,7-hexamethoxyflavone (HxMF), have been shown to be responsible for this CYP3A4 inhibition. This study aimed to investigate the nature of CYP2C9 inhibition by JEx, HpMF, and HxMF. The time-dependent inhibition kinetics of JEx against human recombinant CYP2C9 were investigated in vitro using warfarin as a substrate. The time-independent inhibition kinetics of JEx, HpMF, and HxMF against CYP2C9 were also determined. JEx did not cause time-dependent inhibition of CYP2C9, while JEx, HpMF, and HxMF inhibited CYP2C9 activity in a time-independent manner with IC<inf>50</inf> values of 2.65 % equivalent, 16.2 µM, and 57.8 µM, respectively. HpMF and HxMF were considered to be primarily responsible for CYP2C9 inhibition by JEx. The ingestion of 250 mL of jabara juice was estimated to reduce intestinal CYP2C9 activity to 3 % of the control value assuming of dilution with 210 mL of intestinal fluid, suggesting that jabara juice may cause food-drug interactions via intestinal CYP2C9 inhibition.

  • Ester derivatives of Dictyostelium differentiation-inducing factors exhibit antibacterial activity, possibly via a prodrug-like function

    Katsunori Takahashi, Haruhisa Kikuchi, Takehiro Nishimura, Hirotaka Ishigaki, Yusuke Miura, Ayuko Takahashi, Yuzuru Kubohara

    BMC Research Notes （Springer Science and Business Media LLC）  18 （ 1 ） 40 2025年01月

    責任著者, 査読有り

    　概要を見る

    Objective: Dictyostelium differentiation-inducing factors 1 and 3 [DIF-1 (1) and DIF-3 (2), respectively], along with their derivatives, such as Ph-DIF-1 (3) and Bu-DIF-3 (4), demonstrate antibacterial activity in vitro against Gram-positive bacteria, including methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-sensitive Enterococcus faecalis (VSE), and vancomycin-resistant Enterococcus faecium [VRE (VanA)]. This study investigates the therapeutic potential of DIF compounds against these Gram-positive bacteria. Results: In vitro tests revealed that the antibacterial activity of 3 and 4 was lost in the presence of human serum albumin (HSA), suggesting that HSA might inhibit their effectiveness. Further evaluation of less hydrophobic derivatives, DIF-1-NH<inf>2</inf> (5) and NH<inf>2</inf>-Bu-DIF-3 (6), showed no antibacterial activity, even in the absence of HSA. However, ester derivatives Ph-DIF-1(AHA) (7) and Bu-DIF-3(2Ac) (8) exhibited antibacterial activity against the target bacteria in vitro, although this activity was also lost in the presence of HSA. We hypothesize that these ester derivatives may function as prodrugs, with their antibacterial activity possibly restored by hydrolysis through bacterial esterases. The results suggest that suitable ester modifications could enhance the in vivo antibacterial potential of DIF compounds, particularly if they can bypass HSA binding and be activated by bacterial enzymes.

  • Kinetics of the Inhibition of CYP3A4 and CYP2C19 Activity by Jabara Juice and Identification of the Responsible Inhibitory Components

    Kana Koinuma, Kenji Noto, Tokio Morita, Yoshinori Uekusa, Haruhisa Kikuchi, Miyuki Shimoji, Hiroyuki Seki, Hiroshi Yamazaki, F. Peter Guengerich, Katsunori Nakamura, Koujirou Yamamoto, Ayuko Imaoka, Takeshi Akiyoshi, Hisakazu Ohtani

    Journal of Pharmaceutical Sciences （Elsevier BV）  114 （ 2 ） 849 - 856 2024年10月

    研究論文（学術雑誌）, 査読有り,  ISSN  0022-3549

    　概要を見る

    Some citrus fruits are known to cause clinically significant drug interactions by inhibiting intestinal cytochrome P450 (CYP) enzymes. This in vitro study aimed to investigate the kinetics of the inhibition of CYP3A4 and CYP2C19 by the juice of jabara, a Japanese citrus fruit that does not contain furanocoumarins such as 6′,7′-dihydroxybergamottin, and to identify the inhibitory compound(s). CYP3A4 and CYP2C19 activity levels were determined in vitro using recombinant CYP preparations and their respective substrates. The ethyl acetate extract (EAE) of jabara juice was separated to isolate and identify the compound(s) that inhibited CYP3A4. Then, the time-dependent kinetics of the inhibition of CYP3A4 and CYP2C19 by the EAE and its inhibitory compound(s) were analyzed. The EAE of jabara juice was found to inhibit CYP3A4 in a time-dependent manner. Two flavonoids, 3,3′,4′,5,6,7,8-heptamethoxyflavone (HpMF) and 3,3′,4′,5,6,7-hexamethoxyflavone (HxMF), were identified as the responsible compounds. HpMF and HxMF inhibited CYP3A4 activity in a concentration- and time-dependent manner, with inhibition constants (KI) of 10.0 and 7.90 µM and maximal inactivation rate constants (kinact,max) of 0.00856 and 0.0134 min−1, respectively. The EAE did not inhibit CYP2C19, even when preincubation was employed. These findings imply that jabara juice may cause food-drug interactions via time-dependent inhibition of intestinal CYP3A4.

  • A longer-chain acylated derivative of Dictyostelium differentiation-inducing factor-1 enhances the antimalarial activity against Plasmodium parasites

    Naoko Yoshida, Haruhisa Kikuchi, Makoto Hirai, Betty Balikagala, Denis A. Anywar, Hikari Taka, Naoko Kaga, Yoshiki Miura, Naoyuki Fukuda, Emmanuel I. Odongo-Aginya, Yuzuru Kubohara, Toshihiro Mita

    Biochemical Pharmacology （Elsevier BV）  225   116243 - 116243 2024年07月

    研究論文（学術雑誌）, 査読有り,  ISSN  0006-2952

    　概要を見る

    The spread of malarial parasites resistant to first-line treatments such as artemisinin combination therapies is a global health concern. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one) originally found in the cellular slime mould Dictyostelium discoideum. We previously showed that some derivatives of DIF-1, particularly DIF-1(+2) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) octan-1-one), exert potent antimalarial activities. In this study, we synthesised DIF-1(+3) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) nonan-1-one). We then evaluated the effects of DIF-1(+3) in vitro on Plasmodium falciparum and in vivo over 7 days (50–100 mg/kg/day) in a mouse model of Plasmodium berghei. DIF-1(+3) exhibited a half-maximal inhibitory concentration of approximately 20–30 % of DIF-1(+2) in three laboratory strains with a selectivity index > 263, including in strains resistant to chloroquine and artemisinin. Parasite growth and multiplication were almost completely suppressed by treatment with 100 mg/kg DIF-1(+3). The survival time of infected mice was significantly increased (P = 0.006) with no apparent adverse effects. In summary, addition of an acyl group to DIF-1(+2) to prepare DIF-1(+3) substantially enhanced antimalarial activity, even in drug-resistant malaria, indicating the potential of applying DIF-1(+3) for malaria treatment.

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総説・解説等 【 表示 ／ 非表示 】

  • ケミカルバイオロジーの冒険（6）生体を制御するための化学 天然物関連の生物活性分子開発

    叶 直樹, 菊地晴久, 高岡洋輔

    現代化学  （ 642 ） 45 - 52 2024年09月

  • New Development of Disaster-Related and Tropical Infectious Diseases Control

    Gaowa Bai, Toshiro Niki, Haruhisa Kikuchi, Ayako Sumi, Nobuyuki Kobayashi, Takahiro Haruyama, Jing Zhang, Haorile Chagan-Yasutan, Toshio Hattori

    Reports — Medical Cases, Images, and Videos （MDPI AG）  3 （ 1 ） 5 - 5 2020年03月

    その他, 共著

    　概要を見る

    As described in Japanese essay (Hojoki), written around 1200, various disasters such as big fires, earthquakes, and famines have occurred in Japan. Asian countries have been suffering from the disasters; furthermore, natural disasters are increasing due to global warming. Because tropical-infectious diseases are often disaster-related infectious diseases (DRIDs), the strategies against the former kind of disease could be applicable to DRIDs. Meteorological analysis of the occurrence of DRIDs using a method of time series analysis is important. In situations of disasters, it is desirable if you can identify the pathogen and identify disease severity simultaneously. A dipstick DNA chromatography assay termed as Single-Tag Hybridization—Printed Array Strip (STH—PAS) system was developed based on the DNA sequences of various mosquito-borne diseases. The plasma levels of matricellular proteins including galectin-9 (Gal-9) and osteopontin (OPN) were found to reflect the disease severities in the dengue virus and other DIRDs. Because both proteins have been reported to be immune-check molecules, their inhibition might enhance the immune system against pathogens. We found that brefelamide derivatives could inhibit OPN and other inflammatory molecules synthesis. Very recently, different derivatives were found to inhibit PD-L1 transcription. Applications of these agents should be considered as multi-step strategies against DRIDs.

  • 多様性拡大抽出物を利用した天然化合物様ライブラリーの創出

    菊地晴久, 大島吉輝

    MedChem News 24 （ 2 ） 45 - 51 2014年

    記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）, 共著

  • 未利用微生物・細胞性粘菌から得られた新規生物活性物質（総説）

    菊地晴久

    薬学雑誌 （PHARMACEUTICAL SOC JAPAN）  127 （ 9 ） 1431 - 1439 2007年

    書評論文，書評，文献紹介等, 単著,  ISSN  0031-6903

    　概要を見る

    Cellular slime molds are thought to be excellent model organisms for the study of cell and developmental biology because of their simple pattern of development. However, there have been few reports on secondary metabolites of them. We have focused on the utility of cellular slime molds as novel resources for natural product chemistry, and have studied the diversity of secondary metabolites produced by them as well as their physiological and pharmacological activities. We have recently isolated many novel compounds from the fruiting bodies of various species of Dictyostelium cellular slime molds. Total syntheses and biological evaluation of these compounds have been carried out. It was shown that dictyopyrones and dictyomedins may regulate Dictyostelium development. Amino sugar derivatives such as furanodictines and dictyoglucosamines induced neuronal differentiation of rat PC-12 cells. In addition, brefelarnide inhibited the cellular proliferation of 1321N1 human astrocytorna cells. These results show that cellular slime molds are promising sources in natural product chemistry.

  • 細胞性粘菌の生活環を制御する物質−単細胞から多細胞への移行をコントロールするα-ピロノイド

    大島吉輝, 菊地晴久, 前田靖男

    化学と生物 40 （ 2 ） 76 - 77 2002年

    記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）, 共著,  ISSN  0453-073X

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研究発表 【 表示 ／ 非表示 】

  • リグナンラクトン類の構造を基盤とした抗トリパノソーマ活性化合物の創出

    多田真里菜, 西村壮央, 谷優香, 菊地晴久

    [国内会議]  日本薬学会第145年会, 

    2025年03月
    , 

    ポスター発表

  • エルサルバドル産植物を用いた抗トリパノソーマ活性天然物の探索

    山内雄斗, 西村壮央, 植草義徳, Marvin J. Núñez, 嶋田淳子, 菊地晴久

    [国内会議]  日本薬学会第145年会, 

    2025年03月
    , 

    口頭発表（一般）

  • アビエチン酸の環骨格の再構築戦略に基づく中分子化合物群の創出

    小林史明, 西村壮央, 菊地晴久

    [国内会議]  日本薬学会第145年会, 

    2025年03月
    , 

    口頭発表（一般）

  • β-ラクトン骨格を特徴とする クラス D β-ラクタマーゼ特異的阻害剤 JBIR-155 の合成研究

    吉田慶季, 西村壮央, 菊地晴久

    [国内会議]  日本薬学会第145年会, 

    2025年03月
    , 

    口頭発表（一般）

  • 卵菌 Sprolegnia parasitica が産生する新規コレスタン型化合物の単離および構造決定

    櫻井廣祐，西村壮央，植草義徳，菊地晴久

    [国内会議]  日本生薬学会第70回年会, 

    2024年09月
    , 

    口頭発表（一般）

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • 天然化合物を越える多様性を有した生物活性指向型化合物ライブラリーの構築

    2019年04月
    -
    2022年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 菊地 晴久, 基盤研究(B), 補助金,  研究代表者

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知的財産権等 【 表示 ／ 非表示 】

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受賞 【 表示 ／ 非表示 】

  • 日本生薬学会学術貢献賞

    2022年, 日本生薬学会

  • 第９回インテリジェント・コスモス奨励賞

    2010年

  • 第46回天然有機化合物討論会奨励賞

    2004年

    受賞区分： 国内学会・会議・シンポジウム等の賞

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担当授業科目 【 表示 ／ 非表示 】

  • 日本薬局方

    2025年度

  • 課題研究（天然医薬資源学）

    2025年度

  • 有機機器分析

    2025年度

  • 演習（天然医薬資源学）

    2025年度

  • 卒業研究１（薬学科）

    2025年度

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