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

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

 

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)

 

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

論文 【 表示 / 非表示

  • Mg, K-containing microparticle: A possible active principle of a culture extract produced by a microbial consortium

    Toru Higashinakagawa, Haruhisa Kikuchi, Hidekazu Kuwayama

    PLOS ONE (PLoS ONE)  16 ( 11 ) e0259297 - e0259297 2021年11月

    研究論文(学術雑誌), 共著, 査読有り

     概要を見る

    A synthetic microbial consortium called Effective Microorganisms (EM) consists mainly of photosynthetic bacteria, lactic acid bacteria and yeast. Various effects of EMXGOLD, a health drink produced by EM, on life cycle of Dictyostelium discoideum were described previously. Here, we report our attempt to identify the active principle, termed EMF, that brought about the observed effects. Throughout the purification processes, the presence of the active principle was monitored by promoted fruiting body formation. By liquid-liquid separation the activity was recovered in aqueous phase, which, after concentration, was further subjected to reverse-phase column chromatography. No activity was detected in any eluant, while almost all the activity was recovered in residual insoluble material. The application of conventional organic chemistry procedures to the residual fraction did not lead to any informative results. Acid treatment of the insoluble material produced air bubbles, suggesting it to be composed of some inorganic carbonate. Viewed under scanning electronmicroscope, the residue revealed spherical particles of μm size range. Energy Dispersive X-ray (EDX) Spectroscopy pointed to the existence, on the surface of the particles, of magnesium and, to a certain extent, of potassium. In separate experiments, acid treatment and alkali neutralization of EMXGOLD completely wiped out the stimulatory activity of fruiting body formation. These lines of evidence indicate these Mg, K-containing microparticles to be an active principle of EM culture extract. How these particles exert their effect is currently under intensive investigation.

  • A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo.

    Kokubo, S, Ohnuma, S, Murakami, M, Kikuchi, H, Funayama, S, Suzuki, H, Kajiwara, T, Yamamura, A, Karasawa, H, Sugisawa, N, Ohsawa, K, Kano, K, Aoki, J, Doi, T, Naitoh, T, Ambudkar, S. V, Unno, M

    Int. J. Mol. Sci. (International Journal of Molecular Sciences)  22 ( 22 ) 12502 2021年11月

    研究論文(学術雑誌), 共著, 査読有り,  ISSN  16616596

     概要を見る

    The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been re-ported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dime-thyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Fur-thermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overex-pressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.

  • Derivatives of Dictyostelium differentiation-inducing factors suppress the growth of Plasmodium parasites in vitro and in vivo

    Toshihiro Mita, Makoto Hirai, Yoshiko Maki, Saifun Nahar, Naoko Yoshida, Yoshiteru Oshima, Haruhisa Kikuchi, Yuzuru Kubohara

    Biochemical Pharmacology (Biochemical Pharmacology)  194 2021年11月

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

     概要を見る

    Malaria, which is caused by protozoa of the genus Plasmodium, remains a major endemic public health problem worldwide. Since artemisinin combination therapies are used as a first-line treatment in all endemic regions, the emergence of parasites resistant to these regimens has become a serious problem. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone originally found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivatives exhibit a range of biological activities. In the present study, we investigated the effects of 41 DIF derivatives on the growth of Plasmodium falciparum in vitro using four laboratory strains and 12 field isolates. Micromolar concentrations of several DIF derivatives strongly suppressed the growth of the four laboratory strains, including strains that exhibited resistance to chloroquine and artemisinin, as well as strains that were susceptible to these drugs. In addition, DIF-1(+2), the most potent derivative, strongly suppressed the growth of 12 field isolates. We also examined the effects of DIF-1(+2) on the activity of the rodent malarial parasite Plasmodium berghei in mice. Intraperitoneal administration of DIF-1(+2) over 4 days (50 or 70 mg/kg/day) significantly suppressed the growth of the parasite in the blood with no apparent adverse effects, and a dose of 70 mg/kg/day significantly prolonged animal survival. These results suggest that DIF derivatives, such as DIF-1(+2), could serve as new lead compounds for the development of antimalarial agents.

  • Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts

    Suzuki, Y, Ichinohe, K, Sugawara, A, Kida, S, Murase, S, Zhang, J, Yamada, O, Hattori, T, Oshima, Y, Kikuchi, H

    Frontiers in Chemistry (Frontiers in Chemistry)  9 2021年10月

    研究論文(学術雑誌), 共著, 査読有り

     概要を見る

    Cancer immunotherapy involves the use of the immune system for cancer treatment. Recently, immune checkpoint-blocking antibodies have become integral for the treatment of some cancers. However, small molecules exhibit advantages over monoclonal antibody drugs, such as cell penetration, long half-life, and low manufacturing costs, and the possibility of oral administration. Thus, it is imperative to develop small-molecule immune checkpoint inhibitors. Previously, we have screened a library of synthetic indole-alkaloid-type compounds, which are produced by diversity-enhanced extracts of Japanese cornelian cherry, and reported that an unnatural pentacyclic compound inhibits CTLA-4 gene expression. In this study, immune checkpoint inhibitors with increased potency were developed by introducing substituents and conversion of functional groups based on the unnatural pentacyclic compound. The developed compounds suppressed not only CTLA-4 and PD-L1 gene expression but also protein expression on the cell surface. Their efficacy was not as potent as that of the existing small-molecule immune checkpoint inhibitors, but, to the best of our knowledge, the developed compounds are the first reported dual small-molecule inhibitors of CTLA-4 and PD-L1.

  • Inhibition of Plasmodium falciparum Lysyl-tRNA Synthetase via a Piperidine-Ring Scaffold Inspired Cladosporin Analogues

    Babbar P., Sato M., Manickam Y., Mishra S., Harlos K., Gupta S., Parvez S., Kikuchi H., Sharma A.

    ChemBioChem (ChemBioChem)  22 ( 14 ) 2468 - 2477 2021年07月

    研究論文(学術雑誌), 共著, 査読有り,  ISSN  14394227

     概要を見る

    Plasmodium falciparum lysyl-tRNA synthetase (PfKRS) represents a promising therapeutic anti-malarial target. Cladosporin was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with X-ray crystallography reveal compounds that are moderate in potency. Co-crystals of Cla−B and Cla−C with PfKRS reveal key atomic configurations that allow drug binding to and inhibition of the enzyme. Collectively these piperidine ring scaffold inhibitors lay a framework for further structural editing and functional modifications of the cladosporin scaffold to obtain a potent lead.

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総説・解説等 【 表示 / 非表示

  • 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   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

研究発表 【 表示 / 非表示

  • Development of Natural Product-Like Compound Library Based on Diversity-Enhanced Extracts

    KIKUCHI Haruhisa

    The 5th Japan-Taiwan Joint Symposium for Pharmaceutical Sciences, 

    2019年08月

    シンポジウム・ワークショップ パネル(指名)

  • 創薬シーズを指向した天然物を越える構造多様化合物群の創出

    菊地 晴久

    BINDS: ケミカルシーズ・リード探索ユニットジョイントシンポジウム 2019 IN 仙台, 

    2019年05月

    シンポジウム・ワークショップ パネル(指名)

  • Development of Natural Product-Like Compound Library Based on Diversity-Enhanced Extracts

    KIKUCHI Haruhisa

    The 2nd International Symposium on Chemical Communication, 

    2018年05月

    口頭発表(招待・特別)

  • Diversity enhanced extract: a new approach for increasing chemical diversity of natural product-like compounds

    KIKUCHI Haruhisa

    Tohoku University’s Chemistry Summer School, 

    2016年08月

    口頭発表(基調)

  • 多様性拡大抽出物を活用した天然化合物類縁体ライブラリーの創出

    菊地晴久

    日本薬学会第136年会 シンポジウム MONOTORIの新戦略, 

    2016年03月

    シンポジウム・ワークショップ パネル(指名)

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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

 

担当授業科目 【 表示 / 非表示

  • 日本薬局方

    2022年度

  • 課題研究(天然医薬資源学)

    2022年度

  • 演習(天然医薬資源学)

    2022年度

  • 卒業研究1(薬学科)

    2022年度

  • 生薬学実習

    2022年度

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