Kikuchi, Haruhisa



Faculty of Pharmacy, Department of Pharmacy 天然医薬資源学講座 (Shiba-Kyoritsu)



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Career 【 Display / hide

  • 1998.05

    東北大学, 薬学部, 助手

  • 1999.04

    東北大学, 大学院薬学研究科, 助手

  • 2007.04

    東北大学, 大学院薬学研究科, 助教

  • 2009.04

    東北大学, 大学院薬学研究科, 准教授

  • 2021.04

    慶應義塾大学, 薬学部, 教授


Research Areas 【 Display / hide

  • Life Science / Environmental and natural pharmaceutical resources (Natural Product Chemistry)


Books 【 Display / hide

  • 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

    Scope: 第10章 創薬資源としての細胞性粘菌

Papers 【 Display / hide

  • Pharmacological Evidence That Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake Partly via an Increase in Intracellular cAMP Content in Mouse 3T3-L1 Cells

    Kubohara Y., Fukunaga Y., Kikuchi H., Kuwayama H.

    Molecules (Molecules)  28 ( 23 )  2023.12

     View Summary

    Differentiation-inducing factor 1 (DIF-1) isolated from the cellular slime mold Dictyostelium discoideum can inhibit mammalian calmodulin-dependent cAMP/cGMP phosphodiesterase (PDE1) in vitro. DIF-1 also promotes glucose uptake, at least in part, via a mitochondria- and AMPK-dependent pathway in mouse 3T3-L1 fibroblast cells, but the mechanism underlying this effect has not been fully elucidated. In this study, we investigated the effects of DIF-1 on intracellular cAMP and cGMP levels, as well as the effects that DIF-1 and several compounds that increase cAMP and cGMP levels have on glucose uptake in confluent 3T3-L1 cells. DIF-1 at 20 μM (a concentration that promotes glucose uptake) increased the level of intracellular cAMP by about 20% but did not affect the level of intracellular cGMP. Neither the PDE1 inhibitor 8-methoxymethyl-3-isobutyl-1-methylxanthine at 10–200 μM nor the broad-range PDE inhibitor 3-isobutyl-1-methylxanthine at 40–400 μM had any marked effects on glucose uptake. The membrane-permeable cAMP analog 8-bromo-cAMP at 200–1000 μM significantly promoted glucose uptake (by 20–25%), whereas the membrane-permeable cGMP analog 8-bromo-cGMP at 3–100 μM did not affect glucose uptake. The adenylate cyclase activator forskolin at 1–10 μM promoted glucose uptake by 20–30%. Thus, DIF-1 may promote glucose uptake by 3T3-L1 cells, at least in part, via an increase in intracellular cAMP level.

  • Derivatives of Differentiation-Inducing Factor 1 Differentially Control Chemotaxis and Stalk Cell Differentiation in Dictyostelium discoideum

    Hidekazu Kuwayama, Haruhisa Kikuchi, Yuzuru Kubohara

    Biology (MDPI AG)  12 ( 6 ) 873 - 873 2023.06


     View Summary

    Differentiation-inducing factors 1 and 2 (DIF-1 and DIF-2) are small lipophilic signal molecules that induce stalk cell differentiation but differentially modulate chemotaxis toward cAMP in the cellular slime mold Dictyostelium discoideum; DIF-1 suppresses chemotactic cell movement in shallow cAMP gradients, whereas DIF-2 promotes it. The receptor(s) for DIF-1 and DIF-2 have not yet been identified. We examined the effects of nine derivatives of DIF-1 on chemotactic cell movement toward cAMP and compared their chemotaxis-modulating activity and stalk cell differentiation–inducing activity in wild-type and mutant strains. The DIF derivatives differentially affected chemotaxis and stalk cell differentiation; for example, TM-DIF-1 suppressed chemotaxis and showed poor stalk-inducing activity, DIF-1(3M) suppressed chemotaxis and showed strong stalk-inducing activity, and TH-DIF-1 promoted chemotaxis. These results suggest that DIF-1 and DIF-2 have at least three receptors: one for stalk cell induction and two for chemotaxis modulation. In addition, our results show that the DIF derivatives can be used to analyze the DIF-signaling pathways in D. discoideum.

  • <i>Dictyostelium</i> Differentiation-inducing Factor Derivatives Reduce the Glycosylation of PD-L1 in MDA-MB-231 Human Breast Cancer Cells


    Juntendo Medical Journal (The Jutendo Medical Journal)   2023

    ISSN  2187-9737

  • Elucidation of the inhibitory effect of (+)-hopeaphenol on polyinosinic-polycytidylic acid-induced innate immunity activation in human cerebral microvascular endothelial cells.

    Liu Xu, Zaiqiang Yu, Yoshinori Uekusa, Shogo Kawaguchi, Haruhisa Kikuchi, Kazuyuki Daitoku, Masahito Minakawa, Shigeru Motomura, Ken-Ichi Furukawa, Yoshiteru Oshima, Kazuhiko Seya, Tadaatsu Imaizumi

    Journal of pharmacological sciences (Journal of Pharmacological Sciences)  149 ( 3 ) 147 - 157 2022.07

    ISSN  13478613

     View Summary

    Drug development for regulating the innate immune system is important for the prevention and treatment of autoinflammatory and autoimmune diseases. In this context, we investigated the effect of resveratrol derivatives on the inflammatory reactions in the brain. Resveratrol, which can be found in Vitis plants in the form of oligomers, exhibits neuroprotective effects; however, its regulatory effects on innate immunity are still unclear. We examined the effects of (+)-hopeaphenol, a resveratrol tetramer, and its derivatives on the polyinosinic-polycytidylic acid (poly IC)-induced production of interferon (IFN)-β and C-X-C motif chemokine 10 (CXCL10) in the cultured human cerebral microvascular endothelial cell line hCMEC/D3. (+)-Hopeaphenol (1-10 μM) inhibited the poly IC-induced production of not only CXCL10 but also retinoic acid-inducible gene-I in a dose-dependent manner and significantly reduced the poly IC-induced IFN-β gene expression and protein release from hCMEC/D3 cells by inhibiting the phosphorylation of p65 but not that of the interferon regulatory transcription factor IRF3. A docking study indicated a high affinity of (+)-hopeaphenol for p65. These results suggest that (+)-hopeaphenol can regulate the innate immune system by inhibiting the poly IC/IFN-β/CXCL10 signaling axis via suppression of the phosphorylation of the transcription factor NF-ĸB.

  • Glycidyl Silanes Enable Regioselective Hydrosilylation of In-ternal Propargyl Alcohols and Direct Transformation into Activated Silanes for Further Chemical Transformation

    Akihiro Sugawara, Soya Koremura, Yusuke Sasano, Haruhisa Kikuchi

    ChemRxiv (American Chemical Society (ACS))   2022.04

    Last author

     View Summary

    Herein, we develop glycidyl silanes to facilitate highly regioselective hydrosilylation of internal propargyl alcohols, the products of which can in turn be converted to synthetically useful fluorosilanes for further chemical transfor-mations under mild conditions. Structure–selectivity studies and density functional theory calculations are consistent with high regioselectivity arising from a critical intermolecular hydrogen bond between the glycidyl and propargylic hydroxy groups. A broad substrate scope illustrates the generality of this reaction to form beta-E silylalkenes. Treatment of the beta-E silylalkenes with a fluoride salt induces simultaneous removal of the glycidyl group and activation of the silane under mild conditions. The fluorosilane products can be converted into vinyl arene and ketone derivatives via Hiyama coupling and Tamao–Fleming oxidation reactions, respectively. The discovery that glycidyl silane improves hydrosilylation regioselectivity and is compatible with expedient silylalkene derivatization may prove applicable to a variety of similar alkyne hydrofunctionalization reactions.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • 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 2020.03

    Other, Joint Work

     View Summary

    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.

  • Development of Natural Product-like Library by Using Diversity-enhanced Extracts

    Kikuchi H, Oshima Y

    MedChem News 24 ( 2 ) 45 - 51 2014

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Joint Work

  • Novel biologically active compounds isolated from unexploited organisms, cellular sime molds

    Haruhisa Kikuchi


    Book review, literature introduction, etc., Single Work,  ISSN  0031-6903

     View Summary

    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

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Joint Work,  ISSN  0453-073X

Presentations 【 Display / hide

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

    KIKUCHI Haruhisa

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


    Symposium, workshop panel (nominated)

  • 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, 


    Symposium, workshop panel (nominated)

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

    KIKUCHI Haruhisa

    The 2nd International Symposium on Chemical Communication, 


    Oral presentation (invited, special)

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

    KIKUCHI Haruhisa

    Tohoku University’s Chemistry Summer School, 


    Oral presentation (keynote)

  • 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


    日本薬学会第136年会 シンポジウム MONOTORIの新戦略, 


    Symposium, workshop panel (nominated)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 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


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Principal investigator

Intellectual Property Rights, etc. 【 Display / hide

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Awards 【 Display / hide

  • 日本生薬学会学術貢献賞

    2022, 日本生薬学会

  • 9th Intelligent Cosmos Encouragement Prize


  • Award of 46th Symposium on the Chemistry of Natural Products


    Type of Award: Award from Japanese society, conference, symposium, etc.


Courses Taught 【 Display / hide











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