研究者詳細 - 菊地　晴久

論文 - 菊地　晴久

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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

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.

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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

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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Synthesis of a Library of Terpenoid Alkaloid–Like Compounds Containing Medium-Sized Rings via Reconstruction of the Humulene Skeleton

Nishimura T., Shiga K., Sekiya M., Sugawara A., Yonezawa T., Kikuchi H.

Chemistry - A European Journal 30 （ 48 ） e202402082 2024年06月

研究論文（学術雑誌）, 責任著者, 査読有り, ISSN 09476539

The construction of a chemical library based on natural products is a promising method for the synthesis of natural product-like compounds. In this study, we synthesized a terpenoid alkaloid-like compound library based on the humulene skeleton. Our strategy, which enables access to diverse ring systems such as 11-membered monocyclic, oxabicyclic, and medium-sized aza ring-containing scaffolds, involves the introduction of a nitrogen atom, an intermolecular C−O bond formation via Lewis acid-mediated epoxide-opening transannulation, and a ring-reconstruction strategy based on olefin metathesis. A cheminformatics analysis based on their structural and physicochemical properties revealed that the synthesized compounds have high three-dimensionality and high natural product likeness scores but with structural novelty. The usefulness of the terpenoid alkaloid-like compound library for drug discovery and the accessibility to structure-activity relationship studies were validated by performing an assay for osteoclast-specific tartrate-resistant acid phosphatase activity, resulting in the identification of a seed compound for bone-resorptive diseases such as osteoporosis.

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Isolation and Structure Determination of New Pyrones from Dictyostelium spp. Cellular Slime Molds Coincubated with Pseudomonas spp.

Nishimura T., Murotani T., Sasaki H., Uekusa Y., Eguchi H., Ishigaki H., Takahashi K., Kubohara Y., Kikuchi H.

Molecules （MDPI AG） 29 （ 9 ） 2143 - 2143 2024年05月

研究論文（学術雑誌）, 査読有り

Cellular slime molds are excellent model organisms in the field of cell and developmental biology because of their simple developmental patterns. During our studies on the identification of bioactive molecules from secondary metabolites of cellular slime molds toward the development of novel pharmaceuticals, we revealed the structural diversity of secondary metabolites. Cellular slime molds grow by feeding on bacteria, such as Klebsiella aerogenes and Escherichia coli, without using medium components. Although changing the feeding bacteria is expected to affect dramatically the secondary metabolite production, the effect of the feeding bacteria on the production of secondary metabolites is not known. Herein, we report the isolation and structure elucidation of clavapyrone (1) from Dictyostelium clavatum, intermedipyrone (2) from D. magnum, and magnumiol (3) from D. intermedium. These compounds are not obtained from usual cultural conditions with Klebsiella aerogenes but obtained from coincubated conditions with Pseudomonas spp. The results demonstrate the diversity of the secondary metabolites of cellular slime molds and suggest that widening the range of feeding bacteria for cellular slime molds would increase their application potential in drug discovery.

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Anti-trypanosomal Lignans Isolated from Salvadoran Peperomia pseudopereskiifolia

Castillo U.G., Uekusa Y., Nishimura T., Kiuchi F., Martínez M.L., Menjívar J., Nakajima-Shimada J., Núñez M.J., Kikuchi H.

Journal of Natural Products （American Chemical Society (ACS)） 87 （ 4 ） 1067 - 1074 2024年04月

研究論文（学術雑誌）, 責任著者, 査読有り, ISSN 0163-3864

A search for anti-trypanosomal natural compounds from plants collected in El Salvador, a country particularly endemic for Chagas disease, resulted in the isolation of five lignan-type compounds (1-5) from Peperomia pseudopereskiifolia. The lignan derivatives 1, 2, and 4 are new. Their absolute configuration was determined by chemical derivatization. Compounds 1, 5, 6, and 8 exhibited anti-trypanosomal activity against the amastigote form of T. cruzi comparable to that of the existing drug benznidazole.

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Compound–compound interaction analysis of baicalin and berberine derivatives in aqueous solution

Uekusa Y., Tanioka C., Nakamoto K., Tsutsumi R., Iida C., Enshu N., Nishimura T., Kiuchi F., Kikuchi H.

Journal of Natural Medicines （Springer Science and Business Media LLC） 78 （ 3 ） 590 - 598 2024年04月

研究論文（学術雑誌）, 査読有り, ISSN 1340-3443

Baicalin and berberine are biologically active constituents of the crude drugs Scutellaria root and Coptis rhizome/Phellodendron bark, respectively. Baicalin and berberine are reported to combine together as a 1:1 complex that forms yellow precipitates by electrostatic interaction in decoctions of Kampo formulae containing these crude drugs. However, the structural basis and mechanism for the precipitate formation of this compound–compound interaction in aqueous solution remains unclarified. Herein, we searched for berberine derivatives in the Coptis rhizome that interact with baicalin and identified the chemical structures involved in the precipitation formation. Precipitation assays showed that baicalin formed precipitates with berberine and coptisine but not with palmatine and epiberberine. Thus, the 2,3-methylenedioxy structure may be crucial to the formation of the precipitates, and electrostatic interaction is necessary but is not sufficient. In this multicomponent system experiment, palmatine formed a dissociable complex with baicalin and may competitively inhibit the formation of berberine and coptisine precipitation with baicalin. Therefore, the precipitation formed by berberine and baicalin was considered to be caused by the aggregation of the berberine–baicalin complex, and the 2,3-methylenedioxy structure is likely crucial to the aggregation of the complex. Graphic abstract: (Figure presented.)

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The inhibitory effect of DIF-3 on polyinosinic–polycytidylic acid-induced innate immunity activation in human cerebral microvascular endothelial cells

Araya R., Men S., Uekusa Y., Yu Z., Kikuchi H., Daitoku K., Minakawa M., Kawaguchi S., Furukawa K.I., Oshima Y., Imaizumi T., Seya K.

Journal of Pharmacological Sciences 154 （ 3 ） 157 - 165 2024年03月

研究論文（学術雑誌）, 査読有り, ISSN 13478613

For the treatment and prevention of autoinflammatory diseases, it is essential to develop the drug, regulating the innate immune system. Although differentiation-inducing factor (DIF) derivatives, extracted from the cellular slime mold, Dictyostelium discoideum, exhibit immunomodulatory effects, their effects on the regulation of innate immunity in brain are unknown. In this study, we used the human cerebral microvascular endothelial cell line, hCMEC/D3, to investigate the effects of DIF derivatives on the generation of C-X-C motif chemokine (CXCL) 10 and interferon (IFN)-β induced by polyinosinic–polycytidylic acid (poly IC). DIF-3 (1–10 μM), but not DIF-1 and DIF-2, dose-dependently inhibited the biosynthesis of not only CXCL10 but also CXCL16 and C–C motif chemokine 2 induced by poly IC. DIF-3 also strongly decreased IFN-β mRNA expression and protein release from the cells induced by poly IC through the prohibition of p65, a subtype of NF-ĸB, not interferon regulatory transcription factor 3 phosphorylation. In the docking simulation study, we confirmed that DIF-3 had a high affinity to p65. These results suggest that DIF-3 regulates the innate immune system by inhibiting TLR3/IFN-β signaling axis through the NF-ĸB phosphorylation inhibition.

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Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake via Direct Inhibition of Mitochondrial Malate Dehydrogenase in Mouse 3T3-L1 Cells

Kubohara Y., Fukunaga Y., Shigenaga A., Kikuchi H.

International Journal of Molecular Sciences （MDPI AG） 25 （ 3 ） 1889 - 1889 2024年02月

研究論文（学術雑誌）, 査読有り, ISSN 16616596

Differentiation-inducing factor 1 (DIF-1), found in Dictyostelium discoideum, has antiproliferative and glucose-uptake-promoting activities in mammalian cells. DIF-1 is a potential lead for the development of antitumor and/or antiobesity/antidiabetes drugs, but the mechanisms underlying its actions have not been fully elucidated. In this study, we searched for target molecules of DIF-1 that mediate the actions of DIF-1 in mammalian cells by identifying DIF-1-binding proteins in human cervical cancer HeLa cells and mouse 3T3-L1 fibroblast cells using affinity chromatography and liquid chromatography–tandem mass spectrometry and found mitochondrial malate dehydrogenase (MDH2) to be a DIF-1-binding protein in both cell lines. Since DIF-1 has been shown to directly inhibit MDH2 activity, we compared the effects of DIF-1 and the MDH2 inhibitor LW6 on the growth of HeLa and 3T3-L1 cells and on glucose uptake in confluent 3T3-L1 cells in vitro. In both HeLa and 3T3-L1 cells, DIF-1 at 10–40 μM dose-dependently suppressed growth, whereas LW6 at 20 μM, but not at 2–10 μM, significantly suppressed growth in these cells. In confluent 3T3-L1 cells, DIF-1 at 10–40 μM significantly promoted glucose uptake, with the strongest effect at 20 μM DIF-1, whereas LW6 at 2–20 μM significantly promoted glucose uptake, with the strongest effect at 10 μM LW6. Western blot analyses showed that LW6 (10 μM) and DIF-1 (20 μM) phosphorylated and, thus, activated AMP kinase in 3T3-L1 cells. Our results suggest that MDH2 inhibition can suppress cell growth and promote glucose uptake in the cells, but appears to promote glucose uptake more strongly than it suppresses cell growth. Thus, DIF-1 may promote glucose uptake, at least in part, via direct inhibition of MDH2 and a subsequent activation of AMP kinase in 3T3-L1 cells.

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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 ） 7926 - 7926 2023年12月

研究論文（学術雑誌）, 査読有り

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.

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

Hidekazu Kuwayama, Haruhisa Kikuchi, Yuzuru Kubohara

Biology （Biology） 12 （ 6 ） 873 - 873 2023年06月

研究論文（学術雑誌）, 査読有り

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.

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

AIRI HIRAYAMA, HIROTAKA ISHIGAKI, KATSUNORI TAKAHASHI, YUSUKE MIURA, HARUHISA KIKUCHI, YUZURU KUBOHARA

Juntendo Medical Journal （The Jutendo Medical Journal） 2023年

研究論文（学術雑誌）, 査読有り, ISSN 2187-9737

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

Xu L., Yu Z., Uekusa Y., Kawaguchi S., Kikuchi H., Daitoku K., Minakawa M., Motomura S., Furukawa K.I., Oshima Y., Seya K., Imaizumi T.

Journal of Pharmacological Sciences （Journal of Pharmacological Sciences） 149 （ 3 ） 147 - 157 2022年07月

研究論文（学術雑誌）, 査読有り, ISSN 13478613

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.

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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年04月

最終著者

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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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

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.

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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 - 12502 2021年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 16616596

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.

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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 114834 - 114834 2021年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-2952

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.

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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

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.

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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

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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Dictyostelium differentiation-inducing factor-1 promotes glucose uptake, at least in part, via an ampk-dependent pathway in mouse 3t3-l1 cells

Kubohara Y., Homma Y., Shibata H., Oshima Y., Kikuchi H.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 22 （ 5 ） 1 - 13 2021年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 16616596

Differentiation-inducing factor-1 (DIF-1) is a chlorinated alkylphenone (a polyketide) found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivative, DIF-1(3M) promote glucose consumption in vitro in mammalian cells and in vivo in diabetic rats; they are expected to be the leading antiobesity and antidiabetes compounds. In this study, we investigated the mechanisms underlying the actions of DIF-1 and DIF-1(3M). In isolated mouse liver mitochondria, these compounds at 2–20 μM promoted oxygen consumption in a dose-dependent manner, suggesting that they act as mitochondrial uncouplers, whereas CP-DIF-1 (another derivative of DIF-1) at 10–20 μM had no effect. In confluent mouse 3T3-L1 fibroblasts, DIF-1 and DIF-1(3M) but not CP-DIF-1 induced phosphorylation (and therefore activation) of AMP kinase (AMPK) and promoted glucose consumption and metabolism. The DIF-induced glucose consumption was reduced by compound C (an AMPK inhibitor) or AMPK knock down. These data suggest that DIF-1 and DIF-1(3M) promote glucose uptake, at least in part, via an AMPK-dependent pathway in 3T3-L1 cells, whereas cellular metabolome analysis revealed that DIF-1 and DIF-1(3M) may act differently at least in part.

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Effect of mushroom polysaccharides from Pleurotus eryngii on obesity and gut microbiota in mice fed a high-fat diet

Nakahara D., Nan C., Mori K., Hanayama M., Kikuchi H., Hirai S., Egashira Y.

European Journal of Nutrition （European Journal of Nutrition） 59 （ 7 ） 3231 - 3244 2020年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14366207

Purpose: Mushrooms are reported to have a variety of health-promoting activities. However, little information is available on the effects of intake of polysaccharides from Pleurotus eryngii on obesity. In this study, we investigated the effects of P. eryngii polysaccharides on obesity and gut microbiota in mice fed a high-fat diet. Methods: Soluble polysaccharides were extracted from P. eryngii using hot water. C57BL/6J mice were fed a standard diet (ST), a high-fat diet (HF), or HF with 1% or 5% P. eryngii polysaccharide fraction (LP or HP) for 16 weeks. Adipose tissues were weighed and blood parameters were measured. Expression of genes involved in fatty acid and cholesterol metabolism was assessed by real-time quantitative PCR. The gut microbiota composition was analysed by 16S rRNA gene sequencing. Results: Body weight gain and mesenteric fat tissue were lower in the HP group than in the HF group. In the HP group, serum total cholesterol and LDL cholesterol levels decreased, and lipid and total bile acids in faeces increased. Mice in the HP group showed increased expression of the LDLR gene in the liver and GPR43 in fat. The relative abundance of Firmicutes was significantly higher in the HF and HP groups than in the ST group. The abundance of some short-chain fatty acid-producing gut bacteria was altered by P. eryngii polysaccharides. Conclusions: These results provide the first evidence that P. eryngii polysaccharides have anti-obesity and LDL cholesterol-lowering effects in obese mice through increased excretion of bile acids and lipids and altered microbiota.

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