研究者詳細 - 菊地　晴久

論文 - 菊地　晴久

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Br-DIF-1 accelerates dimethyl sulphoxide-induced differentiation of P19CL6 embryonic carcinoma cells into cardiomyocytes

K. Seya, K. Kanemaru, M. Matsuki, K. Hongo, H. Kitahara, H. Kikuchi, Y. Oshima, Y. Kubohara, K. Okumura, S. Motomura, K-I Furukawa

BRITISH JOURNAL OF PHARMACOLOGY （WILEY-BLACKWELL） 165 （ 4 ） 870 - 879 2012年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0007-1188

BACKGROUND AND PURPOSE
Stem cell transplantation therapy is a promising option for treatment of severe ischaemic heart disease. Dimethyl sulphoxide (DMSO) differentiates P19CL6 embryonic carcinoma cells into cardiomyocyte-like cells, but with low differentiation capacity. To improve the degree of this differentiation, we have assessed several derivatives of the differentiation-inducing factor-1 (DIF-1), originally found in the cellular slime mould Dictyostelium discoideum, on P19CL6 cells.
EXPERIMENTAL APPROACH
P19CL6 cells were cultured with each derivative and 1% DMSO for up to 16 days. Differentiation was assessed by measuring the number of beating and non-beating aggregates, and the expression of genes relevant to cardiac tissue. The mechanism of action was investigated using a T-type Ca2+ channel blocker.
KEY RESULTS
Of all the DIF-1 derivatives tested only Br-DIF-1 showed any effects on cardiomyocyte differentiation. In the presence of 1% DMSO, Br-DIF-1 (0.3-3 mu M) significantly and dose-dependently increased the number of spontaneously beating aggregates compared with 1% DMSO alone, by day 16. Expression of mRNA for T-type calcium channels was significantly increased by Br-DIF-1 + 1% DMSO compared with 1% DMSO alone. Mibefradil (a T-type Ca2+ channel blocker; 100 nM) and a small interfering RNA for the T-type Ca2+ channel both significantly decreased the beating rate of aggregates induced by Br-DIF-1 + 1% DMSO.
CONCLUSIONS AND IMPLICATIONS
Br-DIF-1 accelerated the differentiation, induced by 1% DMSO, of P19CL6 cells into spontaneously beating cardiomyocyte-like cells, partly by enhancing the expression of the T-type Ca2+ channel gene.

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Phenolic Compounds and Terpenoids from Hypericum lanceolatum

Hippolyte K. Wabo, Theodora K. Kowa, Antoine Honore N. Lonfouo, Alembert T. Tchinda, Pierre Tane, Haruhisa Kikuchi, Michel Frederich, Yoshiteru Oshima

RECORDS OF NATURAL PRODUCTS （ACG PUBLICATIONS） 6 （ 2 ） 94 - 100 2012年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1307-6167

A benzophenone, 2,2',5,6'-tetrahydroxybenzophenone (1), and one xanthone, 5-hydroxy-3-methoxyxanthone (2), were newly described as natural products from the leaves and the stem barks of Hypericum lanceolatum, along with the known compounds friedelin (3), betulinic acid (4), allanxanthone A (5), 1,3,6-trihydroxyxanthone (6), isogarcinol (7), sitosterol 3-O-beta-D-glucopyranoside (8), 1-hydroxy-6-methoxyxanthone (9), 6,7-dihydroxy-1,3-dimethoxyxanthone (10), 3-hydroxy-5-methoxyxanthone (11), 1,7-dihydroxy-3,6-dimethoxyxanthone (12) and calophyllumin A (13). Their structures were elucidated by spectroscopic means and comparison with published data.

Coupling of Two Diazotized 3-Aminothieno[3,4-c]coumarins with Aromatic Amines

Emmanuel Sopbue Fondjo, Joseph Tsemeugne, Beibam Luc Sondengam, Thomas Oppenlaender, Hippolyte Kamdem Wabo, Pierre Tane, Joseph D. Connolly, Wim Dehaen, Taoufik Rohand, Haruhisa Kikuchi, Yoshiteru Oshima

JOURNAL OF HETEROCYCLIC CHEMISTRY （WILEY-BLACKWELL） 48 （ 6 ） 1295 - 1301 2011年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-152X

The coupling reactions of two diazotized 3-aminothieno[3,4-c]coumarins were investigated. Compounds 1a,b both react with sodium nitrite in concentrated sulphuric acid at 0-5 degrees C to give the diazotized intermediates 2 and 3, the latter resulting from the acid -catalyzed hydrolysis of the lactonic ring of 2. The in situ formed diazonium salts react with aromatic amines (4) to afford a series of arylazothiophenes dyes in the form of their ammonium sulfate salts. With diazotized aniline, besides the normally expected phenylazothiophene 10 from the reaction with compound 1a, the corresponding product of acid hydrolysis 11 was also isolated. In at least one of the cases, the thienyl diazonium salt 2 undergoes a Gomberg-Bachmann arylation reaction with p-nitroaniline to give the 2-arylthiophene 9. The direct hydrolysis of compounds 1a, b by concentrated sulphuric acid and subsequent oxidative dimerization of the primary product of acid hydrolysis led to compound 12.

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A phytoceramide analog stimulates the production of chemokines through CREB activation in human endothelial cells

Mizuki Sekiya, Kazunori Ueda, Kaori Okazaki, Jun Terashima, Yasuhiro Katou, Haruhisa Kikuchi, Shoichiro Kurata, Yoshiteru Oshima

INTERNATIONAL IMMUNOPHARMACOLOGY （ELSEVIER SCIENCE BV） 11 （ 10 ） 1497 - 1503 2011年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1567-5769

Innate immunity is the front-line of self-defense against microbial infection. In mammals, innate immunity interacts with adaptive immunity and has a key role in the regulated immune response. From a pharmaceutical point of view, innate immunity is an ideal target for the development of immunoregulators. Therefore, we aimed to isolate and characterize a novel mammalian immunoregulator isolated from the thermophilic cellulotic fungus Talaromyces sp. 2'-(R)-hydroxy-C(24) phytoceramide (C(24)(2'OH)Phy) was isolated from Talaromyces sp. using a Drosophila ex vivo culture system. C(24)(2'OH)Phy suppressed the immune deficiency (IMD) pathway-dependent expression of antibacterial peptides in Drosophila, whereas it stimulated the production of chemokines in human cells. Structure activity relationship studies of C(24)(2'OH) Phy analogs revealed that both the 2'-(R)-hydroxylignoceroyl group and phytoceramide backbone are essential for the biologic activity of C(24)(2'OH)Phy. Microarray analysis revealed that C(24)(2'OH)Phy selectively activates the transcription of inflammatory response genes, including chemokines. Furthermore, a reporter gene assay and small interfering RNA analysis demonstrated that C(24)(2'OH)Phy stimulates chemokine production through cAMP response element-binding protein activation in human cells. C(24)(2'OH)Phy may be a lead immunostimulating compound in humans. (C) 2011 Elsevier B.V. All rights reserved.

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Structures of the Dimeric and Monomeric Chromanones, Gonytolides A-C, Isolated from the Fungus Gonytrichum sp and Their Promoting Activities of Innate Immune Responses

Haruhisa Kikuchi, Masato Isobe, Mizuki Sekiya, Yuko Abe, Tsuyoshi Hoshikawa, Kazunori Ueda, Shoichiro Kurata, Yasuhiro Katou, Yoshiteru Oshima

ORGANIC LETTERS （AMER CHEMICAL SOC） 13 （ 17 ） 4624 - 4627 2011年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1523-7060

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Antimicrobial and antioxidant properties of methanol extract, fractions and compounds from the stem bark of Entada abyssinica Stend ex A. Satabie

Gerald N. Teke, Paul K. Lunga, Hippolyte K. Wabo, Jules-Roger Kuiate, Gerard Vilarem, Geraldine Giacinti, Haruhisa Kikuchi, Yoshiteru Oshima

BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE （BIOMED CENTRAL LTD） 11 2011年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1472-6882

Background: The aim of this study was to evaluate the antimicrobial and antioxidant activities of the methanol extract, fractions and isolated compounds from Entada abyssinica stem bark, plant used traditionally against gastrointestinal infections.
Methods: The methanol extract of E. abyssinica stem bark was pre-dissolved in a mixture of methanol and water, and then partitioned between n-hexane, ethyl acetate and n-butanol. The ethyl acetate portion was fractionated by column chromatography and the structures of isolated compounds elucidated by analysis of spectroscopic data and comparison with literature data. Antimicrobial activity was assayed by broth microdilution techniques on bacteria and yeasts. The antioxidant activity was determined by DPPH radical scavenging method.
Results: Four known compounds [(5S,6R,8aR)-5-(carboxymethyl)-3,4,4a,5,6,7,8,8a-octahydro-5,6,8a-trimethylnaphthalenecarboxylic acid (1), methyl 3,4,5-trihydroxybenzoate (2), benzene-1,2,3-triol (3) and 2,3-dihydroxypropyltriacontanoate (4)] were isolated. Compared to the methanol extract, fractionation increased the antibacterial activities of the n-hexane and ethyl acetate fractions, while the antifungal activities increased in ethyl acetate, n-butanol and aqueous residue fractions. The isolated compounds were generally more active on bacteria (9.7 to 156.2 mu g/ml) than yeasts (78.1 to 312.5 mu g/ml). Apart from compound 1, the three others displayed DPPH(center dot) scavenging activity (RSa), with RSa(50) values of 1.45 and 1.60 mu g/ml.
Conclusion: The results obtained from this study support the ethnomedicinal use of E. abyssinica in the treatment of gastrointestinal infections and the isolated compounds could be useful in the standardisation of antimicrobial phytomedicine from this plant.

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Atg1 allows second-signaled autophagic cell death in Dictyostelium

Marie-Francoise Luciani, Corinne Giusti, Birthe Harms, Yoshiteru Oshima, Haruhisa Kikuchi, Yuzuru Kubohara, Pierre Golstein

AUTOPHAGY （LANDES BIOSCIENCE） 7 （ 5 ） 501 - 508 2011年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1554-8627

We investigated the role of Atg1 in autophagic cell death (ACD) in a Dictyostelium monolayer model. The model is especially propitious, not only because of genetic tractability and absence of apoptosis machinery, but also because induction of ACD requires two successive exogenous signals, first the combination of starvation and cAMP, second the differentiation factor DIF-1. This enables one to analyze separately first-signal-induced autophagy and subsequent second-signal-induced ACD. We used mutants of atg1, a gene that plays an essential role in the initiation of autophagy. Upon starvation/cAMP, in contrast to parental cells, atg1 mutant cells showed irreversible lesions, clearly establishing a protective role for Atg1. Upon subsequent exposure to DIF-1 or to more ACD-specific second signals, starved parental cells progressed to ACD, but starved atg1 mutant cells did not, showing that Atg1 was required for ACD. Thus, in the same cells Atg1 was required in two apparently opposite ways, upon first-signaling for cell survival and upon second-signaling for ACD. Our findings strongly suggest that Atg1, thus presumably autophagy, protects the cells from starvation-induced cell death, allowing subsequent induction of ACD by the second signal. ACD is therefore not only "with" autophagy (since it showed signs of autophagy throughout), but is also "allowed by" autophagy. This does not exclude a role for autophagy also after second signaling. These results may account for discrepancies reported in the literature, encourage searches for second signals in different developmental models of ACD, and incite caution in autophagy-related therapeutic attempts.

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Synthesis and innate immunosuppressive effect of 1,2-cyclopentanediol derivatives

Haruhisa Kikuchi, Kaori Okazaki, Mizuki Sekiya, Yasuyuki Uryu, Kazunori Ueda, Yasuhiro Katou, Shoichiro Kurata, Yoshiteru Oshima

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER） 46 （ 4 ） 1263 - 1273 2011年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0223-5234

Innate immunity is the front line of self-defense against infectious microorganisms. In mammals, innate immunity interacts with adaptive immunity and plays a key role in regulating the immune response. Therefore, innate immunity is a good pharmaceutical target for the development of immune regulators. After searching for natural substances that regulate innate immunity using an ex vivo Drosophila culture system, we identified a cyclopentanediol-type compound 1 as an immunosuppressor. In this study, we synthesized and evaluated 1 and its derivatives. Several methylamide- or phenylamide-containing derivatives showed effects that were 20-25 times more potent than those of 1. (c) 2011 Elsevier Masson SAS. All rights reserved.

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Derivatives of Dictyostelium differentiation-inducing factors promote mitogen-activated IL-2 production via AP-1 in Jurkat cells

Katsunori Takahashi, Masami Murakami, Haruhisa Kikuchi, Yoshiteru Oshima, Yuzuru Kubohara

LIFE SCIENCES （PERGAMON-ELSEVIER SCIENCE LTD） 88 （ 11-12 ） 480 - 485 2011年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0024-3205

Aims: Differentiation-inducing factors (DIFs) are chlorinated alkylphenones found in the cellular slime mold Dictyostelium discoideum. DIF derivatives exhibit antiproliferative activities and promote glucose consumption in mammalian cells in vitro. Here, we assessed the ability of DIFs to regulate the immune system in a mammalian cell-line and investigated their mechanisms of action.
Main methods: We examined the effects of 30 DIF derivatives on concanavalin A-induced interleukin-2 (IL-2) production (CIIP) in Jurkat T-cells. We also examined the effects of these DIF derivatives on the activity of three transcription factors required for CIIP: namely, activator protein-1 (AP-1), nuclear factor of activated T-cells (NFAT), and nuclear factor kappa B (NF kappa B).
Key findings: A reporter gene assay suggested that 2 DIF derivatives, termed DIF-1(+ 1) and DIF-3(3 M), significantly promoted CIIP in Jurkat cells, at least in part, by enhancing the activity of AP-1. These 2 DIF derivatives had no significant effect on concanavalin A-induced interferon-gamma production.
Significance: The results suggest that DIF derivatives could be developed as novel drugs for the activation of IL-2 production and resultant stimulation of the immune system. (C) 2011 Elsevier Inc. All rights reserved.

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Artificial Compounds Differentially Control Dictyostelium Chemotaxis and Cell Differentiation

Hidekazu Kuwayama, Haruhisa Kikuchi, Yoshiteru Oshima, Yuzuru Kubohara

CELL STRUCTURE AND FUNCTION （JAPAN SOC CELL BIOLOGY） 36 （ 1 ） 21 - 26 2011年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0386-7196

Differentiation- inducing factor-1 and -2 (DIF-1 and DIF-2) are small lipophilic signal molecules that control both cell differentiation and chemotaxis in the cellular slime mold Dictyostelium discoideum. In this study, we examined the effects of four amide derivatives of DIF-1 on stalk cell differentiation and chemotaxis. The DIF derivatives differentially affected cell differentiation and chemotaxis, suggesting the possible existence of at least three receptors for DIFs: one receptor responsible for stalk cell induction, and two receptors responsible for chemotaxis modulation. Furthermore, our results indicate that DIF derivatives can be utilized to analyze the DIF-signaling pathways.

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Inhibitory effect of hericenone B from Hericium erinaceus on collagen-induced platelet aggregation

Koichiro Mori, Haruhisa Kikuchi, Yutaro Obara, Masaya Iwashita, Yoshihito Azumi, Satomi Kinugasa, Satoshi Inatomi, Yoshiteru Oshima, Norimichi Nakahata

PHYTOMEDICINE （ELSEVIER GMBH, URBAN & FISCHER VERLAG） 17 （ 14 ） 1082 - 1085 2010年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0944-7113

Platelet aggregation in the blood vessel causes thrombosis. Therefore, inhibitors of platelet aggregation promise to be preventive or therapeutic agents of various vascular diseases, including myocardial infarction and stroke. In the present study, we found that hericenone B had a strong anti-platelet activity and it might be a novel compound for antithrombotic therapy possessing a novel mechanism. Prior to this study, we examined anti-platelet aggregation activity of ethanol extracts of several species of mushrooms, and found that extract of Hericium erinaceus potently inhibited platelet aggregation induced by collagen. Therefore, we first fractionated the ethanol extract of H. erinaceus to identify the active substances. The anti-platelet activity of each fraction was determined using washed rabbit platelets. As a result, an active component was isolated and identified as hericenone B. Hericenone B selectively inhibited collagen-induced platelet aggregation, but it did not suppress the aggregation induced by U46619 (TXA(2) analogue), ADP, thrombin, or adrenaline. Furthermore, hericenone B did not inhibit arachidonic acid- or convulxin (GPVI agonist)-induced platelet aggregation. Therefore, hericenone B was considered to block collagen signaling from integrin alpha 2/beta 1 to arachidonic acid release. Moreover, we found that collagen-induced aggregation was inhibited by hericenone B in human platelets, similar to in rabbit platelets. (C) 2010 Elsevier GmbH. All rights reserved.

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P-78 新規生物資源の開拓 : 昆虫寄生糸状菌と卵菌(ポスター発表の部)

菊地晴久, 佐藤雄一, 星朋子, 喜多山実, 関谷瑞樹, 礒辺真人, 三原健, 加藤泰弘, 倉田祥一朗, 大島吉輝, 久保原禅, 佐藤大樹, 島津光明

天然有機化合物討論会講演要旨集（天然有機化合物討論会）（ 52 ） 703 - 708 2010年09月

研究論文（学術雑誌）, 共著, 査読有り

Entomopathogenic fungi infect insects through the cuticle, grow as hyphal bodies or hyphae in the hemocoel, and cause host death by nutritional destruction of tissues, and producint toxic metabolites and pathogenic enzymes. To date, entomopathogenic fungi have not been extensively studied by natural product chemists. We focused on entomopathogenic fungi as new resources for biologically active compounds, and studied the diversity of their secondary metabolites. In this study, we show the isolation and structure elucidation of novel pyrone diterpene-type compounds, metarhizin A-H (1-8) from Metarhizium flavoviride, and their antiproliferative activities on human cancer cell lines. Additionally, we synthesized many metarhizin derivatives, evaluated their antiproliferative activities, and discuss the structural requirements for this activity. A novel pyrone diterpene-type compound, Nf-1 (9), was also isolated from Nectria flammea. Oomycetes from fungus-like mycelium and were calssified as fungi in the past. However, the cell walls of them are c omposed of cellulose rather than chitin, as in the fungi. In the present, the ultrastructure, biochemistry and molecular sequences of them indicate that the oomycetes belong to the Kingdom Chromista, not the Kingdom Fungi. We also focused on oomycetes as new resources for natural product chemistry. A new oxidized lanostane-type compound, St-1 (23), was isolated from the mycelium of oomycete Saprolegnia terrestris. The structure of 23 was determined by spectral means including EIMS, and ^1H and ^<13>C NMR.

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Novel prenylated and geranylated aromatic compounds isolated from Polysphondylium cellular slime molds

Haruhisa Kikuchi, Shinya Ishiko, Koji Nakamura, Yuzuru Kubohara, Yoshiteru Oshima

TETRAHEDRON （PERGAMON-ELSEVIER SCIENCE LTD） 66 （ 32 ） 6000 - 6007 2010年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0040-4020

We have studied the diversity of secondary metabolites of cellular slime molds to utilize them as new biological resources for natural product chemistry. From the methanol extract of fruiting bodies of Polysphondylium tenuissimum, we obtained five prenylated and geranylated aromatic compounds, Pt-1-5 (1-5). An additional aromatic compound, Ppc-1 (6), was isolated from Polysphondylium pseudo-candidum. The structures of these compounds were determined by spectral analysis, and synthetic routes to 4, 5, and 6 were developed. Compound 5 showed the glucose consumption-promotive activity on 3T3-L1 cells. (c) 2010 Elsevier Ltd. All rights reserved.

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Xanthones and a benzophenone from the roots of Pentadesma butyracea and their antiproliferative activity

Hippolyte K. Wabo, Haruhisa Kikuchi, Yasuhiro Katou, Pierre Tane, Yoshiteru Oshima

PHYTOCHEMISTRY LETTERS （ELSEVIER SCIENCE BV） 3 （ 2 ） 104 - 107 2010年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1874-3900

A new xanthone, 3,4-dihydro-8,10,12-trihydroxy-2,2-dimethylpyrano[2,3-b]xanthen-11(2H)-one or butyraxanthone E (1), along with the known compounds 30-epi-cambogin (2), 1,7-dihydroxyxanthone (3) and 1,5-dihydroxyxanthone (4) were isolated from the roots of Pentadesma butyracea. Their structures were elucidated by spectroscopic means and comparison with published data. Their antiproliferative activities were evaluated against Drosophila S2 cells and two human cancer cell lines, THP-1 (leukemia) and HCT116 (colon cancer). Compounds 1 and 2 showed moderate antiproliferative activity against Drosophila S2 cells and the HCT116 cell line, respectively. Compound 2 was active against Drosophila S2 cells. (C) 2010 Phytochemical Society of Europe. Published by Elsevier B. V. All rights reserved.

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Preparation of an antibody that recognizes and neutralizes Dictyostelium differentiation-inducing factor-1

Yuzuru Kubohara, Haruhisa Kikuchi, Koji Nakamura, Yusuke Matsuo, Yoshiteru Oshima

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS （ACADEMIC PRESS INC ELSEVIER SCIENCE） 396 （ 2 ） 364 - 369 2010年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-291X

In the development of the cellular slime mold Dictyostelium discoideum the differentiation-inducing factor-1 (DIF-1; 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one) plays an important role in the regulation of cell differentiation and chemotaxis; however, the cellular signaling systems involving DIF-1 remain to be elucidated. To obtain a probe for DIF-1, we synthesized a DIF derivative (DIF-1-NH(2); 6-amino-1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one), and prepared an anti-DIF-1 antibody using a DIF-1-NH(2)-conjugated macromolecule as the immunogen. A 100-fold dilution of the antibody bound to DIF-1-NH(2)-conjugated resin, and this binding was inhibited by co-addition of 20 mu M DIF-1 or DIF-1-NH(2). In a monolayer culture of HM44 cells, a DIF-deficient D. discoideum strain, 0.5 nM exogenous DIF-1 induced stalk cell formation in similar to 60% of the cells; this induction was dose-dependently inhibited by the antibody (diluted 12.5- or 25-fold). Furthermore, this inhibition by the antibody was recovered by co-addition of 2.5 or10 nM DIF-1. The results indicate that the anti-DIF-1 antibody recognizes DIF-1 and neutralizes its function. (C) 2010 Elsevier Inc. All rights reserved.

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Antimycobacterial Flavonoids from the Leaf Extract of Galenia africana

Sannah P. N. Mativandlela, Tshilidzi Muthivhi, Haruhisa Kikuchi, Yoshiteru Oshima, Chris Hamilton, Ahmed A. Hussein, Martha L. van der Walt, Peter J. Houghton, Namrita Lall

JOURNAL OF NATURAL PRODUCTS （AMER CHEMICAL SOC） 72 （ 12 ） 2169 - 2171 2009年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0163-3864

The bioassay-guided fractionation of the EtOH extract of the leaves of Galenia africana led to the isolation of three known flavonoids, (2S)-5,7,2'-trihydroxyflavanone (1), (E)-3,2',4'-trihydroxychalcone (2), and (E)-2',4'-dihydroxychalcone (3), and the new (E)-3,2',4'-trihydroxy-3'-methoxychalcone (4). Compounds 1 and 3 exhibited moderate antituberculosis activity. During synergistic studies, a combination of compound 4 and an existing antituberculosis drug, isoniazid, reduced their original MICs 4-fold, resulting in a fractional inhibitory concentration of 0.50. The most pronounced effect was demonstrated by compound I and isoniazid reducing their MICs 16-fold and resulting in an FIC of 0.12. Both EtOH extract and isolated compounds failed to exhibit any NADPH oxidase activity at 800.0 mu M concentrations, indicating that mycothiol disulfide reductase is not the target for their antituberculosis activity.

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P-26 天然資源からの自然免疫制御物質の探索(ポスター発表の部)

菊地晴久, 関谷瑞樹, 礒辺真人, 壁谷尚宏, 中村哲也, 上田和則, 加藤泰弘, 倉田祥一朗, 大島吉輝

天然有機化合物討論会講演要旨集（天然有機化合物討論会）（ 51 ） 545 - 550 2009年09月

研究論文（学術雑誌）, 共著, 査読有り

Innate immunity is the first line of defense against infectious microorganisms, and the basic mechanisms of this process, including pathogen recognition and immune response activation, are evolutionarily conserved. In mammals, the innate immunity has an instructive role in the adaptive immune response specific to antigen by inducing co-stimulatory molecules and cytokines, indicating that a concerted and interactive innate and adaptive immune reaction is key for the regulated immune response. Therefore, from a pharmaceutical point of view, innate immunity is a good target for the development of immune regulators to suppress unwanted immune responses, such as septic shock, inflammatory diseases and autoimmunity, and to stimulate protective immune responses to some of the disease that largely elude the immune system, such as infectious diseases and cancer. To screen pharmaceuticals that target innate immunity, we established an ex vivo culture system based on the innate immune response of Drosophila, which is highly useful for idintifying immune regulators that act on human innate immunity. We used this system to search for natural substances that regulate innate immunity, and identified celastramycin A (1) and TP-554 (2) as a potent suppressor and an activator, respectively. The previously reported structure 3 for celastramycin A was corrected to 1 by synthesizing both compounds. In addition, we synthesized some derivatives of celastramycin A (1) to evaluate structure-activity relationship of these compounds.

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Regulation of IL-2 production in Jurkat cells by Dictyostelium-derived factors

Katsunori Takahashi, Masami Murakami, Kohei Hosaka, Haruhisa Kikuchi, Yoshiteru Oshima, Yuzuru Kubohara

LIFE SCIENCES （PERGAMON-ELSEVIER SCIENCE LTD） 85 （ 11-12 ） 438 - 443 2009年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0024-3205

Aims: Differentiation-inducing factors (DIFs) are chlorinated alkylphenones found in the cellular slime mold Dictyostelium discoideum. DIF derivatives exhibit anti proliferative activities and promote glucose consumption in mammalian cells in vitro. In this study, we assessed the ability of DIFs to regulate the immune system and investigated their mechanisms of action.
Main methods: We examined the effects of 30 DIF derivatives on concanavalin A-induced IL-2 production (CIIP) in Jurkat T-cells. We also examined the effects of some DIF derivatives on the activity of AP-1 (activator protein-1), NFAT (nuclear factor of activated T-cells), and NF kappa B (nuclear factor kappa B), which are transcription factors required for CIIP.
Key findings: Of the derivatives tested, some compounds suppressed CIIP as well as the known immunosuppressants cyclosporine A and FK506. A reporter gene assay revealed that 4 DIF derivatives tested suppressed CHIP, at least in part, by inhibiting the activity of AP-1, NFAT, and/or NF kappa B. Unlike cyclosporine A and FK506, the DIF derivatives had little effect on concanavalin A-induced interferon-gamma production in Jurkat cells.
Significance: The present results suggest that DIF derivatives could be developed as novel immunosuppressive drugs. (C) 2009 Elsevier Inc. All rights reserved.

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A reduction of epidermal growth factor receptor is involved in brefelamide-induced inhibition of phosphorylation of ERK in human astrocytoma cells

Shigeyoshi Honma, Masaki Saito, Haruhisa Kikuchi, Yoshinori Saito, Yoshiteru Oshima, Norimichi Nakahata, Makoto Yoshida

EUROPEAN JOURNAL OF PHARMACOLOGY （ELSEVIER SCIENCE BV） 616 （ 1-3 ） 38 - 42 2009年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0014-2999

Brefelamide is an aromatic amide isolated from Dictyostelium cellular slime molds. We found that brefelamide has a potent inhibitory growth effect measured by MTT assay in 1321N1 human astrocytoma cells. The inhibition was associated with reduced phosphorylation of extracellular signal-regulated kinase (ERK). Brefelamide inhibited epidermal growth factor (EGF)-induced phosphorylation of ERK in a concentration-dependent manner. Furthermore, brefelamide diminished EGF-induced phosphorylation of EGF receptor at Tyr(1068), a Grb2 binding site that leads to an activation of the Ras/Raf/ERK system. Brefelamide also reduced the expression level of the EGF receptor. These results suggest that one of the mechanisms of action of brefelamide is assumed to be inhibition of phosphorylation of ERK through a reduction of EGF receptor activity in 1321 NI human astrocytoma cells. (C) 2009 Elsevier B.V. All rights reserved.

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Revised Structure and Synthesis of Celastramycin A, A Potent Innate Immune Suppressor

Haruhisa Kikuchi, Mizuki Sekiya, Yasuhiro Katou, Kazunori Ueda, Takahiro Kabeya, Shoichiro Kurata, Yoshiteru Oshima

ORGANIC LETTERS （AMER CHEMICAL SOC） 11 （ 8 ） 1693 - 1695 2009年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1523-7060

After searching for natural substances that regulate innate immunity using the ex vivo Drosophila culture system, a benzoyl pyrrole-type compound, celastramycin A, was identified and isolated as a potent suppressor. By synthesizing the previously reported structure 1 and another benzoyl pyrrole-type compound 2 reported in a Japanese patent, the correct structure of celastramycin A was confirmed to be 2. Compound 2 suppressed the production of IL-8 (IC(50) 0.06 mu g/mL) in human umbilical vein endothelial cells (HUVECs).

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