研究者詳細 - 菊地　晴久

論文 - 菊地　晴久

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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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Autophagic or necrotic cell death triggered by distinct motifs of the differentiation factor DIF-1

M. F. Luciani, Y. Kubohara, H. Kikuchi, Y. Oshima, P. Golstein

CELL DEATH AND DIFFERENTIATION （NATURE PUBLISHING GROUP） 16 （ 4 ） 564 - 570 2009年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1350-9047

Autophagic or necrotic cell death (ACD and NCD, respectively), studied in the model organism Dictyostelium which offers unique advantages, require triggering by the same differentiation-inducing factor DIF-1. To initiate these two types of cell death, does DIF-1 act through only one or through two distinct recognition structures? Such distinct structures may recognize distinct motifs of DIF-1. To test this albeit indirectly, DIF-1 was modified at one or two of several positions, and the corresponding derivatives were tested for their abilities to induce ACD or NCD. The results strongly indicated that distinct biochemical motifs of DIF-1 were required to trigger ACD or NCD, and that these motifs were separately recognized at the onset of ACD or NCD. In addition, both ACD and NCD were induced more efficiently by DIF-1 than by either its precursors or its immediate catabolite. These results showed an unexpected relation between a differentiation factor, the cellular structures that recognize it, the cell death types it can trigger and the metabolic state of the cell. The latter seems to guide the choice of the signaling pathway to cell death, which in turn imposes the cell death type and the recognition pattern of the differentiation factor.

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Peltophorum Africanum, a Traditional South African Medicinal Plant, Contains an Anti HIV-1 Constituent, Betulinic Acid

Andros Theo, Tracy Masebe, Yasuhiro Sijzuki, Haruhisa Kikuchi, Shoko Wada, Chikwelu Larry Obi, Pascal Obong Bessong, Motoki Usuzawa, Yoshiteru Oshima, Toshio Hattori

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE （TOHOKU UNIV MEDICAL PRESS） 217 （ 2 ） 93 - 99 2009年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0040-8727

The biodiversity of medicinal plants in South Africa makes them rich sources of leading compounds for the development of novel drugs. Peltophorum africanum (Fabaceae) is a deciduous tree widespread in South Africa. The stem bark has been traditionally employed to treat diarrhoea, dysentery, sore throat, wounds, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), venereal diseases and infertility. To evaluate these ethnobotanical clues and isolate lead compounds, butanol and ethyl acetate extracts of the stem bark were screened for their inhibitory activities against HIV-1 using MAGI CCR5+ cells, which are derived from HeLa cervical cancer cells and express HIV receptor CD4, a chemokine receptor CCR5 and HIV-LTR-/3- galactosidase. Bioassay-guided fractionation using silica gel chromatography was also conducted. The ethyl acetate and butanol extracts of the stem bark of Peltophorum africanum showed inhibitory activity against HIV-1, CXCR4 (X4) and CCR5 (R5) tropic viruses. The ethyl acetate and butanol extracts yielded previously reported anti-HIV compounds, (+)-catechin, a flavonoid, and bergenin, a C-galloylglycoside, respectively. Furthermore, we identified betulinic acid from the ethyl acetate fraction for the first time. The fractions, which contained betulinic acid, showed the highest selective index. We therefore describe the presence of betulinic acid, a not well-known anti-HIV compound, in an African medicinal herb, which has been used for therapy, and claim that betulinic acid is the predominant anti-HIV-1 constituent of Peltophorum africanum. These data suggest that betulinic acid and its analogues could be used as potential therapeutics for HIV-1 infection.

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New diterpene pyrone-type compounds, metarhizins A and B, isolated from entomopathogenic fungus, Metarhizium flavoviride and their inhibitory effects on cellular proliferation

Haruhisa Kikuchi, Tomoko Hoshi, Minoru Kitayama, Mizuki Sekiya, Yasuhiro Katou, Kazunori Ueda, Yuzuru Kubohara, Hiroki Sato, Mitsuaki Shimazu, Shoichiro Kurata, Yoshiteru Oshima

TETRAHEDRON （PERGAMON-ELSEVIER SCIENCE LTD） 65 （ 2 ） 469 - 477 2009年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0040-4020

To date, entomopathogenic fungi have not been extensively examined by natural product chemists. In this study, we isolated novel pyrone diterpene-type compounds, metarhizins A (1) and B (2), from methanol extracts of entomopathogenic fungus, Metarhizium flavoviride. They showed potent and selective antiproliferative activity against both insect and human cancer cell lines. These results indicate that metarhizins A (1) and B (2) can be used as novel lead compounds for anti-cancer agents and probes for cell cycle regulation. To further investigate the structural requirements for this inhibitory activity, we synthesized many metarhizin derivatives and evaluated their antiproliferative activities. (C) 2008 Elsevier Ltd. All rights reserved.

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Biological activities of novel derivatives of DIF-1 isolated from Dictyostelium

Haruhisa Kikuchi, Shinya Ishiko, Yoshiteru Oshima, Naomi Gokan, Kohei Hosaka, Yuzuru Kubohara

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS （ACADEMIC PRESS INC ELSEVIER SCIENCE） 377 （ 3 ） 1012 - 1017 2008年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-291X

The differentiation-inducing factor-1 (DIF-1) is a lipophilic signal molecule (chlorinated alkylphenone) that induces stalk cell differentiation in the cellular slime mold Dictyostelium discoideum. in addition, DIF-1 and its derivatives have been shown to possess anti-leukemic activity and glucose Consumption-promoting activity in vitro in mammalian cells. In this study. to assess the chemical structure-effect relationship of DIF-1, we synthesized eight derivatives of DIF-1 and investigated their stalk cell-inducing activity in Dictyostelium cells and pharmacological activities in mammalian cells. Of the derivatives, two amide derivatives of DIF-1, whose hydrophobic indexes are close to that of DIF-1. induced stalk cell differentiation as strongly as DIF-1 in Dictyostelium cells. It Was also found that some derivatives Suppressed cell growth in human K562 leukemia cells and promoted glucose consumption in mouse 3T3-L1 cells. These results give LIS valuable information as to the chemical structure-effect relationship of DIF-1. (C) 2008 Elsevier Inc. All rights reserved.

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Exploitation of the derivatives of Dictyostelium differentiation-inducing factor-1, which promote glucose consumption in mammalian cells

Yuzuru Kubohara, Haruhisa Kikuchi, Yoshiteru Oshima

LIFE SCIENCES （PERGAMON-ELSEVIER SCIENCE LTD） 83 （ 17-18 ） 608 - 612 2008年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0024-3205

Aims: The differentiation-inducing factor-1 (DIF-1) is a signal molecule that induces stalk cell formation in the cellular slime mold Dictyostelium discoideum. DIF-1 has also been shown to possess pharmacological activities, such as the suppression of tumor cell growth and the promotion of glucose uptake in non-transformed mammalian cells. In this study, we tried to develop compounds that possess weaker anti-tumor activity and stronger glucose uptake-promoting activity than DIF-1.
Main methods: We investigated the in Vitro effects of 12 derivatives of DIF-1 on glucose consumption in mouse 3T3-L1 cells and on cell growth in K562 human leukemia cells. We also examined the effect of a good compound oil the blood glucose concentration in KK-Ay diabetic mice.
Key findings: We found that some derivatives at 20 mu M promoted glucose consumption more than twice as fast as the control. Of the derivatives, a compound named DIF-1(3M), which has a weaker anti-leukemic effect than DIF-1, promoted glucose consumption as strongly as DIF-1 in confluent 3T3-L1 cells. While DIF-1 at 20 mu M was inhibitory to the cell growth of 3T3-L1, DIF-1(3M) at 20 mu M exhibited no inhibitory effect on the growing cells. We also found that DIF-1(3M) injected (10-12.5 mg/kg body weight) intraperitoneally in mice tended to lower the blood glucose concentration.
Significance: The present results open the possibility for the development of new agents that possess strong glucose-Uptake-promoting activity but little anti-tumor activity and may have therapeutic potential for the treatment of diabetes and/or obesity. (C) 2008 Elsevier Inc. All rights reserved.

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Satratoxin H generates reactive oxygen species and lipid peroxides in PC12 cells

Punnee Nusuetrong, Thitima Pengsuparp, Duangdeun Meksuriyen, Masaaki Tanitsu, Haruhisa Kikuchi, Michinao Mizugaki, Ken-ichi Shimazu, Yoshiteru Oshima, Norimichi Nakahata, Makoto Yoshida

BIOLOGICAL & PHARMACEUTICAL BULLETIN （PHARMACEUTICAL SOC JAPAN） 31 （ 6 ） 1115 - 1120 2008年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-6158

Satratoxin H, a mycotoxin, is thought to induce apoptosis of PC12 cells through the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) in a glutathione (GSH)-sensitive manner. The present study was undertaken to further elucidate the mechanism by which satratoxin H induces cell death in PC12 cells. Satratoxin H caused apoptosis of PC12 cells within 24-h, as determined by DNA fragmentation and flow cytometric analysis. Satratoxin H increased reactive oxygen species (ROS) production and lipid peroxidation, as determined by malondialdehyde formation. These effects were attenuated by incubation of cells with GSH, suggesting that satratoxin H-induced increase in apoptosis of serum-deprived PC12 cells may be partially mediated through the generation of ROS.

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A cyclopentanediol analogue selectively suppresses the conserved innate immunity pathways, Drosophila IMD and TNF-α pathways.

Mizuki Sekiya, Kazunori Ueda, Kaori Okazaki, Haruhisa Kikuchi, Shoichiro Kurata, Yoshiteru Oshima

Biochemical Pharmacology （PERGAMON-ELSEVIER SCIENCE LTD） 75 （ 11 ） 2165 - 2174 2008年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-2952

Innate immunity comprises evolutionarily conserved self-defense mechanisms against microbial infections. In mammals, innate immunity interacts with adaptive immunity and has a key role in the regulated immune response. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Using Drosophila ex vivo culture systems, we isolated a cyclopentanediol analogue from Aspergillus sp. as an immunosuppressive substance. This compound selectively suppressed activation of the IMD pathway in Drosophila in vivo and the target molecules of the compound lie between the Imd adaptor protein and dTAK1 kinase in the IMD pathway. In human cells, the compound suppressed TNF-alpha, but not IL-1 beta, stimulation-induced activation of NF-kappa B, suggesting that its target molecules are upstream of TAK1 in mammalian innate immunity. (C) 2008 Elsevier Inc. All rights reserved.

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5,19-cyclo-9β,10ξ-androstane-3,17-dione promotes neurotrophic factor biosynthesis in 1321N1 human astrocytoma cells and improves passive avoidance learning impairment.

Yutaro Obara, Asami Haganuma, Shinsuke Murakami, Toshiki Chiba, Koichiro Mori, Osamu Nakagawasai, Takeshi Tadano, Haruhisa Kikuchi, Yoshiteru Oshima, Norimichi Nakahata

Brain Research （ELSEVIER SCIENCE BV） 1184 （ 1 ） 57 - 64 2007年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-8993

Since neurotrophic factors are essential for neurons to form neuronal networks and maintain neuronal functions, neurotrophic factor-like substances or inducers of neurotrophic factors can be useful for the treatment of serious neuronal diseases such as Alzheimer's and Parkinson's diseases. In the present study, we examined an effect of 5,19-cyclo-9 beta,10 xi-androstane-3,17-dione (CAD) on neurotrophic factor synthesis in glial cells and scopolamine-induced impairment of learning in mice. 1321N1 human astrocytoma cells promoted secretion of certain neurotrophic factors in response to CAD with no cytotoxicity, which caused dramatic neurite outgrowth in rat pheochromocytoma (PC12) cells. In fact, CAD significantly enhanced nerve growth factor (NGF) secretion and its gene expression in 1321N1 cells, in a time and concentration-dependent manner. Because second messengers such as cAMP, inositol 1,4,5-trisphosphates and Ca2+ induce NGF gene expression, we measured activities of adenylyl cyclase and phospholipase C and intracellular Ca2+ concentration in 1321N1 cells. However, CAD changed neither second messenger levels. CAD enhanced the gene expression of proto-oncogene, c-fos that is one of the components of transcription factor (AP-1). In addition to those above, the in vivo effects of CAD were also examined. Although injection of muscarinic receptor antagonist scopolamine impaired passive avoidance learning in mice, pretreatment with CAD significantly reversed the adverse effect in a dose-dependent manner. Taking these results together, CAD has enormous therapeutic potential for serious neuronal diseases. (C) 2007 Elsevier B.V. All rights reserved.

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Dihydrodictyopyrone A and C: new members of dictyopyrone family isolated from Dictyostelium cellular slime molds

Haruhisa Kikuchi, Koji Nakamura, Yuzuru Kubohara, Naomi Gokan, Kohel Hosaka, Yasuo Maeda, Yoshiteru Oshima

TETRAHEDRON LETTERS （PERGAMON-ELSEVIER SCIENCE LTD） 48 （ 33 ） 5905 - 5909 2007年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0040-4039

We have explored the diversity of secondary metabolites produced by cellular slime molds to evaluate if they are valuable resources for biologically potential substances. From the methanol extract of fruiting bodies of Dicillosteliumfirinibasis, we obtained new alpha-pyranoids, dihydrodictyopyrone A (1) and C (2). Their structures including absolute configurations were determined by spectyal means and asymmetric total synthesis. Compounds I and 2 are new members of the dictyopyrone family, which are characteristic secondary metabolites of various species of Dictyostelillin cellular slime molds. (c) 2007 Elsevier Ltd. All rights reserved.

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Dictyostelium differentiation-inducing factor-1 induces glucose transporter 1 translocation and promotes glucose uptake in mammalian cells

Waka Omata, Hiroshi Shibata, Masahiro Nagasawa, Itaru Kojima, Haruhisa Kikuchi, Yoshiteru Oshima, Kohei Hosaka, Yuzuru Kubohara

FEBS JOURNAL （BLACKWELL PUBLISHING） 274 （ 13 ） 3392 - 3404 2007年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1742-464X

The differentiation-inducing factor-1 (DIF-1) is a signal molecule that induces stalk cell formation in the cellular slime mold Dictyostelium discoideum, while DIF-1 and its analogs have been shown to possess antiproliferative activity in vitro in mammalian tumor cells. In the present study, we investigated the effects of DIF-1 and its analogs on normal (nontransformed) mammalian cells. Without affecting the cell morphology and cell number, DIF-1 at micromolar levels dose-dependently promoted the glucose uptake in confluent 3T3-L1 fibroblasts, which was not inhibited with wortmannin or LY294002 (inhibitors for phosphatidylinositol 3-kinase). DIF-1 affected neither the expression level of glucose transporter 1 nor the activities of four key enzymes involved in glucose metabolism, such as hexokinase, fluctose 6-phosphate kinase, pyruvate kinase, and glucose 6-phosphate dehydrogenase. Most importantly, stimulation with DIF-1 was found to induce the translocation of glucose transporter 1 from intracellular vesicles to the plasma membranes in the cells. In differentiated 3T3-L1 adipocytes, DIF-1 induced the translocation of glucose trasporter 1 (but not of glucose transporter 4) and promoted glucose uptake, which was not inhibited with wortmannin. These results indicate that DIF-1 induces glucose transporter 1 translocation and thereby promotes glucose uptake, at least in part, via a inhibitors for phosphatidylinositol 3-kinase/Akt-independent pathway in mammalian cells. Furthermore, analogs of DIF-1 that possess stronger antitumor activity than DIF-1 were less effective in promoting glucose consumption, suggesting that the mechanism of the action of DIF-1 for stimulating glucose uptake should be different from that for suppressing tumor cell growth.

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MalariaCount: An image analysis-based program for the accurate determination of parasitemia

Selena W. S. Sio, Weiling Sun, Saravana Kumar, Wong Zeng Bin, Soon Shan Tan, Sim Heng Ong, Haruhisa Kikuchi, Yoshiteru Oshima, Kevin S. W. Tan

JOURNAL OF MICROBIOLOGICAL METHODS （ELSEVIER SCIENCE BV） 68 （ 1 ） 11 - 18 2007年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0167-7012

Malaria is a serious global health problem and rapid, precise determination of parasitemia is necessary for malaria research and in clinical settings. Manual counting by light microscopy is the most widely used technique for parasitemia determination but it is a time-consuming and laborious process. The aim of our study was to develop an automated image analysis-based system for the rapid and accurate determination of parasitemia. We have developed, for the first time, a software, MalariaCount, that automatically generates parasitemias from images of Giemsa-stained blood smears. The potential application and robustness of MalariaCount was tested in normal and drug-treated in vitro cultures of Plasmodium falciparum. The results showed a tight correlation between MalariaCount and manual count parasitemia values. These findings suggest that MalariaCount can potentially be used as a tool to provide rapid and accurate determination of parasitemia in research laboratories where frequent, large-scale, efficient determination of parasitemia is required. (c) 2006 Elsevier B.V. All rights reserved.

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Anti-leukemic activities of Dictyostelium secondary metabolites: A novel aromatic metabolite, 4-methyl-5-n-pentylbenzene-1,3-diol, isolated from Dictyostelium mucoroides suppresses cell growth in human leukemia K562 and HL-60 cells

Haruhisa Kikuchi, Yoshiteru Oshima, Aya Ichimura, Naomi Gokan, Aiko Hasegawa, Kohei Hosaka, Yuzuru Kubohara

LIFE SCIENCES （PERGAMON-ELSEVIER SCIENCE LTD） 80 （ 2 ） 160 - 165 2006年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0024-3205

It has previously been shown that DIF-1, a differentiation-inducing factor of the cellular slime mold Dictyostelium discoideum, possesses antitumor activities in mammalian tumor cells and that neuronal differentiation of PC12 cells can be induced with furanodictines (FDs), aminosugar analogs found in D. discoideum, or dictyoglucosamines (DGs), N-acetyl glucosamine derivatives (DG-A from D. purpureum and DG-B from D. discoideum). Thus, cellular slime molds are attractive natural resources that may provide valuable lead compounds to be utilized in the field of pharmacology and medicine. In this study, we have isolated a novel aromatic compound, 4-methyl-5-n-pentylbenzene-1,3-diol (MPBD), from fruiting bodies of the cellular slime mold D. mucoroides and assessed the in vitro antiproliferative activities of MPBD, FDs, and DGs in human leukemia K562 and HL-60 cells. MPBD at 20-80 mu M dose-dependently suppressed cell growth in both K562 and HL-60 cells. While FDs at 10-80 mu M did not affect cell growth, DGs at 10-40 mu M dose-dependently suppressed cell growth in the cells. Although we failed to find the roles of FDs and DGs in the original organisms, MPBD at 5-20 mu M was found to promote stalk cell formation in D. discoideum. The present results indicate that MPBD, DGs or their derivatives may have therapeutic potential in the treatment of cancer and confirm our expectations regarding cellular slime molds as drug resources. (c) 2006 Elsevier Inc. All rights reserved.

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Establishment of ex vivo systems to identify compounds acting on innate immune responses and to determine their target molecules using transgenic Drosophila

Mizuki Sekiya, Kazunori Ueda, Tomomitsu Fujita, Minoru Kitayama, Haruhisa Kikuchi, Yoshiteru Oshima, Shoichiro Kurata

LIFE SCIENCES （PERGAMON-ELSEVIER SCIENCE LTD） 80 （ 2 ） 113 - 119 2006年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0024-3205

Innate immunity is an evolutionarily conserved self-defense mechanism against microbial infections. In Drosophila, induction of antimicrobial peptides is a major immune response that is regulated by two distinct signaling pathways called the IMD pathway and the Toll pathway, similar to the tumor necrosis factor-alpha signaling and Toll-like receptor/interleukin-1 signaling pathways, respectively, in mammals. In mammals, innate immunity interacts with adaptive immunity and has a key role in the regulated immune response. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Previously, based on the striking conservation between the mechanisms that regulate Drosophila immunity and human innate immunity, we established an ex vivo culture in which compounds acting on innate immunity can be evaluated using a reporter gene that reflects activation of the IMD pathway [Yajima et al. [Yajima, M., Takada, M., Takahashi, N., Kikuchi, H., Natori, S., Oshima, Y., Kurata, S., 2003. A newly established in vitro culture using transgenic Drosophila reveals functional coupling between the phospholipase A2-generated fatty acid cascade and lipopolysaccharide-dependent activation of the immune deficiency (imd) pathway in insect immunity. The Biochemical Journal 37 1 (Pt 1), 205-210] Biochem J 371, 205-210]. Here, we combined the ex vivo culture with a reporter gene that reflects the heat shock response and demonstrated that the resulting systems are useful for screening compounds that act specifically on innate immunity, including mammalian innate immune responses. Identification of target molecules is essential for the development of more potent medicines with fewer side effects. In this study, we also established ex vivo systems capable of identifying target molecules of the identified compounds using targeted activation of the IMD pathway. (c) 2006 Elsevier Inc. All rights reserved.

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Isolation of Cholest-5-en-3-ol formate from the red alga Grateloupia turuturu Yamada and its chemotaxonomic significance

Erwan Plouguerne, Haruhisa Kikuchi, Yoshiteru Oshima, Eric Deslandes, Valerie Stiger-Pouvreau

BIOCHEMICAL SYSTEMATICS AND ECOLOGY （PERGAMON-ELSEVIER SCIENCE LTD） 34 （ 9 ） 714 - 717 2006年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0305-1978

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Exploration of a new type of antimalarial compounds based on febrifugine

Haruhisa Kikuchi, Keisuke Yamamoto, Seiko Horoiwa, Shingo Hirai, Ryota Kasahara, Norimitsu Hariguchi, Makoto Matsumoto, Yoshiteru Oshima

JOURNAL OF MEDICINAL CHEMISTRY （AMER CHEMICAL SOC） 49 （ 15 ） 4698 - 4706 2006年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-2623

Febrifugine (1), a quinazoline alkaloid, isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. The use of 1 as an antimalarial drug has been precluded because of side effects, such as diarrhea, vomiting, and liver toxicity. However, the potent antimalarial activity of 1 has stimulated medicinal chemists to pursue compounds derived from 1, which may be valuable leads for novel drugs. In this study, we synthesized a new series of febrifugine derivatives formed by structural modifications at (i) the quinazoline ring, (ii) the linker, or (iii) the piperidine ring. Then, we evaluated their antimalarial activities. Thienopyrimidine analogue 15 exhibited a potent antimalarial activity and a high therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good antimalarial candidate.

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Isolation and synthesis of a new aromatic compound, brefelamide, from Dictyostelium cellular slime molds and its inhibitory effect on the proliferation of astrocytoma cells

H Kikuchi, Y Saito, J Sekiya, Y Okano, M Saito, N Nakahata, Y Kubohara, Y Oshima

JOURNAL OF ORGANIC CHEMISTRY （AMER CHEMICAL SOC） 70 （ 22 ） 8854 - 8858 2005年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-3263

We have explored the diversity of secondary metabolites produced by cellular slime molds to examine the possible use of such cellular slime molds as a resource for novel drug development. A new aromatic amide, brefelamide (1), was isolated from methanol extracts of the fruiting bodies of Dictyostelium brefeldianum and D. giganteum. The structure of 1 was determined by spectral means including EIMS and H-1 and C-13 NMR. The total synthesis of 1 was carried out to confirm the structure and obtain sufficient samples for performing biological evaluation. Interestingly, compound 1 inhibited the cellular proliferation of 1321N1 human astrocytoma cells.

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Structural requirements of Dictyostelium differentiation-inducing factors for their stalk-cell-inducing activity in Dictyostelium cells and anti-proliferative activity in K562 human leukemic cells

N Gokan, H Kikuchi, K Nakamura, Y Oshima, K Hosaka, Y Kubohara

BIOCHEMICAL PHARMACOLOGY （PERGAMON-ELSEVIER SCIENCE LTD） 70 （ 5 ） 676 - 685 2005年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-2952

The differentiation-inducing factor-1 (DIF-1) is a lipophilic signal molecule (chlorinated alkylphenone) that induces stalk-cell differentiation in the cellular slime mould Dictyostelium discoideum. It has also been shown that DIF-1 and its derivative (DIF-3) suppress cell growth in mammalian tumor cells. In the present study, in order to assess the chemical structure-effect relationship of DIF derivatives and to develop useful agents for the study of both Dictyostelium development and cancer biology, we synthesized 28 analogues of DIF-1 and DIF-3 and investigated their stalk-cell-inducing activity in Dictyostelium HM44 cells (mutant strain) and anti-proliferative activity in human leukemia K562 cells. HM44 cells are defective in endogenous DIF-1 production and should be suitable for the assay for stalk-cell-inducing activity of DIF analogues. DIF-1 and some of its derivatives at nanomolar levels were good stalk-cell inducers in HM44 cells, whereas DIF-3 and some DIF-3 derivatives at micromolar levels were potent anti-proliferative agents in K562 cells. We also tried to search for antagonistic molecules against DIF-1 and DIF-3 but failed to find such molecules from the analogues used here. The present findings would give us hints for identifying the target molecule(s) of DIFs and also for developing novel anti-cancer drugs. (c) 2005 Elsevier Inc. All rights reserved.

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