研究者詳細 - 菊地　晴久

論文 - 菊地　晴久

分割表示 133 件中 61 - 80 件目／全件表示 >>

Weight Loss by Ppc-1, a Novel Small Molecule Mitochondrial Uncoupler Derived from Slime Mold

Toshiyuki Suzuki, Haruhisa Kikuchi, Masato Ogura, Miwako K. Homma, Yoshiteru Oshima, Yoshimi Homma

PLOS ONE （PUBLIC LIBRARY SCIENCE） 10 （ 2 ） 2015年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1932-6203

Mitochondria play a key role in diverse processes including ATP synthesis and apoptosis. Mitochondrial function can be studied using inhibitors of respiration, and new agents are valuable for discovering novel mechanisms involved in mitochondrial regulation. Here, we screened small molecules derived from slime molds and other microorganisms for their effects on mitochondrial oxygen consumption. We identified Ppc-1 as a novel molecule which stimulates oxygen consumption without adverse effects on ATP production. The kinetic behavior of Ppc-1 suggests its function as a mitochondrial uncoupler. Serial administration of Ppc-1 into mice suppressed weight gain with no abnormal effects on liver or kidney tissues, and no evidence of tumor formation. Serum fatty acid levels were significantly elevated in mice treated with Ppc-1, while body fat content remained low. After a single administration, Ppc-1 distributes into various tissues of individual animals at low levels. Ppc-1 stimulates adipocytes in culture to release fatty acids, which might explain the elevated serum fatty acids in Ppc-1-treated mice. The results suggest that Ppc-1 is a unique mitochondrial regulator which will be a valuable tool for mitochondrial research as well as the development of new drugs to treat obesity.

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Synthesis of prenylated quinolinecarboxylic acid derivatives and their anti-obesity activities

Haruhisa Kikuchi, Toshiyuki Suzuki, Masato Ogura, Miwako K. Homma, Yoshimi Homma, Yoshiteru Oshima

BIOORGANIC & MEDICINAL CHEMISTRY （PERGAMON-ELSEVIER SCIENCE LTD） 23 （ 1 ） 66 - 72 2015年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0968-0896

Mitochondrial uncoupling is one of the therapeutic strategies used to control energy metabolism in various metabolic diseases and in obesity. Ppc-1 (1), a prenylated quinolinecarboxylic acid isolated from cellular slime molds, shows uncoupling activity in vitro and anti-obesity activity in vivo. In this study, we synthesized Ppc-1 (1) and its derivatives, and revealed the structure-activity relationship of uncoupling activities. The triprenylated compound 18 showed mitochondrial uncoupling activity that was more potent than that of Ppc-1 (1). Compound 18 also suppressed weight gain in mice without undesired effects such as lesions on tissues. These results indicate that compound 18 could be used as a seed compound for new anti-obesity drugs. (C) 2014 Elsevier Ltd. All rights reserved.

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A Derivative of Differentiation-Inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation.

Oladimeji P, Kubohara Y, Kikuchi H, Oshima Y, Rusch C, Skerl R, Diakonova M

International journal of cancer and clinical research 2 （ 3 ） 1 - 6 2015年

研究論文（学術雑誌）, 共著, 査読有り

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

Vitul Jain, Haruhisa Kikuchi, Yoshiteru Oshima, Amit Sharma, Manickam Yogavel

Journal of Structural and Functional Genomics （Springer Netherland） 15 （ 4 ） 181 - 190 2014年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1570-0267

Aminoacyl-tRNA synthetases (aaRSs) drive protein translation in cells and hence these are essential enzymes across life. Inhibition of these enzymes can halt growth of an organism by stalling protein translation. Therefore, small molecule targeting of aaRS active sites is an attractive avenue from the perspective of developing anti-infectives. Febrifugine and its derivatives like halofuginone (HF) are known to inhibit prolyl-tRNA synthetase of malaria parasite Plasmodium falciparum. Here, we present functional and crystallographic data on P. falciparum prolyl-tRNA synthetase (PfPRS). Using immunofluorescence data, we show that PfPRS is exclusively resident in the parasite cytoplasm within asexual blood stage parasites. The inhibitor HF interacts strongly with PfPRS in a non-competitive binding mode in presence or absence of ATP analog. Intriguingly, the two monomers that constitute dimeric PfPRS display significantly different conformations in their active site regions. The structural analyses presented here provide a framework for development of febrifugine derivatives that can seed development of new anti-malarials.

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ZFC3H1, a Zinc Finger Protein, Modulates IL-8 Transcription by Binding with Celastramycin A, a Potential Immune Suppressor

Takeshi Tomita, Katsuaki Ieguchi, Fredric Coin, Yasuhiro Kato, Haruhisa Kikuchi, Yoshiteru Oshima, Shoichiro Kurata, Yoshiro Maru

PLOS ONE （PUBLIC LIBRARY SCIENCE） 9 （ 9 ） 2014年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1932-6203

Celastramycin A, a small molecule that inhibits the production of antibacterial peptides in an ex vivo culture system of Drosophila, suppresses the TNFa-mediated induction of IL-8 in mammalian cells. To understand its molecular mechanism, we examined Celastramycin A binding proteins and investigated their biological functions. Our screening and subsequent pull-down assay revealed ZFC3H1 (also known as CCDC131 or CSRC2), an uncharacterized zinc finger protein, as a Celastramycin A binding protein. The knockdown of ZFC3H1 reduced IL-8 expression levels in the TNFa-stimulated lung carcinoma cell line, LU99, and UV-irradiated HeLa cells. Based on reporter assay results, we concluded that ZFC3H1 participates in the transcriptional activation of IL-8. The findings of our UV-irradiation experiments implied that ZFC3H1 may indirectly interact with ERCC1 in an activated DNA repair complex. Thus, we designated ZFC3H1 as a mammalian target of Celastramycin A (mTOC).

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Defects in the synthetic pathway prevent DIF-1 mediated stalk lineage specification cascade in the non-differentiating social amoeba, Acytostelium subglobosum

Kurato Mohri, Takashi Hata, Haruhisa Kikuchi, Yoshiteru Oshima, Hideko Urushihara

BIOLOGY OPEN （COMPANY OF BIOLOGISTS LTD） 3 （ 6 ） 553 - 560 2014年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2046-6390

Separation of somatic cells from germ-line cells is a crucial event for multicellular organisms, but how this step was achieved during evolution remains elusive. In Dictyostelium discoideum and many other dictyostelid species, solitary amoebae gather and form a multicellular fruiting body in which germ-line spores and somatic stalk cells differentiate, whereas in Acytostelium subglobosum, acellular stalks form and all aggregated amoebae become spores. In this study, because most D. discoideum genes known to be required for stalk cell differentiation have homologs in A. subglobosum, we inferred functional variations in these genes and examined conservation of the stalk cell specification cascade of D. discoideum mediated by the polyketide differentiation-inducing factor-1 (DIF-1) in A. subglobosum. Through heterologous expression of A. subglobosum orthologs of DIF-1 biosynthesis genes in D. discoideum, we confirmed that two of the three genes were functional equivalents, while DIF-methyltransferase (As-dmtA) involved at the final step of DIF-1 synthesis was not. In fact, DIF-1 activity was undetectable in A. subglobosum lysates and amoebae of this species were not responsive to DIF-1, suggesting a lack of DIF-1 production in this species. On the other hand, the molecular function of an A. subglobosum ortholog of DIF-1 responsive transcription factor was equivalent with that of D. discoideum and inhibition of polyketide synthesis caused developmental arrest in A. subglobosum, which could not be rescued by DIF-1 addition. These results suggest that non-DIF-1 polyketide cascades involving downstream transcription factors are required for fruiting body development of A. subglobosum.

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Metarhizin A suppresses cell proliferation by inhibiting cytochrome c oxidase activity

Yasuhiro Katou, Naoya Endo, Toshiyuki Suzuki, Jiang Yu, Haruhisa Kikuchi, Yoshiteru Oshima, Yoshimi Homma

LIFE SCIENCES （PERGAMON-ELSEVIER SCIENCE LTD） 103 （ 1 ） 1 - 7 2014年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0024-3205

Aims: Metarhizin A was originally isolated from Metarhizium flavoviride as a potent inhibitor of the growth of insect and mammalian cells. In this study, we aimed to understand the molecular targets of metarhizin A involved in its anti-proliferative activity against human cells.
Main methods: Cell cycle regulators and signaling molecules were examined by immunoblotting using specific antibodies. A mitochondria-enriched fraction was prepared from mouse liver, and mitochondrial activity was monitored using an oxygen electrode. Enzyme activity was measured using purified cytochrome c oxidase and permeabilized cells.
Key findings: Metarhizin A inhibits the growth of MCF-7 cells with an IC50 value of similar to 0.2 mu M and other cells in a similar manner; a cell cycle-dependent kinase inhibitor, p21, is selectively induced. Significant amounts of reactive oxygen species (ROS) are generated and ERK1/2 is activated in cells treated with metarhizin A. Metarhizin A completely suppresses oxygen consumption by mitochondria, and potently inhibits the activity of cytochrome c oxidase. It induces cell death when MCF-7 cells are cultured under limiting conditions.
Significance: Metarhizin A is a potent inhibitor of cytochrome c oxidase and activates the MAPK pathway through the generation of ROS, which induces growth arrest of cells, and, under some conditions, enhances cell death. The cytochrome c oxidase system is a possible molecular target of metarhizin A. (C) 2014 Elsevier Inc. All rights reserved.

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Synthesis of febrifugine derivatives and development of an effective and safe tetrahydroquinazoline-type antimalarial

Haruhisa Kikuchi, Seiko Horoiwa, Ryota Kasahara, Norimitsu Hariguchi, Makoto Matsumoto, Yoshiteru Oshima

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER） 76 10 - 19 2014年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0223-5234

Febrifugine, a quinazoline alkaloid isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. Although the use of ferifugine as an antimalarial drug has been precluded because of its severe side effects, its potent antimalarial activity has stimulated medicinal chemists to pursue its derivatives instead, which may provide valuable leads for novel antimalarial drugs. In the present study, we synthesized new derivatives of febrifugine and evaluated their in vitro and in vivo antimalarial activities to develop antimalarials that are more effective and safer. As a result, we proposed tetrahydroquinazoline-type derivative as a safe and effective antimalarial candidate. (C) 2014 Elsevier Masson SAS. All rights reserved.

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Development of Diversity-Enhanced Extracts of Curcuma zedoaria and Their New Sesquiterpene-like Compounds

Haruhisa Kikuchi, Kazuyoshi Sakurai, Yoshiteru Oshima

ORGANIC LETTERS （AMER CHEMICAL SOC） 16 （ 7 ） 1916 - 1919 2014年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1523-7060

Through the combination of natural products chemistry and diversity-oriented synthesis, a new approach, diversity-enhanced extracts, for increasing the diversity of natural product-like compounds is proposed. They are prepared from chemical reactions that remodel molecular scaffolds directly on extracts of natural resources. This method was applied to terpenes extracted from Curcuma zedoaria. Epoxidation and subsequent ring-opening reactions of epoxides were used to modify molecular skeletons. As a result, seven sesquiterpene-like compounds with some containing new molecular skeletons were obtained.

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Properties of a non-bioactive fluorescent derivative of differentiation-inducing factor-3, an anti-tumor agent found in Dictyostelium discoideum

Yuzuru Kubohara, Haruhisa Kikuchi, Yusuke Matsuo, Yoshiteru Oshima, Yoshimi Homma

BIOLOGY OPEN （COMPANY OF BIOLOGISTS LTD） 3 （ 4 ） 289 - 296 2014年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2046-6390

Differentiation-inducing factor-3 (DIF-3), found in the cellular slime mold Dictyostelium discoideum, and its derivatives, such as butoxy-DIF-3 (Bu-DIF-3), are potent anti-tumor agents. To investigate the activity of DIF-like molecules in tumor cells, we recently synthesized a green fluorescent DIF-3 derivative, BODIPY-DIF-3G, and analyzed its bioactivity and cellular localization. In this study, we synthesized a red (orange) fluorescent DIF-3 derivative, BODIPY-DIF-3R, and compared the cellular localization and bioactivities of the two BODIPY-DIF-3s in HeLa human cervical cancer cells. Both fluorescent compounds penetrated the extracellular membrane within 0.5 h and localized mainly to the mitochondria. In formalin-fixed cells, the two BODIPY-DIF-3s also localized to the mitochondria, indicating that the BODIPY-DIF-3s were incorporated into mitochondria independently of the mitochondrial membrane potential. After treatment for 3 days, BODIPY-DIF-3G, but not BODIPY-DIF-3R, induced mitochondrial swelling and suppressed cell proliferation. Interestingly, the swollen mitochondria were stainable with BODIPY-DIF-3G but not with BODIPY-DIF-3R. When added to isolated mitochondria in vitro, BODIPY-DIF-3G increased dose-dependently the rate of O-2 consumption, but BODIPY-DIF-3R did not. These results suggest that the bioactive BODIPY-DIF-3G suppresses cell proliferation, at least in part, by altering mitochondrial activity, whereas the non-bioactive BODIPY-DIF-3R localizes to the mitochondria but does not affect mitochondrial activity or cell proliferation.

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Novel chlorinated dibenzofurans isolated from the cellular slime mold, Polysphondylium filamentosum, and their biological activities

Haruhisa Kikuchi, Yuzuru Kubohara, Van Hai Nguyen, Yasuhiro Katou, Yoshiteru Oshima

Bioorganic and Medicinal Chemistry 21 （ 15 ） 4628 - 4633 2013年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0968-0896

Cellular slime molds are expected to have the huge potential for producing secondary metabolites including polyketides, and we have studied the diversity of secondary metabolites of cellular slime molds for their potential utilization as new biological resources for natural product chemistry. From the methanol extract of fruiting bodies of Polysphondylium filamentosum, we obtained new chlorinated benzofurans Pf-1 (4) and Pf-2 (5) which display multiple biological activities
these include stalk cell differentiation-inducing activity in the well-studied cellular slime mold, Dictyostelium discoideum, and inhibitory activities on cell proliferation in mammalian cells and gene expression in Drosophila melanogaster. © 2013 Published by Elsevier Ltd.

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Mitochondria Are the Target Organelle of Differentiation-Inducing Factor-3, an Anti-Tumor Agent Isolated from Dictyostelium Discoideum

Yuzuru Kubohara, Haruhisa Kikuchi, Yusuke Matsuo, Yoshiteru Oshima, Yoshimi Homma

PLOS ONE （PUBLIC LIBRARY SCIENCE） 8 （ 8 ） 2013年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1932-6203

Differentiation-inducing factor-3 (DIF-3), found in the cellular slime mold Dictyostelium discoideum, and its derivatives such as butoxy-DIF-3 (Bu-DIF-3) are potent anti-tumor agents. However, the precise mechanisms underlying the actions of DIF-3 remain to be elucidated. In this study, we synthesized a green fluorescent derivative of DIF-3, BODIPY-DIF-3, and a control fluorescent compound, Bu-BODIPY (butyl-BODIPY), and investigated how DIF-like molecules behave in human cervical cancer HeLa cells by using both fluorescence and electron microscopy. BODIPY-DIF-3 at 5-20 mu M suppressed cell growth in a dose-dependent manner, whereas Bu-BODIPY had minimal effect on cell growth. When cells were incubated with BODIPY-DIF-3 at 20 mu M, it penetrated cell membranes within 0.5 h and localized mainly in mitochondria, while Bu-BODIPY did not stain the cells. Exposure of cells for 1-3 days to DIF-3, Bu-DIF-3, BODIPY-DIF-3, or CCCP (a mitochondrial uncoupler) induced substantial mitochondrial swelling, suppressing cell growth. When added to isolated mitochondria, DIF-3, Bu-DIF-3, and BOIDPY-DIF-3, like CCCP, dose-dependently promoted the rate of oxygen consumption, but Bu-BODIPY did not. Our results suggest that these bioactive DIF-like molecules suppress cell growth, at least in part, by disturbing mitochondrial activity. This is the first report showing the cellular localization and behavior of DIF-like molecules in mammalian tumor cells.

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Derivatives of Dictyostelium discoideum differentiation-inducing factor-3 suppress the activities of Trypanosoma cruzi in vitro and in vivo

Junko Nakajima-Shimada, Toshimitsu Hatabu, Yukari Hosoi, Yoko Onizuka, Haruhisa Kikuchi, Yoshiteru Oshima, Yuzuru Kubohara

Biochemical Pharmacology 85 （ 11 ） 1603 - 1610 2013年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-2952

Chagas disease (human American trypanosomiasis), which is caused by the protozoan parasite Trypanosoma cruzi, is responsible for numerous deaths each year
however, established treatments for the disease are limited. Differentiation-inducing factor-1 (DIF-1) and DIF-3 are chlorinated alkylphenones originally found in the cellular slime mold Dictyostelium discoideum that have been shown to possess pharmacological activities. Here, we investigated the effects of DIF-3 derivatives on the infection rate and growth of T. cruzi by using an in vitro assay system utilizing host human fibrosarcoma HT1080 cells. Certain DIF-3 derivatives, such as butoxy-DIF-3 (Bu-DIF-3), at micro-molar levels strongly suppressed both the infection rate and growth of T. cruzi in HT1080 cells and exhibited little toxicity for HT1080 cells. For example, the IC50 of DIF-3 and Bu-DIF-3 versus the growth of T. cruzi in HT1080 cells were 3.95 and 0.72 μM, respectively, and the LD50 of the two compounds versus HT1080 cells were both greater than 100 μM. We also examined the effects of DIF-3 and Bu-DIF-3 on T. cruzi activity in C57BL/6 mice. Intraperitoneally administered Bu-DIF-3 (50 mg/kg) significantly suppressed the number of trypomastigotes in blood with no apparent adverse effects. These results strongly suggest that DIF-3 derivatives could be new lead compounds in the development of anti-trypanosomiasis drugs. © 2013 Elsevier Inc. All rights reserved.

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Terresterol, a polyoxygenated lanostanoid, isolated from the oomycete Saprolegnia terrestris, and its innate immune-promoting activity

Haruhisa Kikuchi, Yuichi Sato, Shoichiro Kurata, Yasuhiro Katou, Yoshiteru Oshima

TETRAHEDRON （PERGAMON-ELSEVIER SCIENCE LTD） 69 （ 17 ） 3536 - 3542 2013年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0040-4020

Oomycetes are widely spread eukaryotic microorganisms. However, there have only been a few reports on the secondary metabolites produced by them. In the course of screening for innate immune regulators from natural resources, we isolated a new polyoxygenated lanostanoid, terresterol (1), from the oomycetes Saprolegnia terrestris. Compounds bearing a 21,22,24,25-tetraoxygenated side chain similar to 1 have only been rarely described, and the isolation of such compounds shows that oomycetes are promising resources for natural product chemistry. In addition, terresterol (1) has potential to be used as a lead compound for novel immunostimulating agents against bacterial infections and as probe for the innate immune system. (C) 2013 Elsevier Ltd. All rights reserved.

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The Dictyostelium prestalk inducer DIF-1 directs phosphorylation of a bZIP transcription factor

Yoko Yamada, Yuzuru Kubohara, Haruhisa Kikuchi, Yoshiteru Oshima, Hong-Yu Wang, Susan Ross, Jeffrey G. Williams

INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY （U B C PRESS） 57 （ 5 ） 375 - 381 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0214-6282

DIF-1, a chlorinated hexaphenone produced by developing Dictyostelium cells, induces prestalk differentiation. DimB is a bZIP transcription factor that accumulates in the nucleus upon exposure to DIF-1, where it directly activates transcription of DIF-responsive genes. The signaling steps upstream of DimB and downstream of DIF-1 are entirely unknown. Analysis by mass spectrometry shows that incubation with DIF-1 rapidly stimulates phosphorylation at several sites in DimB. We characterize the most highly responsive site, S590, which is located very close to the C terminus. A point mutation in this site, S590A, does not inhibit DimB nuclear accumulation in response to DIE However, this seems likely to reflect functional redundancy with other sites; because a panel of chemical variants on the structure of DIF-1 show a correlation between their potencies as inducers of DimB nuclear accumulation and their potencies as inducers of phosphorylation at S590. Furthermore, the S590A mutant is fully active in mutant rescue of a dimB null strain, arguing against an alternative role in transcriptional activation of target genes. We conclude that i) DIF-1 directs phosphorylation at S590, ii) although it is not essential for nuclear accumulation in response to DIF-1 correlative evidence, based upon a panel of DIF-1 related molecules, suggests that this modification may play a redundant role in the process. iii) We also present evidence that the kinase activity, which phosphorylates S590, is non-nuclear and that this signalling pathway is, in part at least, independent of the DIF-regulated STATc activation pathway.

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Isolation, synthesis, and biological activity of biphenyl and m-terphenyl-type compounds from Dictyostelium cellular slime molds

Haruhisa Kikuchi, Yusuke Matsuo, Yasuhiro Katou, Yuzuru Kubohara, Yoshiteru Oshima

TETRAHEDRON （PERGAMON-ELSEVIER SCIENCE LTD） 68 （ 43 ） 8884 - 8889 2012年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0040-4020

From the fruiting bodies of Dictyostelium polycephalum, we obtained four aromatic compounds: dictyobiphenyl A (1) and B (2) and dictyoterphenyl A (3) and B (4). The synthesis of 1-4 was performed to confirm the structures and obtain sufficient material for biological evaluation. Compound 3 was the first example of nitrogen-containing natural m-terphenyls, and the isolation of novel classes of compounds such as 3 shows that cellular slime molds are promising sources in natural product chemistry. Moreover, dictyoterphenyl A (3) showed cancer cell-selective antiproliferative activity (IC50 2.3-8.6 mu M). (C) 2012 Elsevier Ltd. All rights reserved.

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Stigmastane derivatives from the roots of Vernonia guineensis and their antimicrobial activity

Arno R. N. Donfack, Ngeh J. Toyang, Hippolyte K. Wabo, Pierre Tane, Maurice D. Awouafack, Haruhisa Kikuchi, Jean D. D. Tamokou, Jules R. Kuiate, Yoshiteru Oshima

PHYTOCHEMISTRY LETTERS （ELSEVIER SCIENCE BV） 5 （ 3 ） 596 - 599 2012年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1874-3900

Chemical investigation of the roots of Vernonia guineensis (Asteraceae) afforded a new stigmastane derivative, vernoguinoside A (1) and the known vernoguinoside (2), stigmasterol 3-O-beta-D-glucoside (3) and sitosterol 3-O-beta-D-glucoside (4). Their structures were elucidated by spectroscopic analysis. Antimicrobial activities of 1-3 and CH2Cl2-MeOH (1:1) extract were evaluated against three bacteria species (Salmonella typhi, Staphylococcus aureus and Shigella flexneri) and three yeasts species (Candida albicans, Candida parapsilosis and Cryptococcus neoformans). Compounds 1 and 2 exhibited both antibacterial and antifungal activities that varied between the microbial species (MIC = 7.81-125 mu g/mL) while S. flexneri and C. albicans were sensitive to all the tested compounds. (C) 2012 Phytochemical Society of Europe. Published by Elsevier B. V. All rights reserved.

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New dimeric and monomeric chromanones, gonytolides D-G, isolated from the fungus Gonytrichum sp.

Haruhisa Kikuchi, Masato Isobe, Shoichiro Kurata, Yasuhiro Katou, Yoshiteru Oshima

TETRAHEDRON （PERGAMON-ELSEVIER SCIENCE LTD） 68 （ 31 ） 6218 - 6223 2012年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0040-4020

In the course of the screening of innate immune regulators from natural resources, we isolated new dimeric and monomeric chromanones, gonytolides D G (4-7), from Gonytrichum sp. along with a known innate immune promoter, gonytolide A (1). The structures of these compounds were determined by spectral analysis, chemical conversion, and biogenetic consideration. The compounds 4-7 were evaluated on the innate immune response, indicating that the 8,8'-linked bischromanone rings were crucial for innate immune-promoting activity. (C) 2012 Elsevier Ltd. All rights reserved.

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Apoptotic effects of satratoxin H is mediated through DNA double-stranded break in PC12 cells

Punnee Nusuetrong, Masaki Saito, Haruhisa Kikuchi, Yoshiteru Oshima, Takahiro Moriya, Norimichi Nakahata

JOURNAL OF TOXICOLOGICAL SCIENCES （JAPANESE SOC TOXICOLOGICAL SCIENCES） 37 （ 4 ） 803 - 812 2012年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0388-1350

Satratoxin H is an important air- and food-borne mycotoxin, which has been implicated in human health damage. Satratoxin H is known to induce apoptosis as well as genotoxicity in PC12 cells. In the present study, we further investigated the mechanism of apoptotic effects of satratoxin H with focus on caspase-3 and poly-ADP-ribose polymerase (PARP) pathway. We also examined whether it induces DNA damage in PC12 cells. In the cells treated with satratoxin H, caspase-3 was cleaved in a time-dependent manner. Furthermore, satratoxin H induced cleavage of PARP, one of the downstream molecules of caspase-3. The cleavage was inhibited by SB203580, a p38 MAPK inhibitor, or SP600125, a JNK inhibitor. Satratoxin H, however, had no effect on expression levels of Bax and Bcl-2. Furthermore, the micronucleus assay revealed that satratoxin H induced chromosome break. Also, satratoxin H increased the level of phosphorylation of histone H2A, indicating that it caused DNA double-stranded breaks in PC12 cells. Meanwhile, no genotoxicity was detected with any of treatments carried out in the alkaline comet assay. These results imply that satratoxin H induces genotoxicity by DNA double-stranded break. Our results suggest a considerable potential for the genotoxic risk associated with the presence of satratoxin H.

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Labdane-type diterpenes and flavones from Dodonaea viscosa

Hippolyte Kamdem Wabo, Philippe Chabert, Pierre Tane, Olivier Note, Michel Feussi Tala, Jean Peluso, Christian Muller, Haruhisa Kikuchi, Yoshiteru Oshima, Annelise Lobstein

FITOTERAPIA （ELSEVIER SCIENCE BV） 83 （ 5 ） 859 - 863 2012年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0367-326X

A new labdane diterpenoid, 2,18-dihydroxylabda-7,13(E)-dien-15-oic acid (1), together with two known labdane diterpenes (3, 4), a new flavone, 5,7-dihydroxy-3,6,4'-trimethoxy-3'-(4-hydroxy-3-methyl-but-2-enyl)flavone (2) with three known flavones (5-7) were isolated from the aerial parts of Dodonaea viscosa. Their structures were determined by extensive analysis of spectroscopic data (1D and 2D NMR, MS) and by comparison with literature data. The anti-inflammatory activity of five compounds (1-5) was evaluated with a flow cytometry TNF-alpha secretion assay on human THP-1 cell line. (C) 2012 Elsevier B.V. All rights reserved.

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