Faculty Profiles - NAKAMURA Yoshimasa

Papers - NAKAMURA Yoshimasa

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alpha-Tocopherol-mediated caspase-3 up-regulation enhances susceptibility to apoptotic stimuli Reviewed

N Miyoshi, K Naniwa, T Kumagai, K Uchida, T Osawa, Y Nakamura

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 334 ( 2 ) 466 - 473 2005.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Although alpha-tocopherol is known as an essential micronutrient involved in various oxidative stress-related processes, its non-antioxidant activities have only been characterized in recent years. In this study, we reveal that (+)-alpha-tocopherol [RRR-alpha-tocopherol] enhances cellular susceptibility to both oxidative and non-oxidative apoptosis-inducing stimuli through up-regulation of caspase-3/ CPP32 expression in several human cell lines. Exposure of (+)-alpha-tocopherol pretreated cells to known apoptosis-inducing stimuli, such as Fas, H2O2, or etoposide, resulted in an increase in cellular apoptotsis. In addition, (+)-alpha-tocopherol also elevated the procaspase-3 protein level and mRNA expression in a time- and dose-dependent manner, while other tocopherol analogues showed no effect. Experiments using a GC-specific DNA binding agent, mithramycin A, and an electrophoretic mobility shift assay demonstrated that Sp1 might mediate the enhanced expression of caspase-3. Our results also confirmed that (+)-a-tocopherol promotes the expression, but not the activation, of caspase-3 in various human cell lines. These findings provide biological evidence showing that (+)-alpha-tocopherol can amplify the apoptotic response by up-regulating the expression of pro-caspase-3. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.06.113

Antioxidative catechol lignans converted from sesamin and sesaminol triglucoside by culturing with Aspergillus Reviewed

Y Miyake, S Fukumoto, M Okada, K Sakaida, Y Nakamura, T Osawa

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 53 ( 1 ) 22 - 27 2005.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Sesamin and sesaminol triglucoside in sesame seeds are major lignans that display an abundance of biological activities. Although their antioxidative activity in vitro is weak, they have been reported to suppress oxidative stress in vivo. We investigated the production of new antioxidative lignans from sesame lignans by culturing with the genus Aspergillus to enhance the function of food materials. Media containing sesamin or sesaminol triglucoside increased antioxidative activity for DPPH radical scavenging by culturing with Aspergillus usamii mut. shirousamii RIB2503. The antioxidative lignans in sesamin medium were identified as sesamin 2,6-dicatechol and episesamin 2,6-dicatechol. Those in sesaminol triglucoside medium were identified as sesaminol 6-catechol and episesaminol 6-catechol, which are novel antioxidative lignans. It is suggested that they may exhibit higher antioxidative activity than sesamin and sesaminol triglucoside because they have the catechol functional moiety.

DOI： 10.1021/jf048043h

Endogenous formation of novel halogenated 2 '-deoxycytidine - Hypohalous acid-mediated DNA modification at the site of inflammation Reviewed

Y Kawai, H Morinaga, H Kondo, N Miyoshi, Y Nakamura, K Uchida, T Osawa

JOURNAL OF BIOLOGICAL CHEMISTRY 279 ( 49 ) 51241 - 51249 2004.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

A potential role of DNA damage by leukocyte-derived reactive species in carcinogenesis has been suggested. Leukocyte-derived peroxidases, such as myeloperoxidase and eosinophil peroxidase, use hydrogen peroxide and halides (Cl- and Br-) to generate hypohalous acids (HOCl and HOBr), halogenating intermediates. It has been suggested that these oxidants lead to the formation of halogenated products upon reaction with nucleobases. To verify the consequences of phagocyte-mediated DNA damage at the site of inflammation, we developed a novel monoclonal antibody (mAb2D3) that recognizes the hypohalous acid-modified DNA and found that the antibody most significantly recognized HOCl/HOBr-modified 2'-deoxycytidine residues. The immunoreactivity of HOCl-treated oligonucleotide was attenuated by excess methionine, suggesting that chloramine-like species may be the plausible epitopes of the antibody. On the basis of further characterization combined with mass spectrometric analysis, the epitopes of mAb2D3 were determined to be novel N-4,5-dihalogenated 2'-deoxycytidine residues. The formation of the dihalogenated 2'-deoxycytidine in vivo was immunohistochemically demonstrated in the lung and liver nuclei of mice treated with lipopolysaccharides, an experimental inflammatory model. These results strongly suggest that phagocyte-derived oxidants, hypohalous acids, endogenously generate the halogenated DNA bases such as a novel dihalogenated 2'-deoxycytidine in vivo. Halogenation ( chlorination and/or bromination) of DNA therefore may constitute one mechanism for oxidative DNA damage at the site of inflammation.

DOI： 10.1074/jbc.M408210200

Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes Reviewed

Y Nakamura, C Yoshida, A Murakami, H Ohigashi, T Osawa, K Uchida

FEBS LETTERS 572 ( 1-3 ) 245 - 250 2004.8

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Zerumbone (ZER), a sesquiterpene compound occurring in tropical ginger Zingiber zerumbet Smith, has been implicated as one of the promising chemopreventive agents against colon and skin cancer. In the present study, we investigated the phase II detoxification enzymes induction of ZER using a cultured rat normal liver epithelial cell line. Exposure of RL34 cells to ZER resulted in the significant induction of glutathione S-transferase, while the reduced analogues of ZER (alpha-humulene and 8-hydroxy-alpha-humulene) did not show any inducing effect. Therefore, the electrophilic property, characterized by the reactivity with intracellular nucleophiles including protein sulfhydryls as well as low molecular weight thiols, at the 8-position alpha, beta-unsaturated carbonyl group plays an important role in the induction of phase II enzymes. ZER induced nuclear localization of the transcription factor Nrf2 that binds to antioxidant response element (ARE) of the phase II enzyme genes, suggesting that ZER is a potential activator of the Nrf2/ARE-dependent detoxification pathway. This is consistent with the observation that ZER potentiated the gene expression of several Nrf2/ARE-dependent phase II enzyme genes, including gamma-glutamylcysteine synthetase, glutathione peroxidase, and hemeoxygenase-1. The present study also implied the antioxidant role of this detoxification system activation by ZER in the neutralization of lipid peroxidation in hepatocytes, providing a new insight for cancer prevention. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

DOI： 10.1016/j.febslet.2004.07.042

Antimicrobial activities of diterpene dialdehydes, constituents from myoga (Zingiber mioga Roscoe), and their quantitative analysis Reviewed

M Abe, Y Ozawa, Y Uda, F Yamada, Y Morimitsu, Y Nakamura, T Osawa

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 68 ( 7 ) 1601 - 1604 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

The antimicrobial activities of the three diterpene dialdehydes, miogadial, galanal A and galanal B, isolated from flower buds of the myoga (Zingiber mioga Roscoe) plant were investigated with some strains of bacteria, yeasts and molds. Among the three compounds, miogadial exhibited relatively greater antimicrobial activity than the others against Gram-positive bacteria and yeasts. Galanals A and B also behaved as antimicrobial agents against Gram-positive bacteria and yeasts. The content of miogadial in the flower buds was much higher than that in the leaves, whereas galanals A and B were contained at high levels in the leaves and rhizomes.

DOI： 10.1271/bbb.68.1601

Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice Reviewed

A Murakami, T Tanaka, JY Lee, YJ Surh, HW Kim, K Kawabata, Y Nakamura, S Jiwajinda, H Ohigashi

INTERNATIONAL JOURNAL OF CANCER 110 ( 4 ) 481 - 490 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

We recently showed that zerumbone, a sesquiterpene found in subtropical ginger, suppresses colonic tumor marker formation in rats and induces apoptosis in colon cancer cell lines. In our present study, the anti-tumor initiating and promoting activities of zerumbone in mouse skin were evaluated using a conventional 2-stage carcinogenesis model. A single topical pretreatment to mouse skin (2 mumol) 24 hr before application of dimethylbenz[a]anthracene (0.2 mumol) markedly suppressed tumor incidence by 60% and the number of tumors by 80% per mouse. Repeated pretreatment (16 nmol) twice weekly during the post-initiation phase reduced the number of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol)-induced tumors by 83% as well as their diameter by 57%. Multiple reverse transcriptase (RT) PCR experiments revealed that zerumbone (2 mumol) enhanced the mRNA expression level of manganese superoxide dismutase, glutathione peroxidase-1, glutathione S-transferase-P1 and NAD(P)H quinone oxidoreductase in the epidermis, but not that of cytochrome P450 1A1 or 1B1. Further, it diminished TPA-induced cyclooxygenase-2 protein expression and phosphorylation of extracellular signal-regulated kinase 1/2, while pretreatment(s), in either the priming or activation stage or both, reduced double TPA application-induced hydrogen peroxide formation and edema induction by 29% to 86%, respectively. Histologic examination revealed that pretreatment(s) with zerumbone suppressed leukocyte infiltration and reduced proliferating cell nuclear antigen-labeling indices. Together, our results indicate that zerumbone is a promising agent for the prevention of both tumor initiating and promoting processes, through induction of anti-oxidative and phase II drug metabolizing enzymes as well as attenuation of proinflammatory signaling pathways. (C) 2004 Wiley-Liss, Inc.

DOI： 10.1002/ijc.20175

Extract of vinegar "Kurosu" from unpolished rice inhibits the proliferation of human cancer cells Reviewed

K Nanda, N Miyoshi, Y Nakamura, Y Shimoji, Y Tamura, Y Nishikawa, K Uenakai, H Kohno, T Tanaka

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 23 ( 1 ) 69 - 75 2004.3

Language：English Publishing type：Research paper (scientific journal) Publisher：APSIT ASSOC PROM STUD IMMUNOL TUMOR

The effects of the ethyl acetate extract of "Kurosu" (EK), Japanese traditional vinegar from unpolished rice, on the proliferation of a variety of human cancer cell lines were investigated by using the alamar blue assay. Cancer cell lines included colon adenocarcinoma (Caco-2), lung carcinoma (A549), breast adenocarcinoma (MCF-7), bladder carcinoma (5637), and prostate carcinoma (LNCaP) cells. EK inhibited the proliferation of all tested cell lines in a dose-dependent manner, with inhibition mostly pronounced in Caco-2 cells (up to 62% inhibition at a dose level of 0.025%). Flow cytometry of EK-treated Caco-2 cells showed a decrease in cell number in the G(2)/M phase and an increase in the sub-G(1) phase (apoptotic). In addition, DNA fragmentation was detected in Caco-2 cells cultured with EK by immunostaining. RT-PCR analysis revealed p21 mRNA expression was induced in EK-treated Caco-2 cells. Moreover, PARP cleavage was promoted in EK-treated Caco-2 cells. These results Suggest that EK causes G(0)/G(1) arrest through p21 induction and, thus, is a potential apoptosis inducer in Caco-2 cells.

Benzyl isothiocyanate modifies expression of the G(2)/M arrest-related genes Reviewed

N Miyoshi, K Uchida, T Osawa, Y Nakamura

BIOFACTORS 21 ( 1-4 ) 23 - 26 2004

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：IOS PRESS

Naturally occurring isothiocyanates are effective chemoprotective agents against chemical carcinogenesis in experimental animals. In the present study, we clarified the molecular mechanism underlying the relationship between benzyl isothiocyanate (BITC)-induced cell cycle arrest and apoptosis. The exposure of HL-60 cells to BITC resulted in the inhibition of the G(2)/M progression that coincided with the apoptosis induction. We demonstrated that BITC significantly up-regulated expression of the G(2)/M cell cycle arrest-regulating genes including p21, GADD45, and 14-3-3sigma. Thus, these gathered data further supported that BITC has a potential to induce apoptosis selectively in the proliferating pre-cancerous cells through a cell cycle arrest-dependent mechanism.

Benzyl isothiocyanate inhibits oxidative stress in mouse skin: Involvement of attenuation of leukocyte infiltration Invited Reviewed

Y Nakamura, N Miyoshi, S Takabayashi, T Osawa

BIOFACTORS 21 ( 1-4 ) 255 - 257 2004

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：IOS PRESS

The exposure of benzyl isothiocyanate (BITC) to mouse skin resulted in the attenuation of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative damage through not only inhibition of the NADPH oxidase system but also leukocyte clearance at inflamed region. In spite of little ability to affect TPA-induced edema formation, pretreatments of mouse skin with BITC before the first or second TPA treatment significantly decrease the H2O2 level. A histological study also demonstrated that BITC enhanced the terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL)-positive index in mouse skin, suggesting that BITC might accelerate the disappearance of infiltrated leukocytes. Thus, these gathered data further supported that BITC has a potential as an anti-inflammatory agent.

Dietary ginger constituents, galanals A and B, are potent apoptosis inducers in Human T lymphoma Jurkat cells Reviewed

N Miyoshi, Y Nakamura, Y Ueda, M Abe, Y Ozawa, K Uchida, T Osawa

CANCER LETTERS 199 ( 2 ) 113 - 119 2003.9

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

The effects of the constituents isolated from ginger species including curcumin, 6-gingerol and labdane-type diterpene compounds on cell proliferation and the induction of apoptosis in the cultured human T lymphoma Jurkat cells were studied. Among the tested compounds, Galanals A and 13, isolated from the flower buds of a Japanese ginger, myoga (Zingiber mioga Roscoe), showed the most potent cytotoxic effect. Exposure Of Jurkat human T-cell leukemia cells to galanals resulted in the induction of apoptotic cell death characterized by DNA fragmentation and caspase-3 activation. The mitochondrial damage pathway was suggested to be involved in galanal-induced apoptosis because the treatment of cells with galanals induced mitochondrial transmembrane potential (Deltapsim) alteration and cytochrome c release. The anti-apoptotic Bcl-2 protein was downregulated by the galanal treatment together with enhancement of the Bax expression. In conclusion, the results from this study provide biological evidence that ginger-specific constituents other than curcuminoids are potential anticancer agents. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3835(03)00381-1

Correlation of antimutagenic activity and suppression of CYP1A with the lipophilicity of alkyl gallates and other phenolic compounds Reviewed

Q Feng, T Kumagai, Y Nakamura, K Uchida, T Osawa

MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 537 ( 1 ) 101 - 108 2003.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Alkyl gallates are widely used as food antioxidants. Methyl, ethyl, propyl, lauryl, and cetyl gallates showed antimuta-genicity to activated 2-aminoanthracene (2AA)-induced SOS responses in Salmonella typhimurium TA1535/pSK1002. They also exhibited a suppressive effect on 3-methylcholanthrene (3-MC)-induced cytochrome P450 1A (CYP1A) in human hepatoma HepG2 cells, as indexed by the 7-ethoxyresorufin-O-deethylase (EROD) activity, and on CYP1A protein level. Both antimutagenicity and suppression of CYP1A appeared to be dependent on alkyl chain lengths, which suggested lipophilicity dependence. Based on those results, we investigated 26 other phenolic compounds for their lipophilicity, antimutagenicity and inhibition of EROD activity. The lipophilicity correlated well with the inhibition of EROD activity (r = 0.78), and the inhibition of EROD activity correlated with the antimutagenicity of those compounds (r = 0.71). The results suggest that the lipophilicity of the phenolic compounds may be an important factor in their ability to inhibit EROD activity. (C) 2003 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S1383-5718(03)00057-3

Dihydrochalcones: Evaluation as novel radical scavenging antioxidants Reviewed

Y Nakamura, S Watanabe, N Miyake, H Kohno, T Osawa

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 51 ( 11 ) 3309 - 3312 2003.5

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Dihydrochalcones are a family of bicyclic flavonoids, defined by the presence of two benzene rings joined by a saturated three carbon bridge. In the present study, we systematically examined the antioxidant activities of dihydrochalcones against the stable free radical (1,1-diphenyl-2-picrylhydrazyl) and lipid peroxidation in the erythrocyte membrane. All dihydrochalcones exhibited higher antioxidant activities than the corresponding flavanones. The H-1 NMR analysis indicated that the active dihydrochalcone has a time-averaged conformation in which the aromatic A ring is orthogonal to the carbonyl group, while the inactive dihydrochalcone such as 2'-O-methyl-phloretin has a strongly hydrogen-bonded phenolic hydroxyl group, suggestive of a coplanar conformation. A hydroxyl group at the 2'-position of the dihydrochalcone A ring, newly formed by reduction of the flavanone C ring, is an essential pharmacophore for its radical scavenging potential.

DOI： 10.1021/jf0341060

Structures of (-)-epicatechin glucuronide identified from plasma and urine after oral ingestion of (-)-epicatechin: Differences between human and rat Reviewed

M Natsume, N Osakabe, M Oyama, M Sasaki, S Baba, Y Nakamura, T Osawa, J Terao

FREE RADICAL BIOLOGY AND MEDICINE 34 ( 7 ) 840 - 849 2003.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

(-)-Epicatechin is one of the most potent antioxidants present in the human diet. Particularly high levels are found in black tea, apples, and chocolate. High intake of catechins has been associated with reduced risk of cardiovascular diseases. There have been several reports concerning the bioavailability of catechins, however, the chemical structure of (-)-epicatechin metabolites in blood, tissues, and urine remains unclear. In the present study, we purified and elucidated the chemical structure of (-)-epicatechin metabolites in human and rat urine after oral administration. Three metabolites were purified from human urine including (-)-epicatechin-3'-O-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-glucuronide, and 4'-O-methyl-(-)-epicatechin-5 or 7-O-glucuronide, according to H-1- and C-13-NMR, HMBC, and LC-MS analyses. The metabolites purified from rat urine were 3'-O-methyl-(-)-epicatechin, (-)-epicatechin-7-O-glucuronide, and 3'-O-methyl-(-)-epicatechin-7-O-glucuronide. These compounds were also detected in the blood of humans and rats by LC-MS. The presence of these metabolites in blood and urine suggests that catechins are metabolized and circulated in the body after administration of catechin-containing foods. (C) 2003 Elsevier Science Inc.

DOI： 10.1016/S0891-5849(02)01434-X

A phase II detoxification enzyme inducer from lemongrass: identification of citral and involvement of electrophilic reaction in the enzyme induction Reviewed

Y Nakamura, M Miyamoto, A Murakami, H Ohigashi, T Osawa, K Uchida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 302 ( 3 ) 593 - 600 2003.3

Authorship：Lead author,　Last author Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

We have developed a simple system for the sensitive detection and measurement of glutathione S-transferase (GST) activity that detoxifies polycyclic aromatic hydrocarbons using the cultured rat normal liver epithelial cell line, RL34 cells. Citral (3,7-dimethyl-2,6-octadienal) was isolated from the methanol extract of lemongrass (Cymbopogon citratus) and identified as a novel inducer of GST. Citral, a mixture of the two stereoisomers geranial and neral, dose- and time-dependently induced the total and pi-class-specific activities of GST. The structure-activity relationship study revealed that geranial, an E-isomer, was mainly responsible for the inducing activity of citral mixture and the aldehyde group conjugated with a trans-double bond is an essential structural factor. The data were consistent with the in vitro observation that both glutathione (GSH) and protein thiol quickly and specifically reacted with the active isomer geranial, but not neral. Pretreatment of the cells with diethyl maleate significantly enhanced not only the basal activity but also the citral-stimulated activity of GST, while pretreatment with N-acetyl-cysteine inhibited it. Moreover, the treatment of RL 34 cells with geranial for 30 min significantly attenuated the intracellular GSH level, while application for 18 h enhanced it. These results strongly suggested that the electrophilic property characterized by the reactivity with intracellular nucleophiles including protein thiol or glutathione (GSH) plays an important role in the induction of GST. The present study also implied the antioxidant role of GST induction by citral in mouse skin, providing a new insight into skin cancer prevention. (C) 2003 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(03)00219-5

Induction of cytochrome P4501Al by autoclavable culture medium change in HepG2 cells Reviewed

Q Feng, T Kumagai, Y Nakamura, K Uchida, T Osawa

XENOBIOTICA 32 ( 11 ) 1033 - 1043 2002.11

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

1. Without the addition of xenobiotics, only by changing the Culture medium can one induce extensively and transiently cytochrome P4501A1 (CYP1A1) protein and mRNA in human hepatoma HepG2 cells. The induction was aryl hydrocarbon receptor (AhR)dependent, and was proven by: (1) the medium change activated the AhR, as judged by a electrophoretic mobility shift assay; and (2) the AhR inhibitor alpha-naphthoflavone inhibited the medium change-mediated induction.
2. Induction of CYP1A1 was related to medium prepared by autoclaving. By screening the ingredients in the medium, the serum had no effect on CYP1A1 induction, whereas both photo-oxidized and autoclaved tryptophan were shown to induce CYP1A1, as indicated by CYP1A1 protein or ethoxyresorufin-O-deethylase activity. The autoclaved tryptophan contained in an autoclavable medium was a more potent inducer of CYP1A1 than photo-oxidized tryptophan.
3. The results provide some practical suggestions with experiments related to CYP1A1.

DOI： 10.1080/0049825021000012583

Isolation and identification of DPPH radical scavenging compounds in Kurosu (Japanese unpolished rice vinegar) Reviewed

Y Shimoji, Y Tamura, Y Nakamura, K Nanda, S Nishidai, Y Nishikawa, N Ishihara, K Uenakai, H Ohigashi

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 50 ( 22 ) 6501 - 6503 2002.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Dihydroferulic acid (DFA) and dihydrosinapic acid (DSA) were isolated from Kurosu (unpolished rice vinegar) as the major constituents responsible for Kurosu's radical scavenging activity. The levels of antioxidative activity of DFA and DSA in DPPH radical scavenging were higher than those of their respective structurally related compounds, ferulic acid and sinapic acid. The concentrations of DFA and DSA were low in common rice vinegar (polished rice vinegar), suggesting that Kurosu is more advantageous than rice vinegars as an antioxidative food item. As the concentrations of DFA and DSA were low in unpolished rice, too, these acids are thought to be produced in Kurosu through the process of the fermentation from ferulic acid and sinapic acid, respectively.

DOI： 10.1021/jf020458f

FA15, a hydrophobic derivative of ferulic acid, suppresses inflammatory responses and skin tumor promotion: comparison with ferulic acid Reviewed

A Murakami, Y Nakamura, K Koshimizu, D Takahashi, K Matsumoto, K Hagihara, H Taniguchi, E Nomura, A Hosoda, T Tsuno, Y Maruta, HW Kim, K Kawabata, H Ohigashi

CANCER LETTERS 180 ( 2 ) 121 - 129 2002.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

In our previous study. FA15 (2-methyl-I-butyl ferulic acid) was chemically synthesized as a novel ferulic acid (FA) analog, and found to notably suppress phorbol ester-induced Epstein-Barr virus activation and superoxide anion generation in vitro. In this report, we demonstrated that FA15 in contrast to FA, markedly Suppressed the combined lipopolysaccharide and interferon-gamma-induced protein expressions of inducible nitric oxide synthase and cyclooxygenase-2, and also inhibited the release of tumor necrosis factor-alpha accompanied by suppression of I-kappaB degradation in RAW264.7, a murine macrophage cell line. In ICR mouse skin, topical application of FA15 significantly attenuated phorbol ester-triggered hydrogen peroxide production and edema formation as well as papilloma development while that of FA did not. Our results suggest that FA15, derived front natural sources. is a novel chemopreventive agent, both structurally and functionally. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3835(01)00858-8

Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the alpha,beta-unsaturated carbonyl group is a prerequisite Reviewed

A Murakami, D Takahashi, T Kinoshita, K Koshimizu, HW Kim, A Yoshihiro, Y Nakamura, S Jiwajinda, J Terao, H Ohigashi

CARCINOGENESIS 23 ( 5 ) 795 - 802 2002.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Zerumbone (ZER), a sesquiterpene from the edible plant Zingiber zerumbet Smith, has recently been found to suppress tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus activation in a potent manner. In the present study, we evaluated the antiinflammatory and chemopreventive potentials of ZER in a variety of cell culture experiments. ZER effectively suppressed TPA-induced superoxide anion generation from both NADPH oxidase in dimethylsulfoxide-differentiated HL-60 human acute promyelocytic leukemia cells and xanthine oxidase in AS52 Chinese hamster ovary cells. The combined lipopolysaccharide- and interferon-gamma-stimulated protein expressions of inducible nitric oxide synthase and cyclooxygenase (COX)-2, together with the release of tumor necrosis factor-alpha, in RAW 264.7 mouse macrophages were also markedly diminished. These suppressive events were accompanied with a combined decrease in the medium concentrations of nitrite and prostaglandin E-2, while the expression level of COX-1 was unchanged. ZER inhibited the proliferation of human colonic adenocarcinoma cell lines (LS174T, LS180, COLO205, and COLO320DM) in a dose-dependent manner, while the growth of normal human dermal (2F0-C25) and colon (CCD-18 Co) fibroblasts was less affected. It also induced apoptosis in COLO205 cells, as detected by dysfunction of the mitochondria transmembrane, Annexin V-detected translocation of phosphatidylserine, and chromatin condensation. Intriguingly, alpha-humulene, a structural analog lacking only the carbonyl group in ZER, was virtually inactive in all experiments conducted, indicating that the alpha,beta-unsaturated carbonyl group in ZER may play some pivotal roles in interactions with unidentified target molecule(s). Taken together, our results indicate that ZER is a food phytochemical that has distinct potentials for use in anti-inflammation, chemoprevention, and chemotherapy strategies.

Screening of edible Japanese plants for suppressive effects on phorbol ester-induced superoxide generation in differentiated HL-60 cells and AS52 cells Reviewed

HW Kim, A Murakami, Y Nakamura, H Ohigashi

CANCER LETTERS 176 ( 1 ) 7 - 16 2002.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

Epithelial xanthine oxidase (XOD) is one of the major enzymes responsible for superoxide (O-2(-)) generation, which is involved in oxidative stress. However, there are few known reports of a convenient bioassay to detect Cellular XOD activity. We tested several cell lines, and found that AS52, from Chinese hamster ovary cells, produced a significant level of O-2(-) in 2 response to 12-O-tetradecanoylphorbol 13-acetate (TPA), and this activity was markedly inhibited by allopurinol, an XOD inhibitor. Using AS52 cells and differentiated HL-60 cells, we conducted screening tests of edible Japanese plant extracts for their inhibitory activities toward TPA-induced O-2(-) generation from both reduced nicotinamide adenine dinucleotide oxidase (HL-60) and XOD (AS52). Notably, the extracts from mioga ginger, rape, avocado, carrot, turnip, taro, and shiineji showed potent inhibition of O-2(-) generation in both cell lines. These results suggest that several edible Japanese plants carry a significant antioxidative and cancer preventive potential. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3835(01)00735-2

A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway Reviewed

Y Morimitsu, Y Nakagawa, K Hayashi, H Fujii, T Kumagai, Y Nakamura, T Osawa, F Horio, K Itoh, K Iida, M Yamamoto, K Uchida

JOURNAL OF BIOLOGICAL CHEMISTRY 277 ( 5 ) 3456 - 3463 2002.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Exposure of cells to a wide variety of chemoprotective compounds confers resistance to a broad set of carcinogens. For a subset of the chemoprotective compounds, protection is generated by an increase in the abundance of the protective phase II detoxification enzymes, such as glutathione S-transferase (GST). We have recently developed a cell culture system, using rat liver epithelial RL 34 cells, that potently responds to the phenolic antioxidants resulting in the induction of GST activity (Kawamoto, Y., Nakamura, Y., Naito, Y., Torii, Y., Kumagai, T., Osawa, T., Ohigashi, H., Satoh, K., Imagawa, M., and Uchida, K. (2000) J. Biol. Chem. 275, 11291-11299.) In the present study, we investigated the phase II-inducing potency of an isothiocyanate compound in vitro and in vivo and examined a possible induction mechanism. Based on an extensive screening of vegetable extracts for GST inducer activity in RL34 cells, we found Japanese horseradish, wasabi (Wasabia japonica, syn. Eutrema wasabi), as the richest source and identified 6-methylsulfinylhexyl isothiocyanate (6-HITC), an analogue of sulforaphane (4-methylsulfinylbutyl isothiocyanate) isolated from broccoli, as the major GST inducer in wasabi. 6-HITC potently induced both class alpha GSTA1 and class pi GSTP1 isozymes in RL34 cells. In animal experiments, we found that 6-MSHI was rapidly absorbed into the body and induced hepatic phase 11 detoxification enzymes more potently than sulforaphane. The observations that W 6-HITC activated the antioxidant response element (ARE), (ii) 6-HITC induced nuclear localization of the transcription factor Nrf2 that binds to ARE, and (iii) the induction of phase 11 enzyme genes by 6-HITC was completely abrogated in the nrf2-deficient mice, suggest that 6-HITC is a potential activator of the Nrf2/ARE-dependent detoxification pathway.

DOI： 10.1074/jbc.M110244200

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