研究者詳細 - 中村　宜督

論文 - 中村　宜督

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

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年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Labdane-type Diterpene Dialdehyde, Pungent Principle of Myoga, Zingiber mioga Roscoe 査読

Masako Abe, Yoshio Ozawa, Yasushi Uda, Yoichi Yamada, Yasujiro Morimitsu, Yoshimasa Nakamura, Toshihiko Osawa

Bioscience, Biotechnology and Biochemistry 66 ( 12 ) 2698 - 2700 2002年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

The pungent principle of myoga (Zingiber mioga Roscoe) was identified as (E)-8β(17)-epoxylabd-12-ene-15,16-dial (miogadial) on the basis of its physical and spectroscopic properties (MS, NMR, IR, and UV). Galanal A and B, isolated as well as miogadial, had no hot taste. Reduced miogadial also was tasteless. The pungency of miogadial depended on the presence of αβ-unsaturated-1,4-dialdehyde group. © 2002 by Japan Society for Bioscience, Biotechnology, and Agrochemistry.

DOI： 10.1271/bbb.66.2698

Black tea polyphenols, theaflavins, prevent cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P450 1A1 in cell cultures 査読

Q Feng, Y Torii, K Uchida, Y Nakamura, Y Hara, T Osawa

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 50 ( 1 ) 213 - 220 2002年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER CHEMICAL SOC

Tea polyphenols have been demonstrated as chemopreventive agents in a number of experimental models. However, less is known about the mechanism of chemoprevention by black tea compared with that of green tea. Some beneficial properties of theaflavins, the black tea polyphenols, were investigated in the present study. Theaflavins showed inhibitory effects on H2O2- and tert-butyl hydroperoxide (tBuOOH)-induced cytotoxicity (evaluated by tetrazolium bromide reduction), cellular oxidative stress (detected by oxidation of 2', 7'-dichlorofluorescin), and DNA damage (measured by amount of 8-OHdG and comet assay) in rat normal liver epithelium cell RL-34 cell lines. In addition, theaflavins also exhibited suppression of cytochrome P450 1A1 induced by omeprazole in the human hepatoma HepG2 cell line. Furthermore, when HepG2 cells were pretreated with omeprazole to induce CYP1A1, then exposed to benzo[a]pyrene (B[a]P), DNA damage was observed using the comet assay. However, theaflavins could inhibit this DNA damage. These results indicated that theaflavins could prevent cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P450 1A1 in cell cultures.

DOI： 10.1021/jf010875c

Role of p38 mitogen-activated protein kinase in the 4-hydroxy-2-nonenal-induced cyclooxygenase-2 expression 査読

T Kumagai, Y Nakamura, T Osawa, K Uchida

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 397 ( 2 ) 240 - 245 2002年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

COX-2 is rapidly expressed by various stimuli and plays a key role in conversion of free arachidonic acid to prostaglandins (PGs). 4-Hydroxy-2-nonenal (HNE), one of the lipid peroxidation end-products, has been recently identified as a potent COX-2 inducer in rat epithelial cell RL34 cells (Kumagai et al (2000) Biochem. Biophys. Res. Commun. 273, 437-441. Here we investigated the molecular mechanism underlying the COX-2 induction by HNE mainly focusing on the activation of p38 mitogen-activated protein kinase (MAPK) pathways. The observations that (i) HNE induced phosphorylation of p38 MAPK and MKK3/MKK6 within 5 min and that (ii) SB203580, a p38 MAPK-specific inhibitor, suppressed the HNE-induced COX-2 expression suggested that the p38 MAPK pathway was involved in the HNE-induced COX-2 expression. Overexpression of p38 MAPK enhanced the HNE-induced COX-2 expression, whereas the overexpression of dominant negative p38 MAPK suppressed it. Furthermore, we also found that HNE upregulated the COX-2 expression by the stabilization of COX-2 mRNA via the p38 MAPK pathway. (C) 2001 Elsevier Science.

DOI： 10.1006/abbi.2001.2601

The amide hydrogen of (-)-indolactam-V and benzolactam-V8's plays a critical role in protein kinase C binding and tumor-promoting activities 査読

Y Nakagawa, K Irie, Y Nakamura, H Ohigashi

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 11 ( 5 ) 723 - 728 2001年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

To investigate the role of the amide hydrogen of (-)-indolactam-V (1) and benzolactam-V8's on protein kinase C (PKC) binding and tumor promotion, 8-decylbenzolactone-V8 (6), a new lactone analogue of 8-decylbenzolactam-V8 (4), was synthesized from 2-nitrophenylpyruvic acid (7) in 11 steps. The PKC binding ability and tumor-promoting activities in vitro of 6 were much lower than those of 1 and 4, suggesting that the amide hydrogen of 1 and benzolactam-V8's plays a critical role in tumor promotion. However, it is noteworthy that 6 showed significant selectivity in the PKC isozyme surrogate binding. (C) 2001 Published by Elsevier Science Ltd.

DOI： 10.1016/S0960-894X(01)00047-6

The C4 hydroxyl group of phorbol esters is not necessary for protein kinase C binding 査読

M Tanaka, K Irie, Y Nakagawa, Y Nakamura, H Ohigashi, PA Wender

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 11 ( 5 ) 719 - 722 2001年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

To investigate the role of the hydroxyl group at position 4 of the phorbol esters in protein kinase C (PKC) binding and function, 4 beta -deoxy-phorbol-12,13-dibutyrate (4 beta -deoxy-PDBu, 5a) and 4 beta -deoxy-phorbol-13-acetate (6a) were synthesized from phorbol (1). The binding affinities of these 4 beta -deoxy compounds (5a, 6a) to the 13 PKC isozyme C1 domains were quite similar to those of the corresponding 4 beta -hydroxy compounds (4a, 4b), suggesting that the C4 hydroxyl group of phorbol esters is not necessary for PKC binding. Moreover, functional assays showed that 4 beta -deoxy-PDBu (5a) exhibited biological activities (Epstein-Barr virus induction and superoxide generation) equally potent to those of PDBu (4a). These solution phase results differ from expectations based on the previously reported solid-phase structure of the complex of PKC delta -C1B and phorbol-13-acetate (4b). (C) 2001 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0960-894X(01)00045-2

Anticarcinogenic antioxidants as inhibitors against intracellular oxidative stress 査読

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

FREE RADICAL RESEARCH 35 ( 6 ) 779 - 788 2001年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：TAYLOR & FRANCIS LTD

Oxidative stress has been implicated in the pathogenesis of numerous diseases, including cancer. In the present study, the protective effect of natural antioxidants, such as quercetin and tea polyphenols, on intracellular oxidative stress was studied. Here we report a novel function of quercetin and tea polyphenols, as potential inhibitors of 4-hydroxy2-nonenal (HNE)-induced intracellular oxidative stress and cytotoxicity In rat liver epithelial RL34 cells, a potent electrophile HNE dramatically induced the productions of reactive oxygen species (ROS), which correlated well with the reduction in cell viability We found that quercetin and tea polyphenols, such as epigallocatechin gallate and theaflavins and their gallate esters, significantly inhibited the HNE-induced ROS production and cytotoxicity. In addition, HNE induced a transient decrease in the mitochondrial membrane potential (Deltapsi), which was also retarded by the antioxidants. These data suggest that the antioxidants, such as quercetin and tea polyphenols, are inhibitors against mitochondrial ROS production.

DOI： 10.1080/10715760100301281

Toxic dose of a simple phenolic antioxidant, protocatechuic acid, attenuates the glutathione level in ICR mouse liver and kidney 査読

Y. Nakamura, K. Torikai, H. Ohigashi

Journal of Agricultural and Food Chemistry 49 ( 11 ) 5674 - 5678 2001年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

It has previously been reported that a toxic dose of protocatechuic acid (PA), a naturally occurring simple phenolic antioxidant in dietary plant foodstuff, has a potential to enhance tumorigenesis and induce contact hypersensitivity in mouse skin. In this study, the modifying effect of a toxic dose of PA on the glutathione (GSH) level in mouse liver and kidney was examined. Intraperitoneal administration of PA (500 mg/kg) caused significant hepatic and nephrotic GSH depletion. Interestingly, slight but significant hepatotoxicity and nephrotoxicity, characterized by the enhancement of plasmic alanine aminotrasferase (ALT) activity and urea level, respectively, were also observed. The subchronic administration of PA (0.1% in drinking water) for 60 days showed not only a significant decrease in the GSH level in kidney but also a significant enhancement of ALT activity in plasma. The protective role of GSH for acute hepatotoxicity using GSH-depleted mice administered a GSH synthesis inhibitor buthionine sulfoximine was also demonstrated. Thus, it is suggested that overdoses of PA can disturb the detoxification of other electrophilic toxicants including ultimate carcinogens.

DOI： 10.1021/jf0106594

Suppression by citrus auraptene of phorbol ester and endotoxin-induced inflammatory responses: role of attenuation of leukocyte activation 査読

A Murakami, Y Nakamura, T Tanaka, K Kawabata, D Takahashi, K Koshimizu, H Ohigashi

CARCINOGENESIS 21 ( 10 ) 1843 - 1850 2000年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Auraptene (AUR), a citrus coumarin derivative, is one of the promising chemopreventive agents against skin, tongue, esophagus and colon carcinogenesis in rodents, We reported previously that AUR suppresses superoxide anion (O-2(-)) generation from inflammatory leukocytes in in vitro experiments, In the present study, we investigated the antiinflammatory activities of AUR using a 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin model, and compared them with those nf umbelliferone (UMB), a structural analog of AUR that is virtually inactive toward O-2(-) generation inhibition. Double pre-treatments of mouse skin with AUR, but not UMB, markedly suppressed edema formation, hydrogen peroxide production, leukocyte infiltration, and the rate of proliferating cell nuclear antigen-stained cells. These inhibitory effects by AUR are attributable to its selective blockade of the activation stage, as revealed by single pre-treatment experiments. In a murine macrophage line, RAW 264.7, AUR significantly attenuated the lipopolysaccharide-induced protein expression of inducible isoforms of both nitric oxide synthase and cyclooxygenase, with decreased production of nitrite anion and prostaglandin E-2, and yet suppressed the release of tumor necrosis factor-alpha. Conversely, UMB did not show any inhibitory effect, This contrasting activity profile between AUR and UMB was rationalized to be a result of their distinct differences in cellular uptake efficiencies, i.e. the geranyloxyl group in AUR was found to play an essential role in incorporation Thus, our findings indicate that AUR is an effective agent to attenuate the biochemical responsiveness of inflammatory leukocytes, which may be essential for a greater understanding of the action mechanism that underlies its inhibition of inflammation-associated carcinogenesis.

DOI： 10.1093/carcin/21.10.1843

Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice 査読

A Murakami, Y Nakamura, K Torikai, T Tanaka, T Koshiba, K Koshimizu, S Kuwahara, Y Takahashi, K Ogawa, M Yano, H Tokuda, H Nishino, Y Mimaki, Y Sashida, S Kitanaka, H Ohigashi

CANCER RESEARCH 60 ( 18 ) 5059 - 5066 2000年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC CANCER RESEARCH

The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Cia rcs unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O(2)(-)) generation was induced by a combination of lipopolysaccharide and IFN-gamma in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting, The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O(2)(-) generation, Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E(2) release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 mu mol)/TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2% (P < 0.001) and 75.7% (P < 0.001), respectively. The present study suggests that nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.

4-hydroxy-2-nonenal, the end product of lipid peroxidation, is a specific inducer of cyclooxygenase-2 gene expression 査読

T Kumagai, Y Kawamoto, Y Nakamura, Hatayama, I, K Satoh, T Osawa, K Uchida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 273 ( 2 ) 437 - 441 2000年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC

Cyclooxygenase-2 (COX-2), an enzyme responsible for catalyzing the committed step in prostanoid biosynthesis, is the product of an immediate early gene capable of being upregulated by diverse stimuli. Based on the experimental evidence that oxidative stress is associated with the upregulation of COX-2, we evaluated the effect of the oxidized fatty acid metabolites on COX-2 induction in rat liver epithelial RL34 cells, Among the compounds tested, only 4-hydroxy-2-nonenal (HNE), a highly mutagenic and genotoxic aldehyde generated during oxidative stress, dramatically induced COX-2. Enhanced gene expression of COX-2 by treatment with HNE was evident as a drastic elevation of the mRNA level. We also found that intracellular glutathione status was strictly related to HNE-induced COX-2 expression. These findings suggest the presence of a signaling pathway in the cellular response mediated by locally produced lipid peroxidation products under oxidative stress. (C) 2000 Academic Press.

DOI： 10.1006/bbrc.2000.2967

Novel nitric oxide and superoxide generation inhibitors, persenone A and B, from avocado fruit 査読

OK Kim, A Murakami, Y Nakamura, N Takeda, H Yoshizumi, H Ohigashi

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 48 ( 5 ) 1557 - 1563 2000年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER CHEMICAL SOC

One known, (2R)-(12Z,15Z)-2-hydroxy-4-oxoheneicosa-12,15-dien-1-yl acetate (1), and two novel compounds, persenone A (2) and B (3), have been isolated from avocado fruit (Persea americana P. Mill), as inhibitors of superoxide (O-2(-)) and nitric oxide (NO) generation in cell culture systems. They showed marked inhibitory activities toward NO generation induced by lipopolysaccharide in combination with interferon-gamma in mouse macrophage RAW 264.7 cells. Their inhibitory potencies of NO generation (1, IC50 = 3.6; 2, IC50 = 1.2; and 3, IC50 = 3.5 mu M) were comparable to or higher than that of a natural NO generation inhibitor, docosahexaenoic acid (DKA; IC50 = 4.3 mu M). Furthermore, compounds 1-3 and DHA markedly suppressed tumor promoter 12-O-tetradecanoylphorbol-13-acetate-induced O-2(-) generation in differentiated human promyelocytic HL-60 cells (1, EC50 = 33.7; 2, IC50 = 1.4; 3, IC50 = 1.8; and DHA, IC50 = 10.3 mu M). It is notable that they were found to be suppressors of both NO- and O-2(-)-generating biochemical pathways but not to be radical scavengers. The results indicate that these compounds are unique antioxidants, preferentially suppressing radical generation, and thus may be promising as effective chemopreventive agent candidates in inflammation-associated carcinogenesis.

DOI： 10.1021/jf990977r

Cyclopentenone prostaglandins as potential inducers of phase II detoxification enzymes. 15-deoxy-δ prostaglandin J2-induced expression of glutathione S-transferases 査読

Yoshiyuki Kawamoto, Yoshimasa Nakamura, Yuko Naito, Yasuyoshi Torii, Takeshi Kumagai, Toshihiko Osawa, Hajime Ohigashi, Kimihiko Satoh, Masayoshi Imagawa, Koji Uchida

Journal of Biological Chemistry 275 ( 15 ) 11291 - 11299 2000年4月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

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 protective enzymes, such as glutathione S-transferases (GSTs). In the present study, we developed a cell culture system that potently responds to phenolic antioxidants and found that antitumor prostaglandins (PGs) are potential inducers of GSTs. We screened primary hepatocytes and multiple cell lines for inducing GST activity upon incubation with the phenolic antioxidant (tert- butylhydroquinone) and found that rat liver epithelial RL34 cells most potently responded. Based on an extensive screening of diverse chemical agents on the induction of GST activity in RL34 cells, the J2 series of PGs, 15-deoxy-Δ 12,14 -prostaglandin J2 (15-deoxy-Δ 12,14 PGJ2) in particular, were found to be potential inducers of GST. Enhanced gene expression of Class π GST isozyme (GSTP1) by 15-deoxy-Δ 12,14 -PGJ2 was evident as a drastic elevation of the mRNA level. Hence, we examined the molecular mechanism underlying the 15-deoxyΔ 12,14 -PGJ2-induced GSTP1 gene expression. From functional analysis of various deletion mutant genes, we found that the 15-deoxy-Δ 12,14 -pGJ2 reponse element was localized in a region containing a GSTP1 enhancer I (GPEI) that consists of two imperfect phorbol 12-0-tetradecanoylphorbol-13-acetate response elements. When the GPEI was combined with the minimum GSTP1 promoter, the element indeed showed an enhancer activity in response to 15-deoxy-Δ 12,14 -PGJ2. Point mutations of either of the two imperfect 12-O-tetradecanoylphorbol-13-acetate response elements in GPEI completely abolished the enhancer activity. Gel mobility shift assays demonstrated that 15-deoxy-Δ 12,14 -pGJ2 specifically stimulated the binding of nuclear proteins including the transcription factor c-Jun, but not Nrf2, to GPEI. These results suggest that 15-deoxy- Δ 12,14 -PGJ2 induces the expression of the rat GSTP1 gene through binding of proteins, including c-Jun, to a specific GPEI.

DOI： 10.1074/jbc.275.15.11291

Search for Naturally-occurring Antioxidative Chemopreventors on the Basis of the Involvement of Leukocyte-derived Reactive Oxygen Species in Carcinogenesis 査読

Yoshimasa Nakamura, Akira Murakami, Hajime Ohigashi

Asian Pacific Journal of Cancer Prevention 1 115 - 120 2000年1月

担当区分：筆頭著者

Chemoprevention with food phytochemicals is currently regarded as one of the most attractive strategies for cancer control. We have been continuously working on the identification and characterization of chemopreventive phytochemicals extracted from a diverse range of edible plants. Recently, we have utilized a convenient assay, the tumor promoter-induced superoxide generation test, with differentiated HL-60 cells for primary screening, and performed chemical studies of antioxidative food phytochemicals. Here, we report our criteria for evaluation of new types of chemopreventors on the basis of the involvement of leukocyte-derived reactive oxygen in carcinogenesis.

Suppressive effects of citrus fruits on free radical generation and nobiletin, an anti-inflammatory polymethoxyflavonoid 査読

A Murakami, Y Nakamura, Y Ohto, M Yano, T Koshiba, K Koshimizu, H Tokuda, H Nishino, H Ohigashi

BIOFACTORS 12 ( 1-4 ) 187 - 192 2000年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Citrus fruit intake is known to be associated with a reduction of cancer incidence. Free radicals, including superoxide (O(2)(-)) and nitric oxide (NO), are involved in some epithelial carcinogenesis processes. In the present study, we screened thirty-one citrus fruits for their suppressive activities toward three lines of free radical generating systems: 1) O(2)(-) generation by the xanthine (XA)-xanthine oxidase (XOD) system; 2) O(2)(-) generation induced by 1 2-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocytic HL-60 cells; and 3) NO generation in murine macrophage RAW264.7 cells stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma. As a result, the inhibitory activities of peel parts were largely found to be higher than those of the corresponding juice sac parts. In particular, the peel portion of Dancy tangerine (Citrus tangerina) showed marked anti-oxidative activities in these systems. In addition, nobiletin, a polymethoxyflavonoid isolated from C. nobilis, showed a higher anti-inflammatory activity than indomethacin in a TPA-induced edema formation test in mouse ears. These results indicate that citrus fruits could be notable sources of anti-oxidative, anti-inflammatory, and cancer preventive compounds.

Kurosu, a traditional vinegar produced from unpolished rice, suppresses lipid peroxidation in vitro and in mouse skin 査読

Shoko Nishidai, Yoshimasa Nakamura, Koji Torikai, Mikako Yamamoto, Nobuhiro Ishihara, Hirotaka Mori, Hajime Ohigashi

Bioscience, Biotechnology and Biochemistry 64 ( 9 ) 1909 - 1914 2000年

記述言語：英語掲載種別：研究論文（学術雑誌）

The in vitro antioxidative activities of various kinds of vinegar were investigated by using a linoleic acid autoxidation model detected by the thiobarbituric acid (TBA) method and the 1,1-diphenyl-2-picrylhydrazyl radical system. An ethyl acetate extract of Kurosu (EK), a vinegar made from unpolished rice, exhibited the highest antioxidative activity in both systems. EK (5 mg) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced edema formation (14%) and myeloperoxidase activity (52%, P&lt
0.01) in female ICR mouse skin. Furthermore, EK significantly suppressed double TPA application-induced H2O2 generation (53%, P&lt
0.01) and lipid peroxidation determined by the TBA-reacting substance level (95%, P&lt
0.01). In a two-stage carcinogenesis experiment with dimethylbenz[a]anthracene/TPA, EK significantly reduced the number of tumors per mouse by 36% (P&lt
0.05) at 15 weeks after promotion. These results suggest that the antitumor-promoting effect may be partially due to the antioxidative properties of EK such as the decomposition of free radicals and interference with free radical-generating leukocytes. © 2000, Taylor &amp
Francis Group, LLC. All rights reserved.

DOI： 10.1271/bbb.64.1909

An avocado constituent, persenone A, suppresses expression of inducible forms of nitric oxide synthase and cyclooxygenase in macrophages, and hydrogen peroxide generation in mouse skin 査読

Oe Kyung Kim, Akira Murakami, Daisuke Takahashi, Yoshimasa Nakamura, Koji Torikai, Ha Won Kim, Hajime Ohigashi

Bioscience, Biotechnology and Biochemistry 64 ( 11 ) 2504 - 2507 2000年

記述言語：英語掲載種別：研究論文（学術雑誌）

We investigated the suppressive effects of an avocado constituent, persenone A, on lipopolysaccharide- and interferon-γ-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in a mouse macrophage cell line RAW 264.7. Persenone A at concentration of 20 μM almost completely suppressed both iNOS and COX-2 protein expression. In mouse skin, double treatments with persenone A (810 nmol) significantly suppressed double 12-O-tetradecanoylphorbol-13-acetate (TPA, 8.1 nmol) application-induced hydrogen peroxide (H2O2) generation. Treatment with persenone A before the second TPA treatment was sufficient to inhibit H2O2 generation, while the first treatment was not. This study thus suggests that persenone A is a possible agent to prevent inflammation-associated diseases including cancer. © 2000, Taylor &amp
Francis Group, LLC. All rights reserved.

DOI： 10.1271/bbb.64.2504

Inhibition by (-)-Persenone A-related compounds of nitric oxide and superoxide generation from inflammatory leukocytes 査読

Oe Kyung Kim, Akira Murakami, Yoshimasa Nakamura, Ha Won Kim, Hajime Ohigashi

Bioscience, Biotechnology and Biochemistry 64 ( 11 ) 2500 - 2503 2000年

記述言語：英語掲載種別：研究論文（学術雑誌）

We have previously reported that persenone A, isolated from avocado fruit, is an effective inhibitor of both nitric oxide (NO) and superoxide (O2−) generation in cell culture systems. In this study, we have prepared four persenone A-related compounds and examined their inhibition of NO and O2− generation from inflammatory leukocytes. Some structural importance in persenone A to attenuate free radical generation is discussed. © 2000, Taylor &amp
Francis Group, LLC. All rights reserved.

DOI： 10.1271/bbb.64.2500

Synthesis and tumor-promoting activities of 12-Epi-phorbol-12,13-dibutyrate 査読

Kazuhiro Irie, Akifumi Nakahara, Yasuyuki Ikawa, Minoru Tanaka, Yu Nakagavva, Yoshimasa Nakamura, Hajime Ohigashi, Paul A. Wender

Bioscience, Biotechnology and Biochemistry 64 ( 11 ) 2429 - 2436 2000年

記述言語：英語掲載種別：研究論文（学術雑誌）

12-Epi-phorbol-12,13-dibutyrate (1), the C12-epimer of the most frequently used phorbol ester probe, phorbol-12,13-dibutyrate (PDBu), has been synthesized from phorbol in 9 steps in order to investigate the structural requirements for tumor-promoting activity. Compound 1 showed about 100-fold weaker in vitro biological activities related to in vivo tumor promotion, Epstein-Barr virus early antigen (EBV-EA)-inducing ability, superoxide (O2 −) generation-inducing ability, and binding to the protein kinase C (PKC) regulatory domain surrogate peptides. The results indicated that the β-stereochemistry at position 12 of the phorbol skeleton is important for optimal activity. Binding selectivity to each PKC C1 domain of 1 was almost equal to that of PDBu. © 2000, Taylor &amp
Francis Group, LLC. All rights reserved.

DOI： 10.1271/bbb.64.2429

Nitric oxide synthase is induced in tumor promoter-sensitive, but not tumor promoter-resistant, JB6 mouse epidermal cells cocultured with interferon-γ-stimulated RAW 264.7 Cells: The role of tumor necrosis factor-α 査読

A. Murakami, K. Kawabata, T. Koshiba, G. Gao, Y. Nakamura, K. Koshimizu, H. Ohigashi

Cancer Research 60 ( 22 ) 6326 - 6331 2000年

記述言語：英語掲載種別：研究論文（学術雑誌）

Expression of inducible nitric oxide synthase (iNOS) has been reported to be involved in certain organs of potential tumorigenesis, including the stomach and colon. The mechanisms for iNOS expression in epithelial cells, however, are not fully understood. In the present study, we investigated the role of macrophages in epithelial iNOS expression by coculturing a stimulated murine macrophage-like cell line, RAW 264.7, with either tumor promoter-sensitive (P+) or promoter-resistant (P-) JB6 murine epidermal cells. After monoculture, treatment of RAW 264.7 cells with IFN-γ for 24 h generated a large amount of nitrite (NO 2 - ), as reported previously, whereas no increase in NO 2 - concentration was observed in the IFN-γ-treated P+ or P- subclones. Interestingly, when IFN-γ-treated RAW 264.7 cells were cocultured with P+ but not P- cells, we observed a marked increase in NO 2 - concentration (30.8 ± 3.6 μM), which significantly exceeded (P < 0.01) the sum of the concentrations (20.0 ± 2.3 μM) added from each cell line monoculture. Western blotting analysis revealed that, after coculture, iNOS protein was up-regulated 55-fold more than the control in JB6 P+ but not in P- cells. IFN-γ-treated RAW 264.7 cells secreted proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β. The addition of IFN-γ-treated RAW 264.7 cell-conditioned media to P+ subclones led to a significant enhancement of NO 2 - formation that was diminished by the TNF-α-specific but not IL-1β-specific antibody. When combined with IFN-γ, the recombinant TNF-α (1-100 ng/ml) enhanced NO 2 - formation in JB6 P+ cells, whereas IL-1β (1-100 ng/ml) did not. These results led us to conclude that IFN-γ-treated RAW 264.7 cells release TNF-α to induce iNOS expression in promoter-sensitive JB6 cells. Thus, we propose the hypothesis that macrophages stimulate neoplastic cells with TNF-α via a paracrine loop to induce epithelial iNOS protein expression.

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