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Activation of stress signaling pathways by the end product of lipid peroxidation - 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production 査読

K Uchida, M Shiraishi, Y Naito, Y Torii, Y Nakamura, T Osawa

JOURNAL OF BIOLOGICAL CHEMISTRY 274 ( 4 ) 2234 - 2242 1999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 SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

In the present study, we studied the signal transduction mechanism that is involved in the expression of c-Jun protein evident after exposure of rat liver epithelial RL34 cells to the major end product of oxidized fatty acid metabolism, 4-hydroxy-2-nonenal (HNE). HNE treatment of the cells resulted in depletion of intracellular glutathione (GSH) and in the formation of protein-bound HNE in plasma membrane. In addition, HNE strongly induced intracellular peroxide production, suggesting that HNE exerted oxidative stress on the cells. Potent expression of c-Jun occurred within 30 min of HNE treatment, which was accompanied by a time-dependent increase in activator protein-1 (AP-1) DNA binding activity. We found that HNE caused an immediate increase in tyrosine phosphorylation in RL34 cells, In addition, HNE strongly induced phosphorylation of c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases and also moderately induced phosphorylation of extracellular signal-regulated kinases. The phosphorylation of JNK was accompanied by a rapid and transient increase in JNK and p38 activities, whereas changes in the activity of extracellular signal-regulated kinase were scarcely observed. GSH depletion by L-buthionine-S,R-sulfoximine, a specific inhibitor of GSH biosynthesis, only slightly enhanced peroxide production and JNK activation, suggesting that HNE exerted these effects independent of GSH depletion. This and the findings that (i) HNE strongly induced intracellular peroxide production, (ii) HNE-induced JNK activation was inhibited by pretreatment of the cells with a thiol antioxidant, N-acetylcysteine, and (iii) H2O2 significantly activated JNK support the hypothesis that pro-oxidants play a crucial role in the HNE-induced activation of stress signaling pathways. In addition, we found that, among the inhibitors of tyrosine kinases, cyclooxygenase, and Ca2+ influx, only quercetin exerted a significant inhibitory effect on HNE-induced JNK activation. In light of the JNK-dependent induction of c-jun transcription and the AP-1-induced transcription of xenobiotic-metabolizing enzymes, these data may show a potential critical role for JNK in the induction of a cellular defense program against toxic products generated from lipid peroxidation.

DOI： 10.1074/jbc.274.4.2234

Isolation and identification of acetylenic spiroketal enol ethers from Artemisia lactiflora as inhibitors of superoxide generation induced by a tumor promoter in differentiated HL-60 cells 査読

Y Nakamura, Y Ohto, A Murakami, S Jiwajinda, H Ohigashi

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 46 ( 12 ) 5031 - 5036 1998年12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）出版者・発行元：AMER CHEMICAL SOC

Six acetylenic compounds were isolated from the leaves of Artemisia lactiflora (Compositae), an edible plant of Thailand. Four of them were identified as the stereoisomers of 3,4-epoxy-2-(2,4-hexadiynylidene)-1,6-dioxaspiro[4.5]decane and its derivatives, whose planar structures have already been reported. The other two were identified as novel chlorohydrin derivatives of the corresponding diacetylene spiroketal enol ethers. The inhibitory effects of the polyacetylenes isolated in the present study together with genistein on TPA-induced O-2(-) generation were examined. It was revealed that an acyloxyl group at the C-2 position enhanced-the inhibitory effect, while the absolute configurations at C-5, -6, and -7 were not important. While polyacetylenes are known to possess several biological roles in various ecosystems, we first found inhibitory effects of the diacetylenes on TPA-induced O-2(-) generation in differentiated HL-60 cells.

DOI： 10.1021/jf980521u

Superoxide scavenging activity of rosmarinic acid from Perilla frutescens Britton var. acuta f. viridis 査読

Y Nakamura, Y Ohto, A Murakami, H Ohigashi

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 46 ( 11 ) 4545 - 4550 1998年11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）出版者・発行元：AMER CHEMICAL SOC

Rosmarinic acid (RoA) has been isolated in high yield (0.1%) from the leaves of Perilla frutescens Britton var, acuta f. viridis, one of the most common garnishes in Japan, as a superoxide scavenger in a xanthine/xanthine oxidase system. The scavenging activity of RoA was significantly higher than that of ascorbic acid (AA). The structure-activity relationships using RoA, caffeic acid (CaA), and its related compounds indicated that the presence of an ortho dihydroxyphenyl group is essential for the scavenging effect. In addition, the conjugated double bond in the C3 carbon chain is important for enhancing the effect. The activity of RoA was then shown to be due to the additive effect of both CaA and (3,4-dihydroxyphenyl)lactic acid units, both of which are hydrolyzed products of RoA. RoA significantly inhibited both intracellular superoxide and peroxide formation in differentiated HL-60 cells, suggesting that RoA effectively exhibited antioxidative activity in the biological systems through the scavenging of superoxide.

DOI： 10.1021/jf980557m

Screening of edible Japanese plants for nitric oxide generation inhibitory activities in RAW 264.7 cells 査読

OK Kim, A Murakami, Y Nakamura, H Ohigashi

CANCER LETTERS 125 ( 1-2 ) 199 - 207 1998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：ELSEVIER SCI IRELAND LTD

A total of 48 (60 test samples) species of plants commonly eaten in Japan were randomly collected and their methanol extracts were tested for in vitro nitric oxide (NO) generation inhibitory activities in a murine macrophage cell line, RAW 264.7, stimulated with both lipopolysaccharide (LPS, 100 ng/ml) and interferon-gamma (IFN-gamma, 100 U/ml). Seventeen (28.3%) of the 48 extracts strongly inhibited NO generation at a concentration of 200 mu g/ml by 70% or more with significant cell viability (>50%). The extracts from avocado, tare, red turnip, sereves, komatsuna, basil, mitsuba and Chinese mustard markedly inhibited iNOS activity. These results suggest that a wide variety of edible plants in Japan contain the secondary metabolites carrying cancer preventive activity through reduction of excess amounts of NO. (C) 1998 Elsevier Science Ireland Ltd.

DOI： 10.1016/S0304-3835(97)00513-2

Synthesis and Biological Activities of (-)-6-n-Octyl-indolactam-V, a New Potent Analogue of the Tumor Promoter (-)-Indolactam-V 査読

Yu Nakagawa, Kazuhiro Irie, Yoshimasa Nakamura, Hajime Ohigashi, Hideo Hayashi

Bioscience, Biotechnology and Biochemistry 62 ( 8 ) 1568 - 1573 1998年

記述言語：英語掲載種別：研究論文（学術雑誌）

(-)-Indolactam-V (1) without a hydrophobic chain at positions 6 and 7 of the indole ring is a weak tumor promoter compared with teleocidin Bs. To investigate the effects of the hydrophobic substituent at position 6 of teleocidin Bs, we synthesized (-)-6-n-octyl-indolactam-V (2) by a palladium-catalyzed coupling reaction from (-)-6-bromo-indolactam-V (7) which had been obtained by microbial conversion with Streptoverticillium blastmyceticum NA34-17 as the key step. (-)-7-n-Octyl-indolactam-V (3) with potent biological activities comparable to those of teleocidin Bs was similarly synthesized from (-)-7-bromo-indolactam-V as a positive control. Compound 2 showed similar biological activities to those of 3, indicating that the effect of the hydrophobic substituent at position 6 of 1 was identical to that at position 7. © 1998, Taylor &amp
Francis Group, LLC. All rights reserved.

DOI： 10.1271/bbb.62.1568

Cellular response to the redox active lipid peroxidation products: Induction of glutathione S-transferase P by 4-hydroxy-2-nonenal 査読

A Fukuda, Y Nakamura, H Ohigashi, T Osawa, K Uchida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 236 ( 2 ) 505 - 509 1997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 JNL-COMP SUBSCRIPTIONS

Membrane lipid peroxidation is known to produce various aldehydic compounds which cause a wide range of biological effects including heart disease, aging, and cancer. To investigate the effect of lipid peroxidation products on the expression of glutathione S-transferases (GSTs), which catalyze the conjugation of reactive chemicals with glutathione and play an important role in protecting cells, normal rat liver epitherial cells (RL34) were exposed to a variety of aldehydic compounds. We found that the GST activity in RL34 cells was induced by alpha,beta-unsaturated aldehydes, such as acrolein (1.3-fold), crotonaldehyde (1.3-fold), 4-hydroxy-2-hexenal (HHE) (1.4-fold), and 4-hydroxy-2-nonenal (HNE) (1.7-fold). The induction of GST activity by HNE was time-dependent, reaching a plateau after 16 h. The immunoblot analysis using the polyclonal antibodies against GST isozymes demonstrated that GST-P (pi-class), a well-known tumor marker, was significantly induced 16 h after the HNE treatment. Also, immunostaining for the presence of GST-P confirmed the enhanced expression of GST-P in the cytoplasm of the cells, Northern blot analysis revealed that the HNE treatment of RL34 cells for 1 h enhanced the expression of GST-P mRNA, which returned to the control level after 16 h. These data suggest that the induction of GST-P by HNE may represent an important cellular defense mechanism against oxidative injury. (C) 1997 Academic Press.

DOI： 10.1006/bbrc.1997.6585

Auraptene, a citrus coumarin, inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in ICR mouse skin, possibly through suppression of superoxide generation in leukocytes 査読

A Murakami, W Kuki, Y Takahashi, H Yonei, Y Nakamura, Y Ohto, H Ohigashi, K Koshimizu

JAPANESE JOURNAL OF CANCER RESEARCH 88 ( 5 ) 443 - 452 1997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：JAPANESE CANCER ASSOC

Coumarin-related compounds, auraptene and umbelliferone, have been isolated from the cold-pressed oil of natsumkian (Citrus natsudaidai HAYATA), and tested as inhibitors of tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus activation in Raji cells. The 50% inhibitory concentration (IC50) of auraptene (18 mu M) was almost equal to that of genistein. Umbelliferone, which lacks a geranyloxyl group present in auraptene, was less active (IC50 = 450 mu M). In a two-stage carcinogenesis experiment with 7,12-dimethylbenz[a]anthracene (topical application at 0.19 mu mol) and TPA (topical application at 1.6 nmol) in ICR mouse skin, topical application of auraptene (at 160 nmol) significantly reduced tumor incidence and the numbers of tumors per mouse by 27% (P < 0.01) and 23% (P < 0.05), respectively. Auraptene at a concentration of 50 mu M markedly suppressed superoxide (O-2(-)) generation induced by 100 nM TPA in differentiated human promyelocytic HL-60 cells. Having no O-2(-) scavenging potential, auraptene may inhibit the multicomponent NADPH oxidase system, Inhibition of intracellular hydroperoxide formation in differentiated HL-60 cells by auraptene was also confirmed by flow-cytometric analysis using 2',7'-dichlorofluorescein diacetate as a fluorescence probe. Quantitative analyses using high-performance liquid chromatography showed the occurrence of auraptene not only in both the peels and sarcocarps of natsumikan, but also in those of hassaku orange (C. hassaku) and grapefruit (C. paradisi), and even in their bottled fresh juice form. These results indicate that auraptene is a chemopreventer of skin tumorigenesis, and implies that suppression of leukocyte activation might be the mechanism through which it inhibits tumor promotion.

Synthesis and Biological Activities of Indolactone-V, the Lactone Analogue of the Tumor Promoter (–)-Indolactam-V 査読

Yu Nakagawa, Kazuhiro Irie, Yoshimasa Nakamura, Hajime Ohigashi, Hideo Hayashi

Bioscience, Biotechnology and Biochemistry 61 ( 8 ) 1415 - 1417 1997年

記述言語：英語掲載種別：研究論文（学術雑誌）

The tumor promoter (–)-indolactam-V (1) exists in two stable conformers (twist and sofa) due to isomerization of the amide group. Indolactone-V (2), the lactone analogue of 1, has been synthesized to investigate the effects of the amide group on its conformation and biological activities. Indolactone-V (2) existed only as the inactive sofa-like conformer, indicating that the amide group of 1 plays a critical role in formation of the active twist conformation. © 1997, Taylor & Francis Group, LLC. All rights reserved.

DOI： 10.1271/bbb.61.1415

Synthesis and biological activities of new conformationally restricted analogues of (-)-indolactam-V: Elucidation of the biologically active conformation of the tumor-promoting teleocidins 査読

K Irie, T Isaka, Y Iwata, Y Yanai, Y Nakamura, F Koizumi, H Ohigashi, PA Wender, Y Satomi, H Nishino

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 118 ( 44 ) 10733 - 10743 1996年11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

The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N-13-desmethyl-N-13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative, Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence beating on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of hew biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.

DOI： 10.1021/ja961727j

1’prime;-Acetoxychavicol acetate, a superoxide anion generation inhibitor, potently inhibits tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in ICR mouse skin 査読

Akira Murakami, Shin Ohura, Yoshimasa Nakamura, Koichi Koshimizu, Hajime Ohigashi

Oncology (Switzerland) 53 ( 5 ) 386 - 391 1996年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

The anti-tumor-promoting activity of 1’-acetoxychavicol acetate (ACA) was examined in a two-stage carcinogenesis experiment in ICR mouse skin using 7,12-dimethylbenz[a]anthracene (0.19 μmol) and 12-O-tetradecanoylphorbol-13-acetate (TPA; 1.6 nmol). Topical application of ACA (160 nmol) markedly reduced the average number of tumors per mouse and the ratio of tumor-bearing mice: inhibition ratios 90% (p < 0.001) and 42% (p < 0.005), respectively. ACA even at a dose equimolar to TPA (1.6 nmol) significantly reduced theaverage number of tumors per mouse: inhibitory ratio 44% (p < 0.05). ACA potently inhibited TPA-induced superoxide (O2) generation in differentiated HL-60 cells (IC50 = 4.3μM) and suppressed the lipid hydroperoxide formation by42% (p < 0.001) in the ethyl linoleate autoxidation test. © 1996 S. Karger AG, Basel.

DOI： 10.1159/000227593

Photocytotoxicity of water-soluble fullerene derivatives 査読

Kazuhiro Irie, Yoshimasa Nakamura, Hajime Ohigashi, Hidetoshi Tokuyama, Shigeru Yamago, Eiichi Nakamura

Bioscience, Biotechnology and Biochemistry 60 ( 8 ) 1359 - 1361 1996年

記述言語：英語掲載種別：研究論文（学術雑誌）

New water-soluble fullerene carboxylic acids (1 and 2) derived from C60 and C70 fullerenes, respectively, were examined for photocytotoxicity toward Raji cells (B lymphocyte). These compounds did not show any photocytotoxic effect even at 50μ m, while pheophorbide a showed significant photocytotoxicity at 0.5 μ m. Therefore, fullerene derivatives derived from C60 and C70 would not be practical agents for photodynamic therapy. © 1996, Taylor &amp
Francis Group, LLC. All rights reserved.

DOI： 10.1271/bbb.60.1359

Identification of Pheophorbide a and Its Related Compounds as Possible Anti-tumor Promoters in the Leaves of Neptunia oleracea 査読

Yoshimasa Nakamura, Akira Murakami, Koichi Koshimizu, Hajime Ohigashi

Bioscience, Biotechnology and Biochemistry 60 ( 6 ) 1028 - 1030 1996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）

Six chlorophyll-related compounds isolated from leaves of Neptunia oleracea (Leguminosae) inhibited the activation of tumor promoter-induced Epstein-Barr virus (EBV). Photo-irradiation of pheophorbide a, the major active constituent, did not enhance this inhibitory activity, and thus ruled out any photosensitizing effect playing the major role. © 1996, Taylor &amp
Francis Group, LLC. All rights reserved.

DOI： 10.1271/bbb.60.1028

GLYCEROGLYCOLIPIDS FROM CITRUS HYSTRIX, A TRADITIONAL HERB IN THAILAND, POTENTLY INHIBIT THE TUMOR-PROMOTING ACTIVITY OF 12-O-TETRADECANOYLPHORBOL 13-ACETATE IN MOUSE SKIN 査読

A MURAKAMI, Y NAKAMURA, K KOSHIMIZU, H OHIGASHI

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 43 ( 10 ) 2779 - 2783 1995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：AMER CHEMICAL SOC

Two glyceroglycolipids were isolated from the leaves of Citrus hystrix (bitter orange), a traditional herb in Thailand. They were identified as 1,2-di-O-alpha-linolenoyl-3-O-beta-galactopyransyl-sn-glycerol (DLGG, I) and a mixture of two compounds, 1-O-alpha-linolenoyl-2-O-palmitoyl-3-O-beta-galactopyranosyl-sn-glycerol (2a) and its counterpart (2b) (LPGG, 2). Both lipids were potent inhibitors of tumor promoter-induced Epstein-Barr virus (EBV) activation. The IC50 values of 1 and 2 were strikingly lower than those of representative cancer preventive agents such as alpha-linolenic acid, beta-carotene, or (-)-epigallocatechin gallate. In a two-stage carcinogenesis experiment on ICR mouse skin with dimethylbenz[alpha]anthracene (DMBA) and 12-O-tetradecanoylphorbol 13-acetate (TPA), compound 1 exhibited anti-tumor-promoting activity even at a dose 10 times lower than that of alpha-linolenic acid. As some synthetic detergents or saponins were entirely inactive in the EBV activation inhibition test, detergency was suggested not to play a major role in the mode of inhibitory action in vivo. The inhibition of the arachidonic acid cascade may be involved in anti-tumor promotion since 1 inhibited TPA-induced edema formation in the anti-inflammation test using ICR mouse ears.

DOI： 10.1021/jf00058a043

SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF NEW CONFORMATIONALLY FIXED ANALOGS OF (-)-INDOLACTAM-V, THE CORE STRUCTURE OF TUMOR-PROMOTING TELEOCIDINS 査読

K IRIE, F KOIZUMI, Y IWATA, T ISHII, Y YANAI, Y NAKAMURA, H OHIGASHI, PA WENDER

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 5 ( 5 ) 453 - 458 1995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

(-)-Indolactam-V(1) exists as two stable conformers, the twist and the sofa form, in solution at room temperature. 3-Aza-Cope rearrangement of (-)-N-13-desmethyl-N-13-allylindolactam-V (5) gave new conformationally restricted analogues (2a and 3) along with a normal rearrangement product (7). Both 2a and 3, whose fixed conformation was the twist form, showed significant biological activities related to tumor promotion.

DOI： 10.1016/0960-894X(95)00047-W

Possible anti-tumor promoting properties of edible plants from thailand, and identification of an active constituent, cardamonin, of boesenbergia pandurata 査読

Akira Murakami, Akira Kondo, Yoshimasa Nakamura, Hajime Ohigashi, Koichi Koshimizu

Bioscience, Biotechnology and Biochemistry 57 ( 11 ) 1971 - 1973 1993年

記述言語：英語掲載種別：研究論文（学術雑誌）

Possible anti-tumor promoting properties of a total of 40 methanol extracts from Thai edible plants, including 5 non-edible species, were estimated in vitro by an inhibition test of tumor promoter-induced Epstein-Barr virus (EBV) activation. Fourteen species (35% of the total) were found to be strongly active. In addition, cardamonin (2′,4′-dihydroxy-6′-methoxychalcone) was identified as a potently active constituent (IC50 = 3.1μM) of Boesenbergia pandurata (Zingiberaceae), suggesting it to be an effective anti-tumor promoter. © 1993 Taylor &amp
Francis Group LLC.

DOI： 10.1080/bbb.57.1971

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