研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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An electron spin resonance study on alkylperoxyl radical in thin-sliced renal tissues from ferric nitrilotriacetate-treated rats: the effect of alpha-tocopherol feeding

Toyokuni S, Masumizu T, Ozeki M, Kondo S, Hiroyasu M, Kohno M, Hiai H

FREE RADICAL RESEARCH 35 巻 ( 3 ) 頁： 245 - 255 2001年

Difference in Thioredoxin Expression in Viral Myocarditis in Inbred Strains of Mice

Miyamoto Miki, Kishimoto Chiharu, Shioji Keisuke, Nakamura Hajime, Toyokuni Shinya, Nakayama Yukie, Kita Masakazu, Yodoi Junji, Sasayama Shigetake

JAPANESE CIRCULATION JOURNAL 65 巻 ( 6 ) 頁： 561 - 564 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：社団法人日本循環器学会

Redox regulating mechanisms may be involved in the pathogenesis of viral myocarditis and thioredoxin (TRX) is a small multifunctional protein that contains a redox active sequence. The present study investigated the histopathology and characteristics of TRX expression in acute coxsackievirus B3 myocarditis in inbred strains of mice (severe myocarditis in DBA/2 mice, moderate myocarditis in BALB/c mice and mild myocarditis in C57BL/6 mice). Thioredoxin was upregulated and its expression correlated with the severity of the disease. In addition, 8-hydroxy-2'-deoxyguanosine, which is an established marker for oxidative stress, was concominantly positive in damaged myocytes. Thus, TRX may be specifically induced by the acute inflammatory stimuli in murine viral myocarditis, and the severity and development of acute viral myocarditis may be regulated by the cellular redox state. (Jpn Circ J 2001; 65: 561 - 564)

DOI： 10.1253/jcj.65.561

PubMed

CiNii Research

境界悪性卵巣粘液性腫ようの再発との細胞学的鑑別が困難であった子宮頚部上皮内腺癌の１例国際誌

小椋聖子, 清水恵子, 小林八郎, 豊國伸哉, 桜井幹己

日本臨床細胞学会雑誌 40 巻 ( 6 ) 頁： 636 - 640 2001年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：特定非営利活動法人日本臨床細胞学会

背景:近年, 診断法や治療法の進歩に伴う治癒率の向上とともに, 婦人科領域の重複癌発生率が上昇している. 婦人科領域の細胞診断の際に重複癌を疑う像に遭遇することがあるが, その判定に苦慮することは少なくない. 今回われわれは, 境界悪性卵巣粘液性腫瘍の再発との鑑別が困難であった子宮頸部上皮内腺癌の1例を報告する. 症例:55歳, 女性. 3年前に右卵巣腫瘍破裂のため, 右付属器摘出術が施行され, 右卵巣境界悪性粘液性腫瘍, 腸上皮型, Ic期と診断された. 外来での経過観察中, 子宮頸部擦過細胞診にて異型腺細胞集団が認められ, 子宮頸部腺系病変あるいは卵巣粘液性腫瘍の再発が疑われた. 単純子宮全摘術および左付属器摘出術が施行され, 摘出標本の組織診で子宮頸部上皮内腺癌と診断された. 子宮体部, 左付属器に悪性所見は認められなかった. 結論:婦人科領域における重複癌の診断においては, 細胞所見のみならず臨床所見や画像診断を加味した総合的な判断が必要である.

DOI： 10.5795/jjscc.40.636

CiNii Research

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Iron-induced oxidative damage in colon carcinoma (Caco-2) cells

Núñez M., Tapia V., Toyokuni S., Okada S.

Free Radical Research 34 巻 ( 1 ) 頁： 57 - 68 2001年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Research

Intestinal epithelial cells have an active apical iron uptake system that is involved in the regulated absorption of iron. By the action of this system, intestinal cells acquire increasing amounts of iron with time. Since intracellular reactive iron is a source of free radicals and a possible cause of colon carcinoma, this study analyzed the oxidative damages generated by iron accumulation in Caco-2 cells. Cells cultured with increasing concentrations of iron increased both total intracellular iron and the reactive iron pool, despite an active IRE/IRP system, which regulates intracellular iron levels. Increasing concentrations of iron resulted in increased protein oxidative damage, as shown by the immunoreactivity for 4-hydroxy-2-nonenal-modified proteins, and markedly induced DNA oxidation determined by 8-hydroxy-2′-deoxyguanidine production. Iron also impaired cell viability, resulting in increased cell death after 6 days of culture. In summary, iron accumulation by intestinal Caco-2 cells correlated with oxidative damage to proteins and DNA. Oxidative damage finally resulted in loss of cell viability. The Fe-induced oxidative damage observed may be relevant in understanding the cascade of events associated with iron-mediated colon carcinogenesis.

DOI： 10.1080/10715760100300061

Scopus

Iron-induced oxidative damage in colon carcinoma (Caco-2) cells 査読有り

MT Nunez, Tapia, V, S Toyokuni, S Okada

FREE RADICAL RESEARCH 34 巻 ( 1 ) 頁： 57 - + 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：HARWOOD ACAD PUBL GMBH

Intestinal epithelial cells have an active apical iron uptake system that is involved in the regulated absorption of iron. By the action of this system, intestinal cells acquire increasing amounts of iron with time. Since intracellular reactive iron is a source of free radicals and a possible cause of colon carcinoma, this study analyzed the oxidative damages generated by iron accumulation in Caco-2 cells. Cells cultured with increasing concentrations of iron increased both total intracellular iron and the reactive iron pool, despite an active IRE/IRP system, which regulates intracellular iron levels. Increasing concentrations of iron resulted in increased protein oxidative damage, as shown by the immunoreactivity for 4-hydroxy-2-nonenal-modified proteins, and markedly induced DNA oxidation determined by 8-hydroxy-2'-deoxyguanidine production. Iron also impaired cell viability, resulting in increased cell death after 6 days of culture. In summary, iron accumulation by intestinal Caco-2 cells correlated with oxidative damage to proteins and DNA. Oxidative damage finally resulted in loss of cell viability. The Fe-induced oxidative damage observed may be relevant in understanding the cascade of events associated with iron-mediated colon carcinogenesis.

Web of Science

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Iron-induced oxidative damage in colon carcinoma (Caco-2) cells

Nunez MT, Tapia V, Toyokuni S, Okada S

FREE RADICAL RESEARCH 34 巻 ( 1 ) 頁： 57 - + 2001年

Helicobacter pylori eradication attenuates oxidative stress in human gastric mucosa 国際誌

Pignatelli B., Bancel B., Plummer M., Toyokuni S., Patricot L., Ohshima H.

American Journal of Gastroenterology 96 巻 ( 6 ) 頁： 1758 - 1766 2001年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Gastroenterology

OBJECTIVE: Helicobacter pylori infection causes gastric diseases, but the responsible mechanisms are not completely understood. They can involve DNA and tissue damage induced by reactive oxygen and nitrogen species. Our aim is to investigate the effects of bacterial eradication on oxidative stress by measuring changes of relevant markers. METHODS: Antral biopsies were obtained from 34 patients with chronic atrophic gastritis and peptic ulcer disease before and after bacterial eradication. The expression of inducible nitric oxide synthase (iNOS) and levels of nitrotyrosine (NTYR) and 8-hydroxy-2′-deoxyguanosine were assessed immunohistochemically as markers of nitric oxide (NO) production and of damage to proteins and DNA, respectively. RESULTS: Before treatment, the percentages of patients with staining were: 56 for iNOS in inflammatory cells, 79 and 61 for NTYR and 8-hydroxy-2′-deoxyguanosine in foveolar cells, respectively, and 82 for 8-hydroxy-2′-deoxyguanosine in lymphoid follicles. NTYR staining was associated with the intensity of inflammation (p = 0.04) and gastritis activity (p = 0.07). The prevalence of 8-hydroxy-2′-deoxyguanosine tended to be associated with that of NTYR. After successful H. pylori eradication, the prevalence of iNOS and NTYR (in mild gastritis) staining decreased (p < 0.001 and p < 0.06, respectively). 8-Hydroxy-2′-deoxyguanosine staining disappeared in 24% of cases but appeared in 18% of previously negative cases despite eradication. CONCLUSION: Targets of oxidative stress associated with H. pylori infection are inflammatory and deep foveolar cells and lymphoid follicles. This is the first report of 8-hydroxy-2′-deoxyguanosine localization in gastric mucosa. Oxidative stress is reduced by bacterial eradication in the first stages of mild gastritis. Moderate-severe gastritis may be a step that is reversible for iNOS, but partly irreversible for NTYR and 8-hydroxy-2′-deoxyguanosine. © 2001 Am. Coll. of Gastroenterology.

DOI： 10.1111/j.1572-0241.2001.03869.x

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Helicobacter pylori eradication attenuates oxidative stress in human gastric mucosa

Pignatelli B., Bancel B., Plummer M., Toyokuni S., Patricot L.M., Ohshima H.

American Journal of Gastroenterology 96 巻 ( 6 ) 頁： 1758 - 1766 2001年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Gastroenterology

DOI： 10.1016/S0002-9270(01)02432-7

Scopus

Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice

Okada K., Wangpoengtrakul C., Tanaka T., Toyokuni S., Uchida K., Osawa T.

Journal of Nutrition 131 巻 ( 8 ) 頁： 2090 - 2095 2001年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Nutrition

Protective effects of curcumin (U1), one of the major yellow pigments in turmeric and its derivative, tetrahydrocurcumin (THU1), against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage were studied in male ddY mice. Single Fe-NTA treatment (5 mg Fe/kg body intraperitoneally) transiently causes oxidative stress, as shown by the accumulation of lipid peroxidation products and 8-hydroxy-2′-deoxyguanosine in the kidney. Mice were fed with a diet containing 0.5 g/100 g U1 or THU1 for 4 wk. THU1 significantly inhibited 2-thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2′-deoxyguanosine formation in the kidney; U1 inhibited only 4-hydroxy-2-nonenal-modified protein formation. To elucidate the mechanisms of protection by U1 and THU1, the pharmacokinetics and radical-scavenging capacities of U1 and THU1 were investigated by HPLC and electron spin resonance spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide, respectively. Induction of antioxidant enzymes was also investigated. The amounts of THU1 and its conjugates (as sulfates and glucuronides) in the liver and serum were larger in the THU1 group than in the U1 group. The amounts of U1 and its conjugates were small even in the U1 group. These results suggest that THU1 is more easily absorbed from the gastrointestinal tract than U1. Furthermore, THU1 induced antioxidant enzymes, such as glutathione peroxidase, glutathione S-transferase and NADPH: quinone reductase, as well as or better than U1 and scavenged Fe-NTA-induced free radicals in vitro better than U1. These results suggest that U1 is converted to THU1 in vivo and that THU1 is a more promising chemopreventive agent.

DOI： 10.1093/jn/131.8.2090

Scopus

Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage

Kallay E., Pietschmann P., Toyokuni S., Bajna E., Hahn P., Mazzucco K., Bieglmayer C., Kato S., Cross H.S.

Carcinogenesis 22 巻 ( 9 ) 頁： 1429 - 1435 2001年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Carcinogenesis

The vitamin D receptor knockout (VDR-KO) mouse presents with a skeletal phenotype typical for complete lack of genomic 1,25-dihydroxycholecalciferol effects. Our previous data from human colorectal tissue suggest that the steroid hormone and its receptor may have protective function against tumour progression. In order to investigate the relevance of the vitamin D system for pre-malignant site-directed changes in the colon, we characterized the amount and site-specific distribution of the VDR along the large intestine in wild-type (WT), heterozygote (HT) and KO mice. We also evaluated expression of proliferating cell nuclear antigen (PCNA), of cyclin D1 and the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative stress. In colon ascendens, proliferative cells were dispersed all along the crypt and expression levels of all three markers were high in WT mice. A decrease of VDR expression did not affect expression significantly. In colon descendens, however, fewer proliferative cells were solely located in the lower third of the crypt, and an inverse relationship between VDR reduction, PCNA positivity and cyclin D1 expression was found in HT and KO mice. In parallel to enhanced proliferation a highly significant increase of 8-OHdG positivity occurred. Therefore, the sigmoid colon of VDR-KO mice, fed on an appropriate lactose/calcium-enriched diet to alleviate impaired calcium homeostasis-related phenotypic changes, is an excellent model for investigating induction and prevention of pre-malignant changes in one of the hotspots for human colorectal cancer incidence.

DOI： 10.1093/carcin/22.9.1429

Scopus

An electron spin resonance study on alkylperoxyl radical in thin-sliced renal tissues from ferric nitrilotriacetate-treated rats: the effect of alpha-tocopherol feeding

Toyokuni S, Masumizu T, Ozeki M, Kondo S, Hiroyasu M, Kohno M, Hiai H

FREE RADICAL RESEARCH 35 巻 ( 3 ) 頁： 245 - 255 2001年

An electron spin resonance study on alkylperoxyl radical in thin-sliced renal tissues from ferric nitrilotriacetate-treated rats: The effect of α-tocopherol feeding

Toyokuni S., Masumizu T., Ozeki M., Kondo S., Hiroyasu M., Kohno M., Hiai H.

Free Radical Research 35 巻 ( 3 ) 頁： 245 - 255 2001年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Research

Formation of excess free radical causes cellular oxidative stress, which has been shown to be associated with a variety of pathologic conditions. While electron spin resonance (ESR) spectroscopy has been the only method to demonstrate the presence of free radicals, its application to tissue samples has been challenging. We report here the successful ESR detection in thin-sliced fresh tissues or frozen sections in a rat model. Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal tubular damage that ultimately leads to high incidence of renal carcinoma in rodents. Twenty minutes after administration of 5 mg iron/kg Fe-NTA to rats, a thin-slice of the kidney was mounted on a tissue-type cell and analyzed by ESR spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). An ESR signal from alkylperoxyl radical adduct was obtained, and the signal was inversely proportional to renal α-tocopherol content which was modulated through diet. Furthermore, we undertook ex vivo study using frozen sections. Fe-NTA (1mM) was added to a rat kidney frozen section for 10 min. After washing the specimen was mounted on a tissue-type cell and analyzed with ESR spin trapping using DMPO. Alkylperoxyl radical signal was dependent on thickness, incubation time and renal tissue levels of α-tocopherol, and was reduced by preincubation with catalase or dimethyl sulfoxide but not with α-tocopherol outside tissue. This versatile method facilitates identification of free radicals in pathologic conditions, and may be useful for selection of antioxidants.

DOI： 10.1080/10715760100300781

Scopus

Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis 査読有り国際誌 Open Access

Kawamura K., Kobayashi Y., Kageyama F., Kawasaki T., Nagasawa M., Toyokuni S., Uchida K., Nakamura H.

American Journal of Gastroenterology 95 巻 ( 12 ) 頁： 3596 - 3601 2000年12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：American Journal of Gastroenterology

OBJECTIVE: The mechanisms responsible for hepatic injury have not been fully clarified in primary biliary cirrhosis (PBC). It has recently been suggested that hepatic lipid peroxidation may be involved in the pathogenesis of PBC. The aims of the current study were to determine whether patients with PBC have evidence of enhanced hepatic lipid peroxidation and to evaluate its relationship to clinicopathological features. METHODS: Immunohistochemical detection of 4-hydroxynonenal (HNE) protein adducts was performed in the liver biopsies of 20 patients with PBC. Histological stages of PBC were evaluated. Orcein or Victoria blue staining was performed for detection of copper-associated proteins. The size of bile ducts was defined as the smallest diameter between the subepithelial basement membranes. RESULTS: All 20 patients had immunodetectable HNE protein adducts in the cytoplasm of damaged, but also intact, biliary cells. The mean diameter of bile ducts with HNE protein adducts was smaller than those without the adducts (61.0 ± 1.9 vs 122.5 ± 24.4 μm, respectively, p < 0.01). Out of 20 patients, 6 (30%) also had immunodetectable HNE protein adducts in hepatocytes preferentially located around the portal tracts. Most of the patients with hepatocytic HNE protein adducts had copper-associated protein granules in hepatocytes around the portal tracts and were classified as histological stage 3, whereas all of the patients without the adducts lacked copper-associated protein granules and were classified as histological stage 1 or 2. The patients with hepatocytic HNE protein adducts had higher levels of serum total bilirubin than did those without the adducts (2.9 ± 0.9 vs 0.7 ± 0.1 mg/dl, respectively, p < 0.01). CONCLUSIONS: Hepatic lipid peroxidation can occur in PBC and may be an early event in bile duct destruction. At advanced stages of PBC, hepatocellular lipid peroxidation may play a role in hepatocyte injury during cholestasis. (C) 2000 by Am. Coll. of Gastroenterology.

DOI： 10.1016/S0002-9270(00)02093-1

Scopus

Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis 国際誌

Kawamura, K; Kobayashi, Y; Kageyama, F; Kawasaki, T; Nagasawa, M; Toyokuni, S; Uchida, K; Nakamura, H

AMERICAN JOURNAL OF GASTROENTEROLOGY 95 巻 ( 12 ) 頁： 3596 - 3601 2000年12月

Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis 査読有り国際誌

Kawamura K, Kobayashi Y, Kageyama F, Kawasaki T, Nagasawa M, Toyokuni S, Uchida K, Nakamura H

AMERICAN JOURNAL OF GASTROENTEROLOGY 95 巻 ( 12 ) 頁： 3596 - 3601 2000年12月

Activating transcripton factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression

Ban N., Yamada Y., Someya Y., Ihara Y., Adachi T., Kubota A., Watanabe R., Kuroe A., Inada A., Miyawaki K., Sunaga Y., Shen Z.P., Iwakura T., Tsukiyama K., Toyokuni S., Tsuda K., Seino Y.

Diabetes 49 巻 ( 7 ) 頁： 1142 - 1148 2000年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Diabetes

Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity o the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV- induced ATF-2 transcriptional activity was not altered by activation of c-Jun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic β- cells, with the transcriptional activity of ATF2 being increased by an elevated concentration of calcium ions.

DOI： 10.2337/diabetes.49.7.1142

Scopus

Activating transcription factor-2 is a positive regulator in CaM kinase IV - Induced human insulin gene expression

Ban N, Yamada Y, Someya Y, Ihara Y, Adachi T, Kubota A, Watanabe R, Kuroe A, Inada A, Miyawaki K, Sunaga Y, Shen ZP, Iwakura T, Tsukiyama K, Toyokuni S, Tsuda K, Seino Y

DIABETES 49 巻 ( 7 ) 頁： 1142 - 1148 2000年7月

Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression. 国際誌

N Ban, Y Yamada, Y Someya, Y Ihara, T Adachi, A Kubota, R Watanabe, A Kuroe, A Inada, K Miyawaki, Y Sunaga, Z P Shen, T Iwakura, K Tsukiyama, S Toyokuni, K Tsuda, Y Seino

Diabetes 49 巻 ( 7 ) 頁： 1142 - 8 2000年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity of the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV-induced ATF-2 transcriptional activity was not altered by activation of cJun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic beta-cells, with the transcriptional activity of ATF-2 being increased by an elevated concentration of calcium ions.

PubMed

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Heat-shock preconditioning reduces oxidative protein denaturation and ameliorates liver injury by carbon tetrachloride in rats 査読有り国際誌

Yamamoto H, Yamamoto Y, Yamagami K, Kume M, Kimoto S, Toyokuni S, Uchida K, Fukumoto M, Yamaoka Y

RESEARCH IN EXPERIMENTAL MEDICINE 199 巻 ( 6 ) 頁： 309 - 318 2000年6月

Expression of stress-response and cell proliferation genes in renal cell carcinoma induced by oxidative stress

Tanaka T, Kondo S, Iwasa Y, Hiai H, Toyokuni S

AMERICAN JOURNAL OF PATHOLOGY 156 巻 ( 6 ) 頁： 2149 - 2157 2000年6月

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