研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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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 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

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

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

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

Effects of geranyl-geranyl-acetone administration before heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers

Yamagami K, Yamamoto Y, Ishikawa Y, Yonezawa K, Toyokuni S, Yamaoka Y

JOURNAL OF LABORATORY AND CLINICAL MEDICINE 135 巻 ( 6 ) 頁： 465 - 475 2000年6月

Detection of lipofuscin-like fluorophore in oxidized human low-density lipoprotein. 4-Hydroxy-2-nonenal as a potential source of fluorescent chromophore Open Access

Itakura K., Oya-Ito T., Osawa T., Yamada S., Toyokuni S., Shibata N., Kobayashi M., Uchida K.

FEBS Letters 473 巻 ( 2 ) 頁： 249 - 253 2000年5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：FEBS Letters

It has recently been shown that the lipid peroxidation product 4- hydroxy-2-nonenal (HNE) forms a fluorescent hydroxyiminodihydropyrrole derivative with the ε-amino group of lysine residue. In this study, we raised a monoclonal antibody (mAb2C12) directed to the fluorophore-protein conjugate and found that the antibody was specific to the chromophore structure of the compound. Immunohistochemical analysis of atherosclerotic lesions from the human aorta showed that the fluorophore was indeed present in the lesions, in which intense positivity was primarily associated with macrophage-derived foam cells and thickening of the neointima of the arterial walls. Antigenic materials were also detected in the oxidatively modified low-density lipoprotein (LDL) with Cu2+ and in the oxidatively modified bovine serum albumin with an iron/linoleic acid autoxidation system, indicating that the HNE, which originated from the peroxidation of polyunsaturated fatty acids, could be a potential source of the fluorescent chromophore in oxidized LDL. (C) 2000 Federation of European Biochemical Societies.

DOI： 10.1016/S0014-5793(00)01539-8

Scopus

Detection of lipofuscin-like fluorophore in oxidized human low-density lipoprotein - 4-Hydroxy-2-nonenal as a potential source of fluorescent chromophore

Itakura K, Oya-Ito T, Osawa T, Yamada S, Toyokuni S, Shibata N, Kobayashi M, Uchida K

FEBS LETTERS 473 巻 ( 2 ) 頁： 249 - 253 2000年5月

Antioxidant alpha-tocopherol ameliorates glycemic control of GK rats, a model of type 2 diabetes. 査読有り国際誌

Ihara Y, Yamada Y, Toyokuni S, Miyawaki K, Ban N, Adachi T, Kuroe A, Iwakura T, Kubota A, Hiai H, Seino Y

FEBS letters 473 巻 ( 1 ) 頁： 24 - 6 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：FEBS Letters

We have shown recently that oxidative stress by chronic hyperglycemia damages the pancreatic β-cells of GK rats, a model of non-obese type 2 diabetes, which may worsen diabetic condition and suggested the administration of antioxidants as a supportive therapy. To determine if natural antioxidant α-tocopherol (vitamin E) has beneficial effects on the glycemic control of type 2 diabetes, GK rats were fed a diet containing 0, 20 or 500 mg/kg diet α-tocopherol. Intraperitoneal glucose tolerance test revealed a significant increment of insulin secretion at 30 min and a significant decrement of blood glucose levels at 30 and 120 min after glucose loading in the GK rats fed with high α-tocopherol diet. The levels of glycated hemoglobin A1c, an indicator of glycemic control, were also reduced. Vitamin E supplementation clearly ameliorated diabetic control of GK rats, suggesting the importance of not only dietary supplementation of natural antioxidants but also other antioxidative intervention as a supportive therapy of type 2 diabetic patients. Copyright (C) 2000 Federation of European Biochemical Societies.

DOI： 10.1016/s0014-5793(00)01489-7

Web of Science

Scopus

PubMed

Antioxidant α-tocopherol improves glycemic control of GK rats, a model of type 2 diabetes

Ihara, Y; Yamada, Y; Toyokuni, S; Ban, N; Kuroe, A; Seino, Y

DIABETES 49 巻頁： A429 - A429 2000年5月

Upregulation of thioredoxin (TRX) expression in giant cell myocarditis in rats. 査読有り国際誌 Open Access

Shioji K, Kishimoto C, Nakamura H, Toyokuni S, Nakayama Y, Yodoi J, Sasayama S

FEBS letters 472 巻 ( 1 ) 頁： 109 - 13 2000年4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：FEBS Letters

To examine the possible involvement of a redox regulating mechanism in the pathogenesis of immune-mediated myocarditis, myocarditis was induced by immunization of porcine cardiac myosin in rats and immunohistochemistry and Western blot for thioredoxin (TRX) were performed. Immunohistochemistry for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear factor kappa-B (NF-κB) was also performed. TRX was upregulated in the acute stage, but not in the chronic stage, and the expression was correlated with the severity of the disease. Damaged myocytes were strongly immunostained for 8-OHdG and NF-κB. Thus, TRX may be specifically induced by acute inflammatory stimuli, and the development of acute immune-mediated myocarditis may be regulated by the cellular redox state via TRX. Copyright (C) 2000 Federation of European Biochemical Societies.

DOI： 10.1016/s0014-5793(00)01446-0

Web of Science

Scopus

PubMed

Upregulation of thioredoxin (TRX) expression in giant cell myocarditis in rats Open Access

Shioji K, Kishimoto C, Nakamura H, Toyokuni S, Nakayama Y, Yodoi J, Sasayama S

FEBS LETTERS 472 巻 ( 1 ) 頁： 109 - 113 2000年4月

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