Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Pericardial fluid from patients with ischemic heart disease induces myocardial cell apoptotis via an oxidant stress-sensitive p38 mitogen-activated protein kinase pathway

Iwakura, A; Fujita, M; Hasegawa, K; Toyokuni, S; Sawamura, T; Nohara, R; Sasayama, S; Komeda, M

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Vol. 33 ( 3 ) page： 419 - 430 2001.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Molecular and Cellular Cardiology

Factors produced by the heart are accumulated at high concentrations in pericardial fluid. We recently reported that pericardial fluid from patients with ischemic heart disease induces apoptosis in an F2 cell line. To characterize factors in pericardial fluid from patients with ischemic heart disease, we investigated signaling pathways by which this pericardial fluid induces apoptosis in cardiac myocytes. Pericardial fluid from patients with ischemic heart disease markedly increased the percentage of TUNEL-positive myocytes compared with fetal bovine serum. Apoptosis was also confirmed by ladder formation and morphologic features. Apoptosis mediated by this pericardial fluid occurs as readily in cardiac myocytes prepared from neonatal mice nullizygous for p53 as in wild-type littermates. This indicates that p53 is not required for this process. We have found that pericardial fluid from ischemic heart disease elicits a robust increase in phosphorylation of p38 mitogen-activated protein kinase. Specific inhibition of the p38 mitogen-activated protein kinase pathway with SB 203580 almost completely blocked apoptosis mediated by pericardial fluid from ischemic heart disease. Activation of p38 mitogen-activated protein kinase is caused by cellular stress, including oxidants. We have also found that anti-oxidant catalase inhibited pericardial fluid-induced activation of p38 mitogen-activated protein kinase and apoptosis. These findings demonstrate that myocardial cell apoptosis induced by pericardial fluid from patients with ischemic heart disease is mediated by an oxidant stress-sensitive p38 mitogen-activated protein kinase pathway. A possible application of SB 203580 to preserve cardiac function in patients with ischemic heart disease should be discussed.

DOI： 10.1006/jmcc.2000.1314

Web of Science

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PubMed

Angiosarcoma of the scalp: absence of vascular endothelial cadherin in primary and metastatic lesions

Tanioka M, Ikoma A, Morita K, Fujii H, Toda KI, Takahashi K, Tanaka T, Nishigori C, Jin G, Higashi S, Toyokuni S, Miyachi Y

BRITISH JOURNAL OF DERMATOLOGY Vol. 144 ( 2 ) page： 380 - 383 2001.2

Angiosarcoma of the scalp: absence of vascular endothelial cadherin in primary and metastatic lesions

Tanioka M, Ikoma A, Morita K, Fujii H, Toda KI, Takahashi K, Tanaka T, Nishigori C, Jin G, Higashi S, Toyokuni S, Miyachi Y

BRITISH JOURNAL OF DERMATOLOGY Vol. 144 ( 2 ) page： 380 - 383 2001.2

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 Vol. 35 ( 3 ) page： 245 - 255 2001

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 Vol. 65 ( 6 ) page： 561 - 564 2001

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Circulation Society

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

A case of cevical adenocarcinoma in situ with difficulty in cytological differentiation from recurrent ovarian tumor of borderline malignancy.

OGURA Seiko, SHIMIZU Keiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, SAKURAI Masami

The Journal of the Japanese Society of Clinical Cytology Vol. 40 ( 6 ) page： 636 - 640 2001

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Clinical Cytology

Background: The incidence of multiple primary cancers of the female genital tract is increaseing, but these are difficult to correctly diagnose by cytological smear. We report a case of heterochronous double cancer consisting of adenocarcinoma in situ of the uterine cervix and mucinous cystic tumor with borderline malignancy of the ovary. Case: A 55-year-old woman with a ruptured right ovarian tumor had right salping000phorectomy 3 years earlier. The histological diagnosis of her ovarian tumor was mucinous cystic tumor with borderline malignancy. Atypical glandular cells were later found in a uterine cervical smear, but no abnormal findings were seen in clinical examination. Total hysterectomy combined with left salpingooophorectomy was done. The histological examination proved to be adenocarcinoma in situ of the uterine cervix. No malignancy was found in the uterine corpus or left adnexa. Conclusion: Multiple malignancies of the female genital tract should be made combining cytology, clinical data, and diagnostic imaging.

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 Vol. 34 ( 1 ) page： 57 - 68 2001

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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

FREE RADICAL RESEARCH Vol. 34 ( 1 ) page： 57 - + 2001

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

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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 Vol. 34 ( 1 ) page： 57 - + 2001

Helicobacter pylori eradication attenuates oxidative stress in human gastric mucosa

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

American Journal of Gastroenterology Vol. 96 ( 6 ) page： 1758 - 1766 2001

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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

Scopus

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 Vol. 96 ( 6 ) page： 1758 - 1766 2001

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Vol. 131 ( 8 ) page： 2090 - 2095 2001

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Vol. 22 ( 9 ) page： 1429 - 1435 2001

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 nitrilotriacetatetreated rats : the effect of alpha-tocopherol feeding

TOYOKUNI S

Free Radic Res Vol. 35 ( 3 ) page： 245 - 255 2001

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 Vol. 35 ( 3 ) page： 245 - 255 2001

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 International journal

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

AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95 ( 12 ) page： 3596 - 3601 2000.12

Enchanced hepatic lipid peroxidation in patients with primary biliary cirrhosis Reviewed International journal

KAWAMURA K

Am J Gastroenterol Vol. 95 ( 12 ) page： 3596 - 3601 2000.12

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 Vol. 49 ( 7 ) page： 1142 - 1148 2000.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Vol. 49 ( 7 ) page： 1142 - 1148 2000.7

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

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 Vol. 49 ( 7 ) page： 1142 - 8 2000.7

Language：English Publishing type：Research paper (scientific journal)

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.

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Papers - TOYOKUNI Shinya