Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter. International journal

Nobuhiro Ban, Yuichiro Yamada, Yoshimichi Someya, Kazumasa Miyawaki, Yu Ihara, Masaya Hosokawa, Shinya Toyokuni, Kinsuke Tsuda, Yutaka Seino

Diabetes Vol. 51 ( 5 ) page： 1409 - 18 2002.5

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

Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene have been linked to subtype 3 of maturity-onset diabetes of the young (MODY), a disease characterized by a primary defect in insulin secretion. Here we show that the human GLUT2 gene is closely regulated by HNF-1alpha via sequences downstream of the transcriptional start site by interaction with transcriptional co-activator p300. The promoter region of the human GLUT2 gene was subcloned into luciferase expression plasmids that were transfected together with HNF-1alpha expression plasmid into a pancreatic beta-cell line, HIT-T15, to evaluate transcriptional activities. HNF-1alpha enhanced human GLUT2 promoter activity sixfold. Site-direct mutagenesis and footprint analyses showed that the HNF-1alpha binding site (+200 to +218) is critical in human GLUT2 gene expression. Furthermore, mammalian two-hybrid and immunoprecipitation studies revealed the transactivation domain of HNF-1alpha (amino acids 391-540) to interact with both the NH(2)-terminal region (amino acids 180-662) and the COOH-terminal region (amino acids 1,818-2,079) of p300. These findings demonstrated that HNF-1alpha binds to the 5'-untranslated region of GLUT2 and that p300 acts as a transcriptional co-activator for HNF-1alpha. In addition, these results provided new insight into the regulatory function of HNF-1alpha by suggesting a molecular basis for human GLUT2 gene expression.

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Increase in oxidative stress in kidneys of diabetic Akita mice Reviewed International journal

Ueno Y, Horio F, Uchida K, Naito M, Nomura H, Kato Y, Tsuda T, Toyokuni S, Osawa T

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY Vol. 66 ( 4 ) page： 869 - 872 2002.4

Increase in Oxidative Stress in Kidneys of Diabetic Akita Mice. International journal

UENO Yuki, HORIO Fumihiko, UCHIDA Koji, NAITO Michitaka, NOMURA Hideki, KATO Yoji, TSUDA Takanori, TOYOKUNI Shinya, OSAWA Toshihiko

Bioscience, Biotechnology, and Biochemistry Vol. 66 ( 4 ) page： 869 - 72 2002.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Society for Bioscience, Biotechnology, and Agrochemistry

New biomarkers for oxidative damage, were used to identify whether hyperglycemia caused oxidative stress in diabetic Akita mice. At 13 weeks of age, the tissues of these mice were obtained, and the levels of Nε-(hexanonyl)lysine (HEL) and dityrosine (DT) were measured, these being related to lipid peroxide-derived protein covalent modification and protein cross-linking. The levels of HEL and DT in the kidneys of Akita mice were significantly increased compared with the control mice without any accumulation of thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified protein. Immunopositive staining was clearly observed in the kidneys of the Akita mice when using the anti-HEL antibody or anti-DT antibody. These results suggest that hyperglycemia in Akita mice induced oxidative stress and increased these markers in the kidneys.

DOI： 10.1271/bbb.66.869

Increase in oxidative stress in kidneys of diabetic Akita mice Reviewed International journal

Ueno Y, Horio F, Uchida K, Naito M, Nomura H, Kato Y, Tsuda T, Toyokuni S, Osawa T

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY Vol. 66 ( 4 ) page： 869 - 872 2002.4

Analysis of suspicious endometrial cytology : based on architectural atypia

SHIMIZU Keiko, OGURA Seiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, NORIMATU Yoshiaki, MORIYA Takuya, SAKURAI Masami

The Journal of the Japanese Society of Clinical Cytology Vol. 41 ( 2 ) page： 89 - 97 2002.3

Analysis of suspicious endometrial cytology : based on architectural atypia

SHIMIZU Keiko, OGURA Seiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, NORIMATU Yoshiaki, MORIYA Takuya, SAKURAI Masami

The Journal of the Japanese Society of Clinical Cytology Vol. 41 ( 2 ) page： 89 - 97 2002.3

Adenovirus-mediated gene delivery and in vitro microinsemination produce offspring from infertile male mice. Reviewed International journal

Mito Kanatsu-Shinohara, Atsuo Ogura, Masaya Ikegawa, Kimiko Inoue, Narumi Ogonuki, Kei Tashiro, Shinya Toyokuni, Tasuku Honjo, Takashi Shinohara

Proceedings of the National Academy of Sciences of the United States of America Vol. 99 ( 3 ) page： 1383 - 8 2002.2

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

Sertoli cells play a pivotal role in spermatogenesis through their interactions with germ cells. To set up a strategy for treating male infertility caused by Sertoli cell dysfunction, we developed a Sertoli cell gene transfer system by using an adenovirus vector, which maintained long-term transgene expression in the testes of infertile mice. Introduction of an adenovirus carrying the mouse Steel (Sl) gene into Sertoli cells restored partial spermatogenesis in infertile Steel/Steel(dickie) (Sl/Sl(d)) mutant mouse testes. Although these males remained infertile, round spermatids and spermatozoa from the testes produced normal fertile offspring after intracytoplasmic injection into oocytes. None of the offspring showed evidence of germ line transmission of adenoviral DNA. Thus, we demonstrate a successful treatment for infertility by using a gene therapy vector. Therefore, adenovirus-mediated gene delivery into Sertoli cells not only provides an efficient and convenient means for studying germ cell-Sertoli cell interactions through manipulation of the germ cell microenvironment in vivo, but also is a useful method to treat male infertility resulting from a Sertoli cell defect.

DOI： 10.1073/pnas.022646399

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Adenovirus-mediated gene delivery and in vitro microinsemination produce offspring from infertile male mice

Kanatsu-Shinohara M, Ogura A, Ikegawa M, Inoue K, Ogonuki N, Tashiro K, Toyokuni S, Honjo T, Shinohara T

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 99 ( 3 ) page： 1383 - 1388 2002.2

Specific allelic loss of p16(INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis

Hiroyasu M, Ozeki M, Kohda H, Echizenya M, Tanaka T, Hiai H, Toyokuni S

AMERICAN JOURNAL OF PATHOLOGY Vol. 160 ( 2 ) page： 419 - 424 2002.2

Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis

Jikimoto T, Nishikubo Y, Koshiba M, Kanagawa S, Morinobu S, Morinobu A, Saura R, Mizuno K, Kondo S, Toyokuni S, Nakamura H, Yodoi J, Kumagai S

MOLECULAR IMMUNOLOGY Vol. 38 ( 10 ) page： 765 - 772 2002.2

Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis.

Jikimoto T, Nishikubo Y, Koshiba M, Kanagawa S, Morinobu S, Morinobu A, Saura R, Mizuno K, Kondo S, Toyokuni S, Nakamura H, Yodoi J, Kumagai S

Molecular immunology Vol. 38 ( 10 ) page： 765 - 72 2002.2

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

There is no doubt that oxidative stress occurs in patients with rheumatoid arthritis (RA) and play an important role in both inflammation and destruction of RA joints. Thioredoxin (TRX) is a ubiquitous redox-active protein and is known to be induced in several cells against oxidative stress and to be secreted extracellularly. To clarify whether plasma thioredoxin levels could be a marker for oxidative stress in patients with RA, we measured plasma TRX levels in patients with RA using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) and investigated its relationship to TRX concentrations in the inflammatory joints. We have found that the plasma TRX levels of RA patients were significantly higher than those of normal subjects (86.8 ± 54.1 ng/ml versus 38.6 ± 18.5 ng/ml, P <0.0001). The plasma levels were correlated with the disease activity of RA and also with serum C-reactive protein (CRP) values (P <0.01). The concentration of TRX in synovial fluid (SF) from RA was 353.3 ± 220.1 ng/ml (mean ± S.D.) which was significantly higher than that in SF from osteoarthritis patients (70.6 ± 31.0 ng/ml, P <0.0001). The SF TRX concentration was significantly correlated with the number of leukocytes infiltrating in SF and with the serum CRP levels. The serum TRX levels were significantly positively correlated with the SF TRX concentrations in RA patients (P <0.05). By the histological examination for synovial tissue of RA patients, TRX was shown to be present on the surface of synovial lining layer as well as in the leukocytes. Moreover, urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage by endogenously generated oxygen radicals, was significantly higher in RA patients than in healthy subjects (11.55 ± 4.71 versus 7.76 ± 2.26 ng/mg creatinine, P <0.0001). Plasma TRX levels were significantly correlated with urinary excretion of 8-OHdG (P <0.005). We concluded that plasma TRX level is a new biomarker for the disease activity of RA and may reflect higher levels of oxidative stress in RA patients. © 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/s0161-5890(01)00113-4

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Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis. International journal

Makoto Hiroyasu, Munetaka Ozeki, Haruyasu Kohda, Michiko Echizenya, Tomoyuki Tanaka, Hiroshi Hiai, Shinya Toyokuni

The American journal of pathology Vol. 160 ( 2 ) page： 419 - 24 2002.2

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

Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers p16(INK4A) is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of p16 (INK4A). By the use of fluorescent in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (1 or 3 signals) at the p16(INK4A) locus was significantly and specifically increased (1 week, 37.2 +/- 2.3%; 3 weeks, 37.8 +/- 1.3% vs control, 22.5 +/- 1.9%; mean +/- SE, N = 8; P < 0.001 and P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the p53 or vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the p16 (INK4A) locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.

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Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis.

Hiroyasu M, Ozeki M, Kohda H, Echizenya M, Tanaka T, Hiai H, Toyokuni S

The American journal of pathology Vol. 160 ( 2 ) page： 419 - 24 2002.2

Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Pathology

Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers p16INK4A is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of p16INK4A. By the use of fluorescent in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (1 or 3 signals) at the p16INK4A locus was significantly and specifically increased (1 week, 37.2 ± 2.3%; 3 weeks, 37.8 ± 1.3% vs control, 22.5 ± 1.9%; mean ± SE, N = 8; P < 0.001 and P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the p53 or vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the p16INK4A locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.

DOI： 10.1016/S0002-9440(10)64860-2

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Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis. International journal

Takumi Jikimoto, Yuko Nishikubo, Masahiro Koshiba, Sugayo Kanagawa, Sahoko Morinobu, Akio Morinobu, Ryuichi Saura, Kosaku Mizuno, Shohei Kondo, Shinya Toyokuni, Hajime Nakamura, Junji Yodoi, Shunichi Kumagai

Molecular immunology Vol. 38 ( 10 ) page： 765 - 72 2002.2

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

There is no doubt that oxidative stress occurs in patients with rheumatoid arthritis (RA) and play an important role in both inflammation and destruction of RA joints. Thioredoxin (TRX) is a ubiquitous redox-active protein and is known to be induced in several cells against oxidative stress and to be secreted extracellularly. To clarify whether plasma thioredoxin levels could be a marker for oxidative stress in patients with RA, we measured plasma TRX levels in patients with RA using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) and investigated its relationship to TRX concentrations in the inflammatory joints. We have found that the plasma TRX levels of RA patients were significantly higher than those of normal subjects (86.8 +/-54.1 ng/ml versus 38.6 +/-18.5 ng/ml, P<0.0001). The plasma levels were correlated with the disease activity of RA and also with serum C-reactive protein (CRP) values (P<0.01). The concentration of TRX in synovial fluid (SF) from RA was 353.3 +/- 220.1 ng/ml (mean +/- S.D.) which was significantly higher than that in SF from osteoarthritis patients (70.6 +/- 31.0 ng/ml, P<0.0001). The SF TRX concentration was significantly correlated with the number of leukocytes infiltrating in SF and with the serum CRP levels. The serum TRX levels were significantly positively correlated with the SF TRX concentrations in RA patients (P<0.05). By the histological examination for synovial tissue of RA patients, TRX was shown to be present on the surface of synovial lining layer as well as in the leukocytes.Moreover, urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage by endogenously generated oxygen radicals, was significantly higher in RA patients than in healthy subjects (11.55 +/- 4.71 versus 7.76 +/- 2.26 ng/mg creatinine, P<0.0001). Plasma TRX levels were significantly correlated with urinary excretion of 8-OHdG (P<0.005). We concluded that plasma TRX level is a new biomarker for the disease activity of RA and may reflect higher levels of oxidative stress in RA patients.

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Heat shock preconditioning reduces the formation of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal modified proteins in ischemia-reperfused liver of rats. Reviewed International journal

Kazuhiko Yamagami, Yuzo Yamamoto, Shinya Toyokuni, Koichiro Hata, Yoshio Yamaoka

Free radical research Vol. 36 ( 2 ) page： 169 - 76 2002.2

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Heat shock preconditioning (HSPC) is a promising strategy for providing ischemic tolerance. The objective of this study is to investigate the effectiveness of HSPC in preventing oxidative damage of cellular proteins and DNA during ischemia-reperfusion of the liver. Male Wistar rats were divided into a heat shock group (group HS) and control (group C). Forty-eight hours prior to ischemia, rats in group HS received HSPC at 42degreesC for 15 min. All rats received hepatic warm ischemia for 30 min and subsequent reperfusion. The formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE) modified proteins in liver tissue, survival rate of the animals, and changes in biochemical and histological parameters were compared between groups. Heat shock protein 72 was produced only in group HS. The 7-day survival of rats was significantly better in group HS (10/10) than in group C (5/10) (p<0.01). The serum release of alanine aminotransferase (n=10, p<0.01) and the concentration of adenosine triphosphate in liver tissue (n=10, p<0.01) 40 min after reperfusion was significantly better in group HS than in group C. The formation of 8-OHdG in liver tissue measured by high-performance liquid chromatography was suppressed in group HS (p<0.01). The production of HNE-modified proteins as determined by Western-blot analysis was also decreased in group HS. These results were also confirmed by immunohistochemical analysis. As determined by levels of 8-OHdG and HNE-modified proteins produced during ischemia-reperfusion of the liver, HSPC reduced the oxidative injury of cellular proteins and DNA in the liver tissue.

DOI： 10.1080/10715760290006385

Amelioration of cisplatin toxicity by a fermented grain food product

Minamiyama Y, Takemura S, Toyokuni S, Nishino Y, Yamasaki K, Hai S, Yamamoto S, Okada S

BIOFACTORS Vol. 16 ( 3-4 ) page： 105 - 115 2002

Iron and carcinogenesis: from Fenton reaction to target genes. International journal

Shinya Toyokuni

Redox report : communications in free radical research Vol. 7 ( 4 ) page： 189 - 97 2002

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

Reactive oxygen species (ROS) have been shown to be associated with a wide variety of pathological phenomena such as carcinogenesis, inflammation, radiation and reperfusion injury. Iron, the most abundant transition metal ion in our body, may work as a catalyst for the generation of ROS in pathological conditions. In the past few years, there have been great advances in the understanding of iron metabolism. These include the discoveries of iron transporters and the gene responsible for hereditary hemochromatosis. Iron overload has been shown to be associated with carcinogenesis. We recently identified the major target genes (p16(INK4A) and p15(INK4B) tumor suppressor genes, which encode cyclin-dependent kinase inhibitors) in a ferric nitrilotriacetate-induced rat renal carcinogenesis model, in which the Fenton reaction is induced in the renal proximal tubules. Allelic loss of the p16 gene occurs early in carcinogenesis and specifically at the p16 loci as compared with other tumor suppressor genes. This led to the novel concept of 'genomic sites vulnerable to the Fenton reaction'. Here, recent new findings on iron metabolism are reviewed and the concept of the vulnerable sites explored. More effort to link iron metabolism with human carcinogenesis is anticipated.

DOI： 10.1179/135100002125000596

Target genes in fenton reaction-induced carcinogenisis: A novel concept

Toyokuni, S; Hiroyasu, M; Ozeki, M; Hiai, H

FREE RADICAL BIOLOGY AND MEDICINE Vol. 33 page： S177 - S177 2002

Target genes in Fenton reaction-induced carcinogenesis: A novel concept

Toyokuni, S; Hiroyasu, M; Ozeki, M; Hiai, H

XI BIENNIAL MEETING OF THE SOCIETY FOR FREE RADICAL RESEARCH INTERNATIONAL page： 459 - 462 2002

Radiation-induced kidney injury: a role for chronic oxidative stress?

Robbins MEC, Zhao WL, Davis CS, Toyokuni S, Bonsib SM

MICRON Vol. 33 ( 2 ) page： 133 - 141 2002

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Papers - TOYOKUNI Shinya