Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice. Reviewed International journal Open Access

Hiroshi Iwakura, Kiminori Hosoda, Choel Son, Junji Fujikura, Tsutomu Tomita, Michio Noguchi, Hiroyuki Ariyasu, Kazuhiko Takaya, Hiroaki Masuzaki, Yoshihiro Ogawa, Tatsuya Hayashi, Gen Inoue, Takashi Akamizu, Hiroshi Hosoda, Masayasu Kojima, Hiroshi Itoh, Shinya Toyokuni, Kenji Kangawa, Kazuwa Nakao

The Journal of biological chemistry Vol. 280 ( 15 ) page： 15247 - 56 2005.4

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

We developed and analyzed two types of transgenic mice: rat insulin II promoter-ghrelin transgenic (RIP-G Tg) and rat glucagon promoter-ghrelin transgenic mice (RGP-G Tg). The pancreatic tissue ghrelin concentration measured by C-terminal radioimmunoassay (RIA) and plasma desacyl ghrelin concentration of RIP-G Tg were about 1000 and 3.4 times higher than those of nontransgenic littermates, respectively. The pancreatic tissue n-octanoylated ghrelin concentration measured by N-terminal RIA and plasma n-octanoylated ghrelin concentration of RIP-G Tg were not distinguishable from those of nontransgenic littermates. RIP-G Tg showed suppression of glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion, pancreatic insulin mRNA and peptide levels, beta cell mass, islet architecture, and GLUT2 and PDX-1 immunoreactivity in RIP-G Tg pancreas were not significantly different from those of nontransgenic littermates. Islet batch incubation study did not show suppression of insulin secretion of RIP-G Tg in vitro. The insulin tolerance test showed lower tendency of blood glucose levels in RIP-G Tg. Taking lower tendency of triglyceride level of RIP-G Tg into consideration, these results may indicate that the suppression of insulin secretion is likely due to the effect of desacyl ghrelin on insulin sensitivity. RGP-G Tg, in which the pancreatic tissue ghrelin concentration measured by C-RIA was about 50 times higher than that of nontransgenic littermates, showed no significant changes in insulin secretion, glucose metabolism, islet mass, and islet architecture. The present study raises the possibility that desacyl ghrelin may have influence on glucose metabolism.

DOI： 10.1074/jbc.M411358200

Other Link： http://orcid.org/0000-0001-8033-0736

CYP3A induction more impairs endotoxemic liver injury via reactive oxygen species in rats

Minamiyama, Y; Takemura, S; Kodai, S; Toyokuni, S; Yoshikawa, T; Okada, S

GASTROENTEROLOGY Vol. 128 ( 4 ) page： A709 - A709 2005.4

Long-term culture of mouse male germline stem cells under serum-or feeder-free conditions. Reviewed International journal

Mito Kanatsu-Shinohara, Hiromi Miki, Kimiko Inoue, Narumi Ogonuki, Shinya Toyokuni, Atsuo Ogura, Takashi Shinohara

Biology of reproduction Vol. 72 ( 4 ) page： 985 - 91 2005.4

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

Spermatogonial stem cells are the only stem cells in the body that transmit genetic information to the next generation. These cells can be cultured for extended periods in the presence of serum and feeder cells. However, little is known about factors that regulate self-renewal division of spermatogonial stem cells. In this investigation we examined the possibility of establishing culture systems for spermatogonial stem cells that lack serum or a feeder cell layer. Spermatogonial stem cells could expand in serum-free conditions on mouse embryonic fibroblasts (MEFs), or were successfully cultivated without feeder cells on a laminin-coated plate. However, they could not expand when both serum and feeder cells were absent. Although the cells cultured on laminin differed phenotypically from those on feeder cells, they grew exponentially for at least 6 mo, and produced normal, fertile progeny following transplantation into infertile mouse testis. This culture system will provide a new opportunity for understanding the regulatory mechanism that governs spermatogonial stem cells.

DOI： 10.1095/biolreprod.104.036400

CYP3A induction more impairs endotoxemic liver injury via reactive oxygen species in rats International journal

Minamiyama, Y, Takemura, S, Kodai, S, Toyokuni, S, Yoshikawa, T, Okada, S

GASTROENTEROLOGY Vol. 128 ( 4 ) page： A709 - A709 2005.4

A resected case of multiple early gallbladder carcinomas

URAI Shunji, HAYAKUMO Takanobu, HABU Yasuki, KAWAMURA Takuji, SHIO Seiji, IKEURA Tsukasa, YOSHINO Takuya, HIRAI Kiyoshi, TOYOKUNI Shinya

Nippon Shokakibyo Gakkai Zasshi Vol. 102 ( 3 ) page： 340 - 345 2005.3

Selenium Supplementation Rescues Cardiac Output in Patients with Severe Heart Failure who are Intractable to ACE Inhibitors and β-Blockers(Heart Failure, Clinical 14 (M), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

Hiraoka Yuuji, Kihara Yasuki, Sarazawa Katsuhiko, Inai Yoshihito, Kitagawa Motoaki, Takahashi Nobuki, Hamanaka Ichirou, Yamazaki Taketoshi, Akagi Tadasu, Hama Norio, Tanabe Masato, Sakurai Hiromu, Toyokuni Shinya, Ueda Kinzou

Circulation journal : official journal of the Japanese Circulation Society Vol. 69 ( 0 ) page： 310 2005.3

Circulation journal : official journal of the Japanese Circulation Society Vol. 69 ( 0 ) 2005.3

Genetic selection of mouse male germline stem cells in vitro: offspring from single stem cells. Reviewed International journal Open Access

Mito Kanatsu-Shinohara, Shinya Toyokuni, Takashi Shinohara

Biology of reproduction Vol. 72 ( 1 ) page： 236 - 40 2005.1

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

Spermatogenesis originates from a small population of spermatogonial stem cells. These cells are believed to divide infinitely and support spermatogenesis throughout life in the male. In this investigation, we examined the possibility of deriving transgenic offspring from single spermatogonial stem cells. Spermatogonial stem cells were transfected in vitro with a plasmid vector containing a drug resistant gene. Stably transfected stem cell clones were isolated by in vitro drug selection; these clones were expanded and used to produce transgenic progeny following spermatogonial transplantation into infertile recipients. An average of 49% of the offspring carried the transgene, and the recipient mice continued to produce monoclonal transgenic progeny a year after transplantation. Thus, a somatic cell-based genetic approach can be used to modify and select clones of spermatogonial stem cells in a manner similar to embryonic stem cells. The feasibility of genetic selection using postnatal spermatogonial stem cells demonstrates their extensive proliferative potential and provides the opportunity to develop new methods for generating stable animal transgenics or for germline gene therapy.

DOI： 10.1095/biolreprod.104.035659

Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis. Reviewed International journal Open Access

Shinichiro Chuma, Mito Kanatsu-Shinohara, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shinya Toyokuni, Mihoko Hosokawa, Norio Nakatsuji, Atsuo Ogura, Takashi Shinohara

Development (Cambridge, England) Vol. 132 ( 1 ) page： 117 - 22 2005.1

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

Primordial germ cells (PGCs) are derived from a population of pluripotent epiblast cells in mice. However, little is known about when and how PGCs acquire the capacity to differentiate into functional germ cells, while keeping the potential to derive pluripotent embryonic germ cells and teratocarcinomas. In this investigation, we show that epiblast cells and PGCs can establish colonies of spermatogenesis after transfer into postnatal seminiferous tubules of surrogate infertile mice. Furthermore, we obtained normal fertile offspring by microinsemination using spermatozoa or spermatids derived from PGCs harvested from fetuses as early as 8.5 days post coitum. Thus, fetal male germ cell development is remarkably flexible, and the maturation process, from epiblast cells through PGCs to postnatal spermatogonia, can occur in the postnatal testicular environment. Primordial germ cell transplantation techniques will also provide a novel tool to assess the developmental potential of PGCs, such as those manipulated in vitro or recovered from embryos harboring lethal mutations.

DOI： 10.1242/dev.01555

Reduction of dibetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice. Reviewed

Naito Y, Akagiri S, Uchiyama K, Kokura S, Yoshida N, Hasegawa G, Nakamura N, Ichikawa H, Toyokuni S, Ijichi T, Yoshikawa T.

Biofactors Vol. 23 page： 85-98 2005

Genetic and epigenetic properties of mouse male germline stem cells during long-term culture. Reviewed

Kanatsu-Shinohara M, Ogonuki N, Iwano T, Lee J, Kazuki Y, Inoue K, Miki H, Takehashi M, Toyokuni S, Shinkai Y, Oshimura M, Ishino F, Ogura A, Shinohara T.

Developmnet Vol. 132 page： 4155-4163 2005

Establishment of a diabetic mouse model with progressive diabetic nephropathy. Reviewed

Inada A, Nagai K, Arai H, Miyazaki J, Nomura K, Kanamori H, Toyokuni S, Yamada Y, Bonner-Weir S, Weir GC, Fukatsu A, Seino Y.

Am. J. Pathol. Vol. 167 page： 327-336 2005

Free radical-induced carcinogenesis: Target genes and fragile genome sites

Toyokuni, S; Akatsuka, S; Aung, TT; Dutta, KK

FREE RADICAL RESEARCH Vol. 39 page： S30 - S30 2005

Imidapril, an angiotensin-converting enzyme inhibitor, reduces diabetes-induced renal oxidative damage in mice

Naito Y, Uchiyama K, Akagiri S, Aoi W, Hasegawa G, Nakamura N, Kokura S, Yoshida N, Ichikawa H, Toyokuni S, Yoshikawa T

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 37 ( 1 ) page： 29 - 37 2005

Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice

Naito Y, Akagiri S, Uchiyama K, Kokura S, Yoshida N, Hasegawa G, Nakamura N, Ichikawa H, Toyokuni S, Ijichi T, Yoshikawa T

BIOFACTORS Vol. 23 ( 2 ) page： 85 - 95 2005

Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice.

Naito Y, Akagiri S, Uchiyama K, Kokura S, Yoshida N, Hasegawa G, Nakamura N, Ichikawa H, Toyokuni S, Ijichi T, Yoshikawa T

BioFactors (Oxford, England) Vol. 23 ( 2 ) page： 85 - 95 2005

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

Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Oxykine is the cantaloupe melon extract rich in vegetal superoxide dismutase covered by polymeric films of wheat matrix gliadin. In this study, we examined whether chronic oral administration of oxykine could prevent the progression of diabetic nephropathy induced by oxidative stress using preclinical rodent model of type 2 diabetes. We used female db/db mice and their non-diabetic db/m littermates. The mice were divided into the following three groups: non-diabetic db/m; diabetic db/db, and diabetic db/db treated with oxykine. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were preformed on 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the oxykine-treated group and the non-treated db/db group, however both groups kept significantly high levels rather than db/m mice. The relative mesangial area calculated by mesangial area/total glomerular area ratio was significantly ameliorated in the oxykine treated group compared with non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with oxykine. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than that of oxykine-treated db/db mice. In this study, treatment of oxykine ameliorated the progression and acceleration of diabetic nephropathy for rodent model of type 2 diabetes. These results indicated that the oxykine reduced the diabetes-induced oxidative stress and renal mesangial cell injury. In conclusion, oxykine might be a novel approach for the prevention of diabetes nephropathy. © 2005 - IOS Press and the authors. All rights reserved.

DOI： 10.1002/biof.5520230204

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Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice Reviewed

Y Naito, S Akagiri, K Uchiyama, S Kokura, N Yoshida, G Hasegawa, N Nakamura, H Ichikawa, S Toyokuni, T Ijichi, T Yoshikawa

BIOFACTORS Vol. 23 ( 2 ) page： 85 - 95 2005

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

Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Oxykine is the cantaloupe melon extract rich in vegetal superoxide dismutase covered by polymeric films of wheat matrix gliadin. In this study, we examined whether chronic oral administration of oxykine could prevent the progression of diabetic nephropathy induced by oxidative stress using preclinical rodent model of type 2 diabetes. We used female db/db mice and their non-diabetic db/m littermates. The mice were divided into the following three groups: non-diabetic db/m; diabetic db/db, and diabetic db/db treated with oxykine. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were preformed on 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the oxykine-treated group and the non-treated db/db group, however both groups kept significantly high levels rather than db/m mice. The relative mesangial area calculated by mesangial area/total glomerular area ratio was significantly ameliorated in the oxykine treated group compared with non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with oxykine. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than that of oxykine-treated db /db mice. In this study, treatment of oxykine ameliorated the progression and acceleration of diabetic nephropathy for rodent model of type 2 diabetes. These results indicated that the oxykine reduced the diabetes-induced oxidative stress and renal mesangial cell injury. In conclusion, oxykine might be a novel approach for the prevention of diabetes nephropathy.

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Imidapril, an angiotensin-converting enzyme inhibitor, reduces diabetes-induced renal oxidative damage in mice Reviewed

Y Naito, K Uchiyama, S Akagiri, W Aoi, G Hasegawa, N Nakamura, S Kokura, N Yoshida, H Ichikawa, S Toyokuni, T Yoshikawa

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 37 ( 1 ) page： 29 - 37 2005

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

The aim of the present study was to determine whether imidapril, an angiotensin-converting enzyme inhibitor, prevents diabetic nephropathy and to determine the effect of imidapril on oxidative damage in the diabetic glomeruli in mice. We used female BKS.cg-m+Lepr(db)/+Lepr(db) (db/db) mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into the following four groups: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with imidapril at doses of 1 mg/kg and 5 mg/kg. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the imidapril-treated group and the non-treated db/db group. The systolic blood pressure was significantly increased in db/db mice compared with db/m mice. The increased blood pressure was significantly reduced by the treatment with imidapril at a dose of 5 mg/kg. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the imidapril-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with imidapril in a dose-dependent manner. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than in the imidapril-treated db/db mice. In conclusion, imidapril prevented the progression of diabetic nephropathy in mice, not only by decreasing the glomerular pressure but also by decreasing the oxidative stress in glomerular cells.

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Control of the peri-operative oxidative stress enables fast recovery from myocardial ischemic damage in cardic surgery. Reviewed

Takaba K, Matsumura K, Miwa S, Yamazaki K, Nishina K, Nomoto T, Toyokuni S, Hyon SH, Ikeda T, Komeda M

International Redox Network 2005（2005.11.9－11. kyoto） 2005

Generation of pluripotent stem cells from neonatal mouse testis. Reviewed International journal

Mito Kanatsu-Shinohara, Kimiko Inoue, Jiyoung Lee, Momoko Yoshimoto, Narumi Ogonuki, Hiromi Miki, Shiro Baba, Takeo Kato, Yasuhiro Kazuki, Shinya Toyokuni, Megumi Toyoshima, Ohtsura Niwa, Mitsuo Oshimura, Toshio Heike, Tatsutoshi Nakahata, Fumitoshi Ishino, Atsuo Ogura, Takashi Shinohara

Cell Vol. 119 ( 7 ) page： 1001 - 12 2004.12

Language：English Publishing type：Research paper (scientific journal) Publisher：7

Although germline cells can form multipotential embryonic stem (ES)/embryonic germ (EG) cells, these cells can be derived only from embryonic tissues, and such multipotent cells have not been available from neonatal gonads. Here we report the successful establishment of ES-like cells from neonatal mouse testis. These ES-like cells were phenotypically similar to ES/EG cells except in their genomic imprinting pattern. They differentiated into various types of somatic cells in vitro under conditions used to induce the differentiation of ES cells and produced teratomas after inoculation into mice. Furthermore, these ES-like cells formed germline chimeras when injected into blastocysts. Thus, the capacity to form multipotent cells persists in neonatal testis. The ability to derive multipotential stem cells from the neonatal testis has important implications for germ cell biology and opens the possibility of using these cells for biotechnology and medicine.

DOI： 10.1016/j.cell.2004.11.011

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Papers - TOYOKUNI Shinya