Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia-reperfusion. Reviewed International journal

Yukio Mano, Tomomi Kotani, Mikako Ito, Taku Nagai, Yuko Ichinohashi, Kiyofumi Yamada, Kinji Ohno, Fumitaka Kikkawa, Shinya Toyokuni

Free radical biology & medicine Vol. 69 page： 324 - 30 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Molecular hydrogen (H-2) scavenges hydroxyl radicals. Recently, H-2 has been reported to prevent a variety of diseases associated with oxidative stress in model systems and in humans. Here, we studied the effects of H-2 on rat fetal hippocampal damage caused by ischemia and reperfusion (IR) on day 16 of pregnancy with the transient occlusion of the bilateral utero-ovarian arteries. Starting 2 days before the operation, we provided the mothers with hydrogen-saturated water ad libitum until vaginal delivery. We observed a significant increase in the concentration of H-2 in the placenta after the oral administration of hydrogen-saturated water to the mothers, with less placental oxidative damage after IR in the presence of H-2. Neonatal growth retardation was observed in the IR group, which was alleviated by the H-2 administration. We analyzed the neuronal cell damage in the CA1 and CA3 areas of the hippocampus at day 7 after birth by immunohistochemical analysis of the 8-oxo-7,8-dihydro-2 '-deoxyguanosine- and 4-hydroxy-2-nonenal-modified proteins. Both oxidative stress markers were significantly increased in the IR group, which was again ameliorated by the H-2 intake. Last, 8-week-old rats were subjected to a Morris water maze test. Maternal H-2 administration improved the reference memory of the offspring to the sham level after IR injury during pregnancy. Overall, the present results support the idea that maternal H-2 intake helps prevent the hippocampal impairment of offspring induced by IR during pregnancy. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.freeradbiomed.2014.01.037

Ovarian mucinous tumors arising from mature cystic teratomas-a molecular genetic approach for understanding the cellular origin Reviewed International journal

Kaho Fujii, Yoriko Yamashita, Toshimichi Yamamoto, Koji Takahashi, Katsunori Hashimoto, Tomoko Miyata, Kumi Kawai, Fumitaka Kikkawa, Shinya Toyokuni, Tetsuro Nagasaka

HUMAN PATHOLOGY Vol. 45 ( 4 ) page： 717 - 724 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

Mucinous tumors of the ovary are frequently associated with mature cystic teratomas, and it has been speculated that the mucinous tumors arise from teratoma components. The cellular origins of mature cystic teratomas are believed to be post-meiotic ovarian germ cells, and the analysis of microsatellite markers such as short tandem repeats is suitable for determining the cellular origin of tumors. In this study, we analyzed 3 ovarian mature cystic teratomas, all of which were associated with simultaneous ovarian mucinous tumors within the same ovary. Two of the 3 mucinous tumors were intestinal-type and the other was endocervical type. A laser capture microdissection technique was used to separate the epithelial component of the mucinous tumor, the components of the mature cystic teratoma, and control ovarian somatic tissue. Using short tandem repeat analysis based on 6 markers (D20S480, D6S2439, D6S1056, D9S1118, D4S2639, and D17S1290), we could distinguish the germ cell (homozygous) or somatic (heterozygous) origin of a given component in each sample. The epithelial components of the intestinal-type mucinous tumors in cases 1 and 2 were homozygous, and the epithelial component in case 3 (endocervical type) was heterozygous. All teratomatous components were homozygous, and the control components were heterozygous. In addition, we analyzed 3 mature cystic teratomas without mucinous tumors, and all 3 were homozygous in the tumor component. Our data suggest that the origin of mucinous tumors in the ovary may differ among histological subtypes, and intestinal-type mucinous tumors may arise from mature cystic teratomas, although endocervical-type mucinous tumors may not. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2013.10.031

From Nagoya to the world Reviewed International journal

Toyokuni S.

Nagoya Journal of Medical Science Vol. 76 ( 1-2 ) page： 1 - 2 2014.3

From Nagoya to the world International journal

Toyokuni S

Nagoya Journal of Medical Science Vol. 76 ( 1-2 ) page： 1 - 2 2014.3

RAT MODEL DEMONSTRATES A HIGH RISK OF TREMOLITE BUT A LOW RISK OF ANTHOPHYLLITE FOR MESOTHELIAL CARCINOGENESIS Reviewed

Dilinuer Aierken, Yasumasa Okazaki, Shan Hwu Chew, Akihiro Sakai, Yue Wang, Hirotaka Nagai, Nobuaki Misawa, Norihiko Kohyama, Shinya Toyokuni

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 76 ( 1-2 ) page： 149 - 160 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：NAGOYA UNIV, SCH MED

Asbestos was abundantly used in industry during the last century. Currently, asbestos confers a heavy social burden due to an increasing number of patients with malignant mesothelioma ( MM), which develops after a long incubation period. Many studies have been conducted on the effects of the asbestos types that were most commonly used for commercial applications. However, there are few studies describing the effects of the less common types, or minor asbestos. We performed a rat carcinogenesis study using Japanese tremolite and Afghan anthophyllite. Whereas more than 50% of tremolite fibers had a diameter of < 500 nm, only a small fraction of anthophyllite fibers had a diameter of < 500 nm. We intraperitoneally injected 1 or 10 mg of asbestos into F1 Fischer-344/Brown-Norway rats. In half of the animals, repeated intraperitoneal injections of nitrilotriacetate (NTA), an iron chelator to promote Fenton reaction, were performed to evaluate the potential involvement of iron overload. Tremolite induced MM with a high incidence (96% with 10 mg; 52% with 1 mg), and males were more susceptible than females. Histology was confirmed using immunohistochemistry, and most MMs were characterized as the sarcomatoid or biphasic subtype. Unexpectedly NTA showed an inhibitory effect in females. In contrast, anthophyllite induced no MM after an observation period of 550 days. The results suggest that the carcinogenicity of anthophyllite is weaker than formerly reported, whereas that of tremolite is as potent as major asbestos as compared with our previous data.

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Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis.

Aierken D, Okazaki Y, Chew SH, Sakai A, Wang Y, Nagai H, Misawa N, Kohyama N, Toyokuni S

Nagoya journal of medical science Vol. 76 ( 1-2 ) page： 149 - 60 2014.2

Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis.

Aierken D, Okazaki Y, Chew SH, Sakai A, Wang Y, Nagai H, Misawa N, Kohyama N, Toyokuni S

Nagoya journal of medical science Vol. 76 ( 1-2 ) page： 149 - 60 2014.2

RAT MODEL DEMONSTRATES A HIGH RISK OF TREMOLITE BUT A LOW RISK OF ANTHOPHYLLITE FOR MESOTHELIAL CARCINOGENESIS

Aierken Dilinuer, Okazaki Yasumasa, Chew Shan Hwu, Sakai Akihiro, Wang Yue, Nagai Hirotaka, Misawa Nobuaki, Kohyama Norihiko, Toyokuni Shinya

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 76 ( 1-2 ) page： 149 - 160 2014.2

Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis. Reviewed International journal

Aierken D., Okazaki Y., Chew S.H., Sakai A., Wang Y., Nagai H., Misawa N., Kohyama N., Toyokuni S.

Nagoya journal of medical science Vol. 76 ( 1-2 ) page： 149 - 160 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Nagoya journal of medical science

Asbestos was abundantly used in industry during the last century. Currently, asbestos confers a heavy social burden due to an increasing number of patients with malignant mesothelioma (MM), which develops after a long incubation period. Many studies have been conducted on the effects of the asbestos types that were most commonly used for commercial applications. However, there are few studies describing the effects of the less common types, or minor asbestos. We performed a rat carcinogenesis study using Japanese tremolite and Afghan anthophyllite. Whereas more than 50% of tremolite fibers had a diameter of < 500 nm, only a small fraction of anthophyllite fibers had a diameter of < 500 nm. We intraperitoneally injected 1 or 10 mg of asbestos into F1 Fischer-344/Brown-Norway rats. In half of the animals, repeated intraperitoneal injections of nitrilotriacetate (NTA), an iron chelator to promote Fenton reaction, were performed to evaluate the potential involvement of iron overload. Tremolite induced MM with a high incidence (96% with 10 mg; 52% with 1 mg), and males were more susceptible than females. Histology was confirmed using immunohistochemistry, and most MMs were characterized as the sarcomatoid or biphasic subtype. Unexpectedly NTA showed an inhibitory effect in females. In contrast, anthophyllite induced no MM after an observation period of 550 days. The results suggest that the carcinogenicity of anthophyllite is weaker than formerly reported, whereas that of tremolite is as potent as major asbestos as compared with our previous data.

Scopus

Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production Reviewed International journal

Shan Hwu Chew, Yasumasa Okazaki, Hirotaka Nagai, Nobuaki Misawa, Shinya Akatsuka, Kyoko Yamashita, Li Jiang, Yoriko Yamashita, Michio Noguchi, Kiminori Hosoda, Yoshitaka Sekido, Takashi Takahashi, Shinya Toyokuni

CARCINOGENESIS Vol. 35 ( 1 ) page： 164 - 72 2014.1

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

Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflammatory condition. Both macrophages and mesothelial cells play crucial roles in the inflammatory response caused by asbestos exposure. Here, we show that adipocytes can also contribute to asbestos-induced inflammation through dysregulated adipocytokine production. 3T3-L1 preadipocytes were differentiated into mature adipocytes prior to use. These cells took up asbestos fibers (chrysotile, crocidolite and amosite) but were more resistant to asbestos-induced injury than macrophages and mesothelial cells. Expression microarray analysis followed by reverse transcriptionPCR revealed that adipocytes respond directly to asbestos exposure with an increased production of proinflammatory adipocytokines [e.g. monocyte chemoattractant protein-1 (MCP-1)], whereas the production of anti-inflammatory adipocytokines (e.g. adiponectin) is suppressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregulated adipocytokine production favors the establishment of a proinflammatory environment. Furthermore, MCP-1 marginally promoted the growth of MeT-5A mesothelial cells and significantly enhanced the wound healing of Y-MESO-8A and Y-MESO-8D human mesothelioma cells. Our results suggest that increased levels of adipocytokines, such as MCP-1, can potentially contribute to the promotion of mesothelial carcinogenesis through the enhanced recruitment of inflammatory cells as well as a direct growth and migration stimulatory effect on mesothelial and mesothelioma cells. Taken together, our findings support a potential cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis.

DOI： 10.1093/carcin/bgt267

Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis. Reviewed International journal Open Access

Shinya Toyokuni

Redox report : communications in free radical research Vol. 19 ( 1 ) page： 1 - 7 2014.1

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

Few people expected that asbestos, a fibrous mineral, would be carcinogenic to humans. In fact, asbestos is a definite carcinogen in humans, causing a rare but aggressive cancer called malignant mesothelioma (MM). Mesothelial cells line the three somatic cavities and thus do not face the outer surface, but reduce the friction among numerous moving organs. MM has several characteristics: extremely long incubation period of 30-40 years after asbestos exposure, difficulty in clinical diagnosis at an early stage, and poor prognosis even under the current multimodal therapies. In Japan, 'Kubota shock' attracted considerable social attention in 2005 for asbestos-induced mesothelioma and, thereafter, the government enacted a law to provide the people suffering from MM a financial allowance. Several lines of recent evidence suggest that the major pathology associated with asbestos-induced MM is local iron overload, associated with asbestos exposure. Preclinical studies to prevent MM after asbestos exposure with iron reduction are in progress. In addition, novel target genes in mesothelial carcinogenesis have been discovered with recently recognized mesothelioma-prone families. Development of an effective preventive strategy is eagerly anticipated

DOI： 10.1179/1351000213Y.0000000075

As a host society to SFRRI 2014 in Kyoto. Open Access

Osamu Handa, Yuji Naito, Shinya Toyokuni

Journal of clinical biochemistry and nutrition Vol. 54 ( 1 ) page： 1 - 1 2014.1

Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production. Reviewed

Chew SH, Okazaki Y, Nagai H, Misawa N, Akatsuka S, Yamashita K, Jiang L, Noguchi M, Hosoda K, Sekido Y, Takahashi T and Toyokuni S.

Carcinogenesis Vol. 35 page： 164-172 2014

Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. Reviewed

Tsujiuchi T, Natsume A, Motomura K, Kondo G, Ranjit M, Hachisu R, Sugimura I, Tomita S, Takehara I, Woolley M, Barua NU, Gill SS, Bienemann AS, Yamashita Y, Toyokuni S, Wakabayashi T.

Am J Transl Res Vol. 15 page： 169-178 2014

Dexamethasone palmitate ameliorates macrophages-1 rich graft-versus-host disease by inhibiting macrophage functions. Reviewed

Nishiwaki S, Nakayama T, Murata M, Nishida T, Terakura S, Saito S, Kato T. Mizuno H, Imahashi N, Seto S, Ozawa Y, Miyamura K, Ito M, Takeshita K, Kato H, Toyokuni S, Nagao K, Ueda R and Naoe T.

PLoS ONE Vol. 9 page： e96252 2014

Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model. Reviewed

Mukaide T, Hatori Y, Misawa N, Funahashi S, Jiang L, Hirayama T, Nagasawa H and Toyokuni S.

Free Radic Res Vol. 48 page： 990-995 2014

Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis. Reviewed

Aierken D, Okazaki Y, Chew SH, Sakai A, Wang Y, Nagai H, Misawa N, Kohyama N and Toyokuni S.

Nagoya J Med Sci Vol. 76 page： 149-160 2014

Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage by in ut ero ischemia-reperfusion. Reviewed

Mano Y, Kotani T, Ito M, Nagai T, Ichinohashi Y, Yamada K, Ohno K, Kikkawa F and Toyokuni S.

Free Radic Biol Med Vol. 69 page： 324-330 2014

Lack of presence of the human cytomegalovirus in human glioblastoma. Modern Pathol 27: 922-929, 2014. Reviewed

Yamashita Y, Ito Y, Isomura H, Takemura N, Okamoto A, Motomura K, Tsujiuchi T, Natsume A, Wakabayashi T, Toyokuni S and Tsurumi T.

Modern Pathology Vol. 27 page： 922-929 2014

Ovarian mucinous tumors arising from mature cystic teratomas-a molecular genetic approach for understanding the cellular origin. Reviewed

Fujii K, Yamashita Y, Yamamoto T, Takahashi K, Hashimoto K, Miyata T, Kawai K, Kikkawa F, Toyokuni S, Nagasaka T.

Human Pathol Vol. 45 page： 717-724 2014

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Papers - TOYOKUNI Shinya