Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model. Reviewed International journal

Ushida T, Kotani T, Tsuda H, Imai K, Nakano T, Hirako S, Ito Y, Li H, Mano Y, Wang J, Miki R, Yamamoto E, Iwase A, Bando YK, Hirayama M, Ohno K, Toyokuni S, Kikkawa F

Free Radic Biol Med. Vol. pii: S0891-5849 ( 16 ) page： 30978-9. 2016.10

Non-thermal plasma prevents progression of endometriosis in mice. Reviewed

Ishida C, Mori M, Nakamura K, Tanaka H, Mizuno M, Hori M, Iwase A, Kikkawa F, Toyokuni S.

Free Radical Research Vol. 50 ( 10 ) page： 1131-1139 2016.10

Non-thermal plasma prevents progression of endometriosis in mice Reviewed International journal

Chiharu Ishida, Masahiko Mori, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Akira Iwase, Fumitaka Kikkawa, Shinya Toyokuni

FREE RADICAL RESEARCH Vol. 50 ( 10 ) page： 1131 - 1139 2016.10

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

Endometriosis is observed in approximate to 10% of reproductive age women. Ovarian endometriosis not only causes dysmenorrhea but also causes infertility and a high risk of adenocarcinoma. Due to its scattered nature, complete surgical resection is difficult. Endometriosis consists of glandular and stromal cells. Previously, we showed that endometrial stromal cells (ESCs) play a role in the protection against pathologic events caused by monthly repeated hemorrhage. Here, we undertook a preclinical study of non-thermal plasma (NTP) as a surgical treatment of endometriosis. Epithelial cells were most sensitive to NTP-activated medium in vitro, whereas ectopic ESCs were most resistant. We then transplanted excised uteruses into BALB/c mice from donors of the same strain with estradiol supplementation. Four weeks after the transplantation, we exposed NTP to each endometriotic lesion after laparotomy. Immunohistochemical analysis revealed that immediately after NTP exposure, epithelial cells exhibited significantly higher levels of nuclear immunostaining for 8-hydroxy-2-deoxyguanosine than did stromal cells. Four weeks after NTP exposure, the total surface area consisting of endometriotic cysts was significantly smaller with less epithelial proliferative activity than the helium-exposed control, whereas the number of endometriotic lesions had not changed. Therefore, NTP exposure may be useful to prevent the progression and recurrence of endometriosis.

DOI： 10.1080/10715762.2016.1211273

Special issue for the 7th Biennial Meeting of Society for Free Radical Research-Asia (SFRR-Asia 2015 Thailand). Reviewed International coauthorship International journal

Malyn Ungsurungsie, Young-Joon Surh, Shinya Toyokuni, Michael Jonathan Davies

Free radical research Vol. 50 ( 10 ) page： 1045 - 1046 2016.10

Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450. Reviewed International journal

Cai Zong, C Edwin Garner, Chinyen Huang, Xiao Zhang, Lingyi Zhang, Jie Chang, Shinya Toyokuni, Hidenori Ito, Masashi Kato, Toshihiro Sakurai, Sahoko Ichihara, Gaku Ichihara

Toxicology letters Vol. 258 page： 249 - 258 2016.9

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

Neurotoxicity of 1-bromopropane (1-BP) has been reported in both human cases and animal studies. To date, neurotoxicity of 1-BP has been induced in rats but not in mice due to the lethal hepatotoxicity of 1-BP. Oxidization by cytochromes P450 and conjugation with glutathione (GSH) are two critical metabolism pathways of 1-BP and play important roles in toxicity of 1-BP. The aim of the present study was to establish a murine model of 1-BP neurotoxicity, by reducing the hepatotoxicity of 1-BP with 1-aminobenzotriazole (1-ABT); a commonly used nonspecific P450s inhibitor. The results showed that subcutaneous or intraperitoneal injection of 1-ABT at 50mg/kg body weight BID (100mg/kg BW/day) for 3days, inhibited about 92-96% of hepatic microsomal CYP2E1 activity, but only inhibited about 62-64% of CYP2E1 activity in brain microsomes. Mice treated with 1-ABT survived even after exposure to 1200ppm 1-BP for 4 weeks and histopathological studies showed that treatment with 1-ABT protected mice from 1-BP-induced hepatic necrosis, hepatocyte degeneration, and hemorrhage. After 4-week exposure to 1-BP, the brain weight of 1-ABT(+)/1200ppm 1-BP group was decreased significantly. In 1-ABT-treated groups, expression of hippocampal Ran protein and cerebral cortical GRP78 was dose-dependently increased by exposure to 1-BP. We conclude that the control of hepatic P450 activity allows the observation of effects of 1-BP on the murine brain at a higher concentration by reduction of hepatotoxicity. The study suggests that further experiments with liver-specific control of P450 activity using gene technology might provide better murine models for 1-bromopropane-induced neurotoxicity.

DOI： 10.1016/j.toxlet.2016.07.006

Biphasic effects of L-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells Reviewed International coauthorship International journal

Lei Shi, Yue Wang, Fumiya Ito, Yasumasa Okazaki, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Des R. Richardson, Shinya Toyokuni

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 605 page： 109 - 16 2016.9

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

Non-thermal plasma (NTP) is a recently developed technology that elicits a variety of biological effects. This includes cancer cell-specific cytotoxicity, which is mainly attributed to the regional generation of reactive oxygen species (ROS). We studied the effects of NTP on malignant mesothelioma (MM) and its modulation by L-ascorbate. L-ascorbate is a major water-soluble anti-oxidant in vivo, but its pro-oxidant activity in vitro has been well recognized. Thus, the effects of ascorbate on the efficacy of NTP is important to examine. NTP exposure dose-dependently killed MM cells, whereas MM cells tolerated 1 mM L-ascorbate. However, brief pre-treatment with a pharmacological dose (250-750 mu M) of L-ascorbate immediately prior to NTP exposure significantly increased its cytotoxicity in a dose-dependent manner, which was inhibited by the iron chelator, deferoxamine. However, paradoxically, this potentiating effect of L-ascorbate was completely abolished by a prolonged 4 h pre-incubation with L-ascorbate (500 mu M). MM cytotoxicity induced by NTP was associated with immediate oxidative stress evaluated by 2',7'-dichlorodihydrofluorecein diacetate, which was followed by an increase in the expression of the autophagosome marker, LC3B-II. In conclusion, MM can be a target for NTP treatment and L-ascorbate can increase or decrease its efficacy depending on the length of the pre-incubation period. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.abb.2016.05.016

Low-temperature plasma in biology and medicine Reviewed International journal

Hori M.

Archives of Biochemistry and Biophysics Vol. 605 page： 1 - 2 2016.9

Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia. Reviewed

Hirako S, Tsuda H, Kotani T, Sumigama S, Mano Y, Nakano T, Imai K, Li H, Toyokuni S, Kikkawa F.

Phytother Res. Vol. 30 ( 9 ) page： 1474-80 2016.9

Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma. Reviewed

Wang S, Jiang L, Han Y, Hwu Chew S, Ohara Y, Akatsuka S, Weng L, Kawaguchi K, Fukui T, Sekido Y, Yokoi K, Toyokuni S.

Oncotarget. 2016 Sep 2. page： 11829 2016.9

Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450. Reviewed

Zong C, Garner CE, Huang C, Zhang X, Zhang L, Chang J, Toyokuni S, Ito H, Kato M, Sakurai T, Ichihara S, Ichihara G.

Toxicol Lett. Vol. 258 page： 249-58 2016.9

Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells. Reviewed

Shi L, Wang Y, Ito F, Okazaki Y, Tanaka H, Mizuno M, Hori M, Richardson DR, Toyokuni S.

Arch Biochem Biophys. Vol. 605 page： 106-16 2016.9

Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia. Reviewed International journal

Shima Hirako, Hiroyuki Tsuda, Tomomi Kotani, Seiji Sumigama, Yukio Mano, Tomoko Nakano, Kenji Imai, Hua Li, Shinya Toyokuni, Fumitaka Kikkawa

Phytotherapy research : PTR Vol. 30 ( 9 ) page： 1474 - 80 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Congenital diaphragmatic hernia (CDH) can induce lung hypoplasia and pulmonary hypertension and is associated with high mortality. The purpose of this study is to examine the efficacy and safety of antenatal Saireito (TJ-114), a traditional Japanese herbal medicine, in a rat CDH model. Sprague-Dawley rats were exposed to an herbicide (nitrofen, 100 mg) on embryonic day 9 (E9) to induce CDH, and antenatal Saireito (2000 mg/kg/day) was orally administered from E10 to E20. On E21, fetuses were delivered. Antenatal Saireito significantly decreased the incidence of CDH (p < 0.01), increased lung volume (p < 0.01), improved alveolarization and pulmonary artery remodeling using histological analysis, and improved respiratory function using gasometric analysis (pH; p < 0.05, and PCO2; p < 0.01). In addition, antenatal Saireito significantly decreased endothelin-1 and endothelin receptor A expression in the pulmonary arteries. Taken together, our results demonstrated that antenatal Saireito can improve fetal pulmonary hypoplasia and pulmonary vascular remodeling and, as a result, can improve respiratory function in a rat CDH model. Copyright (C) 2016 John Wiley & Sons, Ltd.

DOI： 10.1002/ptr.5645

Molecular hydrogen suppresses activated Wnt/beta-catenin signaling Reviewed International journal

Yingni Lin, Bisei Ohkawara, Mikako Ito, Nobuaki Misawa, Kentaro Miyamoto, Yasuhiko Takegami, Akio Masuda, Shinya Toyokuni, Kinji Ohno

SCIENTIFIC REPORTS Vol. 6 ( 6 ) page： 31986 2016.8

Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Molecular hydrogen (H-2) is effective for many diseases. However, molecular bases of H-2 have not been fully elucidated. Cumulative evidence indicates that H-2 acts as a gaseous signal modulator. We found that H-2 suppresses activated Wnt/beta-catenin signaling by promoting phosphorylation and degradation of beta-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of beta-catenin abolished the suppressive effect of H-2. H-2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H-2 has no direct effect on GSK3 itself. Knockdown of adenomatous polyposis coli (APC) or Axin1, which form the beta-catenin degradation complex, minimized the suppressive effect of H2 on beta-catenin accumulation. Accordingly, the effect of H-2 requires CK1/GSK3-phosphorylation sites of beta-catenin, as well as the beta-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H-2 reduces the activation of Wnt/beta-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H-2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating beta-catenin accumulation. We first demonstrate that H-2 suppresses abnormally activated Wnt/beta-catenin signaling, which accounts for the protective roles of H-2 in a fraction of diseases.

DOI： 10.1038/srep31986

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Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis. Reviewed International journal

Fumiya Ito, Takahiro Nishiyama, Lei Shi, Masahiko Mori, Tasuku Hirayama, Hideko Nagasawa, Hiroyuki Yasui, Shinya Toyokuni

Biochemical and biophysical research communications Vol. 476 ( 4 ) page： 600 - 606 2016.8

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

Iron is an essential nutrient for every type of life on earth. However, excess iron is cytotoxic and can lead to an increased cancer risk in humans. Catalytic ferrous iron [Fe(II)] is an initiator of the Fenton reaction, which causes oxidative stress by generating hydroxyl radicals. Recently, it became possible to localize catalytic Fe(II) in situ with a turn-on fluorescent probe, RhoNox-1. Here, we screened each organ/cell of rats to globally evaluate the distribution of catalytic Fe(II) and found that eosinophils showed the highest abundance. In various cells, lysosomes were the major organelle, sharing 40-80% of RhoNox-1 fluorescence. We then used an ovalbumin-induced allergic peritonitis model to study the dynamics of catalytic Fe(II). Peritoneal lavage revealed that the total iron contents per cell were significantly decreased, whereas an increase in the number of inflammatory cells (macrophages, neutrophils, eosinophils and lymphocytes) resulted in an increased total iron content of the peritoneal inflammatory cells. Notably, macrophages, eosinophils and neutrophils exhibited significantly increased catalytic Fe(II) with increased DMT1 expression and decreased ferritin expression, though catalytic Fe(II) was significantly decreased in the peritoneal lavage fluid. In conclusion, catalytic Fe(II) in situ more directly reflects cellular activity and the accompanying pathology than total iron does. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2016.06.003

Molecular hydrogen suppresses activated Wnt/β-catenin signaling. Reviewed

Lin Y, Ohkawara B, Ito M, Misawa N, Miyamoto K, Takegami Y, Masuda A, Toyokuni S, Ohno K.

Sci Rep. Vol. 25 ( 6 ) page： 31986 2016.8

Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis. Reviewed

Ito F, Nishiyama T, Shi L, Mori M, Hirayama T, Nagasawa H, Yasui H, Toyokuni S.

Biochem Biophys Res Commun. Vol. 476 ( 4 ) page： 600-6 2016.8

Iron function and carcinogenesis Reviewed International journal

Akatsuka S., Toyokuni S.

Nihon rinsho. Japanese journal of clinical medicine Vol. 74 ( 7 ) page： 1168 - 1175 2016.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Nihon rinsho. Japanese journal of clinical medicine

Though iron is an essential micronutrient for humans, the excess state is acknowledged to be associated with oncogenesis. For example, iron overload in the liver of the patients with hereditary hemocromatosis highly increases the risk of hepatocellular carcinoma. Also, as to asbestos-related mesothelioma, such kinds of asbestos with a higher iron content are considered to be more carcinogenic. Iron is a useful element, which enables fundamental functions for life such as oxygen carrying and electron transport. However, in the situation where organisms are unable to have good control of it, iron turns into a dangerous element which catalyzes generation of reactive oxygen. In this review, I first outline the relationships between iron and cancer in general, then give an explanation about iron-related animal carcinogenesis models.

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The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. Reviewed

Cahill MA, Jazayeri JA, Catalano SM, Toyokuni S, Kovacevic Z, Richardson DR.

Biochim Biophys Acta. 2016 Jul 22. Vol. pii: S0304-419X ( 16 ) page： 30049-X. 2016.7

Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis Reviewed International journal

Jiang Li, Chew Shan-Hwu, Nakamura Kosuke, Ohara Yuuki, Akatsuka Shinya, Toyokuni Shinya

CANCER SCIENCE Vol. 107 ( 7 ) page： 908 - 915 2016.7

Possible therapeutic option of aqueous plasma for refractory ovarian cancer Reviewed International journal

Kajiyama Hiroaki, Utsumi Fumi, Nakamura Kae, Tanaka Hiromasa, Mizuno Masaaki, Toyokuni Shinya, Hori Masaru, Kikkawa Fumitaka

CLINICAL PLASMA MEDICINE Vol. 4 ( 1 ) page： 14 - 18 2016.7

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Papers - TOYOKUNI Shinya