Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Primary cause of carcinogenesis: what toxicology can contribute

TOYOKUNI Shinya

Annual Meeting of the Japanese Society of Toxicology Vol. 44 ( 0 ) page： S11 - S11 2017

がんと微量金属元素 (Cancer and trace metal element)

伊藤文哉, 豊國伸哉

臨床検査Journal of clinical laboratory medicine Vol. 61 2017

Future perspective of strategic non-thermal plasma therapy for cancer treatment. Reviewed

Kajiyama H, Utsumi F, Nakamura K, Tanaka H, Toyokuni S, Hori M, Kikkawa F.

Journal of Clinical Biochemistry and Nutrition Vol. 60 ( 1 ) page： 33-38 2016.12

Future perspective of strategic non-thermal plasma therapy for cancer treatment. Reviewed International journal

Kajiyama H, Utsumi F, Nakamura K, Tanaka H, Toyokuni S, Hori M, Kikkawa F

Journal of Clinical Biochemistry and Nutrition Vol. 60 ( 1 ) page： 33-38 2016.12

Editorial: The cutting edge of zinc biology. International journal

Taiho Kambe, Toshiyuki Fukada, Shinya Toyokuni

Archives of biochemistry and biophysics Vol. 611 page： 1 - 2 2016.12

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

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

Biochimica et biophysica acta Vol. 1866 ( 2 ) page： 339 - 349 2016.12

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

Takafumi Ushida, Tomomi Kotani, Hiroyuki Tsuda, Kenji Imai, Tomoko Nakano, Shima Hirako, Yumiko Ito, Hua Li, Yukio Mano, Jingwen Wang, Rika Miki, Eiko Yamamoto, Akira Iwase, Yasuko K Bando, Masaaki Hirayama, Kinji Ohno, Shinya Toyokuni, Fumitaka Kikkawa

Free radical biology & medicine Vol. 101 ( 16 ) page： 524 - 533 2016.12

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

Oxidative stress plays an important role in the pathogenesis of preeclampsia. Recently, molecular hydrogen (H2) has been shown to have therapeutic potential in various oxidative stress-related diseases. The aim of this study is to investigate the effect of H2 on preeclampsia. We used the reduced utero-placental perfusion pressure (RUPP) rat model, which has been widely used as a model of preeclampsia. H2 water (HW) was administered orally ad libitum in RUPP rats from gestational day (GD) 12-19, starting 2 days before RUPP procedure. On GD19, mean arterial pressure (MAP) was measured, and samples were collected. Maternal administration of HW significantly decreased MAP, and increased fetal and placental weight in RUPP rats. The increased levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and diacron reactive oxygen metabolites as a biomarker of reactive oxygen species in maternal blood were decreased by HW administration. However, vascular endothelial growth factor level in maternal blood was increased by HW administration. Proteinuria, and histological findings in kidney were improved by HW administration. In addition, the effects of H2 on placental villi were examined by using a trophoblast cell line (BeWo) and villous explants from the placental tissue of women with or without preeclampsia. H2 significantly attenuated hydrogen peroxide-induced sFlt-1 expression, but could not reduce the expression induced by hypoxia in BeWo cells. H2 significantly attenuated sFlt-1 expression in villous explants from women with preeclampsia, but not affected them from normotensive pregnancy. The prophylactic administration of H2 attenuated placental ischemia-induced hypertension, angiogenic imbalance, and oxidative stress. These results support the theory that H2 has a potential benefit in the prevention of preeclampsia.

DOI： 10.1016/j.freeradbiomed.2016.10.491

Web of Science

PubMed

researchmap

Chemical reaction mechanism in non-thermal plasma from the viewpoint of oxidative stress toward clinical cancer applications

Toyokuni, S; Shi, L; Okazaki, Y; Richardson, DR

FREE RADICAL BIOLOGY AND MEDICINE Vol. 100 page： S131 - S131 2016.11

Preclinical Use of CTGF-Specific Monoclonal Antibody for the Treatment of Malignant Mesothelioma

Ohara, Y; Wang, SQ; Jiang, L; Toyokuni, S

FREE RADICAL BIOLOGY AND MEDICINE Vol. 100 page： S127 - S127 2016.11

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

Shenqi Wang, Li Jiang, Yipeng Han, Shan Hwu Chew, Yuuki Ohara, Shinya Akatsuka, Liang Weng, Koji Kawaguchi, Takayuki Fukui, Yoshitaka Sekido, Kohei Yokoi, Shinya Toyokuni

Oncotarget Vol. 7 ( 43 ) page： 69565 - 69578 2016.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Impact Journals LLC

Malignant mesothelioma (MM) is a rare neoplasm associated with asbestos exposure. The prognosis of MM is poor because it is aggressive and highly resistant to chemotherapy. Using a rat model of asbestos-induced MM, we found elevated urokinase-type plasminogen activator receptor (uPAR
Plaur) expression in rat tissues, which was associated with poor prognosis. The proliferation, migration and invasion of MM cells were suppressed by uPAR knockdown and increased by overexpression experiments, irrespective of urokinase-type plasminogen activator (uPA
Plau) levels. More importantly, we found that uPAR expression is associated with sensitivity to cisplatin in MM through the PI3K/AKT pathway, which was demonstrated with specific inhibitors, LY294002 and Akti-1/2. uPAR knockdown significantly increased sensitivity to cisplatin whereas its overexpression significantly decreased cisplatin sensitivity. Furthermore, sera and tissues from MM patients showed significantly high uPAR levels, which suggested the pathogenic role of uPAR in the tumor biology of human MM. In conclusion, our findings indicate that uPAR levels are associated with malignant characteristics and cisplatin sensitivity of MM. In addition to the potential use of uPAR as a prognostic marker, the combination of uPAR abrogation and cisplatin may reveal a promising therapeutic approach for MM.

DOI： 10.18632/oncotarget.11829

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

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

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 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). 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. 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 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

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Papers - TOYOKUNI Shinya