研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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豊國伸哉

日本毒性学会学術年会 44 巻 ( 0 ) 頁： S11 - S11 2017年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本毒性学会

地球の生命体において鉄は必須であり、高等生物の生命は鉄・酸素・食物によって紡がれる。細胞内で電子の流れを作り制御された化学反応を行うのが酸素の主な役割であるが、体内に取り込まれた酸素の数％は活性酸素・フリーラジカルとなり生体分子に切断・修飾・重合などの傷害を与える。この反応は２価鉄触媒によるFenton反応として1894年より認識されていた。当初放射線の生物作用として理解されたが、1968年SOD発見により活性酸素・フリーラジカルの化学反応が細胞内で常時発生していることが認識されるようになった。発がんは1980年代に始まるがん遺伝子・がん抑制遺伝子の概念の確立により、論理的に理解されるようになった。発がん要因分類として、環境因子・習慣・職業曝露・食習慣・感染症・慢性炎症・遺伝的要因などが列挙され、それを防ぐような手立てが取られてきた。しかし日本では1981年以降、がんが死因の第１位であり右上りである。2014年には英国男性で初めてがんが死因の第１位になった。死因としてのがんの独走は今のがん予防法に大きな疑問を投げかける。私はこれまでの研究より、がんの独走を私たちが酸素と鉄を使用する宿命と理解したい。Wild typeのラットにFenton反応を起こすことでヒトのがんのゲノム変化と酷似したがんが発生することはこの仮説を強く支持する。アスベストや多層カーボンナノチューブによる発がんも異物発がんで基本的には過剰鉄を介するものであり、ラットとヒトで極めて類似したゲノム変化が見られることも注目に値する。これまでの観察により、これらの動物発がんは1ヶ月程度までの初期変化と正比例関係にあることは、毒性学にとって極めて重要であると考えたい。鉄の制御こそが今、がん制御に重要であると考えられる。鉄は一旦、血液内に入ると、体外への積極的な排泄経路はない。50才を過ぎると基礎代謝も低下し、女性は閉経を迎え、鉄が余分になる。私が年２回の全血献血を推奨する所以である。

DOI： 10.14869/toxpt.44.1.0_SL5

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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 61 巻 2017年

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

伊藤文哉, 豊國伸哉

臨床検査Journal of clinical laboratory medicine 61 巻 2017年

Future perspective of strategic non-thermal plasma therapy for cancer treatment. 査読有り

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

Journal of Clinical Biochemistry and Nutrition 60 巻 ( 1 ) 頁： 33-38 2016年12月

Future perspective of strategic non-thermal plasma therapy for cancer treatment. 査読有り国際誌

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

Journal of Clinical Biochemistry and Nutrition 60 巻 ( 1 ) 頁： 33-38 2016年12月

Editorial: The cutting edge of zinc biology. 国際誌

Kambe T, Fukada T, Toyokuni S

Archives of biochemistry and biophysics 611 巻頁： 1 - 2 2016年12月

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

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

Biochimica et biophysica acta 1866 巻 ( 2 ) 頁： 339 - 349 2016年12月

Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model 査読有り国際誌

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 RADICAL BIOLOGY AND MEDICINE 101 巻 ( 16 ) 頁： 524 - 533 2016年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Biology and Medicine

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

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

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

FREE RADICAL BIOLOGY AND MEDICINE 100 巻頁： S127 - S127 2016年11月

Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma. 査読有り国際誌

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

Oncotarget 7 巻 ( 43 ) 頁： 69565 - 69578 2016年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncotarget

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. 査読有り

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. pii: S0891-5849 巻 ( 16 ) 頁： 30978-9. 2016年10月

Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model. 査読有り国際誌

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. pii: S0891-5849 巻 ( 16 ) 頁： 30978-9. 2016年10月

Non-thermal plasma prevents progression of endometriosis in mice. 査読有り Open Access

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

Free Radical Research 50 巻 ( 10 ) 頁： 1131-1139 2016年10月

Non-thermal plasma prevents progression of endometriosis in mice. 査読有り国際誌 Open Access

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

Free radical research 50 巻 ( 10 ) 頁： 1131 - 1139 2016年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Research

Endometriosis is observed in ∼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). 査読有り国際共著国際誌

Ungsurungsie M, Surh YJ, Toyokuni S, Davies MJ

Free radical research 50 巻 ( 10 ) 頁： 1045 - 1046 2016年10月

Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450. 査読有り国際誌

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

Toxicology letters 258 巻頁： 249 - 258 2016年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Toxicology Letters

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 50 mg/kg body weight BID (100 mg/kg BW/day) for 3 days, 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 1200 ppm 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(+)/1200 ppm 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. 査読有り国際共著国際誌

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

Archives of biochemistry and biophysics 605 巻頁： 109 - 16 2016年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Archives of Biochemistry and Biophysics

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 μM) 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 μM). 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.

DOI： 10.1016/j.abb.2016.05.016

Low-temperature plasma in biology and medicine 査読有り国際誌

Hori M.

Archives of Biochemistry and Biophysics 605 巻頁： 1 - 2 2016年9月

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

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

Phytother Res. 30 巻 ( 9 ) 頁： 1474-80 2016年9月

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

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. 頁： 11829 2016年9月

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