Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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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

Direct exposure of non-equilibrium atmospheric pressure plasma confers simultaneous oxidative and ultraviolet modifications in biomolecules. Reviewed

Okazaki Y, Wang Y, Tanaka H, Mizuno M, Nakamura K, Kajiyama H, Kano H, Uchida K, Kikkawa F, Hori M and Toyokuni S.

J Clin Biochem Nutr Vol. 55 page： 207-215 2014

Plasma medical science for cancer therapy using non-thermal atomospheric pressure plasma. Reviewed

Tanaka H, Mizuno M, Ishikawa K, Takeda K, Nakamura K, Utsumi F, Kajiyama H, Nano H, Okazaki Y, Toyokuni S, Maruyama S, Kikkawa F and Hori M.

IEEE Trans Plasma Sci Vol. 42 page： 3760-3764 2014

Iron and thiols as two major players in carcinogenesis: friends or foes? Invited Reviewed

Toyokuni S.

Front Pharmacol Vol. 5 page： 200 2014

Genome-wide profiling of 8-oxoguanine reveals its association with spatial positioning in nucleus. Reviewed

Yoshihara M, Jiang L, Akatsuka S, Suyama M and Toyokuni S.

DNA Res Vol. 21 page： 603-612 2014

Iron and thiols as two major players in carcinogenesis: friends or foes? Reviewed International journal Open Access

Shinya Toyokuni

Frontiers in pharmacology Vol. 5 page： 200 - 200 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：FRONTIERS RESEARCH FOUNDATION

Iron is the most abundant metal in the human body and mainly works as a cofactor for proteins such as hemoglobin and various enzymes. No independent life forms on earth can survive without iron. However, excess iron is intimately associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Biomolecules with redox-active sulfhydryl function(s) (thiol compounds) are necessary for the maintenance of mildly reductive cellular environments to counteract oxidative stress, and for the execution of redox reactions for metabolism and detoxification. Involvement of glutathione S-transferase and thioredoxin has long attracted the attention of cancer researchers. Here, I update recent findings on the involvement of iron and thiol compounds during carcinogenesis and in cancer cells. It is now recognized that the cystine/glutamate transporter (antiporter) is intimately associated with ferroptosis, an iron-dependent, non-apoptotic form of cell death, observed in cancer cells, and also with cancer stem cells; the former with transporter blockage but the latter with its stabilization. Excess iron in the presence of oxygen appears the most common known mutagen. Ironically, the persistent activation of antioxidant systems via genetic alterations in Nrf2 and Keapl also contributes to carcinogenesis. Therefore, it is difficult to conclude the role of iron and thiol compounds as friends or foes, which depends on the quantity/distribution and induction/flexibility, respectively. Avoiding further mutation would be the most helpful strategy for cancer prevention, and myriad of efforts are being made to sort out the weaknesses of cancer cells.

DOI： 10.3389/fphar.2014.00200

Iron and thiols as two major players in carcinogenesis: friends or foes? Invited Reviewed

Toyokuni S

Front Pharmacol Vol. 5 page： 200 2014

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

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

American journal of translational research Vol. 6 ( 2 ) page： 169 - 78 2014

Preclinical evaluation of an O6-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains Reviewed International journal

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

American Journal of Translational Research Vol. 6 ( 2 ) page： 169 - 178 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Translational Research

The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O6-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O6-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.

Scopus

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

Takashi Tsujiuchi, Atsushi Natsume, Kazuya Motomura, Goro Kondo, Melissa Ranjit, Rei Hachisu, Itsuro Sugimura, Shinpei Tomita, Isao Takehara, Max Woolley, Neil U. Barua, Steven S. Gill, Alison S. Bienemann, Yoriko Yamashita, Shinya Toyokuni, Toshihiko Wakabayashi

AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH Vol. 6 ( 2 ) page： 169 - 178 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：E-CENTURY PUBLISHING CORP

The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O-6-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O-6-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.

Web of Science

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脳梗塞発症前の運動はsuperoxide dismutase活性を増加させ脳梗塞障害を軽減する

野口泰司, 石田和人, 濱川みちる, 玉越敬悟, 高松泰行, 戸田拓弥, 加藤寛聡, 早稲田雄也, 赤塚慎也, 豊國伸哉

理学療法学Supplement Vol. 2013 ( 0 ) page： 0007 - 0007 2014

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：公益社団法人日本理学療法士協会

【はじめに，目的】脳梗塞の後遺症に苦しむ患者数の増大から,脳梗塞の予防的介入が重要視されている。動物実験では,脳梗塞発症前に一定期間運動を行うことで,脳梗塞後の運動機能障害が軽減し,脳梗塞体積も減少するという報告がなされている（Wang RY. et al., 2001）。この作用機序について,我々の研究室では脳梗塞の二次的傷害の主要な要因である酸化ストレスに着目し,脳梗塞発症前に運動を行うことで酸化ストレス産物（8-OHdG，4-HNE修飾タンパク）の生成が軽減されることを報告し,酸化ストレス抑制の関連を示唆した（Hamakawa M. et al., 2013）。しかし,この酸化ストレス抑制の機序は明らかになっていない。そこで,本研究では脳内の主要な抗酸化ストレス物質の1つであるsuperoxide dismutase（SOD）に着目し,事前の運動による脳梗塞障害軽減効果の作用機序を検討することを目的とする。【方法】実験動物にはWistar系雄性ラット（5週齢）を用いた。無作為にSham群（n=6）,運動＋sham群（n=6）,脳梗塞群（n=8）,運動+脳梗塞群（n=12）の4群に分け,運動＋sham群と運動＋脳梗塞群は3週間のトレッドミル運動（15m/min，30分/日）を毎日行った。Sham群と脳梗塞群は走行させずにトレッドミル装置内に曝露させた。3週間後,脳梗塞群と運動＋脳梗塞群に対し,小泉法により90分間左中大脳動脈を閉塞することで脳梗塞モデル作成手術を施した。手術24時間後に,感覚-運動機能に関し,麻痺の重症度の評価としてneurological deficits（ND）を,前肢の感覚運動機能の評価としてlimb placing test（LP）を,前肢の協調運動機能の評価としてladder testを,歩行時のバランス能力の評価としてbeam walking test（BW）を行った。その直後に脳梗塞周囲の大脳皮質感覚運動野を採取し,SOD-Assay kit-WST（同仁化学研究所）を用いてSOD活性を測定した。また,SODの遺伝子発現について,real-time PCR法によりSOD1（Cu，Zn-SOD）,SOD2（Mn-SOD）,SOD3（EC-SOD）のmRNA発現量を定量化した。統計学的解析はSPSS ver. 16.0を用い,感覚－運動機能評価に関しND，LP，BWについてはMann-Whitney U testを,ladder testについてはStudent's t-testを行った。また,SOD活性,SOD1，2，3の遺伝子発現については一元配置分散分析にて比較し,事後検定としてTukey's testを行った。統計学的検定における有意水準は5%未満とした。【倫理的配慮，説明と同意】本研究における前処置は名古屋大学動物実験指針に従って実施した。【結果】運動＋脳梗塞群は脳梗塞群に比べて,ND，LP，ladder testにおいて有意に障害が軽度であった（p＜0.05）。一方でBWでは群間に有意差は認められなかった。またSOD活性は,運動＋脳梗塞群が脳梗塞群に比べ有意に高値を示した（p＜0.05）。さらにSOD1は,運動＋脳梗塞群が脳梗塞群に比べ有意に発現が高かった（p＜0.05）。SOD2，3は群間に有意差は認められなかった。【考察】脳梗塞モデル作成前に3週間のトレッドミル運動を行うことで,脳梗塞後の感覚－運動機能障害が軽減することが示された。またSOD活性およびSOD1発現量の増加が示された。これらの結果より,事前に運動を行うことは,脳梗塞時のSOD発現,活性が促進され,虚血/再灌流により生じる大量の活性酸素を迅速に消去し,酸化ストレスを抑制する作用があると考えられる。よって,脳梗塞発症前の運動が及ぼす障害軽減効果には,SODの抗酸化ストレス能に伴う神経保護作用が関与していることが示唆された。【理学療法学研究としての意義】脳梗塞発症前の運動による脳梗塞障害軽減効果の作用機序の一端を分子生物学的に示した。これらの結果は,脳梗塞の予防として推奨されている運動の効果を科学的に検討し,予防医療分野における理学療法のさらなる発展に寄与するものと考える。

DOI： 10.14900/cjpt.2013.0007

CiNii Research

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【職業・環境発がん:メカニズムと病理】繊維性ナノマテリアルの発がん機構

豊國伸哉

病理と臨床 Vol. 32 page： 632 - 637 2014

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

Tsujiuchi Takashi, Natsume Atsushi, Motomura Kazuya, Kondo Goro, Ranjit Melissa, Hachisu Rei, Sugimura Itsuro, Tomita Shinpei, Takehara Isao, Woolley Max, Barua Neil U., Gill Steven S., Bienemann Alison S., Yamashita Yoriko, Toyokuni Shinya, Wakabayashi Toshihiko

AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH Vol. 6 ( 2 ) page： 169 - 178 2014

Genotoxicity and carcinogenicity risk of carbon nanotubes. Reviewed International journal

Shinya Toyokuni

Advanced drug delivery reviews Vol. 65 ( 15 ) page： 2098 - 110 2013.12

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

Novel materials are often commercialized without a complete assessment of the risks they pose to human health because such assessments are costly and time-consuming; additionally, sometimes the methodology needed for such an assessment does not exist. Carbon nanotubes have the potential for widespread application in engineering, materials science and medicine. However, due to the needle-like shape and high durability of multiwalled carbon nanotubes (MWCNTs), concerns have been raised that they may induce asbestos-like pathogenicity when inhaled. Indeed, experiments in rodents supported this hypothesis. Notably, the genetic alterations in MWCNT-induced rat malignant mesothelioma were similar to those induced by asbestos. Single-walled CNTs (SWCNTs) cause mitotic disturbances in cultured cells, but thus far, there has been no report that SWCNTs are carcinogenic. This review summarizes the recent noteworthy publications on the genotoxicity and carcinogenicity of CNTs and explains the possible molecular mechanisms responsible for this carcinogenicity. The nanoscale size and needle-like rigid structure of CNTs appear to be associated with their pathogenicity in mammalian cells, where carbon atoms are major components in the backbone of many biomolecules. Publishing adverse events associated with novel materials is critically important for alerting people exposed to such materials. CNTs still have a bright future with superb economic and medical merits. However, appropriate regulation of the production, distribution and secondary manufacturing processes is required, at least to protect the workers. (C) 2013 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.addr.2013.05.011

Deferasirox Induces Mesenchymal-Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats International journal

Toyokuni, S; Nagai, H; Okazaki, Y; Chew, SH; Yasui, H

FREE RADICAL BIOLOGY AND MEDICINE Vol. 65 page： S25 - S25 2013.11

Deferasirox Induces Mesenchymal-Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats Reviewed International journal

Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Hiroyuki Yasui, Shinya Toyokuni

CANCER PREVENTION RESEARCH Vol. 6 ( 11 ) page： 1222 - 30 2013.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction.

DOI： 10.1158/1940-6207.CAPR-13-0244

From nagoya to the world Reviewed International journal

Toyokuni S.

Nagoya Journal of Medical Science Vol. 75 ( 1-2 ) page： 1 - 2 2013.9

From nagoya to the world International journal

Toyokuni S

Nagoya Journal of Medical Science Vol. 75 ( 1-2 ) page： 1 - 2 2013.9

Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15nm in diameter does not induce mesothelial carcinogenesis in rats Reviewed International journal

Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Yasumitsu Miyata, Hisanori Shinohara, Shinya Toyokuni

Pathology International Vol. 63 ( 9 ) page： 457 - 62 2013.9

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

Multiwalled carbon nanotubes (MWCNTs) have attracted public attention not only for their potential applications in engineering and materials science but also for possible environmental risks. MWCNTs share similar properties with asbestos, a definite human carcinogen causing malignant mesothelioma (MM), in that they are both biopersistent thin fibers with a high aspect ratio. Certain types of MWCNTs do induce MM in animal experiments. Though there are many different types of MWCNTs awaiting use in industry, there is little evidence about what types of MWCNTs present a high risk for MMin vivo. We have previously shown that the diameter of MWCNTs is one of the critical factors for mesothelial injury, which eventually leads to MM. Because of the extensive commercial use of MWCNTs, the properties of MWCNTs that determine carcinogenic activity should be clarified. Here we report that a high dose (10mg) of a tangled form of pristine MWCNT (with a diameter of 15nm) did not induce MM after intraperitoneal administration in rats, which were followed for up to 3 years after injection. This observation strengthens our previous finding that the rigidity, diameter, length and surface properties of MWCNTs are important factors in MM induction in vivo. © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

DOI： 10.1111/pin.12093

Erratum to Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice, [International Union of Biochemistry and Molecular Biology, 23, 2, (2005) 85-95] Reviewed International journal

Yuji Naitoa, Satomi Akagiri, Kazuhiko Uchiyama, Satoshi Kokura, Norimasa Yoshida, Goji Hasegawa, Naoto Nakamura, Hiroshi Ichikawa, Shinya Toyokuni, Tetsuo Ijichi, Toshikazu Yoshikawa

BioFactors Vol. 39 ( 5 ) page： 589 - 589 2013.9

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Papers - TOYOKUNI Shinya