Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials. Invited International journal

Toyokuni S

J Clin Biochem Nutr Vol. 56 page： 165 2015

Application of intermittent microwave irradiation to western blot analysis. Reviewed International coauthorship International journal

Liu YT, Toyokuni S

Methods Mol Biol Vol. 1314 page： 185-190 2015

Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury Reviewed International journal

Y. Hattori, T. Kotani, H. Tsuda, Y. Mano, L. Tu, H. Li, S. Hirako, T. Ushida, K. Imai, T. Nakano, Y. Sato, R. Miki, S. Sumigama, A. Iwase, S. Toyokuni, F. Kikkawa

FREE RADICAL RESEARCH Vol. 49 ( 8 ) page： 1026 - 37 2015

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

Maternal inflammation is associated with spontaneous preterm birth and respiratory impairment among premature infants. Recently, molecular hydrogen (H-2) has been reported to have a suppressive effect on oxidative stress and infl ammation. The aim of this study was to evaluate the effects of H-2 on fetal lung injury caused by maternal infl ammation. Cell viability and the production of interleukin-6 (IL-6) and reactive oxygen species (ROS) were examined by treatment with lipopolysaccharide (LPS) contained in ordinal or H-2-rich medium (HM) using a human lung epithelial cell line, A549. Pregnant Sprague Dawley rats were divided into three groups: Control, LPS, and HW + LPS groups. Rats were injected with phosphate-buffered saline (Control) or LPS intraperitoneally (LPS) on gestational day 19 and provided H-2 water (HW) ad libitum for 24 h before LPS injection (HW + LPS). Fetal lung samples were collected on day 20, and the levels of apoptosis, oxidative damage, IL-6, and vascular endothelial growth factor (VEGF) were evaluated using immunohistochemistry. The number of apoptotic cells, and levels of ROS and IL-6 were significantly increased by LPS treatment, and repressed following cultured with HM in A549 cells. In the rat models, the population positive for cleaved caspase-3, 8-hydroxy-2'-deoxyguanosine, IL-6, and VEGF was significantly increased in the LPS group compared with that observed in the Control group and significantly decreased in the HW + LPS group. In this study, LPS administration induced apoptosis and oxidative damage in fetal lung cells that was ameliorated by maternal H-2 intake. Antenatal H-2 administration may decrease the pulmonary mobility associated with infl ammation in premature infants.

DOI： 10.3109/10715762.2015.1038257

Minimal inflammogenicity of pristine single-wall carbon nanotubes Reviewed International journal

Toyokuni S., Jiang L., Kitaura R., Shinohara H.

Nagoya Journal of Medical Science Vol. 77 ( 1-2 ) page： 195 - 202 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：Nagoya Journal of Medical Science

Carbon nanotubes (CNTs) are a novel synthetic material comprising only carbon atoms. Based on its rigidity, its electrical and heat conductivity and its applicability to surface manufacturing, this material is expected to have numerous applications in industry. However, due to the material's dimensional similarity to asbestos fibers, its carcinogenicity was hypothesized during the last decade, and indeed, we have shown that multi-wall CNTs (MWCNTs) of 50 nm in diameter are potently carcinogenic to mesothelial cells after intraperitoneal injection. Additionally, we suggested that inflammogenicity after intraperitoneal injection can predict mesothelial carcinogenesis. However, few data have been published on the intraperitoneal inflammogenicity of single-wall CNTs (SWCNTs). Here, we conducted a series of studies on SWCNTs using both intraperitoneal injection into rats and MeT5A mesothelial cells. Intraperitoneal injection of 10 mg SWCNTs caused no remarkable inflammation in the abdominal cavity, and the exposure of MeT5A cells to up to 25 μg/cm2 SWCNTs did not alter proliferation. MWCNTs of 50 nm in diameter were used as a positive control, and tangled MWCNTs of 15 nm in diameter were used as a negative control. The results suggest that SWCNTs are a low-risk material with respect to mesothelial carcinogenesis.

Scopus

Application of Intermittent Microwave Irradiation to Western Blot Analysis. Reviewed International journal

Yu-Ting Liu, Shinya Toyokuni

Methods in molecular biology (Clifton, N.J.) Vol. 1314 page： 185 - 90 2015

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

We established a shortened protocol for Western blot analysis using intermittent microwave irradiation. With this method, the procedure is completed within 1 h after applying the primary antibody, and thus greatly saves time. This procedure appears to be applicable to any antibody based on our experience of several years.

DOI： 10.1007/978-1-4939-2718-0_20

Receptor role of annexin A2 in the mesothelial endocytosis of crocidolite fibers. Reviewed

Yamashita K, Nagai H, Toyokuni S

Lab Invest Vol. 95 page： 749-764 2015

Elucidation of asbestos-induced mesothelial carcinogenesis and risk assessment of nanomaterials

TOYOKUNI Shinya

Annual Meeting of the Japanese Society of Toxicology Vol. 42 ( 0 ) page： S4 - 2 2015

Establishment of murine model for neurotoxicity of 1-bromopropane, an alternative to ozone-depleting solvents

ZONG Cai, GARNER Edwin, HUANG Chin-Yen, ZHANG Lingyi, ZHANG Xiao, SAKURAI Toshihiro, TOYOKUNI Shinya, ICHIHARA Sahoko, ICHIHARA Gaku

Annual Meeting of the Japanese Society of Toxicology Vol. 42 ( 0 ) page： P - 13 2015

Hepatic distribution of GST cannot explain the gap between human and rodents for induction of cholangiocarcioma following exposure to dichloropropane International journal

ZHANG Lingyi, ZONG Cai, ICHIHARA Sahoko, NAITO Hisao, TOYOKUNI Shinya, KUMAGAI Shinji, ICHIHARA Gaku

Annual Meeting of the Japanese Society of Toxicology Vol. 42 ( 0 ) page： P - 165 2015

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Toxicology

Purpose: 1,2-Dichloropropane(DCP) is thought to induce cholangiocarcinoma(CCA) among Japanese printing workers in 2013. However no studies have shown DCP-induced CCA in rodents. Five kinds of rodents were exposed to DCP to find an appropriate animal model for DCP-induced CCA. Methods: First, 12 C57BL/6J mice, Balb/cA mice, F344 rats, Syrian Hamsters and Guinea Pigs were divided into 4 groups equally and exposed to DCP at 0, 300, 1000 and 3000 ppm respectively. Then 32 Balb/cA mice and Syrian Hamsters were divvied into 4 groups equally and exposed to DCP at 0, 200, 400 and 800ppm respectively. After the last exposure livers were dissected out for immunohistochemistry with anti- GSTT1, GSTM1, GSTPi antibodies. Result: Either in control or exposed group all of the animals expressed GSTT1 both at liver cells and bile duct cells. Conclusion: GSTT1 expression cannot explain the gap between human and rodents in the case of DCP inducing CCA.

DOI： 10.14869/toxpt.42.1.0_P-165

CiNii Research

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鉄過剰症による発がんの分子機構　特集：鉄代謝制御機構と鉄過剰症

豊國伸哉

病理と臨床 Vol. 70 page： 337 - 242 2015

Minimal inflammogenicity of pristine single-wall carbon nanotubes Reviewed International journal

Toyokuni S

Nagoya Journal of Medical Science Vol. 77 ( 1-2 ) page： 195 - 202 2015

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

Minako Yoshihara, Li Jiang, Shinya Akatsuka, Mikita Suyama, Shinya Toyokuni

DNA research : an international journal for rapid publication of reports on genes and genomes Vol. 21 ( 6 ) page： 603 - 12 2014.12

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

8-Oxoguanine (8-oxoG) is one of the most common DNA lesions generated by reactive oxygen species. In this study, we analysed the genome-wide distribution profile of 8-oxoG by combining immunoprecipitation by antibodies specific for the DNA fragments containing 8-oxoG with a microarray that covers rat genome. Genome-wide mapping of 8-oxoG in normal rat kidney revealed that 8-oxoG is preferentially located at gene deserts. We did not observe differences in 8-oxoG levels between groups of genes with high and low expression, possibly because of the generally low 8-oxoG levels in genic regions compared with gene deserts. The distribution of 8-oxoG and lamina-associated domains (LADs) were strongly correlated, suggesting that the spatial location of genomic DNA in the nucleus determines the susceptibility to oxidative modifications. One possible explanation for high 8-oxoG levels in LADs is that the nuclear periphery is more susceptible to the oxidative damage caused by the extra-nuclear factors. Moreover, LADs have a rather compact conformation, which may limit the recruitment of repair components to the modified bases.

DOI： 10.1093/dnares/dsu023

Plasma Medical Science for Cancer Therapy: Toward Cancer Therapy Using Nonthermal Atmospheric Pressure Plasma Reviewed International journal

Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Keigo Takeda, Kae Nakamura, Fumi Utsumi, Hiroaki Kajiyama, Hiroyuki Kano, Yasumasa Okazaki, Shinnya Toyokuni, Shoichi Maruyama, Fumitaka Kikkawa, Masaru Hori

IEEE TRANSACTIONS ON PLASMA SCIENCE Vol. 42 ( 12 ) page： 3760 - 3764 2014.12

Language：English Publishing type：Research paper (scientific journal) Publisher：IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC

We have been developing novel ultrahigh density atmospheric pressure plasma sources and succeeded in the selective killing ovarian cancer cells against normal ones. Furthermore, we have found out the plasma- activated medium (PAM) also killed glioblastoma brain tumor cells selectively against normal ones and the chemical products in the PAM have long lifetime healing effects. To clarify the mechanism, interactions of plasma with the organism and the medium where the organism belongs were investigated on the viewpoint of intracellular molecular mechanism.

DOI： 10.1109/TPS.2014.2353659

Web of Science

Scopus

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

Yasumasa Okazaki, Yue Wang, Hiromasa Tanaka, Masaaki Mizuno, Kae Nakamura, Hiroaki Kajiyama, Hiroyuki Kano, Koji Uchida, Fumitaka Kikkawa, Masaru Hori, Shinya Toyokuni

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 55 ( 3 ) page： 207 - 15 2014.11

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

Thermal plasmas and lasers are used in medicine to cut and ablate tissues and for coagulation. Non-equilibrium atmospheric pressure plasma (NEAPP) is a recently developed, non-thermal technique with possible biomedical applications. Although NEAPP reportedly generates reactive oxygen/nitrogen species, electrons, positive ions, and ultraviolet radiation, little research has been done into the use of this technique for conventional free radical biology. Recently, we developed a NEAPP device with high electron density. Electron spin resonance spin-trapping revealed (OH)-O-center dot as a major product. To obtain evidence of NEAPP-induced oxidative modifications in biomolecules and standardize them, we evaluated lipid peroxidation and DNA modifications in various in vitro and ex vivo experiments. Conjugated dienes increased after exposure to linoleic and a-linolenic acids. An increase in 2-thiobarbituric acid-reactive substances was also observed after exposure to phosphatidylcholine, liposomes or liver homogenate. Direct exposure to rat liver in saline produced immunohistochemical evidence of 4-hydroxy-2-nonenal- and acrolein-modified proteins. Exposure to plasmid DNA induced dose-dependent single/double strand breaks and increased the amounts of 8-hydroxy-2'-deoxyguanosine and cyclobutane pyrimidine dimers. These results indicate that oxidative biomolecular damage by NEAPP is dose-dependent and thus can be controlled in a site-specific manner. Simultaneous oxidative and UV-specific DNA damage may be useful in cancer treatment.

DOI： 10.3164/jcbn.14-40

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 International journal

T Mukaide, Y Hattori, N Misawa, S Funahashi, L Jiang, T Hirayama, H Nagasawa, S Toyokuni

Free radical research Vol. 48 ( 9 ) page： 990 - 5 2014.9

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

Iron overload of a chronic nature has been associated with a wide variety of human diseases, including infection, carcinogenesis, and atherosclerosis. Recently, a highly specific turn-on fluorescent probe (RhoNox-1) specific to labile ferrous iron [Fe(II)], but not to labile ferric iron [Fe(III)], was developed. The evaluation of Fe(II) is more important than Fe(III) in vivo in that Fe(II) is an initiating component of the Fenton reaction. In this study, we applied this probe to frozen sections of an established Fenton reaction-based rat renal carcinogenesis model with an iron chelate, ferric nitrilotriacetate (Fe-NTA), in which catalytic iron induces the Fenton reaction specifically in the renal proximal tubules, presumably after iron reduction. Notably, this probe reacted with Fe(II) but with neither Fe(II)-NTA, Fe(III) nor Fe(III)-NTA in vitro. Prominent red fluorescent color was explicitly observed in and around the lumina of renal proximal tubules 1 h after an intraperitoneal injection of 10-35 mg iron/kg Fe-NTA, which was dose-dependent, according to semiquantitative analysis. The RhoNox-1 signal colocalized with the generation of hydroxyl radicals, as detected by hydroxyphenyl fluorescein (HPF). The results demonstrate the transformation of Fe(III)-NTA to Fe(II) in vivo in the Fe-NTA-induced renal carcinogenesis model. Therefore, this probe would be useful for localizing catalytic Fe(II) in studies using tissues.

DOI： 10.3109/10715762.2014.898844

FREE FERROUS IRON IN AMNIOTIC FLUID AS A PREDICTIVE MARKER OF FETAL DISORDERS IN PREGNANCY Reviewed International journal

Yuka Hattori, Tomomi Kotani, Tomoko Nakano, Yukio Mano, Seiji Sumigama, Hiroyuki Tsuda, Takafumi Usida, Hideko Nagasawa, Shinya Toyokuni, Fumitaka Kikkawa

PLACENTA Vol. 35 ( 9 ) page： A71 - A71 2014.9

Connective tissue growth factor and beta-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma Reviewed International journal

Li Jiang, Yoriko Yamashita, Shan-Hwu Chew, Shinya Akatsuka, Shun Ukai, Shenqi Wang, Hirotaka Nagai, Yasumasa Okazaki, Takashi Takahashi, Shinya Toyokuni

JOURNAL OF PATHOLOGY Vol. 233 ( 4 ) page： 402 - 414 2014.8

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

Due to the formerly widespread use of asbestos, malignant mesothelioma (MM) is increasingly frequent worldwide. MM is classified into epithelioid (EM), sarcomatoid (SM), and biphasic subtypes. SM is less common than EM but is recognized as the most aggressive type of MM, and these patients have a poor prognosis. To identify genes responsible for the aggressiveness of SM, we induced EM and SM in rats, using asbestos, and compared their transcriptomes. Based on the results, we focused on connective tissue growth factor (Ctgf), whose expression was significantly increased in SM compared with EM; EM itself exhibited an increased expression of Ctgf compared with normal mesothelium. Particularly in SM, Ctgf was a major regulator of MM proliferation and invasion through activation of the beta-catenin-TCF-LEF signalling pathway, which is autocrine and formed a positive feedback loop via LRP6 as a receptor for secreted Ctgf. High Ctgf expression also played a role in the epithelial-mesenchymal transition in MM. Furthermore, Ctgf is a novel serum biomarker for both early diagnosis and determining the MM prognosis in rats. These data link Ctgf to SM through the LRP6-GSK3 beta-beta-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target. Copyright (C) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.4377

Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation. Reviewed International journal

Kanako Shinjo, Yoriko Yamashita, Eiko Yamamoto, Shinya Akatsuka, Nozomi Uno, Akihiro Kamiya, Kaoru Niimi, Yuka Sakaguchi, Tetsuro Nagasaka, Takashi Takahashi, Kiyosumi Shibata, Hiroaki Kajiyama, Fumitaka Kikkawa, Shinya Toyokuni

International journal of cancer Vol. 135 ( 2 ) page： 308 - 18 2014.7

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

Ovarian cancer is the most lethal gynecologic malignancy, and clear cell adenocarcinoma of the ovary (OCCA), in particular, has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Chromobox (CBX) 7 is a polycomb repressive complex 1 component that prolongs the lifespan of normal human cells by downregulating the INK4a/ARF expression which promotes cell-cycle progression. However, recent reports studying the relationship between CBX7 expression and patient survival have differed regarding the tumor cell origins, and the precise role of CBX7 in human carcinomas remains obscure. In this study, we analyzed CBX7 expression by immunohistochemistry in 81 OCCA patients and evaluated its association with their clinical outcomes. Both the overall and progression-free survival rates of the CBX7-positive patients were significantly shorter than those of the CBX7-negative patients (p < 0.05). CBX7 knockdown experiments using two OCCA cell lines, TOV21G and KOC-7C, revealed that cell viability was significantly reduced compared to the control cells (p < 0.001). Expression microarray analysis revealed that apoptosis-related genes, particularly tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were significantly upregulated in CBX7 knockdown cells (p < 0.01). We further confirmed that CBX7 knockdown resulted in TRAIL-induced apoptosis in the OCCA cells. Thus, in this study, we showed for the first time that CBX7 was associated with a decreased OCCA prognosis. We also successfully demonstrated that the TRAIL pathway is a novel target for CBX7 expression modulation in these cells, and therapeutic agents utilizing the TRAIL pathway may be particularly effective for targeted OCCA therapy.
What's new? Ovarian cancer is the most lethal gynecologic malignancy, with clear celladenocarcinoma of the ovary (OCCA) having a particularly poor prognosis due to high chemoresistance. Chromobox homolog 7 (CBX7) is a polycomb group transcriptional repressor whose role in human cancer remains controversial. Here, the authors showed for the first time that CBX7 expression is related to worse prognosis in OCCA. Furthermore, knockdown of CBX7 in vitro induced apoptosis in OCCA cell lines, possibly via regulation of the TRAIL-pathway. The findings thus indicate CBX7 as a good prognostic marker, andthe TRAIL-pathway as a potential target for OCCA diagnosis and therapy.

DOI： 10.1002/ijc.28692

Lack of presence of the human cytomegalovirus in human glioblastoma Reviewed International journal

Yoriko Yamashita, Yoshinori Ito, Hiroki Isomura, Naoaki Takemura, Akira Okamoto, Kazuya Motomura, Takashi Tsujiuchi, Atsushi Natsume, Toshihiko Wakabayashi, Shinya Toyokuni, Tatsuya Tsurumi

MODERN PATHOLOGY Vol. 27 ( 7 ) page： 922 - 9 2014.7

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

Recent reports have indicated human cytomegalovirus (HCMV) to be associated with human glioblastoma carcinogenesis. In established examples of viral carcinogenesis, viral DNA and one or more of its products have been detected in most tumor cells of biopsies in the majority of cases. To test whether HCMV is associated with human glioblastoma based on this criterion, we measured the number of viral DNA molecules per cell in both frozen and paraffin-embedded tumor biopsies from 58 patients using real-time quantitative PCR (QPCR). Immunohistochemical and fluorescence in situ hybridization (FISH) to detect HCMV proteins and genome was performed in 10 cases using formalin-fixed paraffin-embedded glioblastoma tissues. Southern blotting using DNA extracted from four glioblastoma cell lines together with immunoblotting using the four cell lines and five glioblastoma tissue samples were also performed. We further confirmed the immunoblot bands using liquid chromatography-tandem mass spectrometry assay. As a result, HCMV DNA was not detected in the tumor cells from any of the glioblastoma cases by QPCR detecting two different HCMV genes, in clear contrast to samples from patients with HCMV infection. Southern blotting and immunoblotting of cell lines and FISH using paraffin sections were all negative. However, immunoblotting and immunohistochemistry using tissue samples were partly positive, but HCMV proteins were not detected by proteomic analysis, suggesting false positivity of the analyses. As our QPCR analysis could detect 10 copies of HCMV DNA mixed with DNA extracted from 10(4) HCMV-negative cells, we conclude that HCMV is not persistent, at least in the tumor cells, of developed human glioblastoma.

DOI： 10.1038/modpathol.2013.219

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

Satoshi Nishiwaki, Takayuki Nakayama, Makoto Murata, Tetsuya Nishida, Seitaro Terakura, Shigeki Saito, Tomonori Kato, Hiroki Mizuno, Nobuhiko Imahashi, Aika Seto, Yukiyasu Ozawa, Koichi Miyamura, Masafumi Ito, Kyosuke Takeshita, Hidefumi Kato, Shinya Toyokuni, Keisuke Nagao, Ryuzo Ueda, Tomoki Naoe

PloS one Vol. 9 ( 5 ) page： e96252 2014.5

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-alpha and IFN-gamma, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

DOI： 10.1371/journal.pone.0096252

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Papers - TOYOKUNI Shinya