Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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

L. Zhang, C. Zong, S. Ichihara, H. Naito, S. Toyokuni, S. Kumagai, G. Ichihara

TOXICOLOGY LETTERS Vol. 238 ( 2 ) page： S245 - S245 2015.10

Malignant mesothelioma as an oxidative stress-induced cancer: An update. International journal

Shan Hwu Chew, Shinya Toyokuni

Free radical biology & medicine Vol. 86 page： 166 - 78 2015.9

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

Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following respiratory exposure to asbestos in humans. Its pathogenesis is closely associated with iron overload and oxidative stress in mesothelial cells. On fiber exposure, mesothelial cells accumulate fibers simultaneously with iron, which either performs physical scissor function or catalyzes free radical generation, leading to oxidative DNA damage such as strand breaks and base modifications, followed by activation of intracellular signaling pathways. Chrysotile, per se without iron, causes massive hemolysis and further adsorbs hemoglobin. Exposure to indigestible foreign materials also induces chronic inflammation, involving consistent generation of free radicals and subsequent activation of NALP3 inflammasomes in macrophages. All of these contribute to mesothelial carcinogenesis. Genomic alterations most frequently involve homozygous deletion of INK4A/4B, and other pathways such as Hippo and TGF-beta pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP] as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still similar to 8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by beta-catenin, has been recognized as a hopeful target for therapy, especially in sarcomatoid subtype. Recent research outcomes related to microRNAs and cancer stem cells also offer additional novel targets for the treatment of MM. Iron reduction as chemoprevention of mesothelioma is helpful at least in an animal preclinical study. Integrated approaches to fiber-induced oxidative stress would be necessary to overcome this currently fatal disease. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.freeradbiomed.2015.05.002

Aging rather than sun exposure is a major determining factor for the density of miR-125b-positive epidermal stem cells in human skin International journal

Shinya Toyokuni, Li Jiang, Shenqi Wang, Ayaka Hirao, Tamae Wada, Chieko Soh, Kazumi Toyama, Akira Kawada

PATHOLOGY INTERNATIONAL Vol. 65 ( 8 ) page： 415 - 9 2015.8

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

Sunlight exposure and aging are two major factors in the deterioration of skin function. In the present study, we used eighty formalin-fixed human skin samples from sun-exposed and unexposed areas from old and young individuals to evaluate the presence of miR-125b-positive epidermal stem cells (ESCs) by in situ hybridization. miR-125b-positive ESCs were detected in the basal layer of the epidermis. The density of miR-125b-positive ESCs was significantly associated with age rather than sun exposure, whereas the density of miR-125b-positive ESCs tended to decrease in the sun-exposed area. These data suggest the potential use of miR-125b as a surrogate marker for the quality of epidermal cells.

DOI： 10.1111/pin.12320

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

Yamashita Kyoko, Nagai Hirotaka, Toyokuni Shinya

LABORATORY INVESTIGATION Vol. 95 ( 7 ) page： 749 - 764 2015.7

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

Shinya Toyokuni

Journal of clinical biochemistry and nutrition Vol. 56 ( 3 ) page： 165 - 165 2015.5

[Plasma-Activated Solution: Mechanism of Action, Clinical Application, and Industrialization].

Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Shoichi Maruyama, Yasuhiro Kodera, Fumitaka Kikkawa, Masaru Hori

Fukuoka igaku zasshi = Hukuoka acta medica Vol. 106 ( 4 ) page： 71 - 6 2015.4

Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells International journal

Funahashi Satomi, Okazaki Yasumasa, Ito Daiki, Asakawa Atsushi, Nagai Hirotaka, Tajima Masafumi, Toyokuni Shinya

Journal of Clinical Biochemistry and Nutrition Vol. 56 ( 2 ) page： 111 - 7 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SOCIETY FOR FREE RADICAL RESEARCH JAPAN

Asbestos exposure is considered a social burden by causing mesothelioma. Despite the use of synthetic materials, multi-walled carbon nanotubes (MWCNTs) are similar in dimension to asbestos and produce mesothelioma in animals. The role of inflammatory cells in mesothelial carcinogenesis remains unclear. Here, we evaluated the differences in inflammatory cell responses following exposure to these fibrous materials using a luminometer and L-012 (8-amino-5-chloro-7-phenylpyrido[3,4-<i>d</i>]pyridazine-1,4-(<i>2H,3H</i>) dione) to detect reactive oxygen species (ROS). Rat peripheral blood or RAW264.7 cells were used to assess the effects on neutrophils and macrophages, respectively. Crocidolite and amosite induced significant ROS generation by neutrophils with a peak at 10 min, whereas that of chrysotile was ~25% of the crocidolite/amosite response. MWCNTs with different diameters (~15, 50, 115 and 145 nm) and different carcinogenicity did not induce significant ROS in peripheral blood. However, the MWCNTs induced a comparable amount of ROS in RAW264.7 cells to that following asbestos treatment. The peaks for MWCNTs (0.5–1.5 h) were observed earlier than those for asbestos (1–5 h). Apocynin and superoxide dismutase significantly inhibited ROS generation for each fiber, suggesting an involvement of NADPH oxidase and superoxide. Thus, asbestos and MWCNTs induce different oxidative responses in inflammatory cells, indicating the importance of mesothelial cell evaluation for carcinogenesis.

DOI： 10.3164/jcbn.14-92

血栓内膜摘除術後に体外循環から離脱できずに死亡した慢性血栓塞栓性肺高血圧症の一剖検例

山下享子, 榎本篤, 大島英揮, 平敷安希博, 近藤隆久, 豊国伸哉, 中村栄男

日本病理学会会誌 Vol. 104 ( 1 ) page： 336 - 336 2015.3

Possible involvement of iron-induced oxidative insults in neurodegeneration International journal

Takeshi Asano, Masato Koike, Shin-ichi Sakata, Yukiko Takeda, Tomoko Nakagawa, Taku Hatano, Satoshi Ohashi, Manabu Funayama, Kenji Yoshimi, Masato Asanuma, Shinya Toyokuni, Hideki Mochizuki, Yasuo Uchiyama, Nobutaka Hattori, Kazuhiro Iwai

NEUROSCIENCE LETTERS Vol. 588 ( 1 ) page： 29 - 35 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2014.12.052

MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES Reviewed International journal

Shinya Toyokuni, Li Jiang, Ryo Kitaura, Hisanori Shinohara

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 77 ( 1-2 ) page： 195 - 202 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：NAGOYA UNIV, SCH MED

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 mu g/cm(2) 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.

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Minimal inflammogenicity of pristine single-wall carbon nanotubes.

Toyokuni S, Jiang LI, Kitaura R, Shinohara H

Nagoya journal of medical science Vol. 77 ( 1-2 ) page： 195 - 202 2015.2

Minimal inflammogenicity of pristine single-wall carbon nanotubes.

Toyokuni S, Jiang LI, Kitaura R, Shinohara H

Nagoya journal of medical science Vol. 77 ( 1-2 ) page： 195 - 202 2015.2

MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES

Toyokuni Shinya, Jiang Li, Kitaura Ryo, Shinohara Hisanori

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 77 ( 1-2 ) page： 195 - 202 2015.2

Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders.

Yuka Hattori, Takahiro Mukaide, Li Jiang, Tomomi Kotani, Hiroyuki Tsuda, Yukio Mano, Seiji Sumigama, Tasuku Hirayama, Hideko Nagasawa, Fumitaka Kikkawa, Shinya Toyokuni

Journal of clinical biochemistry and nutrition Vol. 56 ( 1 ) page： 57 - 63 2015.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SOCIETY FOR FREE RADICAL RESEARCH JAPAN

Amniotic fluid contains numerous biomolecules derived from fetus and mother, thus providing precious information on pregnancy. Here, we evaluated oxidative stress of human amniotic fluid and measured the concentration of catalytic Fe(II). Amniotic fluid samples were collected with consent from a total of 89 subjects in Nagoya University Hospital, under necessary medical interventions: normal pregnancy at term, normal pregnancy at the 2nd trimester, preterm delivery with maternal disorders but without fetal disorders, congenital diaphragmatic hernia, fetal growth restriction, pregnancy-induced hypertension, gestational diabetes mellitus, Down syndrome and trisomy 18. Catalytic Fe(II) and oxidative stress markers (8-hydroxy-2'-deoxyguanosine, 8-OHdG; dityrosine) were determined with RhoNox-1 and specific antibodies, respectively, using plate assays. Levels of 8-OHdG and dityrosine were higher in the 3rd trimester compared with the 2nd trimester in normal subjects, and the abnormal groups generally showed lower levels than the controls, thus suggesting that they represent fetal metabolic activities. In contrast, catalytic Fe(II) was higher in the 2nd trimester than the 3rd trimester in the normal subjects, and overall the abnormal groups showed higher levels than the controls, suggesting that high catalytic Fe(II) at late gestation reflects fetal pathologic alterations. Notably, products of H2O2 and catalytic Fe(II) remained almost constant in amniotic fluid.

DOI： 10.3164/jcbn.14-82

Napsin A is a specific marker for ovarian clear cell adenocarcinoma. International journal

Yoriko Yamashita, Tetsuro Nagasaka, Aya Naiki-Ito, Shinya Sato, Shugo Suzuki, Shinya Toyokuni, Masafumi Ito, Satoru Takahashi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Vol. 28 ( 1 ) page： 111 - 7 2015.1

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

Ovarian clear cell adenocarcinoma has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Differential diagnosis of clear cell adenocarcinoma from other ovarian surface epithelial tumors is important for its treatment. Napsin A is a known diagnostic marker for lung adenocarcinoma, and expression of napsin A is reported in a certain portion of thyroid and renal carcinomas. However, napsin A expression in ovarian surface epithelial tumors has not previously been examined. In this study, immunohistochemical analysis revealed that in 71 of 86 ovarian clear cell adenocarcinoma patients (83%) and all of the 13 patients with ovarian clear cell adenofibroma, positive napsin A staining was evident. No expression was observed in 30 serous adenocarcinomas, 11 serous adenomas or borderline tumors, 19 endometrioid adenocarcinomas, 22 mucinous adenomas or borderline tumors, 10 mucinous adenocarcinomas, or 3 yolk sac tumors of the ovary. Furthermore, expression of napsin A was not observed in the normal surface epithelium of the ovary, epithelia of the fallopian tubes, squamous epithelium, endocervical epithelium, or the endometrium of the uterus. Therefore, we propose that napsin A is another sensitive and specific marker for distinguishing ovarian clear cell tumors (especially adenocarcinomas) from other ovarian tumors.

DOI： 10.1038/modpathol.2014.61

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

Toyokuni S.

J Clin Biochem Nutr Vol. 56 page： 165 2015

Application of intermittent microwave irradiation to western blot analysis. Reviewed

Liu YT, Toyokuni S.

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

Aging rather than sun exposure is a major determining factor for the density of miR-125b-positive epidermal stem cells in human skin. Reviewed

Toyokuni S, Jiang L, Wang S, Hirao A, Wada T, Soh C, Tohyama K and Kawada A.

Pathol Int Vol. 65 page： 415-419 2015

Malignant mesothelioma as an oxidative stress-induced cancer: An update. Reviewed

Chew SH and Toyokuni S.

Free Radic Biol Med Vol. 86 page： 166-178 2015

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

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

Free Radic Res Vol. 49 page： 1026-1037 2015

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Papers - TOYOKUNI Shinya