Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia Reviewed International journal

Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Yukio Mano, Tomoko Nakano, Takafumi Ushida, Hua Li, Rika Miki, Seiji Sumigama, Akira Iwase, Akihiro Hirakawa, Kinji Ohno, Shinya Toyokuni, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura, Fumitaka Kikkawa

FREE RADICAL BIOLOGY AND MEDICINE Vol. 91 page： 154 - 63 2016.2

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

Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H-2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H-2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H-2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H-2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H-2, involved in the process of activating microglia. These results suggested that H-2 holds promise for the prevention of inflammation related to perinatal brain injury. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.freeradbiomed.2015.12.015

Plasma with high electron density and plasma-activated medium for cancer treatment Reviewed International journal

Tanaka Hiromasa, Mizuno Masaaki, Ishikawa Kenji, Kondo Hiroki, Takeda Keigo, Hashizume Hiroshi, Nakamura Kae, Utsumi Fumi, Kajiyama Hiroaki, Kano Hiroyuki, Okazaki Yasumasa, Toyokuni Shinya, Akiyama Shin'ichi, Maruyama Shoichi, Yamada Suguru, Kodera Yasuhiro, Kaneko Hiroki, Terasaki Hiroko, Hara Hirokazu, Adachi Tetsuo, Iida Machiko, Yajima Ichiro, Kato Masashi, Kikkawa Fumitaka, Hori Masaru

CLINICAL PLASMA MEDICINE Vol. 3 ( 2 ) page： 72 - 76 2015.12

Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. Reviewed

Mori M, Ito F, Shi L, Wang Y, Ishida C, Hattori Y, Niwa M, Hirayama T, Nagasawa H, Iwase A, Kikkawa F, Toyokuni S.

Redox Biol. Vol. 6 page： 578-586 2015.12

Cancer therapy using non-thermal atmospheric pressure plasma with ultra-highelectron density Reviewed International journal

H. Tanaka, M. Mizuno, S. Toyokuni, S. Maruyama, Y. Kodera, H. Terasaki, T. Adachi, M. Kato, F. Kikkawa, M. Hori

Phys Plasmas Vol. 22 ( 12 ) page： 122004 2015.12

Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron Reviewed International journal

Masahiko Mori, Fumiya Ito, Lei Shi, Yue Wang, Chiharu Ishida, Yuka Hattori, Masato Niwa, Tasuku Hirayama, Hideko Nagasawa, Akira Iwase, Fumitaka Kikkawa, Shinya Toyokuni

REDOX BIOLOGY Vol. 6 page： 578 - 586 2015.12

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

Ovarian endometriosis is a recognized risk for infertility and epithelial ovarian cancer, presumably due to iron overload resulting from repeated hemorrhage. To find a clue for early detection and prevention of ovarian endometriosis-associated cancer, it is mandatory to evaluate catalytic (labile) ferrous iron (catalytic Fe(II)) and to study iron manipulation in ovarian endometriotic lesions. By the use of tissues from women of ovarian endometriosis as well as endometrial tissue from women with and without endometriosis, we for the first time performed histological analysis and cellular detection of catalytic Fe(II) with a specific fluorescent probe (HMRhoNox-M), and further evaluated iron transport proteins in the human specimens and in co-culture experiments using immortalized human eutopic/ectopic endometrial stromal cells (ESCs) in the presence or absence of epithelial cells (EpCs). The amounts of catalytic Fe(II) were higher in ectopic endometrial stromal cells (ecESCs) than in normal eutopic endometrial stromal cells (n-euESCs) both in the tissues and in the corresponding immortalized ESCs. ecESCs exhibited higher transferrin receptor 1 expression both in vivo and in vitro and lower ferroportin expression in vivo than n-euESCs, leading to sustained iron uptake. In co-culture experiments of ESCs with iron-loaded EpCs, ecESCs received catalytic ferrous iron from EpCs, but n-euESCs did not. These data suggest that ecESC play a protective role for cancer-target epithelial cells by collecting excess iron, and that these characteristics are retained in the immortalized ecESCs. (C) 2015 The Authors. Published by Elsevier B.V.

DOI： 10.1016/j.redox.2015.10.001

Effects of Plasma-Activated Medium on Cells

TANAKA Hiromasa, MIZUNO Masaaki, TOYOKUNI Shinya, MARUYAMA Shoichi, KODERA Yasuhiro, ADACHI Tetsuo, TERASAKI Hiroko, KATO Masashi, KIKKAWA Fumitaka, HORI Masaru

Vol. 91 ( 12 ) page： 776 - 779 2015.12

Effects of Plasma-Activated Medium on Cells

TANAKA Hiromasa, MIZUNO Masaaki, TOYOKUNI Shinya, MARUYAMA Shoichi, KODERA Yasuhiro, ADACHI Tetsuo, TERASAKI Hiroko, KATO Masashi, KIKKAWA Fumitaka, HORI Masaru

Vol. 91 ( 12 ) page： 776 - 779 2015.12

Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury Reviewed International journal

Tomoko Nakano, Tomomi Kotani, Yukio Mano, Hiroyuki Tsuda, Kenji Imai, Takafumi Ushida, Hua Li, Rika Miki, Seiji Sumigama, Yoshiaki Sato, Akira Iwase, Akihiro Hirakawa, Masato Asai, Shinya Toyokuni, Fumitaka Kikkawa

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 57 ( 3 ) page： 178 - 182 2015.11

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

Fetal brain injury is often related to prenatal inflammation; however, there is a lack of effective therapy. Recently, molecular hydrogen (H-2), a specific antioxidant to hydroxyl radical and peroxynitrite, has been reported to have anti-inflammatory properties. The aim of this study was to investigate whether maternal H-2 administration could protect the fetal brain against inflammation. Pregnant C3H/HeN mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15.5 and were provided with H2 water for 24 h prior to LPS injection. Pup brain samples were collected on gestational day 16.5, and the levels of apoptosis and oxidative damage were evaluated using immunohistochemistry. Interleukin-6 (IL-6) levels were examined using real-time PCR. The levels of apoptosis and oxidative damage, as well as the levels of IL-6 mRNA, increased significantly when the mother was injected with LPS than that in the control group. However, these levels were significantly reduced when H2 was administered prior to the LPS-injection. Our results suggest that LPS-induced apoptosis, oxidative damage and inflammation in the fetal brain were ameliorated by maternal H2 administration. Antenatal H2 administration might protect the premature brain against maternal inflammation.

DOI： 10.3164/jcbn.15-90

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Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury. Reviewed

Nakano T, Kotani T, Mano Y, Tsuda H, Imai K, Ushida T, Li H, Miki R, Sumigama S, Sato Y, Iwase A, Hirakawa A, Asai M, Toyokuni S, Kikkawa F.

J Clin Biochem Nutr. Vol. 57 ( 3 ) page： 178-182 2015.11

A trial to find appropriate animal models of dichloropropaneinduced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases

Zhang Lingyi, Zong Cai, Ichihara Sahoko, Naito Hisao, Toyokuni Shinya, Kumagai Shinji, Ichihara Gaku

JOURNAL OF OCCUPATIONAL HEALTH Vol. 57 ( 6 ) page： 548 - 554 2015.11

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

Recent information on the outbreak of cholangiocarcinoma in a printing company

Occupational Health Review Vol. 28 ( 2 ) page： 131 - 156 2015.9

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

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 Reviewed International journal

Tanaka H., Mizuno M., Toyokuni S., Maruyama S., Kodera Y., Kikkawa F., Hori M.

Fukuoka igaku zasshi = Hukuoka acta medica Vol. 106 ( 4 ) page： 71 - 76 2015.4

[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 Reviewed 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

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Papers - TOYOKUNI Shinya