研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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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 57 巻 ( 6 ) 頁： 548 - 554 2015年11月

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

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

TOXICOLOGY LETTERS 238 巻 ( 2 ) 頁： S245 - S245 2015年10月

印刷会社で集団発生した胆管癌の最近の知見

熊谷信二, 久保正二, 竹村茂一, 田中肖吾, 木下正彦, 濱野玄弥, 伊藤得路, 青田哲尚, 江田将樹, 中沼安二, 圓藤吟史, 市原学, 張霊逸, 豊國伸哉

産業医学レビュー 28 巻 ( 2 ) 頁： 131 - 156 2015年9月

Malignant mesothelioma as an oxidative stress-induced cancer: An update. 査読有り国際誌

Chew SH, Toyokuni S

Free radical biology & medicine 86 巻頁： 166 - 78 2015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：Free Radical Biology and Medicine

Abstract 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-β pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP1 as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still ~8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by β-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.

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. 査読有り国際誌 Open Access

Toyokuni S, Jiang L, Wang S, Hirao A, Wada T, Soh C, Toyama K, Kawada A

Pathology international 65 巻 ( 8 ) 頁： 415 - 9 2015年8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：Pathology International

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 査読有り国際誌 Open Access

Yamashita Kyoko, Nagai Hirotaka, Toyokuni Shinya

LABORATORY INVESTIGATION 95 巻 ( 7 ) 頁： 749 - 764 2015年7月

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

Toyokuni S

Journal of clinical biochemistry and nutrition 56 巻 ( 3 ) 頁： 165 - 165 2015年5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：Journal of Clinical Biochemistry and Nutrition

Major causes of human death in developed countries are atherosclerosis(1) and carcinogenesis.(2) Atherosclerosis finally leads to a variety of diseases such as myocardial infarction and cerebral infarction. The essence of these pathologic processes is largely due to free radical reactions or oxidative stress due to our persistent use of oxygen in the presence of iron,(3–5) and the products can be literally rust in our body.(6) Heart may be replaced with transplantation from another person with brain death under his/her own permission, but it is currently impossible to transplant brain. Additionally, highly ethical issues, severe donor deficiency and immunological rejections are always present with transplantation.(7) If brand-new cells and organs of any type to be replaced and of their own immunophenotype were freely available, all the people on earth would benefit from this novel technology. Induced pluripotent stem cells can be established from differentiated somatic cells by the forced induction of four transcription factors: Oct3/4, Klf4, Sox2 and c-Myc.(8) However, premature termination of reprogramming might lead to cancer development through altered epigenetic regulation.(9) Recently, the concept of directly converting one type of somatic cell into another has attracted much attention.(10) However, one of the major drawbacks linked to the current strategies is that they are also based on ectopic expression of important developmental genes (transcription factors, etc.),(11) which might cause unexpected undesired effects. In the present issue of Journal of Clinical Biochemistry and Nutrition, Dai et al.(12) for the first time describe a highly efficient chemical conversion of human fibroblasts to neuronal cells with defined six chemical compounds (Fig. 1). Their protocol used five inhibitors to block distinct signaling pathways including transforming growth factor (TGF)-β (SMAD pathway), bone morphologic protein (BMP), glycogen synthase kinase (GSK)-3β, MEK-ERK and p53, together with a cAMP stimulator. Moreover, the authors emphasize that this protocol shortens the time required for differentiation into neuronal cells to 3 weeks in comparison to the reported protocols(10,13) with ~90% efficiency. Fig. 1 Chemical conversion of human fibroblasts into neuronal cells. Refer to text for details. I believe that this is the dawn of regenerative neurology. In a few years or so, human clinical trials would be performed by the use of this technique. Target diseases would be neurodegenerative diseases(14) such as Alzheimer’s and Parkinson diseases, motor neuron diseases such as amyotropic lateral sclerosis, and cerebral infarction/hemorrhage. Simultaneously, we always have to consider how we can load these new neuronal cells with long-time experience and memory of the recipient if necessary.

DOI： 10.3164/jcbn.56-3-editorial

Plasma-Activated Solution: Mechanism of Action, Clinical Application, and Industrialization 査読有り国際誌

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

Fukuoka igaku zasshi = Hukuoka acta medica 106 巻 ( 4 ) 頁： 71 - 76 2015年4月

プラズマ活性溶液 : 作用機序解明と臨床応用・産業化を目指して Open Access

田中宏昌, 水野正明, 豊國伸哉, 丸山彰一, 小寺泰弘, 吉川史隆, 堀勝

福岡醫學雜誌 106 巻 ( 4 ) 頁： 71 - 6 2015年4月

Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells. 査読有り国際誌 Open Access

Funahashi S, Okazaki Y, Ito D, Asakawa A, Nagai H, Tajima M, Toyokuni S

Journal of clinical biochemistry and nutrition 56 巻 ( 2 ) 頁： 111 - 7 2015年3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：一般社団法人　日本酸化ストレス学会

Asbestos exposure is considered a social burden bycausing meso-thelioma. 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-dlpyridazine-1,4-(2H,3H) dione) to detect reactive oxygen species (ROS). Rat peripheral blood or RAW264.7 cells were used to assess the effects on neutro-phils 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 oxida-tive 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 104 巻 ( 1 ) 頁： 336 - 336 2015年3月

Possible involvement of iron-induced oxidative insults in neurodegeneration. 査読有り国際誌 Open Access

Asano T, Koike M, Sakata S, Takeda Y, Nakagawa T, Hatano T, Ohashi S, Funayama M, Yoshimi K, Asanuma M, Toyokuni S, Mochizuki H, Uchiyama Y, Hattori N, Iwai K

Neuroscience letters 588 巻 ( 1 ) 頁： 29 - 35 2015年2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：Neuroscience Letters

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.

DOI： 10.1016/j.neulet.2014.12.052

MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES 査読有り国際誌 Open Access

Shinya Toyokuni, Li Jiang, Ryo Kitaura, Hisanori Shinohara

NAGOYA JOURNAL OF MEDICAL SCIENCE 77 巻 ( 1-2 ) 頁： 195 - 202 2015年2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：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.

DOI： 10.18999/nagjms.77.1-2.195

Open Access

Web of Science

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Minimal inflammogenicity of pristine single-wall carbon nanotubes. Open Access

Toyokuni S, Jiang LI, Kitaura R, Shinohara H

Nagoya journal of medical science 77 巻 ( 1-2 ) 頁： 195 - 202 2015年2月

Minimal inflammogenicity of pristine single-wall carbon nanotubes. Open Access

Toyokuni S, Jiang LI, Kitaura R, Shinohara H

Nagoya journal of medical science 77 巻 ( 1-2 ) 頁： 195 - 202 2015年2月

MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES Open Access

Toyokuni Shinya, Jiang Li, Kitaura Ryo, Shinohara Hisanori

NAGOYA JOURNAL OF MEDICAL SCIENCE 77 巻 ( 1-2 ) 頁： 195 - 202 2015年2月

Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders. 査読有り Open Access

Hattori Y, Mukaide T, Jiang L, Kotani T, Tsuda H, Mano Y, Sumigama S, Hirayama T, Nagasawa H, Kikkawa F, Toyokuni S

Journal of clinical biochemistry and nutrition 56 巻 ( 1 ) 頁： 57 - 63 2015年1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：Journal of Clinical Biochemistry and Nutrition

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 oxi-dative 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. 査読有り国際誌 Open Access

Yamashita Y, Nagasaka T, Naiki-Ito A, Sato S, Suzuki S, Toyokuni S, Ito M, Takahashi S

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 28 巻 ( 1 ) 頁： 111 - 7 2015年1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：Modern Pathology

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

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

Hattori Y, Mukaide T, Jiang L, Kotani T, Tsuda H, Mano Y, Sumigama S, Hirayama T, Nagasawa H, Kikkawa F and Toyokuni S.

J Clin Biochem Nutr 56: 57-63, 2015. 56 巻頁： 57-63 2015年

Napsin A is a specific marker for ovarian clear cell adenocarcinoma. 査読有り

Yamashita Y, Nagasaka T, Naiki-Ito A, Sato S, Suzuki S, Toyokuni S, Ito M and Takahashi S.

Mod Pathol 28 巻頁： 111-117 2015年

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