研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. 査読有り国際誌

Imai K, Kotani T, Tsuda H, Mano Y, Nakano T, Ushida T, Li H, Miki R, Sumigama S, Iwase A, Hirakawa A, Ohno K, Toyokuni S, Takeuchi H, Mizuno T, Suzumura A, Kikkawa F

Free radical biology & medicine 91 巻頁： 154 - 63 2016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：Free Radical Biology and Medicine

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 (H2), 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. H2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H2 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 H2, involved in the process of activating microglia. These results suggested that H2 holds promise for the prevention of inflammation related to perinatal brain injury.

DOI： 10.1016/j.freeradbiomed.2015.12.015

Plasma with high electron density and plasma-activated medium for cancer treatment 査読有り国際誌

Tanaka H., Mizuno M., Ishikawa K., Kondo H., Takeda K., Hashizume H., Nakamura K., Utsumi F., Kajiyama H., Kano H., Okazaki Y., Toyokuni S., Akiyama S., Maruyama S., Yamada S., Kodera Y., Kaneko H., Terasaki H., Hara H., Adachi T., Iida M., Yajima I., Kato M., Kikkawa F., Hori M.

Clinical Plasma Medicine 3 巻 ( 2 ) 頁： 72 - 76 2015年12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：Clinical Plasma Medicine

Cancer treatment using non-thermal atmospheric pressure plasma is a brand new and challenging approach for cancer therapy. Conventional cancer therapies are surgery, radio-therapy, and chemo-therapy. We propose plasma-therapy as the fourth cancer therapy. Plasma cancer therapy involves direct plasma treatment of cancers including melanomas, head and neck cancer, pancreatic cancer and liver metastasis, and indirect plasma treatment of cancers by using plasma irradiated solutions such as plasma-activated medium (PAM).We have been recently studying plasma cancer therapy using target cancers such as ovarian cancers, brain tumors, gastric cancers and skin cancers. We have developed a plasma source with ultrahigh electron density, which we have applied to these cancer cells. In addition, we found that plasma-irradiated medium itself can kill these cancer cells. This medium was termed plasma-activated medium (PAM). In vitro and in vivo studies have suggested that PAM is an important tool for cancer therapy especially for disseminated cancers that are currently untreatable.Although many dramatic therapeutic effects of plasma therapy on cancer cells have been reported, the molecular mechanisms of the anti-tumor effects of plasma remain to be elucidated. The greatest challenge for plasma medical science is to understand the complex system that mediates plasma inputs resulting in physiological outputs such as cell death of cancer cells and proliferation of normal cells. Intracellular molecular mechanisms of PAM are also being intensively studied in order to understand the mode of action of PAM. In this review, we summarize the latest understanding of plasma cancer treatments.

DOI： 10.1016/j.cpme.2015.09.001

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Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. 査読有り

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. 6 巻頁： 578-586 2015年12月

Cancer therapy using non-thermal atmospheric pressure plasma with ultra-high electron density 査読有り国際誌

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

PHYSICS OF PLASMAS 22 巻 ( 12 ) 頁： 122004 2015年12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：Physics of Plasmas

Cancer therapy using non-thermal atmospheric pressure plasma is a big challenge in plasma medicine. Reactive species generated from plasma are key factors for treating cancer cells, and thus, non-thermal atmospheric pressure plasma with high electron density has been developed and applied for cancer treatment. Various cancer cell lines have been treated with plasma, and non-thermal atmospheric plasma clearly has anti-tumor effects. Recent innovative studies suggest that plasma can both directly and indirectly affect cells and tissues, and this observation has widened the range of applications. Thus, cancer therapy using non-thermal atmospheric pressure plasma is promising. Animal experiments and understanding the mode of action are essential for clinical application in the future. A new academic field that combines plasma science, the biology of free radicals, and systems biology will be established.

DOI： 10.1063/1.4933402

Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. 査読有り国際誌

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 biology 6 巻頁： 578 - 586 2015年12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：Redox Biology

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.

DOI： 10.1016/j.redox.2015.10.001

プラズマ活性溶液の細胞影響 (小特集プラズマが誘導する生体応答とそのバイオ・医療応用)

田中宏昌, 水野正明, 豊國伸哉, 丸山彰一, 小寺泰弘, 足立哲夫, 寺崎浩子, 加藤昌志, 吉川史隆, 堀勝

プラズマ・核融合学会誌 91 巻 ( 12 ) 頁： 776 - 779 2015年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：プラズマ・核融合学会

近年,非平衡大気圧プラズマの医療・バイオ応用が盛んに研究されている.プラズマに含まれる電子,イオン,ラジカル,光など様々な要因が複雑に細胞及び細胞を取り巻く環境に影響を及ぼし,細胞応答を引き起こしていると考えられている.最近,プラズマ照射された溶液(これはプラズマ活性溶液と名付けられた)ががん細胞にプログラム細胞死として知られるアポトーシスを誘導することがわかり,プラズマ活性溶液が細胞に及ぼす影響が活発に研究されている.脳腫瘍培養細胞においてはプラズマ活性溶液が生存・増殖シグナル伝達経路を抑制することによりアポトーシスへと導くことが明らかになった.これまでに,プラズマ活性溶液は脳腫瘍,卵巣がん,胃がん,非小肺がん細胞など様々ながん細胞に有効であり,抗癌剤耐性卵巣がん細胞に関しても有効であることがわかり,従来のがん治療法では困難な腹膜播種等の播種性のがん治療への応用が期待される.ここではこれまで研究で明らかになりつつあるプラズマ活性溶液の細胞影響とその分子機構について紹介する.

CiNii Research

プラズマ活性溶液の細胞影響 (小特集プラズマが誘導する生体応答とそのバイオ・医療応用)

田中宏昌, 水野正明, 豊國伸哉, 丸山彰一, 小寺泰弘, 足立哲夫, 寺崎浩子, 加藤昌志, 吉川史隆, 堀勝

プラズマ・核融合学会誌 91 巻 ( 12 ) 頁： 776 - 779 2015年12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：プラズマ・核融合学会

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Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury 査読有り国際誌

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

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION 57 巻 ( 3 ) 頁： 178 - 182 2015年11月

Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury. 査読有り

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. 57 巻 ( 3 ) 頁： 178-182 2015年11月

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

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

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

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

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

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論文 - 豊國　伸哉