研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Oxidative stress as an iceberg in carcinogenesis and cancer biology 査読有り国際誌

Toyokuni Shinya

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 595 巻頁： 46 - 49 2016年4月

Oxidative stress as an iceberg in carcinogenesis and cancer biology. 査読有り

Toyokuni S.

Arch Biochem Biophys. 2016 Apr 1;595:46-9. 595 巻頁： 46-9 2016年4月

Oxidative stress as an iceberg in carcinogenesis and cancer biology. 査読有り国際誌

Toyokuni S

Arch Biochem Biophys. 2016 Apr 1;595:46-9. 595 巻頁： 46-9 2016年4月

Tribute issue: Helmut Sies and oxidative stress: Venit, vidit, vicit 査読有り国際誌

Forman H.

Archives of Biochemistry and Biophysics 595 巻 2016年4月

Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics.

Kalinowski DS, Stefani C, Toyokuni S, Ganz T, Anderson GJ, Subramaniam NV, Trinder D, Olynyk JK, Chua A, Jansson PJ, Sahni S, Lane DJ, Merlot AM, Kovacevic Z, Huang ML, Lee CS, Richardson DR.

Biochim Biophys Acta. 1863 巻 ( 4 ) 頁： 727-748 2016年4月

Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics. 国際誌

Kalinowski DS, Stefani C, Toyokuni S, Ganz T, Anderson GJ, Subramaniam NV, Trinder D, Olynyk JK, Chua A, Jansson PJ, Sahni S, Lane DJ, Merlot AM, Kovacevic Z, Huang ML, Lee CS, Richardson DR

Biochimica et biophysica acta 1863 巻 ( 4 ) 頁： 727 - 48 2016年4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：Biochimica et Biophysica Acta - Molecular Cell Research

Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics.

DOI： 10.1016/j.bbamcr.2016.01.026

Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. 査読有り

Wang Y, Okazaki Y, Shi L, Kohda H, Tanaka M, Taki K, Nishioka T, Hirayama T, Nagasawa H, Yamashita Y, Toyokuni S.

Cancer Sci. 107 巻 ( 3 ) 頁： 250-257 2016年3月

Pain-reducing anesthesia prevents oxidative stress in human term placenta. 査読有り

Tsuzuki Y, Yamashita Y, Hattori Y, Hua Li G, Akatsuka S, Kotani T, Kikkawa F, Naiki-Ito A, Takahashi S, Nishiwaki K, Toyokuni S.

J Clin Biochem Nutr. 58 巻 ( 2 ) 頁： 156-60 2016年3月

Pain-reducing anesthesia prevents oxidative stress in human term placenta. 査読有り国際誌

Tsuzuki Y, Yamashita Y, Hattori Y, Hua Li G, Akatsuka S, Kotani T, Kikkawa F, Naiki-Ito A, Takahashi S, Nishiwaki K, Toyokuni S

Journal of clinical biochemistry and nutrition 58 巻 ( 2 ) 頁： 156 - 60 2016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

Anesthesia is sometimes used for the reduction of maternal pain in normal human term labor, but whether the drugs affect oxidative stress remains unclear. The placenta serves as an interface between the maternal and fetal vasculature. In this study, we immunohistochemically analyzed two markers for oxidative stress, namely 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-modified proteins (HNE), using placentas from 21 cases of normal tansvaginal delivery (V group), 20 Caesarean sections (C group), and 17 normal transvaginal deliveries with epidural anesthesia (E group). 8-OHdG staining in the nuclei of trophoblasts lining the chorionic villi was significantly stronger in the V group either compared with the C or E group (p<0.001), without significant differences in the C and E groups (p = 0.792). Moderate to intense staining by HNE of the intravascular serum of chorionic villi vasculature was frequently observed in the placentas from the V group, but less frequently of those in either C or E groups (p<0.001), nor the p value comparing the C and E groups was significant (p = 0.128) for HNE staining. Our results suggest that although the role of oxidative stress and its influences on fetal state in the placenta in labor remains unclear, it seems to be lessened by epidural anesthesia.

DOI： 10.3164/jcbn.15-138

Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. 査読有り国際誌

Wang Y, Okazaki Y, Shi L, Kohda H, Tanaka M, Taki K, Nishioka T, Hirayama T, Nagasawa H, Yamashita Y, Toyokuni S

Cancer science 107 巻 ( 3 ) 頁： 250 - 7 2016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：Cancer Science

Multi-wall carbon nanotubes (MWCNT) are a form of flexible fibrous nanomaterial with high electrical and thermal conductivity. However, 50-nm MWCNT in diameter causes malignant mesothelioma (MM) in rodents and, thus, the International Agency of Research on Cancer has designated them as a possible human carcinogen. Little is known about the molecular mechanism through which MWCNT causes MM. To elucidate the carcinogenic mechanisms of MWCNT in mesothelial cells, we used a variety of lysates to comprehensively identify proteins specifically adsorbed on pristine MWCNT of different diameters (50 nm, NT50; 100 nm, NT100; 150 nm, NT150; and 15 nm/tangled, NTtngl) using mass spectrometry. We identified >400 proteins, which included hemoglobin, histone, transferrin and various proteins associated with oxidative stress, among which we selected hemoglobin and transferrin for coating MWCNT to further evaluate cytotoxicity, wound healing, intracellular catalytic ferrous iron and oxidative stress in rat peritoneal mesothelial cells (RPMC). Cytotoxicity to RPMC was observed with pristine NT50 but not with NTtngl. Coating NT50 with hemoglobin or transferrin significantly aggravated cytotoxicity to RPMC, with an increase in cellular catalytic ferrous iron and DNA damage also observed. Knockdown of transferrin receptor with ferristatin II decreased not only NT50 uptake but also cellular catalytic ferrous iron. Our results suggest that adsorption of hemoglobin and transferrin on the surface of NT50 play a role in causing mesothelial iron overload, contributing to oxidative damage and possibly subsequent carcinogenesis in mesothelial cells. Uptake of NT50 at least partially depends on transferrin receptor 1. Modifications of NT50 surface may decrease this human risk.

DOI： 10.1111/cas.12865

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

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 Radic Biol Med. 91 巻頁： 154-163 2016年2月

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

Web of Science

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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) Open Access

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.

Open Access

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) Open Access

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 Open Access

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

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