研究者データベース

安井 博宣(ヤスイ ヒロノブ)
獣医学研究院 獣医学部門 応用獣医科学分野
准教授

基本情報

所属

  • 獣医学研究院 獣医学部門 応用獣医科学分野

職名

  • 准教授

学位

  • 博士(獣医学)(北海道大学)

ホームページURL

科研費研究者番号

  • 10570228

ORCID ID

Researcher ID

  • E-3794-2010

J-Global ID

研究キーワード

  • 核医学   イメージング   放射線生物学   低酸素   放射線腫瘍学   

研究分野

  • 環境・農学 / 化学物質影響
  • 環境・農学 / 放射線影響
  • ライフサイエンス / 獣医学
  • ライフサイエンス / 放射線科学

職歴

  • 2018年07月 - 現在 北海道大学 大学院獣医学研究院応用獣医科学分野放射線学教室 准教授
  • 2016年04月 - 2018年06月 北海道大学 アイソトープ総合センター 准教授
  • 2009年09月 - 2016年03月 北海道大学 大学院獣医学研究科環境獣医科学講座放射線学教室 助教
  • 2009年09月 - 2016年03月 北海道大学 大学院獣医学研究科
  • 2012年03月 - 2012年08月 米国国立癌研究所/米国国立衛生研究所 客員研究員
  • 2008年09月 - 2009年08月 米国国立癌研究所/米国国立衛生研究所 博士研究員
  • 2007年04月 - 2008年08月 日本学術振興会 日本学術振興会特別研究員

学歴

  • 2004年04月 - 2008年03月   北海道大学   獣医学研究科   獣医学専攻
  • 1998年04月 - 2004年03月   北海道大学   獣医学部   獣医学科
  • 1997年04月 - 1998年03月   大阪大学   理学部   物理学科

所属学協会

  • 日本分子イメージング学会   日本癌学会   国際癌治療増感研究協会   電子スピンサイエンス学会   日本酸化ストレス学会   日本放射線影響学会   日本獣医学会   

研究活動情報

論文

  • Yuki Oiwa, Kaori Oka, Hironobu Yasui, Kei Higashikawa, Hidemasa Bono, Yoshimi Kawamura, Shingo Miyawaki, Akiyuki Watarai, Takefumi Kikusui, Atsushi Shimizu, Hideyuki Okano, Yuji Kuge, Kazuhiro Kimura, Yuko Okamatsu-Ogura, Kyoko Miura
    Scientific reports 10 1 19488 - 19488 2020年11月10日 
    The naked mole-rat (NMR) is a heterothermic mammal that forms eusocial colonies consisting of one reproductive female (queen), several reproductive males, and subordinates. Despite their heterothermy, NMRs possess brown adipose tissue (BAT), which generally induces thermogenesis in cold and some non-cold environments. Previous studies suggest that NMR-BAT induces thermogenesis by cold exposure. However, detailed NMR-BAT characteristics and whether NMR-BAT thermogenesis occurs in non-cold environments are unknown. Here, we show beta-3 adrenergic receptor (ADRB3)-dependent thermogenic potential of NMR-BAT, which contributes to thermogenesis in the isolated queen in non-cold environments (30 °C). NMR-BAT expressed several brown adipocyte marker genes and showed noradrenaline-dependent thermogenic activity in vitro and in vivo. Although our ADRB3 inhibition experiments revealed that NMR-BAT thermogenesis slightly delays the decrease in body temperature in a cold environment (20 °C), it was insufficient to prevent the decrease in the body temperatures. Even at 30 °C, NMRs are known to prevent the decrease of and maintain their body temperature by heat-sharing behaviors within the colony. However, isolated NMRs maintained their body temperature at the same level as when they are in the colony. Interestingly, we found that queens, but not subordinates, induce BAT thermogenesis in this condition. Our research provides novel insights into NMR thermoregulation.
  • Zifeng Wang, Kei Higashikawa, Hironobu Yasui, Yuji Kuge, Yusuke Ohno, Akio Kihara, Yenari A Midori, Kiyohiro Houkin, Masahito Kawabori
    Translational stroke research 11 5 1103 - 1116 2020年10月 [査読有り][通常論文]
     
    Injury due to brain ischemia followed by reperfusion (I/R) may be an important therapeutic target in the era of thrombectomy. FTY720, a widely known sphingosine-1-phosphate receptor agonist, exerts various neuroprotective effects. The aim of this study was to examine the protective effect of FTY720 with respect to I/R injury, especially focusing on blood-brain barrier (BBB) protection and anti-inflammatory effects. Male rats were subjected to transient ischemia and administered vehicle or 0.5 or 1.5 mg/kg of FTY720 immediately before reperfusion. Positron emission tomography (PET) with [18F]DPA-714 was performed 2 and 9 days after the insult to serially monitor neuroinflammation. Bovine and rat brain microvascular endothelial cells (MVECs) were also subjected to oxygen-glucose deprivation (OGD) and reperfusion, and administered FTY720, phosphorylated-FTY720 (FTY720-P), or their inhibitor. FTY720 dose-dependently reduced cell death, the infarct size, cell death including apoptosis, and inflammation. It also ameliorated BBB disruption and neurological deficits compared to in the vehicle group. PET indicated that FTY720 significantly inhibited the worsening of inflammation in later stages. FTY720-P significantly prevented the intracellular redistribution of tight junction proteins but did not increase their mRNA expression. These results suggest that FTY720 can ameliorate I/R injury by protecting the BBB and regulating neuroinflammation.
  • Hideo Nambu, Shingo Takada, Satoshi Maekawa, Junichi Matsumoto, Naoya Kakutani, Takaaki Furihata, Ryosuke Shirakawa, Takashi Katayama, Takayuki Nakajima, Katsuma Yamanashi, Yoshikuni Obata, Ippei Nakano, Masaya Tsuda, Akimichi Saito, Arata Fukushima, Takashi Yokota, Junko Nio-Kobayashi, Hironobu Yasui, Kei Higashikawa, Yuji Kuge, Toshihisa Anzai, Hisataka Sabe, Shintaro Kinugawa
    Cardiovascular research 2020年05月13日 [査読有り][通常論文]
     
    AIMS: Exercise intolerance in patients with heart failure (HF) is partly attributed to skeletal muscle abnormalities. We have shown that reactive oxygen species (ROS) play a crucial role in skeletal muscle abnormalities, but the pathogenic mechanism remains unclear. Xanthine oxidase (XO) is reported to be an important mediator of ROS overproduction in ischemic tissue. Here we tested the hypothesis that skeletal muscle abnormalities in HF are initially caused by XO-derived ROS and are prevented by the inhibition of their production. METHODS AND RESULTS: Myocardial infarction (MI) was induced in male C57BL/6J mice, which eventually led to HF, and a sham operation was performed in control mice. The time course of XO-derived ROS production in mouse skeletal muscle post-MI was first analyzed. XO-derived ROS production was significantly increased in MI mice from days 1 to 3 postsurgery (acute phase), whereas it did not differ between the MI and sham groups from 7 to 28 days (chronic phase). Second, mice were divided into three groups: sham+vehicle (Sham+Veh), MI+vehicle (MI+Veh), and MI+febuxostat (an XO inhibitor, 5 mg/kg body weight/day; MI+Feb). Febuxostat or vehicle was administered at 1 hr and 24 hr before surgery, and once-daily on days 1-7 postsurgery. On day 28 postsurgery, exercise capacity and mitochondrial respiration in skeletal muscle fibers were significantly decreased in MI+Veh compared with Sham+Veh mice. An increase in damaged mitochondria in MI+Veh compared with Sham+Veh mice was also observed. The wet weight and cross-sectional area of slow muscle fibers (higher XO-derived ROS) was reduced via the downregulation of protein synthesis-associated mTOR-p70S6K signaling in MI+Veh compared with Sham+Veh mice. These impairments were ameliorated in MI+Feb mice, in association with a reduction of XO-derived ROS production, without affecting cardiac function. CONCLUSIONS: XO inhibition during the acute phase post-MI can prevent skeletal muscle abnormalities and exercise intolerance in mice with HF. A TRANSLATIONAL PERSPECTIVE: We clearly demonstrated that febuxostat, an inhibitor of xanthine oxidase (XO), prevents exercise intolerance and skeletal muscle abnormalities (mitochondrial dysfunction and atrophy) via the suppression of XO-derived reactive oxygen species increase during hypoxia (e.g., myocardial infarction [MI]) in skeletal muscle during the early phase of heart failure (HF) model mouse. Our results shed light on the pathogenic mechanism of skeletal muscle abnormalities in HF after MI. The use of XO inhibitors requires consideration of the time course of XO activity. Our results indicate that the timing of administration is very important to achieve maximum beneficial effects when using XO inhibitors.
  • Tomoki Bo, Tohru Yamamori, Kumiko Yamamoto, Masaki Fujimoto, Hironobu Yasui, Osamu Inanami
    Biochemical and biophysical research communications 522 1 144 - 150 2020年01月29日 [査読有り][通常論文]
     
    Mitochondrial dynamics are crucial for cellular survival in response to various stresses. Previously, we reported that Drp1 promoted mitochondrial fission after x-irradiation and its inhibition resulted in reduced cellular radiosensitivity and mitotic catastrophe. However, the mechanisms of radiation-induced mitotic catastrophe related to mitochondrial fission remain unclear. In this study, we investigated the involvement of cellular ATP production, ROS generation, and Ca2+ levels in mitotic catastrophe in EMT6 cells. Knockdown of Drp1 and Fis1, which are mitochondrial fission regulators, resulted in elongated mitochondria and significantly attenuated cellular radiosensitivity. Reduced mitochondrial fission mainly decreased mitotic catastrophe rather than necrosis and apoptosis after irradiation. Cellular ATP contents in Drp1 and Fis1 knockdown cells were similar to those in control cells. N-acetylcysteine and 2-glucopyranoside ascorbic acid have no effect on mitotic catastrophe after irradiation. The cellular [Ca2+]i level increased after irradiation, which was completely suppressed by Drp1 and Fis1 inhibition. Furthermore, BAPTA-AM significantly reduced radiation-induced mitotic catastrophe, indicating that cellular Ca2+ is a key mediator of mitotic catastrophe induction after irradiation. These results suggest that mitochondrial fission is associated with radiation-induced mitotic catastrophe via cytosolic Ca2+ regulation.
  • Hironobu Yasui, Daisuke Iizuka, Wakako Hiraoka, Mikinori Kuwabara, Akira Matsuda, Osamu Inanami
    Nucleosides, nucleotides & nucleic acids 39 1-3 439 - 452 2020年 [査読有り][通常論文]
     
    The combination of low dose of radiation and an anticancer drug is a potent strategy for cancer therapy. Nucleoside analogs are known to have a radiosensitizing effects via the inhibition of DNA damage repair after irradiation. Certain types of nucleoside analogs have the inhibitory effects on RNA synthesis, but not DNA synthesis, with multiple functions in cell cycle modulation and apoptosis. In this review, the most up-to-date findings regarding radiosensitizing nucleoside analogs will be discussed, focusing especially on the mechanisms of action.
  • Higashikawa K, Horiguchi S, Tarisawa M, Shibata Y, Ohkura K, Yasui H, Takeda H, Kuge Y
    Nuclear medicine and biology 82-83 25 - 32 2019年12月16日 [査読有り][通常論文]
     
    INTRODUCTION: Although liver biopsy is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH), it has several problems including high invasiveness and sampling errors. Therefore, the development of alternative methods to overcome these disadvantages is strongly required. In this study, we evaluated the potential use of our tracer targeting thymidine phosphorylase (TYMP), 5-[123I]iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ([123I]IIMU) for the diagnosis of NASH. METHODS: The mice used as the NASH model (hereafter, NASH mice) were prepared by feeding a methionine- and choline-deficient diet for 4 weeks. A control group was similarly given a control diet. The expression levels of the TYMP gene and protein in the liver were examined by real-time reverse-transcription polymerase chain reaction and western blot analyses. The localizations of [125I]IIMU and the TYMP protein in the liver were examined by autoradiography and immunohistochemical staining, respectively. Finally, the mice were injected with [123I]IIMU and single-photon emission tomography (SPECT) imaging was conducted. RESULTS: The hepatic expression levels of TYMP were significantly lower in the NASH mice than in the control mice at both mRNA and protein levels, suggesting that a decrease in TYMP level could be an indicator of NASH. [125I]IIMU was uniformly distributed in the liver of the control mice, whereas it showed a patchy distribution in that of the NASH mice. The localization of [125I]IIMU was visually consistent with that of the TYMP protein in the liver of the control and NASH mice. SPECT analysis indicated that the hepatic accumulation of [123I]IIMU in the NASH mice was significantly lower than that in the control mice [SUV (g/ml): 4.14 ± 0.87 (Control) vs 2.31 ± 0.29 (NASH)]. CONCLUSIONS: [123I]IIMU may provide a noninvasive means for imaging TYMP expression in the liver and may be applicable to the diagnosis of NASH.
  • Morita A, Aoshima K, Gulay KCM, Onishi S, Shibata Y, Yasui H, Kobayashi A, Kimura T
    Research in veterinary science 127 1 - 10 2019年10月 [査読有り][通常論文]
  • Shiro Watanabe, Tohru Shiga, Kenji Hirata, Keiichi Magota, Shozo Okamoto, Takuya Toyonaga, Kei Higashikawa, Hironobu Yasui, Jun Kobayashi, Ken-Ichi Nishijima, Ken Iseki, Hiroki Matsumoto, Yuji Kuge, Nagara Tamaki
    EJNMMI research 9 1 60 - 60 2019年07月05日 [査読有り][通常論文]
     
    BACKGROUND: To facilitate hypoxia imaging in a clinical setting, we developed 1-(2,2-dihydroxymethyl-3-[18F]-fluoropropyl)-2-nitroimidazole ([18F]DiFA) as a new tracer that targets tumor hypoxia with its lower lipophilicity and efficient radiosynthesis. Here, we evaluated the radiation dosage, biodistribution, human safety, tolerability, and early elimination after the injection of [18F]DiFA in healthy subjects, and we performed a preliminary clinical study of patients with malignant tumors in a comparison with [18F]fluoromisonidazole ([18F]FMISO). RESULTS: The single administration of [18F]DiFA in 8 healthy male adults caused neither adverse events nor abnormal clinical findings. Dynamic and sequential whole-body scans showed that [18F]DiFA was rapidly cleared from all of the organs via the hepatobiliary and urinary systems. The whole-body mean effective dose of [18F]DiFA estimated by using the medical internal radiation dose (MIRD) schema with organ level internal dose assessment/exponential modeling (OLINDA/EXM) computer software 1.1 was 14.4 ± 0.7 μSv/MBq. Among the organs, the urinary bladder received the largest absorbed dose (94.7 ± 13.6 μSv/MBq). The mean absorbed doses of the other organs were equal to or less than those from other hypoxia tracers. The excretion of radioactivity via the urinary system was very rapid, reaching 86.4 ± 7.1% of the administered dose. For the preliminary clinical study, seven patients were subjected to [18F]FMISO and [18F]DiFA positron emission tomography (PET) at 48-h intervals to compare the two tracers' diagnostic ability for tumor hypoxia. The results of the tumor hypoxia evaluation by [18F]DiFA PET at 1 h and 2 h were not significantly different from those obtained with [18F]FMISO PET at 4 h ([18F]DiFA at 1 h, p = 0.32; [18F]DiFA at 2 h, p = 0.08). Moreover, [18F]DiFA PET at both 1 h (k = 0.68) and 2 h (k = 1.00) showed better inter-observer reproducibility than [18F]FMISO PET at 4 h (k = 0.59). CONCLUSION: [18F]DiFA is well tolerated, and its radiation dose is comparable to those of other hypoxia tracers. [18F]DiFA is very rapidly cleared via the urinary system. [18F]DiFA PET generated comparable images to [18F]FMISO PET in hypoxia imaging with shorter waiting time, demonstrating the promising potential of [18F]DiFA PET for hypoxia imaging and for a multicenter trial.
  • Yoneshiro T, Shin W, Machida K, Fukano K, Tsubota A, Chen Y, Yasui H, Inanami O, Okamatsu-Ogura Y, Kimura K
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 4 5196 - 5207 2019年04月 [査読有り][通常論文]
     
    Bone marrow provides progenitors of several types of cells, including muscle and white adipocytes, ensuring peripheral tissue homeostasis. However, the role of bone marrow-derived cells (BMCs) in induction of thermogenic adipocytes is unresolved. The purpose of this study is to examine whether BMCs are involved in the emergence of thermogenic adipocytes through adrenergic activation. Irradiation of mice with 8 Gy of X-ray-depleted BMCs and peripheral blood mononucleated cells (PBMCs), which in turn impaired induction of uncoupling protein 1 (UCP1) through administration of β3 adrenergic receptor agonist, CL 316,243 (CL), in inguinal white adipose tissue (iWAT). In contrast, CL-induced UCP1 induction in brown adipose tissue was unaffected by BMC depletion. Transplantation of normal BMCs into mice depleted of BMCs recovered PBMC levels and rescued the ability of iWAT browning by CL. Furthermore, analyses of mice transplanted with green fluorescent protein (GFP)-labeled BMCs revealed that the number of GFP-positive BMCs and PBMCs were significantly decreased by CL and that GFP-positive stromal cells and GFP-positive UCP1-expressing multilocular adipocytes appeared in iWAT after CL administration, demonstrating differentiation of BMC-derived preadipocytes into UCP1-expressing thermogenic adipocytes. These results unveiled a crucial role of the BMC as a nonresident origin for a subset of thermogenic adipocytes, contributing to browning of white adipose tissue.-Yoneshiro, T., Shin, W., Machida, K., Fukano, K., Tsubota, A., Chen, Y., Yasui, H., Inanami, O., Okamatsu-Ogura, Y., Kimura, K. Differentiation of bone marrow-derived cells toward thermogenic adipocytes in white adipose tissue induced by the β3 adrenergic stimulation.
  • Yoichi Shimizu, Songji Zhao, Hironobu Yasui, Ken-Ichi Nishijima, Hiroki Matsumoto, Tohru Shiga, Nagara Tamaki, Mikako Ogawa, Yuji Kuge
    Molecular imaging and biology 21 1 122 - 129 2019年02月 [査読有り][通常論文]
     
    PURPOSE: Hypoxia in tumor has close relationship with angiogenesis and tumor progression. Previously, we developed 2,2-dihydroxymethyl-3-[18F]fluoropropyl-2-nitroimidazole ([18F]DiFA) as a novel positron emission tomography (PET) probe for diagnosis of hypoxia. In this study, we elucidated whether the accumulation of [18F]DiFA in cells is dependent on the hypoxic state and revealed how [18F]DiFA accumulates in hypoxic cells in combination with imaging mass spectrometry (IMS). PROCEDURES: FaDu human head and neck cancer cells were treated with [18F]DiFA and then incubated under normoxia (21% O2) or hypoxia (1% O2) for 2 h. The cells were extracted using methanol, and the radioactivities of the precipitates (macromolecule fraction) and supernatants (low-molecular-weight fraction) were measured. FaDu-bearing mice were injected intravenously with [18F]DiFA and with pimonidazole 1 h later. The tumors were excised 2 h after the injection of [18F]DiFA. Autoradiography, IMS, and immunohistochemical (IHC) staining for pimonidazole were performed with serial tumor sections. RESULTS: In the in vitro study, the radioactivity of FaDu cells was significantly higher under hypoxia than that under normoxia (0.53 ± 0.02 vs. 0.27 ± 0.02 %dose/mg protein, p < 0.05). The radioactivity of the low-molecular-weight fraction was 66.3 ± 0.6% in the hypoxic cell. In the in vivo study, [18F]DiFA accumulated in the tumor tissues existed mainly as low-molecular-weight compounds (90.4 ± 0.9%). In addition, the glutathione conjugate of reductive DiFA metabolite (amino-DiFA-GS) existed in tumor tissues revealed by the IMS study, and the distribution pattern of amino-DiFA-GS was very similar to that of the radioactivity and the positive staining area of pimonidazole. CONCLUSIONS: Our results suggest that [18F]DiFA undergoes the glutathione conjugation reaction following reductive metabolism in hypoxic cells, which leads hypoxia-specific PET imaging with [18F]DiFA.
  • Hari Narayan Bhilwade, Naoto Tatewaki, Tetsuya Konishi, Miyako Nishida, Takahiro Eitsuka, Hironobu Yasui, Osamu Inanami, Osamu Handa, Yuji Naito, Nobuo Ikekawa, Hiroshi Nishida
    Nutrition and cancer 71 7 1153 - 1164 2019年 [査読有り][通常論文]
     
    Many functional foods or physiologically active ingredients derived from plants and animals are actively being investigated for their role in chronic disease prevention. Squalene (SQ) is found as active ingredient in the functional foods predominantly present in olive oil and shark liver oil. It is known that during chemotherapy anticancer drugs induce inflammation. SQ has been thought to prevent and suppress inflammation; however, there is little direct evidence available. We examined the adjuvant effect of SQ on tumor-transplanted mice along with anticancer drug doxorubicin (DOX). SQ significantly suppressed the DOX-induced increase in prostaglandin E2 (PGE2) concentration (P < 0.05) in plasma of tumor-bearing mice. SQ inhibited the numbers of writhing response (P < 0.05), formalin-induced pain and decreased COX-2 and substance P expression in the tumor tissue compared to control mice and also enhanced the antitumor efficacy of DOX in allograft mice. Thus, SQ reduces inflammation through modulation of PGE2 production indicating its potential as an adjuvant during chemotherapy in tumor-bearing mice.
  • Shibata Y, Yasui H, Higashikawa K, Miyamoto N, Kuge Y
    PloS one 14 12 e0225931  2019年 [査読有り][通常論文]
  • Denis A Komarov, Yuki Ichikawa, Kumiko Yamamoto, Neil J Stewart, Shingo Matsumoto, Hironobu Yasui, Igor A Kirilyuk, Valery V Khramtsov, Osamu Inanami, Hiroshi Hirata
    Analytical chemistry 90 23 13938 - 13945 2018年12月04日 [査読有り][通常論文]
     
    An electron paramagnetic resonance (EPR)-based method for noninvasive three-dimensional extracellular pH mapping was developed using a pH-sensitive nitroxyl radical as an exogenous paramagnetic probe. Fast projection scanning with a constant magnetic field sweep enabled the acquisition of four-dimensional (3D spatial +1D spectral) EPR images within 7.5 min. Three-dimensional maps of pH were reconstructed by processing the pH-dependent spectral information on the images. To demonstrate the proposed method of pH mapping, the progress of extracellular acidosis in tumor-bearing mouse legs was studied. Furthermore, extracellular pH mapping was used to visualize the spatial distribution of acidification in different tumor xenograft mouse models of human-derived pancreatic ductal adenocarcinoma cells. The proposed EPR-based pH mapping method enabled quantitative visualization of regional changes in extracellular pH associated with altered tumor metabolism.
  • Tomita M, Yasui H, Higashikawa K, Nakajima K, Takakura H, Shiga T, Kuge Y, Ogawa M
    EJNMMI research 8 1 82  2018年08月 [査読有り][通常論文]
  • Yamamoto K, Yasui H, Bo T, Yamamori T, Hiraoka W, Yamasaki T, Yamada KI, Inanami O
    Applied Magnetic Resonance 49 8 837 - 851 2018年07月 [査読有り][招待有り]
  • Kumiko Yamamoto, Yoshinori Ikenaka, Takahiro Ichise, Tomoki Bo, Mayumi Ishizuka, Hironobu Yasui, Wakako Hiraoka, Tohru Yamamori, Osamu Inanami
    Free radical research 52 6 648 - 660 2018年06月 [査読有り][通常論文]
     
    To evaluate the metabolic responses in tumour cells exposed to ionizing radiation, oxygen consumption rate (OCR), cellular lipid peroxidation, cellular energy status (intracellular nucleotide pool and ATP production), and mitochondrial reactive oxygen species (ROS), semiquinone (SQ), and iron-sulphur (Fe-S) cluster levels were evaluated in human cervical carcinoma HeLa cells at 12 and 24 h after X-irradiation. LC/MS/MS analysis showed that levels of 8-iso PGF2α and 5-iPF2α-VI, lipid peroxidation products of membrane arachidonic acids, were not altered significantly in X-irradiated cells, although mitochondrial ROS levels and OCR significantly increased in the cells at 24 h after irradiation. LC/UV analysis revealed that intracellular AMP, ADP, and ATP levels increased significantly after X-irradiation, but adenylate energy charge (adenylate energy charge (AEC) = [ATP + 0.5 × ADP]/[ATP + ADP + AMP]) remained unchanged after X-irradiation. In low-temperature electron spin resonance (ESR) spectra of HeLa cells, the presence of mitochondrial SQ at g = 2.004 and Fe-S cluster at g = 1.941 was observed and X-irradiation enhanced the signal intensity of SQ but not of the Fe-S cluster. Furthermore, this radiation-induced increase in SQ signal intensity disappeared on treatment with rotenone, which inhibits electron transfer from Fe-S cluster to SQ in complex I. From these results, it was suggested that an increase in OCR and imbalance in SQ and Fe-S cluster levels, which play a critical role in the mitochondrial electron transport chain (ETC), occur after X-irradiation, resulting in an increase in ATP production and ROS leakage from the activated mitochondrial ETC.
  • Chengbo Tan, Songji Zhao, Kei Higashikawa, Zifeng Wang, Masahito Kawabori, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Naoyuki Ukon, Hironobu Yasui, Nagara Tamaki, Yuji Kuge, Hideo Shichinohe, Kiyohiro Houkin
    EJNMMI research 8 1 35 - 35 2018年05月02日 [査読有り][通常論文]
     
    BACKGROUND: The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [18F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [18F]DPA-714 PET. The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [18F]DPA-714 PET was performed 3 and 10 days after MCAO. RESULTS: Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group. CONCLUSIONS: The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [18F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.
  • Masaki Nagane, M. Lakshmi Kuppusamy, Jennifer An, Jesse M. Mast, Rajan Gogna, Hironobu Yasui, Tohru Yamamori, Osamu Inanami, Periannan Kuppusamy
    Radiation Research 189 5 519 - 528 2018年05月01日 [査読有り][通常論文]
     
    Endothelial nitric oxide synthase (eNOS), a constitutive enzyme expressed in vascular endothelial cells, is the main source of nitric oxide (NO), which plays key roles in diverse biological functions, including regulation of vascular tone. Exposure to radiation has been known to generate nitric oxide from eNOS however, the precise mechanism of its generation and function is not known. The goal of this study was to determine the involvement of radiation-induced DNA damage response (DDR) on eNOS transcription and its effect on cell survival after irradiation. Irradiated bovine aortic endothelial cells showed increased eNOS transcription and NO generation through upregulation of ataxia-telangiectasia mutated (ATM) kinase. Radiation exposure induced NO inhibited cell death, as well as induced cellular senescence postirradiation. This study established that radiation-induced DDR uses ATM kinase to upregulate eNOS transcription and NO generation, leading to cellular senescence, which may play a critical role in radiation-mediated cardiovascular injury.
  • Hironobu Yasui, Nobuo Kubota, Junko Nishizumi, Yuri Sakai, Tohru Yamamori, Osamu Inanami
    Oncology Letters 15 2 1993 - 1998 2018年02月01日 [査読有り][通常論文]
     
    To overcome the radioresistance of hypoxic cells in solid tumor, numerous types of radiosensitizers specifically against them have been developed. Glycididazole has a chemical structure in which two metronidazole forms are combined, and is widely used as a hypoxic radiosensitizer in China. However, a detailed investigation of its radiosensitizing properties has not been performed. The present study reported a comparative assessment of glycididazole and doranidazole, another hypoxic radiosensitizer. All experiments were performed using the murine squamous cell carcinoma cell line SCCVII. Prior to X-irradiation, the cells were treated with the test drugs at concentrations of 10 mM and 200 mg/kg in vitro and in vivo, respectively. Uptake and their intratumor chemical forms were analyzed by high performance liquid chromatography (HPLC). Both drugs enhanced the reproductive cell death induced by X-irradiation under hypoxia. However, the growth delay assay of the transplanted tumor revealed the combination of X-irradiation and glycididazole showed a similar antitumor effect to that of X-irradiation alone, whereas doranidazole significantly sensitized the cells to X-irradiation. HPLC analysis revealed that incorporated glycididazole was decomposed to metronidazole and was therefore present at a lower concentration compared with that of doranidazole. The decomposition of glycididazole to metronidazole reduced its radiosensitizing efficiency in vivo. Elucidation of the kinetics of drugs containing metabolizable chemical forms is necessary for the optimization of clinical treatment.
  • Harue Kubota, Denis A. Komarov, Hironobu Yasui, Shingo Matsumoto, Osamu Inanami, Igor A. Kirilyuk, Valery V. Khramtsov, Hiroshi Hirata
    MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE 30 3 291 - 298 2017年06月 [査読有り][通常論文]
     
    Objectives The aim of this study was to demonstrate the feasibility of in vivo three-dimensional (3D) relaxation time T-2* mapping of a dicarboxy-PROXYL radical using continuous-wave electron paramagnetic resonance (CW-EPR) imaging. Materials and methods Isotopically substituted dicarboxy-PROXYL radicals, 3,4-dicarboxy-2,2,5,5-tetra(H-2(3)) methylpyrrolidin-( 3,4-H-2(2))-(1-N-15)-1-oxyl (H-2, N-15-DCP) and 3,4-dicarboxy-2,2,5,5-tetra(H-2(3)) methylpyrrolidin-(3,4-H-2(2))1- oxyl (H-2-DCP), were used in the study. A clonogenic cell survival assay was performed with the H-2-DCP radical using squamous cell carcinoma (SCC VII) cells. The time course of EPR signal intensities of intravenously injected H-2, N-15-DCP and H-2-DCP radicals were determined in tumor-bearing hind legs of mice (C3H/HeJ, male, n = 5). CW-EPR-based single-point imaging (SPI) was performed for 3D T-2* mapping. Results H-2-DCP radical did not exhibit cytotoxicity at concentrations below 10 mM. The in vivo half-life of H-2, N-15-DCP in tumor tissues was 24.7 +/- 2.9 min (mean +/- standard deviation [SD], n = 5). The in vivo time course of the EPR signal intensity of the H-2, N-15-DCP radical showed a plateau of 10.2 +/- 1.2 min (mean +/- SD) where the EPR signal intensity remained at more than 90% of the maximum intensity. During the plateau, in vivo 3D T-2* maps with H-2, N-15-DCP were obtained from tumor-bearing hind legs, with a total acquisition time of 7.5 min. Conclusion EPR signals of H-2, N-15-DCP persisted long enough after bolus intravenous injection to conduct in vivo 3D T-2* mapping with CW-EPR-based SPI.
  • Tohru Yamamori, Tomoya Sasagawa, Osamu Ichii, Mie Hiyoshi, Tomoki Bo, Hironobu Yasui, Yasuhiro Kon, Osamu Inanami
    JOURNAL OF RADIATION RESEARCH 58 3 292 - 301 2017年05月 [査読有り][通常論文]
     
    Mitochondria strongly contribute to the maintenance of cellular integrity through various mechanisms, including oxidative adenosine triphosphate production and calcium homeostasis regulation. Therefore, proper regulation of the abundance, distribution and activity of mitochondria is crucial for the maintenance of cellular homeostasis. Previous studies have shown that ionizing radiation (IR) alters mitochondrial functions, suggesting that mitochondria are likely to be an important target of IR. Though IR reportedly influences cellular mitochondrial abundance, the mechanism remains largely unknown. In this study, we examined how IR influences mitochondrial abundance in mouse fibroblasts. When mouse NIH/3T3 cells were exposed to X-rays, a time-dependent increase was observed in mitochondrial DNA (mtDNA) and mitochondrial mass, indicating radiation-induced upregulation of mitochondrial abundance. Meanwhile, not only did we not observe a significant change in autophagic activity after irradiation, but in addition, IR hardly influenced the expression of two mitochondrial proteins, cytochrome c oxidase subunit IV and cytochrome c, or the mRNA expression of Polg, a component of DNA polymerase gamma. We also observed that the expression of transcription factors involved in mitochondrial biogenesis was only marginally affected by IR. These data imply that radiation-induced upregulation of mitochondrial abundance is an event independent of macroautophagy and mitochondrial biogenesis. Furthermore, we found evidence that IR induced long-term cell cycle arrest and cellular senescence, indicating that these events are involved in regulating mitochondrial abundance. Considering the growing significance of mitochondria in cellular radioresponses, we believe the present study provides novel insights into understanding the effects of IR on mitochondria.
  • Lue Sun, Takashi Moritake, Kazuya Ito, Yoshitaka Matsumoto, Hironobu Yasui, Hidehiko Nakagawa, Aki Hirayame, Osamu Inanami, Koji Tsuboi
    PLOS ONE 12 4 e0176162  2017年04月 [査読有り][通常論文]
     
    Medulloblastoma is a fatal brain tumor in children, primarily due to the presence of treatment-resistant medulloblastoma stem cells. The energy metabolic pathway is a potential target of cancer therapy because it is often different between cancer cells and normal cells. However, the metabolic properties of medulloblastoma stem cells, and whether specific metabolic pathways are essential for sustaining their stem cell-like phenotype and radioresistance, remain unclear. We have established radioresistant medulloblastoma stem-like clones (rMSLCs) by irradiation of the human medulloblastoma cell line ONS-76. Here, we assessed reactive oxygen species (ROS) production, mitochondria function, oxygen consumption rate (OCR), energy state, and metabolites of glycolysis and tricarboxylic acid cycle in rMSLCs and parental cells. rMSLCs showed higher lactate production and lower oxygen consumption rate than parental cells. Additionally, rMSLCs had low mitochondria mass, low endogenous ROS production, and existed in a low-energy state. Treatment with the metabolic modifier dichloroacetate (DCA) resulted in mitochondria dysfunction, glycolysis inhibition, elongated mitochondria morphology, and increased ROS production. DCA also increased radiosensitivity by suppression of the DNA repair capacity through nuclear oxidization and accelerated the generation of acetyl CoA to compensate for the lack of ATP. Moreover, treatment with DCA decreased cancer stem cell-like characters (e.g., CD133 positivity and sphere-forming ability) in rMSLCs. Together, our findings provide insights into the specific metabolism of rMSLCs and illuminate potential metabolic targets that might be exploited for therapeutic benefit in medulloblastoma.
  • Hironobu Yasui, Kumiko Yamamoto, Motofumi Suzuki, Yuri Sakai, Tomoki Bo, Masaki Nagane, Eri Nishimura, Tohru Yamamori, Toshihide Yamasaki, Ken-ichi Yamada, Osamu Inanami
    CANCER LETTERS 390 160 - 167 2017年04月 [査読有り][通常論文]
     
    It has recently been reported that radiation enhances mitochondrial energy metabolism in various tumor cell lines. To examine how this radiation -induced alteration in mitochondrial function influences tumor cell viability, Various lipophilic triphenylphosphonium (TPP+) cation derivatives and related compounds such as 4-hydroxy-2,2,6,6-tetramethyl-l-oxy-piperidin (Tempol) with TPP+ (named."Mito-") were designed to inhibit the mitochondrial electron transport chain. Mito-(CH2)io-Tempol (M10T) and its derivatives, Mito-(CH2)(5)-Tempol (M5T), Mito-(CH2)(10)-Tempol-Methyl (M10T-Me), Mito-C10H21 (M10), and C10H21-Tempol (10T), were prepared. In HeLa human cervical adenocarcinoma cells and A549 human lung carcinoma cells, the fractional uptake of the compound into mitochondria was highest among the TTP+ analogs conjugated with Tempol (M10T, M5T, and 10T). MlOT, M10T-Me, and M10 exhibited strong cytotoxicity and enhanced X-irradiation -induced reproductive cell death, while 10T and M5T did not. Furthermore, M10T, M10T-Me, and M10 decreased basal mitochondrial membrane potential and intracellular ATP. MIOT treatment inhibited X-ray -induced increases in ATP production. These results indicate that the TPP cation and a long hydrocarbon linker are essential for radiosensitization of tumor cells. The reduction in intracellular ATP by lipophilic TP13(+) is partly responsible for the observed radiosensitization. (C) 2017 Elsevier B.V. All rights reserved.
  • Attempts of Radiation Dose Measurement in the Teeth of Mice Living around the Nuclear Power Plant in Fukushima Using Electron Spin Resonance Spectroscopy
    Kitaya Taichi, Maeda Teruaki, Yasui Hironobu, Mizukawa Hazuki, Inanami Osamu, Nakata Akifumi, Miura Tomisato, Hosokawa Yoichiro, Kuwabara Mikinori
    Radiation Environment and Medicine 6 1 1 - 5 弘前大学出版会 2017年02月 [査読有り][通常論文]
  • Hironobu Yasui, Tatsuya Kawai, Shingo Matsumoto, Keita Saito, Nallathamby Devasahayam, James B. Mitchell, Kevin Camphausen, Osamu Inanami, Murali C. Krishna
    FREE RADICAL RESEARCH 51 9-10 861 - 871 2017年 [査読有り][通常論文]
     
    Hypoxia is considered one of the microenvironmental factors associated with the malignant nature of glioblastoma. Thus, evaluating intratumoural distribution of hypoxia would be useful for therapeutic planning as well as assessment of its effectiveness during the therapy. Electron paramagnetic resonance imaging (EPRI) is an imaging technique which can generate quantitative maps of oxygen in vivo using the exogenous paramagnetic compound, triarylmethyl and monitoring its line broadening caused by oxygen. In this study, the feasibility of EPRI for assessment of oxygen distribution in the glioblastoma using orthotopic U87 and U251 xenograft model is examined. Heterogeneous distribution of pO(2) between 0 and 50mmHg was observed throughout the tumours except for the normal brain tissue. U251 glioblastoma was more likely to exhibit hypoxia than U87 for comparable tumour size (median pO(2); 29.7 and 18.2 mmHg, p = .028, in U87 and U251, respectively). The area with pO(2) under 10mmHg on the EPR oximetry (HF10) showed a good correlation with pimonidazole staining among tumours with evaluated size. In subcutaneous xenograft model, irradiation was relatively less effective for U251 compared with U87. In conclusion, EPRI is a feasible method to evaluate oxygen distribution in the brain tumour.
  • Naoyuki Ukon, Songji Zhao, Wenwen Yu, Yoichi Shimizu, Ken-ichi Nishijima, Naoki Kubo, Yoshimasa Kitagawa, Nagara Tamaki, Kei Higashikawa, Hironobu Yasui, Yuji Kuge
    EJNMMI RESEARCH 6 1 90  2016年12月 [査読有り][通常論文]
     
    Background: Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl-H-3(N)]-3'-fluoro-3'-deoxythythymidine ([H-3]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[F-18]fluoro-3'-deoxythymidine ([F-18] FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [F-18] FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [F-18] FLT. Results: The dynamic pattern of [F-18] FLT levels in the tumor significantly changed after the treatment. The rate constant of [F-18] FLT phosphorylation (k(3)) was significantly higher in the treatment group (0.111 +/- 0.027 [1/min]) than in the control group (0.082 +/- 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [F-18] FLT forward transport (K-1) to reverse transport (k(2)), between the two groups (0.556 +/- 0.073 and 0. 641 +/- 0.052 [mL/g] in the control group). Conclusions: Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic modeling could provide improved understanding of the biochemical processes involved in tumor responses to therapy.
  • Maeda K, Yasui H, Yamamori T, Matsuura T, Takao S, Suzuki M, Matsuda A, Inanami O, Shirato H
    PloS one 11 11 e0166848  2016年11月 [査読有り][通常論文]
     
    The effect of 1-(3-C-ethyny1-beta-D-ribo-pentofuranosyl)cytosine (ECyd) on proton-induced cell death was evaluated in human lung carcinoma cell line A549 and Chinese hamster fibroblast cell line V79 to enhance relative biological effectiveness (RBE) within the spread-out Bragg peak (SOBP) of proton beams. Treatment with ECyd significantly enhanced the proton -induced loss of clonogenicity and increased senescence at the center, but not at the distal edge of SOBP. The p53-binding protein 1 foci formation assay showed that ECyd decelerated the rate of DNA double-strand break (DSB) repair at the center, but not the distal region of SOBP, suggesting that the ECyd-induced enhancement of proton-induced cell death is partially associated with the inhibition of DSB repair. This study demonstrated that ECyd enhances proton-induced cell killing at all positions of SOBP, except for the distal region and minimizes the site-dependent differences in RBE within SOBP. Thus, ECyd is a unique radiosensitizer for proton therapy that may be useful because it levels the biological dose within SOBP, which improves tumor control and reduces the risk of adverse effects at the distal edge of SOBP.
  • Motofumi Suzuki, Tohru Yamamori, Hironobu Yasui, Osamu Inanami
    ANTICANCER RESEARCH 36 6 2783 - 2792 2016年06月 [査読有り][通常論文]
     
    Background/Aim: The monopolar spindle 1 (MPS1) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To determine the possible relationship between MPS1 inhibition and genotoxic stress responses, herein we examined whether MPS1 inhibition influences cellular susceptibility towards two genotoxic treatments, etoposide and ionizing radiation (IR). Materials and Methods: Two murine tumour cell lines, SCCVII and EMT6, were used. The effect of genotoxic treatments with or without two novel MPS1 inhibitors, NMS-P715 and AZ3146, on cellular survival, cell-cycle distribution, centrosome status and mitotic catastrophe (MC) was evaluated. Results: MPS1 inhibition sensitized murine tumour cells to etoposide but not to IR. In addition, MPS1 inhibition altered cell-cycle progression and exacerbated centrosome abnormalities, resulting in enhanced MC induced by etoposide but not by IR. Conclusion: MPS1 inhibition promotes the etoposide-induced aberrant mitosis and, consequently, the induction of tumour cell death.
  • Kenichiro Maeda, Hironobu Yasui, Taeko Matsuura, Tohru Yamamori, Motofumi Suzuki, Masaki Nagane, Jin-Min Nam, Osamu Inanami, Hiroki Shirato
    JOURNAL OF RADIATION RESEARCH 57 3 307 - 311 2016年06月 [査読有り][通常論文]
     
    Variations in relative biological effectiveness (RBE) from a fixed value of 1.1 are critical in proton beam therapy. To date, studies estimating RBE at multiple positions relative to the spread-out Bragg peak (SOBP) have been predominantly performed using passive scattering methods, and limited data are available for spot-scanning beams. Thus, to investigate the RBE of spot-scanning beams, Chinese hamster fibroblast V79 cells were irradiated using the beam line at the Hokkaido University Hospital Proton Therapy Center. Cells were placed at six different depths, including the entrance of the proton beam and the proximal and distal part of the SOBP. Surviving cell fractions were analyzed using colony formation assay, and cell survival curves were obtained by the curve fitted using a linear-quadratic model. RBE10 and RBE37 were 1.15 and 1.21 at the center of the SOBP, respectively. In contrast, the distal region showed higher RBE values (1.50 for RBE10 and 1.85 for RBE37). These results are in line with those of previous studies conducted using passive scattering proton beams. Taken together, these data strongly suggest that variations in RBE should be considered during treatment planning for spot-scanning beams as well as for passive scattering proton beams.
  • Tohru Yamamori, Satoshi Ike, Tomoki Bo, Tomoya Sasagawa, Yuri Sakai, Motofumi Suzuki, Kumiko Yamamoto, Masaki Nagane, Hironobu Yasui, Osamu Inanami
    MOLECULAR BIOLOGY OF THE CELL 26 25 4607 - 4617 2015年12月 [査読有り][通常論文]
     
    Accumulating evidence suggests that mitochondrial dynamics is crucial for the maintenance of cellular quality control and function in response to various stresses. However, the role of mitochondrial dynamics in cellular responses to ionizing radiation (IR) is still largely unknown. In this study, we provide evidence that IR triggers mitochondrial fission mediated by the mitochondrial fission protein dynamin-related protein 1 (Drp1). We also show IR-induced mitotic catastrophe (MC), which is a type of cell death associated with defective mitosis, and aberrant centrosome amplification in mouse embryonic fibroblasts (MEFs). These are attenuated by genetic or pharmacological inhibition of Drp1. Whereas radiation-induced aberrant centrosome amplification and MC are suppressed by the inhibition of Plk1 and CDK2 in wild-type MEFs, the inhibition of these kinases is ineffective in Drp1-deficient MEFs. Furthermore, the cyclin B1 level after irradiation is significantly higher throughout the time course in Drp1-deficient MEFs than in wild-type MEFs, implying that Drp1 is involved in the regulation of cyclin B1 level. These findings strongly suggest that Drp1 plays an important role in determining the fate of cells after irradiation via the regulation of mitochondrial dynamics.
  • Sakata K, Kondo T, Mizuno N, Shoji M, Yasui H, Yamamori T, Inanami O, Yokoo H, Yoshimura N, Hattori Y
    Vascular pharmacology 70 55 - 65 2015年07月 [査読有り][通常論文]
     
    Vascular endothelial cells can absorb higher radiation doses than any other tissue in the body, and post-radiation impaired endothelial nitric oxide synthase (eNOS) function may be developed as a potential contributor to the pathogenesis of vascular injury. In this study, we investigated early alterations of eNOS signaling in human umbilical venous endothelial cells (HUVECs) exposed to X-ray radiation. We found that ionizing radiation increased eNOS phosphorylation at Ser-1177 and dephosphorylation at Thr-495 in HUVECs in a dose-dependent (<= 20 Gy) and time-dependent (6-72 h) manner. The total expression levels of eNOS were unchanged by radiation. Although a transient but significant increase in extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation and a biphasic decline in Akt phosphorylation were observed after irradiation, these inhibitors were without effect on the radiation-induced changes in eNOS phosphorylation. There was an increase in protein kinase C-beta II (PKC-beta II) expression and the ablation of PKC-beta II by small interfering RNA (siRNA) negated the radiation effect on the two eNOS phosphorylation events. Furthermore, when the radiation-induced increase in reactive oxygen species (ROS) generation was prevented by the anti-oxidant N-acetyl-L-cysteine, eNOS Ser-1177 phosphorylation and Thr-495 dephosphorylation in irradiated HUVECs were significantly reduced. However, transfection of PKC-beta siRNA did not alter ROS production after irradiation, and NAC failed to block the radiation-induced increase in PKC-beta II expression. Taken together, our results suggest that ionizing radiation-induced eNOS activation in human vascular endothelial cells is attributed to both the upregulation of PKC-beta II and the increase in ROS generation which were independent of each other. (C) 2015 Elsevier Inc. All rights reserved.
  • Sakai Y, Yamamori T, Yasui H, Inanami O
    Biochemical and biophysical research communications 461 1 35 - 41 2015年05月 [査読有り][通常論文]
     
    The DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in base excision repair and functions as a reductive activator of various transcription factors. Multiple other functionalities have been ascribed to APEI in addition to these major functions. A recent study showed that APE1 knockdown upregulated the expression of a set of genes related to extracellular matrix (ECM) production, indicating an additional novel biological role for this enzyme. Based on this finding, we have investigated the effect of APE1 downregulation on ECM-related gene expression and its biological consequences. Endogenous APEI expression was downregulated in human cervical carcinoma HeLa cells and human lung carcinoma A549 cells using siRNA. When the expression of six ECM-related genes (TGFB1, LAMC1, FN1, COL1A1, COL3A1, and COL4A1) was evaluated, we found that APE1 knockdown upregulated the expression of TGFB1 in both cell lines. APE1 downregulation promoted actin rearrangement, inducing F-actin accumulation in HeLa cells and the dissipation of stress fibers in A549 cells. We also discovered that APE1 knockdown enhanced cellular motility in A549 cells, which was suppressed by the inhibition of transforming growth factor (TGF)-fil signaling. These results suggested that APE1 controls the organization of actin cytoskeleton through the regulation of TGF-131 expression, providing novel insights into the biological significance of APE1. (C) 2015 Elsevier Inc. All rights reserved.
  • Masaki Nagane, Hironobu Yasui, Yuri Sakai, Tohru Yamamori, Koichi Niwa, Yuichi Hattori, Takashi Kondo, Osamu Inanami
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 456 1 541 - 546 2015年01月 [査読有り][通常論文]
     
    In this study, the involvement of ataxia telangiectasia mutated (ATM) kinase and heat shock protein 90 (HSP90) in endothelial nitric oxide synthase (eNOS) activation was investigated in X-irradiated bovine aortic endothelial cells. The activity of nitric oxide synthase (NOS) and the phosphorylation of serine 1179 of eNOS (eNOS-Ser1179) were significantly increased in irradiated cells. The radiation-induced increases in NOS activity and eNOS-Ser1179 phosphorylation levels were significantly reduced by treatment with either an ATM inhibitor (Ku-60019) or an HSP90 inhibitor (geldanamycin). Geldanamycin was furthermore found to suppress the radiation-induced phosphorylation of ATM-Ser1181. Our results indicate that the radiation-induced eNOS activation in bovine aortic endothelial cells is regulated by ATM and HSP90. (C) 2014 Elsevier Inc. All rights reserved.
  • Naoya Nishida, Hironobu Yasui, Masaki Nagane, Tohru Yamamori, Osamu Inanami
    JOURNAL OF RADIATION RESEARCH 55 3 455 - 463 2014年05月 [査読有り][通常論文]
     
    Considerable interest has recently been focused on the special characteristics of cancer metabolism, and several drugs designed to modulate cancer metabolism have been tested as potential anticancer agents. To date, however, very few studies have been conducted to investigate the combined effects of anticancer drugs and radiotherapy. In this study, to evaluate the role of mitochondria-derived reactive oxygen species (ROS) in the radiation-induced cell death of tumor cells, we have examined the effect of 3-methyl pyruvate (MP). MP is a membrane-permeable pyruvate derivative that is capable of activating mitochondrial energy metabolism in human lung carcinoma A549 cells and murine squamous carcinoma SCCVII cells. Pretreatment with MP significantly enhanced radiation-induced cell death in both cell lines, and also led to increases in the mitochondrial membrane potential, intracellular adenosine triphosphate content, and mitochondria-derived ROS production following the exposure of the cells to X-rays. In A549 cells, MP-induced radiosensitization was completely abolished by vitamin C. In contrast, it was partially abolished in SCCVII cells. These results therefore suggest that the treatment of the cells with MP induced radiosensitization via the production of excess mitochondria-derived ROS in tumor cells.
  • Hironobu Yasui, Ryo Takeuchi, Masaki Nagane, Shunsuke Meike, Yoshinari Nakamura, Tohru Yamamori, Yoshinori Ikenaka, Yasuhiro Kon, Hiroki Murotani, Motoi Oishi, Yukio Nagasaki, Osamu Inanami
    CANCER LETTERS 347 1 151 - 158 2014年05月 [査読有り][通常論文]
     
    High atomic number molecules, such as gold and platinum, are known to enhance the biological effect of X-irradiation. This study was aimed to determine the radiosensitizing potential of PEGylated nanogel containing gold nanoparticles (GNG) and the cellular mechanism involved. GNG pretreatment increased the levels of reproductive cell death and apoptosis induced by X-irradiation. GNG accumulated in cytoplasm and increased the expression of endoplasmic reticulum (ER) stress-related protein. GNG suppressed the repair capacity of DNA after X-irradiation by down-regulating DNA repair-related proteins. Our results suggest that GNG radiosensitized cells by enhancing apoptosis and impairing DNA repair capacity via ER stress induction. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Jonathan Goodwin, Katsuya Yachi, Masaki Nagane, Hironobu Yasui, Yusuke Miyake, Osamu Inanami, Andrey A. Bobko, Valery V. Khramtsov, Hiroshi Hirata
    NMR IN BIOMEDICINE 27 4 453 - 458 2014年04月 [査読有り][通常論文]
     
    The in vivo quantification of extracellular pH (pH(e)) in tumours may provide a useful biomarker for tumour cell metabolism. In this study, we assessed the viability of continuous-wave electron paramagnetic resonance (CW-EPR) spectroscopy with a pH-sensitive nitroxide for the measurement of extracellular tumour pH in a mouse model. CW-EPR spectroscopy (750 MHz) of C3H HeJ mice hind leg squamous cell tumour was performed after intravenous tail vein injection of pH-sensitive nitroxide (R-SG, 2-(4-((2-(4-amino-4-carboxybutanamido)-3-(carboxymethylamino)-3-oxoproylthio)methyl)phenyl)-4-pyrrolidino-2,5,5-triethyl-2,5-dihydro-1H-imidazol-1-oxyl) during stages of normal tumour growth and in response to a single 10-Gy dose of X-ray irradiation. An inverse relationship was observed between tumour volume and pH(e) value, whereby, during normal tumour growth, a constant reduction in pH(e) was observed. This relationship was disrupted by X-ray irradiation and, from 2-3 days post-exposure, a transitory increase in pH(e) was observed. In this study, we demonstrated the viability of CW-EPR spectroscopy using R-SG nitroxide to obtain high-sensitivity pH measurements in a mouse tumour model with an accuracy of <0.1 pH units. In addition, the measured changes in pH(e) in response to X-ray irradiation suggest that this may offer a useful method for the assessment of the physiological change in response to existing and novel cancer therapies. Copyright (c) 2014 John Wiley & Sons, Ltd.
  • Tohru Yamamori, Shunsuke Meike, Masaki Nagane, Hironobu Yasui, Osamu Inanami
    FEBS LETTERS 587 20 3348 - 3353 2013年10月 [査読有り][通常論文]
     
    In this study, we provide evidence that endoplasmic reticulum (ER) stress suppresses DNA double-strand break (DSB) repair and increases radiosensitivity of tumor cells by altering Rad51 levels. We show that the ER stress inducer tunicamycin stimulates selective degradation of Rad51 via the 26S proteasome, impairing DSB repair and enhancing radiosensitivity in human lung cancer A549 cells. We also found that glucose deprivation, which is a physiological inducer of ER stress, triggered similar events. These findings suggest that ER stress caused by the intratumoral environment influences tumor radiosensitivity, and that it has potential as a novel target to improve cancer radiotherapy. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
  • Masaki Nagane, Hironobu Yasui, Tohru Yamamori, Songji Zhao, Yuji Kuge, Nagara Tamaki, Hiromi Kameya, Hideo Nakamura, Hirotada Fujii, Osamu Inanami
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 437 3 420 - 425 2013年08月 [査読有り][通常論文]
     
    Tumor hypoxia, which occurs mainly as a result of inadequate tissue perfusion in solid tumors, is a well-known challenge for successful radiotherapy. Recent evidence suggests that ionizing radiation (IR) upregulates nitric oxide (NO) production and that IR-induced NO has the potential to increase intratumoral circulation. However, the kinetics of NO production and the responsible isoforms for NO synthase in tumors exposed to IR remain unclear. In this study, we aimed to elucidate the mechanism by which IR stimulates NO production in tumors and the effect of IR-induced NO on tumor radiosensitivity. Hoechst33342 perfusion assay and electron spin resonance oxymetry showed that IR increased tissue perfusion and pO(2) in tumor tissue. Immunohistochemical analysis using two different hypoxic probes showed that IR decreased hypoxic regions in tumors; treatment with a nitric oxide synthase (NOS) inhibitor, L-NAME, abrogated the effects of IR. Moreover, IR increased endothelial NOS (eNOS) activity without affecting its mRNA or protein expression levels in SCCVII-transplanted tumors. Tumor growth delay assay showed that L-NAME decreased the anti-tumor effect of fractionated radiation (10 Gy x 2). These results suggested that IR increased eNOS activity and subsequent tissue perfusion in tumors. Increases in intratumoral circulation simultaneously decreased tumor hypoxia. As a result, IR-induced NO increased tumor radiosensitivity. Our study provides a new insight into the NO-dependent mechanism for efficient fractionated radiotherapy. (C) 2013 Elsevier Inc. All rights reserved.
  • Shingo Matsumoto, Keita Saito, Hironobu Yasui, H. Douglas Morris, Jeeva P. Munasinghe, Martin Lizak, Hellmut Merkle, Jan Henrik Ardenkjaer-Larsen, Rajani Choudhuri, Nallathamby Devasahayam, Sankaran Subramanian, Alan P. Koretsky, James B. Mitchell, Murali C. Krishna
    MAGNETIC RESONANCE IN MEDICINE 69 5 1443 - 1450 2013年05月 [査読有り][通常論文]
     
    The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation and promote glycolysis for energy production. Thereby, inhibition of glycolysis has the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate blocks glycolysis pathway by inhibiting hypoxia inducible enzymes and enhanced cytotoxicity of 3-bromopyruvate under hypoxic conditions has been reported in vitro. However, the efficacy of 3-bromopyruvate was substantially attenuated in hypoxic tumor regions (pO(2) < 10 mmHg) in vivo using squamous cell carcinoma (SCCVII)-bearing mouse model. Metabolic MRI studies using hyperpolarized C-13-labeled pyruvate showed that monocarboxylate transporter-1 is the major transporter for pyruvate and the analog 3-bromopyruvate in SCCVII tumor. The discrepant results between in vitro and in vivo data were attributed to biphasic oxygen dependent expression of monocarboxylate transporter-1 in vivo. Expression of monocarboxylate transporter-1 was enhanced in moderately hypoxic (8-15 mmHg) tumor regions but down regulated in severely hypoxic (<5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia-activated drugs. (C) 2012 Wiley Periodicals, Inc.
  • Hironobu Yasui, Taketoshi Asanuma, Junichi Kino, Tohru Yamamori, Shunsuke Meike, Masaki Nagane, Nobuo Kubota, Mikinori Kuwabara, Osamu Inanami
    BMC CANCER 13 106  2013年03月 [査読有り][通常論文]
     
    Background: Glioblastoma is one of the intractable cancers and is highly resistant to ionizing radiation. This radioresistance is partly due to the presence of a hypoxic region which is widely found in advanced malignant gliomas. In the present study, we evaluated the effectiveness of the hypoxic cell sensitizer doranidazole (PR-350) using the C6 rat glioblastoma model, focusing on the status of blood brain barrier (BBB). Methods: Reproductive cell death in the rat C6 glioma cell line was determined by means of clonogenic assay. An intracranial C6 glioma model was established for the in vivo experiments. To investigate the status of the BBB in C6 glioma bearing brain, we performed the Evans blue extravasation test. Autoradiography with [C-14]-doranidazole was performed to examine the distribution of doranidazole in the glioma tumor. T2-weighted MRI was employed to examine the effects of X-irradiation and/or doranidazole on tumor growth. Results: Doranidazole significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, but not under normoxia. The BBB in C6-bearing brain was completely disrupted and [C-14]-doranidazole specifically penetrated the tumor regions. Combined treatment with X-irradiation and doranidazole significantly inhibited the growth of C6 gliomas. Conclusions: Our results revealed that BBB disruption in glioma enables BBB-impermeable radiosensitizers to penetrate and distribute in the target region. This study is the first to propose that in malignant glioma the administration of hydrophilic hypoxic radiosensitizers could be a potent strategy for improving the clinical outcome of radiotherapy without side effects.
  • Keita Saito, Shingo Matsumoto, Hironobu Yasui, Nallathamby Devasahayam, Sankaran Subramanian, Jeeva P. Munasinghe, Vyomesh Patel, J. Silvio Gutkind, James B. Mitchell, Murali C. Krishna
    PLOS ONE 7 11 e49456  2012年11月 [査読有り][通常論文]
     
    Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3)) and measurements of tumor pO(2) and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2) levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2)<10 mm Hg) in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy.
  • Masato Eitaki, Tohru Yamamori, Shunsuke Meike, Hironobu Yasui, Osamu Inanami
    BMC CANCER 12 469  2012年10月 [査読有り][通常論文]
     
    Background: Anti-cancer drugs are widely used in cancer treatment frequently combined with surgical therapy and/or radiation therapy. Although surgery and radiation have been suggested to facilitate invasion and metastasis of tumor cells in some cases, there is so far little information about the effect of anti-cancer drugs on cellular invasive ability and metastasis. In this study, using four different anti-cancer drugs (vincristine, paclitaxel, cisplatin and etoposide), we examined whether these drugs influence the invasive ability of tumor cells. Methods: Human gastric adenocarcinoma MKN45 cells were used to evaluate the effect of anti-cancer drugs. After drug treatment, cellular invasive ability was assessed using the Matrigel invasion chamber. Cytoskeletal changes after treatment were examined microscopically with F-actin staining. In addition, we monitored cellular motility in 3D matrigel environment by time-lapse microscopic analysis. The drug-induced activation of RhoA and ROCK was evaluated by pull-down assay and Western blotting using an antibody against phosphorylated myosin light chain (MLC), respectively. Where necessary, a ROCK inhibitor Y27632 and siRNA for guanine nucleotide exchange factor-H1 (GEF-H1) were applied. Results: Among all drugs tested, only vincristine stimulated the invasive ability of MKN45 cells. Microscopic analysis revealed that vincristine induced the formation of non-apoptotic membrane blebs and amoeboid-like motility. Vincristine significantly enhanced RhoA activity and MLC phosphorylation, suggesting the involvement of RhoA/ROCK pathway in the vincristine-induced cytoskeletal reorganization and cellular invasion. Furthermore, we found that Y27632 as well as the siRNA for GEF-H1, a RhoA-specific activator, attenuated MLC phosphorylation, the formation of membrane blebs and the invasive ability after vincristine treatment. Conclusions: These results indicate that vincristine activates GEF-H1/RhoA/ROCK/MLC signaling, thereby promoting amoeboid-like motility and the invasive ability of MKN45 cells.
  • Tohru Yamamori, Hironobu Yasui, Masayuki Yamazumi, Yusuke Wada, Yoshinari Nakamura, Hideo Nakamura, Osamu Inanami
    FREE RADICAL BIOLOGY AND MEDICINE 53 2 260 - 270 2012年07月 [査読有り][通常論文]
     
    Whereas ionizing radiation (Ir) instantaneously causes the formation of water radiolysis products that contain some reactive oxygen species (ROS), ROS are also suggested to be released from biological sources in irradiated cells. It is now becoming clear that these ROS generated secondarily after Ir have a variety of biological roles. Although mitochondria are assumed to be responsible for this Ir-induced ROS production, it remains to be elucidated how It triggers it. Therefore, we conducted this study to decipher the mechanism of Ir-induced mitochondria! ROS production. In human lung carcinoma A549 cells, Ir (10 Gy of X-rays) induced a time-dependent increase in the mitochondrial ROS level. It also increased mitochondrial membrane potential, mitochondrial respiration, and mitochondrial ATP production, suggesting upregulation of the mitochondrial electron transport chain (ETC) function after Ir. Although we found that Ir slightly enhanced mitochondrial ETC complex II activity, the complex II inhibitor 3-nitropropionic acid failed to reduce Ir-induced mitochondrial ROS production. Meanwhile, we observed that the mitochondrial mass and mitochondrial DNA level were upregulated after Ir, indicating that It increased the mitochondrial content of the cell. Because irradiated cells are known to undergo cell cycle arrest under control of the checkpoint mechanisms, we examined the relationships between cell cycle and mitochondrial content and cellular oxidative stress level. We found that the cells in the G2/M phase had a higher mitochondrial content and cellular oxidative stress level than cells in the G1 or S phase, regardless of whether the cells were irradiated. We also found that It-induced accumulation of the cells in the G2/M phase led to an increase in cells with a high mitochondrial content and cellular oxidative stress level. This suggested that Ir upregulated mitochondrial ETC function and mitochondrial content, resulting in mitochondrial ROS production, and that It-induced G2/M arrest contributed to the increase in the mitochondrial ROS level by accumulating cells in the G2/M phase. (C) 2012 Elsevier Inc. All rights reserved.
  • Krishna MC, Matsumoto S, Yasui H, Saito K, Devasahayam N, Subramanian S, Mitchell JB
    Radiation research 177 4 376 - 386 4 2012年04月 [査読有り][通常論文]
     
    Electron paramagnetic resonance imaging (EPRI) can be used to noninvasively and quantitatively obtain three-dimensional maps of tumor PO,. The paramagnetic tracer triarylmethyl (TAM), a substituted trityl radical moiety, is not toxic to animals and provides narrow isotropic spectra, which is ideal for in vivo EPR imaging experiments. From the oxygen-induced spectral broadening of TAM, pO(2) maps can be derived using EPRI. The instrumentation consists of an EPRI spectrometer and 7T magnetic resonance imaging (MRI) system both operating at a common radiofrequency of 300 MHz. Anatomic images obtained by MRI can be overlaid with pO(2) maps obtained from EPRI. With imaging times of less than 3 min, it was possible to monitor the dynamics of oxygen changes in tumor and distinguish chronically hypoxic regions from acutely hypoxic regions. In this article, the principles of pO(2) imaging with EPR and some relevant examples of tumor imaging are reviewed. (C) 2012 by Radiation Research Society
  • Shingo Matsumoto, Sonny Batra, Keita Saito, Hironobu Yasui, Rajani Choudhuri, Chandramouli Gadisetti, Sankaran Subramanian, Nallathamby Devasahayam, Jeeva P. Munasinghe, James B. Mitchell, Murali C. Krishna
    CANCER RESEARCH 71 20 6350 - 6359 2011年10月 [査読有り][通常論文]
     
    Structural and functional abnormalities in tumor blood vessels impact the delivery of oxygen and nutrients to solid tumors, resulting in chronic and cycling hypoxia. Although chronically hypoxic regions exhibit treatment resistance, more recently it has been shown that cycling hypoxic regions acquire prosurvival pathways. Angiogenesis inhibitors have been shown to transiently normalize the tumor vasculatures and enhance tumor response to treatments. However, the effect of antiangiogenic therapy on cycling tumor hypoxia remains unknown. Using electron paramagnetic resonance imaging and MRI in tumor-bearing mice, we have examined the vascular renormalization process by longitudinally mapping tumor partial pressure of oxygen (pO(2)) and microvessel density during treatments with a multi-tyrosine kinase inhibitor sunitinib. Transient improvement in tumor oxygenation was visualized by electron paramagnetic resonance imaging 2 to 4 days following antiangiogenic treatments, accompanied by a 45% decrease in microvessel density. Radiation treatment during this time period of improved oxygenation by antiangiogenic therapy resulted in a synergistic delay in tumor growth. In addition, dynamic oxygen imaging obtained every 3 minutes was conducted to distinguish tumor regions with chronic and cycling hypoxia. Sunitinib treatment suppressed the extent of temporal fluctuations in tumor pO(2) during the vascular normalization window, resulting in the decrease of cycling tumor hypoxia. Overall, the findings suggest that longitudinal and noninvasive monitoring of tumor pO(2) makes it possible to identify a window of vascular renormalization to maximize the effects of combination therapy with antiangiogenic drugs. Cancer Res; 71(20); 6350-9. (C) 2011 AACR.
  • Shunsuke Meike, Tohru Yamamori, Hironobu Yasui, Masato Eitaki, Akira Matsuda, Osamu Inanami
    JOURNAL OF RADIATION RESEARCH 52 4 456 - 463 2011年07月 [査読有り][通常論文]
     
    The combination of a chemotherapeutic agent and radiation is widely applied to enhance cell death in solid tumor cells in cancer treatment. The purine analogue 8-aminoadenosine (8-NH(2)-Ado) is known to be a transcription inhibitor that has proved very effective in multiple myeloma cell lines and primary indolent leukemia cells. In this report, to examine whether 8-NH(2)-Ado had the ability to enhance the radiation-induced cell killing in solid tumor cells, human lung adenocarcinoma A549 cells were irradiated in the presence and absence of 8-NH(2)-Ado. 8-NH(2)-Ado significantly increased reproductive cell death and apoptosis in A549 cells exposed to X-rays. When peptide inhibitors against caspase-3, -8, and -9 were utilized to evaluate the involvement of caspases, all inhibitors suppressed the enhancement of radiation-induced apoptosis, suggesting that not only mitochondria-mediated apoptotic signal transduction pathways but also death receptor-mediated pathways were involved in this enhancement of apoptosis. In addition, in the cells exposed to the treatment combining X-irradiation and 8-NH(2)-Ado, reduction of the intracellular ATP concentration was essential for survival, and down-regulation of the expression of antiapoptotic proteins such as survivin and XIAP was observed. These results indicate that 8-NH(2)-Ado has potential not only as an anti-tumor drug for leukemia and lymphoma but also as a radiosensitizing agent for solid tumors.
  • Meike S, Yamamori T, Yasui H, Eitaki M, Matsuda A, Morimatsu M, Fukushima M, Yamasaki Y, Inanami O
    Molecular Cancer 10 92  2011年07月 [査読有り][通常論文]
     
    Background: A novel anticancer drug 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS106) has been shown to radiosensitize tumor cells and to improve the therapeutic efficiency of X-irradiation. However, the effect of TAS106 on cellular DNA repair capacity has not been elucidated. Our aim in this study was to examine whether TAS106 modified the repair capacity of DNA double-strand breaks (DSBs) in tumor cells. Methods: Various cultured cell lines treated with TAS106 were irradiated and then survival fraction was examined by the clonogenic survival assays. Repair of sublethal damage (SLD), which indicates DSBs repair capacity, was measured as an increase of surviving cells after split dose irradiation with an interval of incubation. To assess the effect of TAS106 on the DSBs repair activity, the time courses of gamma-H2AX and 53BP1 foci formation were examined by using immunocytochemistry. The expression of DNA-repair-related proteins was also examined by Western blot analysis and semi-quantitative RT-PCR analysis. Results: In clonogenic survival assays, pretreatment of TAS106 showed radiosensitizing effects in various cell lines. TAS106 inhibited SLD repair and delayed the disappearance of gamma-H2AX and 53BP1 foci, suggesting that DSB repair occurred in A549 cells. Western blot analysis demonstrated that TAS106 down-regulated the expression of BRCA2 and Rad51, which are known as keys among DNA repair proteins in the homologous recombination (HR) pathway. Although a significant radiosensitizing effect of TAS106 was observed in the parental V79 cells, pretreatment with TAS106 did not induce any radiosensitizing effects in BRCA2-deficient V-C8 cells. Conclusions: Our results indicate that TAS106 induces the down-regulation of BRCA2 and the subsequent abrogation of the HR pathway, leading to a radiosensitizing effect. Therefore, this study suggests that inhibition of the HR pathway may be useful to improve the therapeutic efficiency of radiotherapy for solid tumors.
  • Shingo Matsumoto, Hironobu Yasui, James B. Mitchell, Murali C. Krishna
    CANCER RESEARCH 70 24 10019 - 10023 2010年12月 [査読有り][通常論文]
     
    Cycling hypoxia is now a well-recognized phenomenon in animal and human solid tumors. Cycling hypoxia can exist more than 100-mu m distances from a microvessel, and some of these regions have been shown to exist adjacent to normal tissue. Fluctuations in pO(2) of approximately 20 mm Hg can occur with periodicities of minutes to hours and even days. These fluctuations have been attributed to changes in erythrocyte flux, perfusion, and also development of newer vascular networks. Cycling hypoxia has been shown to induce the expression of hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha) and also confer tumor cells and tumor vascular endothelial cells with enhanced prosurvival pathways, making tumors less responsive to radiation and chemotherapy. Imaging of cycling hypoxia in tumors can provide capabilities to help plan appropriate treatment, by taking into account the magnitude and frequency of fluctuations and also their locations adjacent to normal tissue. Electron paramagnetic resonance imaging (EPRI) provides the ability to distinguish chronic and cycling hypoxic regions and has the required spatial and temporal resolutions to provide quantitative maps of tumor pO(2). EPRI can serve as a valuable tool in examining tumor pO(2) longitudinally in response to treatment and in an experimentally chosen time window to spatially map fluctuations in pO(2) noninvasively in animal models of implanted or orthotopic tumors, with a potential for human applications. Cancer Res; 70(24); 10019-23. (C) 2010 AACR.
  • Hironobu Yasui, Shingo Matsumoto, Nallathamby Devasahayam, Jeeva P. Munasinghe, Rajani Choudhuri, Keita Saito, Sankaran Subramanian, James B. Mitchell, Murali C. Krishna
    CANCER RESEARCH 70 16 6427 - 6436 2010年08月 [査読有り][通常論文]
     
    Tumors exhibit fluctuations in blood flow that influence oxygen concentrations and therapeutic resistance. To assist therapeutic planning and improve prognosis, noninvasive dynamic imaging of spatial and temporal variations in oxygen partial pressure (pO(2)) would be useful. Here, we illustrate the use of pulsed electron paramagnetic resonance imaging (EPRI) as a novel imaging method to directly monitor fluctuations in oxygen concentrations in mouse models. A common resonator platform for both EPRI and magnetic resonance imaging (MRI) provided pO(2) maps with anatomic guidance and microvessel density. Oxygen images acquired every 3 minutes for a total of 30 minutes in two different tumor types revealed that fluctuation patterns in pO(2) are dependent on tumor size and tumor type. The magnitude of fluctuations in pO(2) in SCCVII tumors ranged between 2- to 18-fold, whereas the fluctuations in HT29 xenografts were of lower magnitude. Alternating breathing cycles with air or carbogen (95% O(2) plus 5% CO(2)) distinguished higher and lower sensitivity regions, which responded to carbogen, corresponding to cycling hypoxia and chronic hypoxia, respectively. Immunohistochemical analysis suggests that the fluctuation in pO(2) correlated with pericyte density rather than vascular density in the tumor. This EPRI technique, combined with MRI, may offer a powerful clinical tool to noninvasively detect variable oxygenation in tumors. Cancer Res; 70(16); 6427-36. (C)2010 AACR.
  • Hironobu Yasui, Nozomi Ito, Tohru Yamamori, Hideo Nakamura, Jun Okano, Taketoshi Asanuma, Takayuki Nakajima, Mikinori Kuwabara, Osamu Inanami
    FREE RADICAL RESEARCH 44 6 645 - 654 2010年06月 [査読有り][通常論文]
     
    It has previously been suggested that the spin trap agent alpha-phenyl-N-tert-butylnitrone (PBN) induces neurite outgrowth through activation of the Ras-ERK pathway in PC12 cells. However, the chemical properties of PBN contributing to its biological function and the detailed mechanism for the activation of Ras by PBN remain unknown. This study demonstrates that the hydrophobic structure of PBN is related to the activation of Ras, by comparing with hydrophilic analogues of PBN. [(14)C]-labelled PBN was found to localize in the lipid fraction and activate Ras indirectly. On the other hand, neurite outgrowth by PBN was inhibited by a nitric oxide (NO) scavenger. Moreover, the neurite outgrowth induced by PBN and the NO donor NOR4 was inhibited by the dominant negative Ras or MAPK/ERK inhibitor. Taken together, these results suggest that PBN is incorporated into the plasma membrane and induces neurite outgrowth in PC12 cells by activating the Ras-ERK pathway through NO release.
  • Yasuko Watanabe, Wakako Hiraoka, Manabu Igarashi, Kimihito Ito, Yuhei Shimoyama, Motohiro Horiuchi, Tohru Yamamoria, Hironobu Yasui, Mikinori Kuwabara, Fuyuhiko Inagaki, Osamu Inanami
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 394 3 522 - 528 2010年04月 [査読有り][通常論文]
     
    To explore Cu(II) ion coordination by His(186) in the C-terminal domain of full-length prion protein (moPrP), we utilized the magnetic dipolar interaction between a paramagnetic metal, Cu(II) ion, and a spin probe introduced in the neighborhood of the postulated binding site by the spin labeling technique (SDSL technique) Six moPrP mutants. moPrP(D143C), moPrP(Y148C), moPrP(E151C), moPrP(Y156C), moPrP(T189C). and moPrP(Y156C,H186A), were reacted with a methane thiosulfonate spin probe and a nitroxide residue (R1) was created in the binding site of each one Line broadening of the ESR spectra was induced in the presence of Cu(II) ions in moPrP(Y148R1), moPrP(Y151R1). moPrP(Y156R1), and moPrP(T189R1) but not moPrP(D143R1) This line broadening indicated the presence of electron-electron dipolar interaction between Cu(II) and the rutroxide spin probe, suggesting that each interspin distance was within 20 angstrom The interspin distance ranges between Cu(II) and the spin probes of moPrP(Y148R1), inoPrP(Y151R1), moPrP(Y156R1), and moPrP(T189R1) were estimated to be 12 1 angstrom, 18 1 angstrom, 107 angstrom, and 84 angstrom, respectively In moPrP(Y156R1,H186A), line broadening between Cu(II) and the spin probe was not observed These results suggest that a novel Cu(II) binding site is involved in His186 in the Helix2 region of the C-terminal domain of moPrP(C) (C) 2010 Elsevier Inc All rights reserved
  • Shingo Matsumoto, Hironobu Yasui, Sonny Batra, Yuichi Kinoshita, Marcelino Bernardo, Jeeva P. Munasinghe, Hideo Utsumi, Rajani Choudhuri, Nallathamby Devasahayam, Sankaran Subramanian, James B. Mitchell, Murali C. Krishna
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 106 42 17898 - 17903 2009年10月 [査読有り][通常論文]
     
    Architectural and functional abnormalities of blood vessels are a common feature in tumors. A consequence of increased vascular permeability and concomitant aberrant blood flow is poor delivery of oxygen and drugs, which is associated with treatment resistance. In the present study, we describe a strategy to simultaneously visualize tissue oxygen concentration and microvascular permeability by using a hyperpolarized (1)H-MRI, known as Over-hauser enhanced MRI (OMRI), and an oxygen-sensitive contrast agent OX63. Substantial MRI signal enhancement was induced by dynamic nuclear polarization (DNP). The DNP achieved up to a 7,000% increase in MRI signal at an OX63 concentration of 1.5 mM compared with that under thermal equilibrium state. The extent of hyperpolarization is influenced mainly by the local concentration of OX63 and inversely by the tissue oxygen level. By collecting dynamic OMRI images at different hyperpolarization levels, local oxygen concentration and microvascular permeability of OX63 can be simultaneously determined. Application of this modality to murine tumors revealed that tumor regions with high vascular permeability were spatio- temporally coincident with hypoxia. Quantitative analysis of image data from individual animals showed an inverse correlation between tumor vascular leakage and median oxygen concentration. Immunohistochemical analyses of tumor tissues obtained from the same animals after OMRI experiments demonstrated that lack of integrity in tumor blood vessels was associated with increased tumor microvascular permeability. This dual imaging technique may be useful for the longitudinal assessment of changes in tumor vascular function and oxygenation in response to chemotherapy, radiotherapy, or anti-angiogenic treatment.
  • Saori Kobayashi, Reeko Sato, Yuya Abe, Osamu Inanami, Hironobu Yasui, Katsuhiko Omoe, Jun Yasuda, Careen Hankanga, Shinichi Oda, Juso Sasaki
    VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY 130 3-4 187 - 196 2009年08月 [査読有り][通常論文]
     
    Canine leukocyte adhesion deficiency (CLAD) in Irish setters is caused by genetic defects of leukocyte integrin CD18 leading to recurrent bacterial infections. We report clinical features and analysis of neutrophil function from two mixed-breed canine littermates (one female and one male dog) similar to CLAD. The symptoms of pyogenic infection were first recognized at 3 months of age and since then the patients suffered from recurrent bacterial infections. These clinical findings were strongly suggestive of genetic phagocyte dysfunction. Neutrophil function tests revealed a marked reduction of serum-opsonized zymosan-mediated superoxide production in the two littermates. Neutrophils of the male dog revealed impaired integrin-mediated adherence and phagocytic activity, whereas ability of serum opsonization was normal. There was also a profound decrease of surface expression of CD11b/CD18 and beta 2-integrin transcript level, detected by real-time RT-PCR without missense mutations unlike CLAD. Immunoblot analysis indicated that protein expression of cytochrome 15558 component gp91(phox), the cytosolic components p47(phox) and P67(phox) of NADPH oxidase components increased profoundly in the male. Our study suggests that decreased transcriptional levels of beta 2-integrin without mutations, lead to downregulation of surface expression, resulting in multiple defects in adhesion-related neutrophil functions and consequently, recurrent bacterial infections from puppyhood. (C) 2009 Elsevier B.V. All rights reserved.
  • Aki Ogura, Shigeru Oowada, Yasuhiro Kon, Aki Hirayama, Hironobu Yasui, Shunsuke Meike, Saori Kobayashi, Mikinori Kuwabara, Osamu Inanami
    CANCER LETTERS 277 1 64 - 71 2009年05月 [査読有り][通常論文]
     
    Mitochondria in mammalian cells are well-known to play an important role in the intrinsic pathway of genotoxic-agent-induced apoptosis by releasing cytochrome c into cytosol and to be a major source of reactive oxygen species (ROS). The aim of this study was to examine whether mitochondrial ROS are involved in radiation-induced apoptotic signaling in A549 cells. Post-irradiation treatment with N-acetyl-L-cystein (NAC) inhibited cytochrome c release from mitochondria but did not affect expression levels of Bcl-2, Bcl-X-L and Bax, suggesting that late production of ROS triggered cytochrome c release. Experiments using DCFDA (a classical ROS fluorescence probe) and MitoAR (a novel mitochondrial ROS probe) demonstrated that intracellular and mitochondrial ROS were enhanced 6 h after X irradiation. Furthermore, the O-2(-center dot) production ability of mitochondria isolated from A549 cells was evaluated by ESR spectroscopy combined with a spin-trapping reagent (CYPMPO). When isolated mitochondria were incubated with NADH, succinate and CYPMPO, an ESR spectrum due to CYPMPO-OOH was detected. This NADH/succinate-dependent O-2(-center dot) production from mitochondria of irradiated cells was significantly increased in comparison with that of unirradiated cells. These results indicate that ionizing radiation enhances O-2(-center dot), production from mitochondria to trigger cytochrome c release in A549 cells. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
  • H. Yasui, A. Ogura, T. Asanuma, A. Matsuda, I. Kashiwakura, M. Kuwabara, O. Inanami
    BRITISH JOURNAL OF CANCER 99 9 1442 - 1452 2008年10月 [査読有り][通常論文]
     
    In a previous study, we showed that a novel anticancer drug, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl) cytosine (TAS106, ECyd) increased the antitumour efficacy of X-irradiation. However, its effects on hypoxic cells in tumours remain unclarified. Here, we show that TAS106 enhances the induction of apoptosis in X-irradiated human gastric adenocarcinoma MKN45 and MKN28 cells under hypoxia in vitro. At the same time, the accumulation of HIF-1 alpha observed under hypoxia was shown to be decreased to the level of normoxia in the presence of 0.1 mu M TAS106. To study the function of HIF-1 alpha protein in apoptosis of hypoxic cells, we employed an HIF-1 alpha reductive approach using its specific antisense oligodeoxynucleotide. The reduction of HIF-1 alpha gene expression dramatically enhanced X-ray-induced apoptosis in hypoxic cells. In in vivo experiments in which MKN45 cells were transplanted into severe combined immunodeficient (SCID) mice, TAS106 (0.5 mg kg(-1)) suppressed HIF-1 alpha expression and subsequently reduced the area of the hypoxic region in the tumour and enhanced the induction of apoptosis in the hypoxic region when combined with 2Gy of X-irradiation. These results suggest the possibility that TAS106 acts as a potent radiosensitiser through the inhibition of HIF-1 alpha expression and can be a useful agent against radiotherapy-resistant hypoxic cells in solid tumours.
  • Taketoshi Asanuma, Sabrina Doblas, Yasvir A. Tesiram, Debra Saunders, Rebecca Cranford, Hironobu Yasui, Osamu Inanami, Nataliya Smith, Robert A. Floyd, Yashige Kotake, Rheal A. Towner
    JOURNAL OF MAGNETIC RESONANCE IMAGING 28 3 574 - 587 2008年09月 [査読有り][通常論文]
     
    Purpose: To apply fiber tractography to assess the effect of a possible antiglioma drug, phenyl N-tert-butyl nitrone (PBN), on glioma-affected neuronal fibers. The fiber tractography method was able to differentiate between different tumor types. such as the C6 and F98 rat glioma models. Materials and Methods: C6 or F98 cells were intracranially injected into the cortex of male Fischer 344 rats. PBN treatment was initiated before or after cell implantation. Tumor growth was monitored with diffusion tensor imaging (DTI) and fiber tractography using diffusion-weighting gradients in 30 noncolinear directions. neuronal fiber tractography. we were able to evaluate the protective effect of PBN against invasive glioma growth in rat brains. PBN provided protection of the neuronal fibers against tumor-induced ischemia and tumor invasion. Results: Although proton density-weighted (PDw) and T2-weighted (T2w) images did not show any difference between C6 and F98 gliomas without edema, the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were able to discriminate between these two tumor models. Fiber tractography was used to) visualize C6 glioma-induced ischemia of tumor-surrounding tissues, whereas F98 glioma was found to infiltrate and penetrate into the corpus callosum (CC). During glioma growth, neuronal fibers were found to disappear at the border regions between the tumor and surrounding tissues. PBN treatment was shown to inhibit glioma growth with accompanying changes in the surrounding tissue. Conclusion: By noninvasively monitoring the degree of neuronal fiber integrity and connectivity with the use of
  • Taketoshi Asanuma, Hironobu Yasui, Masayasu Sato, Osamu Inanami, Mikinori Kuwabara
    JAPANESE JOURNAL OF VETERINARY RESEARCH 56 2 99 - 107 2008年08月 [査読有り][通常論文]
     
    This study was performed to examine whether the brain activities induced by noxious algesic chemical substances in anesthetized animals could be detected by blood oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI). Multislice gradient echo images of the primary somatosensory cortex were obtained using a 7.05 T superconducting system and a one-turned surface coil centered over the primary somatosensory cortex of the 1.0%-isoflurane-anesthetized rat. The Z-score t-map of BOLD signals and its time-course analysis revealed that subcutaneous injection of formalin into the left forepaw immediately induced an early response in the contralateral primary sensory cortex lasting for a few minutes, followed by a late response until 20 min after stimulation. In contrast, injection of capsaicin into the left forepaw evoked only the early response. Furthermore, pretreatment with morphine completely abolished these responses induced by the chemical algesic substances. Thus BOLD-fMRI is a useful method to analyze the brain activities of painful stimulation in anesthetized animals.
  • Momoko Takahashi, Hironobu Yasui, Aki Ogura, Taketoshi Asanuma, Nobuo Kubota, Michihiko Tsujitan, Mikinori Kuwabara, Osamu Inanami
    JOURNAL OF RADIATION RESEARCH 49 2 153 - 161 2008年03月 [査読有り][通常論文]
     
    Our previous study showed that X irradiation induced the expression of death receptor DR5 on the cell surface in tumor cell lines under not only normoxia but also hypoxia. X irradiation combined with TNF alpha-related apoptosis-inducing ligand (TRAIL), which is the ligand of DR5, induced apoptosis in vitro (Takahashi et al., (2007) Journal of Radiation Research, 48: 461-468). In this report, we examined the in vivo antitumor efficacy of X irradiation combined with TRAIL treatment in tumor xenograft models derived from human gastric adenocarcinoma MKN45 and MKN28 cells in SCID mice. X irradiation combined with TRAIL synergistically suppressed the tumor growth rates in the xenograft models derived from MKN45 and MKN28 cells, which have wild type Tp53 and mutated Tp53, respectively, indicating that the antitumor effects occurred in a Tp53-independent manner. Histological analysis showed that the combination of X irradiation and TRAIL induced caspase-3-dependent apoptotic cell death. Moreover, the immunohistochemical detection of hypoxic regions using the hypoxic marker pimonidazole revealed that caspase-3-dependent apoptosis occurred in the hypoxic regions in the tumors. These results indicated that X irradiation combined with TRAIL may be a useful treatment to reduce tumor growth in not only normoxic but also hypoxic regions.
  • Aki Ogura, Yasuko Watanabe, Daisuke Iizuka, Hironobu Yasui, Makoto Amitani, Saorl Kobayashi, Mikinori Kuwabara, Osamu Inanami
    CANCER LETTERS 259 1 71 - 81 2008年01月 [査読有り][通常論文]
     
    To investigate the mechanism of radioresistance of solid tumor cells, we created two expression vectors encoding Survivin mutants, T34A and D53A. When T34A and D53A were overexpressed in NIH3T3, A549 and HeLa cells, radiation-induced apoptosis was significantly enhanced. Furthermore, we examined the binding capability of Survivin with Smac/DIABLO in the cells that overexpressed these mutants. Coimmunoprecipitation analysis revealed that mutant form of Survivin, D53A and T34A could bind to Smac/DIABLO, but with much less affinity compared to the authentic form. These results suggest that radiation-induced apoptosis of tumor cells is increased by inhibition of the interaction between Survivin and Smac/DIABLO through overexpression of T34A and D53A. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
  • Momoko Takahashi, Osamu Inanami, Nobuo Kubota, Michihiko Tsujitan, Hironobu Yasui, Aki Ogura, Mikinori Kuwabara
    JOURNAL OF RADIATION RESEARCH 48 6 461 - 468 2007年11月 [査読有り][通常論文]
     
    Our previous study showed that ionizing radiation induced the expression of death receptor DR5 on the cell surface in tumor cell lines and that the death receptor of the TNF alpha-related apoptosis-inducing ligand TRAIL enhanced the apoptotic pathway (Hamasu et al., (2005) Journal of Radiation Research, 46:103-110). The present experiments were performed to examine whether treatment with TRAIL enhanced the cell killing in tumor cells exposed to ionizing radiation under hypoxia, since the presence of radioresistant cells in hypoxic regions of solid tumors is a serious problem in radiation therapy for tumors. When human lung carcinoma A549 cells were irradiated under normoxia and hypoxia, respectively, radiation-induced enhancement of expression of DR5 was observed under both conditions. Incubation in the presence of TRAIL enhanced the caspase-dependent and chymotrypsin-like-protease-dependent apoptotic cell death in A549 cells exposed to X rays. Furthermore, it was shown that treatment with TRAIL enhanced apoptotic cell death and loss of clonogenic ability in A549 cells exposed to X rays not only under normoxia but also under hypoxia, suggesting that combination treatment with TRAIL and X irradiation is effective for hypoxic tumor cells.
  • Hironobu Yasui, Osamu Inanami, Taketoshi Asanuma, Daisuke Iizuka, Takayuki Nakajima, Yasuhiro Kon, Akira Matsuda, Mikinori Kumwabara
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 68 1 218 - 228 2007年05月 [査読有り][通常論文]
     
    Purpose: To examine the in vivo antitumor efficacy of X-irradiation combined with administration of a ribonucleoside anticancer drug, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd), to tumor cell-transplanted mice. Methods and Materials: Colon26 murine rectum adenocarcinoma cells and MKN45 human gastric adenocarcinoma cells were inoculated into the footpad in BALB/c mice and severe combined immunodeficient mice, respectively. They were treated with a relatively low dose of X-irradiation (2 Gy) and low amounts of TAS106 (0.1 mg/kg and 0.5 mg/kg). The tumor growth was monitored by measuring the tumor volume from Day 5 to Day 16 for Colon26 and from Day 7 to Day 20 for MKN45. Histologic analyses for proliferative and apoptotic cells in the tumors were performed using Ki-67 immunohistochemical and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. The expression of survivin, a key molecule related to tumor survival, was assessed by quantitative polymerase chain reaction and immunohistochemical analysis. Results: When X-irradiation and TAS106 treatment were combined, significant inhibition of tumor growth was observed in both types of tumors compared with mice treated with X-irradiation or TAS106 alone. Marked inhibition of tumor growth was observed in half of the mice that received the combined treatment three times at 2-day intervals. Parallel to these phenomena, the suppression of survivin expression and appearance of Ki-67-negative and apoptotic cells were observed. Conclusions: X-irradiation and TAS106 effectively suppress tumor growth in mice. The inhibition of survivin expression by TAS106 is thought to mainly contribute to the suppression of the tumor growth. (c) 2007 Elsevier Inc.
  • Hironobu Yasui, Taketoshi Asanuma, Yasuko Watanabe, Kenji Waki, Osamu Inanami, Mikinori Kuwabara
    BIOFACTORS 29 2-3 113 - 121 2007年 [査読有り][通常論文]
     
    Oxidative damage due to ischemia/reperfusion has been implicated as one of the leading causes for delayed neuronal cell death in a number of neurodegenerative diseases, including stroke. The purpose of this research was to investigate whether oral administration of a fermented grain food mixture (AOB((R))) might offer protective effects against ischemia/reperfusion-induced neuronal damage in Mongolian gerbils, a model known for delayed neuronal death in the hippocampal CA1 region. Histological analysis revealed that AOB administration ad libitum for 3 weeks (preoperative administration) and I week (postoperative administration) dose-dependently suppressed the induction of transient ischemia/reperfusion-induced neuronal cell death. TUNEL assay also revealed that AOB suppressed it by inhibiting the induction of apoptosis. A significant increase of superoxide dismutase-like (SOD-like) activity was observed in the hippocampal CA1 region of the AOB-treated gerbil. Furthermore, immunoblot analysis showed that AOB administration down-regulated the expression of heat shock proteins HSP27 and HSP70 in the same region. These results indicated that oral administration of AOB protected against ischemia/reperfusion-induced brain injury by minimizing oxidative damage via its SOD-like activity and inhibiting apoptosis.
  • Taketoshi Asanuma, Hironobu Yasui, Osamu Inanami, Kenji Waki, Momoko Takahashi, Daisuke Iizuka, Taketo Uemura, Gregory Durand, Ange Polidori, Yasuhiro Kon, Bernard Pucci, Mikinori Kuwabara
    CHEMISTRY & BIODIVERSITY 4 9 2253 - 2267 2007年 [査読有り][通常論文]
     
    An amphiphilic alpha-phenyl-N-(tert-butyl) nitrone (PBN) derivative, N-{[4-(lactobionamido)methyl]-benzylidene}-1,1-dimethyl-2-(octylsulfanyl)ethylamine N-oxide (LPBNSH), newly synthesized from its original form PBN in hopes of clinical use, was intraperitoneally administered to Long-Evans Cinnamon (LEC) rats every 2 days at the concentrations of 0.1, 0.5, 1.0, and 2.0 mg/kg. We found that LPBNSH protected against copper-induced hepatitis with jaundice in LEC rats at concentrations of 0.1 and 0.5 mg/ kg, which were extremely low compared with that of PBN. It also effectively prevented the loss of body weight, reduced the death rate, and suppressed the increase in serum aspartate aminotransferase and alanine aminotransferase values arising from fulminant hepatitis with jaundice at the same concentrations. Similar results were observed when PBN was administered at the concentration of 150 mg/kg. immunohistochemical analysis of 8-hydroxy-2'-deoxyguanosine and measurement of thiobarbituric acid-reactive substances in the liver showed that LPBNSH largely suppressed the formation of these oxidative products at same concentrations. No difference in the abnormal accumulation of copper in the liver between the LPBNSH administered and control groups was observed. From these results, it was concluded that LPBNSH exhibited liver-protective effects against fulminant hepatitis with jaundice at ca. 1/1000, 500 the molar concentration of PBN and, therefore, was clinically promising.

書籍

  • 放射線生物学
    安井 博宣 (担当:共著範囲:放射線の利用と環境放射線)
    近代出版 2015年03月
  • 酸化ストレスの医学 改訂第二版
    安井 博宣 (担当:共著範囲:放射線と酸化ストレス)
    2014年09月
  • 小動物の実践歯科学
    安井 博宣 (担当:共訳範囲:獣医歯科放射線学)
    緑書房 2013年03月
  • 酸化ストレスの医学 第一版
    安井 博宣 (担当:共著範囲:放射線・紫外線と酸化ストレス)
    診断と治療社 2008年

講演・口頭発表等

  • チミジンホスホリラーゼ標的プローブを非アルコール性脂肪肝炎診断に応用するためのin vivo機能解析  [通常講演]
    上原里穂, 東川桂, 堀口紗和子, 足澤誠, 柴田悠貴, 大久保直登, 北浦廣剛, 安井博宣, 久下裕司, 武田宏司
    第3回日本核医学会分科会放射薬品科学研究会/第19回放射性医薬品・画像診断薬研究会 2019年11月 口頭発表(一般)
  • A basic study on PET imaging technique for predicting cancer sensitivity to ferroptosis-targeting cancer therapy  [通常講演]
    Shibata Y, Higashikawa K, Yasui H, Kuge Y
    The 26th Annual Meeting of the Society for Free Radical Biology and Medicine 2019年11月 ポスター発表
  • ヒト肺腺がん A549細胞におけるグルタミノリシス阻害は放射線誘導性細胞老化を増強する  [通常講演]
    東山りつ子, 安井博宣, 房知輝, 山本久美子, 藤本政毅, 稲波修
    日本放射線影響学会第62回大会 2019年11月 ポスター発表
  • ヒト肺がん由来 A549細胞における解糖系の放射線応答性に関する研究  [通常講演]
    福島佑一郎, 安井博宣, 藤本政毅, 山本久美子, 房知輝, 稲波修
    日本放射線影響学会第62回大会 2019年11月 ポスター発表
  • 固形腫瘍株化細胞におけるエネルギー代謝の放射線応答の解析  [通常講演]
    山本久美子, 安井博宣, 藤本政毅, 福島佑一郎, 房知輝, 稲波修
    日本放射線影響学会第62回大会 2019年11月 口頭発表(一般)
  • ヒト肺腺がん由来 A549細胞においてグルタミノリシス依存性のエネルギー代謝の阻害は放射線の効果を増強する  [通常講演]
    藤本政毅, 房知輝, 山本久美子, 安井博宣, 稲波修
    日本放射線影響学会第62回大会 2019年11月 口頭発表(一般)
  • ミトコンドリア分裂とその Ca2+ 制御は照射後の分裂期崩壊に寄与する  [通常講演]
    房知輝, 山盛徹, 山本久美子, 藤本政毅, 安井博宣, 稲波修
    日本放射線影響学会第62回大会 2019年11月 シンポジウム・ワークショップパネル(公募)
  • ESR 法を用いた培養細胞における細胞外 pH 評価法の開発  [通常講演]
    山本久美子, 安井博宣, 藤本政毅, 房知輝, Valery V. Khramtsov, 平田拓, 稲波修
    第57回電子スピンサイエンス学会年会 2019年11月 口頭発表(一般)
  • ヒト肺腺がん由来A549細胞におけるグルタミノリシス阻害による放射線誘発性細胞死増強メカニズムの解明  [通常講演]
    藤本政毅, 房知輝, 山本久美子, 安井博宣, 稲波修
    第5回北大部局横断シンポジウム 2019年11月 ポスター発表
  • 陽子線照射中のがん細胞における亜致死損傷回復速度のLET依存性検証  [通常講演]
    笠松幸生, 細田芽生, 南璡旼, 安井博宣, 田中創大, 平山嵩祐, 宮本直樹, 梅垣菊男, 白土博樹, 松浦妙子
    第5回北大部局横断シンポジウム 2019年11月 ポスター発表
  • 超偏極核磁気共鳴法に裏付けされた細胞老化誘導治療の樹立  [通常講演]
    安井博宣, 松元慎吾
    第5回北大部局横断シンポジウム 2019年11月 ポスター発表
  • 光免疫療法が腫瘍に及ぼす変化に関する[18F]FDGと[18F]FMISOを用いた検討  [通常講演]
    中島孝平, 杉川晃代, 安井博宣, 東川桂, 高倉栄男, 志賀哲, 久下裕司, 小川美香子
    第78回日本癌学会学術総会 2019年09月 ポスター発表
  • Mitochondrial fission contributes to radiation-induced cell death by altering mitochondrial function  [通常講演]
    Bo T, Yamamori T, Yamamoto K, Fujimoto M, Yasui H, Inanami O
    The 7th Sapporo Summer Seminar for One Health 2019年09月 口頭発表(一般)
  • Dependence of the Sub-Lethal Damage Repair Rate on LET in Proton Irradiation : An Initial Study  [通常講演]
    Kasamatsu K, Hosoda M, Nam J.M, Yasui H, Tanaka S, Hirayama S, Miyamoto N, Umegaki K, Shirato H, Matsuura T
    第118回日本医学物理学会学術大会 2019年09月 ポスター発表
  • Glutamine代謝阻害がX線照射による早期細胞老化およびアポトーシスの誘導に与える影響の検討  [通常講演]
    東山りつ子, 安井博宣, 房知輝, 山本久美子, 藤本政毅, 稲波修
    第162 回日本獣医学会学術集会 2019年09月 口頭発表(一般)
  • ヒト肺腺がん由来A549細胞におけるグルタミノリシスを標的とする放射線増感効果  [通常講演]
    藤本政毅, 房知輝, 山本久美子, 安井博宣, 稲波修
    第162 回日本獣医学会学術集会 2019年09月 口頭発表(一般)
  • 種々のがん細胞におけるミトコンドリア電子伝達系の放射線応答の解析  [通常講演]
    山本久美子, 安井博宣, 藤本政毅, 房知輝, 稲波修
    第162 回日本獣医学会学術集会 2019年09月 口頭発表(一般)
  • ミトコンドリア分裂はCa2+制御を通じて放射線による分裂期崩壊誘導に寄与する  [通常講演]
    房知輝, 山盛徹, 山本久美子, 藤本政毅, 安井博宣, 稲波修
    第162 回日本獣医学会学術集会 2019年09月 口頭発表(一般)
  • In vivo extracellular pH mapping of tumor mouse models using EPR  [招待講演]
    Komarov D.A, Ichikawa Y, Yamamoto K, Stewart N.J, Matsumoto S, Yasui H, Kirilyuk I.A, Khramtsov V.V, Inanami O, Hirata H
    XIth Conference of European Federation of EPR Groups (EFEPR) 2019年09月 口頭発表(招待・特別)
  • X-Irradiation enhances energy metabolism derived from mitochondrial electron transport chain and glycolysis in cancer cells  [通常講演]
    Yamamoto K, Yasui H, Bo T, Fujimoto M, Fukushima Y, Hiraoka W, Inanami O
    16th International Congress of Radiation Research 2019年08月 ポスター発表
  • Inhibition of mitochondrial fission reduces radiation-induced mitotic catastrophe via Ca2+ regulation  [通常講演]
    Bo T, Yamamori T, Yamamoto K, Fujimoto M, Yasui H, Inanami O
    16th International Congress of Radiation Research 2019年08月 ポスター発表
  • チミジンホスホリラーゼ標的核医学イメージングプローブを用いた非侵襲的NASH診断法の開発研究  [通常講演]
    東川桂, 上原里穂, 堀口紗和子, 柴田悠貴, 足澤誠, 北浦廣剛, 安井博宣, 武田宏司, 久下裕司
    第72 回日本酸化ストレス学会学術集会 2019年06月 シンポジウム・ワークショップパネル(指名)
  • 放射線治療を併用したフェロトーシス誘導がん治療法の検討  [通常講演]
    柴田悠貴, 安井博宣, 東川桂, 宮本直樹, 久下裕司
    第72 回日本酸化ストレス学会学術集会 2019年06月 口頭発表(一般)
  • イヌ骨肉腫細胞株由来Cancer stem-like cellsのミトコンドリアの放射線反応性の解析  [通常講演]
    出口辰弥, 細谷謙次, 金尚昊, 山本久美子, 房知輝, 安井博宣, 稲波修, 奥村正裕
    第72 回日本酸化ストレス学会学術集会 2019年06月 口頭発表(一般)
  • ESR法によるがん細胞のミトコンドリア機能の放射線応答の解析  [通常講演]
    山本久美子, 安井博宣, 房知輝, 藤本政毅, 稲波修
    第72 回日本酸化ストレス学会学術集会 2019年06月 ポスター発表
  • ヒト肺腺がん由来A549細胞のエネルギー代謝におけるグルタミノリシス依存性とその放射線応答  [通常講演]
    藤本政毅, 房知輝, 山本久美子, 安井博宣, 稲波修
    第72 回日本酸化ストレス学会学術集会 2019年06月 ポスター発表
  • 放射線誘発細胞死に対するミトコンドリア分裂の寄与メカニズムの検討  [通常講演]
    房知輝, 山盛徹, 山本久美子, 藤本政毅, 安井博宣, 稲波修
    第72 回日本酸化ストレス学会学術集会 2019年06月 ポスター発表
  • Evaluation of [18F]FDG uptake after anti PD-1 therapy in mice  [通常講演]
    Tomita M, Yasui H, Higashikawa K, Nakajima K, Takakura H, Shiga T, Kuge Y, Ogawa M
    SNMMI 2019 Annual Meeting 2019年06月 ポスター発表
  • ミトコンドリア形態制御機構を標的とした放射線感受性変化の検討とそのメカニズムの解析  [通常講演]
    房知輝, 山盛徹, 山本久美子, 藤本政毅, 安井博宣, 稲波修
    第57回日本放射線腫瘍学会生物部会学術大会 2019年06月 口頭発表(一般)
  • Investigation of the potentials of a thymidine phosphorylase imaging probe for the differential diagnosis of nonalcoholic steatohepatitis  [通常講演]
    Higashikawa K, Uehara R, Horiguchi S, Shibata Y, Tarisawa M, Kitaura H, Yasui H, Takeda H, Kuge Y
    The 23th International Symposium on Radiopharmaceutical Sciences (ISRS2019) 2019年05月 ポスター発表
  • Preclinical evaluation of [18F]DiFA, a novel hypoxia PET probe, in a rat intracranial glioma model  [通常講演]
    Yasui H, Higashikawa K, Shibata Y, Matsumoto H, Shiga T, Tamaki N. Kuge Y
    The 23th International Symposium on Radiopharmaceutical Sciences (ISRS2019) 2019年05月 口頭発表(一般)
  • 低酸素標的 PET プローブ[18F]DiFA のラット脳室内腫瘍モデルへの適用  [通常講演]
    安井博宣, 東川桂, 柴田悠貴, 松本博樹, 志賀哲, 久下裕司
    第14 回日本分子イメージング学会総会・学術集会 2019年05月 ポスター発表
  • 光免疫療法による腫瘍環境の変化に関する[18F]FDG と[18F]FMISO を用いた検討  [通常講演]
    中島孝平, 杉川晃代, 安井博宣, 東川桂, 高倉栄男, 志賀哲, 久下裕司, 小川美香子
    第14 回日本分子イメージング学会総会・学術集会 2019年05月 ポスター発表
  • がんのフェロトーシス感受性評価のためのイメージング法開発に向けた基礎的検討  [通常講演]
    柴田悠貴, 東川桂, 安井博宣, 久下裕司
    第14 回日本分子イメージング学会総会・学術集会 2019年05月 ポスター発表
  • チミジンホスホリラーゼイメージングプローブを用いた非アルコール性脂肪肝炎の鑑別法の開発研究  [通常講演]
    東川桂, 上原里穂, 堀口紗和子, 柴田悠貴, 足澤誠, 北浦廣剛, 安井博宣, 武田宏司, 久下裕司
    第14 回日本分子イメージング学会総会・学術集会 2019年05月 ポスター発表
  • 腫瘍内低酸素変動の可視化と放射線生物学における意義  [招待講演]
    安井博宣
    第117回日本医学物理学会学術大会 2019年04月 シンポジウム・ワークショップパネル(指名)
  • メトホルミンのイヌ骨肉腫細胞株由来のCancer stem-like cellsにおける放射線増感効果の解析  [通常講演]
    出口辰弥, 細谷謙次, 金尚昊, 山本久美子, 房知輝, 安井博宣, 稲波修, 奥村正裕
    第21回菅原・大西記念癌治療増感シンポジウム 2019年02月 口頭発表(一般)
  • ヒト肺腺がん由来A549細胞のエネルギー代謝におけるグルタミノリシス依存性とその放射線応答  [通常講演]
    藤本政毅, 房知輝, 山本久美子, 安井博宣, 稲波修
    第21回菅原・大西記念癌治療増感シンポジウム 2019年02月 口頭発表(一般)
  • ホットセルに格納可能な小型RIガス貯留装置の開発  [通常講演]
    阿保憲史, 野矢洋一, 東川桂, 安井博宣, 久下裕司
    日本放射線安全管理学会第17回学術大会 2018年12月 口頭発表(一般)
  • 新規低酸素トレーサー[18F]DiFAと[18F]FMISOの悪性腫瘍における低酸素集積の比較  [通常講演]
    渡邊史郎, 平田健司, 小林健太郎, 安井博宣, 松本博樹, 久下裕司, 志賀哲
    第58回日本核医学会学術総会 2018年11月 口頭発表(一般)
  • 光免疫療法による[18F]FDGおよび[18F]FMISOの集積変化に関する検討  [通常講演]
    中島孝平, 杉川晃代, 安井博宣, 東川桂, 高倉栄男, 志賀哲, 久下裕司, 小川美香子
    第58回日本核医学会学術総会 2018年11月 口頭発表(一般)
  • ESR法による新規ミトコンドリア機能評価法を用いたがん細胞の放射線応答の解析  [通常講演]
    山本久美子, 安井博宣, 房知輝, 山盛徹, 稲波修
    日本放射線影響学会第61回大会 2018年11月 口頭発表(一般)
  • DNA 損傷応答は内皮型一酸化窒素合成酵素の活性化を介して血管内皮細胞を老化させる  [通常講演]
    永根大幹, 安井博宣, 山盛徹, 稲波修, 山下匡, クプサミー ペリアナン
    日本放射線影響学会第61回大会 2018年11月 ポスター発表
  • 電子スピン共鳴酸素イメージングによる脳室内移植グリオーマの放射線感受性評価  [通常講演]
    安井博宣, 河合辰哉, 松元慎吾, 齋藤圭太, Kevin Camphausen, 稲波修, Murali C. Krishna
    日本放射線影響学会第61回大会 2018年11月 ポスター発表
  • Potentials of a thymidine phosphorylase imaging agent in the diagnosis of nonalcoholic steatohepatitis  [通常講演]
    Horiguchi S, Higashikawa K, Uehara R, Tarisawa M, Shibata Y, Ohkura K, Yasui H, Kuge Y, Takeda H
    the 10th China-Japan-Korea Symposium on Radiopharmaceutical Sciences (CJKSRS2018) 2018年11月 口頭発表(一般)
  • マウス脳室内グリオーマモデルにおける放射線感受性評価へのESR酸素分圧イメージングの適用  [通常講演]
    安井博宣, 河合辰哉, 松元慎吾, 齋藤圭太, Kevin Camphausen, Murali C. Krishna, 稲波修
    第57回電子スピンサイエンス学会年会 2018年11月 ポスター発表
  • 新規ミトコンドリアストレス評価法を用いたがん細胞のミトコンドリア機能の解析  [通常講演]
    山本久美子, 安井博宣, 房知輝, 藤本政毅, 稲波修
    第57回電子スピンサイエンス学会年会 2018年11月 口頭発表(一般)
  • 学内ネットワークを用いた被ばく記録のメール配信の試み  [通常講演]
    野矢洋一, 阿保憲史, 東川桂, 安井博宣, 平田雄一, 久保直樹, 久下裕司
    平成30年度放射線安全取扱部会年次大会 2018年10月 ポスター発表 仙台銀行ホール イズミティ21 (仙台市, 宮城)
  • Longitudinal imaging of tumor oxygenation by pulsed ESR optimizes radiotherapy combined with a metabolic-targeted drug dichloroacetate in a murine squamous cell carcinoma model  [招待講演]
    Yasui H, Saito K, Matsumoto S, Yamamori T, Krishna M.C, Inanami O
    3th Joint Conference of Asia-Pacific EPR/ESR Symposium - International EPR/ESR Society Symposium 2018年09月 口頭発表(一般) the University of Queensland (Brisbane, Australia)
  • 非アルコール性脂肪肝炎の診断におけるチミジンホスホリラーゼイメージング剤の有用性の検討  [通常講演]
    堀口紗和子, 東川桂, 上原里穂, 足澤誠, 柴田悠貴, 大倉一枝, 安井博宣, 久下裕司, 武田宏司
    第2回日本核医学会分科会放射薬品科学研究会/第18回放射性医薬品・画像診断薬研究会 2018年09月 口頭発表(一般) 東京都健康長寿医療センター研究所 (板橋区,東京)
  • Promising methods for radiotherapy using molecular imaging and radioisotopes  [招待講演]
    安井 博宣
    Hokkaido Summer Institute 2018-Radiation Biology School 2018年08月 公開講演,セミナー,チュートリアル,講習,講義等
  • Feasibility and potentials of thymidine phosphorylase (TP) as an imaging biomarker and its nuclear medicine imaging for the diagnosis of non-alcoholic steatohepatitis.  [通常講演]
    Higashikawa K, Horiguchi S, Ebita Y, Tarisawa M, Komatsu Y, Ohkura K, Yasui H, Takeda H, Kuge Y
    2018年06月 ポスター発表 Pennsylvania Convention Center (Philadelphia, PA)
  • チミジンホスホリラーゼイメージングプローブによる非アルコール性脂肪肝炎の診断法の開発研究  [通常講演]
    東川桂, 堀口紗和子, 足澤誠, 小松由紀子, 大倉一枝, 安井博宣, 武田宏司, 久下裕司
    第13 回日本分子イメージング学会総会・学術集会 2018年05月 ポスター発表 東京大学 (文京区, 東京)
  • 低酸素標的PETプローブ[18F]DiFAの腫瘍内局在に対するグルタチオン環境の影響評価  [招待講演]
    安井博宣, 東川桂, 志水陽一, 松本博樹, 志賀哲, 玉木長良, 久下裕司
    第13 回日本分子イメージング学会総会・学術集会 2018年05月 口頭発表(一般) 東京大学 (文京区, 東京)
  • 放射線照射および脂溶性TPP+化合物ががん細胞のミトコンドリア機能に与える影響の評価  [通常講演]
    山本久美子, 安井博宣, 房知輝, 山盛徹, 平岡和佳子, 山崎俊栄, 山田健一, 稲波修
    第71 回日本酸化ストレス学会学術集会 / 第18 回日本NO学会 合同学術集会 2018年05月 ポスター発表 京都ホテルオークラ (京都市, 京都)
  • 放射線は内皮型一酸化窒素合成酵素の活性化により血管内皮細胞の老化を誘導する  [通常講演]
    永根大幹, 安井博宣, 山盛徹, 稲波修, 山下匡, クプサミー ペリアナン
    第71 回日本酸化ストレス学会学術集会 / 第18 回日本NO学会 合同学術集会 2018年05月 口頭発表(一般) 京都ホテルオークラ (京都市, 京都)
  • 新規ESRオキシメトリー法によるがん細胞のミトコンドリア電子伝達系の放射線応答の解析  [通常講演]
    山本久美子, 安井博宣, 房知輝, 山盛徹, 稲波修
    量子生命科学研究会第2回学術集会 2018年05月 口頭発表(一般) 東京大学 (文京区, 東京)
  • [18F]DiFA, a new hypoxic imaging PET probe: A first human study in healthy subjects  [通常講演]
    Watanabe S, Shiga T, Magota K, Hirata K, Okamoto S, Toyonaga T, Higashikawa K, Yasui H, Kobayashi J, Nishijima K.I, Iseki K, Matsumoto H, Kuge Y, Tamaki N
    WFNMB 2018 2018年04月 ポスター発表 the Melbourne Exhibition and Convention Centre (Melbourne, Australia)
  • Investigation of the influence of intratumoral glutathione status on the distribution of a hypoxic probe [18F]FMISO  [通常講演]
    Yasui H, Higashikawa K, Shimizu Y, Shibata Y, Zhao S, Matsumoto H, Shiga T, Tamaki N, Kuge Y
    WFNMB 2018 2018年04月 ポスター発表 the Melbourne Exhibition and Convention Centre (Melbourne, Australia)
  • フェロトーシス誘導剤Erastinによる放射線増感効果の検討  [通常講演]
    柴田悠貴, 安井博宣, 東川桂, 久下裕司
    日本薬学会第138年会 2018年03月 口頭発表(一般) 石川県立音楽堂 他 (金沢市, 石川)
  • [18F]FDG PETを用いたPD-1治療効果の早期予測に関するin vivoでの検討  [通常講演]
    安井 博宣富田真由, 高倉栄男, 安井博宣, 東川桂, 久下裕司, 小川美香子
    日本薬学会第138年会 2018年03月 口頭発表(一般) 石川県立音楽堂 他 (金沢市, 石川)
  • ミトコンドリア依存性エネルギー代謝の放射線応答と電子伝達系阻害による放射線増感  [通常講演]
    稲波修, 山本久美子, 房知輝, 山田健一, 安井博宣, 山盛徹
    第20回癌治療増感研究シンポジウム 2018年02月 口頭発表(一般) 奈良県文化会館 (奈良市, 奈良)
  • 電子スピン共鳴pO2イメージングによる脳室内移植グリオーマのキャラクタリゼーション  [通常講演]
    安井博宣, 河合辰哉, 松元慎吾, 齋藤圭太, Kevin Camphausen, 稲波修, Murali C. Krishna
    第20回癌治療増感研究シンポジウム 2018年02月 口頭発表(一般) 奈良県文化会館 (奈良市, 奈良)
  • Three-Dimensional In Vivo Measurements of Tumor Acidification by Electron Paramagnetic Resonance Imaging  [通常講演]
    Komarov D.A, Ichikawa Y, Stewart N, Yamamoto K, Matsumoto S, Yasui H, Kumiko Y, Inanami O, Hirata H
    第三回北大部局横断シンポジウム 2018年01月 口頭発表(一般) 北海道大学 (札幌市, 北海道)
  • ミトコンドリアイメージングによるフェロトーシス検出法の開発  [通常講演]
    柴田悠貴, 安井博宣, 東川桂, 久下裕司
    第三回北大部局横断シンポジウム 2018年01月 ポスター発表 北海道大学 (札幌市, 北海道)
  • Quantitative pO(2) Mapping Using Electron Paramagnetic Resonance Imaging in Orthotopic Murine Glioma  [通常講演]
    Yasui H, Kawai T, Matsumoto S, Saito K, Saito K, Devasahayam N, Mitchell J.B, Camphausen K, Inanami O, Krishna M
    The 20th Annual Meeting of the Society for Free Radical Biology and Medicine 2017年11月 ポスター発表
  • 窒素同位体標識ニトロキシルラジカルによる腫瘍モデルマウスの酸素分圧イメージング  [通常講演]
    久保田晴江, 安井博宣, 松元慎吾, 稲波修, Kirilyuk I.A, Khramtsov V.V, 平田拓
    第56回電子スピンサイエンス学会年会 2017年11月 ポスター発表
  • 癌の低酸素およびエネルギー代謝が放射線感受性に及ぼす影響に関する研究  [招待講演]
    安井博宣
    日本放射線影響学会第60回大会 奨励賞受賞講演 2017年10月 口頭発表(招待・特別)
  • 全学放射線管理システムの更新とeラーニングによる教育訓練の試み  [通常講演]
    野矢洋一, 阿保憲史, 東川桂, 安井博宣, 久下裕司
    平成29年度放射線安全取扱部会年次大会 2017年10月 ポスター発表
  • 放射性ヨウ素標識チミジンホスホリラーゼイメージング剤の非アルコール性脂肪肝炎診断用プローブとしての可能性の検討  [通常講演]
    東川桂, 堀口紗和子, 海老田曜子, 足澤誠, 小松由紀子, 大倉一枝, 安井博宣, 武田宏司, 久下裕司
    第57回日本核医学会学術総会 2017年10月 口頭発表(一般)
  • 腫瘍内グルタチオン環境が低酸素標的PETプローブ[18F]FMISOの分布に与える影響  [通常講演]
    安井博宣, 東川桂, 志水陽一, 趙松吉, 松本博樹, 玉木長良, 久下裕司
    第160 回日本獣医学会学術集会 2017年09月 口頭発表(一般)
  • 非アルコール性脂肪肝炎診断用プローブとしてのチミジンホスホリラーゼイメージング剤の可能性の検討  [通常講演]
    東川桂, 堀口紗和子, 海老田曜子, 足澤誠, 小松由紀子, 大倉一枝, 安井博宣, 武田 宏司, 久下裕司
    第1回放射性薬品科学研究会 2017年09月 口頭発表(一般)
  • マクロファージの極性化が18F-FMISOと125I-BMIPPの集積に及ぼす影響  [通常講演]
    本村新, 志水陽一, 高倉栄男, 安井博宣, 東川桂, 玉木長良, 久下裕司, 小川美香子
    第1回放射性薬品科学研究会 2017年09月 口頭発表(一般)
  • Application of electron spin resonance (ESR/EPR) pO2 and redox imaging to improve cancer radiotherapy  [招待講演]
    Yasui H
    2017 KSMI-FASMI Joint Conference 2017年08月 口頭発表(招待・特別)
  • Introduction to Radiation Biology  [招待講演]
    Yasui H
    GI-CoRE 医学物理サマースクール2017 2017年08月 公開講演,セミナー,チュートリアル,講習,講義等
  • Three-dimensional oxygen mapping using a pair of isotopic nitroxyl radicals and CW-EPR-based single-point imaging  [通常講演]
    Kubota H, Komarov D.A, Matsumoto S, Yasui H, Kumiko Y, Inanami O, Kirilyuk I.A, Khramtsov V.V, Hirata H
    International Conference on Electron Paramagnetic Resonance Spectroscopy and Imaging of Biological Systems (EPR-2017) 2017年07月 口頭発表(一般)
  • 転写調節因子Id1はp53依存的に放射線誘発細胞老化を抑制する  [通常講演]
    安井博宣, 竹内麻依, 山盛徹, 松本英樹, 高橋昭久, 稲波修
    第23回癌治療増感研究会 2017年07月 口頭発表(一般)
  • 全学放射線管理システムの更新とeラーニングによる教育訓練の試み  [通常講演]
    野矢洋一, 安井博宣, 阿保憲史, 久保直樹, 東川桂, 久下裕司
    日本放射線安全管理学会第16回学術大会 2017年06月 ポスター発表
  • ホットセルに格納可能な小型RIガス貯留装置の開発  [通常講演]
    阿保憲史, 野矢洋一, 東川桂, 安井博宣, 久下裕司
    日本放射線安全管理学会第16回学術大会 2017年06月 口頭発表(一般)
  • Accumulation mechanism of novel PET imaging probe “[18F]DiFA” in hypoxic cells revealed by imaging mass spectrometry.  [通常講演]
    Shimizu Y, Zhao S, Kishi R, Yasui H, Nishijima K, Matsumoto H, Tamaki N, Ogawa M, Kuge Y
    SNMMI 2017 Annual Meeting 2017年06月 口頭発表(一般)
  • Preclinical evaluation of [18F]DiFA, a novel PET probe for tumor hypoxia, in comparison with [18F]MISO.  [通常講演]
    Yasui H, Zhao S, Higashikawa K, Ukon N, Shimizu Y, Matsumoto H, Tamaki N, Kuge Y
    SNMMI 2017 Annual Meeting 2017年06月 ポスター発表
  • 18F -MISOとの比較による新規低酸素標的PETプローブ18F -DiFAの有用性評価  [招待講演]
    安井博宣, 趙松吉, 東川桂, 右近直之, 志水陽一, 松本博樹, 玉木長良, 久下裕司
    第12 回日本分子イメージング学会総会・学術集会 2017年05月 口頭発表(一般)
  • 新規低酸素標的PETプローブ18F -DiFAの有効性評価を目的とした腫瘍集積能および腫瘍内代謝物の解析  [通常講演]
    安井博宣, 志水陽一, 趙松吉, 東川桂, 右近直之, 岸伶美, 西嶋剣一, 松本博樹, 小川美香子, 玉木長良, 久下裕司
    第二回北大部局横断シンポジウム 2017年03月 ポスター発表
  • Noninvasive imaging of cycling hypoxia to improve cancer therapy  [招待講演]
    Yasui H
    CIS WORKSHOP 2017 2017年01月 シンポジウム・ワークショップパネル(指名)
  • ホットセルに格納可能な小型RIガス貯留装置の開発  [通常講演]
    阿保憲史, 野矢洋一, 東川桂, 安井博宣, 久下 裕司
    日本放射線安全管理学会第15回学術大会 2016年11月 口頭発表(一般) 岡山大学 (岡山市, 岡山)
  • “腫瘍内酸素イメージングのための同位体標識ニトロキシルラジカル混合溶液の特性評価  [通常講演]
    久保田晴江, 安井博宣, 松元慎吾, 稲波修, Kirilyuk I.A, Khramtsov V.V, 平田拓
    第55回電子スピンサイエンス学会年会 2016年11月 口頭発表(一般) 大阪市立大学 (大阪市, 大阪)
  • 親脂質性Tetraphenylphosphonium誘導体は放射線によるがん細胞の致死作用を増強する  [通常講演]
    稲波修, 安井博宣, 西村英里, 山本久美子, 鈴木基史, 酒井友里, 房知輝, 山盛徹, 山崎俊栄, 山田健一
    第55回電子スピンサイエンス学会年会 2016年11月 口頭発表(一般) 大阪市立大学 (大阪市, 大阪)
  • X線照射後のヒト子宮頸がん由来HeLa細胞におけるセミキノンラジカルおよびFe-SクラスターのESRによる評価  [通常講演]
    山本久美子, 池中良徳, 一瀬貴大, 石塚真由美, 安井博宣, 鵜飼光子, 山盛徹, 稲波修
    第55回電子スピンサイエンス学会年会 2016年11月 ポスター発表 大阪市立大学 (大阪市, 大阪)
  • HeLa細胞における放射線照射後のミトコンドリアのセミキノンラジカルとFe-Sクラスターの電子スピン共鳴法による評価  [通常講演]
    稲波修, 山本久美子, 房知輝, 酒井友里, 鈴木基史, 平岡和佳子, 安井博宣, 山盛徹
    日本放射線影響学会第59回大会 2016年10月 口頭発表(一般) JMSアステールプラザ (広島市, 広島)
  • がん細胞の放射線応答における転写調節因子Id1の役割  [通常講演]
    安井博宣, 竹内麻依, 山盛徹, 松本英樹, 高橋昭久, 稲波修
    日本放射線影響学会第59回大会 2016年10月 口頭発表(一般) JMSアステールプラザ (広島市, 広島)
  • Comparative assessment of hypoxic radiosensitizing properties of glycididazole and doranidazole in vitro and in vivo  [通常講演]
    Yasui H, Kubota N, Yamamori T, Inanami O
    62th Annual International Meeting Radiation Research Society 2016年10月 ポスター発表 Hilton Waikoloa Village (Waikoloa Village, HI)
  • CW-EPR-based oxygen mapping technique using a pair of isotopic nitroxyl radicals  [通常講演]
    Kubota H, Komarov D.A, Yasui H, Matsumoto S, Inanami O, Kirilyuk I.A, Khramtsov V.V, Hirata H
    10th International Workshop on EPR in Biology and Medicine 2016年10月 口頭発表(一般) International Cultural Centre (Krakow, Poland)
  • 新規低酸素イメージング剤“18F-DiFA”の腫瘍集積能・腫瘍内代謝物評価  [通常講演]
    志水陽一, 趙松吉, 岸伶美, 安井博宣, 西嶋剣一, 松本博樹, 玉木長良, 小川美香子, 久下裕司
    第16回放射性医薬品・画像診断薬研究会 2016年10月 口頭発表(一般) みやこめっせ (京都市,京都)
  • 新規低酸素標的PETプローブ18F -DiFAの有効性評価のための18F -MISOとの比較検討  [通常講演]
    安井博宣, 趙松吉, 東川桂, 右近直之, 志水陽一, 松本博樹, 玉木長良, 久下裕司
    第16回放射性医薬品・画像診断薬研究会 2016年10月 口頭発表(一般) みやこめっせ (京都市,京都)
  • X線照射したヒト子宮頸がん由来HeLa細胞におけるミトコンドリア機能を中心としたエネルギー代謝応答の解析  [通常講演]
    山本久美子, 池中良徳, 一瀬貴大, 石塚真由美, 安井博宣, 鵜飼光子, 山盛徹, 稲波修
    第159 回日本獣医学会学術集会 2016年09月 口頭発表(一般) 日本大学 (藤沢市, 神奈川)
  • ヒト子宮頸部がんHeLa細胞における放射線照射後のミトコンドリア応答  [通常講演]
    山本久美子, 池中良徳, 一瀬貴大, 安井博宣, 鵜飼光子, 山盛徹, 稲波修
    第69 回日本酸化ストレス学会学術集会 2016年08月 ポスター発表 仙台国際センター (仙台市, 宮城)
  • Development of a CW-EPR-based oxygen-mapping technique using a pair of isotopic nitroxyl radicals  [通常講演]
    Hirata H, Kubota H, Yasui H, Matsumoto S, Inanami O, Kirilyuk I.A, Khramtsov V.V
    Asia-Pacific EPR/ESR Symposium 2016 2016年08月 口頭発表(一般) Mayak Hotel (Irkutsk, Russia)
  • FMISO PETイメージングによるeribulinの腫瘍内低酸素状態解除作用の実証―小動物用PETと乳癌モデルを用いた検討―  [通常講演]
    趙松吉, 于聞文, 右近直之, 西嶋剣一, 志水陽一, 東川桂, 安井博宣, 山下啓子, 玉木長良, 久下裕司
    第12回小動物インビボイメージング研究会 2016年07月 口頭発表(一般) 福島県立医科大学 (福島市,福島)
  • Characteristics of 14N- and 15N-labeled dicarboxy-PROXYLs as oxygen-sensitive probes for CW-EPR-based single-point imaging (SPI)  [通常講演]
    Kubota H, Yasui H, Matsumoto S, Inanami O, Kirilyuk I.A, Khramtsov V.V, Hirata H
    58th Annual Rocky Mountain Conference on Magnetic Resonance (39th International EPR Symposium) 2016年07月 口頭発表(一般) Beaver Run Resort & Conference Center (Breckenridge, CO)
  • Feasibility study of a CW-EPR-based oxygen mapping technique using a pair of isotopic nitroxyl radicals  [通常講演]
    Hirata H, Kubota H, Yasui H, Matsumoto S, Inanami O, Kirilyuk I.A, Khramtsov V.V
    58th Annual Rocky Mountain Conference on Magnetic Resonance (39th International EPR Symposium) 2016年07月 口頭発表(一般) Beaver Run Resort & Conference Center (Breckenridge, CO)
  • ヒト子宮頸部がんHeLa細胞における放射線照射後のエネルギー産生とその意義  [通常講演]
    稲波修, 山本久美子, 西村英里, 房知輝, 酒井友里, 鈴木基史, 池中良徳, 一瀬貴大, 石塚真由美, 安井博宣, 鵜飼光子, 山田健一, 山崎俊栄, 山盛徹
    第54回日本放射線腫瘍学会生物部会学術大会 2016年07月 口頭発表(一般) I-site なんば (大阪市,大阪)
  • X線照射後のミトコンドリア形態変化が細胞の放射線応答に与える役割  [通常講演]
    山盛徹, 池悟志, 房知輝, 市居修, 笹川朋哉, 安井博宣, 稲波修
    第二回北大部局横断シンポジウム 2016年03月 ポスター発表 北海道大学 (札幌市, 北海道)
  • 電子スピン共鳴イメージングによるがん代謝標的薬剤と放射線併用治療の最適化  [通常講演]
    安井博宣, 齋藤圭太, 松元慎吾, 山盛徹, Krishna MC, 稲波修
    第二回北大部局横断シンポジウム 2016年03月 ポスター発表 北海道大学 (札幌市, 北海道)
  • がん治療のための新規放射線増感剤の開発  [通常講演]
    稲波修, 安井博宣, 山盛徹, 山田健一, 白土博樹, 松田彰
    第二回北大部局横断シンポジウム 2016年03月 ポスター発表 北海道大学 (札幌市, 北海道)
  • EPR imaging (pO2)  [招待講演]
    安井博宣
    第6回放射線生物学セミナー 2016年02月 公開講演,セミナー,チュートリアル,講習,講義等 名古屋市立大学 (名古屋市, 愛知)
  • 非侵襲イメージングに基づくin vivo微小環境を標的とした放射線増感治療の可能性  [招待講演]
    安井博宣, 齋藤圭太, 松元慎吾, 山盛徹, Krishna MC, 稲波修
    第18回癌治療増感研究シンポジウム 2016年02月 シンポジウム・ワークショップパネル(指名) 奈良県文化会館 (奈良市, 奈良)
  • Application of electron spin resonance (ESR) pO2 imaging to improve tumor radiotherapy  [招待講演]
    Yasui H, Krishna M.C, Inanami O
    18th Seoul National University-Hokkaido University Joint Symposium 2015年11月 口頭発表(一般) Seoul University (Seoul, Korea)
  • ESR based imaging biomarkers to guide treatment in tumor bearing mice  [通常講演]
    Matsumoto S, Saito K, Kishimoto Shun, Takakusagi Y, Yasui H, Matsuo M, Krishna M.C
    第54回電子スピンサイエンス学会年会 2015年11月 口頭発表(一般) 朱鷺メッセ (新潟市, 新潟)
  • 酸素感受性同位体ニトロキシルラジカルの特性評価実験  [通常講演]
    久保田晴江, 安井博宣, 松元慎吾, 三宅祐輔, 稲波修, Kirilyuk I.A, Khramtsov V.V, 平田拓
    第54回電子スピンサイエンス学会年会 2015年11月 ポスター発表 朱鷺メッセ (新潟市, 新潟)
  • 電子スピン共鳴法を用いたがんの生理機能と放射線応答機構の解明に向けた研究  [招待講演]
    安井博宣
    第54回電子スピンサイエンス学会年会 2015年11月 口頭発表(招待・特別) 朱鷺メッセ (新潟市, 新潟)
  • X線照射したがん細胞のESRオキシメトリーを用いた酸素消費率を指標としたミトコンドリア機能の解析  [通常講演]
    山本久美子, 安井博宣, 山盛徹, 中村秀夫, 鵜飼光子, 稲波修
    第54回電子スピンサイエンス学会年会 2015年11月 ポスター発表 朱鷺メッセ (新潟市, 新潟)
  • 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl) cytosine (ECyd)併用による陽子線増感治療の実現に向けた基礎研究  [通常講演]
    前田憲一郎, 安井博宣, 山盛徹, 松浦妙子, 高尾聖心, 鈴木基史, 松田彰, 稲波修, 白土博樹
    第1回放射線ワークショップ 2015年10月 口頭発表(一般) 富山大学 (富山市, 富山)
  • ミトコンドリア指向性化合物における分子骨格と放射線増感作用との相関性に関する研究  [通常講演]
    安井博宣, 西村英里, 山盛徹, 山本久美子, 山崎俊栄, 山田健一, 稲波修
    第1回放射線ワークショップ 2015年10月 口頭発表(一般) 富山大学 (富山市, 富山)
  • 転写調節因子Id1ノックダウンが放射線感受性に与える影響とそのメカニズムの解明  [通常講演]
    竹内麻依, 安井博宣, 鈴木基史, 酒井友里, 山盛徹, 稲波修
    第158回日本獣医学会学術総会 2015年09月 口頭発表(一般) 北里大学 (十和田市, 青森)
  • 放射線照射後のミトコンドリア分裂におけるDrp1リン酸化の意義  [通常講演]
    房知輝, 山盛徹, 池悟志, 鈴木基史, 酒井友里, 安井博宣, 稲波修
    第158回日本獣医学会学術総会 2015年09月 口頭発表(一般) 北里大学 (十和田市, 青森)
  • MPS1を介したスピンドル形成チェックポイントが哺乳動物細胞の放射線/化学療法剤感受性に与える影響の解析  [通常講演]
    鈴木基史, 山盛徹, 安井博宣, 稲波修
    第158回日本獣医学会学術総会 2015年09月 口頭発表(一般) 北里大学 (十和田市, 青森)
  • がん代謝標的薬剤ジクロロ酢酸処理後の腫瘍内酸素環境の経時的解析と放射線併用プロトコールの最適化  [通常講演]
    安井博宣, 齋藤圭太, 西田直哉, 松元慎吾, 山盛徹, Murali C. Krishna, 稲波修
    若手放射線生物学研究会2015年度専門研究会 2015年08月 口頭発表(一般) 東京医科歯科大学 (文京区, 東京)
  • 酸素バイオロジーと磁気共鳴  [招待講演]
    安井博宣
    第13回ESR夏の学校 2015年07月 公開講演,セミナー,チュートリアル,講習,講義等 温泉旅館「千鶴」 (湯河原町, 神奈川県)
  • 親脂質性triphenylphosphonium(TPP)化合物によるがん細胞における放射線増感作用  [通常講演]
    稲波修, 安井博宣, 西村英里, 永根大幹, 笹川朋哉, 山盛徹, 山崎俊栄, 山田健一
    第68 回日本酸化ストレス学会学術集会 2015年06月 口頭発表(一般) かごしま県民交流センター (鹿児島市, 鹿児島)
  • The Relationship between Radiation-induced Cell Cycle Arrest and Reactive Oxygen Species Production from Mitochondria  [通常講演]
    Yamamori T, Yasui H, Inanami O
    15th International Congress of Radiation Research 2015年05月 シンポジウム・ワークショップパネル(指名) Kyoto International Conference Center (Kyoto)
  • Inhibition of The Mitochondrial Fission Protein Dynamin-related Protein 1 Impairs Mitotic Catastrophe After X-irradiation  [通常講演]
    Yamamori T, Ike S, Bo T, Sasagawa T, Suzuki M, Sakai Y, Yasui H, Inanami O
    15th International Congress of Radiation Research 2015年05月 ポスター発表 Kyoto International Conference Center (Kyoto)
  • Drp1 Phosphorylation at Ser616 but Not Ser637 Is Required for Radiation-Induced Mitochondrial Fission  [通常講演]
    Bo T, Yamamori T, Ike S, Suzuki M, Yasui H, Inanami O
    15th International Congress of Radiation Research 2015年05月 ポスター発表 Kyoto International Conference Center (Kyoto)
  • A Feasibility Study for the Establishment of Proton Therapy Combined with 1-(3-C-Ethynyl-β-D-ribo-pentofuranosyl) Cytosine (ECyd)  [通常講演]
    Maeda K, Yasui H, Matsuura T, Yamamori T, Takao S, Suzuki M, Matsuda A, Inanami O, Shirato H
    15th International Congress of Radiation Research 2015年05月 ポスター発表 Kyoto International Conference Center (Kyoto)
  • MPS1 Inhibitors Enhance Chemosensitivity to Etoposide and Paclitaxel but Not Radiosensitivity in Murine SCCVII Cells  [通常講演]
    Suzuki M, Yamamori T, Yasui H, Inanami O
    15th International Congress of Radiation Research 2015年05月 ポスター発表 Kyoto International Conference Center (Kyoto)
  • Radiosensitizing Effect by Mitochondria-targeted Nitroxides in Tumor Cells  [通常講演]
    Inanami O, Yasui H, Nishimura E, Nagane M, Sasagawa T, Yamamori T, Yamasaki T, Yamada K
    15th International Congress of Radiation Research 2015年05月 ポスター発表 Kyoto International Conference Center (Kyoto)
  • The Effect of Intermittent Hypoxia on the Cellular Sensitivities to X-irradiation and to Boron Neutron Capture Reaction in Rat Glioma Cells  [通常講演]
    安井 博宣Yasui H, Nagane M, Yamamori T, Hirayama R, Kondo N, Masunaga SI, Inanami O
    15th International Congress of Radiation Research 2015年05月 ポスター発表 Kyoto International Conference Center (Kyoto)
  • ミトコンドリア指向性ニトロキシドにおける分子骨格と放射線増感作用との相関性に関する研究  [通常講演]
    安井博宣, 西村英里, 永根大幹, 笹川朋哉, 山盛徹, 山崎俊栄, 山田健一, 稲波修
    第17回癌治療増感研究シンポジウム 2015年02月 口頭発表(一般) 奈良県文化会館 (奈良市, 奈良)

その他活動・業績

  • Hironobu Yasui, Shingo Matsumoto, Osamu Inanami, Murali Cherukuri Krishna Igaku butsuri : Nihon Igaku Butsuri Gakkai kikanshi = Japanese journal of medical physics : an official journal of Japan Society of Medical Physics 40 (1) 13 -18 2020年 [査読無し][通常論文]
     
    Hypoxia has been known to be a feature associated with tumor radioresistance. So far, clinical strategies to overcome chronic hypoxia due to the limitation of the oxygen diffusion have been designed. However, intermittent or acute/cycling hypoxia, whose frequency can range between a few cycles per minutes to hours, is receiving increased attention, because this type of hypoxia has been reported to have an influence on tumor malignancy as well as treatment resistance via increased expression of pro-survival pathways. Therefore, a priori information on fluctuating hypoxia can be important in clinical treatment planning, but complicated dynamics makes it difficult to elucidate biological significance of intermittent hypoxia.Here, we illustrate the use of pulsed electron spin resonance imaging (ESRI) as a novel imaging method to directly monitor fluctuating oxygenation i.e. cycling hypoxia in transplanted tumors. A common resonator platform for both ESRI and magnetic resonance imaging (MRI) provided pO2 maps with anatomical guidance without positional movement. Oxygen images every 3 min in pO2 could visualize the rapid oxygen fluctuation and distinguish the cycling hypoxia and chronic hypoxia. Furthermore, we have examined the vascular renormalization process by longitudinally pO2 mapping during treatments with a multi-tyrosine kinase inhibitor sunitinib. Transient improvement in tumor oxygenation and the decrease of cycling tumor hypoxia were visualized by ESRI 2 to 4 days following antiangiogenic treatments. Radiation treatment during this time period of improved oxygenation by antiangiogenic therapy resulted in a synergistic delay in tumor growth.In conclusion, this ESRI technique combined with MRI, may offer a powerful clinical tool to noninvasively detect variable hypoxic status in tumors and to identify a window of vascular renormalization to maximize the effects of combination therapy with antiangiogenic drugs.
  • 光免疫療法による腫瘍環境の変化に関する[18F]FDG と[18F]FMISO を用いた検討
    中島孝平, 杉川晃代, 安井 博宣, 東川桂, 高倉栄男, 志賀哲, 久下裕司, 小川美香子 日本分子イメージング学会誌 JSMI Report 13 (1) 17 -22 2020年01月 [査読有り][招待有り]
  • Osamu Inanami, Kumiko Yamamoto, Tomoki Bo, Tohru Yamamori, Hironobu Yasui, Wakako Hiraoka FREE RADICAL BIOLOGY AND MEDICINE 120 S137 -S137 2018年05月 [査読無し][通常論文]
  • Hironobu Yasui, Tatsuya Kawai, Shingo Matsumoto, Keita Saito, Nallathamby Devasahayam, James B. Mitchell, Kevin Camphausen, Osamu Inanami, Murali C. Krishna FREE RADICAL BIOLOGY AND MEDICINE 112 106 -106 2017年11月 [査読無し][通常論文]
  • 阿保 憲史, 野矢 洋一, 東川 桂, 安井 博宣, 久下 裕司 日本放射線安全管理学会誌 16 (2) 85 -90 2017年11月 [査読無し][通常論文]
  • 放射線照射後の血管内皮細胞における一酸化窒素産生の亢進は固形腫瘍を再酸素化する
    永根大幹, 安井博宣, 山盛徹, Periannan Kuppusamy, 稲波修 放射線生物研究 52 (2) 173 -182 2017年07月 [査読有り][通常論文]
  • Yoichi Shimizu, Songji Zhao, Reimi Kishi, Hironobu Yasui, Ken-ichi Nishijima, Hiroki Matsumoto, Nagara Tamaki, Mikako Ogawa, Yuji Kuge JOURNAL OF NUCLEAR MEDICINE 58 2017年05月 [査読無し][通常論文]
  • Hironobu Yasui, Songji Zhao, Kei Higashikawa, Naoyuki Ukon, Yoichi Shimizu, Hiroki Matsumoto, Nagara Tamaki, Yuji Kuge JOURNAL OF NUCLEAR MEDICINE 58 2017年05月 [査読無し][通常論文]
  • 安井 博宣, 戒田 篤志, 兵藤 文紀, 三浦 大典, 久下 裕司, 松本 孔貴 放射線生物研究 49 (3) 263 -283 2014年09月 [査読有り][通常論文]
     
    がんの放射線感受性を規定する因子は細胞周期、低酸素、エネルギー代謝、レドックスなど多岐に渡っている上に、腫瘍組織内の不均一性がその理解を一層難しいものとしている。がん微小環境と呼ばれるこの特性はがんの進行や治療応答に対し刻々と変化するため、既存の病理固定組織によるスナップショット的な空間情報では統合的に捉え難い。しかしながら、近年の工学、薬学ならびに遺伝子工学領域の発展により、非侵襲的な生体機能の画像化を高分解能で行うことが可能となってきている。さらにや上記に述べた放射線感受性因子の各々に特化した経時的解析も確立されつつあり、新たながん治療開発への道標になりうるものと期待される。本稿では、電子スピンや核スピンに対する磁気共鳴イメージング法、in situ質量分析イメージング法、リアルタイム細胞周期蛍光イメージング法ならびに核医学イメージング法といった先進的画像化技術について概説し、これら手法を用いた複雑ながん微小環境の解明と放射線治療戦略の近未来の展望について考察する。(著者抄録)
  • Masaki Nagane, Hironobu Yasui, Tohru Yamamori, Yuri Sakai, Koichi Niwa, Osamu Inanami FREE RADICAL BIOLOGY AND MEDICINE 65 S102 -S102 2013年11月 [査読無し][通常論文]
  • Hironobu Yasui, Keita Saito, Naoya Nishida, Shingo Matsumoto, Tohru Yamamori, Murali Cherukuri Krishna, Osamu Inanami FREE RADICAL BIOLOGY AND MEDICINE 65 S26 -S26 2013年11月 [査読無し][通常論文]
  • Masaki Nagane, Hironobu Yasui, Tohru Yamamori, Songji Zhao, Yuji Kuge, Nagara Tamaki, Hiromi Kameya, Hideo Nakamura, Osamu Inanami FREE RADICAL BIOLOGY AND MEDICINE 53 S48 -S48 2012年11月 [査読無し][通常論文]
  • T. Yamamori, H. Yasui, M. Yamazumi, Y. Wada, H. Nakamura, O. Inanami FREE RADICAL BIOLOGY AND MEDICINE 53 S65 -S65 2012年09月 [査読無し][通常論文]
  • X線照射後のがん細胞におけるESRオキシメトリーによる酸素消費率を指標としたミトコンドリア機能解析
    安井博宣 電子スピンサイエンス 16 42 -43 2011年03月 [査読無し][招待有り]
  • 低酸素環境を標的としたがん治療の新たな展開
    安井博宣, 山盛徹, 女池俊介, 永瀧正人, 飯塚大輔, 桑原幹典, 稲波修 放射線生物研究 45 (1) 45 -57 2010年 [査読無し][通常論文]
  • Aki Ogura, Daisuke Iizuka, Hironobu Yasui, Mikinori Kuwabara, Osamu Inami FREE RADICAL BIOLOGY AND MEDICINE 43 S131 -S131 2007年 [査読無し][通常論文]
  • G2期チェックポイント阻害による放射線誘導細胞致死効果のメカニズム
    飯塚大輔, 稲波修, 安井博宣, 小倉亜希, 桑原幹典 放射線生物研究 42 (4) 444 -455 2007年 [査読無し][通常論文]
  • 桑原 幹典, 稲波 修, 安井 博宣, 飯塚 大輔, 松田 彰 癌の臨床 52 (1) 31 -36 2006年04月 [査読無し][通常論文]
     
    ヒトおよびマウスの腫瘍細胞を用い,X線致死効率がこのエチニルシチジン(ECyd)との併用によりそれぞれ単独処理の和に比べて上昇するか否かを培養細胞および移植固形腫瘍で検討した.全ての細胞でX線照射のみではほとんどアポトーシスは誘導されなかった.X線とECydを併用した場合,それぞれ単独の和に比べて大きくアポトーシスが誘導された.ECydによるアポトーシス増感がそのまま線量効果曲線での増感に繋がることが判明した.シチジン添加によりECydのアポトーシス増感が消失することから,ウリジン/シチジン2によるECydのリン酸化がこの化合物の活性化の必要条件であった.マウスの固形移植腫瘍においても腫瘍組織内の増殖性細胞数の低下とアポトーシス細胞数の増加を観察した
  • Daisuke Iizuka, Osamu Inanami, Hironobu Yasui, Mikinori Kuwabara FREE RADICAL BIOLOGY AND MEDICINE 41 S159 -S159 2006年 [査読無し][通常論文]
  • Aki Ogura, Osamu Inanami, Daisuke Iizuka, Hironobu Yasui, Mikinori Kuwabara FREE RADICAL BIOLOGY AND MEDICINE 41 S159 -S159 2006年 [査読無し][通常論文]
  • Hironobu Yasui, Taketoshi Asanuma, Osamu Inanami, Gregory Durand, Ange Polidori, Yasuhiro Kon, Bernard Pucci, Mikinori Kuwabara FREE RADICAL BIOLOGY AND MEDICINE 41 S77 -S77 2006年 [査読無し][通常論文]

特許

  • 特開2016- 216404:陽子線治療用増感剤および陽子線治療方法  
    稲波修, 白土博樹, 松田彰, 山盛徹, 安井博宣, 前田憲一郎

受賞

  • 2017年10月 日本放射線影響学会 日本放射線影響学会奨励賞
     
    受賞者: 安井 博宣
  • 2015年11月 電子スピンサイエンス学会 電子スピンサイエンス学会奨励賞
     
    受賞者: 安井 博宣
  • 2015年09月 日本放射線影響学会 放射線ワークショップ優秀発表賞
     
    受賞者: 安井 博宣
  • 2014年03月 Informa Healthcare Young Investigator Award 2014
     
    受賞者: 安井 博宣
  • 2012年02月 19th JSPS Core-to-Core Seminar Winter School Young Investigator Award
     
    受賞者: 安井 博宣
  • 2010年11月 第49回電子スピンサイエンス学会年会若手優秀発表賞

共同研究・競争的資金等の研究課題

  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 2019年 -2021年 
    代表者 : 安井 博宣
  • 文部科学省:科学研究費補助金(挑戦的研究(萌芽))
    研究期間 : 2019年 -2020年 
    代表者 : 安井 博宣
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2018年 -2020年 
    代表者 : 松浦妙子
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 2018年 -2020年 
    代表者 : 志賀哲
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 2017年 -2019年 
    代表者 : 稲波修
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2017年 -2019年 
    代表者 : 岡本祥三
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2015年 -2017年 
    代表者 : 安井 博宣
  • 文部科学省:科学研究費補助金(基盤研究(A))
    研究期間 : 2014年 -2017年 
    代表者 : 平田 拓
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2014年 -2016年 
    代表者 : 山盛徹
  • 文部科学省:科学研究費補助金(若手研究(B))
    研究期間 : 2013年 -2014年 
    代表者 : 安井 博宣
  • 文部科学省:科学研究費補助金(挑戦的萌芽研究)
    研究期間 : 2012年 -2013年 
    代表者 : 稲波 修, 山盛 徹, 安井 博宣
     
    悪性脳腫瘍は依然として根治困難な疾患であり、その予後に低酸素領域が関与していることが分かっている。一方、低酸素状態には従来から良く知られている慢性低酸素に加え、短時間で変化する間欠的な低酸素が存在し、より浸潤転移などの腫瘍の悪性形質獲得に影響を与えることが分かってきた。本課題の目的は、「低酸素領域の量ではなく変動度合い(間欠的低酸素)がグリオーマの治療予後に大きく関わっている」と仮説を立て、これを検証することである。24年度では、C6ラットグリオーマモデルを樹立し、18F-FMISOを間隔をあけて投与することで低酸素領域の変化を描出するSequential PET撮像を試みた。microPET装置を使用することによって、18F-FMISOの低酸素領域への集積をPET画像として画像化することに成功した。しかし、このsequential PET法では、PETの解像度で認識できる領域の変化を認めることはできなかった。次に低酸素ダイナミクスを標的とした治療法の開発に向けて、まず新規低酸素細胞標的放射線増感剤ドラニダゾールのC6ラット悪性脳腫瘍モデルに対する抗腫瘍効果を検討した。その結果、ドラニダゾールがC6ラットグリオーマの血液脳関門の破綻を介して脳腫瘍内に到達すること、またX線照射との組み合わせにより、効果的な抗腫瘍効果の増感が得られることを明らかにした。以上、これまでの実験により、低酸素ダイナミクスを追跡することは依然難しいが、microPET-CTを用いることで、ラットグリオーマ内の低酸素領域を描出することに成功し、この領域に効果的に作用する制がん剤の薬効評価を行うことが可能となった。
  • 文部科学省:科学研究費補助金(若手研究(B))
    研究期間 : 2011年 -2012年 
    代表者 : 安井 博宣
     
    これまで一般的に治療抵抗性に関わっているとされる腫瘍内低酸素は、慢性的な低酸素であったが、近年、未成熟な血管が原因で起こる血流の鬱滞や閉塞による短時間で変動する間欠的な低酸素領域が存在することが明らかとなってきた。本課題の目的は、間欠的低酸素が腫瘍細胞の放射線抵抗性に及ぼす影響とその機構についてin vitroおよびin vivoの両面から明らかにすることである。 23年度では、低酸素の長さ、頻度ならびに回数を精査することで、最も細胞の放射線抵抗性を増強する条件を検討した。その結果、1時間の低酸素と30分の再酸素化を6回繰り返すことで最も放射線照射後の生存率は向上し、良い再現性も得られた。また間欠的低酸素に特徴的な現象として、再酸素化に伴う活性酸素種(ROS)生成が考えられるため、各サイクルで回収した細胞におけるROS産生量をその特異的プローブである2,7-dichlorodihydro flurescein diacetateにより定量した。その結果、再酸素化の曝露回数が増える毎に、細胞内ROS量の増加が観察された。このROS産生の上昇によって抗酸化関連因子の活性化が起こっている可能性が考えられたため、細胞内のスーパーオキシドジスムターゼ(SOD)の活性を検討した。間欠的低酸素に曝された細胞でSODの活性が上昇している傾向が明らかとなった。これまでの実験により、間欠的低酸素による放射線感受性制御機構を明らかにする上で重要なin vitroでの実験条件が整備され、ROSの産生とそれに伴う細胞内レドックス状態の変化が起こっていることが示唆された。

教育活動情報

主要な担当授業

  • 医学総論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 医理工連携放射線防護学
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 放射線防護、国際的基準、国内法令、被ばく線量、リスク、安全取扱 Radiation Protection, International Standard, National Law, Exposed Dose, Risk, Safe Handling
  • 獣医科学基礎科目 環境獣医科学特論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学院
  • 基本医学総論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : トレーサー(分子プローブ)・生体機能/病態分析・マイクロドージング Tracer(Molecular Probe)/Patho-Functional Bioanalysis/Micro-dosing
  • 放射線生物学
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 放射線生物学、癌浸潤、細胞外微小環境、細胞表面受容体、低酸素 Radiation biology, Cancer invasion, Microenvironment, Cell surface receptor, Hypoxia
  • 医学総論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : トレーサー(分子プローブ)・生体機能/病態分析・マイクロドージング Tracer(Molecular Probe)/Patho-Functional Bioanalysis/Micro-dosing
  • 放射線生物学演習
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 獣医学部
    キーワード : 放射線生物学、放射線の生物影響、放射線計測
  • 健康と社会
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 全学教育
    キーワード : アイソトープ・放射線の基礎, 社会生活に密接にかかわるアイソトープ・放射線, 先端医療におけるアイソトープ・放射線の利用,
  • 家畜管理学
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 獣医学部
    キーワード : 家畜の環境,飼養管理,家畜の行動,乳牛,泌乳

大学運営

委員歴

  • 2020年06月 - 現在   日本放射線影響学会   学術評議員
  • 2020年04月 - 現在   日本アイソトープ協会   放射線安全取扱部会 企画専門委員
  • 2018年06月 - 現在   泊発電所環境保全監視協議会委員
  • 2015年04月 - 現在   電子スピンサイエンス学会   電子スピンサイエンス編集委員
  • 2017年01月 - 2017年12月   若手放射線生物学研究会   運営委員
  • 2015年01月 - 2016年12月   若手放射線生物学研究会   副運営委員
  • 2013年01月 - 2013年12月   若手放射線生物学研究会   運営委員

学術貢献活動

  • NISTEP専門調査員
    期間 : 2020年04月01日 - 現在
    役割 : 学術調査立案・実施
    種別 : 学術調査
    主催者・責任者 : 科学技術予測センター


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