研究者データベース

尾崎 倫孝(オザキ ミチタカ)
保健科学研究院 保健科学部門 基盤看護学分野
教授

基本情報

所属

  • 保健科学研究院 保健科学部門 基盤看護学分野

職名

  • 教授

学位

  • 医学博士

ホームページURL

J-Global ID

研究キーワード

  • 生体イメージング   酸化ストレス   細胞死   肝傷害   肝再生   redox regulation   signal transduction   organ transplantation   liver regeneration   

研究分野

  • ライフサイエンス / 外科学一般、小児外科学 / 肝臓病態生理

職歴

  • 2016年 北海道大学大学院 保健科学研究院 生体応答制御医学分野 教授(兼任)
  • 2013年 北海道大学大学院 保健科学研究院 健康イノベーションセンター 生体分子・機能イメージング部門 教授(兼任)
  • 2007年 - 2012年 北海道大学 医学部大学院医学研究科 分子制御外科学講座 特任教授
  • 2012年 北海道大学大学院 保健科学研究院 教授
  • 2004年 - 2007年 北海道大学 医学部大学院医学研究科 置換外科・再生医学講座 助教授
  • 2003年 - 2004年 岡山大学大学院 医歯学総合研究科 食品健康科学講座 助教授
  • 1999年 - 2003年 国立成育医療センター研究所 移植・外科研究部 実験外科研究室 主任研究員
  • 1998年 - 1999年 米国 ジョンズ・ホプキンズ大学 医学部心臓病外科学講座 博士研究員
  • 1993年 - 1999年 東京女子医科大学 腎臓病総合医療センター第三外科 助手
  • 1997年 - 1998年 米国 ジョンズ・ホプキンズ大学 医学部移植外科 博士研究員
  • 1996年 - 1997年 南大和病院 外科 副院長
  • 1995年 - 1996年 南大和病院 外科 外科部長
  • 1991年 - 1993年 東京女子医科大学 腎臓病総合医療センター第三外科 研究生
  • 1989年 - 1991年 山口南陽病院 外科 外科医長
  • 1987年 - 1989年 倉敷第一病院 外科 研修医
  • 1984年 - 1989年 岡山大学 医学部第二外科学教室 一般外科・呼吸器外科 臨床研修医

学歴

  • 1984年 - 1988年   岡山大学大学院博士課程
  • 1978年 - 1984年   岡山大学   医学部   医学科
  • 1975年 - 1978年   岡山県立岡山操山高等学校

所属学協会

  • 米国遺伝子治療学会   日本透析療法学会   日本肝臓学会   会員:日本外科学会   評議員:日本移植学会   日本再生医療学会   企画委員:細胞情報伝達系北海道研究会   米国移植学会   日本生化学会   国際移植学会   米国移植学会:Awards委員会   日本臓器保存生物医学会   日本遺伝子治療学会   American Transplant Society) 2005-2007年度   

研究活動情報

論文

  • 尾崎 倫孝
    Seminars in Cell and Developmental Biology 100 62 - 73 2020年04月 [査読有り][招待有り]
  • Extracts of bilberry (Vaccinium myrtillus L.) fruits improve liver steatosis and injury in mice by preventing lipid accumulation and cell death.
    尾崎 倫孝
    Bioscience, Biotechnology, and Biochemistry 83 11 2110 - 2120 2019年06月 [査読有り][通常論文]
  • Activation of caspase-3 during Chlamydia trachomatis-induced apoptosis at a late stage.
    尾崎 倫孝
    Canadian Journal of Microbiology 65 135 - 143 2019年01月 [査読有り][通常論文]
  • Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe-Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding.
    尾崎 倫孝
    Oncology Research 26 11 503 - 513 2018年 [査読有り][通常論文]
  • Photo-Activatable Akt Probe: A New Tool to Study the Akt-Dependent Physiopathology of Cancer Cells.
    尾崎 倫孝
    Oncology Research 26 6 467 - 472 2018年 [査読有り][通常論文]
  • Mika Watanabe, Ken Natsuga, Wataru Nishie, Yasuaki Kobayashi, Giacomo Donati, Shotaro Suzuki, Yu Fujimura, Tadasuke Tsukiyama, Hideyuki Ujiie, Satoru Shinkuma, Hideki Nakamura, Masamoto Murakami, Michitaka Ozaki, Masaharu Nagayama, Fiona M. Watt, Hiroshi Shimizu
    ELIFE 6 2017年07月 [査読有り][通常論文]
     
    Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
  • Michitaka Ozaki, Sanae Haga, Takeaki Ozawa, Naoki Morita, Toshiyuki Hamada
    Organ Biology 24 2 87 - 91 2017年 [査読有り][通常論文]
  • Sanae Haga, Yimin, Michitaka Ozaki
    BMC GASTROENTEROLOGY 17 1 9  2017年01月 [査読有り][通常論文]
     
    Background: Liver injury and regeneration involve complicated processes and are affected by various physiopathological conditions. Surgically, severe liver injury after surgical resection often leads to fatal liver failure, especially with some underlying pathological conditions such as steatosis. Therefore, protection from the injury of hepatocytes and liver is a serious concern in various clinical settings. Methods: We studied the effects of the farnesoid X receptor (FXR) on cell survival and steatosis in mouse hepatocytes (AML12 mouse liver cells) and investigated their molecular mechanisms. We next studied whether or not FXR improves liver injury, regeneration and steatosis in a mouse model of partial hepatectomy (PH) with steatosis. Results: An FXR-specific agonist, GW4064, induced expressions of the p62/SQSTM1 gene and protein in AML12 mouse liver cells. Because we previously reported p62/SQSTM1 as a key molecule for antioxidation and cell survival in hepatocytes, we next examined the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and induction of the antioxidant molecules by GW4064. GW4064 activated Nrf2 and subsequently induced antioxidant molecules (Nrf2, catalase, HO-1, and thioredoxin). We also examined expressions of pro-survival and cell protective molecules associated with p62/SQSTM1. Expectedly, GW4064 induced phosphorylation of Akt, expression of the anti-apoptotic molecules (Bcl-xL and Bcl-2), and reduced harmful hepatic molecules (Fas ligand and Fas). GW4064 promoted hepatocyte survival, which was cancelled by p62/SQSTM1 siRNA. These findings suggest the potential relevance of the FXR-p62/SQSTM1 pathway for the survival and protection of hepatocytes. Furthermore, GW4064 induced the expression of small heterodimer partners (SHP) and suppressed liver X receptor (LXR)-induced steatosis in hepatocytes, expecting the in vivo protective effect of FXR on liver injury especially with steatosis. In the hepatectomy model of db/db mice with fatty liver, pre-treatment by GW4064 significantly reduced post-PH liver injury (serum levels of LDH, AST & ALT and histological study) and improved steatosis. The key molecules, p62/SQSTM1, Nrf2 and SHP were upregulated in fatty liver tissue by GW4064 treatment. Conclusions: The present study is the first to demonstrate the relevance of FXR-p62/SQSTM1 and-SHP in the protection against injury of hepatocytes and post-PH liver, especially with steatosis.
  • Richard Thomas Jennings, Erdenezaya Odkhuu, Akina Nakashima, Naoko Morita, Toshihiko Kobayashi, Ikuko Yamai, Miyako Tanaka, Takayoshi Suganami, Sanae Haga, Michitaka Ozaki, Yasuharu Watanabe, Yoshinori Nagai, Kiyoshi Takatsu, Takane Kikuchi-Ueda, Isao Ichimonji, Yoshihiro Ogawa, Hidekazu Takagi, Tatsuya Yamazaki, Kensuke Miyake, Sachiko Akashi-Takamura
    INTERNATIONAL IMMUNOLOGY 28 10 503 - 512 2016年10月 [査読有り][通常論文]
     
    Novel antibodies detect the increased level of soluble MD-1 during inflammation.Radioprotective 105 (RP105) is a type I transmembrane protein, which associates with a glycoprotein, MD-1. Monoclonal antibody (mAb)-mediated ligation of RP105/MD-1 robustly activates B cells. RP105/MD-1 is structurally similar to Toll-like receptor 4 (TLR4)/MD-2. B-cell responses to TLR2 and TLR4/MD-2 ligands are impaired in the absence of RP105 or MD-1. In addition to RP105/MD-1, MD-1 alone is secreted. The structure of MD-1 shows that MD-1 has a hydrophobic cavity that directly binds to phospholipids. Little is known, however, about a ligand for MD-1 and the role of MD-1 in vivo. To study the role of RP105/MD-1 and MD-1 alone, specific mAbs against MD-1 are needed. Here, we report the establishment and characterization of two anti-MD-1 mAbs (JR2G9, JR7G1). JR2G9 detects soluble MD-1, whereas JR7G1 binds both soluble MD-1 and the cell surface RP105/MD-1 complex. With these mAbs, soluble MD-1 was detected in the serum and urine. The MD-1 concentration was altered by infection, diet and reperfusion injury. Serum MD-1 was rapidly elevated by TLR ligand injection in mice. The quantitative PCR and supernatant-precipitated data indicate that macrophages are one of the sources of serum soluble MD-1. These results suggest that soluble MD-1 is a valuable biomarker for inflammatory diseases.
  • Shigeki Jin, Hideki Hyodoh, Kotaro Matoba, Fei Feng, Akira Hayakawa, Katsuhiro Okuda, Keiko Shimizu, Sanae Haga, Michitaka Ozaki, Koichi Terazawa
    LEGAL MEDICINE 22 18 - 22 2016年09月 [査読有り][通常論文]
     
    Thiosulfate measurement is crucial to diagnosis of hydrogen sulfide (H2S) poisoning in forensic toxicology. Although GC-MS method is currently regarded as a standard thiosulfate measurement, it requires complicated sample preparation prior to analysis. This study presents a simple, rapid, and highly sensitive method for the quantitative analysis of serum thiosulfate by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This method is based on selected reaction monitoring and has high sensitivity with a lower quantification limit of 0.5 mu M. Precision and accuracy of this method meet the basic requirements for quantitative analysis (intra- and inter-day tests have a relative standard deviation of <= 10.4%;range of analytical recovery is 94.3-102.6%). On the measurements of serum thiosulfate by our developed method, a thiosulfate concentration as 57.5 mu M was detected clearly in the H2S poisoning case comparing to the non poisoning case in which only a trace amount of thiosulfate was observed. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Nobuki Ichikawa, Kenichiro Yamashita, Tohru Funakoshi, Shin Ichihara, Moto Fukai, Masaomi Ogura, Nozomi Kobayashi, Masaaki Zaitsu, Tadashi Yoshida, Susumu Shibasaki, Yasuyuki Koshizuka, Yusuke Tsunetoshi, Masanori Sato, Takahiro Einama, Michitaka Ozaki, Kazuo Umezawa, Tomomi Suzuki, Satoru Todo
    INFLAMMATION RESEARCH 65 3 245 - 260 2016年03月 [査読有り][通常論文]
     
    Objective and design To examine the effect of 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G), a novel anti-inflammatory agent that inhibits lipopolysaccharide (LPS) activation of RAW264.7 macrophages, on murine models of colitis and RAW264.7 cells. Materials and methods Colitis was induced by rectally infusing trinitrobenzenesulfonic acid (TNBS) (1.5 mg in 50 % ethanol) in BALB/c mice or orally administering 3 % dextran sulfate sodium (DSS) for 5 days in C57BL/6 mice. The severity of colitis was assessed after intraperitoneally injecting DTCM-G (40 mg/kg). The anti-inflammatory properties of DTCM-G and its mechanisms were investigated in LPS-stimulated RAW264.7 cells. Results DTCM-G significantly ameliorated TNBS-induced colitis, according to the body weight loss, disease activity index, colonic obstruction, macroscopic colonic inflammation score, mucosal myeloperoxidase activity, and histopathology. Immunohistochemistry and isolated lamina propria mononuclear cells showed significantly reduced colonic F4/80(+) and CD11b(+) macrophage infiltration. DTCM-G significantly suppressed tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 messenger RNA expression in the colon and attenuated DSS-induced colitis, according to the disease activity index and histopathology. In RAW264.7 cells, DTCM-G suppressed LPS-induced TNF-alpha/IL-6 production and enhanced glycogen synthase kinase-3 beta phosphorylation. Conclusions DTCM-G attenuated murine experimental colitis by inhibiting macrophage infiltration and inflammatory cytokine expression. Thus, DTCM-G may be a promising treatment for inflammatory bowel disease.
  • Naoki Morita, Sanae Haga, Yoshihiro Ohmiya, Michitaka Ozaki
    ANALYTICAL BIOCHEMISTRY 497 24 - 26 2016年03月 [査読有り][通常論文]
     
    We propose a new concept of tumor progression monitoring using dual luciferases in living animals to reduce stress for small animals and the cost of luciferin. The secreted Cypridina luciferase (CLuc) was used as an ex vivo indicator to continuously monitor tumor progression. On the other hand, the non-secreted firefly luciferase was used as an in vivo indicator to analyze the spatial distribution of the tumor at suitable time points indicated by CLuc. Thus, the new monitoring systems that use dual luciferases are available, allowing long-term bioluminescence imaging under minimal stress for the experimental animals. (C) 2015 Elsevier Inc. All rights reserved.
  • Yuma Yamada, Kohei Nakamura, Jiro Abe, Mamoru Hyodo, Sanae Haga, Michitaka Ozaki, Hideyoshi Harashima
    JOURNAL OF CONTROLLED RELEASE 213 86 - 95 2015年09月 [査読有り][通常論文]
     
    We herein report on a mitochondrial therapeutic effect based on the delivery of coenzyme Q(10) (CoQ(10)), an anti-oxidant, to in vivo mitochondria using a MITO-Porter, a liposome-based mitochondrial delivery system that functions via membrane fusion. To evaluate the effects, we used a mouse liver ischemia/reperfusion injury (I/R injury) model, in which mitochondrial reactive oxygen species are overexpressed. We packaged CoQ(10) in the lipid phase of a MITO-Porter and optimized the mitochondrial fusogenic activities to produce the CoQ(10)-MITO-Porter. A histological observation of the carriers in the liver by confocal laser scanning microscopy was done and the accumulation of the carrier labeled with a radio isotope in the liver confirmed that the CoQ(10)-MITO-Porter was delivered to liver mitochondria via systemic injection. These analytical results permitted us to optimize the compositions of the CoQ(10)-MITO-Porter so as to permit it to efficiently accumulate in mouse liver mitochondria. Finally, we applied the optimized CoQ(10) -MITO-Porter to mice via tail vein injection, and hepatic I/R injury was then induced, followed by measuring serum alanine aminotransferase (ALT) levels, a marker of liver injury. We confirmed that the use of the CoQ(10)-MITO-Porter resulted in a significant decrease in serum ALT levels, indicating that in vivo mitochondrial delivery of the CoQ(10) via MITO-Porter prevents I/R injury in mice livers. This provides a demonstration of the potential use of such a delivery system in mitochondrial therapies. (C) 2015 Elsevier B.V. All rights reserved.
  • Yuka Inaba, Tomoko Furutani, Kumi Kimura, Hitoshi Watanabe, Sanae Haga, Yoshiaki Kido, Michihiro Matsumoto, Yasuhiko Yamamoto, Kenichi Harada, Shuichi Kaneko, Seiichi Oyadomari, Michitaka Ozaki, Masato Kasuga, Hiroshi Inoue
    HEPATOLOGY 61 4 1343 - 1356 2015年04月 [査読有り][通常論文]
     
    The liver has robust regenerative potential in response to damage, but hepatic steatosis (HS) weakens this potential. We found that the enhanced integrated stress response (ISR) mediated by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2) impairs regeneration in HS and that growth arrest and DNA damage-inducible 34 (Gadd34)-dependent suppression of ISR plays a crucial role in fatty liver regeneration. Although mice fed a high-fat diet for 2 weeks developed moderate fatty liver with no increase in eIF2 phosphorylation before 70% hepatectomy, they showed impaired liver regeneration as a result of reduced proliferation and increased death of hepatocytes with increased phosphorylation of eIF2 and ISR. An increased ISR through Gadd34 knockdown induced C/EBP homologous protein (CHOP)-dependent apoptosis and receptor-interacting protein kinase 3-dependent necrosis, resulting in increased hepatocyte death during fatty liver regeneration. Furthermore, Gadd34 knockdown and increased phosphorylation of eIF2 decreased cyclin D1 protein and reduced hepatocyte proliferation. In contrast, enhancement of Gadd34 suppressed phosphorylation of eIF2 and reduced CHOP expression and hepatocyte apoptosis without affecting hepatocyte proliferation, clearly improving fatty liver regeneration. In more severe fatty liver of leptin receptor-deficient db/db mice, forced expression of hepatic Gadd34 also promoted hepatic regeneration after hepatectomy. Conclusion: Gadd34-mediated regulation of ISR acts as a physiological defense mechanism against impaired liver regeneration resulting from steatosis and is thus a possible therapeutic target for impaired regeneration in HS. (Hepatology 2015;61:1343-1356)
  • Sanae Haga, Takeaki Ozawa, Yuma Yamada, Naoki Morita, Izuru Nagashima, Hiroshi Inoue, Yuka Inaba, Natsumi Noda, Riichiro Abe, Kazuo Umezawa, Michitaka Ozaki
    ANTIOXIDANTS & REDOX SIGNALING 21 18 2515 - 2530 2014年12月 [査読有り][通常論文]
     
    Aims: Liver injury and regeneration involve complicated processes and are affected by various physio-pathological factors. We investigated the mechanisms of steatosis-associated liver injury and delayed regeneration in a mouse model of partial hepatectomy. Results: Initial regeneration of the steatotic liver was significantly delayed after hepatectomy. Although hepatocyte proliferation was not significantly suppressed, severe liver injury with oxidative stress (OS) occurred immediately after hepatectomy in the steatotic liver. Fas-ligand (FasL)/Fas expression was upregulated in the steatotic liver, whereas the expression of antioxidant and anti-apoptotic molecules (catalase/MnSOD/Ref-1 and Bcl-2/Bcl-xL/FLIP, respectively) and p62/SQSTM1, a steatosis-associated protein, was downregulated. Interestingly, pro-survival Akt was not activated in response to hepatectomy, although it was sufficiently expressed even before hepatectomy. Suppression of p62/SQSTM1 increased FasL/Fas expression and reduced nuclear factor erythroid 2-related factor-2 (Nrf-2)-dependent antioxidant response elements activity and antioxidant responses in steatotic and nonsteatotic hepatocytes. Exogenously added FasL induced severe cellular OS and necrosis/apoptosis in steatotic hepatocytes, with only the necrosis being inhibited by pretreatment with antioxidants, suggesting that FasL/Fas-induced OS mainly leads to necrosis. Furthermore, p62/SQSTM1 re-expression in the steatotic liver markedly reduced liver injury and improved liver regeneration. Innovation: This study is the first which demonstrates that reduced expression of p62/SQSTM1 plays a crucial role in posthepatectomy acute injury and delayed regeneration of steatotic liver, mainly via redox-dependent mechanisms. Conclusion: In the steatotic liver, reduced expression of p62/SQSTM1 induced FasL/Fas overexpression and suppressed antioxidant genes, mainly through Nrf-2 inactivation, which, along with the hypo-responsiveness of Akt, caused posthepatectomy necrotic/apoptotic liver injury and delayed regeneration, both mainly via a redox-dependent mechanism. Antioxid. Redox Signal. 21, 2515-2530.
  • Yimin, Masashi Kohanawa, Songji Zhao, Michitaka Ozaki, Sanae Haga, Guangxian Nan, Yuji Kuge, Nagara Tamaki
    PLoS ONE 8 9 e74287  2013年09月13日 [査読有り][通常論文]
     
    Staphylococcus aureus is a common pathogen that causes a wide range of infectious diseases. The function of TLRs, specifically TLR2, during S. aureus infection is still debated. In this study, we investigated the extent to which TLR2 contributes to the host innate response against the bacterial infection using TLR2-deficient mice. Intravenous inoculation with S. aureus resulted in all TLR2-deficient mice dying within 4 d, along with a high bacterial burden in the livers. However, histological examination showed the same degree of macrophage and neutrophil accumulation in the livers of infected TLR2-deficient mice as that in infected wild-type (WT) mice. TLR2-deficient mouse macrophages also showed normal phagocytic activity, although they failed to express CD36 that appeared on the surface of WT mouse cells upon challenge with heat-killed S. aureus. These data indicate that TLR2, as well as CD36, does not directly affect S. aureus clearance and that CD36 expression on macrophages depends on the presence of TLR2. In vivo infection with S. aureus caused significantly elevated production of TNF-α and IL-6 in the livers and blood of TLR2-deficient mice compared with those in WT mice, while the hepatic and serum levels of IL-10 decreased in these mice. In contrast, lower expression of IL-6 and IL-10, but not of TNF-α, at both the gene and protein levels was found in TLR2-deficient mouse macrophages compared to that in WT mouse cells, in response to challenge with heat-killed S. aureus. These findings suggest that the S. aureus-induced pro-inflammatory cytokine response is not dependent on macrophages and that TLR2 deficiency results in decreased IL-10 release by macrophages, which contributes to dysregulated cytokine balance, impaired bacterial clearance, and mouse death. Therefore, TLR2 possesses a protective function during S. aureus infection by regulating pro- and anti-inflammatory cytokine responses. © 2013 Yimin et al.
  • Watanabe M, Yamashita K, Kamachi H, Kuraya D, Koshizuka Y, Shibasaki S, Asahi Y, Ono H, Emoto S, Ogura M, Yoshida T, Ozaki M, Umezawa K, Matsushita M, Todo S
    Transplantation 96 5 454 - 462 2013年09月 [査読有り][通常論文]
     
    Background. Long-term graft deterioration remains a major obstacle in the success of pancreatic islet transplantation (PITx). Antigen-independent inflammatory and innate immune responses strengthen subsequent antigen-dependent immunity; further, activation of nuclear factor (NF)-kappa B plays a key role during these responses. In this study, we tested our hypothesis that, by the inhibition of NF-kappa B activation, the suppression of these early responses after PITx could facilitate graft acceptance. Methods. Full major histocompatibility complex (MHC) Ymismatched BALB/c (H-2(d)) mice islets were transplanted into streptozotocin-induced diabetic C57BL/6 (B6: H-2(b)) mice. The NF-kappa B inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) was administered for either 3 or 14 days after PITx. To some PITx recipients, tacrolimus was also administered. Islet allograft survival, alloimmune responses, and in vitro effects of DHMEQ on dendritic cells (DCs) were assessed. Results. With a vehicle treatment, 600 islet allografts were promptly rejected after PITx. In contrast, 3-day treatment with DHMEQ, followed by 2-week treatment with tacrolimus, allowed permanent acceptance of islet allografts. The endogenous danger-signaling molecule high mobility group complex 1 (HMGB1) was elevated in sera shortly after PITx, whereas DHMEQ administration abolished this elevation. DHMEQ suppressed HMGB1-driven cellular activation and proinflammatory cytokine secretion in mouse bone marrowYderived DCs and significantly reduced the capacity of DCs to prime allogeneic T-cell proliferation in vitro. Finally, the DHMEQ plus tacrolimus regimen reverted the diabetic state with only 300 islet allografts. Conclusions. Inhibition of NF-kappa B activation by DHMEQ shortly after PITx suppresses HMGB1, which activates DCs and strengthens the magnitude of alloimmune responses; this permits long-term islet allograft acceptance, even in case of fewer islet allografts.
  • Mitsuru Hattori, Sanae Haga, Hideo Takakura, Michitaka Ozaki, Takeaki Ozawa
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110 23 9332 - 9337 2013年06月 [査読有り][通常論文]
     
    Regulation of an intracellular acidic environment plays a pivotal role in biological processes and functions. However, spatiotemporal analysis of the acidification in complex tissues of living subjects persists as an important challenge. We developed a photo-inactivatable bioluminescent indicator, based on a combination of luciferase-fragment complementation and a photoreaction of a light, oxygen, and voltage domain from Avena sativa Phototropin1 (LOV2), to visualize temporally dynamic acidification in living tissue samples. Bioluminescence of the indicator diminished upon light irradiation and it recovered gradually in the dark state thereafter. The recovery rate was remarkably sensitive to pH changes but unsusceptible to fluctuation of luciferin or ATP concentrations. Bioluminescence imaging, taken as an index of the recovery rates, enabled long-time recording of acidification in apoptotic and autophagous processes in a cell population and an ischemic condition in living mice. This technology using the indicator is widely applicable to sense organelle-specific acidic changes in target biological tissues.
  • Hongjiang Qiao, Riichiro Abe, Nao Saito, Yasuyuki Fujita, Inkin Hayashi-Ujiie, Gang Wang, Sanae Haga, Chun Wu, Yoshihiro Ohmiya, Michitaka Ozaki, Hiroshi Shimizu
    JOURNAL OF INVESTIGATIVE DERMATOLOGY 133 3 841 - 843 2013年03月 [査読有り][通常論文]
  • Susumu Shibasaki, Kenichiro Yamashita, Ryoichi Goto, Kenji Wakayama, Yusuke Tsunetoshi, Masaaki Zaitsu, Rumi Igarashi, Sanae Haga, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    Transplantation 95 4 542 - 550 2013年02月27日 [査読有り][通常論文]
     
    Background: A newly developed compound, 3-[(dodecylthiocarbonyl)methyl]- glutarimide (DTCM-G), has been shown to inhibit nuclear translocation of c-Fos/c-Jun in a murine macrophage cell line. Herein, we studied the immunosuppressive properties and potency of DTCM-G. METHODS: Using purified mouse T cells, the in vitro effects of DTCM-G on activation, cytokine production, proliferation, and cell cycle progression were assessed, and a possible molecular target of DTCM-G was investigated. In a BALB/c (H-2) to C57BL/6 (H-2) mouse heart transplantation model, transplant recipients were administered DTCM-G, a calcineurin inhibitor (tacrolimus), and a nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ). Treatment drugs were administered daily for 14 days after transplantation. Alloimmune responses were assessed in addition to graft survival time. RESULTS: After anti-CD3+anti-CD28 monoclonal antibody stimulation, DTCM-G significantly suppressed proliferation, interferon-γ production, and cell cycle progression of activated T cells but not CD25 expression or interleukin-2 production. These effects were accompanied by inhibition of 70-kDa S6 protein kinase phosphorylation, a downstream kinase of the mammalian target of rapamycin. The addition of tacrolimus and DHMEQ to DTCM-G resulted in a robust inhibition of T-cell proliferation. In vivo combination therapy of DTCM-G plus either tacrolimus or DHMEQ significantly suppressed alloreactive interferon-γ-producing precursors and markedly prolonged cardiac allograft survival. Furthermore, combination of all three agents markedly inhibited alloimmune responses and permitted long-term cardiac allograft survival. Conclusions: DTCM-G inhibits T cells by suppressing the downstream signal of mammalian target of rapamycin. DTCM-G in combination with tacrolimus and DHMEQ induces a strong immunosuppressive effect in vivo. © 2013 by Lippincott Williams & Wilkins.
  • Nao Saito, Naoya Yoshioka, Riichiro Abe, Hongjiang Qiao, Yasuyuki Fujita, Daichi Hoshina, Asuka Suto, Satoru Kase, Nobuyoshi Kitaichi, Michitaka Ozaki, Hiroshi Shimizu
    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 131 2 434 - + 2013年02月 [査読有り][通常論文]
     
    Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions caused by drugs or infections and exhibiting widespread epidermal necrosis. Currently, there is no animal model that reproduces SJS/TEN symptoms. Objective: We sought to develop a novel mouse model of SJS/TEN by using PBMCs and skin from patients who had recovered from SJS/TEN. Methods: For our mouse model, patients' PBMCs were injected intravenously into immunocompromised NOD/Shi-scid, IL-2R gamma(null) (NOG) mice, followed by oral administration of a causative drug. Subsequently, to replace human skin, unaffected skin specimens obtained from patients who had recovered from SJS/TEN were grafted onto NOG mice, after which patient-derived PBMCs and the causative drug were applied. Results: Mice injected with PBMCs from patients with SJS/TEN and given the causative drug showed marked conjunctival congestion and numerous cell death of conjunctival epithelium, whereas there were no symptoms in mice injected with PBMCs from patients with ordinary drug skin reactions. CD8(+) T lymphocyte-depleted PBMCs from patients with SJS/TEN did not elicit these symptoms. In addition, skin-grafted mice showed darkening of the skin-grafted areas. Cleaved caspase-3 staining showed that dead keratinocytes were more numerous in the skin-grafted mice than in the healthy control animals. Conclusion: We have established a novel human-oriented SJS/TEN mouse model and proved the importance of CD8(+) T lymphocytes in SJS/TEN pathogenesis. The mouse model promises to promote diagnostic and therapeutic approaches. (J Allergy Clin Immunol 2013;131:434-41.)
  • Sato M, Nakanishi K, Haga S, Fujiyoshi M, Baba M, Mino K, Yimin, Niwa H, Yokoo H, Umezawa K, Ohmiya Y, Kamiyama T, Todo S, Taketomi A, Ozaki M
    Oncology research 21 6 333 - 343 2013年 [査読有り][通常論文]
     
    The transcription factor nuclear factor-kappa B (NF-kappa B) plays a crucial role in pancreatic cancer (PC) progression. NF-kappa B is also involved in resistance to anoikis, a special type of apoptosis induced when cells are detached from the extracellular matrix or other cells. Anoikis resistance is related to the metastatic abilities of tumor cells; however, little is known about anoikis induction as it relates to inhibition of PC metastasis by NF-kappa B inhibitors. Here we used a specific NF-kappa B inhibitor, (-)-dehydroxymethylepoxyquinomicin (DHMEQ), to investigate anoikis induction and peritoneal metastasis suppression following NF-kappa B inhibition. We transduced Glue, a secretory form of luciferase, into a PC cell line, AsPC-1 (AsPC-1-Gluc), for our in vivo experiments. (-)-DHMEQ induced anoikis in AsPC-1-Gluc cells as measured by cell survival assays and flow cytometry. The DNA-binding activity of p65 was enhanced immediately after cell detachment from culture dishes in ELISA assays. Some antiapoptotic proteins such as cellular inhibitor of apoptotic protein-1 were consequently upregulated on Western blots. (-)-DHMEQ prevented this increase in p65 activity and the subsequent expressions of antiapoptotic molecules. In a murine xenograft model, anoikis-resistant PC cell lines tended to metastasize to the peritoneum more than anoikis-sensitive cells, suggesting a correlation between anoikis sensitivity and peritoneal metastasis. (-)-DHMEQ successfully inhibited peritoneal metastasis of AsPC-1-Gluc cells. We monitored metastasis inhibition by ex vivo chemiluminescent detection of Glue secreted from tumor cells into murine plasma and by in vivo imaging. Our results suggest that (-)-DHMEQ inhibited peritoneal dissemination by preventing anoikis resistance of PC cells.
  • Kuraya D, Watanabe M, Koshizuka Y, Ogura M, Yoshida T, Asahi Y, Kamachi H, Nakamura T, Harashima H, Ozaki M, Umezawa K, Matsushita M, Yamashita K, Todo S
    Transplantation 96 5 445 - 453 2013年 [査読有り][通常論文]
     
    BACKGROUND: Pancreatic islet transplantation (PITx) is an attractive treatment option for restoring appropriate glucose homeostasis in type 1 diabetes patients. Although islet grafts can successfully engraft after PITx, large numbers of islet grafts are required mainly because immune reactions, including inflammation, destroy islet grafts. In these processes, nuclear factor (NF)-κB plays a central role. We hypothesized that the inhibition of NF-κB activation would ameliorate inflammatory responses after PITx and aid successful engraftment. METHODS: To test this hypothesis, a newly developed NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was used on a syngeneic mouse PITx model. One hundred seventy-five islets from C57BL/6 (B6) mice were transplanted into streptozotocin-induced diabetic B6 mice. The recipient mice were administered DHMEQ for 1, 2, or 3 days after PITx. The underlying mechanisms of DHMEQ on islet graft protection were investigated in an in vitro coculture model of pancreatic islets and macrophages. RESULTS: With a vehicle treatment, only 11.1% of the islet-recipients achieved normoglycemia after PITx. In sharp contrast, DHMEQ treatment markedly improved the normoglycemic rate, which was associated with the suppression of serum high mobility group complex-1 (HMGB1) and proinflammatory cytokines, including tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, interleukin-1β, and interleukin-6, after PITx. In a murine macrophage-like cell line, DHMEQ inhibited HMGB1-driven activation and proinflammatory cytokine secretion and further prevented death isolated islets after coculture with these activated macrophages. CONCLUSIONS: Inhibition of NF-κB activation by DHMEQ after PITx reduces the HMGB1-triggered proinflammatory responses and results in engraftment of transplanted islets even with fewer islet grafts. Copyright © 2013 by Lippincott Williams & Wilkins.
  • Chun Wu, Ke-Yong Wang, Xin Guo, Masanori Sato, Michitaka Ozaki, Shyohei Shimajiri, Yoshihiro Ohmiya, Yasuyuki Sasaguri
    LUMINESCENCE 28 1 38 - 43 2013年01月 [査読有り][通常論文]
     
    We demonstrate a novel rapid direct detection method for immunohistochemistry, using a bioluminescent probe. An anti-CEA antibody-fused far-red bioluminescent protein can monitor the accumulation of this type of probe in tumour tissues. The bimodal spectrum (max=460 and 675nm) of this bioluminescent probe is extremely stable under different conditions of pH and ion concentration. The sensitivity of our bioluminescent labelling was at the same level of enzymatic labelling, e.g. peroxidase, as an indirect system. Our novel technique is simple and can shorten the pretreatment time of paraffin sections to around 30min. The utility of our bioluminescent labelling covers all imaging in vitro, in vivo and ex vivo, suggesting that our antibody-fused bioluminescent probe has the potential to detect tumour antigens with a high sensitivity in routine immune histological examinations. Copyright (c) 2012 John Wiley & Sons, Ltd.
  • Kohei Oashi, Hiroshi Furukawa, Hiroshi Nishihara, Michitaka Ozaki, Akihiko Oyama, Emi Funayama, Toshihiko Hayashi, Yuji Kuge, Yuhei Yamamoto
    Journal of Investigative Dermatology 133 2 537 - 544 2013年 [査読有り][通常論文]
     
    In-transit metastasis (ITM) is a unique manifestation of intralymphatic tumor dissemination, characterized by the presence of melanoma cells between the primary lesion and the draining regional lymph node basin that is clinically associated with poor prognosis. In this study, we aimed to establish an experimental animal model of melanoma ITM, as research progress in this field has been hampered by a lack of suitable experimental models. We reproduced melanoma ITM in a mouse hind limb by transplanting melanoma cells into the footpad of a mouse with lymphedema (LE). The tumor cells at the ITM site were highly proliferative, and mice with ITMs were more likely than control mice to develop distant lymph node and lung metastases. Peritumoral lymphatic vessels and tumor-associated blood vessels were increased in the primary tumor site of the LE mice. Our established ITM melanoma mouse model enabled us to clarify the molecular determinants and pathophysiology of ITM. This ITM model is also comparable to the unfavorable clinical behavior of melanoma ITM in humans and, moreover, underlined the importance of lymphangiogenic factors in the tumor dissemination through the lymphatic system. © 2013 The Society for Investigative Dermatology.
  • Hiroshi Hirata, Yimin, Shuichi Segawa, Moeko Ozaki, Naoyuki Kobayashi, Tatsuro Shigyo, Hitoshi Chiba
    PLOS ONE 7 11 e49415  2012年11月 [査読有り][通常論文]
     
    Background: Xanthohumol is expected to be a potent anti-atherosclerotic agent due to its inhibition of cholesteryl ester transfer protein (CETP). In this study, we hypothesized that xanthohumol prevents atherosclerosis in vivo and used CETP-transgenic mice (CETP-Tg mice) to evaluate xanthohumol as a functional agent. Methodology/Principal Findings: Two strains of mice, CETP-Tg and C57BL/6N (wild-type), were fed a high cholesterol diet with or without 0.05% (w/w) xanthohumol ad libitum for 18 weeks. In CETP-Tg mice, xanthohumol significantly decreased accumulated cholesterol in the aortic arch and increased HDL cholesterol (HDL-C) when compared to the control group (without xanthohumol). Xanthohumol had no significant effect in wild-type mice. CETP activity was significantly decreased after xanthohumol addition in CETP-Tg mice compared with the control group and it inversely correlated with HDL-C (%) (P<0.05). Furthermore, apolipoprotein E (apoE) was enriched in serum and the HDL-fraction in CETP-Tg mice after xanthohumol addition, suggesting that xanthohumol ameliorates reverse cholesterol transport via apoE-rich HDL resulting from CETP inhibition. Conclusions: Our results suggest xanthohumol prevents cholesterol accumulation in atherogenic regions by HDL-C metabolism via CETP inhibition leading to apoE enhancement.
  • K. Shimizu, S. Konno, M. Ozaki, K. Umezawa, K. Yamashita, S. Todo, M. Nishimura
    CLINICAL AND EXPERIMENTAL ALLERGY 42 8 1273 - 1281 2012年08月 [査読有り][通常論文]
     
    Background Dehydroxymethylepoxyquinomicin (DHMEQ) is a newly developed compound that inhibits nuclear factor kappa B activation and is reported to ameliorate animal models of various inflammatory diseases without significant adverse effects. Because nuclear factor jB is a transcription factor that plays a critical role in the pathophysiology of asthma, DHMEQ may be of therapeutic benefit in asthma. Objective The purpose of this study was to evaluate the effects of DHMEQ on airway inflammation and remodelling in murine models of asthma. Methods The BALB/c mice were sensitized and then challenged acutely or chronically with ovalbumin and administered DHMEQ intraperitoneally before each challenge. Inflammation of airways, lung histopathology and airway hyper responsiveness to methacholine challenge were evaluated. In addition, the effect of DHMEQ on production of cytokines and eotaxin-1 by murine splenocytes, human peripheral blood mononuclear cells and bronchial epithelial cells was investigated. Results Airway hyper responsiveness was ameliorated in both acutely and chronically challenged models by treatment with DHMEQ. DHMEQ significantly reduced eosinophilic airway inflammation and levels of Th2 cytokines in bronchoalveolar lavage fluid in the acute model. It also inhibited parameters of airway remodelling including mucus production, peribronchial fibrosis and the expression of alpha-smooth muscle actin. Moreover, the production of Th2 cytokines from murine splenocytes and human peripheral blood mononuclear cells and the production of eotaxin-1 by bronchial epithelial cells were inhibited by DHMEQ. Conclusions and Clinical Relevance These results indicate that DHMEQ inhibits allergic airway inflammation and airway remodelling in murine models of asthma. DHMEQ may have therapeutic potential in the treatment of asthma.
  • Kenji Wakayama, Moto Fukai, Kenichiro Yamashita, Taichi Kimura, Gentaro Hirokata, Susumu Shibasaki, Daisuke Fukumori, Sanae Haga, Mitsuru Sugawara, Tomomi Suzuki, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Toshiya Kamiyama, Satoru Todo
    TRANSPLANT INTERNATIONAL 25 6 696 - 706 2012年06月 [査読有り][通常論文]
     
    Since prolonged cold preservation of the heart deteriorates the outcome of heart transplantation, a more protective preservation solution is required. We therefore developed a new solution, named Dsol, and examined whether Dsol, in comparison to UW, could better inhibit myocardial injury resulting from prolonged cold preservation. Syngeneic heterotopic heart transplantation in Lewis rats was performed after cold preservation with UW or Dsol for 24 or 36 h. In addition to graft survival, myocardial injury, ATP content, and Ca2+ -dependent proteases activity were assessed in the 24-h preservation group. The cytosolic Ca2+ concentration of H9c2 cardiomyocytes after 24-h cold preservation was assessed. Dsol significantly improved 7-day graft survival after 36-h preservation. After 24-h preservation, Dsol was associated with significantly faster recovery of ATP content and less activation of calpain and caspase-3 after reperfusion. Dsol diminished graft injury significantly, as revealed by the lower levels of infarction, apoptosis, serum LDH and AST release, and graft fibrosis at 7-day. Dsol significantly inhibited Ca2+ overload during cold preservation. Dsol inhibited myocardial injury and improved graft survival by suppressing Ca2+ overload during the preservation and the activation of Ca2+ -dependent proteases. Dsol is therefore considered a better alternative to UW to ameliorate the outcome of heart transplantation.
  • Susumu Shibasaki, Kenichiro Yamashita, Yoshiki Yanagawa, Ryoichi Goto, Kenji Wakayama, Gentaro Hirokata, Yusuke Tsunetoshi, Masaaki Zaitsu, Rumi Igarashi, Sanae Haga, Michitaka Ozaki, Satoru Todo
    TRANSPLANTATION 93 12 1229 - 1237 2012年06月 [査読有り][通常論文]
     
    Background. Pharmacologically modulated dendritic cells (DCs) can potentially regulate alloimmune responses. We examined the characteristics of immunoregulatory DCs induced by a novel triazolopyrimidine derivative, NK026680, which has been previously shown to inhibit DC maturation. Methods. DCs were generated from bone marrow progenitor cells from C57BL/6 (B6, H-2(b) haplotype) mice with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. DCs were cultured with allogeneic BALB/c (H-2(d)) splenocyte lysates with or without NK026680. DC functions were examined in vitro after stimulation of tumor necrosis factor alpha and in vivo by the intravenous injection of C3He/J (C3H, H-2(k)) DCs cultured with B6 cell lysates and NK026680 into C3H mice. Seven days later, DC-treated mice received B6 heart allografts, and graft survival and alloimmune responses were assessed. Results. In NK026680-treated DCs (NK-DCs), significant inhibition of the up-regulation of surface activation markers (CD40, CD80, CD86, and major histocompatibility complex class II) and IL-12 p40 production was observed after stimulation of tumor necrosis factor alpha compared with that of control DCs. Furthermore, NK-DCs suppressed alloreactive T-cell proliferation. The modulation of NK-DCs was likely associated with the inhibition of phosphorylation of p38 mitogen-activated protein kinase and the up-regulation of indolamine 2,3-dioxygenase expression. Compared with both noninjected and control DC-injected mice, mice that received a single in vivo infusion of NK-DCs showed significant increases in splenocyte IL-10 production and the splenic CD4(+) IL-10(high) T-cell population 7 days after injection, a significantly increased splenic CD4(+)CD25(+)FoxP3(+) T-cell population 14 days after injection, and markedly prolonged cardiac allograft survival. Conclusions. Ex vivo NK026680 conditioning allows DCs to acquire immunoregulatory properties that suppress alloimmune responses and prolong cardiac allograft survival.
  • Goto R, Yamashita K, Aoyagi T, Ueki S, Uno M, Oura T, Kobayashi N, Igarashi R, Shibasaki S, Wakayama K, Hirokata G, Shibata T, Zaitsu M, Umezawa K, Ozaki M, Todo S
    Transplantation 93 8 777 - 786 2012年04月 [査読有り][通常論文]
     
    Background. Nuclear factor-kappa B (NF-kappa B) is a key molecule in alloimmune responses, however, its role in tolerance induction is not clear. We have previously reported that dehydroxymethylepoxyquinomycin (DHMEQ), a novel NF-kappa B inhibitor, prolongs cardiac allograft survival. In this study, we evaluated the immunomodulatory effects of DHMEQ when combined with a donor-specific blood transfusion (DST), and assessed whether the treatment induces tolerance in a mouse heart transplantation model. Methods. DST (20 x 10(6) splenocytes) was given intravenously at day -7. DHMEQ (30 mg/kg/day) was administered intraperitoneally for 14 days after DST. Graft survival and histology were evaluated. The underlying mechanisms of immunomodulation by DST and DHMEQ treatments were investigated by assessing alloimmune responses after transplantation. Results. In fully mismatched H2(d)-to-H2(b) heart transplants, DST alone prolonged allograft median survival time to 15 days, whereas when DST was combined with DHMEQ treatment, the graft median survival time was prolonged to 39.5 days. When the donor-recipient strain combination was reversed, that is, H2(b)-to-H2(d), heart transplants were accepted (>150 days survival) in more than 60% of recipients treated with a DST and DHMEQ, whereas control allografts were all rejected within 8 days. The combined therapy markedly inhibited immune responses by both the direct and indirect allorecognition pathways mainly attributed to promotion of activation-induced cell death and Treg generation. Conclusions. Our results demonstrate the distinctive ability of NF-kappa B inhibition in combination with donor alloantigen to promote transplantation tolerance through multiple cellular mechanisms.
  • Naoki Morita, Sanae Haga, Takeaki Ozawa, S. James Remington, Michitaka Ozaki
    LUMINESCENCE 27 2 143 - 145 2012年03月 [査読有り][通常論文]
  • Funakoshi T, Yamashita K, Ichikawa N, Fukai M, Suzuki T, Goto R, Oura T, Kobayashi N, Katsurada T, Ichihara S, Ozaki M, Umezawa K, Todo S
    Journal of Crohn's & colitis 6 2 215 - 225 2012年03月 [査読有り][通常論文]
     
    Background: In inflammatory bowel disease (IBD), gut inflammation is associated with the activation of nuclear factor kappa B (NE-kappa B), a key pro-inflammatory transcription factor. Aim: To investigate the therapeutic potential of a novel, specific NE-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), we examined its effect on IBD using murine experimental colitis models. Methods: The in vitro effect of DHMEQ was evaluated by inflammatory cytokine production and p65 immunostaining using HT-29 and RAW264.7 cells. The in vivo therapeutic effect of DHMEQ was studied in colitis induced by dextran sulphate sodium (DSS) and trinitrobenzenesulphonic acid (TNBS). In these, progression and severity of colitis was mainly assessed by the disease activity index (DAI), histopathology, cellular infiltration, and mRNA expression levels of proinflammatory cytokines in the colonic tissues. Results: In RAW264.7 cells, DHMEQ significantly inhibited tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 production induced by LPS in a dose-dependent manner by blocking the nuclear translocation of NE-kappa B. In addition, DHMEQ inhibited IL-8 production induced by LPS in HT-29 cells. DHMEQ significantly ameliorated DSS colitis as assessed by DAI scores, colonic oedema, and histological scores. Immunohistochemistry revealed that DHMEQ inhibited colonic infiltration of nuclear p65(+) cells, CD4(+) lymphocytes, and F4/80(+) macrophages. mRNA expression levels of the pro-inflammatory cytokines, such as IL-1 beta, TNF-alpha, IL-6, IL-12p40, IL-17, and MCP-1 were also suppressed by DHMEQ administration. Furthermore, DHMEQ significantly ameliorated TNBS colitis as assessed by body-weight changes and histological scores. Conclusion: DHMEQ ameliorated experimental colitis in mice. These results indicate that DHMEQ appears to be an attractive therapeutic agent for IBD. (C) 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
  • Susumu Shibasaki, Kenichiro Yamashita, Ryoichi Goto, Tetsu Oura, Kenji Wakayama, Gentaro Hirokata, Tomohiro Shibata, Rumi Igarashi, Sanae Haga, Michitaka Ozaki, Satoru Todo
    TRANSPLANT IMMUNOLOGY 26 1 42 - 49 2012年01月 [査読有り][通常論文]
     
    NK026680 is a triazolopyrimidine derivative that has been shown to inhibit dendritic cell maturation and activation. Here, we examined the immunosuppressive properties of NK026680 on T-cell function and assessed its immunosuppressive efficacy in an ACI (RT1(av1) haplotype) to Lewis (RT1(I)) rat heart transplantation model. The effects of NK026680 on T-cell proliferation, activation, and cytokine production were investigated in vitro. Heart transplant recipient rats were administered NK026680 daily for 14 days post-transplantation. In addition to graft survival time, alloimmune responses and graft histology at 4-10 days post-transplantation were assessed. NK026680 was found to inhibit proliferation, CD25 upregulation, IL-2 production, and cell cycle progression in alpha CD3/alpha CD28-stimulated murine T cells. These effects were likely due to suppression of the p38 mitogen-activated protein kinase pathway and the subsequent inhibition of p65, c-Fos, and to a lesser extent, c-Jun. Daily NK026680 treatment suppressed alloimmune responses, prevented cellular infiltration into allografts, and prolonged graft survival. The anti-rejection effects of NK026680 were enhanced by tacrolimus. In conclusion, NK026680 inhibits the activation of T cells and prolongs cardiac allograft survival in rats. These features make it a potential candidate immunosuppressant for the treatment of organ transplant patients in the future. (C) 2011 Elsevier B.V. All rights reserved.
  • Kamiyama T, Takahashi M, Nakanishi K, Yokoo H, Kamachi H, Kobayashi N, Ozaki M, Todo S
    World journal of gastroenterology 18 4 340 - 348 2012年01月 [査読有り][通常論文]
     
    AIM: To investigate whether a-fetoprotein (AFP) and vascular endothelial growth factor receptor (VEGFR)-1 correlate with early recurrence of hepatoma/hepatocellular carcinoma (HCC). METHODS: From 2000 to 2005, 114 consecutive patients with HCC underwent primary curative hepatectomy. The mean age was 60.7 (8.7) years and 94 patients were male. The median follow-up period was 71.2 mo (range: 43-100 mo). Immediately prior to commencing laparotomy, 5 nnL bone marrow was aspirated from the sternum and collected in citrate-coated test tubes. The initial 2 mL of bone marrow aspirate was discarded in each case. AFP mRNA and VEGFR-1 mRNA in the bone marrow and peripheral blood (BM- and PH-AFP mRNA and BM- and PH-VEGFR-1 mRNA, respectively) were measured by real-time quantitative reverse transcription polymerase chain reaction. As normal controls, VEGFR-1 mRNA in the bone marrow and peripheral blood was also measured in 11 living liver donors. These data were evaluated for any correlation with early recurrence, comparing clinical and pathological outcomes. RESULTS: The cut-off value of the BM-AFP mRNA and PH-AFP mRNA level in patients with HCC was set at 1.92 x 10(-7) and zero, respectively, based on data from the controls. A total of 34 (29.8%) and six (5.4%) patients were positive for BM-AFP mRNA and PH-AFP mRNA, respectively. The BM-VEGFR-1 mRNA levels in all HCC patients were higher than those in the normal controls, and this was the case also for PH-VEGFR-1mRNA. The 25-percentile values for the BM- and PH-VEGFR-1 mRNA in HCC patients were used as the cut-off values for assigning the patients into two groups based on these transcript levels. The High group for BM- VEGFR-1 mRNA contained 81(71.1%) HCC cases and the Low group was assigned 33 (28.9%) patients. These numbers for PH-VEGFR-1mRNA were 78 (75.0%) and 26 (25.0%), respectively. HCC recurred in 80 patients; in the remnant liver in 48 cases, in the remnant liver and remote tissue in 20, and in the remote tissue alone in 12. BM-AFP nnRNA-positive cases showed a significantly higher rate of early recurrence (within 1 year of surgical treatment) compared with BM-AFP mRNA-negative patients (P = 0.0091). Patients were classified into four groups according to the level/status of their BM-VEGFR-1 and BM-AFP mRNA as follows: group A (n = 23), BM-VEGFR-1/BM-AFP mRNA = low/negative; group B (n = 57) high/negative; group C (n = 10)low/positive; group D (n = 24), high/positive. This classification was found to correlate with a recurrence of this disease within 1 year (P = 0.0228). The disease-free survival curve of group A was significantly better than that of groups B, C or D (P = 0.0437, P = 0.0325, P = 0.0225). No other classification (i.e., PH-VEGF-R1/BM-AFP, BM-VEGF-R1/PH-AFP, and PH-VEGF-R1/PH-AFP mRNA) showed such a correlation. CONCLUSION: The evaluation of BM-AFP and BM-VEGFR-1 mRNA in patients with HCC may be a valuable predictor of disease recurrence following curative resection. (C) 2012 Baishideng. All rights reserved.
  • Michitaka Ozaki, Sanae Haga, Takeaki Ozawa
    THERANOSTICS 2 2 207 - 214 2012年 [査読有り][通常論文]
     
    Real-time monitoring of cellular and organ conditions improves our understanding of various physiopathological phenomena. Such monitoring is expected to provide important alternatives for clinical diagnosis and therapy. We have sought to show physiopathological changes of organs as well as cells. Here, we present an example of in vivo imaging of liver states using the luciferase-based caspase-3 optical probe. We examined dynamic changes of apoptosis (caspase-3 activity) of a mouse liver as well as those of liver cells, proving that the emitted signals reflected the biochemically evaluated apoptotic cell death. In live liver cell (AML 12) experiments, the optical probe for caspase-3 activity emitted signals in response to Fas-ligand, staurosporine and hypoxia/reoxygenation, demonstrating that the probe can measure cellular apoptosis quantitatively. We therefore applied this probe for mouse liver ischemia/reperfusion (I/R) and drug-toxicity to liver. By expressing the probe in a mouse liver adenovirally, we imaged liver caspase-3 activity (i.e. apoptotic damage) non-invasively and chronologically in the hepatic I/R model of mice. The duration of liver ischemia affected the post-ischemic caspase-dependent damage. Ischemia (up to 60 min) enhanced liver damage after reperfusion, but prolonged ischemia (90 min of ischemia) induced not apoptotic cell death but necrotic cell death. Direct observations of the changes of organ conditions elucidated the dynamism of organ function and damage. These technologies clearly possess clinical relevance. They are expected to provide a new diagnostic tool for various clinical settings in the future.
  • Michitaka Ozaki
    Seikagaku 84 8 685 - 692 2012年 [査読有り][通常論文]
  • Takahiro Einama, Hirofumi Kamachi, Hiroshi Nishihara, Shigenori Homma, Hiromi Kanno, Kenta Takahashi, Ayami Sasaki, Munenori Tahara, Kuniaki Okada, Shunji Muraoka, Toshiya Kamiyama, Yoshihiro Matsuno, Michitaka Ozaki, Satoru Todo
    PANCREAS 40 8 1276 - 1282 2011年11月 [査読有り][通常論文]
     
    Objectives: Recent studies have shown that the high affinity of mesothelin-CA125 interaction might cause intracavitary tumor metastasis. We examined the clinicopathologic significance and prognostic implication of mesothelin and CA125 expression in pancreatic ductal adenocarcinoma. Methods: Tissue samples from 66 pancreatic ductal adenocarcinomas were immunohistochemically examined. Proportion and intensity of constituent tumor cells with mesothelin and CA125 expression were analyzed and classified as high-level expression, defined as expression by more than 50% of tumor cells and/or moderate to strong staining, or low-level expression otherwise. Results: A high level of mesothelin was correlated with a higher histological grade (P = 0.049) and the level of blood vessel permeation (P = 0.0006), whereas a high level of CA125 expression was correlated with a higher recurrence rate (P = 0.015). The expression of mesothelin was strongly correlated with that of CA125 (P = 0.0041). Co-expression of mesothelin and CA125 were associated with an unfavorable patient outcome (P = 0.0062). Conclusions: This is the first report showing that co-expression of mesothelin and CA125 were in pancreatic ductal adenocarcinoma, and such co-expression is associated with a poor prognosis. Our finding suggests that co-expression of these two factors plays a significant role in the acquisition of aggressive clinical behavior.
  • Michitaka Ozaki, Sanae Haga, Kaikobad Irani, Naoki Morita, Yoshimi Kaneshima, Takeaki Ozawa
    HEPATOLOGY 54 686A - 687A 2011年10月 [査読有り][通常論文]
  • Masatoshi Takeiri, Miyuki Tachibana, Ayumi Kaneda, Ayumi Ito, Yuichi Ishikawa, Shigeru Nishiyama, Ryoichi Goto, Kenichiro Yamashita, Susumu Shibasaki, Gentaro Hirokata, Michitaka Ozaki, Satoru Todo, Kazuo Umezawa
    INFLAMMATION RESEARCH 60 9 879 - 888 2011年09月 [査読有り][通常論文]
     
    We have previously synthesized a novel piperidine compound, 3-[(dodecylthiocarbonyl)methyl]glutarimide (DTCM-glutarimide), that inhibits LPS-induced NO production, and in the present research we studied further the anti-inflammatory activity of DTCM-glutarimide in a macrophage cell line and in mice bearing transplanted hearts. Mouse macrophage-like RAW264.7 cells were employed for the evaluation of cellular inflammatory activity. DTCM-glutarimide was synthesized in our laboratory. The AP-1 activity was measured by nuclear translocation and phosphorylation. For the heart transplantation experiment, male C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donor and recipient, respectively. DTCM-glutarimide was administered intraperitoneally. DTCM-glutarimide inhibited the LPS-induced expression of iNOS and COX-2 in macrophages; but, unexpectedly, it did not inhibit LPS-induced NF-kappa B activation. Instead, it inhibited the nuclear translocation of both c-Jun and c-Fos. It also inhibited LPS-induced c-Jun phosphorylation. Moreover, it inhibited the mixed lymphocyte reaction in primary cultures of mouse spleen cells; and furthermore, in mice it prolonged the graft survival in heart transplantation experiments. The novel piperidine compound, DTCM-glutarimide, was found to be a new inhibitor of macrophage activation, inhibiting AP-1 activity. It also inhibited graft rejection in mice, and thus may be a candidate for an anti-inflammatory agent.
  • Kazuhiro Mino, Michitaka Ozaki, Kazuaki Nakanishi, Sanae Haga, Masanori Sato, Masaya Kina, Masato Takahashi, Norihiko Takahashi, Akihiko Kataoka, Kazuyoshi Yanagihara, Takahiro Ochiya, Toshiya Kamiyama, Kazuo Umezawa, Satoru Todo
    CANCER SCIENCE 102 5 1052 - 1058 2011年05月 [査読有り][通常論文]
     
    Currently, patients with peritoneal dissemination of gastric cancer must accept a poor prognosis because there is no standard effective therapy. To inhibit peritoneal dissemination it is important to inhibit interactions between extracellular matrices (ECM) and cell surface integrins, which are important for cancer cell adhesion. Although nuclear factor-kappa B (NF-kappa B) is involved in various processes in cancer progression, its involvement in the expression of integrins has not been elucidated. We used a novel NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), to study whether NF-kappa B blocks cancer cell adhesion via integrins in a gastric cancer dissemination model in mice and found that DHMEQ is a potent suppressor of cancer cell dissemination. Dehydroxymethylepoxyquinomicin suppressed the NF-kappa B activity of human gastric cancer cells NUGC-4 and 44As3Luc and blocked the adhesion of cancer cells to ECM when compared with the control. Dehydroxymethylepoxyquinomicin also inhibited expression of integrin (alpha 2, alpha 3, beta 1) in in vitro studies. In the in vivo model, we injected 44As3Luc cells pretreated with DHMEQ into the peritoneal cavity of mice and performed peritoneal lavage after the injection of cancer cells. Viable cancer cells in the peritoneal cavities were evaluated sequentially by in vivo imaging. In mice injected with DHMEQ-pretreated cells and lavaged, live cancer cells in the peritoneum were significantly reduced compared with the control, and these mice survived longer. These results indicate that DHMEQ could inhibit cancer cell adhesion to the peritoneum possibly by suppressing integrin expression. Nuclear factor-kappa B inhibition may be a new therapeutic option for suppressing postoperative cancer dissemination. (Cancer Sci 2011; 102: 1052-1058).
  • Masato Fujiyoshi, Michitaka Ozaki
    JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 18 1 13 - 22 2011年01月 [査読有り][通常論文]
     
    Liver regeneration is a necessary process that most liver damage depends on for recovery. Regeneration is achieved by a complex interactive network consisting of liver cells (hepatocytes, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells, and stem cells) and extrahepatic organs (thyroid gland, adrenal gland, pancreas, duodenum, and autonomous nervous system). The restoration of liver volume depends on hepatocyte proliferation, which includes initiation, proliferation, and termination phases. Hepatocytes are "primed" mainly by Kupffer cells via cytokines (IL-6 and TNF-alpha) and then "proliferation" and "cell growth" of hepatocytes are induced by the stimulations of cytokines and growth factors (HGF and TGF-alpha). Liver regeneration is achieved by cell proliferation and cell growth, where the IL-6/STAT3 and PI3-K/PDK1/Akt pathways play pivotal roles, respectively. IL-6/STAT3 pathway regulates hepatocyte proliferation via cyclin D1/p21 and protects against cell death by upregulating FLIP, Bcl-2, Bcl-xL, Ref1, and MnSOD. PI3-K/PDK1/Akt is known to be responsible for regulation of cell size via its downstream molecules such as mTOR in addition to being known for its survival, anti-apoptotic and anti-oxidative properties. Although the molecular mechanisms of liver regeneration have been actively studied, the mechanisms of liver regeneration must be elucidated and leveraged for the sufficient treatment of liver diseases.
  • Sanae Haga, Naoki Morita, Kaikobad Irani, Masato Fujiyoshi, Tetsuya Ogino, Takeaki Ozawa, Michitaka Ozaki
    LABORATORY INVESTIGATION 90 12 1718 - 1726 2010年12月 [査読有り][通常論文]
     
    Liver regeneration involves complicated processes and is affected by various patho-physiological conditions. This study was designed to examine the molecular mechanisms underlying the aging-associated impairment of liver regeneration. Male C57BL/6J mice were used as young and aged mice (<10 weeks and >20 months old, respectively). These mice were subjected to 70% partial hepatectomy (PH). Liver regeneration and liver injury/stresses were evaluated chronologically after PH. Post-hepatectomy liver regeneration was markedly impaired in aged mice. Though the extent of hepatocyte proliferation in the regenerating liver was similar in aged and young mice, cell growth was absent in aged mice. Oxidative stress (OS) was observed immediately after hepatectomy, followed by marked apoptosis in aged mice. Signaling molecules regarding cell proliferation (mitogen-activated protein kinase, STAT3, p46/52(Shc)) and anti-oxidation (catalase, superoxide dismutase, Ref-1, glutathione peroxidase) were expressed/activated after hepatectomy in livers of both aged and young mice. Akt was not activated in aged-mouse liver, but its expression was similar to that in young mice. p66(Shc), known as an age-/oxidant-associated protein, was strongly phosphorylated. By knocking down p66(Shc), the impairment of liver regeneration was normalized. OS immediately after hepatectomy induced subsequent liver injury (apoptosis), and deletion of p66(Shc) suppressed both OS and hepatocyte apoptosis in the regenerating liver of aged mice. Though we need additional data in other animal models to fully understand the mechanism, p66(Shc) may have a pivotal function in the impairment of liver regeneration in aged mice by triggering OS and subsequent apoptosis. This data may provide a clue to understanding the mechanism underlying the association between aging and the impairment of liver regeneration. Laboratory Investigation (2010) 90, 1718-1726; doi:10.1038/labinvest.2010.119; published online 21 June 2010
  • Tetsuya Ogino, Michitaka Ozaki, Akihiro Matsukawa
    FREE RADICAL RESEARCH 44 11 1328 - 1337 2010年11月 [査読有り][通常論文]
     
    This paper studied the effects of physiologically available oxidants on HL 60 differentiation induced by all-trans retinoic acid (ATRA) or dimethyl sulfoxide (DMSO). Hydrogen peroxide (15 mu M) and taurine chloramine (200 mu M) induced HL 60 differentiation, which was detected by CD11b expression and superoxide production. Cd11b and p67(phox) mRNA expression was also augmented by these oxidants. In contrast, reducing chemicals, such as dithiothreitol, 2,3-dimercapto-1-propanol and N-acetylcysteine inhibited CD11b expression. Notably, DMSO inhibited methionine sulfoxide reductase activity, induced heme oxygenase-1 (ho-1) mRNA and enhanced oxidant-induced cell death, which indicated that DMSO intensified oxidative stress. After the addition of oxidants, ho-1 expression preceded the cd11b expression. Vicinal dithiol-reactive phenylarsine oxide (50 nM) also increased CD11b expression induced by DMSO or ATRA. These observations suggested that oxidative stress enhanced granulocytic differentiation of HL 60 cells and that leukaemic cell differentiation was affected by cellular redox status.
  • Shusaku Takahashi, Toshiya Kamiyama, Utano Tomaru, Akihiro Ishizu, Toshiyuki Shida, Mineji Osaka, Yutaka Sato, Yutaka Saji, Michitaka Ozaki, Satoru Todo
    ONCOLOGY REPORTS 24 5 1201 - 1212 2010年11月 [査読有り][通常論文]
     
    CD133 has been reported to be a cancer stem cell marker in colorectal cancer (CRC). The aim of this study was to examine the frequency and pattern of CD133 expression by immunohistochemical methods and evaluate their correlation with clinicopathological features, including patient survival (PS) and recurrence. Tissue specimens of 151 CRC patients who underwent surgical treatment for well-differentiated/moderately differentiated adenocarcinoma and stage I-IV tumors (TNM classification) were immunostained for analyzing CD133 expression. The frequency of CD 133 expression was 91.4% (138/151), and the pattern of expression was divided into membranous and cytoplasmic expression. Of the 151 patients, 136 (90.1%) showed membranous expression, whereas 44 (29.1%) showed cytoplasmic expression. Both expression patterns were seen in 42 (27.8%) patients. The frequency of CD133 overexpression (>50% of stained cells) was 27.2% (41/151); univariate analysis showed CD133 overexpression to be significantly associated with PS, but not recurrence, and multivariate analysis indicated it to be an independent prognostic factor. Multivariate analysis showed membranous overexpression (>50% of stained tumor cells on the membrane), which significantly correlated with histology and chemoresistance of recurrent and stage IV tumors, to be an independent prognostic factor for PS and recurrence. However, multivariate analysis did not indicate cytoplasmic expression, which significantly correlated with histology, lymph node metastasis, TNM stage and lymphatic invasion, as an independent prognostic factor for PS and recurrence. Our results demonstrated that evaluation of the frequency and pattern of CD133 expression is useful for predicting prognosis, recurrence, and chemosensitivity in CRC patients.
  • Tohru Takahashi, Shuichiro Matsumoto, Michiaki Matsushita, Hirofumi Kamachi, Yosuke Tsuruga, Hironori Kasai, Masaaki Watanabe, Michitaka Ozaki, Hiroyuki Furukawa, Kazuo Umezawa, Satoru Todo
    JOURNAL OF SURGICAL RESEARCH 163 1 E23 - E34 2010年09月 [査読有り][通常論文]
     
    Background. Currently, pancreatic islet transplantation to achieve normoglycemia in insulin-dependent diabetes mellitus (IDDM) requires two or more donors. This may be due to the inability to transplant functionally preserved and viable islets after isolation. Islets have already been subjected to various harmful stresses during the isolation process leading to apoptosis. One of the intracellular signaling pathways, the transcription factor nuclear factor-kappa B (NF-kappa B)-related pathway, is relevant to the mechanism of beta-cell apoptosis in isolated islets. We attempted to prevent islet apoptosis during isolation by a novel NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ). Materials and Methods. DHMEQ was injected intra-peritoneally into donor mice 2 h prior to isolation. NF-kappa B activation, the functioning of isolated islets, apoptosis after isolation, and cytokine- and apoptosis-related genes were analyzed. After 160 equivalents of islets were transplanted into diabetic mice, graft survival and function were evaluated. Results. Intra-islet NF-kappa B was activated immediately after isolation, and DHMEQ inhibited NF-kappa B activation without deterioration of islet function. DHMEQ significantly prevented apoptosis by inhibiting caspase 3/7 activities and down-regulated Bax, a proapoptotic gene. Donor pretreatment with DHMEQ significantly improved engraftment in syngeneic islet transplantation in mice, thus preserving insulin contents in the graft liver, as assessed by functional and histologic analyses. Conclusions. DHMEQ is a promising agent in islet transplantation because it protects islets from apoptosis during isolation stress. Donor pretreatment with DHMEQ can significantly affect the success of islet engraftment. (C) 2010 Elsevier Inc. All rights reserved.
  • Masahiro Oka, Masanobu Sakaguchi, Taro Okada, Hiroshi Nagai, Michitaka Ozaki, Toyo Yoshioka, Hiroshi Inoue, Naofumi Mukaida, Ushio Kikkawa, Chikako Nishigori
    EXPERIMENTAL DERMATOLOGY 19 8 E50 - E55 2010年08月 [査読有り][通常論文]
     
    Many melanoma cells continuously produce interleukin-8 (IL-8). The involvement of signal transducer and activator of transcription 3 (STAT3) in the constant production of IL-8 in melanoma cells was examined. The level of IL-8 production correlated well with that of the phosphorylated (activated) STAT3 in six human melanoma cell lines. Introduction of the constitutively activated form of STAT3 (STAT3-C) into WM35 melanoma cells, that show low levels of IL-8 and phosphorylated STAT3, enhanced IL-8 production. Knockdown of STAT3 suppressed IL-8 production in WM1205Lu cells that contain a high level of IL-8 accompanied by STAT3 phosphorylation. Introduction of STAT3-C markedly increased the luciferase activity in WM1205Lu cells transfected with reporter vectors linked to the 5'-flanking region of the IL-8 gene from -546 to +44 base pair (bp) and from -272 to +44 bp, but not in cells expressing reporter plasmids from -133 to +44 bp and from -98 to +44 bp. These results indicate that the upregulation of IL-8 production is caused by constitutive STAT3 activation at the level of gene transcription in melanoma cells.
  • Ayami Sasaki, Toshiya Kamiyama, Hideki Yokoo, Kazuaki Nakanishi, Kanako Kubota, Hironori Haga, Michiaki Matsushita, Michitaka Ozaki, Yoshihiro Matsuno, Satoru Todo
    ONCOLOGY REPORTS 24 2 537 - 546 2010年08月 [査読有り][通常論文]
     
    CD133 antigen has been used to identify cancer stem cells in several solid tumor types, including hepatocellular carcinomas (HCCs). The aim of this study was to investigate whether the expression and subcellular localization of CD133 correlated with the clinicopathological factors, recurrence, and survival in HCC patients. Tissue specimens from 136 HCC patients who underwent curative primary hepatectomy between 2000 and 2005 were collected and immunohistochemically analyzed for CD133 expression. Positive immunohistochemical results and subcellular localization of CD133 were determined, and the correlation between CD133 expression and clinicopathological factors of HCC patients were evaluated. CD133-positive tumor cells were observed in 30 (22.1%) cases. Cytoplasmic and membranous expressions were observed in 22 (16.2%) and 20 (14.7%) of the CD133-positive cases, respectively. Positive cytoplasmic expression of CD133 was found to be associated with the overall survival of HCC patients, especially in stage III and IVA HCC patients (p=0.0092). Univariate analysis revealed that pre-operative serum albumin, alpha-fetoprotein (AFP) levels, tumor size, portal venous invasion, and cytoplasmic CD133 expression were important risk factors in HCC. Multivariate analysis revealed that among the factors related to tumor aggressiveness, cytoplasmic expression of CD133 showed the most significant association with overall survival, although the difference was not statistically significant (P=0.0681). Cytoplasmic expression of CD133 was a significant risk factor for the overall survival of HCC patients. Patients with stage III and IVA HCC showing positive cytoplasmic expression of CD133 are more likely to have a worse prognosis.
  • Riichiro Abe, Satoshi Kishino, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo, Hiroshi Shimizu
    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 126 2 400 - 403 2010年08月 [査読有り][通常論文]
  • Nobumoto Tomioka, Keiko Morita, Nozomi Kobayashi, Mitsuhiro Tada, Tomoo Itoh, Soichiro Saitoh, Masao Kondo, Norihiko Takahashi, Akihiko Kataoka, Kazuaki Nakanishi, Masato Takahashi, Toshiya Kamiyama, Michitaka Ozaki, Takashi Hirano, Satoru Todo
    CANCER GENETICS AND CYTOGENETICS 201 1 6 - 14 2010年08月 [査読有り][通常論文]
     
    Unlike the case with some other solid tumors, whole genome array screening has not revealed prognostic genetic aberrations in primary gastric cancer. Comparative genomic hybridization (CGH) using bacterial artificial chromosome (BAC) arrays for 56 primary gastric cancers resulted in identification of four prognostic loci in this study: 6q21 (harboring FOXO3A; previously FKHRL1), 9q32 (UGCG), 17q21.1 similar to q21.2 (CASC3), and 17q21.32 (HOXB3 through HOXB9). If any one of these four loci was deleted, the prognosis of the patient was significantly worse (P = 0.0019). This was true even for advanced tumors (stage IIIA, JIB, or IV, n = 39) (P = 0.0113), whereas only 1 of the 17 patients with less advanced tumors (stage IA, IB, or II; n = 17) died of disease after surgery. Multivariate analysis according to the status of four BACs or pathological stage based on the Japanese Classification of Gastric Carcinoma (stages IA, IB, and II vs. stages IIIA, IIIB, and IV) demonstrated that the BAC clone status was also an independent prognostic factor (P = 0.006). These findings may help predict which patients with malignant potential need more intensive therapy, or may point to new therapeutic approaches especially for advanced tumors. The parameter here termed the integrated genomic prognostic biomarker may therefore be of clinical utility as a prognostic biomarker. (C) 2010 Elsevier Inc. All rights reserved.
  • Daiju Iwata, Nobuyoshi Kitaichi, Akiko Miyazaki, Kazuya Iwabuchi, Kazuhiko Yoshida, Kenichi Namba, Michitaka Ozaki, Shigeaki Ohno, Kazuo Umezawa, Kenichiro Yamashita, Satoru Todo, Susumu Ishida, Kazunori Onoe
    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 51 4 2077 - 2084 2010年04月 [査読有り][通常論文]
     
    PURPOSE. Experimental autoimmune uveoretinitis (EAU), a Th1/Th17 cell-mediated autoimmune disease induced in mice, serves as a model of human endogenous uveitis. In this model, proinflammatory cytokines and various stimuli activate the transcriptional factor, nuclear factor-kappa B (NF-kappa B), in the retina. The therapeutic effect of the NF-kappa B inhibitor, dehydroxy methyl epoxyquinomicin (DHMEQ), was examined on EAU. METHODS. EAU was induced in B10.BR mice by K2 peptide immunization. DHMEQ (40 mg/kg/d) was administered daily by intraperitoneal injection. Clinical severity and histopathologic severity were assessed. Translocation of NF-kappa B p65 into the nucleus in EAU retina was assessed. T cells were collected from draining lymph nodes of the K2-immunized mice to examine antigen (Ag)-specific T-cell active responses and cytokine production in vitro. RESULTS. Disease onset was significantly delayed in DHMEQ-treated mice (15.6 days) compared with untreated mice (12.6 days; P < 0.01). Histologic severity was significantly milder in DHMEQ-treated mice (score, 1.13) than in controls (score, 2.33; P < 0.05). DHMEQ suppressed the Ag-specific T-cell active responses and downregulated the productions of Th-1 type cytokines in vitro in a dose-dependent manner. Alternation was not observed in Th-2 type cytokines. Pretreatment of primed T cells or Ag-presenting cells with DHMEQ reduced T-cell activation and Th1/Th17 cytokine production. DHMEQ treatment suppressed the translocation of the NF-kappa B p65 subunit into the nuclei. CONCLUSIONS. Systemic administration of DHMEQ suppressed NF-kappa B translocation in the retina, which might have reduced the inflammation of ocular tissues. DHMEQ-mediated regulation of NF-kappa B p65 could be a therapeutic target for the control of endogenous ocular inflammatory diseases. (Invest Ophthalmol Vis Sci. 2010; 51: 2077-2084) DOI:10.1167/iovs.09-4030
  • Toshiaki Takezawa, Maya Fukuda, Winnette McIntosh-Ambrose, Ji-Ae Ko, Jennifer Elisseeff, Sanae Haga, Michitaka Ozaki, Kiyoko Kato, Pi-Chao Wang, Tadashi Uchino, Teruo Nishida
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 130 4 565 - 574 2010年04月 [査読有り][通常論文]
     
    The white of an egg, rendered opaque by boiling, can be converted into a thin, transparent and rigid material like glass by evaporating the moisture. This phenomenon is known as the vitrification of heat-denatured proteins. We applied vitrification technology to a collagen gel and converted it into a rigid glass-like material. We attempted to rehydrate the glass-like material and succeeded in preparing a novel stable state of collagen gel that was a thin and transparent membrane with excellent gel strength and protein permeability. We called it "collagen vitrigel" because it was produced from the vitrification process of a traditional hydrogel. Further, a framework-embedded collagen vitrigel membrane that can be easily turned inside out with tweezers was prepared by inserting a nylon membrane ring in the collagen sol prior to the gelation, thereby allowing the membrane to function as a removable cell culture substratum. Different types of anchorage-dependent cells could be cultured on both surfaces of the substratum by the manipulation of two-dimensional cultures, and consequently a three-dimensional crosstalk model with paracrine effects from each cell type was reconstructed. Also, the collagen vitrigel membrane containing a bioactive molecule provided a drug delivery system (DDS) with sustainable release. In this review, we summarize the recent progress of applied studies using the collagen vitrigel membrane as follows: a corneal model for eye irritant and permeability tests, a skin model for sensitization test, a renal glomerular model for evaluating blood filtration, an endometrial model for developing a new treatment and a DDS of hepatocyte growth factor for improving liver disorder.
  • Michitaka Ozaki, Sanae Haga, S. James Remington, Naoki Morita, Takeaki Ozawa
    HEPATOLOGY 50 4 640A - 640A 2009年10月 [査読有り][通常論文]
  • Sanae Haga, S. James Remington, Naoki Morita, Keita Terui, Michitaka Ozaki
    ANTIOXIDANTS & REDOX SIGNALING 11 10 2563 - 2572 2009年10月 [査読有り][通常論文]
     
    Noninvasive evaluation of organ redox states provides invaluable information in many clinical settings. We evaluated a newly developed reduction/oxidation-sensitive green fluorescent protein (roGFP) probe that reports cellular redox potentials and their dynamic changes in live cells. On hypoxia/reoxygenation (H/R) of AML12 liver cells, roGFP indicated mild reduction during hypoxia, but immediate transient oxidation after reoxygenation. The roGFP probe confirmed the antioxidative effects of N-acetylcysteine, catalase, redox factor-1, and Mn-SOD/CuZn-SOD against H/R-induced cellular oxidative stress (OS). In a mouse liver ischemia/reperfusion (I/R) model, roGFP transduced by using an adenoviral vector revealed immediate reduction of the liver under ischemia, and two distinct peaks of OS: (a) early, observed within 60 min after reperfusion, similar to the in vitro study; and (b) later, at 24 h. The early peak levels paralleled the ischemic time up to 75 min and the postischemic liver injury (sGOT/GPT/LDH) in the later phase (6 and 24 h after I/R). The roGFP probe successfully indicated postischemic OS of the liver in living mice, accurately predicting postischemic liver injury. This probe may represent an effective OS marker indicating organ redox states and also predicting the damage/function. Antioxid. Redox Signal. 11, 2563-2572.
  • Chun Wu, Kazuhiro Mino, Hidetoshi Akimoto, Makiko Kawabata, Koji Nakamura, Michitaka Ozaki, Yoshihiro Ohmiya
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 106 37 15599 - 15603 2009年09月 [査読有り][通常論文]
     
    We aimed to develop a far-red luminescence imaging technology for visualization of disease specific antigens on cell surfaces in a living body. First, we conjugated a far-red fluorescent indocyanine derivative to biotinylated Cypridina luciferase. This conjugate produced a bimodal spectrum that has long-wavelength bioluminescence emission in the far-red region as a result of bioluminescence resonance energy transfer. To generate a far-red luminescent probe with targeting and imaging capabilities of tumors, we then linked this conjugate to an anti-human Dlk-1 monoclonal antibody via the biotin-avidin interaction. This far-red luminescent probe enabled us to obtain high-resolution microscopic images of live, Dlk-1-expressing Huh-7 cells without an external light source, and to monitor the accumulation of this probe in tumor-bearing mice. Thus this far-red luminescent probe is a convenient analytical tool for the evaluations of monoclonal antibody localization in a living body.
  • Y. Umeda, H. Iwagaki, M. Ozaki, T. Ogino, T. Iwamoto, R. Yoshida, S. Shinoura, H. Matsuda, H. Sadamori, N. Tanaka, T. Yagi
    HEPATO-GASTROENTEROLOGY 56 93 971 - 977 2009年07月 [査読有り][通常論文]
     
    Background/Aims: Liver regeneration after surgical resection is important. The present study was designed to understand the effect of background liver damage on the rate of liver tissue regeneration after hepatectomy and the mechanism of any defective regeneration. Methodology: The subjects were 40 patients who underwent liver resection. They comprised 22 patients with chronic viral hepatitis-hepatocellular carcinoma (liver damage group) and 18 patients with hepatic metastases from colorectal cancer (normal liver group). Liver regeneration was evaluated by histopathological and immunohistochemical examination of the surgically resected tissue and by CT-scanning of the regenerated liver mass. The resected liver specimens were stained for c-met, gp-130 and nuclear factor-kappaB (NF-kappa B) proteins. Results: Liver regeneration was significantly less in the liver-damage group than in the normal-liver group. Histopathological examination showed marked inflammatory cell infiltration in the liver-damage group. Expression of c-met, but not gp-130, was significantly higher on parenchymal cells of the liver-damage group than the normal-liver group. NF-kappa B expression in parenchymal liver cells was significantly higher than in non-parenchymal cells of the normal-liver group. In the liver-damage group, liver regeneration correlated negatively with the staining intensity of NF-kappa B protein in non-parenchymal cells. These findings suggest that non-parenchymal cells are constitutively activated in the damaged liver, probably explaining the refractoriness of hepatocytes to cytokine-induced proliferation after hepatectomy, in spite of increased receptor (c-met) expression. Conclusions: The refractory response of injured hepatocytes to cytokines may explain the impaired postoperative liver regeneration in patients with damaged liver.
  • Osamu Ikeda, Michitaka Ozaki, Soichiro Murata, Ryota Matsuo, Yoritaka Nakano, Motonobu Watanabe, Katsuji Hisakura, Andriy Myronovych, Takuya Kawasaki, Keisuke Kohno, Nobuhiro Ohkohchi
    JOURNAL OF SURGICAL RESEARCH 152 2 218 - 223 2009年04月 [査読有り][通常論文]
     
    Background/Aims. The autonomic vagus nerve is thought to play an essential role in liver regeneration since hepatic vagotomy delays hepatic DNA synthesis. However, how the parasympathetic vagus nerve is involved in liver regeneration remains obscure. Kupffer cells are located in liver sinusoids adjacent to hepatocytes and might regulate liver regeneration by releasing interleukin-6 (IL-6). The present study examines the role of the vagus nerve and how Kupffer cells are involved in parasympathetic nerve-mediated liver regeneration in mice. Methods. We performed surgical vagotomy of the hepatic branch and then partial hepatectomy (PH); some mice received acetylcholine (ACh) agonist/antagonist before PH. We then evaluated liver regeneration and signal transducer and activator of transcription-3 (STAT3) activation. We also investigated whether ACh stimulates IL-6 release from Kupffer cells. Results. Surgical vagotomy impaired liver regeneration. STAT3, which is activated by IL-6 after hepatectomy and plays a pivotal role in liver regeneration, was less activated in vagotomized mice after PH. Post-PH STAT3 activation was recovered by administering vagotomized mice with an ACh agonist. Furthermore, ACh stimulated IL-6 release in Kupffer cells in vitro. Conclusion. The parasympathetic system (vagus nerve) contributes to liver regeneration after hepatectomy by stimulating IL-6 release from Kupffer cells followed by STAT3 activation in hepatocytes. (C) 2009 Elsevier Inc. All rights reserved.
  • Hidetoshi Akimoto, Hyuck Joon Kwon, Michitaka Ozaki, Kazunori Yasuda, Ken-ichi Honma, Yoshihiro Ohmiya
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 380 4 844 - 849 2009年03月 [査読有り][通常論文]
     
    It has been accepted that bone marrow cells infiltrate the brain and play important roles in neuroinflammation. However, there is no good tool for the visualization of these cells in living animals. In this study, we generated mice that were transplanted with GFP- or luciferase-expressing bone marrow cells, and performed in vivo fluorescence imaging (FLI) and in vivo bioluminescence imaging (BLI) to visualize the infiltrated cells. Brain inflammation was induced by intrahippocampal injection of lipopolysaccharide (LIPS). Immunohistochemical investigation demonstrated an increase in the infiltration of bone marrow cells into the hippocampus because of the LPS injection and differentiation of the infiltrated cells into microglia, but not into neurons or astrocytes. BLI, but not FLI, successfully detected an increase in signal intensity with the LPS injection, and the increase of BLI coincided with that of luciferase activity in hippocampus. BLI could quantitatively and continuously monitor bone marrow-derived cells in vivo. (C) 2009 Elsevier Inc. All rights reserved.
  • Tetsuya Ogino, Michitaka Ozaki, Mutsumi Hosako, Masako Omori, Shigeru Okada, Akihiro Matsukawa
    LEUKEMIA RESEARCH 33 1 151 - 158 2009年01月 [査読有り][通常論文]
     
    Leukemic cell apoptosis may be enhanced by appropriate oxidative stress. We report here the mechanism of Jurkat cell apoptosis by monochloramine (NH(2)Cl), a neutrophil-derived oxidant. NH(2)Cl induced caspase-dependent apoptosis, which was preceded by cytochrome c and Smac/Diablo release from mitochondfia. Within 10 min of NH(2)Cl treatment, c-Jun N-terminal kinase (JNK) activation and elevation of cytosolic Ca(2+) were observed. JNK inhibitors (SP600125 or JNK inhibitor VIII) significantly suppressed the apoptosis as well as caspase cleavage and cytochrome c release. In contrast, Ca(2+) chelation by EGTA + acetoxymethyl-EGTA had no effects on apoptosis. Our results indicated that JNK activation contributed most importantly to the NH(2)Cl-induced apoptosis. (C) 2008 Elsevier Ltd. All fights reserved.
  • Sanae Haga, Michitaka Ozaki, Hiroshi Inone, Yasuo Okamoto, Wataru Ogawa, Kiyoshi Takeda, Shizuo Akira, Satoru Todo
    HEPATOLOGY 49 1 204 - 214 2009年01月 [査読有り][通常論文]
     
    Liver regeneration comprises a series of complicated processes. The current study was designed to investigate the roles of phosphoinositide-dependent protein kinase 1 (PDK1)-associated pathways in liver regeneration after partial hepatectomy (PH) using liver-specific Pdk1-knockout (L-Pdk1KO) and Pdk1/STAT3 double KO (L-DKO) mice. There was no liver regeneration, and 70% PH was lethal in L-Pdk1KO mice. Liver regeneration was severely impaired equally in L-Pdk1KO and L-DKO mice, even after nonlethal 30% PH. There was no cell growth (measured as increase of cell size) after hepatectomy in L-Pdk1KO mice, although the post-PH mitotic response was the same as in controls. As expected, hepatectomy did not induce hepatic Akt-phosphorylation (Thr308) in L-Pdk1KO mice, and post-PH phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase (P70(S6K)), and S6 were also reduced. To examine the specific role of PDK1-associated signals, a "pif-pocket" mutant of PDK1, which allows PDK1 only to phosphorylate Akt, was used. Liver regeneration was recovered in L-Pdk1KO mice with a "pif-pocket" mutant of PDK1. This re-activated Akt in L-Pdk1KO mice liver and induced post-PH cell growth, without affecting cell proliferation. Further deletion of STAT3 (L-DKO mice) did not further deteriorate liver regeneration, although this certainly reduced post-PH mitotic response. These findings indicate that PDK1/Akt contribute to liver regeneration by regulating cell size. Regarding phosphatidylinositol-3 kinase (PI3-K), immediate upstream signal of PDK1, activation of PI3-K induced cell proliferation via STAT3 activation in the liver of L-Pdk1KO mice but did not improve impaired liver regeneration. This confirmed the pivotal role of PDK1 in liver regeneration and cell growth. Conclusion: PDK1/Akt-mediated responsive cell growth is essential for normal liver regeneration after PH, especially when cell proliferation is impaired. (HEPATOLOGY 2009;49:204-214.)
  • Tetsuya Ogino, Tint Aung Than, Mutsumi Hosako, Michitaka Ozaki, Masako Omori, Shigeru Okada
    Taurine 7 643 451 - 461 2009年 [査読有り][通常論文]
     
    Taurine is abundant in polymorphonuclear leukocytes (PMNs) where it reacts with PMN-derived hypochlorous acid to form taurine chloramine (Tau-NHCl), a substance that does not readily cross the cell membrane. When PMNs were stimulated in PBS lacking taurine, extracellular oxidant concentration was low, but the concentration increased 3-4 fold when 15 mM taurine was added, indicating that taurine lowers oxidant levels inside the cell. When Tau-NHCl was added to Jurkat cells in suspension, its half life was about 75 min. In contrast, membrane-permeable ammonia mono-chloramine (NH(2)Cl) has a half life of only 6 min. Accordingly, NH(2)Cl oxidizes cytosolic proteins, such as I kappa B, and inhibits NF-kappa B activation, whereas Tau-NHCl exhibits no comparable effect. However, when NH(4)(+) was added to the medium, Tau-NHCl oxidizes I kappa B and inhibits NF-kappa B activation, probably through oxidant transfer to NH(4)(+) leading to NH(2)Cl formation. These results indicate that Tau-NHCl can serve as an oxidant reservoir, exhibiting either delayed oxidant effects or acting as an oxidant at a distant site.
  • Yimin, Masashi Kohanawa, Michitaka Ozaki, Sanae Haga, Keiko Fujikawa, Songji Zhao, Yuji Kuge, Nagara Tamaki
    MICROBES AND INFECTION 10 14-15 1450 - 1458 2008年11月 [査読有り][通常論文]
     
    The interaction between interleukin-10 (IL-10) and interleukin-6 (IL-6) was investigated in the inflammatory response to Rhodococcus aurantiacus (R. aurantiacus) infection, in which both cytokines act as anti-inflammatory cytokines. Compared with wild-type (WT) counterparts, IL-6 gene-deficient (IL-6(-)/(-)) mice mounted a more robust production of IL-10 and tumor necrosis factor-alpha (TNF-alpha) during the initial phase of infection. Administration of anti-IL-10 antibody resulted in all the mice dying within 3 days post-infection as well as a further elevated TNF-alpha release. In vitro challenge of the macrophages from IL-6(-)/(-) and WT mice with heat-killed R. aurantiacus also showed similar results. Addition of exogenous IL-6 depressed IL-10 and TNF-alpha production by either IL-6(-)/(-) mice or IL-6(-)/(-) mouse macrophages. Likewise, WT mouse macrophages pretreated with anti-IL-10 or anti-IL-6 antibody exhibited increased production of TNF-alpha and IL-6 or IL-10 respectively. Moreover, neutralization of both IL-10 and IL-6 induced a further increase in TNF-alpha production by WT mouse cells. Overall, we conclude that IL-10 is a key element in protecting mice against mortality, and that IL-10 and IL-6 production are negatively regulated by each other although they are additive in suppressing TNF-alpha release in R. aurantiacus-infected mouse model. (C) 2008 Elsevier Masson SAS. All rights reserved.
  • Tomomi Suzuki, Kenichiro Yamashita, Wataru Jomen, Shinya Ueki, Takeshi Aoyagi, Moto Fukai, Hiroyuki Furukawa, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo
    JOURNAL OF SURGICAL RESEARCH 149 1 69 - 75 2008年09月 [査読有り][通常論文]
     
    Background. Nuclear factor-kappa B regulates the expression of several genes involved in inflammation, the immune response, apoptosis, cell survival, and proliferation. Many of these same genes are activated during ischemia/reperfusion (I/R) injury. Here, we examined the anti-inflammatory efficacy of a newly developed nuclear factor-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in the intestinal I/R injury model of rats. Materials and methods. Intestinal ischemia was induced by occluding the superior mesenteric artery for 60 min. The experimental animals were divided into two groups: untreated group, control; treated group, DHMEQ-treated (20 mg/kg). DHMEQ were administered intraperitoneally at 60 min prior to clamping and 5 min prior to reperfusion. Animal survival rates, intestinal tissue blood flow, serum levels of tumor necrosis factor-alpha, and interleukin-6, and the histopathology of both the intestine and the lung were analyzed. Results. The DHMEQ-treated animals exhibited higher values of intestinal tissue blood flow and suppression of tumor necrosis factor-alpha and interleukin-6 production, resulting in marked prolongation of their survival times. Histopathological findings obtained by examining tissues from control animals revealed severe intestinal mucosal damage and disruption of the lung alveolar architecture accompanied by hemorrhage and marked neutrophilic infiltration. These findings were significantly ameliorated in DHMEQ-treated animals. Conclusion. DHMEQ effectively prevented both intestine and lung injuries in rat intestinal I/R models. This agent may possess a good potency for clinical application in various pathological settings including intestinal I/R and/or inflammatory acute lung injury. (c) 2008 Elsevier Inc. All rights reserved.
  • Etsuko Watanabe, Nobuo Mochizuki, Hidetomo Ajima, Keiko Ohno, Mitsuhiro Shiino, Kazuo Umezawa, Moto Fukai, Michitaka Ozaki, Hiroyuki Furukawa, Satoru Todo, Satoshi Kishino
    JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES 871 1 32 - 36 2008年08月 [査読有り][通常論文]
     
    We have developed a simple and reliable method for determining plasma concentration of dehydroxymethylepoxyquinomicin (DHMEQ), a new low molecular weight NF-kappa B inhibitor, using high performance liquid chromatography with mass spectrometry (LC-MS). An experiment of mass spectrometry with electrospray ionization in the negative ionization mode was performed to detect ion transitions at m/z 260.05 [M-H](-) for DHMEQ and 240.29 for mefenamic acid as an internal standard. The samples were purified using liquid-liquid extraction with ethyl acetate. The method yielded a standard curve which was linear for the concentration range of 0.1-125 ng/mL when 0.05 mL plasma was used. The correlation coefficients of all standard curves were greater than or equal to 0.999. The limit of detection was 50 pg/mL (signal/noise >3). Daily fluctuation of plasma standard curve was small. The intra- and inter-assay precision ranged from 2.84 to 4.76% (n = 6) and 2.91 to 7.03% (n = 6), respectively. The LC-MS technique described provides a simple and reliable liquid chromatographic method for the determination of DHMEQ level and for use in studies involving pharmacokinetics. (C) 2008 Elsevier B.V. All rights reserved.
  • Naoto Gotohda, Hiromi Iwagaki, Michitaka Ozaki, Taira Kinoshita, Masaru Konishi, Toshio Nakagohri, Shinichiro Takahashi, Shinya Saito, Takahito Yagi, Noriaki Tanaka
    HEPATO-GASTROENTEROLOGY 55 85 1400 - 1403 2008年07月 [査読有り][通常論文]
     
    Background/Aims: Liver damage after hepatectomy is still a serious concern. The present study was designed to clarify the relations between liver injury/surgical stress and cytokines after hepatectomy, in patients with viral hepatitis. Methodology: Ten consecutive patients undergoing hepatectomy were studied, all with hepatocellular carcinoma due to viral hepatitis. Blood samples for interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), hepatocyte growth factor (HGF), soluble Fas (sFas), soluble Fas Ligand and soluble tumor necrosis factor receptor (sTNFR) assays were collected before the operation and at the end of the operation. Results: There was a significant and positive correlation between the change in the serum level of HGF and preoperative liver function (ICG-R15). Notably, there were significant correlations between surgical stress and IL-6, HGF and sFas, but not sIL-6R and sTNFR. Furthermore, there was significant correlation between postoperative Ever function (total bilirubin, albumin) and HGF, IL-6. Conclusions: There was a close relationship between surgical stress and HGF, IL-6 and sFas after hepatectomy in patients with viral hepatitis. It was useful for the evaluation of surgical stress of hepatectomy to estimate the serum level of HGF, IL-6 and sFas.
  • Naoto Gotohda, Hiromi Iwagaki, Michitaka Ozaki, Taira Kinoshita, Masaru Konishi, Toshio Nakagohri, Shinichiro Takahashi, Shinya Saito, Takahito Yagi, Noriaki Tanaka
    HEPATO-GASTROENTEROLOGY 55 85 1439 - 1444 2008年07月 [査読有り][通常論文]
     
    Background/Aims: Liver regeneration after surgical resection is still a serious concern. The present study is designed to understand the relations between liver injury/regeneration and cytokines after hepatectomy with viral hepatitis. Methodology: Twenty-one consecutive patients undergoing liver resection were studied, which included two patients with biliary tract cancer, three patients with hepatic metastases from colorectal cancer, and sixteen patients with primary liver tumor. They were also divided into two groups according to the existence of chronic viral hepatitis: 10 patients with viral hepatitis and 11 patients without viral hepatitis. Results: Viral hepatitis reduced pre-operative liver function (ICG-R15 and platelet count) with raised levels of sFas. Interestingly, this also reduced postoperative surge of IL-6, but not HGF, though they were equally at basal levels pre-operatively. Recovery of liver size, calculated with resected liver mass and volumetry with CT scan, was deteriorated in liver with viral hepatitis, but any difference of postoperative liver damage was observed between two groups. Conclusions: Viral infection, somehow, increased sFas level pre-operatively, but does not influence the post-operative liver injury. Deficient response of IL-6, but not HGF, may be a major cause for poor liver regeneration after hepatectomy in patients with viral hepatitis independent from liver injury.
  • Ryota Matsuo, Nobuhiro Ohkohchi, Soichiro Murata, Osamu Ikeda, Yoritaka Nakano, Motonobu Watanabe, Katsuji Hisakura, Andriy Myronovych, Tomomi Kubota, Hisashi Narimatsu, Michitaka Ozaki
    JOURNAL OF SURGICAL RESEARCH 145 2 279 - 286 2008年04月 [査読有り][通常論文]
     
    Background. It is well known that platelets have a thrombotic effect. However, platelets play an important role not only in hemostasis but also in wound healing and tissue regeneration. Platelets have been reported to accumulate in the liver and promote liver regeneration after an extended hepatectomy, but the mechanism is unclear. The present study was designed to clarify the mechanism by which platelets have a direct proliferative effect on hepatocytes in vitro. Materials and methods. Hepatocytes obtained from male BALB/c mice by collagenase digestion and immortalized hepatocytes (TLR2) were used. To elucidate the mechanism of the proliferative effect of platelets, DNA synthesis of hepatocytes was measured under various conditions and the related cellular signals were analyzed. Chromatographic analysis was also performed to clarify which elements of platelets have mitogenic activity. Results. DNA synthesis significantly increased in the hepatocytes cultured with platelets (P < 0.001). However, when the platelets and hepatocytes were separated, the platelets did not have a proliferative effect. Whole disrupted platelets, the supernatant fraction, and fresh isolated platelets had a similar proliferative effect, while the membrane fraction did not. After the addition of platelets, both Akt and extracellular signal-regulated kinases ERK1/2 were activated, but extracellular signal-regulated kinase STAT3 was not activated. Some mitogenic fractions were obtained from the platelet extracts by gel exclusion chromatography; the fractions were rich in hepatocyte growth factor and IGF-1. Conclusions. Direct contact between platelets and hepatocytes was necessary for the proliferative effect. The direct contact initiated signal transduction involved in growth factor activation. Hepatocyte growth factor, vascular endothelial growth factor, and insulin-like growth factor-1, rather than platelet-derived growth factor, mainly contributed to hepatocyte proliferation. (C) 2008 Elsevier Inc. All rights reserved.
  • Hui-Qi Zhang, Sanae Haga, Moto Fukai, Yuko Oikawa, Hiroshi Inoue, Wataru Ogawa, Arihiko Kano, Atsushi Maruyama, Xin-Yuan Fu, Satoru Todo, Shin Enosawa, Michitaka Ozaki
    Hepatology Research 38 4 374 - 384 2008年04月 [査読有り][通常論文]
     
    The process of liver regeneration is regulated by complex mechanisms. Although signal transducer and activator of transcription-3 (STAT3), a transcription factor which targets mainly mitotic genes, definitely plays an important role in liver regeneration, the exact roles of STAT3 are not completely understood. Aim: In this report, we tried to search for a new target of STAT3 involved in liver regeneration in mice. Methods: We generated liver-specific STAT3 knockout (L-S3KO) mice and a STAT3 knockout cell line of mouse origin. Using chromatin immunoprecipitation, we screened 12 genes to which STAT3 binds after partial hepatectomy (PH). Of these genes, we analyzed the S3-IE3 clone that is located on chromosome-3 and possesses STAT3 binding sites in it. Results: We showed that STAT3 binds to a specific site on S3-IE3, and that interleukin-6 (IL-6) stimulates its transcriptional activity. The mRNA and protein levels of the net gene, which is located downstream of S3-IE3, were negatively regulated in the control cells, but not in the STAT3 knockout cells after IL-6 stimulation. Similarly in in vivo mouse PH, the mRNA and protein levels of net were also negatively regulated after PH, but not in L-S3KO mice. Conclusion: The net gene is located downstream of a newly-recognized STAT3 binding site (S3-IE3) and negatively regulated after IL-6 stimulation and PH, although its role is still unclear. © 2007 The Japan Society of Hepatology.
  • Sanae Haga, Keita Terui, Moto Fukai, Yuko Oikawa, Kaikobad Irani, Hiroyuki Furukawa, Satoru Todo, Michitaka Ozaki
    JOURNAL OF HEPATOLOGY 48 3 422 - 432 2008年03月 [査読有り][通常論文]
     
    Background/Aims:Ischemia/reperfusion damage to the liver remains a serious concern in many clinical situations. Major mechanisms for this certainly include oxidative stress. Methods:The effects of ablating the p66 isoform of ShcA (p66(shc)) on hypoxia/reoxygenation (H/R)-induced oxidative stress and cell injury in hepatocytes were investigated. Results: Immediately after reoxygenation, AML12 cells were clearly under oxidative stress; many cells underwent apoptosis. However, knockdown of p66(shc) by specific RNAi markedly decreased cellular oxidative stress and H/R-induced apoptosis, as well as conferring resistance to H2O2 insult. These data suggest that prevention of apoptosis conferred by ablation of p66(shc) results from changed ROS-scavenging, but not inhibition of ROS generation. These data were also confirmed in fibroblasts from p66(shc) knockout mice. Anti-oxidant molecules, such as MnSOD and Ref-1 and the anti-apoptotic molecule Bcl-xL were up-regulated, and pro-apoptotic FLICE was down-regulated, by ablation of p66. Interestingly, catalase expression was not affected in p66(shc)-knockdown-AML12 cells although it is a major target in other cell types. Conclusions: Our findings suggest that in hepatocytes, ablation of p66 A, is cytoprotective against H/R-induced oxidative stress, with MnSOD and Ref-1 playing critical roles, and with up-regulation of Bcl-xL and down-regulation of FLICE contributing jointly to preventing cells from undergoing oxidant-induced apoptosis. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Yoshiaki Miura, Megumi Hato, Yasuro Shinohara, Hiromitsu Kuramoto, Jun-ichi Furukawa, Masaki Kurogochi, Hideyuki Shimaoka, Mitsuhiro Tada, Kazuaki Nakanishi, Michitaka Ozaki, Satoru Todo, Shin-Ichiro Nishimura
    MOLECULAR & CELLULAR PROTEOMICS 7 2 370 - 377 2008年02月 [査読有り][通常論文]
     
    Recent progress in mass spectrometry has led to new challenges in glycomics, including the development of rapid glycan enrichment techniques. A facile technique for exploration of a carbohydrate-related biomarker is important because proteomics research targets glycosylation, a posttranslational modification. Here we report an "all-in-one" protocol for high throughput clinical glycomics. This new technique integrates glycoblotting-based glycan enrichment onto the BlotGlycoABC(TM) bead, on-bead stabilization of sialic acids, and fluorescent labeling of oligosaccharides in a single workflow on a multiwell filter plate. The advantage of this protocol and MALDI-TOF MS was demonstrated through differentiation of serum N-glycan profiles of subjects with congenital disorders of glycosylation and hepatocellular carcinoma and healthy donors. The method also permitted total cellular glycomics analysis of human prostate cancer cells and normal human prostate epithelial cells. These results demonstrate the potentials of glycan enrichment/processing for biomarker discovery.
  • Michitaka Ozaki
    Seikagaku 80 5 399 - 408 2008年 [査読有り][通常論文]
  • Michitaka Ozaki, Satoru Todo
    LIVER TRANSPLANTATION 13 12 1623 - 1626 2007年12月 [査読有り][通常論文]
  • Hiroki Suemoto, Yasuteru Muragaki, Katsuhiro Nishioka, Misako Sato, Akira Ooshima, Shunji Itoh, Ikuji Hatamura, Michitaka Ozaki, Attila Braun, Erika Gustafsson, Reinhard Faessler
    DEVELOPMENTAL BIOLOGY 312 2 572 - 581 2007年12月 [査読有り][通常論文]
     
    Mutations in the TRPSl gene lead to the tricho-rhino-phalangeal syndrome, which is characterized by skeletal defects and abnormal hair development. The TRPSl gene encodes an atypical member of the GATA-type family of transcription factors. Here we show that mice with a disrupted Trpsl gene develop a chondrodysplasia characterized by diminished chondrocyte proliferation and decreased apoptosis in growth plates. Our analyses revealed that Trpsl is a repressor of Stat3 expression, which in turn controls chondrocyte proliferation and survival by regulating the expression of cyclin Dl and Bcl2. Our conclusion is supported (i) by siRNA-mediated depletion of Stat3 in Trpsl-deficient chondrocytes, which normalized the expression of cyclin Dl and Bcl2, (ii) by overexpression of Trpsl in ATDC5 chondrocytes, which diminished Stat3 levels and increased proliferation and apoptosis, and (iii) by mutational analysis of the GATA-binding sites in the Stat3 gene, which revealed that their integrity is critical for the direct association with Trpsl and for Trpsl-mediated repression of Stat3. Altogether our findings identify Trpsl as a novel regulator of chondrocytes proliferation and survival through the control of Stat3 expression. (c) 2007 Elsevier Inc. All rights reserved.
  • Hiroshi Murata, Takahito Yagi, Hiromi Iwagaki, Tetsuya Ogino, Hiroshi Sadamori, Hiroyoshi Matsukawa, Yuzoh Umeda, Sanae Haga, Noriaki Takaka, Michitaka Ozaki
    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 22 12 2173 - 2180 2007年12月 [査読有り][通常論文]
     
    Background and Aim: The mechanism of injury in steatotic liver under pathological conditions been extensively examined. However, the mechanism of an impaired regeneration is still not well understood. The aim of this study was to analyze the mechanism of impaired regeneration of steatotic liver after partial hepatectomy (PH). Methods: db/db fatty mice and lean littermates were used for the experiments. Following 70% PH, the survival rate and recovery of liver mass were examined. Liver tissue was histologically examined and analyzed by western blotting and RT-PCR. Results: Of 35 db/db mice, 25 died within 48 h of PH, while all of the control mice survived. Liver regeneration of surviving db/db mice was largely impaired. In db/db mice, mitosis of hepatocytes after PH was disturbed, even though proliferating cell nuclear antigen (PCNA) expression (G1 to S phase marker) in hepatocytes was equally observed in both mice groups. Interestingly, phosphorylation of Cdc2 in db/db mice was suppressed by reduced expression of Wee1 and Myt1, which phosphorylate Cdc2 in S to G2 phase. Conclusions: In steatotic liver, cell-cycle-related proliferative disorders occurred at mid-S phase after PCNA expression. Reduced expression of Wee1 and Myt1 kinases may therefore maintain Cdc2 in an unphosphorylated state and block cell cycle progression in mid-S phase. These kinases may be critical factors involved in the impaired liver regeneration in fatty liver.
  • Takanori Oyama, Hiroshi Sadamori, Hiroyoshi Matsukawa, Hiroshi Murata, Yuzou Umeda, Yasuhiro Watanabe, Michitaka Ozaki, Hiromi Iwagaki, Noriaki Tanaka, Takahito Yagi
    HEPATO-GASTROENTEROLOGY 54 79 2078 - 2083 2007年10月 [査読有り][通常論文]
     
    Background/Aims: The mechanisms whereby grafts in the recipients can be primed for regeneration following living donor liver transplantation (LDLT) are poorly understood. The present study was designed to understand the mechanism for post-transplant regeneration in small-for-size liver graft. Methodology: Out of LDLT cases, we examined patients with end-stage liver cirrhosis and subsequent transplantation. A total of 16 patients were divided into 2 groups, group L (large graft) and group S (small graft). We examined the serum biochemical markers and cytokines preoperatively and postoperatively. We also carried out hemodynamic analysis by measuring the portal and arterial peak velocity. Results: The differences in ages, preoperative bio-chemical markers and MELD score between the two groups were not statistically significant. Though differences in the preoperative levels of IL-6, sIL-6R and HGF were not significant between the two groups, IL-6 and HGF levels in group S significantly increased postoperatively. Immediate and significant increase of Vp max was also observed in group S. Two weeks after LDLT, the regeneration rate in group S was significantly higher than that in group L. Conclusions: These findings may allow us to speculate that immediate increase of portal pressure, reflecting sinusoidal tensile/shear stress, accelerates liver regeneration through immediate induction of IL-6 and HGF.
  • SF-044-3 副交感神経のもつ肝再生制御メカニズムの解明(第107回日本外科学会定期学術集会)
    池田, 治, 村田, 聡一郎, 松尾, 亮太, 中野, 順隆, 渡辺, 基信, 久倉, 勝治, 尾崎, 倫孝, 大河内, 信弘
    日本外科学会雑誌 108 2 228  社団法人日本外科学会 2007年03月 [査読無し][通常論文]
  • Shinya Ueki, Kenichiro Yamashita, Takeshi Aoyagi, Sanae Haga, Tomomi Suzuki, Tomoo Itoh, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    TRANSPLANTATION 82 12 1720 - 1727 2006年12月 [査読有り][通常論文]
     
    Background. Nuclear factor (NF)-kappa B plays a crucial role in lymphocyte activation, proliferation, and survival. We examined the immunosuppressive effect of a newly developed NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) in allotransplantation. Methods. Purified C57BL/6 (H-2(b)) T cells were used for in vitro studies examining activation, proliferation, cytokine production and nuclear NF-kappa B and nuclear factor of activated T cells (NFAT) protein levels. A fully major histocompatibility complex incompatible BALB/c (H-2(d))-to-C57BL/6 mice cardiac transplantation model was utilized for in vivo studies. DHMEQ was given intraperitoneally to transplant recipients at a various dose starting from day 0. In some, DHMEQ was administered concomitantly with tacrolimus. Results. DHMEQ significantly suppressed alpha CD3 + alpha CD28 monoclonal antibody-triggered T-cell proliferation, CD25/CD69 expressions, and both interleukin-2 and interferon (IFN)-gamma production in a dose-dependent fashion. DHMEQ blocked nuclear translocation of NF-kappa B but not NFAT in activated T cells. Combined treatment with DHMEQ and tacrolimus significantly suppressed T cell activation as compared to that of mono-therapy with either agent alone. Single DHMEQ treatment moderately prolonged cardiac allograft survival. Further, combination of DHMEQ plus tacrolimus markedly prolonged graft mean survival time (MST) to 59.5 days when compared to either DHMEQ (MST: 10 days) or tacrolimus (MST: 13 days) treatment alone. Such effect was associated with inhibition of mixed lymphocyte reaction against donor antigen, IFN-gamma producing splenocytes and graft cellular infiltration as examined at 5 and 12 days posttransplantation. Conclusion. DHMEQ inhibits nuclear translocation of NF-kappa B but not NFAT inactivated T cells, and prolongs allograft survival. Blocking both NF-kappa B and NFAT by DHMEQ and tacrolimus induces potent immunosuppression, which may become a new modality in controlling allograft rejection.
  • Hideaki Miyaso, Yoshinori Morimoto, Michitaka Ozaki, Sanae Haga, Susumu Shinoura, Yasuhiro Choda, Hiroshi Murata, Goutaro Katsuno, Kamul Huda, Hideo Takahashi, Noriaki Tanaka, Hiromi Iwagaki
    DIGESTIVE DISEASES AND SCIENCES 51 11 2007 - 2012 2006年11月 [査読有り][通常論文]
     
    Nafamostat mesilate (NM) is a synthetic protease inhibitor with various biological effects. To determine its effect on liver injury related to sepsis, we investigated the effects of NM on lipopolysaccharide (LPS)-induced liver injury. Wistar rats were allocated into two groups; the NM group underwent intraperitoneal NM administration 30 min before LPS administration, and the control group underwent PBS administration. Serum AST and ALT levels were significantly decreased in NM-treated rats. Reduced levels of TNF-alpha, IL-1 beta, and IFN-gamma were observed after LPS administration in NM-treated rats. No significant differences were observed in IL-6 levels between the NM and the control group. In contrast, HGF levels were significantly increased only in control rats. NM treatment decreased protein and mRNA levels of TLR-4 and CD14. Our data suggest that NM treatment has protective effects against LPS-induced hepatotoxicity through downregulation of TLR4 and CD14 in liver, which decreased TNF-alpha, IL-1 beta, and IFN-gamma production in liver.
  • Toshiya Kamiyama, Masato Takahashi, Takahito Nakagawa, Kazuaki Nakanishi, Hirofumi Kamachi, Tomomi Suzuki, Tsuyoshi Shimamura, Masahiko Taniguchi, Michitaka Ozaki, Michiaki Matsushita, Hiroyuki Furukawa, Satoru Todo
    ANNALS OF SURGERY 244 3 451 - 463 2006年09月 [査読有り][通常論文]
     
    Objective: To determine whether detection of hepatocellular carcinoma (HCC) cells by real-time quantitative RT-PCR targeting of alpha-fetoprotein mRNA (AFP mRNA) before or after curative hepatectomy predicts HCC recurrence and patient survival. Summary Background Data: The presence of cancer cells in peripheral blood and/or bone marrow in patients with malignant disease has been reported to correlate with outcome. Methods: Between July 2000 and June 2005, 136 consecutive HCC patients underwent primary curative hepatectomy. Bone marrow aspirated preoperatively, and peripheral blood samples collected before and after operation were subjected to real-time quantitative RT-PCR analysis using AFP mRNA as a target molecule. Median follow-up was 23 months (range, 6-54 months). Patient survival (PS), disease-free survival (DFS), and clinicopathologic features were compared between patients with positive and negative AFP mRNA. Results: Twenty-four patients died (22 from HCC). HCC recurred in 66 patients (hepatic in 37 [56.1%]; hepatic and remote in 17 [25.8%], and remote alone in 12 [18.2%]). Bone marrow was positive for AFP mRNA in 38 patients (27.9%) and negative in 98 (72.1%). One- and 3-year PS was 96.6% and 91.4%, respectively, with negative AFP mRNA versus 86.2% and 55.5%, respectively, with positive AFP mRNA (P < 0.0001). One- and 3-year DFS were 73.2% and 44.8%, respectively, with negative AFP mRNA versus 54.5% and 25.8%, respectively, with positive AFP mRNA (P = 0.0399). Portal vascular invasion, tumor size, multiple tumors, and tumor differentiation correlated with inferior PS and DFS on univariate analysis. On multivariate analysis, positive AFP mRNA was the most important risk factor for PS (P = 0.001) and DFS (P = 0.0165). In addition, positive AFP mRNA in peripheral blood after operation tended to predict reduced DFS. Conclusion: AFP mRNA in the bone marrow and systemic circulation during the perioperative period predicts patient survival and recurrence after curative hepatic resection for HCC.
  • KASM Huda, L Guo, S Haga, H Murata, T Ogino, M Fukai, T Yagi, H Iwagaki, N Tanaka, M Ozaki
    TRANSPLANT INTERNATIONAL 19 5 415 - 423 2006年05月 [査読有り][通常論文]
     
    Signal transducer and activator of transcription-3 (STAT3) is one of the most important transcription factors for liver regeneration. This study was designed to examine the effects of constitutively activated STAT3 (STAT3-C) on post-transplant liver injury and regeneration in a rat 20% partial liver transplant (PLTx) model by ex vivo adenoviral gene transfer. Adenovirus encoding the STAT3-C gene was introduced intraportally into liver grafts and clamped for 30 min during cold preservation. After orthotopic PLTx, liver graft/body weights and serum biochemistry were monitored, and both a histological study and DNA binding assay were performed. STAT3-C protein expression and its binding to DNA in the liver graft were confirmed by Western blotting and electrophoretic mobility shift assay (EMSA), respectively. This treatment modality promoted post-Tx liver regeneration effectively and rapidly. The serum levels of alanine aminotransferase/aspartate aminotransferase (AST/ALT) and bilirubin decreased in rats with STAT3-C. However, albumin (a marker of liver function) did not. Ex vivo gene transfer of STAT3-C to liver grafts reduced post-Tx injury and promoted liver regeneration. Thus, the activation of STAT3 in the liver graft may be a potentially effective clinical strategy for improving the outcome of small-for-size liver transplantation.
  • Hiramatsu K, Ogino T, Ozaki M, Okada S
    Biochimica et biophysica acta 1763 2 188 - 196 2006年02月 [査読有り][通常論文]
  • Naoto Gotohda, Hiromi Iwagaki, Michitaka Ozaki, Masaru Konishi, Toshio Nakagohri, Shinichiro Takahashi, Takahiro Yagi, Taira Kinoshita and Noriaki Tanaka. The role of a Protease Inhibitor against Hepatectomy. Hepato-Gastroenterology 53: 115-119, 2006
    2006年 [査読無し][通常論文]
  • S Tsukiyama, M Matsushita, S Matsumoto, T Morita, S Kobayashi, H Tamura, H Kamachi, M Ozaki, S Todo
    TISSUE ENGINEERING 12 1 131 - 140 2006年01月 [査読有り][通常論文]
     
    In vitro proliferation of functional islet mass/beta-cells by transduction of cell cycle regulatory genes has not been well documented due to the lack of either an effective method for gene transduction to islets or effective genes for beta-cell proliferation. Signal transducers and activators of transcription-3 (Stat3) are among the most important molecules for cell proliferation and for cell antiapoptosis. In this study, adenovirus-mediated gene transduction was performed on dispersed islet cells, and reaggregated islet mass functions, such as capabilities for reaggregation, proliferation, and glucose-stimulated insulin secretion (GSIS), were evaluated. The constitutively activated form of Stat3 (Stat3-C) was effectively transduced to most of the islet cells, even at a low density of adenovirus vector. There was no difference in the spontaneous reaggregation capability between Stat3-C transduced and control islet cells. BrdU incorporation in Stat3-C-transduced islet cells was significantly higher (2.8-fold) than that in the control cells, and it was significantly elevated (4-fold) by the addition of HGF in culture media. GSIS in Stat3-C-transduced islet cells was preserved to the level in controls by 5 days in culture. The results indicated that gene transduction into islet cells could be enhanced by first dispersing the cells. Stat3-C induced cell proliferation of beta-cells without loss of insulin secretion activity at the glucose challenge, and HGF enhanced the beta-cell proliferative activity of Stat3-C.
  • N Gotohda, H Iwagaki, M Ozaki, M Konishi, T Nakagohri, S Takahashi, T Yagi, T Kinoshita, N Tanaka
    HEPATO-GASTROENTEROLOGY 53 67 115 - 119 2006年01月 [査読有り][通常論文]
     
    Background/Aims: Nafamostat Mesilate (NM) is a synthetic serine protease inhibitor that is capable of inhibiting the various coagulation factors. To determine whether NM may also be useful in attenuating operative invasiveness, we investigated the effects of perioperative administration of NM on postoperative serum levels of proinflammatory cytokine IL-6 and hepatocyte growth factor (HGF). Methodology: Thirty patients undergoing hepatectomy with hepatocellular carcinoma, biliary carcinoma and metastatic colorectal cancer were enrolled in this study. These patients were separated into two groups; high invasive group (resected liver volume: 1000cm(3) <) and less invasive group (resected liver volume: 1000cm(3) >). The high invasive group of 11 patients received perioperative administration of NM (G roup NM), while the less invasive group of 19 patients did not (Group C). Serum levels of IL-6, HGF and soluble IL-6 receptor (sIL-6R) were simultaneously measured on preoperative and postoperative day ('day 0', 'day 7'). Results: Serum IL-6 levels on day 0 were significantly elevated and returned to preoperative levels on day 7 in both groups, and the serum IL-6 level in Group NM on day 0 was significantly lower than that in Group C on day 0. Serum HGF levels on day 0 and day 7 were significantly higher in Group NM than those in Group C. Compared with healthy control subjects, the higher serum level of HGF on the preoperative day in all patients was attributable to tumor-burden. The sIL-6R levels on day 0 decreased in both groups, and their levels in Group NM were significantly lower than those in Group C, suggesting that increased synthesis of IL-6/sIL-6R complex which could accelerate liver regeneration. Conclusions: These results suggested that perioperative administration of NM may attenuate surgical stress by decreasing production of proinflammatory cytokine IL-6, and may accelerate liver regeneration through stimulation with the IL-6/sIL-6R complex and possible involvement of increased production of HGF.
  • H Miyaso, Y Morimoto, M Ozaki, S Haga, S Shinoura, Y Choda, H Iwagaki, N Tanaka
    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 20 12 1859 - 1866 2005年12月 [査読有り][通常論文]
     
    Background: Patients with obstructive jaundice are prone to sepsis after biliary tract surgery. The present study was designed to determine the effect of biliary obstruction on cytokine responses to lipopolysaccharide (LPS). Methods: Wister rats were allocated into two groups; the BDL group underwent bile duct ligation, followed 2 weeks later by administration of LPS into the duodenum. The control group underwent sham operation, and similarly received enteral LPS. Specimens were collected serially, and applied for the assays. Results: Serum aspartate aminotransferase and alanine aminotransferase levels were significantly increased in BDL rats. High tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 levels in peripheral blood were observed 2 h after LPS administration in BDL rats. In contrast, no increases in both cytokines were noted in peripheral and portal blood in control rats. Baseline HGF levels in portal and peripheral blood in BDL rats were significantly higher than in control rats. LPS significantly increased hepatocyte growth factor (HGF) levels in portal blood and decreased in peripheral blood in BDL rats, but not in control rats. Immunohistochemical analysis revealed that BDL increased expressions of Toll-like receptor (TLR)4, CD14 and CD68 both in the small intestine and liver. Both TLR4 and CD14 mRNAs were upregulated in the small intestine and liver after LPS administration in BDL rats. Conclusion: Obstructive jaundice and LPS stimulation induced TLR4 upregulation both in the liver and small intestine, which led to increased TNF-alpha and IL-6 production in liver and HGF production in the small intestine. The upregulation of TLR4 may lead to pathological and host defense reactions in obstructive jaundice complicated with Gram-negative bacterial infection. (C) 2005 Blackwell Publishing Asia Pty Ltd.
  • Ogino T, Hosako M, Hiramatsu K, Omori M, Ozaki M, Okada S
    Biochimica et biophysica acta 1746 2 135 - 142 2005年12月 [査読有り][通常論文]
  • S Haga, W Ogawa, H Inoue, K Terui, T Ogino, R Igarashi, K Takeda, S Akira, S Enosawa, H Furukawa, S Todo, M Ozaki
    JOURNAL OF HEPATOLOGY 43 5 799 - 807 2005年11月 [査読有り][通常論文]
     
    Background/Aims: Liver regeneration following hepatectomy is complicated and involves a variety of interacting factors. The present study was designed to study the roles of proliferation and hypertrophy of hepatocytes in liver regeneration following hepatectomy in liver-specific STAT3-knockout (LS3-KO) mice lacking mitogenic activity. Methods: Partial hepatectomy was performed in LS3-KO and control mice. Liver regeneration was estimated by the liver weight, cell proliferation and cell size, and the related cellular signals were analyzed. Results: Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Analysis of hepatocellular growth revealed that cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70(S6K), mTOR and GSK-3 beta in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy. Conclusions: PI3-K/Akt-mediated responsive hepatocellular hypertrophy may be essential for liver regeneration following hepatectomy and sufficiently compensated liver regeneration even in STAT3-deficient liver, in which cell proliferation is impaired. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • K Maemura, QZ Zheng, T Wada, M Ozaki, S Takao, T Aikou, GB Bulkley, AS Klein, ZL Sun
    IMMUNOLOGY AND CELL BIOLOGY 83 4 336 - 343 2005年08月 [査読有り][通常論文]
     
    Kupffer cells (KC) act as APC in the liver and play a major role in the clearance of gut-derived antigens and pathogens entering the liver with portal venous blood. Antigen presentation by KC has been implicated in regulation of the local and systemic immune responses. In this study, modulation of KC antigen presentation by antioxidants and the role of reactive oxygen species (ROS) as essential mediators of antigen presentation in KC were investigated. Co-culture of KC with ovalbumin (OVA) antigens resulted in upstream intracellular endogenous ROS generation and increased expression of MHC class II and costimulator molecules, and consequent OVA-specific CD4(+) T-cell proliferation in response to antigen presentation by KC. Scavenging of KC ROS by antioxidants, or blocking of KC ROS generation by specific inhibitors of NADPH oxidase and/or xanthine oxidase, or by specific inhibitors of the mitochondrial electron transport chain, significantly decreased OVA-specific T-cell proliferation in response to antigen presentation by KC. Increased expression of MHC class II and costimulatory molecules in KC pulsed with OVA antigens was blocked by inhibiting ROS generation enzymatically. Intracellular endogenous ROS generation during antigen processing may therefore provide essential secondary signalling for KC antigen presentation.
  • XP Yang, K Irani, S Mattagajasingh, A DiPaula, F Khanday, M Ozaki, K Fox-Talbot, WM Baldwin, LC Becker
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 25 7 1395 - 1400 2005年07月 [査読有り][通常論文]
     
    Objective-Intercellular adhesion molecule-1 (ICAM-1) is upregulated rapidly on endothelial cells during ischemia reperfusion (I-R) and mediates tissue leukocyte accumulation. The ICAM-1 proximal promoter contains a signal transducer and activator of transcription (Stat) binding motif (gamma-interferon activation site [GAS] sequence), which flanks a specificity protein 1 (Sp1) binding site. We examined the roles of Stat and Sp1 in the regulation of ICAM-1 after myocardial I-R. Methods and Results-Open-chest anesthetized rats underwent coronary artery occlusion for 35 minutes and reperfusion for 0 to 240 minutes. Stat became activated within 15 minutes after reperfusion, primarily in vascular endothelial cells; the activated Stat protein was identified as Stat3 (alpha-isoform). After phosphorylation on serine 727 (p-S727), Stat3 alpha was found in association with the transcriptional regulator Sp1, and the complex bound to an ICAM-1-GAS probe. ICAM-1 expression increased after I-R and lagged shortly behind Stat3 alpha activation. In cultured human umbilical vein endothelial (HUVE) cells, activation of Stat3 alpha after hypoxia-reoxygenation (H-R) was dependent on the small GTPase Rac1. Transfection of a dominant-negative Stat3 (Y705F) adenovirus or a GAS decoy oligonucleotide reduced ICAM-1 mRNA expression after H-R. Using a reporter gene transfected into HUVE cells, mutation of the GAS element in the ICAM-1 promoter resulted in reduced transcriptional activity after H-R. Sp1 coimmunoprecipitated with p-S727 Stat3 during H-R, and Sp1 or Stat3 alpha interfering RNA markedly reduced ICAM-1 mRNA expression. Conclusion-The Sp1-Stat3 complex appears to play an important role in the upregulation of ICAM-1 transcription after reoxygenation or reperfusion.
  • Y Fujimoto, H Iwagaki, M Ozaki, T Ogino, H Murata, DS Sun, H Sadamori, HK Takahashi, N Tanaka, T Yagi
    INTERNATIONAL IMMUNOPHARMACOLOGY 5 7-8 1131 - 1139 2005年07月 [査読有り][通常論文]
     
    Background: Prostaglandin E2 (PGE2) is known to modulate immune responses and is widely viewed as a general immunosuppressant. There have been recognized four receptors for PGE2 (EP1-EP4 receptor) so far, and EP2 and EN receptors are mainly involved in the immunosuppressive effect of PGE2 in vitro. In the present study we examined the in vivo immuno suppressive effects of selective EP receptor agonists using a high-responder rat skin transplantation model. Materials and methods: Skin allografts from ACI donors were transplanted onto LEW recipients. Agents were injected everyday between day 0 and day 5 after skin transplantation at the dose of 300 mu g/kg subcutaneously. Survival of the skin allograft, histological changes and changes of the intragraft cytokine expressions were analyzed using the reverse transcription polymerase chain reaction (RT-PCR). We also assessed the mixed lymphocyte reaction (MLR) assay using splenocytes. Results: PGE2 significantly prolonged allograft survival (18.8 +/- 1.5 days) compared with untreated control (14.8 +/- 0.8 days). EP2R+EP3R+EP4R agonists also prolonged allograft survival (18.0 +/- 1.0 days) although EP3R agonist or EP2R+EP4R agonists alone failed (15.5 +/- 0.7, 15.4 +/- 1.3 days, respectively). RT-PCR analysis in the skin grafts demonstrated IL-10 upregulation and IFN-gamma down-regulation in all groups except untreated control and EP2R agonist-treated groups. MLR was significantly reduced in groups of EP2R+EP4R agonists, EP2R+EP3R+EP4R agonists and PGE2, compared with untreated control. Conclusions: The effect of PGE2 to prolong the survival of skin transplant requires the action of a combination of three receptors, i.e., EP2+EP3+EP4. (C) 2005 Elsevier B.V. All rights reserved.
  • Keita Terui, Michitaka Ozaki
    Drugs of Today 41 7 461 - 469 2005年07月 [査読有り][通常論文]
     
    Liver regeneration is a process in which the liver recovers its mass and function after injury due to various causes such as hepatectomy, virus infection and intoxication. This regeneration invokes a series of complex processes which may involve the actions of various cytokines, cell proliferation and cell growth. In response to cytokine stimuli, receptor-mediated signaling systems are activated, and many proteins are transcriptionally up-regulated to increase liver mass and improve liver function. In this review, we focus on the roles of signal transducer and activator of transcription-3 (STAT3) and its functions in mitogenic and other responses during liver regeneration following hepatectomy. We also describe newly discovered target genes of STAT3 and discuss their potential roles in liver regeneration after injury due to various causes. © 2005 Prous Science. All rights reserved.
  • DS Sun, H Iwagaki, M Ozaki, T Ogino, S Kusaka, Y Fujimoto, H Murata, H Sadamori, H Matsukawa, N Tanaka, T Yagi
    TRANSPLANT IMMUNOLOGY 14 1 17 - 20 2005年03月 [査読有り][通常論文]
     
    It has been reported that intraportal administration of donor antigens induced donor-specific hyporesponsiveness. We studied here the effects of transplantation of BM-derived immature dendritic cells (imDCs) and mature DCs (mDCs) via portal vein on rat small intestinal allograft survival. This study comprised four treatment groups: 1) untreated controls; 2) FK506 alone; 3) intraportal donor-specific BM-derived imDCs transplantation+FK506; 4) mDCs/Tx+FK506. Allograft survival was minimal in control group (5.2 +/- 0.8 days) and maximal in imDC+FK506 group (28.4 +/- 3.0 days). The rats in mDC+FK506 group showed systemic inflammatory reaction due to GVHR, and died within 10 days after transplantation. The in vitro MLR reaction using imDCs was also strongly inhibited both in direct and indirect recognition pathways. The impact of imDCs for the specific induction of transplant tolerance may suggest that immunization with donor-specific imDCs has therapeutic potential in organ transplantation. (c) 2004 Elsevier B.V. All rights reserved.
  • Xiao Ping Yang, Kaikobad Irani, Subhendra Mattagajasingh, Anthony DiPaula, Firdous Khanday, Michitaka Ozaki, Karen Fox-Talbot, William M. Baldwin, III, and Lewis C. Becker. Signal Transducer and Activator of Transcription 3{alpha} and Specificity Prote・・・
    2005年 [査読無し][通常論文]
     
    Xiao Ping Yang, Kaikobad Irani, Subhendra Mattagajasingh, Anthony DiPaula, Firdous Khanday, Michitaka Ozaki, Karen Fox-Talbot, William M. Baldwin, III, and Lewis C. Becker. Signal Transducer and Activator of Transcription 3{alpha} and Specificity Protein 1 Interact to Upregulate Intercellular Adhesion Molecule-1 in Ischemic-Reperfused Myocardium and Vascular Endothelium. Arterioscl Throm Vas 25:1395-1400, 2005
  • Tetsuya Ogino, Mutsumi Hosako, Kazuhisa Hiramatsu, Masako Omori, Michitaka Ozaki, Shigeru Okada. Oxidative modification of Ik-B by monochloramine inhibits tumor necrosis factor-alpha-induced NF-kB activation. Biochimica et Biophysica Acta (BBA) - Molec・・・
    2005年 [査読無し][通常論文]
     
    Tetsuya Ogino, Mutsumi Hosako, Kazuhisa Hiramatsu, Masako Omori, Michitaka Ozaki, Shigeru Okada. Oxidative modification of Ik-B by monochloramine inhibits tumor necrosis factor-alpha-induced NF-kB activation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 15;1746:135-42.
  • Kosei Maemura, Qizhi Zheng, Tatehiko Wada, Michitaka Ozaki, Sonshin Takao, Takashi Aikou, Gregory B Bulkley, Andrew S Klein, Zhaoli Sun. Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells. Immunol Cell Biol 83 (4):・・・
    2005年 [査読無し][通常論文]
     
    Kosei Maemura, Qizhi Zheng, Tatehiko Wada, Michitaka Ozaki, Sonshin Takao, Takashi Aikou, Gregory B Bulkley, Andrew S Klein, Zhaoli Sun. Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells. Immunol Cell Biol 83 (4): 336 - 343, 2005.
  • Sanae Haga, Wataru Ogawa, Hiroshi Inoue, Keita Terui, Tetsuya Ogino, Rumi Igarashi, Kiyoshi Takeda, Shizuo Akira, Hiroyuki Furukawa, Satoru Todo, Shin Enosawa, Michitaka Ozaki*. Compensatory recovery of liver mass by Akt-mediated cellular hypertrophy i・・・
    2005年 [査読無し][通常論文]
     
    Sanae Haga, Wataru Ogawa, Hiroshi Inoue, Keita Terui, Tetsuya Ogino, Rumi Igarashi, Kiyoshi Takeda, Shizuo Akira, Hiroyuki Furukawa, Satoru Todo, Shin Enosawa, Michitaka Ozaki*. Compensatory recovery of liver mass by Akt-mediated cellular hypertrophy in liver-specific STAT3-deficient mice. J Hepatol 43(5): 799-807, 2005.
  • Dong Sheng Sun, Hiromi Iwagaki, Michitaka Ozaki, Tetsuya Ogino, Satoshi Kusaka, Yoshimi Fujimoto, Hiroshi Murata, Hiroshi Sadamori, Hiroyoshi Matsukawa, Noriaki Tanaka, Takahito Yagi: Intraportal administration of bone-marrow-derived immature dendritic・・・
    2005年 [査読無し][通常論文]
     
    Dong Sheng Sun, Hiromi Iwagaki, Michitaka Ozaki, Tetsuya Ogino, Satoshi Kusaka, Yoshimi Fujimoto, Hiroshi Murata, Hiroshi Sadamori, Hiroyoshi Matsukawa, Noriaki Tanaka, Takahito Yagi: Intraportal administration of bone-marrow-derived immature dendritic cells prolonged donor-specific rat intestinal allograft survival. Transpl Immunol 14: 17-20, 2005.
  • Frank Hoentjen, R. Balfour Sartor, Michitaka Ozaki, and Christian Jobin: Impaired STAT3 activation enhances LPS-induced NF-κB recruitment to the IL-12p40 promoter in IL-10 deficient mice. Blood 105: 689-696, 2005.
    2005年 [査読無し][通常論文]
  • Hideaki Miyaso, Yoshinori Morimoto, Michitaka Ozaki, Sanae Haga, Susumu Shinoura, Yasuhiro Choda, Hiromi Iwagaki and Noriaki Tanaka. Obstructive jaundice increases sensitivity to lipopolysaccharide via TLR4 upregulation: Possible involvement in gut-der・・・
    2005年 [査読無し][通常論文]
     
    Hideaki Miyaso, Yoshinori Morimoto, Michitaka Ozaki, Sanae Haga, Susumu Shinoura, Yasuhiro Choda, Hiromi Iwagaki and Noriaki Tanaka. Obstructive jaundice increases sensitivity to lipopolysaccharide via TLR4 upregulation: Possible involvement in gut-derived hepatocyte growth factor-protection of hepatocytes. J Gastroen Hepatol 20 (12), 1859-1866, 2005.
  • Kenji Matsushita, Munekazu Yamakuchi, Craig N Morrell, Michitaka Ozaki, Brian O'Rourke, Kaikobad Irani, and Charles J Lowenstein Vascular endothelial growth factor regulation of Weibel-Palade body exocytosis: Blood 105: 207 - 214, 2005.
    2005年 [査読無し][通常論文]
  • Yoshimi Fujimoto, Hiromi Iwagaki, Michitaka Ozaki, Hiroshi Murata, Sun Dong Sheng, Hiroshi Sadamori, Hideo Kohka Takahashi, Masahiro Nishibori, Noriaki Tanaka, Takahito Yagi: Involvement of Prostaglandin receptors (EPR2-4) in in vivo immunosuppression ・・・
    2005年 [査読無し][通常論文]
     
    Yoshimi Fujimoto, Hiromi Iwagaki, Michitaka Ozaki, Hiroshi Murata, Sun Dong Sheng, Hiroshi Sadamori, Hideo Kohka Takahashi, Masahiro Nishibori, Noriaki Tanaka, Takahito Yagi: Involvement of Prostaglandin receptors (EPR2-4) in in vivo immunosuppression of PGE-2 in rat skin transplant model. Int Immunopharmacol 11:1131-1139, 2005.
  • F Hoentjen, RB Sartor, M Ozaki, C Jobin
    BLOOD 105 2 689 - 696 2005年01月 [査読有り][通常論文]
     
    Interleukin-10-deficient (IL-10(-/-)) mice develop an IL-12-mediated intestinal inflammation in the absence of endogenous IL-10. The molecular mechanisms of the dysregulated IL-12 responses in IL-10(-/-) mice are poorly understood. In this study, we investigated the role of nuclear factor-kappa B (NF-kappaB) and signal transducers and activators of transcription 3 (STAT3) in lipopolysaccharide (LPS)-induced IL12p40 gene expression in bone marrow derived-dendritic cells (BMDCs) isolated from wild-type (WT) and IL-10(-/-) mice. We report higher IL-12p40 mRNA accumulation and protein secretion in LPS-stimulated BMDCs isolated from IL-10(-/-) compared with WT mice. LPS-induced NF-kappaB signaling is similar in IL-10(-/-) and WT BMDCs as measured by IkappaBalpha phosphorylation and degradation, ReIA phosphorylation and nuclear translocation. and NF-kappaB transcriptional activity, with no down-regulatory effects of exogenous IL-10. Chromatin immunoprecipitation demonstrated enhanced NF-kappaB (cRel, ReIA) binding to the IL-12p40 promoter in IL10(-/-) but not WT BMDCs. Interestingly, LPS induced STAT3 phosphorylation in WT but not IL-10(-/-) BMDCs, a process blocked by IL-10 receptor blocking antibody. Adenoviral gene delivery of a constitutively active STAT3 but not control green fluorescence protein (GFP) virus blocked LPS-induced IL-12p40 gene expression and cRel recruitment to the IL-12p40 promoter. In conclusion, dysregulated LPS-induced IL-12p40 gene expression in IL10(-/-) mice is due to enhanced NF-kappaB recruitment to the IL-12p40 promoter in the absence of activated STAT3.
  • K Matsushita, M Yamakuchi, CN Morrell, M Ozaki, B O'Rourke, K Irani, CJ Lowenstein
    BLOOD 105 1 207 - 214 2005年01月 [査読有り][通常論文]
     
    Vascular endothelial growth factor (VEGF) not only regulates angiogenesis, vascular permeability, and vasodilation but also promotes vascular inflammation. However, the molecular basis for the proinflammatory effects of VEGF is not understood. We now show that VEGF activates endothelial cell exocytosis of Weibel-Palade bodies, releasing vasoactive substances capable of causing vascular thrombosis and inflammation. VEGF triggers endothelial exocytosis in part through calcium and phospholipase C-gamma (PLC-gamma) signal transduction. However, VEGF also modulates endothelial cell exocytosis by activating endothelial nitric oxide synthase (eNOS) production of nitric oxide (NO), which nitrosylates N-ethylmaleimide sensitive factor (NSF) and inhibits exocytosis. Thus, VEGF plays a dual role in regulating endothelial exocytosis, triggering pathways that both promote and inhibit endothelial exocytosis. Regulation of endothelial exocytosis may explain part of the proinflammatory effects of VEGF. (C) 2005 by The American Society of Hematology.
  • K Terui, S Enosawa, S Haga, HQ Zhang, H Kuroda, K Kouchi, T Matsunaga, H Yoshida, JF Engelhardt, K Irani, N Ohnuma, M Ozaki
    JOURNAL OF HEPATOLOGY 41 6 957 - 965 2004年12月 [査読有り][通常論文]
     
    Background/Aims: Hypoxia/reoxygenation (H/R) causes oxidative stress to the cell and induces apoptotic cell death. Signal transducer and activator of transcription-3 (Stat3) is one of the most important molecules involved in the initiation of liver development and regeneration, and has recently been shown to protect cells against various pathogens. In order to investigate the hepatoprotective effects of Stat3, we examined whether it protects against H/R-induced injury in primary hepatocytes. Methods: Primary cultured hepatocytes were prepared from SD rats. Adenoviruses and cytokines were added 2 days and 1 h prior to the H/R insult, respectively. Hepatocytes and culture media were harvested for the assays before and after H/R insult. Results: Interleukin-6 and cardiotropin-1, which may function mainly through Stat3 activation, protected cells from H/R-induced apoptosis. Adenoviral overexpression of the constitutively activated form of Stat3 (Stat3-C) reduced H/R-induced apoptosis as well as generation of reactive oxygen species (ROS) in hepatocytes. Interestingly, Stat3-C induced Mn-SOD, but not Cu/Zn-SOD, both at the protein and mRNA levels. Overexpression of Mn-SOD significantly reduced H/R-induced ROS and apoptosis by inhibiting redox-sensitive activation of caspase-3 activity. Conclusions: Stat3 protects hepatocytes from H/R-induced cell injury at least partly by upregulating Mn-SOD and inactivating caspase-3. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • N Mitsuoka, H Iwagaki, M Ozaki, SD Sheng, A Sadamori, H Matsukawa, Y Morimoto, J Matsuoka, N Tanaka, T Yagi
    TRANSPLANT IMMUNOLOGY 13 3 155 - 160 2004年11月 [査読有り][通常論文]
     
    Background: Intraportal administration of alloantigen is reported to reduce antigen-specific immune responses, although the underlying mechanisms for the reduced immunological reactions, especially those of the graft, are poorly understood. We examined intracellular cytokine production by graft-infiltrating lymphocytes (GILs) and peripheral blood lymphocytes (PBLs) to elucidate the underlying mechanisms of beneficial effects on intraportal infusion of donor cells in rat small bowel transplantation (SBT). Methods: Recipient rats (Lewis) were transplanted with small bowel from ACl rats. Tacrolimus (Tac) was injected daily from days 0 to 4. Bone marrow cells of ACI rats were infused via the portal or tail vein on the day of surgery. On day 5, both GILs and PBLs collected from SBT graft and peripheral blood, respectively, were analyzed for intracellular cytokine production of recipient-derived alphabeta-T cells. The Th1/ Th2 balance in each group was designated as the ratio of the percentage of GILs or PBLs staining positive for intracellular IL-4 or IFN-gamma, respectively. The total cell numbers of GILs from SBT graft were also counted. Results: Survival of recipients was markedly prolonged by the combination of Tac and donor-specific bone marrow infusion via the portal vein (DSBMI-PV-Tac) compared with the untreated control, Tac alone, or DSBM1 tail vein plus Tac. DSBM1-PV-Tac significantly decreased the total cell numbers of GILs and also induced remarkable Th2-type response in G1Ls. Conclusions: Our results indicate that DSBMI-PV-Tac decreased GILs and enhanced Th2-type response in SBT graft, both of which are associated with a significant prolongation of graft survival in SBT. (C) 2004 Elsevier B.V. All rights reserved.
  • BH Jeon, G Gupta, YC Park, B Qi, A Haile, FA Khanday, YX Liu, JM Kim, M Ozaki, AR White, DE Berkowitz, K Irani
    CIRCULATION RESEARCH 95 9 902 - 910 2004年10月 [査読有り][通常論文]
     
    The dual-function protein apurinic/apyrmidinic endonuclease/redox factor-1 (APE1/ref-1) is essential for DNA repair and also governs the reductive activation of many redox-sensitive transcription factors. We examined the role of APE1/ref-1 in regulation of endothelium-dependent tone and systemic blood pressure. APE1/ref-1(+/-) mice have impaired endothelium-dependent vasorelaxation, reduced vascular NO levels, and are hypertensive. APE1/ref-1 upregulates H-ras expression and leads to H-ras-mediated, phosphoinositide-3 kinase/Akt kinase-dependent calcium sensitization of endothelial NO synthase (eNOS), stimulating NO production. The reducing property of APE1/ref-1 is essential for upregulation of H-ras and for the calcium sensitization of eNOS. These findings uncover a novel physiological role for APE1/ref-1 in regulating vascular tone by governance of eNOS activity and bioavailable NO.
  • L Guo, S Haga, S Enosawa, K Naruse, Y Harihara, Y Sugawara, K Irani, M Makuuchi, M Ozaki
    AMERICAN JOURNAL OF TRANSPLANTATION 4 6 879 - 887 2004年06月 [査読有り][通常論文]
     
    Redox factor-1 (Ref-1) has been shown to function in a redox-dependent manner in the cell. This study was designed to examine the effects of Ref-1 on liver regeneration as well as protection against postischemic injury in a rat model of 20% partial liver transplantation. Adenovirus carrying the full length of Ref-1 gene was introduced into liver grafts by ex vivo perfusion via the portal vein during preservation. Liver graft weights were assessed, as well as graft histology, serum levels of alanine aminotransferase (ALT)/bilirubin, DNA binding activities of AP-1 and Stat3. Redox factor-1 successfully expressed in the liver graft, improved regeneration by promoting cell proliferation. Overexpression of Ref-1 protein also reduced post-transplant injury and inflammatory reactions in the grafts. The increased serum levels of ALT and bilirubin observed after transplantation were significantly reduced by Ref-1 overexpression. Furthermore, adenovirally overexpressed Ref-1 in mouse liver successfully promoted liver regeneration after simple partial hepatectomy. Interestingly, Ref-1 significantly increased DNA binding of Stat3, but not AP-1. Overexpressed Ref-1 effectively promoted graft regeneration and reduced postischemic injury in a small-sized liver transplantation model. The results of the present study may open a new avenue to clinical transplantation of disproportionately sized grafts in living-related liver transplantation.
  • K Terui, S Haga, S Enosawa, N Ohnuma, M Ozaki
    BIOCHEMICAL JOURNAL 380 203 - 209 2004年05月 [査読無し][通常論文]
     
    Keita Terui, Shin Enosawa, Sanae Haga, Naomi Ohnuma, Michitaka Ozaki: Hypoxia/reoxygenation-induced, redox-dependent activation of STAT1 (signal transducer and activator of transcription 1) confers resistance to apoptotic cell death via hsp70 induction. Biochem J 380: 203-209, 2004.
  • H Inoue, W Ogawa, M Ozaki, S Haga, M Matsumoto, K Furukawa, N Hashimoto, Y Kido, T Mori, H Sakaue, K Teshigawara, SY Jin, H Iguchi, R Hiramatsu, D LeRoith, K Takeda, S Akira, M Kasuga
    NATURE MEDICINE 10 2 168 - 174 2004年02月 [査読有り][通常論文]
     
    The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.
  • Keita Terui, Shin Enosawa, Sanae Haga, Hui Qi Zhang, Naomi Onuma, Michitaka Ozaki: Stat3 confers resistance against hypoxia/reoxygenation-induced oxidative injury in hepatocytes via Mn-SOD. J Hepatol 41: 957-965, 2004.
    2004年 [査読無し][通常論文]
  • Lei Guo, Sanae Haga, Shin Enosawa, Katsutoshi Naruse, Yasushi Harihara, Yasuhiko Sugawara, Masatoshi Makuuchi, Michitaka Ozaki: Improved Hepatic Regeneration With Reduced Post-Ischemic Injury By Redox Factor-1 Gene Transfer In A Rat Small Size-Liver Tr・・・
    2004年 [査読無し][通常論文]
     
    Lei Guo, Sanae Haga, Shin Enosawa, Katsutoshi Naruse, Yasushi Harihara, Yasuhiko Sugawara, Masatoshi Makuuchi, Michitaka Ozaki: Improved Hepatic Regeneration With Reduced Post-Ischemic Injury By Redox Factor-1 Gene Transfer In A Rat Small Size-Liver Transplant Model. Am J Transplant 4: 879- 887, 2004.
  • Hiroshi Inoue, Wataru Ogawa, Michitaka Ozaki, Sanae Haga, Michihiro Matsumoto, Hiroyuki Mori, Kensuke Furukawa, Naoko Hashimoto, Yoshiaki Kido, Toshiyuki Mori, Hiroshi Sakaue, Kiyoshi Teshigawara, Shiyu Jin, Haruhisa Iguchi, Ryuji Hiramatsu, Delek Lero・・・
    2004年 [査読無し][通常論文]
     
    Hiroshi Inoue, Wataru Ogawa, Michitaka Ozaki, Sanae Haga, Michihiro Matsumoto, Hiroyuki Mori, Kensuke Furukawa, Naoko Hashimoto, Yoshiaki Kido, Toshiyuki Mori, Hiroshi Sakaue, Kiyoshi Teshigawara, Shiyu Jin, Haruhisa Iguchi, Ryuji Hiramatsu, Delek Leroith, Kiyoshi Takeda, Shizuo Akira & Masato Kasuga: Role of Stat-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Med 10(2): 168 -174, 2004.
  • Naoshi Mitsuoka, Hiromi Iwagaki, Michitaka Ozaki, Sun Dong Sheng, Hiroshi Sadamori, Hiroyoshi Matsukawa, Yoshinori Morimoto, Junji Matsuoka, and Noriaki Tanaka, Takahito Yagi: The impact of portal infusion with donor-derived bone marrow cells and intra・・・
    2004年 [査読無し][通常論文]
     
    Naoshi Mitsuoka, Hiromi Iwagaki, Michitaka Ozaki, Sun Dong Sheng, Hiroshi Sadamori, Hiroyoshi Matsukawa, Yoshinori Morimoto, Junji Matsuoka, and Noriaki Tanaka, Takahito Yagi: The impact of portal infusion with donor-derived bone marrow cells and intracellular cytokine expression of graft-infiltrating lymphocytes on the graft survival in rat small bowel transplant model. Transpl Immunol 13: 155-160, 2004.
  • Ozaki M, Irani K
    Methods in Enzymology 381 184 - 191 2004年 [査読有り][通常論文]
  • S Haga, K Terui, HQ Zhang, S Enosawa, W Ogawa, H Inoue, T Okuyama, K Takeda, S Akira, T Ogino, K Irani, M Ozaki
    JOURNAL OF CLINICAL INVESTIGATION 112 7 989 - 998 2003年10月 [査読有り][通常論文]
     
    Signal transducer and activator of transcription-3 (Stat3) is one of the most important molecules involved in the initiation of liver development and regeneration. In order to investigate the hepatoprotective effects of Stat3, we examined whether Stat3 protects against Fas-mediated liver injury in the mouse. A constitutively activated form of Stat3 (Stat3-C) was adenovirally overexpressed in mouse liver by intravenous injection, and then a nonlethal dose of Fas agonist (Jo2) was injected intraperitoneally into the mouse (0.3 mug/g body wt). Stat3-C dramatically suppressed both apoptosis and necrosis induced by Jo2. In contrast, liver-specific Stat3-knockout mice failed to survive following Jo2 injection. Stat3-C upregulated expression of FLICE inhibitor protein (FLIP), Bcl-xL, and Bcl-2, and accordingly downregulated activities of FLICE and caspase-3 that were redox-independent. Interestingly, Stat3-C also upregulated the redox-associated protein redox factor-1 (Ref-1) and reduced apoptosis in liver following Jo2 injection by suppressing oxidative stress and redox-sensitive caspase-3 activity. These findings indicate that Stat3 activation protects against Fas-mediated liver injury by inhibiting caspase activities in redox-dependent and -independent mechanisms.
  • N Sakamoto, ZL Sun, ML Brengman, K Maemura, M Ozaki, GB Bulkley, AS Klein
    LIVER TRANSPLANTATION 9 9 940 - 948 2003年09月 [査読有り][通常論文]
     
    The relationship between hepatic ischemia-reperfusion (I-R) and subsequent injury through neutrophil accumulation is well described. Although alterations in reticuloendothelial system (RES) function (specifically Kupffer cell function) after I-R have been delineated, the degree to which discrete components of RES function (phagocytosis and killing) are independently modulated under these conditions has not been quantified. A hepatic segmental I-R model was established in mice, in which blood supply to the left lateral lobe of the liver was occluded for 45 minutes, the liver was reperfused, and the laparotomy incision was closed. Experimental animals were pretreated with either vinblastin (1.5 mg/kg) to induce neutropenia or anti-P-selectin monoclonal antibody (mAb; 50 mug/mice) 4 days and 5 minutes before ischemia, respectively. We previously reported that after intravenous injection of chromium 51 (Cr-51) and iodine 125 (I-125) double-labeled Escherichia coli, hepatic Cr-51 levels could be used to reliably quantify hepatic phagocytic clearance (HPC) of bacteria from blood, whereas the subsequent release of 125(I) from the liver accurately paralleled hepatic bacterial killing efficiency (HKE). Using this double-label bacteria clearance assay, HPC and HKE were depressed after I-R, in association with hepatic neutrophil accumulation. Segmental I-R resulted in decreased HPC and HKE activity in both ischemic and nonischemic hepatic lobes. Depressions in HPC and HKE were attenuated by either vinblastin-induced neutropenia or blocking neutrophil adhesion to the hepatic endothelium with anti-P-selectin mAb. These findings support the hypothesis that I-R induces hepatic RES dysfunction, at least in part, through P-selectin-mediated neutrophil accumulation.
  • M Ozaki, S Haga, HQ Zhang, K Irani, S Suzuki
    CELL DEATH AND DIFFERENTIATION 10 5 508 - 515 2003年05月 [査読有り][通常論文]
     
    Rac1-regulated reactive oxygen species (ROS) production has been implicated in apoptosis. In contrast, pleiotropic protein kinase At protects against apoptosis. However, the pro- and antiapoptotic mechanisms of rac1 and Akt, respectively, and the intersection between these mechanisms are incompletely understood. In a model of oxidative stress and apoptosis induced by hypoxia/reoxygenation (H/R) in primary hepatocytes, activation of the PI3-K Akt axis by the prosurvival hepatocyte growth factor (HGF) inhibited H/R-stimulated rac1 activation and intracellular ROS production, and suppressed apoptosis. Suppression of PI3-K or Akt activity abrogated the inhibitory effect of HGF on rac1 activity and rac1-regulated oxidative stress. Furthermore, constitutive activation of Akt or PI3-K in the absence of HGF was sufficient to phosphorylate rac1, inhibit rac1 activation, and suppress rac1-regulated ROS production. These findings demonstrate that growth factor-stimulated activation of PI3-K-Akt is necessary and sufficient to suppress intracellular oxidative stress and apoptosis by inhibiting activation of proapoptotic, prooxidative rac1 GTPase.
  • BH Jeon, F Khanday, S Deshpande, A Haile, M Ozaki, K Irani
    CIRCULATION RESEARCH 92 6 586 - 588 2003年04月 [査読有り][通常論文]
  • Ozaki M, Enosawa S, Suzuki S
    Nihon rinsho. Japanese journal of clinical medicine 61 3 498 - 503 2003年03月 [査読有り][通常論文]
  • Sanae Haga, Keita Terui, Hui Qi Zhang, Shin Enosawa, Wataru Ogawa, Hiroshi Inoue, Torayuki Okuyama, Kiyoshi Takeda, Shizuo Akira, Kaikobad Irani, Michitaka Ozaki:Stat3 protects against Fas-mediated liver injury in redox-dependent and -independent mecha・・・
    2003年 [査読無し][通常論文]
     
    Sanae Haga, Keita Terui, Hui Qi Zhang, Shin Enosawa, Wataru Ogawa, Hiroshi Inoue, Torayuki Okuyama, Kiyoshi Takeda, Shizuo Akira, Kaikobad Irani, Michitaka Ozaki:Stat3 protects against Fas-mediated liver injury in redox-dependent and -independent mechanisms. J Clin Invest 112:989-998, 2003.
  • Byeong Hwa Jeon, Firdous Khanday, Shailesh Deshpande, Azeb Haile, Michitaka Ozaki, Kaikobad Irani: Tie-ing the antiinflammatory effect of antiopoietin-1 to inhibition of NF- B. Circ Res 92: 586-588, 2003.
    2003年 [査読無し][通常論文]
  • Michitaka Ozaki, Sanae Haga, Hui Qi Zhang, Kaikobad Irani, and Seiichi Suzuki. Inhibition of hypoxia/reoxygenation-induced and rac1-regulated oxidative stress in HGF-stimulated anti-apoptotic signaling: role of PI3-K and Akt kinase. Cell Death Differ 1・・・
    2003年 [査読無し][通常論文]
     
    Michitaka Ozaki, Sanae Haga, Hui Qi Zhang, Kaikobad Irani, and Seiichi Suzuki. Inhibition of hypoxia/reoxygenation-induced and rac1-regulated oxidative stress in HGF-stimulated anti-apoptotic signaling: role of PI3-K and Akt kinase. Cell Death Differ 10: 508-515, 2003.
  • Sakamoto N, Sun Z, Brengman ML, Maemura K, Ozaki M, Bulkley GB, Klein AS: Hepatic reticuloendothelial system dysfunction after ischemia-reperfusion: role of P-selectin-mediated neutrophil accumulation. Liver Transplant 9(9): 940-8. 2003.
    2003年 [査読無し][通常論文]
  • M Ozaki, S Haga, K Irani, H Amemiya, S Suzuki
    TRANSPLANTATION PROCEEDINGS 34 7 2640 - 2642 2002年11月 [査読有り][通常論文]
  • T Kuroda, S Enosawa, M Endo, M Ozaki, N Morikawa, S Suzuki, H Amemiya
    TRANSPLANTATION PROCEEDINGS 34 7 2582 - 2584 2002年11月 [査読有り][通常論文]
  • M Endo, S Enosawa, M Ozaki, S Tsuruoka, S Hiramatsu, K Kim, T Omasa, T Matsumura, T Aoki, Y Koyanagi, S Suzuki
    ARTIFICIAL ORGANS 26 9 806 - 811 2002年09月 [査読有り][通常論文]
     
    We designed a membrane culture unit on which 2 different cell lines were co-cultured to achieve selective and active transport of toxins. Hepatic origin HepG2 and renal origin multidrug-resistant gene-transduced proximal convoluted tubular cell line (PCTL-MDR) were cultured on the opposite sides of an expanded polytetrafluoroethylene membrane. The activity of testosterone hydroxylation by original HepG2 was very low; however, the cytochrome P450 (CYP) 3A4-transduced recombinant HepG2 metabolized the substrate efficiently. Testosterone added into the outer medium was hydrolyzed by HepG2, and the metabolites were preferentially transported to the inner medium by PCTL-MDR. [H-3]-digoxin and [C-14]-inulin were added to the outer medium; the digoxin was transported from the outer to inner space through the cell monolayer but the inulin was not, suggesting that the membrane actively transported only the substrate of the channel protein, MDR. The cells were irradiated (10 Gy) to prevent a membrane leak due to overgrowth. The irradiation did not induce apoptosis but resulted in long-lasting membrane function without leakage. The membrane co-cultured with hepatic and renal origin cells will enable a novel hemofiltration system with selective and active transport activities.
  • P Angkeow, SS Deshpande, B Qi, YX Liu, YC Park, BH Jeon, M Ozaki, K Irani
    CELL DEATH AND DIFFERENTIATION 9 7 717 - 725 2002年07月 [査読有り][通常論文]
     
    The rac1 GTPase promotes oxidative stress through reactive oxygen species (ROS) production, whereas the DNA repair enzyme and transcriptional regulator redox factor-1 (ref-1) protects against cell death due to oxidative stimuli. However, the function of ref-1 in regulating intracellular oxidative stress, particularly that induced by rac1, has not been defined, We examined the role of ref-1 in vascular endothelial cell oxidative stress and apoptosis. Ref-1 was expressed in both the cytoplasm and nuclei of resting endothelial cells. Cytoplasmic ref-1 translocated to the nucleus with the oxidative trigger hypoxia/reoxygenation (H/R). Forced cytoplasmic overexpression of ref-1 suppressed H/R-induced oxidative stress (H2O2 production), NF-kappaB activation, and apoptosis, and also mitigated rac1-regulated H2O2 production and NF-kappaB transcriptional activity. We conclude that inhibition of oxidative stress is another mechanism by which ref-1 protects against apoptosis, and that this is achieved through modulation of cytoplasmic rac1-regulated ROS generation. This suggests a novel extra-nuclear function of ref-1.
  • Ozaki M, Suzuki S, Irani K
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 8 889 - 890 2002年06月 [査読有り][通常論文]
  • Michitaka Ozaki, Seiichi Suzuki, Kaikobad Irani. Redox factor-1/APE suppresses oxidative stress by inhibiting the rac1 GTPase. FASEB J 16: 889-890, 2002.
    2002年 [査読無し][通常論文]
  • T.Kuroda, S.Enosawa, M.Endo, M.Ozaki, N.Morikawa, S.Suzuki, H.Amemiya. Early infantile kidney as marginal donation resources; histology and pathophysiology. Transplant P 34: 2582-2584, 2002.
    2002年 [査読無し][通常論文]
  • レンチウイルスベクターをもちいたin vitroでの安定した遺伝子導入
    Organ Biology 9 285 - 293 2002年 [査読無し][通常論文]
  • P. Angkeow, S. Deshpande, B. Qi Y-X Liu, Y.C. Park, B. Jeon, M. Ozaki, K. Irani. Redox factor-1: An extra-nuclear role in the regulation of endothelial oxidative stress and apoptosis. Cell Death Differ 9: 717-725, 2002.
    2002年 [査読無し][通常論文]
  • M.Ozaki, S.Haga, K. Irani, H.Amemiya, S.Suzuki: Overexpression of Redox Factor-1 protects against post-ischemic liver injury by reducing oxidative stress and NF-kB activity. Transplant P 34: 2640-2642, 2002.
    2002年 [査読無し][通常論文]
  • 24. M.Ozaki: New Strategy For Preventing Ischemia / Reperfusion-Induced Organ Injury And Promoting Regeneration. - A Novel Trial For Improving Transplant Organ Function By Targeted Regulation Of Cellular Signals-. Transplant P 34: 2637-2639, 2002.
    2002年 [査読無し][通常論文]
  • Mitsufumi Endo, Shin Enosawa, Michitaka Ozaki, Shuichi Tsuruoka, Shinya Hiramatsu, Kazumi Kim, Takeshi Omasa, Toshiharu Matsumura, Tatsuya Aoki, Yasuhisa Koyanagi, Seiichi Suzuki. Artificial Mimicking of physiological active transport by a membrane co-・・・
    2002年 [査読無し][通常論文]
     
    Mitsufumi Endo, Shin Enosawa, Michitaka Ozaki, Shuichi Tsuruoka, Shinya Hiramatsu, Kazumi Kim, Takeshi Omasa, Toshiharu Matsumura, Tatsuya Aoki, Yasuhisa Koyanagi, Seiichi Suzuki. Artificial Mimicking of physiological active transport by a membrane co-cultured with two different cells: hepatic origin HepG2 and renal origin PCTL-MDR. Artif Organs 26:806-811, 2002.
  • M Ozaki, S Deshpande, P Angkeow, J Bellan, CJ Lowenstein, MC Dinauer, P Goldschmidt-Clermont, S Suzuki, K Irani
    TRANSPLANTATION PROCEEDINGS 33 1-2 863 - 864 2001年02月 [査読有り][通常論文]
  • Ozaki M, Deshpande S, Angkeow P, Bellan J, Lowenstein CJ, Dinauer MC, Goldschmidt-Clermont P, Suzuki S and Irani K. Targeted inhibition of the small GTPase protects against ischemia/reperfusion liver injury in mice. Transplant P 33, 863-864. 2001.
    2001年 [査読無し][通常論文]
  • M Ozaki, SS Deshpande, P Angkeow, S Suzuki, K Irani
    JOURNAL OF BIOLOGICAL CHEMISTRY 275 45 35377 - 35383 2000年11月 [査読有り][通常論文]
     
    The signaling pathway by which environmental stresses activate heat shock factors (HSFs) is not completely understood. We show that the small GTPase rad, and Rad-regulated reactive oxygen species (ROS) play an important role in stress-stimulated heat shock response. A dominant-negative allele of Rad (Rac1N17) inhibits the hypoxia/reoxygenation and sodium arsenite-induced transcriptional activity of HSF-1 and the transcription of heat shock protein 70. Rac1N17 also suppresses the production of intracellular ROS induced by hypoxia/reoxygenation or sodium arsenite. Moreover, direct suppression of intracellular ROS levels by antioxidants decreases stress-stimulated HSF activity. However, expression of a constitutively active mutant of Rad (Rac1V12) in the absence of extracellular stresses does not increase intracellular ROS levels or induce the heat shock response. These results show that Rad is a necessary but insufficient component of the stress-induced signaling pathway that leads to ROS production, activation of HSFs, and transcription of heat shock proteins.
  • SS Deshpande, P Angkeow, JP Kuang, M Ozaki, K Irani
    FASEB JOURNAL 14 12 1705 - 1714 2000年09月 [査読有り][通常論文]
     
    Reactive oxygen species (ROS) have been implicated as mediators of tumor necrosis factor-alpha (TNF) -induced apoptosis. In addition to leading to cell death, ROS can also promote cell growth and/or survival. We investigated these two roles of ROS in TNF-induced endothelial cell apoptosis. Human umbilical vein endothelial cells (HUVECs) stimulated with TNF produced an intracellular burst of ROS. Adenoviral-mediated gene transfer of a dominant negative form of the small GTPase Rad (Rac1N17) partially suppressed the TNF-induced oxidative burst without affecting TNF-induced mitochondrial ROS production. HUVECs were protected from TNF-induced apoptosis. Expression of Rac1N17 blocked TNF-induced activation of nuclear factor-kappa B (NF-kappa B), increased activity of caspase-3, and markedly augmented endothelial cell susceptibility to TNF-induced apoptosis. Direct inhibition of NF-kappa B through adenoviral expression of the super repressor form of inhibitor of kappa B alpha (I-kappa B S32/36A) also increased susceptibility of HUVECs to TNF-induced apoptosis. Rotenone, a mitochondrial electron transport chain inhibitor, suppressed TNF-induced mitochondrial ROS production, proteolytic cleavage of procaspase-3, and apoptosis. These findings show that Rad is an important regulator of TNF-induced ROS production in endothelial cells. Moreover, they suggest that Rad-dependent ROS, directly or indirectly, lead to protection against TNF-induced death, whereas mitochondrial-derived ROS promote TNF-induced apoptosis.
  • M Ozaki, SS Deshpande, P Angkeow, J Bellan, CJ Lowenstein, MC Dinauer, PJ Goldschmidt-Clermont, K Irani
    FASEB JOURNAL 14 2 418 - 429 2000年02月 [査読有り][通常論文]
     
    Reperfusion of ischemic tissue results in the generation of reactive oxygen species that contribute to tissue injury. The sources of reactive oxygen species in reperfused tissue are not fully characterized. We hypothesized that the small GTPase Rac1 mediates the oxidative burst in reperfused tissue and thereby contributes to reperfusion injury. Zn an in vivo model of mouse hepatic ischemia/reperfusion injury, recombinant adenoviral expression of a dominant negative Rac1 (Rac1N17) completely suppressed the ischemia/reperfusion-induced production of reactive oxygen species and lipid peroxides, activation of nuclear factor-kappa B, and resulted in a significant reduction of acute liver necrosis, Expression of Rac1N17 also suppressed ischemia/reperfusion-induced acute apoptosis, The protection offered by Rac1N17 was also evident in knockout mice deficient for the gp91phox component of the phagocyte NADPH oxidase. This work demonstrates the crucial role of a Rac1-regulated oxidase in mediating the production of injurious reactive oxygen species, which contribute to acute necrotic and apoptotic cell death induced by ischemia/reperfusion in vivo. Targeted inhibition of this oxidase, which is distinct from the phagocyte NADPH oxidase, should provide a new avenue for in vivo therapy aimed at protecting organs at risk from ischemia/reperfusion injury.
  • Michitaka Ozaki, Shailesh S. Deshpande, Piamsook Angkeow, John Bellan, Charles J. Lowenstein, Mary C. Dinauer, Pascal J. Goldschmidt-Clermont and Kaikobad Irani: Inhibition of the Rac1 GTPase protects against non-lethal ischemia/reperfusion-induced nec・・・
    2000年 [査読無し][通常論文]
     
    Michitaka Ozaki, Shailesh S. Deshpande, Piamsook Angkeow, John Bellan, Charles J. Lowenstein, Mary C. Dinauer, Pascal J. Goldschmidt-Clermont and Kaikobad Irani: Inhibition of the Rac1 GTPase protects against non-lethal ischemia/reperfusion-induced necrosis and apoptosis in vivo. FASEB J 14: 418-429, 2000.
  • N. Paolocci, U. E. G. Ekelund, T. Isoda, M. Ozaki, K. Vandegaer, D. Georgakopoulos, R. W. Harrison, D. A. Kass, and J. M. Hare. cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation. Am J Physiol-・・・
    2000年 [査読無し][通常論文]
     
    N. Paolocci, U. E. G. Ekelund, T. Isoda, M. Ozaki, K. Vandegaer, D. Georgakopoulos, R. W. Harrison, D. A. Kass, and J. M. Hare. cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation. Am J Physiol-Heart C 279: H1982-H1988, 2000.
  • Michitaka Ozaki, Piamsook Angkeow, Shailesh S. Deshpande, Seiichi Suzuki and Kaikobad Irani: Rac1 regulates stress-induced, redox-dependent heat shock factor activation. J Biol Chem 275: 35377-35383, 2000.
    2000年 [査読無し][通常論文]
  • Shailesh S. Deshpande, Piamsook Angkeow, Jianping Huang, Michitaka Ozaki, and Kaikobad Irani: Rac1 Inhibits TNF- -Induced Endothelial Cell Apoptosis: Dual Regulation by Reactive Oxygen Species. FASEB J 14, 1705-1714, 2000.
    2000年 [査読無し][通常論文]
  • cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation.
    Paolocci, U. E. G. Ekelund, T. Isoda, M. Ozaki, K. Vandegaer, D. Georgakopoulos, R. W. Harrison, D. A. Kass, J. M. Hare
    American Journal of Physiology-Heart and Circulatory Physiology 279 4 H1982 - H1988 2000年 [査読有り][通常論文]
  • K Tanaka, JB Pracyk, K Takeda, ZX Yu, VJ Ferrans, SS Deshpande, M Ozaki, PM Hwang, CJ Lowenstein, K Irani, T Finkel
    JOURNAL OF BIOLOGICAL CHEMISTRY 273 40 25922 - 25928 1998年10月 [査読有り][通常論文]
     
    We have constructed a recombinant adenovirus (Ad.Id1) that allows for efficient expression of the helix-loop-helix protein Idl, After infection with Ad.Id1, neonatal cardiac myocytes display a significant reduction in viability, which was proportional to the level of Idl expression, A similar effect was observed in adult myocytes, Morphological and biochemical assays demonstrated that Id1 expression resulted in myocyte apoptosis. In contrast, expression of Idl in endothelial cells, vascular smooth muscle cells, or fibroblasts did not affect the viability of these cells, Along with the induction of apoptosis, the expression of Idl in neonatal cardiac myocytes resulted in an increase in the level of intracellular reactive oxygen species. The source of these reactive oxygen species appears to be the mitochondria, Reducing the ambient oxygen concentration or treatment with a cell-permeant H2O2 scavenger prevented Id1-stimulated apoptosis in cardiac myocytes, These results suggest that the expression of Idl leads to the induction of apoptosis in cardiac myocytes through a redox-dependent mechanism.
  • Koichi Tanaka, John D.Pracyk, Kazuyo Takeda, Zu-Xi Yu, Victor J.Ferrans, Shailesh S.Deshpande, Michitaka Ozaki, Paul M.Hwang, Charles J.Lowenstein, Kaikobad Irani, Toren Finkel: Expression of Id1 results in apoptosis of cardiac myocytes through a redox・・・
    1998年 [査読無し][通常論文]
     
    Koichi Tanaka, John D.Pracyk, Kazuyo Takeda, Zu-Xi Yu, Victor J.Ferrans, Shailesh S.Deshpande, Michitaka Ozaki, Paul M.Hwang, Charles J.Lowenstein, Kaikobad Irani, Toren Finkel: Expression of Id1 results in apoptosis of cardiac myocytes through a redox-dependent mechanism. J Biol Chem 273: 25922-25928, 1998.
  • M Nakamura, M Ozaki, S Fuchinoue, S Teraoka, K Ota
    TRANSPLANT INTERNATIONAL 10 2 89 - 95 1997年03月 [査読有り][通常論文]
     
    Ischemia-reperfusion injury by free radicals and lipid peroxides is observed in various organs. Ascorbic acid (AsA) or glutathione (GSH) in various doses (AsA:2, 0.5, 0.1 mmol/kg, GSH:2 mmol/kg) was intraperitoneally administered to male Wistar rats. The entire small intestines were resected just before ischemia, after ischemia, and after 20 min of reperfusion (n = 7-10 at each time point). At each time point, the specimens were subjected to assays of lipid peroxides, GSH, and glutaminase activity of the tissues; they were also examined histologically. In the AsA group, the production of lipid peroxides after reperfusion was significantly suppressed in a dose-dependent manner. and the ratio of oxidized GSH to total GSH was also significantly low. Tissue glutaminase activity decreased to a lesser extent, and the degree of in jury was apparently less marked in the AsA group. This study indicates that AsA acts as an antioxidant against peroxidative tissue injury, possibly by scavenging radicals, preserving reduced GSH, and reducing the peroxidative reaction.
  • M Ozaki, M Nakamura, S Teraoka, K Ota
    TRANSPLANT INTERNATIONAL 10 2 96 - 102 1997年03月 [査読有り][通常論文]
     
    The present study was designed to examine the in vivo effect of ebselen on reperfusion injury to the liver. Lipid peroxidation and glutathione (GSH) levels of the reperfused liver tissue, as well as hepatocellular damage (serum GOT, GPT, LDH: and histology) were examined. The production of thiobarbituric acid-reactive substance did not increase in the 60-min-reperfused liver tissue in the ebselen group. Ebselen completely suppressed the increase in lipid hydroperoxide production in the reperfused liver tissue. After the tissue GSH level was reduced by buthionine sulphoximine. ebselen failed to suppress the lipid peroxidation of the reperfused liver tissue. Serum levels of GOT CPT, and LDI-I, histological analysis, and the tissue level of GSH clearly showed that ebselen protects the reperfused liver tissue, both structurally and functionally, We conclude that ebselen's primary effect on ischemia-reperfusion injury may be due to a GSH-peroxidase-like effect and/or the inhibitor effect of leukocyte infiltration.
  • Michitaka Ozaki, Michio Nakamura, Satoshi Teraoka, Kazuo Ota: Ebselen, a novel anti-oxidant compound, protects against the hepatic ischemia-reoxygenation injury of the rats. Transplant Int 10:96-102, 1997.
    1997年 [査読無し][通常論文]
  • Michio Nakamura, Michitaka Ozaki, Shohei Fuchinoue, Satoshi Teraoka, Kazuo Ota: Ascorbic acid prevents ischemia-reperfusion injury in the rat small intestine. Transplant Int 10: 89-95, 1997.
    1997年 [査読無し][通常論文]
  • Preventive effects of ascorbic acid on the ischemia/reoxygenation injury in the rat small intestine.
    Michio Nakamura, Michitaka Ozaki, Shohei Fuchinoue, Satoshi Teraoka, Kazuo Ota
    Journal of Tokyo Women’s Medical College 66 11 898 - 907 1996年 [査読有り][通常論文]
  • S Teraoka, T Babazono, O Tomonaga, S Sato, M Nakamura, H Ishida, T Hoshino, T Koike, M Abe, M Shinkai, H Haruguchi, S Hirotani, K Kitajima, M Akamatsu, M Ozaki, S Fujita, Y Nakagawa, Nakajima, I, T Kawai, S Fuchinoue, H Ohgawara, Y Ohmori, K Ota
    TRANSPLANTATION PROCEEDINGS 27 6 3097 - 3100 1995年12月 [査読有り][通常論文]
  • M OZAKI, S FUCHINOUE, S TERAOKA, K OTA
    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 318 2 439 - 445 1995年04月 [査読有り][通常論文]
     
    The in vivo effects of ascorbic acid on the reoxygenated liver tissue were examined, with regard to the following effects: (i) the effects of scavenging radicals and/or reducing peroxidative reactions, and (ii) the effects of the chelation with low-molecular-weight iron and increasing its reactivity (radical production). Ascorbic acid is one of the water-soluble vitamins known to have various physiological effects involving both chelating and reducing properties at once. Lipid peroxidation of the reoxygenated liver tissue estimated by the production of TEARS (thiobarbituric acid-reactive substance) and LPO (lipid hydroperoxides) was suppressed effectively by the preischemic intraperitoneal administration of ascorbic acid. Ascorbic acid also showed this anti-oxidant effect in a dose-dependent manner. The analysis of the levels of ascorbic acid and glutathione of the liver tissue revealed that ascorbic acid works as an anti-oxidant probably by being oxydized finally to dehydroascorbic acid just after the reoxygenation. The latter was reduced to ascorbic acid again, coupled with the conversion of GSH to GSSG in the postischemic time course. The predominant effect of ascorbic acid on the reoxygenated liver tissue seems to be caused by the scavenging radicals and/or reducing peroxidative reactions, rather than by chelating iron and increasing its reactivity (radical production). Cellular integrity (estimated by the release of GOT, GPT, and LDH) and the energy state of the postischemic liver tissue (estimated by the tissue ATP level) were also well preserved by the administration of ascorbic acid. (C) 1995 Academic Press, Inc.
  • S TERAOKA, T BABAZONO, T KOIKE, M ABE, M KIMIKAWA, M SHINKAI, H HARUGUCHI, S HIROTANI, K KITAJIMA, M AKAMATSU, M OZAKI, S FUJITA, NAKAJIMA, I, T KAWAI, S FUCHINOUE, K OTA, O TOMONAGA, K YANO, Y TASAKA, Y OMORI
    TRANSPLANTATION PROCEEDINGS 27 1 1335 - 1339 1995年02月 [査読有り][通常論文]
  • S. Teraoka, T. Babazono, T.Koike, M.Abe, M.Kimikawa, M.Shinkai, H.Haruguchi, S.Hirotani, K.Kitajima, M.Akamatsu, M.Ozaki, S.Fujita, I.Nakagawa, T.Kawai, S.Fuchinoue, K.Ota, O.Tomonaga, K.Yano, Y.Tasaka and Y.Omori: Effect of rescue therapy using FK506 ・・・
    1995年 [査読無し][通常論文]
     
    S. Teraoka, T. Babazono, T.Koike, M.Abe, M.Kimikawa, M.Shinkai, H.Haruguchi, S.Hirotani, K.Kitajima, M.Akamatsu, M.Ozaki, S.Fujita, I.Nakagawa, T.Kawai, S.Fuchinoue, K.Ota, O.Tomonaga, K.Yano, Y.Tasaka and Y.Omori: Effect of rescue therapy using FK506 on relapsing rejection after combined pancreas and kidney transplantation. Transplant P 27: 1335-1339, 1995.
  • Ozaki M, Fuchinoue S, Teraoka S, Ota K: The in vivo cytoprotection of ascorbic acid on the ischemia/reoxygenation injury of rat liver. Arch Biochem Biophys 318: 439-445, 1995.
    1995年 [査読無し][通常論文]
  • M OZAKI, H OZASA, S FUCHINOUE, S TERAOKA, K OTA
    TRANSPLANTATION 58 6 753 - 755 1994年09月 [査読有り][通常論文]
  • Michitaka Ozaki, Shohei Fuchinoue, Satoshi Teraoka, Kazuo Ota
    Transplantation Proceedings 26 2 918 - 921 1994年04月 [査読有り][通常論文]
  • Michitaka Ozaki, Hisashi Ozasa, Shouhei Fuchinoue, Satoshi Teraoka, Kazuo Ota: Protective effects of glycine and esterified gamma-glutamylcysteine on ischemia/reoxygenation injury of rat liver. Transplantation 58: 753-755, 1994.
    1994年 [査読無し][通常論文]
  • Michitaka Ozaki, Shohei Fuchinoue, Satoshi Teraoka, Kazuo Ota: Effects of deferrioxamine on lipid peroxidation of reoxygenated rat liver. Transplant P 26: 918-921, 1994.
    1994年 [査読無し][通常論文]
  • M OZAKI, T KAWABATA, M AWAI
    BIOCHEMICAL JOURNAL 250 2 589 - 595 1988年03月 [査読有り][通常論文]
  • Michitaka Ozaki, Teruyuki Kawabata, Michiyasu Awai: Iron release from haemosiderin and production of iron catalysed hydroxyl radical in vitro. Biochem J 250: 589-595, 1988.
    1988年 [査読無し][通常論文]
  • Y SADAHIRA, M MORI, M OZAKI, M AWAI
    ACTA PATHOLOGICA JAPONICA 37 11 1719 - 1729 1987年11月 [査読有り][通常論文]
  • Yoshito Sadahira, Masayasu Mori, Michitaka Ozaki, Michiyasu Awai: Characteristics of histiocytic lesions in the reticuloendothelial system of NZB mice. Acta Pathologica Japonica 37: 1719-1729, 1987.
    1987年 [査読無し][通常論文]
  • 肺結核症経過中皮膚の硬結性紅斑とImmunoblastic Lymphoadinopathy(Lukes)様リンパ節腫脹を続発した一剖検例
    倉敷中央病院年報(Ann Kurashiki Cent Hospital) 56 27 - 43 1987年 [査読無し][通常論文]
  • Angioimmunoblastic Lymphadenopathy with Dysproteinemia(AILD)の組織像で発症したAdult T-cell Lynphoma-Leukemia(ATLL)の一剖検例
    倉敷中央病院年報(Ann Kurashiki Cent Hospital) 56 91 - 102 1987年 [査読無し][通常論文]

書籍

  • 「移植のための臓器摘出と保存」
    尾崎 倫孝 (担当:共著)
    シュプリンガー・ジャパン 2012年

講演・口頭発表等

  • In vivo multi-recording system of clock gene expression in deep areas of the body using a photomultiplier tube.  [通常講演]
    Kazuko Hamada, Ryoga Ito, Yoshihiro Kikuchi, Kanako Nakajima, Masayori Ishikawa, Michitaka Ozaki, Toshiyuki Hamada
    Resonance Bio International Symposium 2019年10月 シンポジウム・ワークショップパネル(公募)
  • 肝傷害および進展におけるPoly(ADP-ribose) polymerase-1(PARP1) の役割  [招待講演]
    尾崎 倫孝
    第31回日本肝臓医生物学研究会LBSG-J(プロメテウスの会) 2019年10月 シンポジウム・ワークショップパネル(指名)
  • Fasリガンド/酸化ストレスによって引き起こされるプログラム細胞死の機序解析  [通常講演]
    芳賀早苗, 森田直樹, 尾崎倫孝
    第92回日本生化学会総会 2019年09月 ポスター発表
  • 非アルコール性脂肪肝炎に対するFBRAの抑制効果の検討  [招待講演]
    尾崎 倫孝
    第41回FBRA全国研究会 2019年09月 シンポジウム・ワークショップパネル(指名)
  • 肝虚血・再灌流、酸化ストレスと細胞死(臓器傷害)とその制御 -マウス肝における虚血再灌流傷害進展の分子機構 -  [招待講演]
    尾崎 倫孝, 芳賀 早苗, 森田 直樹, 小澤 岳昌
    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)
  • 脂肪肝における易傷害性メカニズム解析の基礎的研究  [通常講演]
    芳賀早苗, 浅野真未, 森田直樹, 尾崎倫孝
    第26回肝細胞研究会 2019年05月 ポスター発表
  • The molecular mechanisms of oxidative stress, cell death and protection in liver/hepatocytes  [招待講演]
    尾崎 倫孝
    Invited Lecture at Dalian Medical University 2018年12月 公開講演,セミナー,チュートリアル,講習,講義等
  • 細胞・臓器の病態生理の時空間イメージングと研究・臨床への応用- 外科医が望むもの、そして今していること -  [招待講演]
    尾崎倫孝, 芳賀早苗, 森田直樹, 浜田俊幸, 小澤岳昌
    第16回医用分光学研究会 2018年11月 シンポジウム・ワークショップパネル(指名)
  • 「発光プローブによるプログラム細胞死(アポトーシス、ネクロプトーシス)動的解析の試み」  [通常講演]
    芳賀 早苗, 菅野 憲, 小澤 岳昌, 森田 直樹, 浅野 真未, 伊 敏, 尾崎 倫孝
    第27回日本Cell Death学会 2018年 京都府立医科大学 図書館ホール、京都
  • 「光による細胞生存能(Akt/PKB分子)制御に関する研究」  [通常講演]
    芳賀 早苗, 小澤 岳昌, 森田 直樹, 伊 敏, 尾崎 倫孝
    第91回日本生化学会 2018年 国立京都国際会館、京都
  • 「マウス脂肪肝モデルをもちいたビルベリーの予防効果に関する検討」  [通常講演]
    芳賀 早苗, 伊 敏, 森田 直樹, 浅野 真未, 荘厳 哲哉, 尾崎 倫孝
    第39会日本肥満学会 2018年 神戸国際会議場、神戸
  • Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver with steatosis.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Yimi
    IBD and Liver: East Meets West 2018年 京都
  • 「レドックスが制御するネクローシス型細胞死(ネクロプトーシス)の光プローブによる動的解析」  [通常講演]
    芳賀 早苗, 菅野 憲, 小澤 岳昌, 森田 直樹, 浅野 真未, 尾崎 倫孝
    第25回肝細胞研究会 2018年 東京大学伊藤謝恩ホール、東京
  • 「光プローブをもちいたプログラム細胞死(アポトーシス、ネクロプトーシス)の動的解析」  [通常講演]
    尾崎 倫孝, 芳賀 早苗
    第22回日本がん分子標的治療学会学術集会 2018年 都市センターホテル、東京
  • 「肝におけるレドックスバイオロジ−<制御と生理・病態> Redox Biology in Liver−regulation and physio-pathology ?」  [通常講演]
    尾崎倫孝
    MPO研究会 2018年 北海道大学、札幌
  • Type XVII collagen suppresses interfollicular epidermal proliferation in neonatal and aged skin, and helps rejuvenate epidermis.  [通常講演]
    Mika Watanabe, Ken Natsuga, Wataru Nishie, Giacomo Donati, Yu Fujimura, Tadasuke Tsukiyama, Hideyuki Ujiie, Michitaka Ozaki, Fiona M Watt, Hiroshi Shimizu
    47th Annual ESDR Meeting 2017年 オーストリア
  • Spatio-temporal imaging of cell/organ physio-pathology and its clinical application.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Toshiyuki Hamada, Takeaki Ozawa, Yuma Yamada
    CIS Workshop 2017 “Innovative Bio-imaging toward Diagnosis and Therapy” 2017年 北海道
  • 脂肪化肝細胞・脂肪肝に対するビルベリーの効果とその機序の検討  [通常講演]
    芳賀 早苗, 荘厳 哲哉, 伊 敏, 森田 直樹, 浅野 真未, 尾崎 倫孝
    第24回肝細胞研究会 2017年 旭川市民文化会館、旭川
  • 肝核内受容体FXRはp62/SQSTM1およびSHPを経由して、それぞれ抗酸化・細胞保護効果、脂肪化抑制効果を示す  [通常講演]
    尾崎 倫孝, 芳賀 早苗, 伊 敏
    第24回肝細胞研究会 2017年 旭川市民文化会館、旭川
  • マウス脂肪化肝細胞・脂肪肝に対するビルベリーの抑制効果の検討  [通常講演]
    芳賀 早苗, 荘厳 哲哉, 伊 敏, 森田 直樹, 浅野 真未, 尾崎 倫孝
    第38回日本肥満学会 2017年 大阪国際会議場、大阪
  • 肝細胞におけるレドックス依存性ネクロプトーシスの動態解析  [通常講演]
    芳賀 早苗, 菅野 憲, 小澤 岳昌, 森田 直樹, 浅野 真未, 伊 敏, 尾崎 倫孝
    ConBio2017 2017年 神戸国際会議場、神戸
  • ビルベリー抽出物の糖尿病性網膜症発症・進行予防効果に関する基礎的研究  [通常講演]
    浅野 真未, 芳賀 早苗, 柴崎 彩, 黒澤 和也, 荘厳 哲哉, 尾崎 倫孝
    ConBio2017 2017年 神戸国際会議場、神戸
  • カスパーゼ3プローブ発現細胞を用いたクラミジア感染宿主細胞内のアポトーシス制御機構の探索  [通常講演]
    松尾 淳司, 芳賀 早苗, 大久保 寅彦, 中村 眞二, 小澤 岳昌, 尾崎 倫孝, 山口 博之
    ConBio2017 2017年 神戸国際会議場、神戸
  • Type XVII collagen regulates proliferation in the interfollicular epidermis.  [通常講演]
    Mika Watanabe, Ken Natsuga, Yasuaki Kobayashi, Wataru Nishie, Giacomo Donati, Shotaro Suzuki, Yu Fujimura, Tadasuke Tsukiyama, Hideyuki Ujiie, Satoru Shinkuma, Masamoto Murakami, Michitaka Ozaki, Masaharu Nagayama, Fiona. M Watt, Hiroshi Shimizu
    日本研究皮膚科学会 第42回年次学術大会・総会 2017年 高知市文化プラザ かるぽーと、高知
  • Optical evaluation and monitoring of oxidative stress & damage in vivo.  [通常講演]
    Sanae Haga, Takeaki Ozawa, Naoki Morita, Mami Asano, James Remington, Michitaka Ozaki
    19th International Symposium on Bioluminescence & Chemiluminescence(ISBC2016). 2016年 筑波
  • Long-term ex vivo and in vivo monitoring of tumor progression by using dual luciferases.  [通常講演]
    Naoki Morita, Sanae Haga, Yoshihiro Ohmiya, Michitaka Ozaki
    19th International Symposium on Bioluminescence & Chemiluminescence (ISBC2016). 2016年 筑波
  • Function of Toll-like receptor 2 in the murine inflammatory response to Rhodococcus aurantiacus infection.  [通常講演]
    Yimin, Masashi Kohanawa, Sanae Haga, Michitaka Ozaki
    4th Annual Meeting of the International Cytokine and Interferon Society (ICIS) . 2016年 米国
  • ビルベリーによる非アルコール性脂肪肝炎(NASH)の予防に向けた基礎的検討」(ポスター)  [通常講演]
    芳賀 早苗, 荘厳 哲哉, 森田 直樹, 浅野 真未, 尾崎 倫孝
    第23回肝細胞研究会 2016年 大阪大学中之島センター、大阪
  • ビルベリーの糖尿病性網膜症初期病変抑制効果の検討  [通常講演]
    芳賀早苗, 荘厳哲哉, 森田直樹, 浅野真未, 尾崎倫孝
    第89回日本生化学会大会 2016年 仙台国際センター、仙台
  • 光プローブをもちいた時空間的病態解析と積極的病態制御の試み  [通常講演]
    尾崎 倫孝, 芳賀 早苗, 小澤 岳昌, 山田 勇磨
    第71回日本消化器外科学会総会 特別企画「光エネルギーの医療への展開」( 2016年 あわぎんホール、徳島
  • FXRを起点とした脂肪肝傷害抑制と 脂肪化改善の機序  [通常講演]
    尾崎 倫孝, 芳賀 早苗, 森田 直樹
    第25回日本肝臓医生物学研究会;LBSG-J(プロメテウスの会) 2016年 ナスパニューオータニ、新潟
  • 「光技術を用いた臓器・細胞機能評価と制御の可能性」  [通常講演]
    尾崎倫孝, 芳賀早苗, 小澤岳昌, 森田直樹, 浜田俊幸
    第43回日本臓器保存生物医学会学術集会 2016年 東京薬科大学、東京
  • “光”を利用した肝細胞機能制御技術の開発  [通常講演]
    芳賀 早苗, 小澤 岳昌, 森田 直樹, 野田 なつみ, 尾崎 倫孝
    第22回肝細胞研究会 ポスターセッション6「創薬・新しい実験系の開発」 2015年 米子コンベンションセンター、鳥取
  • 統合的ストレス応答による脂肪肝再生障害の分子メカニズムの解明  [通常講演]
    稲葉 有香, 芳賀 早苗, 尾崎 倫孝, 春日 雅人, 井上 啓
    第22回肝細胞研究会 一般口演5「肝再生」 2015年 米子コンベンションセンター、鳥取
  • 種々の病態における肝臓ストレスの解析−生体イメージング法による動的解析の試み−  [通常講演]
    尾崎倫孝
    金沢大学脳・肝インターフェースメディシン研究センター研究セミナー 2015年 金沢大学医学図書館十全記念スタジオ、金沢
  • 肝における酸化ストレス、傷害と炎症  [通常講演]
    尾崎倫孝
    鳥取大学セミナー 2015年 鳥取大学医学部、鳥取県
  • 肝細胞(とくに脂肪化肝細胞)における酸化ストレスと細胞死について  [通常講演]
    尾崎倫孝
    第22回日本肝臓医生物学研究会;LBSG-J(プロメテウスの会) 2015年 しいのき迎賓館3階セミナー室B、金沢
  • 光イメージングによる虚血再灌流傷害の動的・質的解析  [通常講演]
    尾崎倫孝
    第115回日本外科学会定期学術集会 2015年 名古屋国際会議場、名古屋
  • 脂肪肝における肝切除後肝傷害・肝再生不全の機序について  [通常講演]
    尾崎 倫孝, 芳賀 早苗, 小澤 岳昌, 森田 直樹, 井上 啓, 稲葉 有香
    第22回肝細胞研究会 2015年 米子コンベンションセンター、鳥取県
  • 肝臓ストレスと生活習慣病  [通常講演]
    尾崎倫孝
    第46回北海道大学白菊会総会 2015年 北海道大学 学術交流会館、札幌
  • 核内受容体を介した肝細胞機能制御  [通常講演]
    尾崎倫孝
    第23回日本肝臓医生物学研究会;LBSG-J(プロメテウスの会) 2015年 丸駒温泉旅館、千歳
  • 光技術を応用した移植臓器(組織)のモニタリングと制御の試み  [通常講演]
    尾崎 倫孝, 芳賀 早苗, 森田 直樹, 伊 敏, 菅野 憲, 小澤 岳昌
    第51回日本移植学会総会 2015年 ホテル日航熊本、熊本県
  • Development of a novel in vivo optic imaging technology for biological diagnosis and therapy. (生物学的診断と治療のための新たな生体光イメージング技術の開発)  [通常講演]
    尾崎倫孝, 芳賀早苗, 森田直樹, 伊 敏, 山田勇磨, 小澤岳昌
    第74回 日本癌学会学術総会 2015年 名古屋国際会議場、名古屋
  • p62/SQSTM1 を基軸とした新たな肝臓・肝細胞保護・機能維持法の探索  [通常講演]
    尾崎 倫孝, 芳賀 早苗, 森田 直樹, 伊 敏
    第42回日本臓器保存生物医学会学術集会、シンポジウム 2015年 いわて県民情報交流センター、岩手
  • 種々の病態下における肝再生の分子機構 −増殖・成長と傷害−  [通常講演]
    尾崎 倫孝
    京都肝胆膵外科カンファランス(特別講演) 2015年 芝蘭会館、京都
  • Application of an Optic Imaging Techology for Organ Transplantation “移植におけるイメージング技術の応用”  [通常講演]
    Michitaka Ozaki
    Harvard Medical School - Harvard University 2014年 米国
  • Development of a New in vivo Optic Probe for Biological Diagnosis and Therapy. Session ? “New Technology for Innovative Medicine”,  [通常講演]
    Michitaka Ozaki, Takeaki Ozawa, Yuma Yamada
    The Uehara Memorial Foundation Symposium 2014 “INNOVATIVE MEDICINE” Basic Research and Development 2014年 東京
  • 新規分泌型発光プローブをもちいたマウス腫瘍の増殖モニタリング  [通常講演]
    森田 直樹, 尾崎 倫孝
    第18回日本がん分子標的治療学会学術集会 2014年 仙台市情報産業プラザ(AER)、ホテルメトロポリタン仙台、仙台
  • p62/SQSTM1が制御する肝細胞障害機序の解析  [通常講演]
    芳賀 早苗, 小澤 岳昌, 山田 勇磨, 森田 直樹, 野田 なつみ, 尾崎 倫孝
    第21回肝細胞研究会 2014年 東京医科歯科大学、東京
  • 高血糖および脂肪化状態が肝虚血/再灌流傷害に及ぼす影響 Impact of high glucose and steatosis upon ischemia/reperfusion-induced liver injury in mouse.  [通常講演]
    芳賀 早苗, 小澤 岳昌, 森田 直樹, 野田 なつみ, 尾崎 倫孝
    第87回日本生化学会 2014年 京都国際会議場、京都
  • 光イメージング技術を用いた肝病態の解析  [通常講演]
    尾崎 倫孝, 芳賀 早苗, 野田 なつみ, 森田 直樹, 小澤 岳昌
    第21回肝細胞研究会 シンポジウム1「肝疾患の病態を制御するメカニズム」 2014年 東京医科歯科大学、東京
  • 肝臓のストレス応答(傷害と再生)について -脂肪肝からNASHへ-  [通常講演]
    尾崎倫孝
    国立病院機構福山医療センター オープンカンファレンス 2014年 国立病院機構福山医療センター熊ヶ峰ホール、福山
  • “ 光” を利用した新たな細胞・臓器保存法の開発  [通常講演]
    芳賀 早苗, 小澤 岳昌, 森田 直樹, 野田 なつみ, 尾崎 倫孝
    第41回日本臓器保存生物医学会学術集会 平成25 年度日本臓器保存生物医学会奨励賞 受賞記念講演 2014年 千里ライフサイエンスセンター、大阪
  • 肝臓ストレスとストレス応答(傷害と再生)の分子機構の解析と動的理解の試み  [通常講演]
    尾崎倫孝
    第43回染色体工学研究セミナー 2014年 鳥取大学染色体工学研究センター 臨床講義棟2階421講義室、鳥取県
  • p62/SQSTM1 plays a protective role from oxidative injury of steatotic liver in mouse hepatectomy model.  [通常講演]
    Sanae Haga, Takeaki Ozawa, Naoki Morita, Yayoi Seki, Yuma Yamada, Yukari Yasuzaki, Kazuo Umezawa, Michitaka Ozaki
    The 20th Annual Meeting of the Japanese Society for the Research of Hepatic Cells,Osaka. 2013年 大阪(International Convention Center)
  • 「光を応用した生物学的診断・治療法の開発」  [通常講演]
    尾崎倫孝
    上原記念生命科学財団特定研究「革新的医療を創生する医学研究」 2013年 下田セントラルホテル、静岡
  • Bioluminescent imaging of hepatic caspase-3 activity in mice.  [通常講演]
    Sanae Haga, Takeaki Ozawa, Michitaka Ozaki
    第14回国際組織細胞化学会議 2012年 京都(国立京都国際会館)
  • STAT3 plays a pivotal role in cell adhesion in mouse hepatocytes by regulating E-cadherin expression.  [通常講演]
    Sanae Haga, Hiroshi Inoue, A.Kano, X.-Y.Fu, K.Terui, Michitaka Ozaki
    25 th European Congress of Pathology. 2012年 Prague,Czech(Prague Congress Centre)
  • Bio-imaging of surgical stress: Dynamic analysis of liver oxidative stress and damage.  [通常講演]
    Naoki Morita, Sanae Haga, Takeaki Ozawa, S. J. Remington, Michitaka Ozaki
    17th International Symposium on Bioluminescence and Chemiluminescence(ISBC2012) 2012年 カナダ
  • Collagen Vitrigel Sheet’as a Novel Drug Delivery Bio-material.  [通常講演]
    Sanae Haga, Toshiaki Takezawa, Takeaki Ozawa, James Remington, Naoki Morita, Michitaka Ozaki
    5th European Conference of the International Federation for Medical and Biological Engineering. 2011年 Bdapest/Hungary(Bdapest Congress&World Trade Center)
  • Bio-imaging of Surgical Stresses-Dynamic Analyses of Liver Oxidative Stress and Damage.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Takeaki Ozawa, Naoki Morita, Yoshimi Kaneshima, J. Remington
    5TH European Conference of the International Federation for Medical and Biological Engineering. 2011年 Bdapest/Hungary(Bdapest Congress&World Trade Center)
  • Age-associated p66Shc induced redox-dependent liver damage and impaired regeneration after hepatectomy in aged mice.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Kaikobad Irani, NaokiMorita, Yoshimi Kaneshima, Takeaki Ozawa
    62th Annual meeting of AASLD. 2011年 San Francisco/USA(Moscone West Convention Center)
  • Effects of a Novel Immunosuppressive Agent, DTCM?Glutarimide Alone or in Combination with Donor Specific Transfusion in Mouse Cardiac Allo?Transplantation.  [通常講演]
    Yusuke Tsunetoshi, Kenichiro Yamashita, Susumu Shibasaki, Ryoichi Goto, KenjiWakayama, Gentaro Hirokata, Masaaki Zaitsu, Shoko Kimura, Rumi Igarashi, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    2010 American Transplant Congress (ATC). 2010年 San Diego/USA
  • Immunosuppressive Effects of Regulatory Dendritic Cells Induced by NK026680.  [通常講演]
    Susumu Shibasaki, Kenichiro Yamashita, Ryoichi Goto, Kenji Wakayama, Gentaro Hirokata, Yusuke Tsunetoshi, Masaaki Zaitsu, Rumi Igarashi, Sanae Haga, Yoshiki Yanagawa, Michitaka Ozaki, Satoru Todo
    2010 American Transplant Congress (ATC). 2010年 San Diego/USA
  • A Novel Solution for Rat Liver Preservation Composed of Heavy Water and Swan Buffer; a Pilot Study.  [通常講演]
    Daisuke Fukumori, Moto Fukai, Kenji Wakayama, Kenichiro Yamashita, Shinya Ueki, Mitsuru Sugawara, Sanae Haga, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo
    2010 American Transplant Congress (ATC). 2010年 San Diego/USA
  • Heavy Water Containing Solution Ameliorates Cold Preservation Injury of the Rat Heart.  [通常講演]
    Kenji Wakayama, Moto Fukai, Kenichiro Yamashita, Daisuke Fukumori, Mitsuru Sugawara, Susumu Shibasaki, Gentaro Hirokata, Masaaki Zaitsu, Yusuke Tsunetoshhi, Michitaka Ozaki, Satoru Todo
    2010 American Transplant Congress (ATC). 2010年 San Diego/USA
  • Heavy Water (D2O) Universally Ameliorates Cold Preservation Injury: Precise Analyses of Cytoprotective Mechanisms In Vitro.  [通常講演]
    Moto Fukai, Kenji Wakayama, Daisuke Fukumori, Kenichiro Yamashita, Mitsuru Sugawara, Sanae Haga, Shinya Ueki, Gentaro Hirokata, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo
    2010 American Transplant Congress (ATC). 2010年 San Diego/USA
  • DTCM?Glutarimide, a New Activator Protein?1 (AP?1) Inhibitor Ameliorates Chronic Allograft Vasculopathy in Mice.  [通常講演]
    Masaaki Zaitsu, Kenichiro Yamashita, Susumu Shibasaki, Ryoichi Goto, Kenji Wakayama, Gentaro Hirokata, Shoko Kimura, Yusuke Tsunetoshi, Rumi Igarashi, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    2010 American Transplant Congress (ATC). 2010年 San Diego/USA
  • CD40?CD154 Costimulation Blockade Plus NF?κB Inhibition Permits a Successful Single?Donor Islet Transplantation in Mice.  [通常講演]
    Yasuyuki Koshizuka, Kenichiro Yamashita, Masaaki Watanabe, Daisuke Kuraya, Masaomi Ogura, Tadashi Yoshida, Hirofumi Kamachi, Michiaki Matsushita, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo
    2010 American Transplant Congress (ATC). 2010年 San Diego/USA
  • Immunosuppressive Effect of DTCM?Glutarimide, a Novel AP?1 Inhibitor, onAllogeneic Islet Transplantation in Mice.  [通常講演]
    Tadashi Yoshida, Kenichiro Yamashita, Masaaki Watanabe, Yasuyuki Koshizuka, Daisuke Kuraya, Masaomi Ogura, Hirofumi Kamachi, Michitaka Ozaki, Michiaki Matsushita, Kazuo Umezawa, Satoru Todo
    2010 American Transplant Congress (ATC). 2010年 San Diego/USA
  • A single infusion of the ex-vivo generated immuno-regulatory dendritic cells under a novel agent, NK026680 markedly prolongs cardiac allograft survival.  [通常講演]
    Susumu. Shibasaki, Kenichiro Yamashita, Y. Yanagawa, Kenji Wakayama, Hirokata Gentaro, Yusuke Tsunetoshi, Masaaki Zaitsu, Rumi Igarashi, Sanae Haga, Michitaka Ozaki, Satoru Todo
    XXIII International Congress of the Transplantation Society. 2010年 Vancouver/Canada
  • Heavy water containing organ preservation solution, Dsol, ameliorates graft survival and function of the rat hearts after extended cold preservation.  [通常講演]
    Kenji Wakayama, Moto Fukai, Kenichiro Yamashita, Daisuke Fukumori, Susumu Shibasaki, Gentaro Hirokata, Masaaki Zaitsu, Yusuke Tsunetoshi, Mitsuru Sugawara, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo
    XXIII International Congress of the Transplantation Society. 2010年 Vancouver/Canada
  • Important characteristics of heavy water (D2O) containing cold preservation solution.  [通常講演]
    Moto Fukai, Daisuke Fukumori, Kenji Wakayama, Kenichiro Yamashita, Mitsuru Sugawara, Sanae Haga, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo
    XXIII International Congress of the Transplantation Society. 2010年 Vancouver/Canada
  • Successful islet transplantation from a single-donor based on CD40-CD154 costimulation blockade plus NF-κB inhibition.  [通常講演]
    Yasuyuki Koshizuka, Kenichiro Yamashita, Masayuki Watanabe, Daisuke Kuraya, Masaomi Ogura, Takashi Yoshida, Hirohumi Kamachi, Michiaki Matsushita, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo
    XXIII International Congress of the Transplantation Society. 2010年 Vancouver/Canada
  • DTCM-glutarimide, a new activator protein-1 (AP-1) inhibitor ameliorates transplant vasculopathy in mice.  [通常講演]
    Masaaki Zaitsu, Kenichiro Yamashita, Susumu Shibasaki, Ryoichi Goto, Krnji Wakayama, Hirokata Gentaro, Yusuke Tsunetoshi, Rumi Igarashi, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    XXIII International Congress of the Transplantation Society. 2010年 Vancouver/Canada
  • A novel immunosuppressive agent, DTCM-glutarimide markedly prolongs cardiac allograft survival in mouse when combined with Donor specific transfusion.  [通常講演]
    Yusuke Tsunetoshi, Kenichiro Yamashita, Susumu Shibasaki, Ryoichi Goto, Kenji Wakayama, Gentaro Hirokata, Masaaki Zaitsu, Shoko Kimura, Rumi Igarashi, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    XXIII International Congress of the Transplantation Society. 2010年 Vancouver/Canada
  • Heavy water containing solution reduces injury of grafts subjected to extended cold preservation in an isolated perfused rat liver model.  [通常講演]
    Daisuke Fukumori, Moto. Fukai, Kenji Wakayama, Kenichiro Yamashita, Mitsuru Sugawara, Hirokata. Gentaro, M. Zaitsu, Yusuke Tsunetoshi, Masahiko Taniguchi, Tomomi Suzuki, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo
    XXIII International Congress of the Transplantation Society. 2010年 Vancouver/Canada
  • The immune-regulatory function of ex-vivo modulated dendritic cells by a novel immunosuppressive agent, NK026680.  [通常講演]
    Susumu Shibasaki, Kenichiro Yamashita, Yoshiki Yanagawa, Kenji Wakayama, Gentaro Hirokata, Yusuke Tsunetoshi, Masaaki Zaitsu, Rumi Igarashi, Sanae Haga, Michitaka Ozaki, Satoru Todo
    14th International Congress of Immunology 2010年 神戸
  • Analysis of genomic abnormal area concerning biological malignant potential and prognosis of hepatocellular carcinoma by high sensitive array CGH.  [通常講演]
    Kazuaki Nakanishi, Keiko Morita, Mituhiro Tada, Nobumoto Tomioka, Toshiya Kamiyama, Hideki Yokoo, Masato Takahashi, Michitaka Ozaki, Michiaki Matushita, Satoru Todo, Takashi Hirano
    2009 The American Hepato-Pancreato-Biliary Association annual meeting. 2009年 Miami/USA
  • The Immunomodulatory Effect of NF-κB Blockade Is Augmented or Abrogated by NFAT Inhibition When Given with Donor-Specific Transfusion.  [通常講演]
    Ryoichi Goto, Kenichiro Yamashita, Shinya Ueki, Masahiko Taniguchi, Tomomi Suzuki, Tsuyoshi Shimamura, Hiroyuki Furukawa, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo
    American Transplant Congress. 2009年 Boston/USA
  • NK026680, a Novel Triazolopyrimidine Derivative, for Allogeneic Islet Transplantation in Mice.  [通常講演]
    Yasuyuki Koshizuka, Kenichiro Yamashita, Masaaki Watanabe, Susumu Shibasaki, Daisuke Kuraya, Shigeru Nakakimura, Michitaka Ozaki, Hirofumi Kamachi, Michiaki Matsushita, Satoru Todo
    American Transplant Congress. 2009年 Boston/USA
  • A Novel Triazolopyrimidine Derivative, NK026680 Inhibits T Cell Function, and Prolongs Cardiac Allograft Survival in Rats.  [通常講演]
    Susumu Shibasaki, Kenichiro Yamashita, Ryoichi Goto, Tetsu Oura, Kenji Wakayama, Gentaro Hirokata, Tomohiro Shibata, Rumi Igarashi, Sanae Haga, Masahiko Taniguchi, Tomomi Suzuki, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo
    American Transplant Congress. 2009年 Boston/USA
  • Prevention of Graft Failure Caused by IBMIR with a Novel NF-κB Inhibitor, Dehydroxymethylepoxyquinomicin (DHMEQ) after Intraportal Islet Transplantation in Mice.  [通常講演]
    Daisuke Kuraya, Hirofumi Kamachi, Masaaki Watanabe, Yasuyuki Koshizuka, Shigeru Nakakimura, Michitaka Ozaki, Kazuo Umezawa, Kenichiro Yamashita, Michiaki Matsushita, Satoru Todo
    American Transplant Congress. 2009年 Boston/USA
  • Combined Treatment with a Nuclear Factor (NF)-κB Inhibitor, DHMEQ, and Tacrolimus Permits a Long-Term Allogeniec Islet Engraftment in Mice.  [通常講演]
    Masaaki Watanabe, Kenichiro Yamashita, Hirofumi Kamachi, Daisuke Kuraya, Yasuyuki Koshizuka, Shigeru Nakakimura, Michitaka Ozaki, Kazuo Umezawa, Michiaki Matsushita, Satoru Todo
    American Transplant Congress. 2009年 Boston/USA
  • Re-Evaluation of Heavy Water for Organ Preservation Solution; In Vitro Study.  [通常講演]
    Moto Fukai, Kenichiro Yamashita, Kenji Wakayama, Daisuke Fukumori, Ryoichi Goto, Sanae Haga, Gentaro Hirokata, Shigeru Nakakimura, Mitsuru Sugawara, Hirofumi Kamachi, Tomomi Suzuki, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michiaki Matsushita, Michitaka Ozaki, Satoru Todo
    American Transplant Congress. 2009年 Boston/USA
  • Extended Preservation of Rat Hearts with Novel Organ Preservation Solution:Role of Actin Cytoskeleton and ATP Maintenance.  [通常講演]
    Kenji Wakayama, Moto Fukai, Kenichiro Yamashita, Daisuke Fukumori, Susumu Shibasaki, Gentaro Hirokata, Tomohiro Shibata, Tetsu Oura, Ryoichi Goto, Masahiko Taniguchi, Tomomi Suzuki, Tsuyoshi Shimamura, Michiaki Matsushita, Hiroyuki Furukawa, Michitaka Ozaki, Taisuke Ono, Mitsuru Sugawara, Satoru Todo
    American Transplant Congress. 2009年 Boston/USA
  • A novel NF-κB inhibitor DHMEQ could suppress peritoneal dissemination of gastric cancer by anti-tumor /-adhesive effects in mice.  [通常講演]
    Kazuhiro Mino, Kazuaki Nakanishi, Sanae Haga, Masanori Sato, Masaya Kina, Hideki Yokoo, Toshiya Kamiyama, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo
    ECCO 15 / ESMO 34 Multidisciplinary Congress 2009年 Berlin/Germany
  • A novel NF-κBinhibitor DHMEQ suppressed peritoneal dissemination of pancreatic cancer in mouse xenograftmodel.  [通常講演]
    Masanori Sato, M. Ozaki, K. Nakanishi, T. Watanabe, S. Haga, K. Mino, H. Yokoo, K. Umezawa, Y. Ohmiya, T. Kamiyama, S. Todo
    ECCO 15 / ESMO 34 Multidisciplinary Congress 2009年 Berlin/Germany
  • Hepatic ischemia induced immediate oxidative stress after reperfusion and determined the severity of the reperfusion-induced damage. ? in vivo dynamic analysis of liver oxidative stress and damage ?  [通常講演]
    Sanae Haga, S. James Remington, Takeaki Ozawa, Naoki Morita, Keita Terui, Michitaka Ozaki
    60th Annual meeting of AASLD. 2009年 Boston/USA
  • Heavy Water Reduced Cold Hypoxic Injury Of Cardiomyocytes.  [通常講演]
    Moto Fukai, Kenichiro Yamashita, Kenji Wakayama, Daisuke Fukumori, Sanae Haga, Masahiko Taniguchi, Tomomi Suzuki, Tsuyoshi Shimamura, Taisuke Ono, Shintaro Kinugawa, Mitsuru Sugawara, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo
    AHA2009-82nd Scientific Sessions of the American Heart Association. 2009年 Orlando/USA
  • Myocardial protection with a novel organ preservation solution containing deuterium oxide for prolonged cold ischemia of the heart.  [通常講演]
    Kenji Wakayama, Moto Fukai, Kenichiro Yamashita, Daisuke Fukumori, Susumu Shibasaki, Gentaro Hirokata, Tetsu Oura, Ryoichi Goto, Masahiko Taniguchi, Tomomi Suzuki, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo
    AHA2009-82nd Scientific Sessions of the American Heart Association. 2009年 Orlando/USA
  • #1 molecular mechanism of liver injury, protection and regeneration, #2 bio-imaging of molecular functions and tumor by optic probes.  [通常講演]
    Michitaka Ozaki
    Japan-Denmark Joint Workshop on “Molecular Cancer Research 2009年 東京
  • Bio-imagimg of Surgical Stress dynamic analysis of liver oxidative stress and damage.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Takeaki Ozawa, S. James Remington, Naoki Morita, Yoshihiro Ohmiya
    Molecular Imaging for Systems Biology 2009年 岡崎
  • .“The immunomodulatory effect of donor specific transfusion plus NF-kB blockade by utilizing a novel inhibitor, DHMEQ”  [通常講演]
    Ryoichi Goto, Kenichiro Yamashita, Takeshi Aoyagi, Shinya Ueki, Rumi Igarashi, Motohiro Uno, Tetsu Oura, Masaaki Watanabe, Tomohiro Shibata, Masahiko Taniguchi, Tomomi Suzuki, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    8th international conference 2008年 Berlin/Germany
  • Inhibition of NF-kB Activation Augments Immunomodulatory Effect of Donor Specific Transfusion  [通常講演]
    Goto R, Yamashita K, Aoyagi T, Ueki S, Uno M, Ohura T, Taniguchi M, Suzuki T, Shimamura T, Furukawa H, Umezawa K, Ozaki M, Todo S
    Americn Transplant Congress 2011. 2008年 Berlin/Germany
  • A Novel NF-kappa B inhibitor, DHMEQ, Attenuates Arterial Vasculopathy.  [通常講演]
    Uno M, Yamashita K, Shibata T, Aoyagi T, Ohura T, Haga S, Watanabe M, Umezawa K, Ozaki M, Todo S
    Americn Transplant Congress 2010. 2008年 Toronto/Canada
  • A Novel Nuclear Factor kappa B inhibitor, DHMEQ Ameliorates Development of Obliterative Bronchiolitis in Heterotopic Murine Airway-Transplantation.  [通常講演]
    Oshima Y, Uno M, Yamashita K, Shibata T, Aoyagi T, Umezawa K, Ozaki M, Todo S
    Americn Transplant Congress 2009. 2008年 Toronto/Canada
  • Induction of Immunosuppressive Dendritic Cells by a Novel NF-kB inhibitor, DHMEQ.  [通常講演]
    Takeshi Aoyagi, Kenichiro Ymashita, Y Yanagawa, Ryoichi Goto, Rumi Igarashi, Sanae Haga, Michitaka Ozaki, K Onoue, Kazuo Umezawa, Hiroyuki Furukawa, Satoru Todo
    Americn Transplant Congress 2008. 2008年 Toronto/Canada
  • Effect of NF-FEB Inhibition by DHMEQ on Islet Transplantation in Mice.  [通常講演]
    Masaaki Watanabe, Kenichiro Yamashita, Shuichiro Matsumoto, Yousuke Tsuruga, Thoru Takahashi, TetsuOura, Michitaka Ozaki, Kazuo Umezawa, Michiaki Matsushita, Satoru Todo
    The Tranplantation Society2008 2008年 Sydney/Australian
  • A novel NF-kB inhibitor, DHMEQ, Attenuates arterial Vasculopathy.  [通常講演]
    Motohiro Uno, Kenichiro Yamashita, Tomohiro Shibata, Ryoichi Goto, Tetsu Oura, Masaaki Watanabe, Sanae Haga, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo
    The Tranplantation Society2008 2008年 Sydney/Australian
  • Inhibition of NF-kB and/or NFAT Activation Augments or Abrogates Immunomodulatory Effects of Donor Specific Transfusion.  [通常講演]
    Ryoichi Goto, Kenichiro Yamashita, Ueki S, Masahiko Taniguchi, Tomomi Suzuki, Thuyoshi Shimamura, Hiroyuki Furukawa, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo
    The Tranplantation Society2008 2008年 Sydney/Australian
  • The Effect of DHMEQ, A Novel NF-kB Inhibitor on Development of Obliterative Bronchiolitis in Heterotopic Murine Airway Allo-transplantatin.  [通常講演]
    Oshima Y, Uno M, Shibata T, Oura T, Watanabe M, Goto R, Umezawa K, Ozaki M, Yamashita K, Todo S
    The Tranplantation Society2008 2008年 Sydney/Australian
  • The Novel NF-EB Inhibitor, DHMEQ Prevents local and remote organ Injury Following Intestinal Ischemia/Reperfusion in Rats.  [通常講演]
    Tomomi Suzuki, Kenichiro Yamashita, W Jomen, Shinya Ueki, Takeshi Aoyagi, Moto Fukai, Hiroyuki Furukawa, Kazuo Umezawa, Michitaka Ozaki, Satoru Todo
    The Tranplantation Society2008 2008年 Sydney/Australian
  • Induction of Immunosuppressive Dendritic Cells by Novel Nuclear Factor-KappaB Inhibitor DHMEQ.  [通常講演]
    Takeshi Aoyagi, Kenishiro Yamashita, R Yanagawa, Ryoichi Goto, Michitaka Ozaki, K Onoue, Kazuo Umezawa, Satoru Todo
    The Tranplantation Society2008. 2008年 Sydney/Australian
  • Non-invasive realtime monitoring of oxidative stress and damage by newly developed optical probes in mouse liver ischemia/reperfusion.  [通常講演]
    Michitaka Ozaki, Sanae Haga, S. James Remington, Takeaki Ozawa, Yuko Oikawa, Satoru Todo
    AASLD annual meeting. 2008年 San Fransisco/USA
  • “Effect of A Novel NF-kB Inhibitor, Dehydroxymethylepoxyquinomicin in Combination with Dnonor Specific Transfusion in Mouse Heart Transolantation.”  [通常講演]
    Goto R, Yamashita K, Aoyagi T, Uno M, Ueki S, Itoh T, Taniguchi M, Suzuki T, Shimamura T, Furukawa H, Ozaki M, Umezawa K, Todo S
    American Transplant Congress 2007年 San Francisco/USA
  • Donor pretreatment with a novel NF-kB inhibitor, DHMEQ can alleviate the graft damage in syngenic marginal islet transplantation.  [通常講演]
    Takahashi T, Matsushita M, Matsumoto S, Tsuruga Y, Kasai H, Watanabe M, Ozaki M, Furukawa H, Umezawa K, Todo S
    Joint congress of JSAO and IFAOaka 2007年 Osaka
  • p66shc, an ageing protein, plays a pivotal role in post-hepatectomized liver regeneration in aged mice.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Tadahiro Osada, Yuko Oikawa, Hiroyuki Furukawa, Kaikobad Irani, Satoru Todo
    AASLD annual meeting 2007年 Boston/USA
  • Prevention of Intraportal Islet Graft Failure by a Novel NF-kB Inhibitor DHMEQ.  [通常講演]
    Shuichiro Matsumoto, Michiaki Matsushita, Tohru Takahashi, Hironori Kasai, Yosuke Tsuruga, Hirofumi Kamachi, Michitaka Ozaki, Hiroyuki Furukawa, Kazuo Umezawa, Satoru Todo
    World Transplant Congress 2006年 Boston/USA
  • Control of allograft rejection by appling a novel NF-kB inhibitor, dehydroxymethylepoxyquinomicin.  [通常講演]
    Kenichiro Yamashita, Shinya Ueki, Takeshi Aoyagi, Sanae Haga, Tomomi Suzuki, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    World Transplant Congress 2006年 Boston/USA
  • A Novel NF-κB Inhibitor, Dehydroxymethylepoxyquinomicin Suppresses Donor Specific Memory/Effector Cells and Attenuates Development of Cardiac Allograft Vasculopathy.  [通常講演]
    Shinya Ueki, Kenichiro Yamashita, Takeshi Aoyagi, Tomoo Itoh, Tomomi Suzuki, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
    World Transplant Congress 2006年 Boston/USA
  • PDK1/Akt pathway Plays a Critical Role in Liver Regeneration in Mouse Partial Hepatectomy Model.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Tadahiro Osada, Keita Terui, Hiroshi Inoue, Yasuo Okamoto, Wataru Ogawa, Hiroyuki Furukawa, Satoru Todo
    FASEB Summer Research Conference. 2006年 Aspen/USA
  • James Remington, Michitaka Ozaki. Real-time monotoring of cellular redox states by newly developed redox-sensitive GFP probe.  [通常講演]
    Sanae Haga, Rumi Igarashi, Hiroyuki Furukawa, Satoru Todo
    International Symposia for Bioimaging 2006 2006年 Kyoto
  • Ex vivo stat3 gene transfer prevents liver graft failure and elongates survival in rat fatty liver transplant model.  [通常講演]
    Dong Sheng Sun, Tetsuya Ogino, Takahito Yagi, Hiroshi Sadamori, Hiroyoshi Matsukawa, Susumu Shinoura, Hiroshi Murata, Yuzo Umeda, Hiromi Iwagaki, Noriaki Tanaka, Michitaka Ozaki
    ATC2005. 2005年 Seattle/USA
  • Ex vivo adenoviral gene transfer of constitutively activated stat3 reduced ischemia-reperfusion induced injury and promoted liver regeneration in 20% rat partial liver transplant model.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Lei Guo, Hiroyuki Furukawa, Michiaki Matsushita, Satoru Todo
    11th International Liver Transplantation Society (ILTS) annual meeting 2005年 Los Angeles/USA
  • Impaired Regeneration And Fatal Liver Failure After Resection Of Steatotic Liver By Cell Cycle Arrest.  [通常講演]
    Hiroshi Murata, Takahito Yagi, Tetsuya Ogino, Hiroshi Sadamori, Hiroyoshi Matsukawa, Susumu Shinoura, Dong Sheng Sun, Yuzo Umeda, Hiromi Iwagaki, Noriaki Tanaka, Michitaka Ozaki
    12th Congress Of The European Society For Organ Transplantation. 2005年 Geneva/Swiss
  • STAT3 Confers Resistance against Hyoxia/reoxygenation Injury in Hepatocytes via Mn-SOD.  [通常講演]
    Keita Terui, Hiroaki Kuroda, Katsunori Kouchi, Tadashi Matsunaga, Hideo, Yoshida, Naomi Ohnuma, Sanae Haga, Shin Enosawa, Michitaka Ozaki
    37th Annual Meeting of the Pacific Association of Pediatric Surgeons. 2004年 Seoul/Korea
  • Analysis of regulatory signals of liver regeneration -signals regulating hepatocellular proliferation and growth.  [通常講演]
    Sanae Haga, Shin Enosawa, Keita Terui, Wataru Ogawa, Hiroshi Inoue, Michitaka Ozaki
    2004 American Transplant Congress. 2004年 Boston/USA
  • Stat3 confers resistance against hypoxia/reoxygenation-induced oxidative injury in hepatocytes via mn-SOD.  [通常講演]
    Keita Terui, Sanae Haga, Shin Enosawa, Naomi Onuma, Michitaka Ozaki
    2004 American Transplant Congress. 2004年 Boston/USA
  • Improved Hepatic Regeneration With Reduced Injury By Redox Factor-1 in a Rat Small Size-Liver Transplant Model.  [通常講演]
    Michitaka Ozaki, Lei Guo, Sanae Haga, Shin Enosawa, Katsutoshi Naruse, Yasushi Harihara, Yasuhiko Sugawara, Masatoshi Makuuchi, Kaikobad Irani
    XX International Congress of The Transplantation Society.( 2004年 Vienna/Austria
  • Constitutive activation of STAT3 confers resistance to liver against Fas-mediated liver injury: redox-dependent and ?independent mechanisms.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Wataru Ogawa, Hiroshi Inoue, Keita Terui, Shin Enosawa
    55th Annual Meeting of the American Association for the Study of Liver Diseases. 2004年 Boston/USA
  • Novel targets of STAT3 and its clinical application.  [通常講演]
    Michitaka Ozaki
    University of Iowa. 2004年 Iowa city
  • Recent topics in redox-dependent signal regulation in liver. Invited lecture at Department of Cardiology.  [通常講演]
    Michitaka Ozaki
    Johns Hopkins University School of Medicine 2004年 Baltimore
  • Ex Vivo Adenoviral Gene Transfer of Constitutively Activated Stat3 Reduced Ischemia-Reperfusion Induced Injury and Promoted Liver Regeneration in 20% Rat Partial Liver Transplant Model.  [通常講演]
    Michitaka Ozaki, Lei Guo, Sanae Haga, Keita Terui, Hui Qi Zhang, Shin Enosawa, Seiichi Suzuki
    2003 American Transplant Congress. 2003年 Washington D.C./USA
  • Constitutive Activation of Stat3 by Adenoviral Gene Transfer Confers Resistance to Liver Against Fas-Mediated Liver Injury: Caspase Inhibition and Redox-Dependent Mechanisms.  [通常講演]
    Michitaka Ozaki, Sanae Haga, Hui Qi Zhang, Keita Terui, Wataru Ogawa, Hiroshi Inoue, Torayuki Okuyama, Kiyoshi Takeda, Shizuo Akira, Shin Enosawa, Seiichi Suzuki
    6th Annual Meeting of the American Society of Gene Therapy. 2003年 Washington D.C./USA
  • Redox Regulation in Liver Injury.  [通常講演]
    Michitaka Ozaki
    International Meeting of the Society of Free Radical Research (SFRR)-Asia. 2003年 Seoul
  • Redox-dependent activation of Stat1 confers resistance against hypoxia/reoxygenation-induced apoptotic cell death in rat hepatocytes.  [通常講演]
    Keita Terui, Michitaka Ozaki, Sanae Haga, Hui Qi Zhang, Shin Enosawa, Seiichi Suzuki
    2002年 Redox Kyoto
  • Over-expressed redox factor-1 (REF-1) by ex vivo adenovirus-mediated gene transfer promotes liver regeneration with reduced liver injury in rat partial liver transplant model.  [通常講演]
    Michitaka Ozaki, Lei Guo, Sanae Haga, Seiichi Suzuki
    2002 American Transplant Congress. 2002年 Washington D.C./USA
  • Redox Gene Therapy in Liver Transplantation. (Grand Round Seminar)  [通常講演]
    Michitaka Ozaki
    Pittsburgh University Medical School 2002年 Pittsburgh(USA)
  • Prevention of ischemia/reperfusion-induced liver injury by modulating redox sensitive signals. (Invited lecture)  [通常講演]
    Michitaka Ozaki
    International Symposium For Redox Signaling And Stress Diseases (Redox Kyoto 2002). 2002年 Kyoto
  • Early infantile kidney as a marginal donation resource; histology and pathophysiology.  [通常講演]
    Tatsuo Kuroda, Shin Enosawa, Mitsufumi Endo, Michitaka Ozaki, Nobuyuki Morikawa, Seiichi Suzuki, Hiroshi Amemiya
    The 6th Congress of the International Society for Organ Sharing. 2001年 Nagoya
  • Overexpression of Redox Factor-1 protects against post-ischemic liver injury by reducing oxidative stress and NF-kB DNA binding activity.  [通常講演]
    Michitaka Ozaki, Hiroshi Amemiya, Seiichi Suzuki
    The 6th Congress of the International Society for Organ Sharing. 2001年 Nagoya
  • HGF protects hepatocytes against hypoxia/reoxygenation-induced cell death by reducing mitochondrial generation of reactive oxygen species through activation of PI3K-Akt pathway.  [通常講演]
    Michitaka Ozaki, Yuko Nagata, Seiichi Suzuki
    American Society of Transplantation 2001. 2001年 Chicago/USA
  • New strategy for preventing ischemia/ reperfusion-induced organ injury and promoting regeneration. ? a novel trial for improving transplanted graft function by targeted regulation of cellular signals-  [通常講演]
    Michitaka Ozaki
    The 6th congress of the international society for organ sharing 2001年 名古屋
  • Adenovirally over-expressed redox factor-1(Ref-1) protects against post-ischemic liver injury by reducing oxidative stress and NF-kB DNA binding activity.  [通常講演]
    Michitaka Ozaki, Kaikobad Irani, Seiichi Suzuki
    American Society of Transplantation 2001 2001年 Chicago(USA)
  • The novel protective mechanism of HGF -redox protection against hypoxia/reoxygenation-induced apoptosis-  [通常講演]
    Michitaka Ozaki
    Department of Medicine, Johns Hopkins University School of Medicine 2001年 USA
  • Inhibition of the small GTPase, Rac1, protects against ischemia/reperfusion liver injury in mice.  [通常講演]
    Ozaki M, Deshpande S, Angkeow P, Bellan J, Lowenstein CJ, Dinauer MC, Goldschmidt-Clermont P, Suzuki S, Irani K
    18th International Congress of the Transplantation Society. 2000年 Rome/Itary
  • Inhibition of the small GTPase, Rac1, protects against reperfusion-induced liver injury by reducing intracellular reactive oxygen species and NF-kB DNA binding activity.  [通常講演]
    Michitaka Ozaki, Shailesh S Deshpande, Piamsook Angkeow, John Bellan, Charles J Lowenstein, Mary C Dinauer, Pascal J Goldschmidt-Clermont, Seiichi Suzuki, Kaikobad Irani
    International Hepato-Pancreatico-Biliary Association General Assembly 2000. 2000年 Brisbane/Australia
  • Inhibition of the small GTPase, Rac1, protects against post-ischemic liver injury by suppressing generation of intracellular reactive oxygen species and NF-kB binding activity.  [通常講演]
    Michitaka Ozaki, Shailesh S Deshpande, Piamsook Angkeow, John Bellan, Charles J Lowenstein, Mary C Dinauer, Pascal J Goldschmidt-Clermont, Seiichi Suzuki, Kaikobad Irani
    American Society of Transplantation General Meeting 2000 2000年 Chicago(USA)
  • Anti-P selectin monoclonal antibldy protects against reticuloendothelial system dysfunction following hepatic ischemia/reperfusion.  [通常講演]
    N Sakamoto, ML Bregman, K Maemura, ZL Sun, M Ozaki, GB Bulkley, AS Klein
    Digestive Disease Week-USA 1998年 New Orleans,LA/USA
  • Effects of an hepatic sinusoidal endothelial cell fraction on Kupffer cell antigen presentation.  [通常講演]
    K Maemura, ZL Sun, N Sakamoto, M Ozaki, GB Bulkley, AS Klein
    Digestive Disease Week-USA 1998年 New Orleans,LA/USA
  • Immunomodulatory effects of Kupffer cells on antigen stimulated T-lymphocyte proliferation in vitro.  [通常講演]
    ZL Sun, K Maemura, N Sakamoto, M Ozaki, GB Bulkley, AS Klein
    Digestive Disease Week-USA. 1998年 New Orleans, LA(USA)
  • Iron release from haemosiderin and production of iron catalysed hydroxyl radical in vitro.  [通常講演]
    M.Ozaki, T.Kawabata, M.Awai
    The 4th Biennial General Meeting of the Society for Free Radical Research 1987年 Kyoto
  • “光”を通じて今見えること、そして将来できること ?医療へそして日常へ-  [通常講演]
    尾崎倫孝
    北海道大学大学院保健科学研究院 公開講座2014「ようこそ!ヘルスサイエンスの世界へ」 北海道大学大学院保健科学研究院、札幌
  • 生体リズムの乱れを超高感度で検出する組織密着型センサーの開発 ~疾患発症解明への応用を目指して~  [通常講演]
    狩野晴美, 伊藤遼河, 浜田和子, 菊池祥裕, 中島かな子, 石川正純, 尾崎 倫孝, 浜田俊幸
    第26回日本時間生物学会学術大会 口頭発表(一般)

作品等

  • 「肝再生・障害におけるJak/STAT3およびPI3K/PDK1/Aktの意義と機能解析」
    2005年
  • 種々の原因による肝障害・肝再生のシグナル解析とその臨床応用への可能性
    2005年
  • 「肝臓の虚血再還流障害、肝再生の病態・生理」 岡山大学・大学院特別講義
    2005年
  • 教育講演「肝虚血・再潅流障害と再生の分子機構」
    2005年
  • 急性肝不全の病態解明とSTAT3をターゲットとした治療の展望
    2005年
  • HCV肝硬変に対する生体肝移植の対策―IFN-beta術前投与とHCV再発の組織学的早期診断― 第40回日本移植学会総会 パネルディスカッション
    2004年
  • 肝におけるSTAT3の制御と機能解析
    2004年
  • 肝再生における細胞内シグナル伝達機構の解析とその治療への可能性 シンポジウム 第11回日本臓器保存生物医学会総会
    2004年
  • 肝再生における細胞内シグナル伝達機構の解析とその治療への可能性 シンポジウム 第11回日本臓器保存生物医学会総会
    2004年
  • シグナル解析と臓器機能制御(肝疾患におけるシグナル解析とその治療への展望) 大阪市立大学大学院医学研究科 大学院特別講義
    2004年
  • シグナル解析と臓器機能制御(肝疾患におけるシグナル解析とその治療への展望)
    2004年
  • シグナル解析と臓器機能制御
    2003年
  • 肝におけるSTAT3の新たなターゲットとその機能解析
    2003年
  • STAT3の新たなターゲットとその機能解析
    2003年
  • 細胞内シグナル解析からみた保存液の条件
    2003年
  • STAT蛋白の臓器・細胞機能調節機構と移植・再生医療への応用 ―STAT蛋白をもちいた新しい治療戦略―、第38回日本移植学会 シンポジウム
    2002年
  • 臓器虚血・再潅流傷害 -傷害抑制・再生促進のための新たな戦略- 第38回日本移植学会 Pre-Congress Educational Program
    2002年
  • 細胞内シグナル制御による肝傷害抑制および再生促進 第1回日本再生医療学会総会 シンポジウム1「21世紀の再生医療の現状とその実用化に向けて―肝臓」
    2002年
  • HGFによる肝虚血再潅流傷害抑制メカニズム(PI3-K/Akt/Rac1 pathwayによる細胞内活性酸素消去系)、第102回日本外科学会総会 サージカルフォーラム「HGF」
    2002年
  • Adenovirus vectorをもちいたex vivo Redox Factor-1 gene transductionによる移植肝再生促進、第102回日本外科学会総会 サージカルフォーラム「肝移植1」
    2002年
  • シグナル制御による臓器虚血再潅流傷害抑制の試み、第102回日本外科学会総会 サージカルフォーラム「虚血再潅流傷害3」
    2002年
  • 移植遺伝子、蛋白治療 ―臓器傷害の抑制とすみやかな再生をめざして― 北海道大学第一外科特別セミナー
    2002年
  • 外科領域における遺伝子、蛋白治療の展望 ―臓器傷害の抑制とすみやかな再生をめざして― 東京医科大学大学院特別講義
    2002年
  • 移植遺伝子蛋白治療 移植臓器傷害の抑制とすみやかな再生をめざして、第37回日本移植学会 特別シンポジウム2「21世紀臓器移植のニューステージ」
    2001年
  • 移植医療における臓器虚血・再潅流傷害抑制および再生促進にたいする新しい治療法の確立 - a novel trial for improving transplanted graft function by targeted regulation of cellular signals- 招待講演 神奈川県立小児医療センター
    2001年
  • 「細胞内シグナル修飾による移植臓器機能制御の可能性」
    2001年
  • Redox regulation of signal transduction in the reperfused liver
    2000年
  • Redox Gene Therapy - 肝虚血再潅流障害克服への新たな展望 -、第7回日本臓器保存生物医学会総会 シンポジウム
    2000年
  • - Redox Gene Therapy - 虚血・再潅流傷害抑制、再生促進に向けた遺伝子治療の可能性、シンポジウム「遺伝子工学的手法をもちいた臓器保存」、第30回日本低温医学会総会
  • 肝虚血・再潅流傷害-レドックスシグナル伝達による傷害・再生の機序-、第10回臓器保存生物医学会総会 シンポジウムS-3「各臓器における臓器障害の機序の共通点と相違点」
  • 肝再生おける細胞内シグナルの解析 -Stat3経路およびPI3-K/PDK/Akt経路の重要性- 第104回日本外科学会定期学術集会 サージカルフォーラム
  • 肝再生おける細胞内シグナルの解析 -Stat3経路およびPI3-K/PDK/Akt経路の重要性- 第104回日本外科学会定期学術集会 サージカルフォーラム

その他活動・業績

受賞

  • 2018年09月 IBD and Liver: East Meets West Posters of Distinction.
     Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver with steatosis. 
    受賞者: Michitaka Ozaki
  • 2015年05月 北海道大学大学院保健科学研究院 第7回北海道大学大学院保健科学研究院長賞
     
    受賞者: 尾崎 倫孝
  • 2005年 ILTS 2005 Travel Award
     International Liver Transplantation Society. 
    受賞者: 尾崎 倫孝
  • 2002年 ACT 2002 International Investigator Award (Dr. Lei Guo as awardee)
     American Congress of Transplantation 
    受賞者: 尾崎 倫孝
  • 2001年 AST 2001 International Investigator Award
     American Society of Transplantation 
    受賞者: 尾崎 倫孝
  • 2000年 Johns Hopkins University Department of Medicine Research Fellow Investigator Award
     
    受賞者: 尾崎 倫孝
  • 1999年 American Liver Foundation Amgen Postdoctoral Research Fellowship Award
     
    受賞者: 尾崎 倫孝
  • 1999年 Johns Hopkins University Department of Surgery Transplant Research Award
     
    受賞者: 尾崎 倫孝

共同研究・競争的資金等の研究課題

  • ランタニド・ナノ粒子(LNP)を利用した癌細胞特異的光治療法の開発
    文部科学省:科学研究費 挑戦的研究(開拓)
    研究期間 : 2019年 -2022年 
    代表者 : 尾崎 倫孝
  • 肝虚血・再灌流傷害における多段階多元的傷害進展のメカニズム解析
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2019年 -2022年 
    代表者 : 森田 直樹
  • 生体分子の量と活性を測るオプトバイオ分析の創発
    文部科学省:科学研究費 基盤研究(A)
    研究期間 : 2019年 -2022年 
    代表者 : 小澤 岳昌
  • 毒性関連ビッグデータを用いた人工知能による次世代型安全性予測手法の開発
    経済産業省:平成29年度省エネ型電子デバイス材料の評価技術の開発事業(機能性材料の社会実装を支える高速・高効率な安全性評価技術の開発)
    研究期間 : 2017年 -2021年 
    代表者 : 船津 公人
  • 意識下手術における聴覚刺激に伴う精神活動の可視化とストレスマネジメント方略
    文部科学省:科学研究費 基盤研究(C)
    研究期間 : 2017年 -2020年 
    代表者 : 溝部佳代
  • 炎症誘導性の細胞死に着目した、慢性炎症性疾患の病態の解明と治療法の開発
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2017年 -2020年 
    代表者 : 浅野真未
  • 時計遺伝子発現の自動定量化技術を用いた体内時計関連疾患発症機構解析システムの開発
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2017年 -2019年 
    代表者 : 浜田 俊幸
  • 分子イメージングを基軸とする生細胞内分子計測・光操作法の開発
    文部科学省:科学研究費 基盤研究(S)
    研究期間 : 2014年 -2019年 
    代表者 : 小澤岳昌
  • 慢性肝疾患・肝障害を標的とした機能性食品スクリーニング法の開発
    北海道科学技術総合振興センター:イノベーション創出研究支援事業(スタートアップ研究補助金)
    研究期間 : 2016年 -2017年 
    代表者 : 尾崎倫孝
  • 肝臓代謝系を指標とした機能性食品等の機能性・安全性の解析法の開発
    北海道科学技術総合振興センター:
    研究期間 : 2014年 -2015年 
    代表者 : 尾崎倫孝
  • 消化器癌の微小転移同定システムの臨床応用
    文部科学省:科学研究費 基盤研究(C)
    研究期間 : 2012年 -2015年 
    代表者 : 崎浜秀康
  • 消化器癌におけるMesothelin分子発現の意義と癌悪性度との関係
    文部科学省:科学研究費 基盤研究(C)
    研究期間 : 2012年 -2015年 
    代表者 : 蒲池浩文
  • 肝ストレスの動的解析による肝機能障害・予備能の評価
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2012年 -2014年 
    代表者 : 佐藤直樹
  • 光プローブを応用した生体イメージング法による画期的術中ライブ診断法の開発
    文部科学省:科学研究費 基盤研究(A)
    研究期間 : 2011年 -2014年 
    代表者 : 尾崎倫孝
  • 腹腔内転移のバイオイメージングと抑制物質の分子デザイン
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2011年 -2014年 
    代表者 : 梅澤一夫
  • 分子標的薬による新たな膵島移植法の開発:重症糖尿病の克服に向けた新戦略
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2011年 -2014年 
    代表者 : 山下健一郎
  • 細胞情報伝達に関わる蛋白質活性を可視化する発光プローブ分子の開発
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2011年 -2014年 
    代表者 : 森田直樹
  • 生体内分子をターゲットとした革新的バイオイメージング法による診断・治療法の開発
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2012年 -2013年 
    代表者 : 藤堂省
  • 光を応用した生物学的診断・治療法の開発
    上原記念生命科学財団:第8回特定研究助成金
    研究期間 : 2011年 -2013年 
    代表者 : 尾崎倫孝
  • 消化器癌におけるMesothelinおよびCA125発現の検討
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2011年 -2012年 
    代表者 : 嶋村剛
  • マウス肝移植における抗体プローブイメージング法を用いた拒絶反応の診断と病態解析
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2011年 -2012年 
    代表者 : 細田充主
  • 新規分泌型発光デュアルプローブを用いたin vivo での癌細胞上皮間葉移行解析
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2011年 -2012年 
    代表者 : 片岡昭彦
  • 細胞死(オートファジー・アポトーシス)による肝再生制御メカニズムの解析
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2011年 -2012年 
    代表者 : 細田充主
  • 肝臓移植における重水を主体とした臓器保存液の開発
    文部科学省:科学研究費 基盤研究(A)
    研究期間 : 2010年 -2012年 
    代表者 : 藤堂省
  • 光イメージングによる癌転移機構解明‐メラノーマがリンパから血流に入る瞬間を捉える-
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2010年 -2012年 
    代表者 : 古川洋志
  • 臓器ストレス測定法の開発と外科領域への応用
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2010年 -2011年 
    代表者 : 藤堂省
  • 大腸癌微小転移における癌幹細胞の役割
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2010年 -2011年 
    代表者 : 崎浜秀康
  • 患者末梢血を用いた重症薬疹モデルマウスの作成および発症機序の解明
    厚生労働省:厚生労働省科学研究費補助金(免疫アレルギー疾患等予防・治療研究事業)
    研究期間 : 2009年 -2011年 
    代表者 : 阿部理一郎
  • 迅速遺伝子解析による胆道閉鎖症細菌プロファイリングと胆管炎早期発見及び予後予測
    文部科学省:科学研究費 基盤研究(C)
    研究期間 : 2009年 -2011年 
    代表者 : 岡田忠雄
  • 生体材料(コラーゲンビトリゲル)をもちいた新しい治療材料の開発
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2009年 -2010年 
    代表者 : 古川博之
  • 分泌型光プローブによる生体内リポーターシステムの開発と腫瘍診断・治療法への応用
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2009年 -2010年 
    代表者 : 尾崎倫孝
  • 光プローブをもちいたバイオイメージングによる多角的診断・治療法の開発
    文部科学省:科学研究費 基盤研究(A)
    研究期間 : 2008年 -2010年 
    代表者 : 尾崎倫孝
  • 個別化医療の実現のための技術融合バイオ診断技術開発/染色体解析技術開発」に係る、がん組織バンクの構築とCGH解析
    経済産業省:NEDO独立行政法人新エネルギー・産業技術総合開発機構委託事業
    研究期間 : 2006年 -2010年 
    代表者 : 藤堂省
  • 新規低分子NF-kB阻害剤による新たな免疫抑制療法の開発(06-44)
    医薬基盤研究所:平成18年度保健医療分野における基礎研究推進事業
    研究期間 : 2006年 -2010年 
    代表者 : 藤堂省
  • 新規分子機能プローブ開発による生体・臓器内分子機能診断への応用
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2008年 -2009年 
    代表者 : 尾崎倫孝
  • 転写因子NFkBをターゲットとした新しい薬剤流出ステントの開発
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2008年 -2009年 
    代表者 : 藤堂省
  • 疾患早期診断のための糖鎖自動分析装置開発
    文部科学省:JST(先端計測分析技術・機器開発事業)
    研究期間 : 2007年 -2009年 
    代表者 : 西村紳一郎
  • 新規NF-KB活性阻害剤(DHMEQ)の小腸虚血再灌流障害に対する治療効果
    文部科学省:科学研究費 基盤研究(C)
    研究期間 : 2007年 -2008年 
    代表者 : 鈴木友巳
  • CHIP-chip法/Oligofish法によるヒトがん組織の網羅的転写機能解析
    文部科学省:科学研究費 基盤研究(C)
    研究期間 : 2007年 -2008年 
    代表者 : 中西一彰
  • 転写因子NF-KB制御による安全な肝臓移植法の開発
    文部科学省:科学研究費 基盤研究(A)
    研究期間 : 2006年 -2008年 
    代表者 : 藤堂省
  • 高解像度アレイCGHによる胃癌のゲノム異常獲得形式と病理組織学的因子との統合解析
    文部科学省:科学研究費 基盤研究(C)
    研究期間 : 2006年 -2008年 
    代表者 : 富岡伸元
  • 水素の動きを制御することにより阻血再灌流障害のシグナルを制御する試み
    文部科学省:科学研究費 挑戦的萌芽研究
    研究期間 : 2006年 -2007年 
    代表者 : 深井原
  • 消化器外科領域における分子標的治療に向けた包括的基盤研究
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2005年 -2007年 
    代表者 : 尾崎倫孝
  • 血小板を用いた新しい重症肝疾患に対する治療法の開発
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2005年 -2007年 
    代表者 : 大河内信弘
  • 新たに開発されたレドックス・プローブをもちいた新しい臓器機能評価法の開発
    文部科学省:科学研究費 萌芽研究
    研究期間 : 2005年 -2006年 
    代表者 : 尾崎倫孝
  • 遺伝子治療を用いた小腸移植の新しい戦略
    文部科学省:科学研究費 基盤研究(B)
    研究期間 : 2004年 -2006年 
    代表者 : 古川博之
  • アデノシン関連物質による臓器虚血再潅流障害の予防
    文部科学省:科学研究費 萌芽研究
    研究期間 : 2004年 -2006年 
    代表者 : 藤堂省
  • 氷温域における臓器保存法の開発(飛躍的な保存時間の延長と機能回復にむけて)
    文部科学省:科学研究費 奨励研究(A)
    研究期間 : 1998年 -1999年 
    代表者 : 尾崎倫孝
  • 移植を目的とした新しい臓器保存法の開発(アミノ酸,短鎖脂肪酸の効果について)
    文部科学省:科学研究費 奨励研究(A)
    研究期間 : 1996年 -1997年 
    代表者 : 尾崎倫孝
  • signal regulation of liver regeneration, liver transplantation from marginal donors, redox regulation of cellular signals

教育活動情報

主要な担当授業

  • 基盤看護科学特講
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 保健科学院
  • 病態生理学特論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 保健科学院
    キーワード : 消化器疾患およびストレス・移植疾患を中心とした各種疾患の病態生理、疾病の原因(成り立ち)と経過・進行 
  • 基盤看護科学特講演習
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 保健科学院
  • 臨床腫瘍学特論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 保健科学院
    キーワード : がん、病態生理、診断、治療、予防、緩和医療、疫学
  • 成人健康障害論Ⅰ
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
  • がん・再生医療特論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 保健科学院
    キーワード : 1)細胞・臓器へのストレス・ストレス応答(再生を含む)とそのメカニズム 2)がん発生および生物学・病態・進展、治療による影響
  • 成人健康障害論Ⅱ
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
  • 大学院共通授業科目(教育プログラム):社会と健康
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 大学院共通科目
    キーワード : 健康科学,環境,人類生態,遺伝・細胞,代謝,ストレス応答,生体計測,健康情報,栄養、精神・心理
  • 看護研究Ⅱ
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
  • 大学院共通授業科目(教育プログラム):JICA開発大学院連携プログラム
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 大学院共通科目
  • 健康科学特論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 保健科学院
    キーワード : 健康科学,環境,人類生態,遺伝・細胞,代謝,ストレス応答,生体計測,健康情報,栄養、精神・心理
  • 感染・生体ストレス応答学演習
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 保健科学院
    キーワード : 科学的な論拠、感染症、病原微生物、病原因子、難治性感染症、持続感染、環境、多剤耐性菌、疫学動向、論理性、生体ストレス、酸化ストレス、レドックス制御、細胞の生存・成長・死、ストレスに関連する病態と疾患
  • 感染・生体ストレス応答学特論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 保健科学院
    キーワード : 科学的な論拠、感染症、病原微生物、病原因子、難治性感染症、持続感染、環境、多剤耐性菌、疫学動向、生体ストレス、酸化ストレス、レドックス制御、細胞の生存・成長・死、ストレスに関連する病態と疾患
  • 生体情報機能解析学特講
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 保健科学院
    キーワード : 病原微生物、免疫エスケープ機構、アポトーシス、自己寛容機構、アレルギー疾患モデル動物、自己免疫疾患モデル動物、デジタル形態学、Image-J、質量分析、プロテオーム解析、医用放射線、超音波、MRI、細胞ストレス、制御された細胞死と臓器傷害・機能、脂肪肝・NASH
  • 生体情報機能解析学特講演習
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 保健科学院
    キーワード : 病原微生物、免疫エスケープ機構、アポトーシス、自己寛容機構、アレルギー疾患モデル動物、自己免疫疾患モデル動物、デジタル形態学、Image-J、質量分析、プロテオーム解析、医用放射線、超音波、MRI、細胞ストレス、制御された細胞死と臓器障害・機能、脂肪肝・NASH
  • 基盤看護科学特講演習
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 保健科学院
    キーワード : 看護,管理,教育,制度,協働
  • 基盤看護科学特講
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 保健科学院
    キーワード : 看護,管理,教育,制度,協働
  • 保健薬理学
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 疾病、病態生理、薬物療法、薬理作用
  • 看護研究Ⅱ
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 看護研究,研究計画,文献検索,研究方法,エビデンス
  • 疾患病態学概論
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 解剖学、生理学、病態・疾患学
  • 保健解剖学特講
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 解剖学、生理学、病態・疾患学
  • 保健生理学
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 細胞・組織生理、循環生理、呼吸生理、消化・吸収の生理、代謝・内分泌生理、外部環境からの防御、発生と老化、神経・筋生理
  • 成人健康障害論Ⅰ
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 内科的疾患、血液疾患、呼吸器疾患、循環器疾患、 代謝・免疫学的疾患、感染症、腎・泌尿器疾患、神経疾患
  • 成人健康障害論Ⅱ
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 血液疾患、呼吸器疾患、循環器疾患、消化器疾患 代謝・免疫学的疾患、感染症、腎・泌尿器疾患、神経疾患
  • 成人健康障害論
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 呼吸器疾患、循環器疾患、消化器疾患
  • 臨床病態学Ⅲ
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 貧血、白血病、血小板系疾患、凝固・線溶異常、Mたんぱく血症、消化管疾患、肝・胆・膵疾患、呼吸器疾患、糸球体腎炎、間質性腎炎、ネフローゼ症候群、酸・塩基平衡、電解質異常

大学運営

委員歴

  • 2018年05月 - 現在   日本がん分子標的治療学会   評議員
  • 2018年04月 - 現在   (一社)日本臓器保存生物医学会   臓器保存機能再生プロジェクト小委員会委員
  • 2018年04月 - 現在   (一社)日本臓器保存生物医学会   会則委員会委員長
  • 2015年11月 - 現在   日本臓器保存生物医学会   理事
  • 2015年11月 - 現在   日本臓器保存生物医学会   評議員
  • 2005年 - 2007年   米国移植学会   Awards委員会委員(Awards Committee, American Transplant Society)

その他

  • 2016年10月 - 2016年10月  農林水産省・食品産業科学技術研究推進事業Smart-Hアドバイザー 
    農林水産省・食品産業科学技術研究推進事業Smart-Hのアドバイザー
  • 2016年05月 - 2016年05月  The Science Advisory Board 委員 
    平成28年7月から石油精製物質等の新たな化学物質規制に必要な国際先導的有害性試験法の開発(肝臓毒性、腎臓毒性及び神経毒性in vitro試験法の開発)の事業成果検討会委員を行った。
  • 2014年06月 - 2014年06月  報道と新聞掲載 
    脂肪肝障害の分子メカニズムの解明および非アルコール性脂肪性肝炎(NASH: non-alcoholic steato-hepatitis)の発生・進行において中心的役割を果たすp62/SQSTM1分子の同定とその分子メカニズムの解明に成功。報道と各新聞に掲載されました。 報道:WEB掲載;ASAHI WEB News (2014.6.28)、Yahoo Japan News (2014.6.25)、Yomiuri Online (2014.6.26)、ガジェット通信 (2014.6.26)、マイナビニュース (2014.6.27)、The Wall Street Journal (2014.6.26)、北海道新聞Doshin (2014.6.26) 新聞掲載;北海道新聞(2014.6.26)、読売新聞(2014.6.26)、朝日新聞(2014.6.28)、北海道医療新聞 (2014.7.25)にて掲載。
  • 2014年06月 - 2014年06月  プレス・リリース:北海道大学大学院 保健科学研究院において 
    脂肪肝障害の分子メカニズムの解明および非アルコール性脂肪性肝炎(NASH: non-alcoholic steato-hepatitis)の発生・進行において中心的役割を果たすp62/SQSTM1分子の同定とその分子メカニズムの解明に成功にし、研究発表を行いました。
  • 2009年02月 - 2009年02月  テレビ出演 
    NHK教育番組:サイエンスZEROにて、「生体の機能を照らし出せ ~光イメージング~」に関する研究についてテレビ出演。


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