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Research on a novel mechanism for oxidative stress mediated by NO-induced nucleic acid nitration.

Research Project

Project/Area Number 15390107
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKumamoto University

Principal Investigator

AKAIKE Takaaki  Kumamoto University, Graduate School of Medical Sciences, Associate Professor, 大学院・医学薬学研究部, 助教授 (20231798)

Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2003: ¥2,400,000 (Direct Cost: ¥2,400,000)
KeywordsNO / Nucleic acid nitration / 8-Nitroguanosine / Anti-8-nitroguanosine antibody / Cytoprotective effect / Redox signaling / Cell signal transduction / Heme oxvgenase-1 / 生体内ニトロ化反応
Research Abstract

Nitric oxide(NO) plays important roles in the pathogenesis and defense mechanism involved in various diseases, including microbial infections, inflammation, cardiovascular and neurodegenerative diseases, and cancer.
We currently explored NO-induced nucleic acid modifications with a focus on guanine nitration(e.g., 8-nitroguanine formation) and its signaling potential contributing to host defense against microbial pathogens(Akaike T.et al.Proc.Natl.Acad.Sci.USA,100:685-690,2003). Formation of 8-nitroguanine and its related compounds in vivo and in cultured cells was assessed immunochemically with an antibody for 8-nitroguanosine. Wild-type mice and littermate mice deficient in inducible NO synthase(iNOS) were infected with various pathogens including influenza virus and Salm onella.
Strong 8-nitroguanosine immunostaining was observed primarily in the cytosol of epithelial cells and inflammatory cells such as exudate macrophages in the infectious foci of wild-type mice but not iNOS-deficie … More nt mice. This staining generally co-localized with iNOS immunostaining in the tissues and cells. NO was generated in excess in wild-type mice but was eliminated in iNOS-deficient mice after infections ; this result also correlated well with formation of 8-nitroguanosine. Similar immunostaining for 8-nitroguanosine was evident with various cells in culture depending on endogenous and exogenous NO production. It is intriguing that 8-nitroguanosine shows unique redox activity affecting NADPH-dependent reductases including NADPH-cytochrome P450 reductase and all isoforms of NOS to produce superoxide. More importantly, 8-nitroguanosine stimulated the cultured cells to significantly increase the expression of a cytoprotective enzyme heme oxygenase-1, so that the cells became resistant to apoptosis and cell death induced by infection-associated cytotoxicity and nutrient starvation.
The present results prompt us a new paradigm for redox signaling via guanine nitration caused by oxidative and nitrative stress(i.e., nitrative signaling), which may thus contribute in a critical way to the cytoprotection and host defense occurring during many disease processes. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (54 results)

All 2005 2004 2003 Other

All Journal Article (40 results) Patent(Industrial Property Rights) (2 results) Publications (12 results)

  • [Journal Article] Influence of membrane fluidity on human immunodeficiency virus type 1 entry.2005

    • Author(s)
      Harada, S. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 329

      Pages: 480-486

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] NOマーカー2005

    • Author(s)
      芥 照夫他
    • Journal Title

      臨床検査 49

      Pages: 139-143

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nitrative stress through formation of 8-nitroguanine.2005

    • Author(s)
      Akuta, T. et al.
    • Journal Title

      Nitric Oxide (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interleukin-1beta induces death in chondrocyte-like ATDC5 cells through mitochondrial dysfunction and energy depletion in a reactive nitrogen and oxygen species-dependent manner.2005

    • Author(s)
      Yasuhara, R. et al.
    • Journal Title

      Biochem J. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nitric oxide-induced nitrative stress involved in microbial pathogenesis.2005

    • Author(s)
      Zaki M.H.et al.
    • Journal Title

      J.Pharmacol.Sci. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nitric oxide-induced nitrative stress involeved in microbial pathogenesis.2005

    • Author(s)
      Zaki M.H.et al.
    • Journal Title

      J.Pharmacol.Sci. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interleukin-1β induces death in chondrocyte-like ATDC5 cells through mitochondrial dysfunction and energy depletion in a reactive nitrogen and oxygen species-dependent manner.2005

    • Author(s)
      Yasuhara, R. et al.
    • Journal Title

      Biochemical J. (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Nitric oxide-induced nitrative stress involved in microbial pathogenesis.2005

    • Author(s)
      Zaki, H.M.et al.
    • Journal Title

      J.Pharmacol.Sci. (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Quantitative assessment of protein-bound tyrosine nitration in airway secretions from patients with inflammatory airway diseases.2004

    • Author(s)
      Sugiura, H. et al.
    • Journal Title

      Free Rad.Res. 38

      Pages: 49-57

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice.2004

    • Author(s)
      Okamoto, T. et al.
    • Journal Title

      Am.J.Physiol.Lung Cell.Mol.Physiol. 286

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Adsorption and infectivity of human immunodeficiency virus type 1 are modified by the fluidity of the plasma membrane for multiple-site binding.2004

    • Author(s)
      Harada, S. et al.
    • Journal Title

      Micobiol.Immunol. 48

      Pages: 347-355

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enhanced chemotherapeutic effect against tumor cells by heme oxygenase inhibitor combined with anticancer agents.2004

    • Author(s)
      Fang, J. et al.
    • Journal Title

      Int.J.Cancer 109

      Pages: 1-8

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] SMA-doxorubicin, a new polymeric micellar drug for effective antitumor targeting.2004

    • Author(s)
      Greish, K. et al.
    • Journal Title

      J.Control Release 97

      Pages: 219-230

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antioxidative and antimutagenic activities of 4-vinyl-2, 6-dimethoxyphenol (canolol) isolated from canola oil.2004

    • Author(s)
      Kuwahara, H. et al.
    • Journal Title

      J.Agric.Food Chem. 52

      Pages: 4380-4387

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Proapoptotic effect of proteolytic activation of matrix metalloproteinases by Streptococcus pyogenes thiol proteinase/Streptococcus pyrogenic exotoxin B.2004

    • Author(s)
      Tamura, F. et al.
    • Journal Title

      Infect.Immun. 72

      Pages: 4836-4847

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Nitric oxide as an endogenous mutagen for Sendai virus without antiviral activity.2004

    • Author(s)
      Yoshitake, J. et al.
    • Journal Title

      J.Virol. 78

      Pages: 8709-8719

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment.2004

    • Author(s)
      Fang, J. et al.
    • Journal Title

      Apoptosis 9

      Pages: 27-35

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Molecular mechanism for activation of matrix metalloproteinases during bacterial infections and respiratory inflammation.2004

    • Author(s)
      Okamoto, T. et al.
    • Journal Title

      Biol.Chem. 385

      Pages: 997-1006

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Quantitative assessment of protein-bound tyrosine nitration in airway secretions from patients with inflammatory airway diseases.2004

    • Author(s)
      Sugiura, H. et al.
    • Journal Title

      Free Rad.Res 38

      Pages: 49-57

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antioxidative and antimutagenic activities of 4-vinyl-2, 6-dimethoxyphenol(canolol) isolated from canola oil.2004

    • Author(s)
      Kuwahara, H. et al.
    • Journal Title

      J.Agric.Food Chem. 52

      Pages: 4380-4387

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antiapoptotic role of heme oxygenase(HO) and the potential of HO as a target in anticancer treatment.2004

    • Author(s)
      Fang, J. et al.
    • Journal Title

      Apoptosis 9

      Pages: 27-35

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enhanced chemotherapeutic effect against tumor cells by hemeoxygenase inhibitor combined with anticancer agents.2004

    • Author(s)
      Fang, J. et al.
    • Journal Title

      Int.J.Cancer 109

      Pages: 1-8

    • Related Report
      2004 Annual Research Report
  • [Journal Article] SMA-doxorubicin, a new polymeric micellar drug for effective antitumor targeting.2004

    • Author(s)
      Gareish, K. et al.
    • Journal Title

      J.Control Release 97

      Pages: 219-230

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Molecular mechanism for activation of matrix metalloproteinases during bacterial infections and respiratory inflammation.2004

    • Author(s)
      Okamoto, T. et al.
    • Journal Title

      Biol.Chem. 2385

      Pages: 997-1006

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Adsorption and infectivity of human immunodeficiency virus type 1 are modified by the fluidity of the plasma membrane for multiple-site binding.2004

    • Author(s)
      Harada, S. et al.
    • Journal Title

      Microbiol.Immunol. 48

      Pages: 347-355

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis.2003

    • Author(s)
      Akaike, T. et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 100

      Pages: 685-690

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antiapoptotic effect of haem oxygenase-1 induced by nitric oxide in experimental solid tumour.2003

    • Author(s)
      Tanaka, S. et al.
    • Journal Title

      Br.J.Cancer 88

      Pages: 902-909

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] In vivo antitumor activity of pegylated zinc protoporphyrin : Targeted inhibition of heme oxygenase in solid tumor.2003

    • Author(s)
      Fang, J. et al.
    • Journal Title

      Cancer Res. 63

      Pages: 3567-3574

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in porcine coronary microvessels.2003

    • Author(s)
      Matoba, T. et al.
    • Journal Title

      Arterioscler.Thromb.Vasc.Biol. 23

      Pages: 1224-1230

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Modulation of tumor-selective vascular blood flow and extravasation by stable prostaglandin I_2 analogue, beraprost sodium.2003

    • Author(s)
      Tanaka, S. et al.
    • Journal Title

      J.Drug Target. 11

      Pages: 45-51

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Superoxide generation mediated by 8-nitroguanosine, a highly redox-active nucleic acid derivative.2003

    • Author(s)
      Sawa, T. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 311

      Pages: 300-306

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Pivotal role of Cu,Zn-SOD in endethelium-dependent hyperpolarization.2003

    • Author(s)
      Morikawa, K. et al.
    • Journal Title

      J.Clin.Invest. 112

      Pages: 1871-1879

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] インフルエンザウイルスとA群レンサ球菌複合感染モデルマウスにおけるオセルタミビルとセフジニルの併用効果2003

    • Author(s)
      田村文雄他
    • Journal Title

      新薬と臨床 52

      Pages: 83-88

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] NOによる腫瘍増殖および転移促進のメカニズム2003

    • Author(s)
      林田和之他
    • Journal Title

      放射線生物学 38

      Pages: 1-9

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] NOによる微生物遺伝子変異と感染制御異常2003

    • Author(s)
      赤池孝章他
    • Journal Title

      化学療法の領域 19

      Pages: 85-90

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] インフルエンザと抗生剤2003

    • Author(s)
      田村文雄他
    • Journal Title

      インフルエンザ 4

      Pages: 25-34

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 呼吸器疾患における酸化・ニトロ化ストレスの評価法2003

    • Author(s)
      赤池孝章
    • Journal Title

      呼吸 22

      Pages: 222-228

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 感染症の病態を操る分子:NO2003

    • Author(s)
      赤池孝章
    • Journal Title

      医学のあゆみ 別冊「NOと病態」 204

      Pages: 702-706

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in porcine coronary microvessels.2003

    • Author(s)
      Matoba, T. et al.
    • Journal Title

      Arterioscler.Thromb.Vase.Biol. 23

      Pages: 1224-1230

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Pivotal role of Cu, Zn-SOD in endethelium-dependent hyperpolarization.2003

    • Author(s)
      Morikawa, K. et al.
    • Journal Title

      J.Clin.Invest. 112

      Pages: 1871-1879

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] ニトログアノシン-3',5'-サイクリック1リン酸化合物およびプロテインキナーゼG活性化剤2005

    • Inventor(s)
      赤池 孝章, 芥 照夫
    • Industrial Property Rights Holder
      国立大学法人熊本大学
    • Industrial Property Number
      2005-052649
    • Filing Date
      2005-02-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] ニトログアノシン-3',5'-サイクリック1リン酸化合物およびプロテインキナーゼG活性化剤2005

    • Inventor(s)
      赤池 孝章
    • Industrial Property Rights Holder
      国立大学法人熊本大学
    • Industrial Property Number
      2005-052649
    • Filing Date
      2005-02-28
    • Related Report
      2004 Annual Research Report
  • [Publications] Akaike, T. et al.: "8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis"Proc.Natl.Acad.Sci.U.S.A.. 100. 685-690 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fang, J. et al.: "In vivo antitumor activity of pegylated zinc protoporphyrin : targeted inhibition of heme oxygenase in solid tumor"Cancer Res.. 63. 3567-3574 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matoba, T. et al.: "Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in porcine coronary microvessels"Arterioscler.Thromb.Vasc.Biol.. 23. 1224-1230 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sawa, T. et al.: "Superoxide generation mediated by 8-nitroguanosine, a highly redox-active nucleic acid derivative"Biochem.Biophys.Res.Commun.. 311. 300-306 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Morikawa, K. et al.: "Pivotal role of Cu, Zn-SOD in endethelium-dependent hyperpolarization"J.Clin.Invest.. 112. 1871-1879 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanaka, S. et al.: "Modulation of tumor-selective vascular blood flow and extravasation by stable prostaglandin I_2 analogue, beraprost sodium"J.Drug Target.. 11. 45-51 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fang, J. et al.: "Enhanced chemotherapeutic effect against tumor cells by heme oxygenase inhibitor combined with anticancer agents"Int.J.Cancer. 109. 1-8 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sugiura, H. et al.: "Quantitative assessment of protein-bound tyrosine nitration in airway secretions from patients with inflammatory airway diseases"Free Rad.Res.. 38. 49-57 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Okamoto, T. et al.: "Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice"Am.J.Physiol.Lung Cell.Mol.Physiol.. 286. L198-L209 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fang, J. et al.: "Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment"Apoptosis. 9. 27-35 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshitake, J. et al.: "Nitric oxide as an endogenous mutagen for Sendai virus without antiviral activity"J.Virol.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tamura, F. et al.: "Proapoptotic effect of proteolytic activation of matrix metalloproteinases by Streptococcus pyogenes thiol proteinase/Streptococcus pyrogenic exotoxin B"Infect.Immun.. (in press). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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