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分野紹介
■システム生物学領域
■生命情報システム領域
 Molecular Mechanisms of Induction of Protective Responses by Oxidative Stress
教授
野口 範子
Professor Noriko NOGUCHI
専門分野: 酸化ストレスの細胞生物化学
研究内容: 酸化ストレスによる細胞の防御システム誘導のメカニズム
     ■Pickup publications
 ■原著論文

酸化ストレスによる細胞の
防御システム誘導のメカニズムの解明

酸化ストレスに対する血管内皮細胞遺伝子発現応答

  動脈硬化や肥満、糖尿病などの生活習慣病の成因に酸化ストレスが重要なはたらきをすることが知られている。動脈硬化の発症には酸化変性を受けた低比重リポ蛋白質(OxLDL)が重要な役割を担うとされる。 OxLDLに含まれる多種類の脂質酸化生成物はそれぞれ特有の生理活性をもち、血管細胞を傷害したり刺激を与えたりする。細胞はこの刺激に対して遺伝子発現の変動を介して応答し、その結果、動脈硬化の進展を促す場合がある。 その一方で、細胞はこのような酸化ストレスに対して細胞防御にはたらく遺伝子を発現し、自らを守ろうとする。当研究室では酸化ストレスに対する血管内皮細胞の応答を遺伝子発現の網羅的解析により研究している。

脂質酸化生成物による細胞防御発現メカニズム

  当研究室は酸化生成物による防御機構昂進のメカニズムの解明に力をいれている。 脂質酸化生成物は細胞を傷害して細胞死にも導くが、低濃度で細胞を前処理した後、高い濃度で引き続き処理すると細胞死が抑制される。これは低濃度の脂質酸化生成物が細胞の防御機構を昂進させたことによるが、そのメカニズムは前処理する酸化生成物の種類によって異なることがわかってきた(図1)。 転写因子を活性化して一連の酸化ストレス応答遺伝子を発現させ、チオレドキシンシステムを活性化する場合や、グルタチオン合成酵素の遺伝子発現を上昇させ、細胞内グルタチオン濃度を増加させる場合などがある。 酸化生成物のなかには、同じく細胞内グルタチオン濃度を増加させるのであるが、酵素の遺伝子には影響を与えることなく、その活性を上げることにより細胞内グルタチオン濃度を高めて細胞防御を行うものもある。

細胞内活性酸素生成とシグナル伝達

  脂質酸化生成物は細胞を刺激して細胞内に活性酸素種を産生させる。この活性酸素が細胞内シグナル伝達に重要なはたらきをすることがわかっている。 活性酸素は細胞膜のNADPH oxidase やnitric oxide synthaseなどの酵素に加え、ミトコンドリアなどが主な発生源となるが(図2)、刺激の種類と細胞の種類によって異なる。 活性酸素の生成を促し、遺伝子発現にまで導くのは脂質の酸化物だけでなく、血流によって生じる物理的刺激(shear stress)によってもおこる。 種々な刺激と細胞内活性種生成の場の特定、そして、それらによる細胞内シグナル伝達に興味をもって研究をおこなっている。

 

図1 脂質酸化生成物による細胞防御システムの亢進メカニズム

図2 リゾリン脂質刺激による内皮細胞のミトコンドリアからの活性酸素産生


Pickup publications

25-HCのコレステロール合成の抑制作用はOSBP非依存的である

  25-hydroxycholesterol(25-HC)はコレステロールの酸化物のひとつで、コレステロール生合成を抑制する機能が知られている。 25-HCと結合するoxysterol-binding protein (OSBP)が細胞質に存在し、25-HCを細胞に添加するとゴルジ体へ移行することから、このOSBPが25-HCのコレステロール合成の抑制作用に重要な働きをすると推測されていた。
  この論文において、OSBP をsiRNAにより90%程度発現抑制しても、25-HCによるコレステロール合成酵素の抑制作用に影響しないことを示した。また、これらの酵素を誘導する作用をもつlysophosphatidylcholine (LPC)を同時に添加すると、25-HCのコレステロール合成の抑制作用は消失することも示した。
  これらの結果から、25-HCのコレステロール合成の抑制作用はOSBP非依存的であることが示された。

原著論文
T. Nishimura, T. Inoue, N. Shibata, A. Sekine, W. Takabe, N. Noguchi, Arai H.
Inhibition of cholesterol biosynthesis by 25-hydroxycholesterol is independent of OSBP
Genes to Cells, 10, 793-801, 2005.


Nrf2もしくはTR1をノックダウンすると、低濃度HNEによる細胞死抑制作用は失われる

  4-hydroxy 2 nonenal (HNE)は脂質酸化の最終産物であるアルデヒドの一つで、強い細胞毒性により細胞死を起こす。一方、HNEは親電子性化合物であるため、転写因子Nrf2の核移行を促すことも知られている。
  本論文では、低濃度のHNEで細胞(PC12)を前処理すると、その後の高濃度添加によるアポトーシスが抑制されることを見い出しし、その分子メカニズムを明らかにした。低濃度のHNEによってNrf2が活性化し、thioredoxin reductase 1 (TR1)が誘導され、蛋白合成、活性ともに上昇する。
  Nrf2もしくはTR1をsiRNAによりノックダウンすると、低濃度HNEによる細胞死抑制作用は失われることを示した。

原著論文
4-Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance primarily through induction of thioredoxin reductase 1 via transcriptional activation of Nrf2
Zhi-Hua Chen *, Yoshiro Saito , Yasukazu Yoshida , Azusa Sekine, Noriko Noguchi, and Etsuo Niki
J. Biol. Chem. In press 2005


原著論文

I. Original paper (peer reviewed)

  1. N. Noguchi, H.-A. Yamamoto, H. Naitoh, S. Misawa
    Cardio-respiratory effects of paraquat with and without emetics in wistar rats.
    Vet. Hum. Toxicol., 27, 508-510,1985
  2. K. Kohno, N. Noguchi
    Large myelinated club ending on the Mauthner cell in the goldfish; A study with thin sectioning and freeze-fracturing.
    Anat. Embryol., 173, 361-370, 1986
  3. N. Noguchi, H.-A. Yamamoto, E. Tanaka, S. Misawa
    Initial accumulation of paraquat in the heart leading to acute death.
    Jpn. J. Legal Med., 44, 6-11, 1990
  4. N. Noguchi, Y. Yoshida, H. Kaneda, Y. Yamamoto, E. Niki
    Action of ebselen as an antioxidant against lipid peroxidation.
    Biochem. Pharmacol., 44, 39-44, 1992
  5. N. Gotoh, K. Shimizu, E. Komuro, J. Tsuchiya, N. Noguchi, E. Niki
    Antioxidant activities of probucol against lipid peroxidations.
    Biochim. Biophys. Acta, 1128, 147-154, 1992
  6. N. Noguchi, H.-A. Yamamoto, S. Misawa
    Effects of paraquat on mitochondrial and microsomal Mg2+-ATPase activity in rat liver.
    Arch. Environ. Contam. Toxicol., 24, 483-486, 1993
  7. N. Noguchi, N. Gotoh, E. Niki
    Dynamics of the oxidation of low density lipoprotein induced by free radicals.
    Biochim. Biophys. Acta, 1168, 348-357, 1993
  8. N. Noguchi, N. Gotoh, E. Niki
    Effects of ebselen and probucol on oxidative modifications of lipid and protein of low density lipoprotein induced by free radicals.
    Biochim. Biophys. Acta, 1213, 176-182, 1994
  9. N. Noguchi, E. Komuro, E. Niki, R. L. Willson
    Action of curcumin as an antioxidant against lipid peroxidation.
    J. Jpn. Oil Chem. Soc., 43, 1045-1051, 1994
  10. H. Yasuda, N. Noguchi, M. Miki, W. Morinobu, K. Hirano, T. Ogihara, T. Tanabe, M. Mino, K. Terao, E. Niki
    Hepatic damage induced by perfusion of radical generating azo compound and its inhibition by vitamin E.
    Chem. Biol. Inter., 97, 11-23, 1995
  11. N. Noguchi, E. Niki
    Dynamics of free radical formation from the reaction of peroxides with haemproteins as studied by stopped-flow chemiluminescence.
    Free Rad. Res., 23, 329-338, 1995
  12. K. Hayashi, N. Noguchi, E. Niki
    Action of nitric oxide as an antioxidant against oxidation of soybean phosphatidylcholine liposomal membranes.
    FEBS Lett., 370, 37-40, 1995
  13. E. Niki, N. Noguchi, H. Tsuchihashi, N. Gotoh
    Interaction among vitamin C, vitamin E, and b-carotene.
    Am. J. Clin. Nutr., 62 (Suppl), 1322S-1326S, 1995
  14. N. Gotoh, N. Noguchi, J. Tsuchiya, K. Morita, H. Sakai, H. Shimasaki, E. Niki
    Inhibition of oxidation of low density lipoprotein by vitamin E and related compounds.
    Free Rad. Res., 24, 123-134, 1996
  15. N. Noguchi, H. Sakai, Y. Katoh, J. Tsuchiya, Y. Yamamoto, E. Niki, H. Horikoshi, T. Kodama
    Inhibition of oxidation of low density lipoprotein by troglitazone.
    Atherosclerosis, 123, 227-234, 1996
  16. N. Noguchi, Y. Iwaki, M. Takahashi, E. Komuro, Y. Kato, K. Tamura, O. Cynshi, T. Kodama, E. Niki
    2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran: Design and evaluation as a novel radical-scavenging antioxidant against lipid peroxidation.
    Arch. Biochem. Biophys., 342, 236-243, 1997
  17. N. Noguchi, Y. Okimoto, J. Tsuchiya, O. Cynshi, T. Kodama, E. Niki
    Inhibition of oxidation of low density lipoprotein by a novel antioxidant BO-653 prepared by theoretical design.
    Arch. Biochem. Biophys., 347, 141-147, 1997
  18. 野口範子、西野公大、鷲尾英一、石 紅朕、陳 京生、二木鋭雄
    イチョウ葉エキスの抗酸化作用.
    J. Jpn. Oil Chem. Soc., 12, 1481-1488, 1997
  19. N. Noguchi, H. Yamashita, N. Gotoh, Y. Yamamoto, R. Numano, E. Niki
    2,2'-Azobis(4-methoxy-2,4-dimethylvaleronitrile), a new lipid-soluble azo initiator: Application to oxidations of lipids and low density lipoprotein in solution and in aqueous dispersions.
    Free Rad. Biol. Med., 24, 259-268, 1998
  20. N. Noguchi, M. Takahashi, J. Tsuchiya, H. Yamashita, E. Komuro, E. Niki
    Aaction of 21-aminosteroid U74006F as an antioxidant against lipid peroxidation. Biochem. Pharmacol., 55, 785-791, 1998
  21. K. Uchida, M. Kanematsu, K. Sakai, T. Matsuda, N. Hattori, Y. Mizuno, D. Suzuki, T. Miyata, N. Noguchi, E. Niki, T. Osawa
    Protein-bound acrolein: Potential markers for oxidative stress.
    Proc. Natl. Acad. Sci., 95, 4882-4887, 1998
  22. K. Uchida, M. Kanematsu, Y. Morimitsu, T. Osawa, N. Noguchi, E. Niki
    Acrolein is a product of lipid peroxidation reaction. Formation of free acrolein and its conjugate with lysine residues in oxidized low-density lipoproteins.
    J. Biol. Chem., 273, 16058-16066, 1998
  23. O.Cynshi, Y. Kawabe, T. Suzuki, Y. Takashima, H. Kaise, M. Nakamura, Y. Ohba, Y. Kato, K. Tamura, A. Hayasaka, A. Higashida, H. Sakaguchi, M. Takeya, K. Takahashi, K. Inoue, N. Noguchi, E. Niki, T. Kodama
    Antiatherogenic effects of the antioxidant BO-653 in three different animal models.
    Proc. Natl. Acad. Sci., 95, 10123-10128, 1998
  24. N. Noguchi, E. Niki
    Dynamics of vitamin E action against LDL oxidation.
    Free Rad. Res., 28, 561-572, 1998
  25. N. Noguchi, R. Numano, H. Kaneda, E. Niki
    Oxidation of lipids in low density lipoprotein particles.
    Free Rad. Res., 29, 43-52, 1998
  26. H. Yamashita, A. Nakamura, N. Noguchi, E. Niki, H. Kuhn
    Oxidation of low density lipoprotein and plasma by 15-lipoxygenase and free radicals.
    FEBS Letters, 445, 287-290, 1999
  27. H. Shi, N. Noguchi, Y. Xu, E. Niki
    Formation of phospholipid hydroperoxides and its inhibition by a-tocopherol in rat brain synaptosomes induced by peroxynitrite.
    Biochem. Biophys. Res. Commun., 257, 651-656, 1999
  28. N. Noguchi, E. Damiani, L. Greci, E. Niki
    Action of quinolinic and indolinonic aminoxyls as radical-scavenging antioxidant. Chem. Phys. Lipids, 99, 11-19, 1999
  29. H. Shi, N. Noguchi, E. Niki
    Dynamics of antioxidant action of ubiquinol: a reappraisal.
    BioFactors, 9, 141-148, 1999
  30. N. Yoshida, T. Yoshikawa, H. Manabe, Y. Terasawa, M. Kondo, N. Noguchi, E. Niki
    Vitamin E protects against polymorphonuclear leukocyte-dependent adhesion to endothelial cells.
    J. Leukocyte Biol., 65, 757-763, 1999
  31. A. Watanabe, N. Noguchi, M. Takahashi, E. Niki
    Rate constants for hydrogen atom abstraction by a-tocopheroxyl radical from lipid, hydroperoxide and ascorbic acid.
    Chem. Letters, 613-615, 1999
  32. H. Shi, N. Noguchi, E. Niki
    Comparative study on dynamics of antioxidative action of a-tocopheryl hydroquinone, ubiquinol, and a-tocopherol against lipid peroxidation.
    Free Rad. Biol. Med., 27, 334-346, 1999
  33. H. Shi, N. Noguchi, Y. Xu, E.Niki
    1-Methyl - 4-phenyl-2,3-dihydropyridinium is transformed by ubiquinone to the selective nigrostriatal toxin 1-methyl-4-phenylpyridinium
    FEBS Lett., 461, 196-200, 1999
  34. K. Nishino, N. Noguchi, E. Niki
    Dynamics of action of bisphenol as radical-scavenging antioxidant against lipid peroxidation in solution and liposomal membranes
    Free Rad. Res., 31, 535-548, 1999
  35. K. Miyauchi, T. Urakami, H. Abeta, H. Shi, N. Noguchi, E. Niki
    Action of Pyrroloquinolinequinol as an antioxidant against lipid peroxidatiion in solution
    Antioxidants and Redox Signaling, 1, 547-554, 1999
  36. M. Takaku, Y. Wada, K. Jinnouchi, M. Takeya, K. Yakahashi, H. Usuda, M. Naiti, H. Kurihara, Y. Yazaki, Y. Kumazawa, Y. Okimoto, M. Umetani, N. Noguchi, E. Niki, T. Hamakubo, T. Kodama
    An in vitro coculture model of transmigrant monocytes and foam cell formation
    Arterioscler. Thromb. Vascr. Biol., 19, 2330-2339, 1999
  37. Y.H. Kim, M. Takahashi, N. Noguchi, E. Suzuki, K. Suzuki, N. Taniguchi, E. Niki
    Inhibition of c-Jun expression induces antioxidant enzymes under serum deprivation
    Arch. Biochem. Biophys., 374, 339-346, 2000
  38. N. Noguchi, K. Nishino, E. Niki
    Antioxidant action of antihypertensive drug, carvedilol, against lipid peroxidation
    Biochem. Pharmacol., 59, 1069-1076, 2000
  39. A. Watanabe, N. Noguchi, S. Fujisawa, T. Kodama, K. Tamura, O. Cynshi, E. Niki
    Stability and reactivity of aryloxyl radicals derived from a novel antioxidant BO-653 and related compounds. Effects of substituent and side chain in solution and membranes
    J. Am. Chem. Soc., 122, 5438-5442, 2000
  40. Y. Okimoto, A. Watanabe, E. Niki, T. Yamashita, N. Noguchi
    A novel fluorescent probe diphenyl-1-pyrenylphosphine to follow lipid peroxidation in cell membrane
    FEBS Lett., 474, 137-140, 2000
  41. N. Noguchi, K. Nakano, Y. Aratani, H. Koyama, T. Kodama, E. Niki
    Role of myeloperoxidase in the neutrophil-induced oxidation of low density lipoprotein as studied by myeloperoxidase-knockout mouse
    J. Biochem.,127, 971-976, 2000
  42. W. Takabe, C. Mataki, Y. Wada, M. Ishii, A Izumi, H. Aburatani, T. Hamakubo, E. Niki, T. Kodama, N. Noguchi
    Gene expression induced by BO-653, probucol and BHQ in human endothelial cells.
    J. Atheroscler. Thromb., 7, 223-230, 2000
  43. W. Takabe, E. Niki, K. Uchida, S. Yamada, T. Satoh, N. Noguchi
    Oxidative stress promotes the development of transformation: involvement of a potent mutagenic lipid peroxidation product, acrolein.
    Carcinogenesis, 22, 935-941, 2001
  44. A. I. Kuzmenko, E. Niki, N. Noguchi
    New functions of 20-hydroxyecdysone in lipid peroxidation.
    J. Oleo Sci., 50, 31(497)-40(506), 2001
  45. W. Takabe, T. Kodama, T. Hamakubo, K. Tanaka, T. Suzuki, H. Aburatani, N. Matsukawa, N. Noguchi
    Anti-atherogenic antioxidants regulate the expression and function of proteasome a-type subunits in human endothelial cells.
    J. Biol. Chem., 276, 40497-40501, 2001
  46. S. Mashiba, Y. Wada, M. Takeya, A. Sugiyama, T. Hamakubo, A. Nakamura, N. Noguchi, E. Niki, A. Izumi, M. Kobayashi, K. Uchida, T. Kodama
    In vivo complex formation of oxidized a1-antitrypsin and LDL.
    Arterioscl. Thromb. Vasc. Biol., 21, 1801-1808, 2001
  47. N. Noguchi, A. Nakada, Y. Itoh, A. Watanabe, E. Niki
    Formation of active oxygen species and lipid peroxidation induced by hypochlorite.
    Arch. Biochem. Biophys., 397, 440-447, 2002
  48. Y. Nakamura, Q. Feng, T. Kumagai, K. Torikai, H. Ohigashi, T. Osawa, N. Noguchi, E. Niki, K. Uchida
    Ebselen, a glutathione peroxidase mimeic seleno-organic compound, as a multifunctional antioxidant: Implication for inflammation-associated carcinogenesis.
    J. Biol. Chem., 277, 2687-2694, 2002
  49. S. Mine, T. Tabata, Y. Wada, T. Fujisaki, T. Iida, N. Noguchi, E. Niki, T. Kodama, Y. Tanaka
    Oxidized low density lipoprotein-induced LFA-1-dependent adhesion and transendothelial migration of monocytes via the protein kinase C pathway.
    Atherosclerosis, 160, 281-288, 2002.
  50. N. Noguchi, H. Yamashita, J. Hamahara, A. Nakamura, H. Kuhn, E. Niki
    The specific of lipoxygenase-catalyzed lipid peroxidation and the effects of radical scavenging antioxidants.
    Biol. Chem., 383, 619-626, 2002.
  51. M. Kondo, T. Shibata, T. Kumagai, T. Osawa, N. Noguchi, K. Uchida
    15-Deoxy-△12,14-prostaglandins J2: The edogenous electrophile that induces neuronal apoptosis.
    Proc. Natl. Acad. Sci. 99, 7367-7372, 2002.
  52. N. Noguchi
    Novel insights into the molecular mechanisms of the anti-atherosclerotic properties of antioxidants; the alternatives to radical scavenging.
    Free Rad. Biol. Med., 33, 1480-1489, 2002.
  53. Y. Yoshida, N. Noguchi, A. Watanabe, Y. Iwaki, M. Yanagisawa, T. Kodama, O. Cynshi, E. Niki
    Antioxidant action of 2,2,4,6-tetra-substituted 2,3-dihydro-5-hydroxybenzofuran against lipid peroxidation: effects of substituents and side chain.
    Free Rad. Res., 36, 1171-1178, 2002
  54. T. Ogihara, T. asano, K. Ando, Y. Chiba, H. Sakoda, M. Anai, N. Shojima, H. Ono, Y. Onishi, M. Fujishiro, H. Katagiri, Y. Fukushima, M. Kikuchi, N. Noguchi, H. Aburatani, I. Komuro, T. Fujita
    Angiortensin II-induced insulin resistance is associated with enhanced insulin signaling.
    Hypertension, 40, 872-879, 2002.
  55. Y. Wada, A. Sugiyama, T. Yamamoto, M. Naito, N. Noguchi, S. Yokoyama, M. Tsujita, Y. Kawabe, M. Kobayashi, A. Izumi, T. Kohro, T. Tanaka, H. Taniguchi, H. Koyama, K. Hirano, S. Yamashita, Y. Matsuzawa, E. Niki, T. Hamakubo, T. Kodama
    Lipid accumulation in smooth muscle cells under LDL loading is independent of LDL receptor pathway and enhanced by hypoxic conditions.
    Arterioscler. Thromb. Vasc. Biol. 22, 1712-1719, 2002.
  56. Y. Yoshida, E. Niki, N. Noguchi
    Comparative study on the action of tocopherols and tocotrienols as antioxidant: chemical and physical effects.
    Chem. Physic. Lipid, 123, 63-75, 2003.
  57. N. Noguchi, R. Hanyu, A. Nonaka, Y. Okimoto, T. Kodama
    Inhibition of THP-1 cell adhesion to endothelial cells by a-tocopherol and a-tocotrienol is dependent on intracellular concentration of the antioxidants.
    Free Rad. Biol. Med.34, 1614-1620, 2003.
  58. Y. Okimoto, E. Warabi, Y. Wada, E. Niki, T. Kodama, N. Noguchi
    A novel method of following oxidation of low-density lipoprotein using a sensitive fluorescent probe, diphenyl-1-pyrenylphosphine. Free Rad. Biol. Med., 5, 576-585, 2003.
  59. T. Ogihara, T. Asano, H. Katagiri, H. Sakoda, M. Anai, N. Shojima, H. Ono, M. Fujishiro, A. Kushiyama, Y. Fukushima, M. Kikuchi, N. Noguchi, H. Aburatani, Y. Gotoh , I. Komuro, T. Fujita.
    Oxidative stress induces insulin resistance by activating the nuclear factor-kappaB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase.
    Diabetologia., 47, 794-805, 2004.
  60. E. Niki , N. Noguchi.
    Dynamics of antioxidant action of vitamin E.
    Acc. Chem. Res., 37, 45-51, 2004
  61. W. TakabeP, Y. KanaiPP, A. ChairoungduaPP, N. ShibataPP, S. ToiP, M. KobayashiPP, T. KodamaPP, N. NoguchiP
    Lysophosphatidylcholine enhances cytokine production of endothelial cells via induction of L-type amino acid transporter 1 and cell surface antigen 4F2.
    Arterioscl. Thromb. Vasc. Biol., 24, 1640-1645, 2004
  62. E. Warabi, Y. Wada, H. Kajiwara, M. Kobayashi, N. Koshiba, T. Hisada, M. Shibata, J. Ando, M. Tsuchiya, T. Kodama, N. Noguchi
    Endothelial cell gene expression by shear stress, oxygen concentration, low-density lipoprotein as studied by a novel flow cell culture system.
    Free Rad. Biol. Med., 37, 682-694, 2004
  63. N. Itoh, Y. Yoshida, M. Hayakawa, N. Noguchi, T. Kodama、O. Cynshi, E. Niki Inhibition of plasma lipid peroxidation by anti-atherogenic antioxidant BO-653,2,3-dihydro-5-hydroxy-4,6-di-tert-butyl-2,2-dipentylbenzofuran.
    Biochemical Pharmacology, 68, 813-818, 2004
  64. T. Aoki, I. Otake, N. Gotoh, N. Noguchi, S. Wada
    Quantification method for triacylglyceride molecular species in fish oil
    with high performance liquid chromatography-ultraviolet detector.
    J. OleoSci., 53, 285-294, 2004
  65. T. Minami, K. Horiuchi, M. Miura, R. Abid, W. Takabe, N. Noguchi, T. Kohro, X. Ge, H. Aburatani, T. Hamakubo, T. Kodama, w.C. Aird
    Vascular endothelial growth factor- and thrombin-induced termination factor, down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis.
    J. Biol. Chem., 279, 50537-50554, 2004
  66. Y. Watanabe, S. Jiang, W. Takabe, R. Ohashi, T. Tanaka, Y. Uchiyama, K. Katsumi , H. Iwanari, N. Noguchi, M. Naito, T. Hamakubo, T. Kodama.
    Expression of the LXR{alpha} Protein in Human Atherosclerotic Lesions.
    Arterioscler Thromb Vasc Biol. 25, 622-627, 2005
  67. Y. Urano, I. Hayashi, N.Isoo, P.C. Reid, Y. Shibasaki, N. Noguchi, T. Tomita, T. Iwatsubo, T. Hamakubo, T. Kodama
    Association of active g-secretase complex with lipid rafts.
    J. Lipid Res.46, 904-912, 2005
  68. Y. Naito, M. Shimozawa, N. Nakabe, H. Manabe, K. Katada, M. Kuroda, S. Kokura, H. Ichikawa, N. Yoshida, N. Noguchi, T. Yoshikawa
    Tocotrienols reduce 25-hydroxycholesterol-induced monocyte-endothelial cell interaction by inhibiting the surface expression of adhesion molecules
    Atherosclerosis, 180, 19-25, 2005
  69. T. Hosoya, A. Maruyama,M-I. Kang. Y. Kawatani, T. Shibata, K. Uchida, E. Warabi, N. Noguchi, K. Itoh, M. Yamamoto,
    Differential responses of the Nrf2-Keap1 System to laminar and oscillatory shear stress in endothelial cells.
    J. Biol. Chem., 280, 27244-27250, 2005
  70. T. Nishimura, T. Inoue, N. Shibata, A. Sekine, W. Takabe, N. Noguchi,
    H. Arai H.
    Inhibition of cholesterol biosynthesis by 25-hydroxycholesterol is independent of OSBP.
    Genes Cells. 2005 10(8):793-801
  71. S. Wada, Y. Satomi, M. Murakoshi, N .Noguchi , T. Yoshikawa, H. Nishino
    Tumor suppressive effects of tocotrienol in vivo and in vitro.
    Cancer Lettesr, in press, 2005.
  72. Z.-H. Chen, Y. Saito, Y Yoshida, A. Sekine, N. Noguchi, E. Niki
    4-Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance primarily through induction of thioredoxin reductase 1 via transcriptional activation of Nrf2
    J. Biol. Chem., in press, 2005
  73. W. Takabe, N. Matsukawa, T. Kodama, K. Tanaka, N. Noguchi1
    Chemical structure dependent gene expression of proteasome subunits via
    regulation of the antioxidant response element.
    Free Radical Res. In press, 2005

II. Review paper

  1. 野口範子,二木鋭雄
    LDLの酸化とその抑制  実験医学 10, 42-47, 1992, 羊土社
  2. E. Niki, N. Noguchi, N. Gotoh
    Dynamics of lipid peroxidation and its inhibition by antioxidants. Mechanisms of free radical damage in the vascular and central nervous systems and control by antioxidant intervention
    Biochem. Soc. Transact., 21, 313-317, 1993
  3. 野口範子
    動脈硬化, Up date フリーラジカルー基礎と臨床  現代医療 25, 89-95, 1993, 現代医療社
  4. E. Niki, N. Noguchi, N. Gotoh
    Inhibition of oxidative modification of low dinsity lipoprotein by antioxidants
    J. Nutr. Sci. Vitaminol., 39, S1-S8, 1993
  5. 野口範子
    血管とフリーラジカル, フリーラジカルの臨床, Mebio 11, No.4, 36-42, 1993, メジカルビュー社
  6. 野口範子
    動脈硬化と過酸化脂質,Geriatric Medicine, 32, No.9, 1047-1053, 1994, ライフサイエンス出版
  7. 野口範子
    酸化LDL,臨床栄養, 85, NO.7, 802-808, 1994, 医歯薬出版
  8. 野口範子、二木鋭雄
    生体の酸化傷害と防御機構, FRAGNANCE JOURNAL , April, 9-16, 1997
  9. 野口範子
    新規抗酸化物質の設計・合成とその活性評価, 日本油化学会誌, 46, 1167-1174, 1997
  10. 野口範子、二木鋭雄
    酸化変性のメカニズム, 治療学, 32, 9-15, 1998, ライフサエンス出版
  11. N. Noguchi, E. Niki
    Dynamics of vitamin E action against LDL oxidation.
    Free Rad. Res., 28, 561-572, 1998
  12. 野口範子
    生体にとってフリーラジカルとは何か.
    ヒューマンサイエンス, 10, 16-18, 1999, ヒューマンサイエンス振興財団
  13. N. Noguchi, E. Niki
    Phenolic antioxidants: A rationale for design and evaluation of novel
    antioxidant drug for atherosclerosis.
    Free Rad. Biol. Med., 28, 1538-1546, 2000
  14. N. Noguchi, A. Watanabe, H. Shi
    Diverse functions of antioxidants.
    Free Rad. Res., 33, 809-817, 2000
  15. 野口範子
    Gombergのフリーラジカル発見から100年
    ISOTOPE NEWS, No. 559, 24-28, 2000
  16. 野口範子
    ラジカル消去を作用機序とする疾患治療薬
    日本病院薬剤師会雑誌, 37,29(205)-31(207), 2001
  17. 二木鋭雄、野口範子
    CHAOS [Cambridge Heart Antioxidant Study]
    日本臨床, 高脂血症(下巻), 59,3, 448-451, 2001
  18. N. Noguchi, E. Niki
    Evaluation of antioxidant capacity. What capacity is being measured by which method?
    IUBMB Life, 50, 323-329, 2001
  19. 二木鋭雄、野口範子
    ストレスの生命科学
    オレオサイエンス、1(5), 509-514, 2001
  20. 野口範子
    酸化ストレスと動脈硬化
    総合臨床, 50:3171-3173, 2001, 医歯薬出版
  21. 野口範子
    抗酸化物質による血管障害の防御
    血管医学, 3:41-47, 2002 , メジカルビュー社
  22. E. Niki, N. Noguchi
    Effects of antioxidants against atherosclerosis
    Mol. Cell. Biochem., 234: 19-25, 2002
  23. 二木鋭雄、野口範子
    トコトリエノールの生理作用
    ビタミン, 77: 172-175, 2003
  24. 野口範子
    運動に関連する酸化ストレスと抗酸化作用
    日本運動生理学雑誌, 10: 1-8, 2003
  25. E. Niki, N.Noguchi
    Dynamics of antioxidant action of vitamin E
    Accounts of Chemical Research, 37: 45-51, 2004
  26. 野口範子
    酸化脂質の生成メカニズムと生物学的作用
    The Lipid, 15: 33-38, 2004, メジカルビュー社
  27. 野口範子
    オキシステロールの生物活性と血管
    血管医学, 5: 13-18, 2004, メジカルビュー社
  28. 野口範子
    酸化ストレスによる血管内皮細胞の遺伝子応答プロファイリング
    血管医学, 6: 41-45, 2005, メジカルビュー社

III. Books

  1. 河野邦雄,大野良樹,野口範子
    神経細胞の構造的研究法
    実験生物学講座 9 神経生物学 pp.271-289, 1986, 丸善株式会社, 東京
  2. 二木鋭雄,野口範子
    生体内に生じるフリーラジカル 
    体内動態と生体傷害機序(近藤元治編)最新医学からのアプローチ4 「フリーラジカル」分担執筆 pp. 7-26, 1992, メジカルビュー社, 東京 
  3. 野口範子,後藤直宏,二木鋭雄
    LDLの酸化とその抑制  
    フリーラジカルの臨床 7(近藤元治監,大柳善彦,吉川敏一編)pp. 49-54, 1993, 日本医学館, 東京
  4. N. Noguchi, E. Niki
    Apo B protein oxidation in LDL.
    Oxygen radicals in biological systems, part C, Methods in Enzymology (L. Packer ed.) 233, 490-494, 1994, Academic Press, Calif.
  5. E. Niki, N. Noguchi, N. Gotoh, H. Sakai
    Antioxidants in Food: Their Actions as Studied by ESR.
    Magnetic Resonance in Medicine (H. Kamada, H. Ohya-Nishiguchi, T. Yoshikawa, eds.) pp. 301-301, 1994, NIHON-IGAKUKAN, Tokyo
  6. 野口範子
    細胞分画法
    過酸化脂質 フリーラジカル実験法 生物化学実験法34(島崎弘幸,五十嵐脩編)pp.192-198,1995, 学会出版センター, 東京 
  7. E. Niki, N. Noguchi, M. Iwatsuki
    Antioxidant Activities of Phenolic Compounds in Solutions, Membranes, and Lipoproteins.
    Nutrition, Lipids, Health, and Disease (A. S. H. Ong., E. Niki, L. Packer, eds.) pp. 1-7, 1995, AOCS Press, Champaign, IL
  8. 二木鋭雄,野口範子
    フリーラジカルによる各種疾病の発症と抗酸化物による予防
    新食品機能材料の開発 (太田明一監) pp. 28-36,1996, シーエムシー, 東京
  9. E. Niki, N. Noguchi
    Antioxidant properties of probucol.
    Handbook of Synthetic Antioxidants (L. Packer, E. Cadenas, eds), pp.
    225-239, 1997, Marcel Dekker, New York
  10. N. Noguchi, E. Niki
    Antioxidant properties of ebselen.
    Handbook of Synthetic Antioxidants (L. Packer, E. Cadenas, eds), pp. 285-303, 1997, Marcel Dekker, New York
  11. N. Noguchi, E. Niki
    Inhibition of plasma cholesterol ester hydroperoxide and phosphatidylcholine hydroperoxide formation as measures of antioxidant status.
    Methods in Enzymology (D.B. MacCormick, J.W. Suttie, C. Wagner eds.), 282, 271-278, 1997, Academic Press, New York
  12. E. Niki, N. Noguchi
    Protection of human low-density lipoprotein from oxidative modification by vitamin C.
    Vitamin C in health and disease, (L. Packer, E. Cadenas, eds), pp. 183-192, 1997, Marcel Dekker, New York
  13. N. Noguchi, Y. Okimoto, O. Cynshi, T. Kodama, E. Niki
    Inhibition of oxidative modification of low density lipoprotein by novel antioxidant BO-653 prepared by theoretical design.
    Nutirition, Lipids, Health, and Disease (L. Packer, ed.), pp. 139-152, 1998, AOCS Press, Champaign, IL
  14. N. Noguchi, E. Niki
    Chemistry of oxygen species and antioxidant.
    Antioxidant Status, Diet, Nutrition and Health (A.M. Papas ed.), pp. 3-20, 1998, CRC press, FL
  15. 野口範子
    プロブコール
    抗酸化物質のすべて(吉川敏一編), pp. 200-205, 1998, 先端医学社, 東京
  16. 野口範子
    動脈硬化 
    抗酸化物質のすべて(吉川敏一編), pp. 241-247, 1998, 先端医学社, 東京
  17. N. Noguchi, K. Nishino, E. Washio, H. Shi, E. Niki
    Action of ginkgo biloba extract as an antioxidant.
    Antioxidants & Disease (N. J. Temple ed.), pp. 131-140, 1999, CAB International, Oxford
  18. 野口範子
    血管の老化とフリーラジカル
    老化予防食品の開発 (吉川敏一監) pp. 79-85,1999, シーエムシー, 東京
  19. H. Shi, N. Noguchi, E. Niki
    Galvinoxyl method for standardizing electron and proton donation activity
    Methods in Enzymology, 335, 157-166, 2001, Academic Press, New York
  20. 野口範子
    老化の制御方法
    老化に対する防御機構 (吉川敏一監) pp. 61-68, 2001, シーエムシー, 東京
  21. H. Shi, N. Noguchi, E. Niki
    Natural antioxidants
    Antioxidants in food (F. Dodds ed.), Chapter 3, 2001, Woodhead Publishing Limited
  22. 野口範子
    抗酸化物質の新規機能の追究
    酸化ストレス/フリーラジカル医学生物学の最前線 (吉川敏一監) 医学のあゆみ別冊, pp. 142-144, 2001, 医歯薬出版, 東京

IV. Proceedings

  1. N. Noguchi, N. Gotoh, E. Komuro, Y. Yamamoto, E. Niki, H. Shimasaki
    The oxidative modification of low density lipoprotein induced by copper or water-soluble radical initiator.
    Oxygen Radicals ( K. Yagi, M. Kondo, E. Niki, T. Yoshikawa, eds.), pp. 377-380,1992, Elsevier Science Publishers, Amsterdam (International Conference on Oxygen Radicals, Nov., 1991, Kyoto)
  2. 後藤直宏,野口範子,土屋順一,二木鋭雄,島崎弘幸
    LDLの酸化に対するビタミンEの抗酸化作用
    ビタミンE研究の進歩III (ビタミンE研究会編), pp. 57-62, 1993, 共立出版株式会社(ビタミンE研究会, Feb., 1992, 東京)
  3. 野口範子,保田 浩,二木鋭雄,三木正之,美濃 真
    脳脂質の酸化に対するビタミンEの抗酸化作用
    ビタミンE研究の進歩IV (ビタミンE研究会編), pp. 80-84, 1994, 共立出版株式会社(ビタミンE研究会, Feb., 1993, 京都)
  4. N. Noguchi, N. Gotoh, T. Yoshino, E. Niki
    Antioxidant effects of probucol and ebselen against oxidative modification of LDL induced by free radicals generated at different sites.
    (K. Asada, T. Yoshikawa eds.), pp.191-194, 1994, Elsevier Science Publisher, Amsterdam (SOD meeting, Oct., 1993, Kyoto)
  5. N. Gotoh, T. Yoshino, N. Noguchi, E. Niki
    2,2'-Azobis(4-methoxy-2,4-dimethylvaleronitrile), a new lipid-soluble azo radical initiator.
    (K. Asada, T. Yoshikawa eds.) pp. 59-62, 1994, Elsevier Science Publisher, Amsterdam (SOD meeting, Oct., 1993, Kyoto)
  6. 野口範子,山本裕子,二木鋭雄
    低比重リポ蛋白質の酸化におけるアポリポ蛋白Bの変性に対するビタミンEの抑制作用
    ビタミンE研究の進歩VII (ビタミンE研究会編), pp. 84-88, 1997, 共立出版株式会社 (ビタミンE研究会, Mar., 1996, 浜松)
  7. E. Niki, N. Noguchi
    Dynamics of oxidation of LDL and its inhibition by antioxidants.
    BioFactors, 6, 201-208, 1997 (Workshop Oxidative Stress, July, 1996, Graz)
  8. N. Noguchi, E. Niki
    Cooperative antioxidant action of probucol, a-tocopherol and ascorbic acid against the oxidation of LDL of human and rabbit.
    BioFactors, 6, 259-260, 1997 (Lipid and Thrombosis, Aug., 1996, Marstricht)
  9. N. Noguchi, E. Niki
    Inhibition of oxidation of low density lipoprotein by antioxidants.
    Pathophysiology of lipid peroxides and related free radicals (K. Yagi, ed), pp. 91-101, 1998, Jpn. Sci. Soc. Press, Tokyo (International Conference on Lipid Peroxide and Related Free Radicals, Nov., 1997, Gifu)
  10. N. Noguchi, N. Gotoh, E. Niki
    Action of vitamin E as antioxidant against oxidative modification of low density lipoprotein.
    Biofactors, 7, 41-50, 1998. (International Conference on Vitamin E, Feb., 1997, Kyoto)
  11. 野口範子, 二木鋭雄
    a-トコフェロールの化学構造を基に設計合成した新規抗酸化物質の抗酸化作用
    ビタミンE研究の進歩VII (ビタミンE研究会編), pp. 59-65, 1998, 共立出版株式会社 (ビタミンE研究会, Feb., 1997, 京都)
  12. 野口範子, 伊藤靖浩, 二木鋭雄, 新井洋由, 柴田 亮
    a-TTPノックアウトマウスにみられる酸化傷害
    ビタミンE研究の進歩VIII (ビタミンE研究会編), pp. 72-77, 2001, 共立出版株式会社 (ビタミンE研究会, Jan., 2001, 東京)
  13. 野口範子, 伊藤靖浩, 二木鋭雄, 新井洋由, 柴田 亮行
    a-TTPノックアウトマウスにみられる酸化傷害
    ビタミンE研究の進歩X (ビタミンE研究会編), pp. 45-49, 2002, 共立出版株式会社 (ビタミンE研究会, Jan, 2001, 東京)

V. 国際会議招待講演

  1. N. Noguchi
    Oxidative modification low density lipoprotein induced by free radicals generated inside and outside of LDL.
    6th Biennial Scientific Meeting of International Society for Free Radical Reserach, Jun. 1992 (Torino, Italy)
  2. N. Noguchi
    Mechanism of oxidation of low density lipoprotein and vitamin E.
    Satellite Symposium of The 2nd International Congress of Pathophysiology, Nov. 1994 (Kyoto, Japan)
  3. N. Noguchi
    Cooperative antioxidant action of probucol, a-tocopherol and ascorbic acid against the oxidation of LDL of human and rabbit.
    Workshop Oxidative Stress, Jul. 1996 (Graz, Austria)
  4. N. Noguchi
    Inhibition of oxidation of low density lipoprotein by antioxidants.
    International Symposium on Pathophysiology of Lipid Peroxides and Related Free Radicals, Nov. 1996 (Gifu, Japan)
  5. N. Noguchi
    Action of vitaminE as antioxidant against oxidative modification of low density lipoprotein.
    International Conference on Vitamin E, Feb. 1997 (Kyoto, Japan)
  6. N. Noguchi
    Inhibition of oxidative modification of low density lipoprotein by novel antioxidant B0-653 prepared by theoretical design.
    Scientific Meeting of Society for Free Radical Reserach Asia, Sep. 1997 (Penang, Malaysia)
  7. N. Noguchi
    Molecular design and action mechanism of novel antioxidant drug.
    COE Symposium on Lipid and Oxygen, Dec. 1997 (Tokyo, Japan)
  8. N. Noguchi
    Ebselen inhibits free radical-induced oxidation of LDL by reducing lipid hydroperoxides.
    1st Regional Meeting on Medical Science, Mar. 1998 (Jerusalem, Israel)
  9. N. Noguchi
    Theoretical design, synthesis and evaluation of antiatherogenic novel antioxidant BO-653.
    International Conference on Pathophysiology, Jul. 1998 (Lahti, Finland)
  10. N. Noguchi
    Interaction and competition between a- and g-tocopherol : A reappraisal
    International Conference on Food Factors, Dec. 1999 (Kyoto, Japan)
  11. N. Noguchi
    Advantage and disadvantage to use animal models for study of atherogenesis
    10th Biennial Meeting of the International Society for Free Radical Research, Oct. 2000 (Kyoto, Japan)
  12. N. Noguchi
    Regulation of gene expression by antiatherogenic phenolic antioxidants
    1 st Taiwan-Japan combined meeting on atherosclerosis, Apr., 2001 (Tasee, Taiwan)
  13. N. Noguchi
    Novel functions of anti-atherogenic antioxidants explored by trancriptome analyses
    International Conference of Redox Life Sciences, Nov., 2001(Tokyo)
  14. N. Noguchi
    Regulation of gene expression of mitochondrial proteins and proteasome by antiatherogenic antioxidants
    Gordon Conference, Feb. 10-15, 2002 (Ventura, USA)
  15. Noriko Noguchi
    Gene expression induced by lipid peroxidation products in endothelial cell
    SFRR Europe, June 27-29, 2003 (Greek)
  16. N. Noguchi
    Gene regulation by oxidation products of LDL in endothelial
    SFRR Asia, Nov. 6-8, 2003 (Souel, Korea)
  17. N. Noguchi
    Title: Gene expression by oxidative stress and shear stress
    JST-ERATO Yamamoto Environmental Response Project International Symposium, Mar. 10-12, 2005 (Tsukuba)