Faculty Profiles - FUJITA Hirofumi

Papers - FUJITA Hirofumi

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羅布麻抽出物（ベネトロン）の抗酸化作用とその解析 Reviewed

藤田洋史, 沖村祐弥, 内海俊彦

医学と薬学 54 491 - 503 2005

Molecular mechanism of diclofenac-induced apoptosis of promyelocytic leukemia: Dependency on reactive oxygen species, Akt, Bid, cytochrome c, and caspase pathway

A Inoue, S Muranaka, H Fujita, T Kanno, H Tamai, K Utsumi

FREE RADICAL BIOLOGY AND MEDICINE 37 ( 8 ) 1290 - 1299 2004.10

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in a variety of cells, but the mechanism of this effect has not been fully elucidated. We report that diclofenac, a NSAID, induces growth inhibition and apoptosis of HL-60 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS), Akt, caspase-8, and Bid. ROS generation occurs in an early stage of diclofenac-induced apoptosis preceding cytochrome c release, caspase activation, and DNA fragmentation. N-Acetyl-L-CySteine, an antioxidant, suppresses ROS generation, Akt inactivation, caspase-8 activation, and DNA fragmentation. Cyclic AMP, an inducer of Akt phosphorylation, suppresses Akt inactivation, Bid cleavage, and DNA fragmentation. LY294002, a PI3 kinase inhibitor, enhances Akt inactivation and DNA fragmentation. Ac-IETD-CHO, a caspase-8 inhibitor, suppresses Bid cleavage and DNA fragmentation. z-VAD-fmk, a universal caspase inhibitor, but not cyclosporin A (CsA), an inhibitor of mitochondrial membrane permeability transition, suppresses DNA fragmentation. These results suggest the sequential mechanism of diclofenac-induced apoptosis of HL-60 cells: ROS generation suppresses Akt activity, thereby activating caspase-8, which stimulates Bid cleavage and induces cytochrome c release and the activation of caspase-9 and -3 in a CsA-insensitive mechanism. Furthermore, we found that 2-methoxyestradiol (2-ME), a superoxide dismutase inhibitor, significantly enhances diclofenac-induced apoptosis; that is, diclofenac combined with 2-ME may have therapeutic potential in the treatment of human leukemia. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.freeradbiomed.2004.07.003

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Involvement of ceramide in the mechanism of Cr(VI)-induced apoptosis of CHO cells

S Muranaka, T Kanno, H Fujita, H Kobuchi, J Akiyama, T Yasuda, K Utsumi

FREE RADICAL RESEARCH 38 ( 6 ) 613 - 621 2004.6

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Mitochondria reduce Cr(VI) to Cr(V) with concomitant generation of reactive oxygen species, thereby exhibiting cytotoxic effects leading to apoptosis in various types of cells. To clarify the mechanism by which Cr(VI) induces apoptosis, we examined the effect of Cr(VI) on Chinese hamster ovary (CHO) cells. Cr(VI) increased cellular levels of ceramide by activating acid sphingomyelinase (ASMase) and inhibiting the phosphorylation of pleckstrin homology domain-containing protein kinase B (Akt). Cr(VI) also induced cyclosporin A- and trifluoperazine-sensitive depolarization of mitochondria and activated caspase-3, 8 and 9, thereby causing fragmentation of cellular DNA. The presence of desipramine, an inhibitor of ASMase, and membrane permeable pCPT-cAMP suppressed the Cr(VI)-induced activation of caspases and DNA fragmentation. These results suggested that accumulation of ceramide play an important role in the Cr(VI)-induced apoptosis of CHO cells through activation of mitochondrial membrane permeability transition.

DOI： 10.1080/10715760410001694035

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アクトネル（リセドロネート）によるU937細胞のアポトーシスとその機構 Reviewed

藤田洋史, 菅野智子, 内海俊彦, 村中式部, 藤原拓造, 内海耕慥

医学と薬学 51 697 - 710 2004

Mitochondrial swelling and cytochrome c release: Sensitivity to cyclosporin A and calcium Reviewed

Tomoko Kanno, Hirofumi Fujita, Shikibu Muranaka, Hiromi Yano, Toshihiko Utsumi, Tamotsu Yoshioka, Masayasu Inoue, Kozo Utsumi

Physiological Chemistry and Physics and Medical NMR 34 ( 2 ) 91 - 102 2002

Language：English Publishing type：Research paper (scientific journal)

The opening of mitochondrial membrane permeability transition (MPT) pores, which results in a cyclosporin A (CsA)-sensitive and Ca 2+-dependent dissipation of the membrane potential (delta psi) and swelling (classical MPT), has been postulated to play an important role in the release of cytochrome c (Cyt.c) and also in apoptotic cell death. Recently, it has been reported that CsA-insensitive or Ca 2+-independent MPT can be classified as non-classic MPT. Therefore, we studied the effects of apoptosis-inducing agents on mitochondrial functions with respect to their CsA-sensitivity and Ca 2+-dependency. CsA-sensitive mitochondrial swelling, depolarization, and the release of Ca 2+ and Cyt.c were induced by low concentrations of arachidonic acid, triiodothyronine (T 3), or 6-hydroxdopamine but not by valinomycin and high concentrations of the fatty acid or T 3. Fe 2+/VADP and 2,2,-azobis-(2-amidinopropane) dihydrochloride (AAPH) induced swelling of mitochondria and the release of Ca 2+ and Cyt.c were not coupled with depolarization or CsA-sensitivity while dibucaine-induced swelling occurred without depolarization, Cyt.c-release or by a CsA-sensitive mechanism. A protonophoric FCCP and SF-6847 induced depolarization and Ca 2+-release occurred in a CsA-insensitive manner and failed to stimulate the release of Cyt.c. These results indicate that ambient conditions of mitochondria can greatly influence the state of membrane stability and that Cyt.c release may occur not only via a CsA-sensitive MPT but also by way of a CsA-insensitive membrane deterioration.

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CHARACTERIZATION AND EXPRESSION OF CDNA-ENCODING COPROPORPHYRINOGEN OXIDASE FROM A PATIENT WITH HEREDITARY COPROPORPHYRIA Reviewed

H FUJITA, M KONDO, S TAKETANI, N NOMURA, K FURUYAMA, R AKAGI, T NAGAI, M TERAJIMA, RA GALBRAITH, S SASSA

HUMAN MOLECULAR GENETICS 3 ( 10 ) 1807 - 1810 1994.10

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS UNITED KINGDOM

Hereditary coproporphyria (HCP) is an acute hepatic porphyria with autosomal dominant inheritance, but with a variable degree of clinical expression. Molecular cloning, sequencing and expression of the defective gene for coproporphyrinogen oxidase (CPO) in a patient with HCP were carried out. Enzyme assays revealed that CPO activity in EBV-transformed lymphoblastoid cells from the proband and one of her sisters was approximate to 50% of normal. Nucleotide sequence analysis of CPO cDNAs isolated from the proband's cells demonstrated three base substitutions, and three accompanying amino acid substitutions. An A514 --> C transition causing a Asn172 --> His substitution occurred in one allele, while two other transitions, G265 --> A and G580 --> A, caused Gly89 --> Ser and Val194 --> lle substitutions, respectively, in the other allele. The A514 --> C and the G580 --> A transitions are known genetic polymorphisms. Transfection of CPO cDNA into Escherichia coli demonstrated that cDNA with the G265 --> A transition produced a protein with less than 5% of normal enzyme activity. These findings indicate that the G265 --> A transition, involving the highly conserved glycine residue at the 89th position, is responsible for the CPO defect in the patient and accounts for the partial deficiency of CPO activity in this pedigree.

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