Takashi Yagi

University of Yamanashi, Kōhu, Yamanashi, Japan

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Publications (100)398.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cisplatin (cis-diamminedichloroplatinum(II)), a widely used anticancer drug, forms inter- and intra-strand DNA crosslinks. The major intra-strand crosslinks are Pt adducts at 1,2-d(GpG) and 1,3-d(GpNpG) (Pt-GG and Pt-GNG, respectively). Although most of the intra-strand crosslinks are removed by the nucleotide excision repair (NER), the remaining crosslinks can cause mutations through the translesion DNA synthesis (TLS) during chromosome replication. To understand the precise mechanism of cisplatin mutagenesis in human cells, the plasmid carrying a single Pt-GG or 1,3-d(GpTpG) crosslink (Pt-GTG) site-specifically in lacZ gene was constructed and propagated in NER-defective xeroderma pigmentosum cells. The plasmids retrieved from the cells were introduced into indicator bacterial cells to access frequencies of TLS and mutations. The experiments revealed that Pt-GTG blocked DNA replication more strongly and caused more mutations (29.1%) than Pt-GG (1.7%). Most mutations were G to A or T base changes at 5′ G residue in the Pt-GTG crosslinks. These results indicate that the Pt-GTG crosslinks become effective obstacles for cancer cell division, and have an important role for cisplatin cancer therapy.
    Mutation Research/Genetic Toxicology and Environmental Mutagenesis 08/2014; · 2.48 Impact Factor
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    ABSTRACT: Omeprazole (OME), a proton pump inhibitor used to treat gastritis, is also an aryl hydrocarbon receptor (AhR) activator. OME activates AhR in human hepatocytes and hepatoma cells but not in mouse in vivo or in vitro. We recently discovered that this species-specific difference results from a difference in a few amino acids in the ligand-binding domain of AhR. However, OME activates both mouse and human AhR in the yeast reporter assay system. Nevertheless, the cause of this discrepancy in OME responses remains unknown. We here report that CYP1A1 mRNA expression in mouse cecum was elevated after OME administration, although mouse is regarded as an OME-unresponsive animal. Using the yeast reporter assay system with human and murine AhRs, we found AhR agonist-like activity in the cecal extracts of OME-treated mice. We speculated that OME metabolites produced by cecal bacteria might activate murine AhR in vivo. In HPLC analysis, AhR agonist-like activity of cecal bacterial culture and cecal extracts were detected at the same retention time. AhR agonist-like activity was also detected in the HPLC fractions of yeast culture media containing OME. This unknown substance could induce reporter gene expression via mouse and human AhRs. The agonist-like activity of the OME metabolite was reduced by concomitant α-naphthoflavone exposure. These results indicate that a yeast-generated OME metabolite elicited the response of mouse AhR to OME in the yeast system and that bacterial OME metabolites may act as AhR ligands in human and mouse intestines.
    Drug metabolism and disposition: the biological fate of chemicals 07/2014; · 3.74 Impact Factor
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    ABSTRACT: We describe a case of arteriovenous fistula (AVF) successfully treated by coil embolization with an anchor coil inserted in the varix to facilitate dense packing at the shunting site. AVF of the left anterior choroidal artery (AChoA) draining into the ipsilateral basal vein of Rosenthal was incidentally found in a newborn female. A single detachable coil was inserted as an anchor into the varix adjacent to the shunt, and the microcatheter was pulled back to the shunting point. Three more detachable coils were delivered at the shunting point without migration under the support of the anchor coil, and the AVF was successfully obliterated with preservation of AChoA blood flow. The anchor coil technique can reduce the risk of coil migration and the number of coils required.
    Interventional Neuroradiology 06/2014; 20(3):283-6. · 0.73 Impact Factor
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    ABSTRACT: Introduction Retinoic acids are essential for embryonic development, tissue organization, and homeostasis and act via retinoic acid receptors (RARs) that form heterodimers with retinoid X receptors (RXRs). Human RARs and RXRs include the three subtypes α, β, and γ, which have varying distributions and physiological functions among human tissues. Recent reports show that subtype-specific binding of several chemicals to RARs or RXRs may lead to endocrine disruption. To evaluate these ligand-like chemicals, convenient assay systems for each receptor subtype are required. Methods We developed reporter assay yeasts to screen ligands for RXR subtype receptor homodimers. To screen RAR ligands, yeasts were engineered to express RAR subtypes with defective RXRα, which fails to bind to coactivators because of its shortened c-terminus. Results These assay yeasts were validated using known RXR- and RAR-specific ligands and subtype-specific responses were clearly shown. Subtype-specific ligand activities of the suspected chemical RAR or RXR ligands o-t-butylphenol, triphenyltin chloride, tributyltin chloride, and 4-nonylphenol were determined. Discussion The present assay yeasts may be valuable tools for subtype-specific assessments of unidentified environmental ligand chemicals and receptor-specific pharmaceuticals.
    Journal of pharmacological and toxicological methods 05/2014; · 2.32 Impact Factor
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    ABSTRACT: Various synthetic compounds are frequently discharged into the environment via human activities. Among them, certain contaminants may disrupt normal physiological functions of wildlife and humans via interactions with nuclear receptors. To protect human health and the environment, it is important to detect environmental ligands for human nuclear receptors. In this study, yeast-based reporter gene assays were used to investigate the occurrence of xenobiotic ligands for retinoid X receptors (RXR) and thyroid hormone receptors (TR) in the aquatic environment of Taiwan. Experimental results revealed that RXR agonist/antagonist activity was detected in river water and sediment samples. In particular, high RXR agonist/antagonist activity was found in the samples collected near river mouths. Additionally, few samples also elicited significant TR antagonist activity. Our findings show that the aquatic environment of Taiwan was contaminated with RXR and TR ligands. Further study is necessary to identify these xenobiotic RXR and TR agonists and antagonists.
    Marine Pollution Bulletin 01/2014; · 2.79 Impact Factor
  • Japanese Journal of Neurosurgery 01/2014; 23(7):597-603.
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    ABSTRACT: Omeprazole (OME) induces the expression of genes encoding drug-metabolizing enzymes such as cytochrome P450 1A1 (CYP1A1) via activation of the aryl hydrocarbon receptor (AhR) both in vivo and in vitro. However, the precise mechanism of OME-mediated AhR activation is still under investigation. While elucidating species-specific susceptibility to dioxin, we found that OME-mediated AhR activation was mammalian species specific. Moreover, we previously reported that OME has inhibitory activity toward CYP1A1 enzymes. From these observations, we speculated that OME-mediated AhR target gene transcription is due to AhR activation by increasing amounts of putative AhR ligands in serum by inhibition of CYP1A1 activity. We compared the amino acid sequences of OME-sensitive rabbit AhR and non-sensitive mouse AhR to identify the residues responsible for the species-specific response. Chimeric AhRs were constructed by exchanging domains between mouse and rabbit AhRs to define the region required for the response to OME. OME-mediated transactivation was observed only with the chimeric AhR that included the ligand-binding domain (LBD) of the rabbit AhR. Site-directed mutagenesis revealed three amino acids (M328, T353, and F367) in the rabbit AhR that were responsible for OME-mediated transactivation. Replacing these residues with those of the mouse AhR abolished the response of the rabbit AhR. In contrast, substitutions of these amino acids with those of the rabbit AhR altered non-sensitive mouse AhR to become sensitive to OME. These results suggest that OME-mediated AhR activation requires a specific structure within LBD that is probably essential for binding with enigmatic endogenous ligands.
    Molecular pharmacology 11/2013; · 4.12 Impact Factor
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    ABSTRACT: Neck clipping of a large middle cerebral artery aneurysm was performed using a newly developed surgical microscope integrated with modules for both indocyanine green (ICG) and fluorescein videoangiography. During surgery, ICG and fluorescein videoangiography by intra-arterial or intravenous injection were safely carried out without interrupting the surgical procedure. Based on the findings obtained from the case, we evaluated the differences between the dyes and the injection routes. With intra-arterial injection, fluorescein offered sharper contrast images and was better at depicting fine arteries than ICG. Patchy staining of vessel walls was observed in intravenous fluorescein videoangiography, while it was not evident in ICG. Intra-arterial injection method had a great advantage in the rapid clearance of the dyes, which allowed us to perform repeated videoangiography within a short period, and was useful in detecting incomplete clipping in this case; however, catheter insertion requires additional work and carries a potential risk. Use of a microscope integrated for both ICG and fluorescein videoangiography would be another method for repeated evaluation. Namely, alternate use of the dyes enables us to perform videoangiography in a short time even via intravenous injection.
    Neurologia medico-chirurgica 10/2013; · 0.49 Impact Factor
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    ABSTRACT: To analyze translesion DNA synthesis (TLS) across lesions derived from the air pollutant 3-nitrobenzanthrone in Escherichia coli (E. coli), we constructed site-specifically modified plasmids containing single molecule adducts derived from 3-nitrobenzanthrone. For this experiment, we adopted a modified version of the method developed by Fuchs et al. ([29] N. Koffel-Schwartz, et al., Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 7805-7810). Each plasmid contained one of the following lesions in its LacZ' gene: N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG-C8-N-ABA); 2-(2'-deoxyguanosin-N(2)-yl)-3-aminobenzanthrone (dG-N(2)-C2-ABA); 2-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG-C8-C2-ABA); 2-(2'-deoxyadenosin-N(6)-yl)-3-aminobenzanthrone (dA-N(6)-C2-ABA); N-(2'-deoxyguanosin-8-yl)-3-acetylaminobenzanthrone (dG-C8-N-AcABA); or 2-(2'-deoxyguanosin-8-yl)-3-acetylaminobenzanthrone (dG-C8-C2-AcABA). All of the adducts inhibited DNA synthesis by replicative DNA polymerases in E. coli; however, the extent of the inhibition varied among the adducts. All five dG-adducts strongly blocked replication by replicative DNA polymerases; however, the dA-adduct only weakly blocked DNA replication. The induction of the SOS response increased the frequency of TLS, which was higher for the dG-C8-C2-ABA, dG-C8-N-AcABA and dG-C8-C2-AcABA adducts than for the other adducts. In our previous study, dG-C8-N-ABA blocked DNA replication more strongly and induced mutations more frequently than dG-N(2)-C2-ABA in human cells. In contrast, in E. coli the frequency of TLS over dG-N(2)-C2-ABA was markedly reduced, even under the SOS(+) conditions, and dG-N(2)-C2-ABA induced G to T mutations. All of the other adducts were bypassed in a less mutagenic manner. In addition, using E. coli strains that lacked particular DNA polymerases we found that DNA polymerase V was responsible for TLS over dG-C8-N-AcABA and dG-C8-C2-AcABA adducts.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 04/2013; · 4.44 Impact Factor
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    ABSTRACT: 3-Nitrobenzanthrone (3-nitro-7H-benz[d,e]anthracen-7-one, 3-NBA) is a potent environmental mutagen that is found in diesel exhaust fumes and airborne particulates. It is known to produce several DNA adducts, including three major adducts N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG-C8-N-ABA), 2-(2'-deoxyadenosin-N(6)-yl)-3-aminobenzanthrone (dA-N(6)-C2-ABA), and 2-(2'-deoxyguanosin-N(2)-yl)-3-aminobenzanthrone (dG-N(2)-C2-ABA) in mammalian cells. In the present study, we measured the quantity of the formation and subsequent reduction of these adducts in human hepatoma HepG2 cells that had been treated with 3-NBA using LC-MS/MS analysis. As a result, dG-C8-N-ABA and dG-N(2)-C2-ABA were identified as major adducts in the HepG2 cells, and dA-N(6)-C2-ABA was found to be a minor adduct. Treatment with 1μg/mL 3-NBA for 24hours induced the formation of 2,835±1,509 dG-C8-N-ABA and 3,373±1,173 dG-N(2)-C2-ABA per 10(7) dG and 877±330 dA-N(6)-C2-ABA per 10(7) dA in the cells. The cellular DNA repair system removed the dG-C8-N-ABA and dA-N(6)-C2-ABA adducts more efficiently than the dG-N(2)-C2-ABA adducts. After a 24-hour repair period, 86.4±11.1% of the dG-N(2)-C2-ABA adducts remained, whereas only 51.7±2.7% of the dG-C8-N-ABA adducts and 37.8±1.7% of the dA-N(6)-C2-ABA adducts were present in the cells. We also evaluated the efficiency of bypasses across these three adducts and their mutagenic potency by introducing site-specific mono-modified plasmids into human cells. This translesion DNA synthesis (TLS) assay showed that dG-C8-N-ABA blocked DNA replication markedly (its replication frequency was 16.9±2.7%), while the replication arrests induced by dG-N(2)-C2-ABA and dA-N(6)-C2-ABA were more moderate (their replication frequencies were 33.3±6.2% and 43.1±7.5%, respectively). Mutagenic TLS was observed more frequently in replication across dG-C8-N-ABA (30.6%) than in replication across dG-N(2)-C2-ABA (12.1%) or dA-N(6)-C2-ABA (12.1%). These findings provide important insights into the molecular mechanism of 3-NBA-mutagenesis.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 04/2013; · 4.44 Impact Factor
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    ABSTRACT: We examined the genotoxicity of magnetite nanoparticles (primary particle size: 10 nm) on human A549 and Chinese hamster ovary (CHO) AA8 cells. Six hours' treatment with the particles dose-dependently increased the frequency of micronuclei (MN) in the A549 and CHO AA8 cells up to 5.2% and 5.0% at a dose of 200 µg/ml (34 µg/cm(2)), respectively. In A549 cells, treatment with the nano-particles (2 µg/ml) for 1 hr induced H2AX phosphorylation, which is suggestive of DNA double strand breaks (DSB). Treating CHO AA8 cells with 2 µg/ml (0.34 µg/cm(2)) magnetite for 1 hour resulted in a five times higher frequency of sister chromatid exchange (SCE) than the control level. We detected reactive oxygen species (ROS) in CHO cells treated with the particles. These findings indicate that magnetite nano-particles induce ROS in mammalian cells, leading to the direct or indirect induction of DSB, followed by clastogenic events including MN and SCE.
    The Journal of Toxicological Sciences 01/2013; 38(3):503-511. · 1.38 Impact Factor
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    ABSTRACT: A protein with strong removal activity against the natural estrogen estriol was purified from a culture supernatant of Pleurotus eryngii var. tuoliensis C.J. Mou. The protein was characterized as a laccase and had a molecular mass of 60kDa on SDS-PAGE. The enzyme was most active at pH 7.0 and 50°C. The partial N-terminal amino acid sequence of the enzyme showed homology with laccases from mushrooms, such as Pleurotus ostreatus, Coriolus versicolor (current name: Trametes versicolor), Pycnoporus cinnabarinus, and P. eryngii. A recombinant yeast assay confirmed that laccase treatment was very efficient for removing the estrogenic activity of steroid estrogens. Our results suggest that the enzyme may be applicable as a potential factor for removing natural steroid hormones.
    Enzyme and microbial technology. 12/2012; 51(6-7):402-7.
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    ABSTRACT: Benzo[a]pyrene (BaP) is metabolically activated by cytochrome P450 enzymes, and forms DNA adduct leading to mutations. Cytochrome P450 1A1 plays a central role in this activation step, and this enzyme is strongly induced by chemical agents that bind to the aryl hydrocarbon receptor (AhR), which is also known as a dioxin receptor. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand has not been shown to form any DNA adduct, but has a possibility to aggravate the toxicity of precarcinogenic polycyclic hydrocarbons through the induction of metabolic enzymes. We treated human hepatoma cells (HepG2) with TCDD, and subsequently exposed them to BaP to elucidate the synergistic effects on mutations. Surprisingly, mutant frequency induced by BaP at the hypoxanthine-guanine phosphribosyltransferase (HPRT) locus was decreased by pretreatment with TCDD. In correlation with decrease in the mutant frequencies, BaP-DNA adduct formation was also decreased by TCDD pretreatment. This suppressive effect of TCDD was more potent when the cells were exposed to (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), a reactive metabolic intermediate of BaP. Among the enzymes catalyzing BaP oxidation and conjugation, cytochrome P450 1A1, 1A2, 3A4 and UDP-glucuronosyltransferase 1A1 mRNAs were induced by the exposure to TCDD. In cytochrome P450 1A1-deficient murine cells and cytochrome P450 1A1-uninducible human cells, TCDD could not suppress BPDE-DNA adduct formation. Further experiments using "Tet-On" cytochrome P450 1A1-overexpressing cells and a recombinant cytochrome P450 1A1 enzyme demonstrated that this is the key enzyme involved in the biotransformation of BaP, that is, both production and inactivation of BPDE. We conclude that TCDD-induced cytochrome P450 catalyzes the metabolism of BPDE to as yet-unidentified products that are not apparently DNA-reactive, thereby reducing mutations in hepatoma cells.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 10/2012; · 4.44 Impact Factor
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    ABSTRACT: The CROMIS AhR kit, a simple and rapid yeast bioassay kit, was developed and used to detect dioxins and dioxin-like compounds in 20 gas and solid samples collected from refuse incineration plants in Japan. The World Health Organization toxic equivalent (WHO-TEQ) values of the samples were also calculated using high-resolution gas chromatography/high--resolution mass spectrometry. The WHO-TEQ values of the samples varied greatly, ranging from 0.0021-6.3 ng/g to 0.00013-16 ng/m(3)N (normal cubic meter) in the solid and gas samples, respectively. 2,3,4,7,8-Pentachlorodibenzofuran (23478-PeCDF) and 1,2,3,7,8-pentachlorodibenzo-p-dioxin (12378-PeCDD) were the major contributors to the samples' WHO-TEQ values. The yeast in the bioassay responded to these congeners, and the EC(50) values of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2378-TeCDD), 12378-PeCDD, and 2,3,4,7,8-PeCDF were 490, 560, and 590 nM, respectively. The incinerator samples were subjected to the bioassay to obtain 2378-TeCDD equivalent values (CROMIS-TEQ values). The CROMIS-TEQ values of the solid and gas samples ranged from 0.0019 to 5.64 ng/g and from 0.14 to 20 ng/m(3)N, respectively. The CROMIS-TEQ and WHO-TEQ values displayed good correlations (r (2) = 0.94 and 0.95 in the solid and gas samples, respectively), except for those of the samples with low dioxin concentrations (below the Japanese emission standards). Therefore, the CROMIS AhR kit is a useful tool for the initial screening of samples containing dioxin-like compounds.
    Environmental Science and Pollution Research 09/2012; 20(5). · 2.76 Impact Factor
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    ABSTRACT: The size of the subarachnoid space in the optic nerve sheath (ONS) on MR images is thought to reflect intracranial pressure. The diagnostic value of this space was investigated in patients with spontaneous intracranial hypotension (SIH) syndrome. Coronal fat-saturated T2-weighted MRI of the orbit was performed in 15 patients with SIH fulfilling the diagnostic criteria for headache caused by low CSF pressure of the International Classification of Headache Disorders or the criteria for spontaneous spinal CSF leaks and intracranial hypotension. The size of the subarachnoid space in the ONS was measured in 2 slices behind the eyeballs. The images were compared before and after treatment. The CSF pressure was measured by lumbar puncture. Before treatment, the diameter of the ONS subarachnoid space ranged from 2.58 to 4.21 mm (mean 3.34 mm) and the thickness from 0 to 0.48 mm (mean 0.15 mm). Both measurements showed significant correlations with CSF opening pressure, and 8 patients had no CSF space before treatment. The size of CSF space increased in many patients after effective treatment. Disappearance of the CSF space in the ONS was frequently observed in patients with SIH. This characteristic finding may be useful in the diagnosis of SIH as well as in the evaluation of treatment effectiveness.
    Journal of Neurosurgery 06/2012; 117(2):372-7. · 3.15 Impact Factor
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    ABSTRACT: Multiple arterial dissections in the anterior circulation with simultaneous onset are extremely rare. We report a patient with infarctions caused by simultaneous arterial dissections in the right anterior cerebral artery and the left middle cerebral artery and discuss the characteristic feature of this vascular disorder. A 53-year-old woman presented with a severe headache and a mild aphasia. Magnetic resonance imaging revealed multiple acute cerebral infarctions in the left temporal and right frontal lobes. The initial angiographic findings revealed arterial dissections of the anterior cerebral, left middle cerebral, and right vertebral arteries. The follow-up angiographic examination found improvement of the stenosis in both the anterior cerebral and middle cerebral arteries. We have concluded that the lesion of the vertebral artery was not in an acute stage, because no interval change was seen during the radiologic evaluation. She underwent conservative therapy, and her symptoms disappeared. Multiple arterial dissections are rare, especially those developing simultaneously in different arteries. This is the first case of multiple arterial dissections of the different arteries in the anterior circulation manifesting cerebral infarction simultaneously.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 04/2012; · 1.99 Impact Factor
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    ABSTRACT: Abstract The genotoxic effects of multi-walled carbon nanotubes (MWCNTs) were examined by using in vitro and in vivo assays. MWCNTs significantly induced micronuclei in A549 cells and enhanced the frequency of sister chromatid exchange (SCE) in CHO AA8 cells. When ICR mice were intratracheally instilled with a single dose (0.05 or 0.2 mg/animal) of MWCNTs, DNA damage of the lungs, analysed by comet assay, increased in a dose-dependent manner. Moreover, DNA oxidative damage, indicated by 8-oxo-7,8-dihydro-2'-deoxyguanosine and heptanone etheno-deoxyribonucleosides, occurred in the lungs of MWCNT-exposed mice. The gpt mutation frequencies significantly increased in the lungs of MWCNT-treated gpt delta transgenic mice. Transversions were predominant, and G:C to C:G was clearly increased by MWCNTs. Moreover, many regions immunohistochemically stained for inducible NO synthase and nitrotyrosine were observed in the lungs of MWCNT-exposed mice. Overall, MWCNTs were shown to be genotoxic both in in vitro and in vivo tests; the mechanisms probably involve oxidative stress and inflammatory responses.
    Nanotoxicology 03/2012; · 7.34 Impact Factor
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    ABSTRACT: We have discovered that 3,3',5-triiodothyronine (T3) inhibits binding of a PIP-box sequence peptide to proliferating cell nuclear antigen (PCNA) protein by competing for the same binding site, as evidenced by the co-crystal structure of the PCNA-T3 complex at 2.1 Å resolution. Based on this observation, we have designed a novel, non-peptide small molecule PCNA inhibitor, T2 amino alcohol (T2AA), a T3 derivative that lacks thyroid hormone activity. T2AA inhibited interaction of PCNA/PIP-box peptide with an IC(50) of ~1 μm and also PCNA and full-length p21 protein, the tightest PCNA ligand protein known to date. T2AA abolished interaction of PCNA and DNA polymerase δ in cellular chromatin. De novo DNA synthesis was inhibited by T2AA, and the cells were arrested in S-phase. T2AA inhibited growth of cancer cells with induction of early apoptosis. Concurrently, Chk1 and RPA32 in the chromatin are phosphorylated, suggesting that T2AA causes DNA replication stress by stalling DNA replication forks. T2AA significantly inhibited translesion DNA synthesis on a cisplatin-cross-linked template in cells. When cells were treated with a combination of cisplatin and T2AA, a significant increase in phospho(Ser(139))histone H2AX induction and cell growth inhibition was observed.
    Journal of Biological Chemistry 03/2012; 287(17):14289-300. · 4.60 Impact Factor
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    ABSTRACT: We have discovered that triiodothyronin T3 inhibits binding of a PIP-Box sequence peptide to PCNA protein by competing for the same binding site, as evidenced by the co-crystal structure of the PCNA/T3 complex in 2.1 Å resolution. Based on this observation, we have designed a novel, non-peptide small molecule PCNA inhibitor, T2AA, a T3 derivative that lacks thyroid hormone activity. T2AA inhibited interaction of PCNA/PIP-Box peptide with an IC50~ 1 μM and also PCNA and full-length p21 protein, the tightest PCNA ligand protein known to date. T2AA abolished interaction of PCNA and DNA polymerase δ in cellular chromatin. De novo DNA synthesis was inhibited by T2AA and the cells were arrested in S-phase. T2AA inhibited growth of cancer cells with induction of early apoptosis. Concurrently, Chk1 and RPA32 in the chromatin are phosphorylated, suggesting that T2AA causes DNA replication stress by stalling DNA replication forks. T2AA significantly inhibited TLS on a cisplatin-crosslinked template in cells. When cells were treated with a combination of cisplatin and T2AA, a significant increase in γH2AX induction and cell growth inhibition was observed.
    Journal of Biological Chemistry 02/2012; · 4.60 Impact Factor
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    ABSTRACT: In the 1970s and 1980s, Planel et al. reported that the growth of paramecia was decreased by shielding them from background radiation. In the 1990s, Takizawa et al. found that mouse cells displayed a decreased growth rate under shielded conditions. The purpose of the present study was to confirm that growth is impaired in organisms that have been shielded from background radiation. Radioprotection was produced with a shielding chamber surrounded by a 15 cm thick iron wall and a 10 cm thick paraffin wall that reduced the γ ray and neutron levels in the chamber to 2% and 25% of the background levels, respectively. Although the growth of Paramecium tetraurelia was not impaired by short-term radioprotection (around 10 days), which disagreed with the findings of Planel et al., decreased growth was observed after long-term (40-50 days) radiation shielding. When mouse lymphoma L5178Y cells were incubated inside or outside of the shielding chamber for 7 days, the number of cells present on the 6th and 7th days under the shielding conditions was significantly lower than that present under the non-shielding conditions. These inhibitory effects on cell growth were abrogated by the addition of a ¹³⁷Cs γ-ray source disk to the chamber. Furthermore, no growth retardation was observed in XRCC4-deficient mouse M10 cells, which display impaired DNA double strand break repair.
    Journal of Radiation Research 01/2012; 53(3):404-10. · 1.45 Impact Factor

Publication Stats

1k Citations
398.18 Total Impact Points


  • 2011–2014
    • University of Yamanashi
      • Department of Neurosurgery
      Kōhu, Yamanashi, Japan
  • 2000–2014
    • Osaka Prefecture University
      • • Radiation Research Center
      • • Graduate School of Science
      • • Frontier Science Innovation Center
      • • Research Institute for Advanced Nursing Technology (RIANT)
      Sakai, Ōsaka, Japan
  • 2009
    • National Cancer Center, Japan
      Edo, Tōkyō, Japan
  • 2004
    • International Research Center for Japanese Studies
      Kioto, Kyōto, Japan
  • 1989–2001
    • Kyoto University
      • • Department of Radiation Genetics
      • • Department of Dermatology
      Kyoto, Kyoto-fu, Japan
  • 1993
    • Hôpital Charles-Nicolle
      Tunis-Ville, Tūnis, Tunisia