Takashi Yagi

University of Yamanashi, Kōhu, Yamanashi, Japan

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Publications (122)430.54 Total impact

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    ABSTRACT: The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are members of the nuclear receptor superfamily and ligand-dependent transcription factors, whose major ligands are glucocorticoid and mineralocorticoid, so-called corticosteroids. The corticosteroids are a class of substances that include steroid hormones naturally produced in the adrenal cortex of vertebrates and analogues of these hormones that are synthesized in industry. They are involved in a wide range of physiological processes including stress and immune responses, and the regulation of carbohydrate metabolism, protein catabolism, sodium homeostasis, and inflammation. These substances are potential environmental contaminants because they are clinically consumed in large amounts worldwide. To develop a simple and sensitive bioassay to detect corticosteroids, we newly established reporter assay yeasts expressing human GR and MR. Ligand responses of the established assay yeasts were improved by forced expression of a human transcription coactivator SRC-1e. Further enhancement of the responses was achieved by inactivating the CWP and PDR genes that encode cell wall mannoproteins and plasma membrane efflux pumps, respectively, which may be attributable to an increased intracellular concentration of ligands. These new assay yeasts were more responsive to both natural and synthetic agonist ligands than the conventional assay yeasts. They detected both agonistic and antagonistic activities of mifepristone, spironolactone, and eplerenone in a receptor-selective manner. They also detected ligand activities contained in oral pharmaceutical tablets and human urine. This assay system will be a valuable tool to detect agonists as well as antagonists of corticosteroid receptors, in the fields of drug discovery and the assessment of environmental pollutants. Copyright © 2015. Published by Elsevier Inc.
    Journal of pharmacological and toxicological methods 06/2015; 74. DOI:10.1016/j.vascn.2015.06.001 · 2.39 Impact Factor
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    ABSTRACT: ABSTRACT Indoor dust serves as a potential sink for various synthetic chemicals used in our daily lives, while exposure to theseanthropogenic contaminants via dust contact, ingestion, or inhalation may pose potential threats to human health. In thisstudy, in vitro biological assays were used to investigate the endocrine disrupting activity and genotoxicity in dust samples collected from a university located in southern Taiwan. Contents of polycyclic aromatic hydrocarbons (PAHs) in indoor dust were also analysed by gas chromatography mass spectrometry. Our results showed that significant aryl hydrocarbon receptor (AhR) agonist, antiandrogenic, antithyroid hormonal, and genotoxic activities were found in dust samples. In particular, high AhR agonist activities were found in indoor dust collected from computer room and laboratory (16112 and 9686 ng benzo(a)pyrene equivalent/g dust dry weight), whereas AhR agonistic PAHs were responsible for only a small percentage of the bioassay-derived activities. Higher antiandrogenic and genotoxic activities were found in indoor dust from office and classroom, respectively, suggesting that contaminants varied in different indoor dust samples. After fractionating by high performance liquid chromatography, AhR agonist activities were detected in several fractions of indoor dust from computer room and laboratory, indicating the presence of unknown AhR agonist contaminants in these indoor dust samples. Further isolation and identification of novel AhR agonistic and antiandrogenic contaminants is necessary to protect the environment and human health.
    Aerosol and Air Quality Research 06/2015; 15(15):1412–1421. DOI:10.4209/aaqr.2015.06.0404 · 2.09 Impact Factor
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    Takashi Yagi ·

    Genes and Environment 06/2015; 37(1):4. DOI:10.1186/s41021-015-0007-7
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    ABSTRACT: Object: The severity of cerebral hemodynamic disturbance caused by retrograde leptomeningeal venous drainage (RLVD) of a dural arteriovenous fistula (dAVF) is related to neurological morbidity and unfavorable outcome. However, the cerebral hemodynamics of this disorder have not been elucidated well. The aim of this study was to assess the relationship between the cerebral venous congestive encephalopathy represented as a high-intensity area (HIA) on T2-weighted MR images and the cerebral hemodynamics examined by (123)I-iodoamphetamine (IMP) single photon emission computed tomography (SPECT), as well as the predictive value of (123)I-IMP SPECT for the development and reversibility of venous congestion encephalopathy. Methods: Based on the pre- and posttreatment T2 HIAs associated with venous congestion encephalopathy, patients were divided into 3 groups: a normal group, an edema group, and an infarction group. The regional cerebral blood flow (rCBF) at the region with RLVD was analyzed by (123)I-IMP SPECT, and the results were compared among the groups. Results: There were 11, 6, and 3 patients in the normal, edema, and infarction groups, respectively. No patients in the normal group showed any symptoms related to venous congestion. In contrast, all patients in the edema and infarction groups developed neurological symptoms. The rCBF in the edema group was significantly lower than that in the normal group, and significantly higher than that in the infarction group. The cerebral vascular reactivity (CVR) of the infarction group was significantly lower than that of the normal and edema groups. After treatment, the neurological signs disappeared in the edema group, but only partial improvement was seen in the infarction group. The rCBF also significantly increased in the normal and edema groups, but not in the infarction group. Conclusions: Quantitative rCBF measurement is useful for evaluating hemodynamic disturbance in dAVF with RLVD. The reduction of rCBF was strongly correlated with the severity of venous congestive encephalopathy, and loss of CVR is a reliable indicator of irreversible venous infarction caused by RLVD.
    Journal of Neurosurgery 04/2015; 123(1):1-8. DOI:10.3171/2014.10.JNS141576 · 3.74 Impact Factor
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    ABSTRACT: Dural arteriovenous fistula (DAVF) involving the hypoglossal canal is rare but increasingly reported. To achieve complete obliteration without a procedure-related complication, understanding of the precise anatomy of this DAVF is essential. Here, we describe a 72-year-old man who underwent selective intra-arterial injection computed tomography angiography which allowed us to understand the detailed anatomy of the complex DAVF regarding access routes and the target regions for transvenous embolization (TVE). With the aid of this novel neuroimaging technique successful target TVE was achieved safely and completely. © The Author(s) 2015 Reprints and permissions:]br]sagepub.co.uk/journalsPermissions.nav.
    Interventional Neuroradiology 02/2015; 21(1). DOI:10.15274/INR-2015-10104 · 0.78 Impact Factor
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    ABSTRACT: We report a case of posterior reversible encephalopathy syndrome (PRES) during the subacute period of subarachnoid hemorrhage (SAH). An 84-year-old female with a ruptured basilar top aneurysm underwent successful embolization. Administration of antihypertensive drugs was discontinued to avoid hypotension during the period of vasospasm. On day 17 post embolization, her consciousness level deteriorated, and her MRI showed vasogenic edema in the bilateral occipital lobes. Under the diagnosis of PRES, antihypertensive therapy was resumed, and her symptoms and MRI findings improved. Thirteen cases of PRES after SAH have been reported, and it has been suggested that endothelial cell dysfunction due to primary brain damage due to SAH and hypertension during the period of vasospasm induces PRES. Though the occurrence of PRES after SAH is rare, neurosurgeons should be aware of this potential complication during the subacute period of SAH, because complete resolution of this syndrome is attainable with appropriate blood pressure control.
    Japanese Journal of Neurosurgery 01/2015; 24(2):126-131. DOI:10.7887/jcns.24.126

  • International Journal of Stroke 10/2014; 9:115-115. · 3.83 Impact Factor

  • International Journal of Stroke 10/2014; 9:123-123. · 3.83 Impact Factor

  • International Journal of Stroke 10/2014; 9:119-120. · 3.83 Impact Factor
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    Masanobu Kawanishi · Tomonari Matsuda · Takashi Yagi ·
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    ABSTRACT: Formaldehyde is commonly used in the chemical industry and is present in the environment, such as vehicle emissions, some building materials, food, and tobacco smoke. It also occurs as a natural product in most organisms, the sources of which include a number of metabolic processes. It causes various acute and chronic adverse effects in humans if they inhale its fumes. Among the chronic effects on human health, we summarize data on genotoxicity and carcinogenicity in this review, and we particularly focus on the molecular mechanisms involved in the formaldehyde mutagenesis. Formaldehyde mainly induces N-hydroxymethyl mono-adducts on guanine, adenine and cytosine, and N-methylene crosslinks between adjacent purines in DNA. These crosslinks are types of DNA damage potentially fatal for cell survival if they are not removed by the nucleotide excision repair pathway. In the previous studies, we showed evidence that formaldehyde causes intra-strand crosslinks between purines in DNA using a unique method (Matsuda et al., 1998). Using shuttle vector plasmids, we also showed that formaldehyde as well as acetaldehyde induces tandem base substitutions, mainly at 5′-GG and 5′-GA sequences, which would arise from the intra-strand crosslinks. These mutation features are different from those of other aldehydes such as crotonaldehyde, acrolein, glyoxal, and methylglyoxal. These findings provide molecular clues to improve our understanding of the genotoxicity and carcinogenicity of formaldehyde.
    09/2014; 2. DOI:10.3389/fenvs.2014.00036
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    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; 770. DOI:10.1016/j.mrgentox.2014.05.006 · 2.42 Impact Factor
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    Kazuhiro Shiizaki · Masanobu Kawanishi · Takashi Yagi ·
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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; 42(10). DOI:10.1124/dmd.114.058966 · 3.25 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. DOI:10.15274/INR-2014-10054 · 0.78 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; 69(3). DOI:10.1016/j.vascn.2014.01.007 · 2.39 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; 85(2). DOI:10.1016/j.marpolbul.2014.01.025 · 2.99 Impact Factor
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    ABSTRACT: We report a rare case of spontaneous intracranial hypotension accompanying thrombosis of the cerebral cortical veins and the superior sagittal sinus. A 43-year-old female who had suffered from orthostatic headache was admitted to a local hospital under the diagnosis of intracranial hypotension. At 15 days after onset, the headache had worsened and was combined with epileptic seizures, in spite of the patient being restricted to bed rest and the administration of intravenous hydration. Magnetic resonance (MR) imaging and cerebral angiography taken in our institute on day 22 revealed a thrombosis of the superior sagittal sinus and the adjacent cortical veins. Radionuclide cisternography demonstrated a cerebrospinal fluid leak at the lower thoracic spine. After anticoagulation therapy was administered followed by an epidural blood patch, the patient recovered with no neurological deficits. Intracranial hypotension accompanying cerebral venous thrombosis is very rare ', however, we should be aware of this complication and alert to its possible manifestation, especially when patients show changes in their headache features and symptoms even when observing a regime of strict bed rest.
    Japanese Journal of Neurosurgery 01/2014; 23(7):597-603. DOI:10.7887/jcns.23.597

  • Surgery for Cerebral Stroke 01/2014; 42(1):31-36. DOI:10.2335/scs.42.31
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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; 85(2). DOI:10.1124/mol.113.088856 · 4.13 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; 54(3). DOI:10.2176/nmc.cr2012-0256 · 0.72 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 06/2013; 38(3):503-511. DOI:10.2131/jts.38.503 · 1.29 Impact Factor

Publication Stats

2k Citations
430.54 Total Impact Points


  • 2011-2015
    • University of Yamanashi
      • Department of Neurosurgery
      Kōhu, Yamanashi, Japan
  • 2000-2015
    • Osaka Prefecture University
      • • Graduate School of Science
      • • Radiation Research Center
      • • Frontier Science Innovation Center
      • • Research Institute for Advanced Nursing Technology (RIANT)
      Sakai, Ōsaka, Japan
  • 1980-2000
    • Kyoto University
      • • Department of Radiation Genetics
      • • Department of Dermatology
      • • Radiation Biology Center
      Kioto, Kyōto, Japan