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FacultyDepartment of Life Science
Commentator Guide
Last Updated :2020/09/30

Education and Career

Academic & Professional Experience

  •   2019 04 ,  - 現在, Faculty of Science and Engineering, Kindai University
  •   2008 ,  - 2019 03 , Faculty of Science and Engineering, Kindai University

Research Activities

Research Areas

  • Life sciences, Clinical pharmacy
  • Life sciences, Physiology

Research Interests

  • Methylmercury, Thimerosal, Organomercury, Lung fluid clearance

Published Papers

  • Tsubasa Tagawa, Teruki Hagiwara, Shigeru Shimamoto, and Yuji Hidaka, 2018, 101 - 101, Mar. 2019 , Refereed
  • Cilia movement of ependymal cells in the third ventricular surface is inhibited by the administration of methylmercury to mouse, Takeshi Minami, Kaho Ueda·, Teruki Hagiwara, Journal of Clinical and Experimental Toxicology, Journal of Clinical and Experimental Toxicology, 1(1), 1 - 6, Oct. 2017 , Refereed
  • Methylation of the Guanidino Group of Arginine Residues Prevents Citrullination by, Teruki Hagiwara, Yuji Hidaka, Michiyuki Yamada, FEBS Letters, FEBS Letters, 579, 4088 - 4092, 2005 , Refereed
  • Maternal exposure to methylmercury causes an impairment in ependymal cilia motility in the third ventricle and dilation of lateral ventricles in mice offspring, Teruki Hagiwara, Hajime Hagino, Kaho Ueda, Mina Nakama, Takeshi Minami, Birth Defects Research, Birth Defects Research, Jul. 10 2020 , Refereed
  • Colocalization of GPR120 and anterior pituitary hormone-producing cells in female Japanese Black cattle, Sho NAKAMURA, Kohei NODA, Masafumi MIWA, Shiori MINABE, Teruki HAGIWARA, Akira HIRASAWA, Shuichi MATSUYAMA, Ryutaro MORIYAMA, Journal of Reproduction and Development, Journal of Reproduction and Development, 66(2), 135 - 141, 2020 , Refereed
  • AMP-activated protein kinase activation reduces the transcriptional activity of the murine luteinizing hormone β-subunit gene, Ryutaro MORIYAMA, Koichi IWAMOTO, Teruki HAGIWARA, Saishu YOSHIDA, Takako KATO, Yukio KATO, Journal of Reproduction and Development, Journal of Reproduction and Development, 66(2), 97 - 104, 2020 , Refereed
  • Sodium influx through cerebral sodium-glucose transporter type 1 exacerbates the development of cerebral ischemic neuronal damage, Yui Yamazaki, Shinichi Harada, Tetsuyuki Wada, Teruki Hagiwara, Shigeru Yoshida, Shogo Tokuyama, EUROPEAN JOURNAL OF PHARMACOLOGY, EUROPEAN JOURNAL OF PHARMACOLOGY, 799, 103 - 110, Mar. 2017 , Refereed
    Summary:We recently reported that cerebral sodium-glucose transporter type 1 (SGLT-1) plays a role in exacerbation of cerebral ischemia. However, the mechanism by which cerebral SGLT-1 acts remains unclear. Here we demonstrated that sodium influx through cerebral SGLT-1 exacerbates cerebral ischemic neuronal damage. SGLT-specific sodium ion influx was induced using alpha-methyl-D-glucopyranoside (alpha-MG). Intracellular sodium concentrations in primary cortical neurons were estimated using sodium-binding benzofuran isophthalate fluorescence. SGLT-1 knockdown in primary cortical neurons and mice was achieved using SGLT-1 siRNA. The survival rates of primary cultured cortical neurons were assessed using biochemical assays 1 day after treatment. Middle cerebral artery occlusion (MCAO) was used to generate a focal cerebral ischemic model in SGLT-1 knockdown mice. The change in fasting blood glucose levels, infarction development, and behavioral abnormalities were assessed 1 day after MCAO. Treatment with 200 mM alpha-MG induced a continuous increase in the intracellular sodium concentration, and this increase was normalized after a-MG removal. Neuronal SGLT-1 knockdown had no effect on 100 mu M H2O2-induced neuronal cell death; however, the knockdown prevented the neuronal cell death induced by 17.5 mM glucose and the co-treatment of 100 mu M H2O2/8.75 mM glucose. Neuronal SGLT-1 knockdown also suppressed the cell death induced by alpha-MG alone and the co-treatment of 100 mu M H2O2/0.01 mM alpha-MG. Our in vivo results showed that the exacerbation of cerebral ischemic neuronal damage induced by the intracerebroventricular administration of 5.0 mu g alpha-MG/mouse was ameliorated in cerebral SGLT-1 knockdown mice. Thus, sodium influx through cerebral SGLT-1 may exacerbate cerebral ischemia-induced neuronal damage.
  • Gene expression of the concentration-sensitive sodium channel is suppressed in lipopolysaccharide-induced acute lung injury in mice, Teruki Hagiwara, Shigeru Yoshida, Yuji Hidaka, EXPERIMENTAL LUNG RESEARCH, EXPERIMENTAL LUNG RESEARCH, 43(3), 150 - 157, 2017 , Refereed
    Summary:Purpose: The concentration-sensitive sodium channel (Na-C) is expressed in alveolar type II epithelial cells and pulmonary microvascular endothelial cells in mouse lungs. We recently reported that Na-C contributes to amiloride-insensitive sodium transport in mouse lungs (Respiratory Physiology & Neurobiology, 2016). However, details regarding its physiological role in the lung remain unknown. To examine whether Na-C is involved in alveolar fluid clearance during an acute lung injury (ALI), we analyzed the relationship between Na-C gene expression in the lung and the development of pulmonary edema in lipopolysaccharide (LPS)-induced ALI mice. Methods: LPS-induced ALI mice were prepared by the intratracheal administration of LPS. Bronchoalveolar lavage (BAL) neutrophils and lung water content (LWCs) were used as a marker of ALI and pulmonary edema, respectively. Na-C protein production in the lung was detected by immunoblotting and immunofluorescence. The gene expressions of Na-C and the epithelial sodium channel (ENaC) of LPS-induced ALI mice were examined by quantitative RT-PCR over a time course of 14 days. Results: The BAL neutrophil count increased until day 2 after LPS administration and had nearly recovered by day 6. LWCs in LPS-induced mice gradually increased until day 8 and had recovered by day 14. The expression of the Na-C protein in the lungs of LPS-induced mice dramatically decreased from day 2 to day 6, but recovered by day 8. The mRNA expression of Na-C decreased in the lung, as well as those for alpha-, beta-, and gamma-ENaC during ALI. Thus, Na-C expression is suppressed during the development stage of pulmonary edema and then recovers in the convalescent phase. Conclusion: Our results suggest that suppression of the gene expression of Na-C is involved in the development of pulmonary edema in ALI.
  • The organic mercury compounds, methylmercury and ethylmercury, inhibited ciliary movement of ventricular ependymal cells in the mouse brain around the concentrations reported for human poisoning, Shigeru Yoshida, Shinsaku Matsumoto, Takuya Kanchika, Teruki Hagiwara, Takeshi Minami, NEUROTOXICOLOGY, NEUROTOXICOLOGY, 57, 69 - 74, Dec. 2016 , Refereed
    Summary:Functions of the nervous system are supported by the flow of cerebrospinal fluid (CSF), which is driven by the ciliary beating of ventricular ependymal cells. The aim of the present study was to examine whether methylmercury (MeHg), a substance with potent neurotoxicity in humans, affects the ciliary movement. The effects of another organic mercury compound, ethylmercury (EtHg), were also assessed for comparison. Toxicity of MeHg or EtHg was evaluated by measuring alterations in the ciliary beat frequency of ependymal cells lining the third ventricle of mouse brain slices. The obtained results were: (1) Both MeHg and EtHg started to inhibit ciliary motility between 1 and 3 mu M, the reported threshold limit of MeHg in humans. (2) An abrupt increase was observed in the inhibitory curves from 3 to 6 mu M for MeHg and EtHg. (3) The "give-in" concentration, i.e., concentration at which the cilia lose the ability to recover, for MeHg and EtHg was 6 mu M and 12 mu M, respectively. (4) Ciliary beating was irreversibly halted by MeHg and EtHg at concentrations above 12 mu M and 30 mu M, respectively. (5) The estimated half maximal inhibitory concentration (IC50) for MeHg and EtHg was 5.53 mu M and 5.80 mu M, respectively. Based on these findings, we conclude that: (a) Ependymal cell cilia movement in mice was inhibited by MeHg in a concentration-dependent manner around concentrations reported to cause poisoning in humans; EtHg inhibited ciliary motility to a less extent. (b) Inhibition of CSF flow by suppression of ciliary movement is suggested to be an additional route for MeHg poisoning in humans, especially in prenatal exposure than in adult exposure. (C) 2016 Elsevier B.V. All rights reserved.
  • Contribution of concentration-sensitive sodium channels to the absorption of alveolar fluid in mice, Teruki Hagiwara, Shigeru Yoshida, RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY, RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY, 231, 45 - 54, Sep. 2016 , Refereed
    Summary:The concentration-sensitive sodium channel (Na-c) is activated by an increase in the extracellular sodium concentration. Although the expression of Na-c in alveolar type II epithelial cells (AEC II) has been reported previously, the physiological role of Na-c in the lung has not been established. We characterized Na-c expression and examined amiloride-insensitive sodium transport mediated by Na-c in mouse lung. Immunofluorescence studies revealed that Na-c did not colocalize with either aquaporin 5 or cystic fibrosis transmembrane conductance regulator, but partially colocalized with the epithelial sodium channel)0 subunit. Immunoelectron microscopy studies showed that Na-c localized at the basolateral membrane of pulmonary microvascular endothelial cells (PMVECs). Na-c mRNA and protein were expressed in PMVECs isolated from the lungs of mice. Image analysis indicated that sodium influx into the alveolar wall was dependent on increases in extracellular sodium concentration. We conclude that Na, expressed in PMVECs and AEC II contributes to the reabsorption of sodium via an amiloride-insensitive pathway during alveolar fluid clearance. (C) 2016 Elsevier B.V. All rights reserved.
  • Dynamic Expression of Peptidylarginine Deiminase 2 in Human Monocytic Leukaemia THP-1 Cells During Macrophage Differentiation, Ikuko Hojo-Nakashima, Ryo Sato, Katsuhiko Nakashima, Teruki Hagiwara, Michiyuki Yamada, JOURNAL OF BIOCHEMISTRY, JOURNAL OF BIOCHEMISTRY, 146(4), 471 - 479, Oct. 2009 , Refereed
    Summary:Peptidylarginine deiminases (PADs) consist of five enzymes which are widely distributed in human and rodent tissues. The two types of enzymes are found in human peripheral blood cells; PAD4 mainly in granulocytes and monocytes and PAD2 in lymphocytes and macrophages. Little is known about the regulation of PAD expression in macrophages. Here, we report that PAD2 is expressed in human monocytic leukaemia THP-1 cells during differentiation into macrophages by 12-O-tetradecanoylphorbol-13-acetate. During this differentiation, the levels of PAD2 mRNA and protein increased concomitantly, indicating the transcriptional regulation of PAD2 gene expression in the cells. The treatment of THP-1-derived macrophages with calcium ionophore A23187 generated vimentin deimination and resulted in the disruption of vimentin filament organization. We discuss the possible role of vimentin deimination in cell physiology.
  • Deimination of histone H2A and H4 at arginine 3 in HL-60 granulocytes, T Hagiwara, Y Hidaka, M Yamada, BIOCHEMISTRY, BIOCHEMISTRY, 44(15), 5827 - 5834, Apr. 2005 , Refereed
    Summary:Interplay of various covalent modifications of histone tails has an essential role in regulation of chromatin function. Peptidylarginine deiminase (PADI) 4 deiminates protein arginine to citrulline in a Ca2+-dependent manner and is present in the nucleus of granulocyte-differentiated HL-60 cells. When these cells are treated with the calcium ionophore A23187, core histone deimination occurs. To determine the deimination sites of histones, histone species were purified by reverse-phase high-performance liquid chromatography (RP-HPLC) from the cells. Immunoblotting using antimodified citrulline antibody indicated that histones H2A, H3, and H4 but not H2B were deiminated. H2A and H4 were digested with Staphylococcus aureus V8 protease, and the digests were separated by RP-HPLC. Immuno dot-blotting and mass spectrometry showed that the deiminated residues were present in H2A (1-56) and H4 (1-52) regions but not in other regions. The H2A peptide (1-56) was digested with alpha-chymotrypsin, and the deiminated peptide was separated from the corresponding nondeiminated peptide by RP-HPLC. The deiminated residue was found to be limited to residues 1-23. Similarly, digestion of the H4 peptide (1-52) with endoproteinase Asp-N and separation of the deiminated peptide from the nondeiminated peptide indicated that the deiminated residue was limited to residues 1-23. Mass spectrometry of lysylendopeptidase digests of the H2A (1-23) and H4 (1-23) peptides showed that deimination occurred at arginine 3 of the N-terminal sequence Ac-SGRGK common to H2A and H4. These results suggest that PADI4 deiminates only a restricted site of target proteins in cells. Deimination of histones is discussed in relation to chromatin structure and function.
  • Mechanism of the substrate recognition of peptidylarginine Deiminase V, Yuji Hidaka, Teruki Hagiwara, Michiyuki Yamada, Peptides 2004, Proceedings, Peptides 2004, Proceedings, 637 - 638, 2005 , Refereed
  • Histone deimination antagonizes arginine methylation, GL Cuthbert, S Daujat, AW Snowden, H Erdjument-Bromage, T Hagiwara, M Yamada, R Schneider, PD Gregory, P Tempst, AJ Bannister, T Kouzarides, CELL, CELL, 118(5), 545 - 553, Sep. 2004 , Refereed
    Summary:Methylation of arginine residues within histone H3 has been linked to active transcription. This modification appears on the estrogen-regulated pS2 promoter when the CARM1 methyltransferase is recruited during transcriptional activation. Here we describe a process, deimination, that converts histone arginine to citrulline and antagonizes arginine methylation. We show that peptidyl arginine deiminase 4 (PADI4) specifically deiminates, arginine residues R2, R8, R17, and R26 in the H3 tail. Deimination by PADI4 prevents arginine methylation by CARM1. Dimethylation of arginines prevents deimination by PADI4 although monomethylation still allows deimination to take place. In vivo targeting experiments on an endogenous promoter demonstrate that PADI4 can repress hormone receptor-mediated gene induction. Consistent with a repressive role for PADI4, this enzyme is recruited to the pS2 promoter following hormone induction when the gene is transcriptionally downregulated. The recruitment of PADI4 coincides with deimination of the histone H3 N-terminal tail. These results define deimination as a novel mechanism for antagonizing the transcriptional induction mediated by arginine methylation.
  • Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes, K Nakashima, T Hagiwara, M Yamada, JOURNAL OF BIOLOGICAL CHEMISTRY, JOURNAL OF BIOLOGICAL CHEMISTRY, 277(51), 49562 - 49568, Dec. 2002 , Refereed
    Summary:Peptidylarginine deiminase (PAD) deiminates 2 arginine residues in proteins to citrulline residues Ca2+ dependently. There are four types of PADs, I, II, III, and V, in humans. We studied the subcellular distribution of PAD V in HL-60 granulocytes and peripheral blood granulocytes. Expression of green fluorescent protein-tagged PADs in HeLa cells revealed that PAD V is localized in the nucleus, whereas PAD I, II, and III are localized in the cytoplasm. PAD V deletion mutants indicated that the sequence residues 45-74 have a nuclear localization signal (NLS). A sequence feature of this NLS is a three-lysine residue cluster preceded by a proline residue and is not found in the three other PADs. Substitution of the lysine cluster by an alanine cluster abrogated the nuclear import activity. These results suggested that the NLS is a classical monopartite NLS. HL-60 granulocytes, neutrophils, and eosinophils stained with antibody specific for PAD V exhibited distinct positive signals in the nucleus. Subcellular fractionation of HL-60 granulocytes also showed the nuclear localization of the enzyme. When neutrophils were stimulated with calcium ionophore A23187, protein deimination occurred in the nucleus. The major deiminated proteins were identified as histones H2A, H3, and H4. The implication of PAD V in histone modifications is discussed.
  • Deimination of arginine residues in nucleophosmin/B23 and histones in HL-60 granulocytes, T Hagiwara, K Nakashima, H Hirano, T Senshu, M Yamada, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 290(3), 979 - 983, Jan. 2002 , Refereed
    Summary:Peptidylarginine deiminases (PADS) convert arginine residues in proteins into citrulline residues Ca2+-dependently. PAD V was recently found in granulocyte-differentiated BL-60 cells. To find a target of PAD V, we incubated BL-60 granulocytes with the calcium ionophore A23187 and studied deiminated proteins by immunocytochemistry and immunoblotting using a monospecific antibody to modified citrulline residues. Immunocytochemical signals were found in the nucleus upon incubation with A23187. Immunoblotting indicated that 40-, 18-, 17-, and 14-kDa proteins were preferentially deiminated. The 40-kDa protein, which was focused to pI 5.0 on two-dimensional gel electrophoresis, was identified as nucleophosmin/B23 by mass spectrometry. The 18-, 17-, and 14-kDa proteins extracted with 0.4 N H2SO4 comigrated with histones H3, H2A, and H4, respectively, on two-dimensional gel electrophoresis specialized for histones. The citrulline content of histones amounted to about 10% of the histone molecules. We discuss the implications of deimination of these proteins for their nuclear functions. (C) 2002 Elsevier Science (USA).
  • Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1 alpha,25-dihydroxyvitamin D-3, K Nakashima, T Hagiwara, A Ishigami, S Nagata, H Asaga, M Kuramoto, T Senshu, M Yamada, JOURNAL OF BIOLOGICAL CHEMISTRY, JOURNAL OF BIOLOGICAL CHEMISTRY, 274(39), 27786 - 27792, Sep. 1999 , Refereed
    Summary:Three types of peptidylarginine deiminase (PAD), which converts a protein arginine residue to a citrulline residue, are widely distributed in animal tissues. Little is known about PAD of hemopoietic cells. We found that PAD activity in human myeloid leukemia HL-60 cells was induced with the granulocyte-inducing agents retinoic acid and dimethyl sulfoxide and with the monocyte-inducing agent 1 alpha,25-dihydroxyvitamin D-3. We cloned and characterized a PAD cDNA from retinoic acid-induced cells. The cDNA was 2,238 base pairs long and encoded a 663-amino acid polypeptide. The HL-60 PAD had 50-55% amino acid sequence identities with the three known enzymes and 73% identity with the recently cloned keratinocyte PAD. The recombinant enzyme differs in kinetic properties from the known enzymes. Immunoblotting and Northern blotting with an antiserum against the enzyme and the cDNA, respectively, showed that a protein of approximately 67 kDa increased concomitantly with increase of mRNA of approximately 2.6 kilobases during granulocyte differentiation. During monocyte differentiation the same mRNA and protein increased as in granulocyte differentiation. Neither the enzyme activity nor the protein was found in macrophage-induced cells. These results suggested that expression of the PAD gene is tightly linked to myeloid differentiation.

Conference Activities & Talks

  • In search of the evolutionary meaning of natriuretic peptides for cardiac function in terrestrial animals., XXth International Congress of Zoology,   2008 08 , XXth International Congress of Zoology
  • EXPRESSION REGULATION OF CONCENTRATION-SENSITIVE SODIUM CHANNEL IN MOUSE LUNG, 33rd FEBS Congress and 11th IUBMB Conference,   2008 07 , 33rd FEBS Congress and 11th IUBMB Conference
  • Expressional regulation of concentration-sensitive sodium channel in mouse lung,   2007 12
  • The concentration-sensitive Na+ channel (NaC) regulates growth of rat C6 glioma cells., 5th Forum of European Neuroscience,   2006 07 , 5th Forum of European Neuroscience
  • Regulation of gene expression by concentration-sensitive sodium channel in rat C6 glioma cells, The 20th IUBMB Congress and 11th FAOBMB Congress,   2006 06 , The 20th IUBMB Congress and 11th FAOBMB Congress
  • Concntration-sensitive Na+ channel (NaC) is involved in the regulation of proliferation in rat C6 glioma cells,   2006 03
  • Effects of methylmercury and its chelators on mouse ependymal ciliary beat frequency, Takeshi Minami, Kaho Ueda, Dai Ogino, Teruki Hagiwara, 2nd International Caparica Conference on Pollutant Toxic Ions and Molecules,   2017 11 , 招待有り
  • Suppression of Concentration-Sensitive Sodium Channel during Lipopolysaccharide-Induced Acute Lung Injury in Mice, Teruki Hagiwara, Shigeru Yoshida, IUBMB congress,   2016 07


  • 不飽和脂肪酸によるマウス精子の運動活性化メカニズムについて, 森山 隆太郎, 佐藤 弘章, 山本 悠人, 楳田 千明, 山本 悠愛, 若狭 郁美, 萩原 央記, 和田 哲幸, The Journal of Reproduction and Development, 65, Suppl., j107, j107,   2019 09