N Taniguchi

RIKEN, Вако, Saitama, Japan

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Publications (716)2756.36 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The vascular endothelial glycocalyx contains several anionic sugars, one of which is a sialic acid attached to both N- and O-glycans. Platelet endothelial cell adhesion molecule (PECAM), a member of the Ig superfamily that plays multiple roles in cell adhesion, mechanical stress sensing, antiapoptosis, and angiogenesis, has recently been shown to recognize α2,6-sialic acid. In endothelial cells that lack α2,6-sialic acid because of sialyltransferase ST6Gal I deficiency, impairment of the homophilic PECAM interaction and PECAM-dependent cell survival signaling is observed. In this review, we will introduce part of the biological role of PECAM, and discuss how the lectin activity of PECAM is related to angiogenesis.
    Glycobiology 09/2014; · 3.54 Impact Factor
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    ABSTRACT: The luminal sides of vascular endothelial cells are heavily covered with a so-called glycocalyx, but the precise role of the endothelial glycocalyx remains unclear. Our previous study showed that N-glycan α2,6-sialylation regulates the cell surface residency of an anti-apoptotic molecule, platelet endothelial cell adhesion molecule (PECAM), as well as the sensitivity of endothelial cells toward apoptotic stimuli. As PECAM itself was shown to be modified with biantennary N-glycans having α2,6-sialic acid, we expected that PECAM would possess lectin-like activity toward α2,6-sialic acid to ensure its homophilic interaction. To verify this, a series of oligosaccharides were initially added to observe their inhibitory effects on the homophilic PECAM interaction in vitro. We found that a longer α2,6-sialylated oligosaccharide exhibited strong inhibitory activity. Furthermore, we found that a cluster-type α2,6-sialyl N-glycan probe specifically bound to PECAM-immobilized beads. Moreover, addition of the α2,6-sialylated oligosaccharide to endothelial cells enhanced the internalization of PECAM as well as the sensitivity to apoptotic stimuli. Collectively, these findings suggest that PECAM is a sialic acid-binding lectin and that this binding property supports endothelial cell survival. Notably, our findings that α2,6-sialylated glycans influenced the susceptibility to endothelial cell apoptosis shed light on the possibility of using a glycan-based method to modulate angiogenesis.
    The Journal of biological chemistry. 08/2014;
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    ABSTRACT: We have previously demonstrated that chronic obstructive pulmonary disease (COPD) patients who do not have Siglec-14 are less prone to exacerbation of the disease. Siglec-14 is a myeloid cell protein that recognizes bacteria and triggers inflammatory responses. Therefore, soluble mediators secreted by myeloid cells responding to Siglec-14 engagement could be involved in the pathogenesis of exacerbation and could potentially be utilized as biomarkers of exacerbation. To find out, we sought genes specifically induced in Siglec-14+ myeloid cells and evaluated their utility as biomarkers of COPD exacerbation. Using DNA microarray, we compared gene expression levels in Siglec-14+ and control myeloid cell lines stimulated with or without nontypeable Haemophilus influenzae to select genes that were specifically induced in Siglec-14+ cells. The expressions of several cytokine and chemokine genes were specifically induced in Siglec-14+ cells. The concentrations of seven gene products were analyzed by multiplex bead array assays in paired COPD patient sera (n = 39) collected during exacerbation and stable disease states. Those gene products that increased during exacerbation were further tested using an independent set (n = 32) of paired patient sera. Serum concentration of interleukin-27 (IL-27) was elevated during exacerbation (discovery set: P = 0.0472; verification set: P = 0.0428; combined: P = 0.0104; one-sided Wilcoxon matched-pairs signed-rank test), particularly in exacerbations accompanied with sputum purulence and in exacerbations lasting more than a week. We concluded that IL-27 might be mechanistically involved in the exacerbation of COPD and could potentially serve as a systemic biomarker of exacerbation.
    Physiological Reports. 07/2014; 2(7).
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    ABSTRACT: Acrolein, a toxic unsaturated aldehyde generated as a result of oxidative stress, readily reacts with a variety of nucleophilic biomolecules. Polyamines, which produced acrolein in the presence of amine oxidase, were then found to react with acrolein to produce 1,5-diazacyclooctane, a previously unrecognized but significant downstream product of oxidative stress. Although diazacyclooctane formation effectively neutralized acrolein toxicity, the diazacyclooctane hydrogel produced through a sequential diazacyclooctane polymerization reaction was highly cytotoxic. This study suggests that diazacyclooctane formation is involved in the mechanism underlying acrolein-mediated oxidative stress.
    Organic & Biomolecular Chemistry 06/2014; · 3.57 Impact Factor
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    ABSTRACT: Myelin, a multilamellar structure extended from oligodendrocytes or Schwann cells, plays a critical role in maintenance of neuronal function, and damage or loss of myelin causes demyelinating diseases such as multiple sclerosis. For precise alignment of the myelin sheath, there is a requirement for expression of galactosylceramide (GalCer), a major glycosphingolipid in myelin. Synthesis of GalCer is strictly limited in oligodendrocytes in a developmental stage-specific manner. Ceramide galactosyltransferase (CGT), a key enzyme for biosynthesis of GalCer, exhibits restricted expression in oligodendrocytes but the mechanism is poorly understood. Based on our assumption that particular oligodendrocyte lineage-specific transcription factors regulate CGT expression, we co-expressed a series of candidate transcription factors with the human CGT promoter driving luciferase expression in oligodendroglioma cells to measure the promoter activity. We found that Nkx2.2 strongly activated the CGT promoter. In addition, we identified a novel repressive DNA element in the first intron of CGT and OLIG2, an oligodendrocyte-specific transcription factor, as a binding protein of this element. Moreover, overexpression of OLIG2 completely canceled the activating effect of Nkx2.2 on CGT promoter activity. Expression of CGT mRNA was also upregulated by Nkx2.2, but this upregulation was cancelled by co-expression of OLIG2 with Nkx2.2. Our study suggests that CGT expression is controlled by balanced expression of the negative modulator OLIG2 and positive regulator Nkx2.2, providing new insights into how expression of GalCer is tightly regulated in cell type- and stage-specific manners.
    Glycobiology 05/2014; · 3.54 Impact Factor
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    ABSTRACT: Glycans play key roles in a variety of protein functions under normal and pathological conditions, but several glycosyltransferase deficient mice exhibit no or only mild phenotypes due to redundancy or compensation of glycan functions. However, we have only a limited understanding of the underlying mechanism for these observations. Our previous studies indicated that 70% of Fut8 deficient (Fut8(-/-)) mice that lack core fucose structure die within 3 days after birth, but the remainder survive for up to several weeks even though they show growth retardation as well as emphysema. In this study, we show that, in mouse embryonic fibroblasts (MEFs) from Fut8(-/-) mice, another N-glycan branching structure, bisecting GlcNAc, is specifically upregulated by enhanced gene expression of a responsible enzyme N-acetylglucosaminyltransferase III (GnT-III). As candidate target glycoproteins for bisecting GlcNAc modification, we confirmed that level of bisecting GlcNAc on β1-integrin and N-cadherin was increased in Fut8(-/-) MEFs. Moreover using mass spectrometry, glycan analysis of IgG1 in Fut8(-/-) mouse serum demonstrated that bisecting GlcNAc contents were also increased by Fut8 deficiency in vivo. As an underlying mechanism, we found that in Fut8(-/-) MEFs Wnt/β-catenin signaling is upregulated and an inhibitor against Wnt-signaling was found to abrogate GnT-III expression, indicating that Wnt/β-catenin is involved in GnT-III upregulation. Furthermore, various oxidative stress-related genes were also increased in Fut8(-/-) MEFs. These data suggest that Fut8(-/-) mice adapted to oxidative stress, both ex vivo and in vivo, by inducing various genes including GnT-III, which may compensate for the loss of core fucose functions.
    Journal of Biological Chemistry 03/2014; · 4.65 Impact Factor
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    ABSTRACT: Expression of glycosyltransferase genes is essential for glycosylation. However, the detailed mechanisms of how glycosyltransferase gene expression is regulated in a specific tissue or during disease progression are poorly understood. In particular, epigenetic studies of glycosyltransferase genes are limited, although epigenetic mechanisms, such as histone and DNA modifications, are central to establish tissue-specific gene expression. We previously found that epigenetic histone activation is essential for brain-specific expression of N-acetylglucosaminyltransferase-IX (GnT-IX, also designated GnT-Vb), but the mechanism of brain-specific chromatin activation around GnT-IX gene (Mgat5b) has not been clarified. To reveal the mechanisms regulating the chromatin surrounding GnT-IX, we have investigated the epigenetic factors that are specifically involved with the mouse GnT-IX locus by comparing their involvement with other glycosyltransferase loci. We first found that a histone deacetylase (HDAC) inhibitor enhanced the expression of GnT-IX but not of other glycosyltransferases tested. By overexpression and knockdown of a series of HDACs, we found that HDAC11 silenced GnT-IX. We also identified the O-GlcNAc transferase (OGT) and ten-eleven translocation-3 (TET3) complex as a specific chromatin activator of GnT-IX gene. Moreover, chromatin immunoprecipitation (ChIP) analysis in combination with OGT- or TET3-knockdown showed that this OGT-TET3 complex facilitates the binding of a potent transactivator, NeuroD1, to the GnT-IX promoter, suggesting that epigenetic chromatin activation by the OGT-TET3 complex is a prerequisite for the efficient binding of NeuroD1. These results reveal a new epigenetic mechanism of brain-specific GnT-IX expression regulated by defined chromatin modifiers, providing new insights into the tissue-specific expression of glycosyltransferases.
    Journal of Biological Chemistry 03/2014; · 4.65 Impact Factor
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    ABSTRACT: A general probe designed to induce a cascading sequence of reactions on a target protein was efficiently synthesized. The cascading reaction sequence involved (i) ligand-directed azaelectrocyclization with lysine and (ii) the autooxidation-induced release of a fluorescence quencher from the labeled protein. The probe was linked to a cyclic RGDyK peptide to enable the selective visualization of integrin αVβ3 on the surfaces of live cells.
    Organic & Biomolecular Chemistry 01/2014; · 3.57 Impact Factor
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    ABSTRACT: In the nervous system, various unique glycans not found in other tissues are expressed on glycoproteins, and their expression/functions have been studied using specific antibodies/lectins. Among brain-specific glycans in mammals, we focus on human natural killer-1 (HNK-1) and related Cat-315 epitopes, which can be detected using specific antibodies. It is known that the HNK-1 epitope is expressed on N- and O-mannosylated glycans and that Cat-315 mAb preferentially recognizes the HNK-1 epitope on brain-specific "branched O-mannose glycan." The β1,6-branched O-mannose structure is synthesized by a brain-specific glycosyltransferase, N-acetylglucosaminyltransferase-IX (GnT-IX, also designated as GnT-Vb). Using GnT-IX gene-deficient mice and specific antibodies/lectins, the function of GnT-IX was found to be quite different from that of its ubiquitous homologue, GnT-V. Using Cat-315 mAb, the receptor protein tyrosine phosphatase-beta (RPTPβ) was identified as an in vivo target glycoprotein for GnT-IX. Analysis of the function of branched O-mannose glycan on RPTPβ indicated that its loss promoted the recovery process after myelin injury (called remyelination) in brain and that this phenomenon is probably caused in vivo by reduced activation of astrocytes in GnT-IX-deficient brain.
    Advances in neurobiology. 01/2014; 9:117-127.
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    ABSTRACT: N-Acetylglucosaminyltransferase (GnT) III is a glycosyltransferase which produces bisected N-glycans by transferring GlcNAc to the 4-position of core mannose. Bisected N-glycans are involved in physiological and pathological processes through the functional regulation of their carrier proteins. An understanding of the biological functions of bisected glycans will be greatly accelerated by use of specific inhibitors of GnT-III. Thus far, however, such inhibitors have not been developed and even the substrate-binding mode of GnT-III is not fully understood. To gain insight into structural features required of the substrate, we systematically synthesized four N-glycan units, the branching parts of the bisected and non-bisected N-glycans. The series of syntheses were achieved from a common core trimannose, giving bisected tetra- and hexasaccharides as well as non-bisected tri- and pentasaccharides. A competitive GnT-III inhibition assay using the synthetic substrates revealed a vital role for the Manβ(1-4)GlcNAc moiety. In keeping with previous reports, GlcNAc at the α1,3-branch is also involved in the interaction. The structural requirements of GnT-III elucidated in this study will provide a basis for rational inhibitor design.
    Bioorganic & Medicinal Chemistry Letters. 01/2014;
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    ABSTRACT: In our previous study, the CS-56 antibody, which recognizes a chondroitin sulfate moiety, labeled a subset of adult brain astrocytes, yielding a patchy extracellular matrix pattern. To explore the molecular nature of CS-56-labeled glycoproteins, we purified glycoproteins of the adult mouse cerebral cortex using a combination of anion exchange, charge-transfer, and size-exclusion chromatographies. One of the purified proteins was identified as tenascin-R (TNR) by mass spectrometric analysis. When we compared TNR mRNA expression patterns with the distribution patterns of CS-56-positive cells, TNR mRNA was detected in CS-56-positive astrocytes. To examine the functions of TNR in astrocytes, we first confirmed that cultured astrocytes also expressed TNR protein. TNR knockdown by siRNA expression significantly reduced glutamate uptake in cultured astrocytes. Furthermore, expression of mRNA and protein of excitatory amino acid transporter 1 (GLAST), which is a major component of astrocytic glutamate transporters, was reduced by TNR knockdown. Our results suggest that TNR is expressed in a subset of astrocytes and contributes to glutamate homeostasis by regulating astrocytic GLAST expression.
    Journal of Biological Chemistry 12/2013; · 4.65 Impact Factor
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    ABSTRACT: Disruption of the circadian rhythm is a contributory factor to clinical and pathophysiological conditions, including cancer, the metabolic syndrome, and inflammation. Chronic and systemic inflammation are a potential trigger of type 2 diabetes and cardiovascular disease and are caused by the infiltration of large numbers of inflammatory macrophages into tissue. Although recent studies identified the circadian clock gene Rev-erbα, a member of the orphan nuclear receptors, as a key mediator between clockwork and inflammation, the molecular mechanism remains unknown. In this study, we demonstrate that Rev-erbα modulates the inflammatory function of macrophages through the direct regulation of Ccl2 expression. Clinical conditions associated with chronic and systemic inflammation, such as aging or obesity, dampened Rev-erbα gene expression in peritoneal macrophages from C57BL/6J mice. Rev-erbα agonists or overexpression of Rev-erbα in the murine macrophage cell line RAW264 suppressed the induction of Ccl2 following an LPS endotoxin challenge. We discovered that Rev-erbα represses Ccl2 expression directly through a Rev-erbα-binding motif in the Ccl2 promoter region. Rev-erbα also suppressed CCL2-activated signals, ERK and p38, which was recovered by the addition of exogenous CCL2. Further, Rev-erbα impaired cell adhesion and migration, which are inflammatory responses activated through the ERK- and p38-signaling pathways, respectively. Peritoneal macrophages from mice lacking Rev-erbα display increases in Ccl2 expression. These data suggest that Rev-erbα regulates the inflammatory infiltration of macrophages through the suppression of Ccl2 expression. Therefore, Rev-erbα may be a key link between aging- or obesity-associated impairment of clockwork and inflammation.
    The Journal of Immunology 12/2013; · 5.52 Impact Factor
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    ABSTRACT: The glycolipid Glc3Man9GlcNAc2-pyrophosphate-dolichol serves as the precursor for asparagine (N)-linked protein glycosylation in mammals. The biosynthesis of dolichol-linked oligosaccharides (DLOs) is arrested in low-glucose environments via unknown mechanisms, resulting in abnormal N-glycosylation. Here, we show that under glucose deprivation, DLOs are prematurely degraded during the early stages of DLO biosynthesis by pyrophosphatase, leading to the release of singly phosphorylated oligosaccharides into the cytosol. We identified that the level of GDP-mannose (Man), which serves as a donor substrate for DLO biosynthesis, is substantially reduced under glucose deprivation. We provide evidence that the selective shutdown of the GDP-Man biosynthetic pathway is sufficient to induce the release of phosphorylated oligosaccharides. These results indicate that glucose-regulated metabolic changes in the GDP-Man biosynthetic pathway cause the biosynthetic arrest of DLOs and facilitate their premature degradation by pyrophosphatase. We propose that this degradation system may avoid abnormal N-glycosylation with premature oligosaccharides under conditions that impair efficient DLO biosynthesis.
    Proceedings of the National Academy of Sciences 11/2013; · 9.81 Impact Factor
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    ABSTRACT: Heregulin signaling is involved in various tumor proliferations and invasions, thus receptors of heregulin are targets for the cancer therapy. In the present study, we prepared extracellular domains of ErbB2, ErbB3, and ErbB4 (soluble ErbB = sErbB), and examined the suppressing effects on heregulin β signaling in human breast cancer cell line MCF7. It was found that sErbB3 suppresses ligand-induced activation of ErbB receptors, PI3K/Akt and Ras/Erk pathways most effectively; sErbB2 scarcely suppresses ligand-induced signaling, and sErbB4 suppresses receptor activation at around 10% efficiency of sErbB3. sErbB3 suppresses heregulin β signaling under a large excess of ligands, indicating that sErbB3 does not decrease the effective ligands but decreases the effective receptors. By using small interfering RNA (siRNA) for ErbB receptors, we determined that sErbB3 suppresses the heregulin β signaling by interfering ErbB3-containting heterodimers including ErbB2/ErbB3. The immunostaining study indicated that sErbB3 colocalized ErbB2 and ErbB3, suggesting that sErbB3 binds to ErbB2/ErbB3 heterodimers. By introducing the mutation of N418Q to sErbB3, the signaling-inhibitory effects were increased by 2-3 folds. Moreover, the sErbB3 N418Q mutant enhanced anticancer effects of lapatinib more effectively than the wild type. We also determined the structures of N-glycan on Asn418. Results suggested that the N-glycan deleted mutant of sErbB3 suppresses heregulin signaling via ErbB2/ErbB3 heterodimers more effectively than the wild type. Thus, we demonstrated that the sErbB3 N418Q mutant is a potent inhibitor for heregulin β signaling.
    Journal of Biological Chemistry 10/2013; · 4.65 Impact Factor
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    ABSTRACT: Although the aberrant assembly of mutant superoxide dismutase 1 (mSOD1) is implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS), the molecular basis of SOD1 oligomerization remains undetermined. We investigated the roles of transglutaminase 2 (TG2), an endogenous cross-linker in mSOD1-linked ALS. TG2 interacted preferentially with mSOD1 and promoted its oligomerization in transfected cells. Purified TG2 directly oligomerized recombinant mutant SOD1 and the apo-form of the wild-type SOD1 proteins in a calcium-dependent manner, indicating that misfolded SOD1 is a substrate of TG2. Moreover, the non-cell-autonomous effect of extracellular TG2 on the neuroinflammation was suggested, since the TG2-mediated soluble SOD1 oligomers induced tumor necrosis factor-α, interleukin-1β, and nitric oxide in microglial BV2 cells. TG2 was up-regulated in the spinal cord of presymptomatic G93A SOD1 transgenic mice and in the hypoglossal nuclei of mice suffering nerve ligation. Furthermore, inhibition of spinal TG2 by cystamine significantly delayed the progression and reduced SOD1 oligomers and microglial activation. These results indicate a novel role of TG2 in SOD1 oligomer-mediated neuroinflammation, as well as in the involvement in the intracellular aggregation of misfolded SOD1 in ALS.
    Journal of Neurochemistry 08/2013; · 3.97 Impact Factor
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    ABSTRACT: Our previous studies on a β1,6-N-acetylglucosaminyltransferase, GnT-IX (GnT-Vb), a homolog of GnT-V, indicated that the enzyme has a broad GlcNAc-transfer activity toward N-linked and O-mannosyl glycan core structures and its brain-specific gene expression is regulated by epigenetic histone modifications. In this study, we demonstrate the existence of an endogenous inhibitory factor for GnT-IX that functions as a key regulator for GnT-IX enzymatic activity in Neuro2a (N2a) cells. We purified this factor from N2a cells and found that it is identical to ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) as evidenced by mass spectrometry and on the knocking down and overexpression of ENPP3 in cultured cells. Kinetic analyses revealed that the mechanism responsible for the inhibition of GnT-IX caused by ENPP3 is the ENPP3-mediated hydrolysis of the nucleotide-sugar donor substrate, UDP-GlcNAc, with the resulting generation of UMP, a potent and competitive inhibitor of GnT-IX. Indeed, ENPP3-knockdown cells had significantly increased levels of intracellular nucleotide sugars and displayed changes in the total cellular glycosylation profile. In addition to chaperones or other known regulators of glycosyltransferases, the ENPP3-mediated hydrolysis of nucleotide sugars would have widespread and significant impacts on glycosyltransferase activities and would be responsible for altering the total cellular glycosylation profile and modulating cellular functions.
    Journal of Biological Chemistry 08/2013; · 4.65 Impact Factor
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    ABSTRACT: High-sensitivity capillary electrophoresis-electrospray ionization quadrupole ion trap time-of-flight mass spectrometry (CE-ESI-QIT-TOF MS) was developed to structurally characterize four kinds of pyridylaminated (PA) oligosaccharides, i.e., lactose (Lac)-PA, globotriose (Gb3)-PA, globotetraose (Gb4)-PA, and IV(3) αGalNAc-Gb4 (Forssman antigen)-PA, derived from neutral glycosphingolipids. The CE-MS system included the head-column field-amplified sample stacking (HC-FASS) method for effective sample injection into a capillary column in CE, a sheathless interface between CE and a mass spectrometer, and MS and tandem MS (MS(2)) measurements with narrow mass range repeated high-speed switching. The total sensitivity of the developed CE-MS system was about 20 000 times higher than that of the conventional CE-MS system consisting of pressure injection, a sheath-flow interface, and a wide mass range measurement. The MS and MS(2) spectra of the four PA-oligosaccharides at a concentration of 25 amol/μL in mixtures (each 250 amol/10 μL in a tube) clearly showed protonated molecular ions ([M + H](+)) and the fragment ions responsible for the sequential elimination of saccharides. The developed CE-MS system is a powerful method for the structural characterization of glycosphingolipids extracted from very small amounts of biological materials and could be extended to the structural characterization of oligosaccharides derived from glycoproteins.
    Analytical Chemistry 08/2013; · 5.82 Impact Factor
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    ABSTRACT: Most Alzheimer disease (AD) patients show deposition of amyloid β (Aβ) peptide in blood vessels as well as the brain parenchyma. We previously found that vascular endothelial cells express amyloid β precursor protein (APP) 770, a different APP isoform from neuronal APP695, and that they produce Aβ. We analyzed the glycosylation of APP770 and found that O-glycosylated sAPP770 is preferentially processed by proteases for Aβ production. Because the soluble APP cleavage product sAPP is considered to be a possible marker for AD diagnosis, sAPP, consisting of a mixture of these variants, has been widely measured. We hypothesized that measurement of the endothelial APP770 cleavage product in patients separately from that of neuronal APP695 would enable us to discriminate between endothelial and neurological dysfunctions. Our recent findings, showing that the level of plasma sAPP770 is significantly higher in patients with acute coronary syndrome, raise the possibility that sAPP770 could be an indicator of endothelial dysfunction. In this review, we first describe the expression, glycosylation, and processing of APP770, and then discuss sAPP770 as a novel biomarker candidate of acute coronary syndrome. This article is protected by copyright. All rights reserved.
    PROTEOMICS - CLINICAL APPLICATIONS 07/2013; · 1.81 Impact Factor
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD), manifested as emphysema and chronic airway obstruction, can be exacerbated by bacterial and viral infections. Although the frequency of exacerbations increases as the disease progresses, the mechanisms underlying this phenomenon are largely unknown and there is a need for a simple in vivo exacerbation model. In this study, we compared four groups of mice treated with phosphate-buffered saline alone, elastase alone, lipopolysaccharide (LPS) alone, and elastase plus LPS. We found that a single intratracheal administration of LPS to elastase-induced emphysema mice provoked infiltration of inflammatory cells, especially CD8+ T-cells, into alveolar spaces and increased matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and perforin production in bronchoalveolar lavage fluid at the acute inflammatory phase compared with the other groups. We also measured the percentages of low-attenuation area (LAA%) in the above mice using micro-computed X-ray tomography. The LAA% was the most sensitive parameter for quantitative assessments of emphysema among all the parameters we evaluated. Using the parameter of LAA%, we found significantly more severe alveolar destruction in the group treated with elastase plus LPS compared with the other groups during long-term longitudinal observations. Furthermore, we built three-dimensional images of the emphysema and confirmed that the lungs of elastase plus LPS-treated mice contained larger emphysematous areas than mice treated with elastase alone. Even though human exacerbation of COPD is clinically and pathologically complicated, this simple mouse model would mimic human cases to some extent, and will be useful for elucidating its mechanism and developing therapeutic strategies.
    American Journal of Respiratory Cell and Molecular Biology 07/2013; · 4.15 Impact Factor
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    ABSTRACT: In demyelinating diseases such as multiple sclerosis, a critical problem is failure of remyelination, which is important for protecting axons against degeneration and restoring conduction deficits. However, the underlying mechanism of demyelination/remyelination remains unclear. N-acetylglucosaminyltransferase-IX (GnT-IX; also known as GnT-Vb) is a brain-specific glycosyltransferase that catalyzes the branched formation of O-mannosyl glycan structures. O-Mannosylation of α-dystroglycan is critical for its function as an extracellular matrix receptor, but the biological significance of its branched structures, which are exclusively found in the brain, is unclear. In this study, we found that GnT-IX formed branched O-mannosyl glycans on receptor protein tyrosine phosphatase β (RPTPβ) in vivo. Since RPTPβ is thought to play a regulatory role in demyelinating diseases, GnT-IX-deficient mice were subjected to cuprizone-induced demyelination. Cuprizone feeding for 8 weeks gradually promoted demyelination in wild-type mice. In GnT-IX-deficient mice, the myelin content in the corpus callosum was reduced after 4 weeks of treatment, but markedly increased at 8 weeks, suggesting enhanced remyelination under GnT-IX deficiency. Furthermore, astrocyte activation in the corpus callosum of GnT-IX-deficient mice was significantly attenuated, and an oligodendrocyte cell lineage analysis indicated that more oligodendrocyte precursor cells differentiated into mature oligodendrocytes. Together, branched O-mannosyl glycans in the corpus callosum in the brain are a necessary component of remyelination inhibition in the cuprizone-induced demyelination model, suggesting that modulation of O-mannosyl glycans is a likely candidate for therapeutic strategies.
    Journal of Neuroscience 06/2013; 33(24):10037-47. · 6.91 Impact Factor

Publication Stats

14k Citations
2,756.36 Total Impact Points

Institutions

  • 2010–2014
    • RIKEN
      • • RIKEN-Max Planck Joint Research Center for Systems Chemical Biology
      • • Chemical Biology Team
      Вако, Saitama, Japan
    • University of Queensland 
      • Institute for Molecular Bioscience
      Brisbane, Queensland, Australia
  • 2013
    • The University of Tokyo
      • Department of Pharmaceutical Sciences
      Tokyo, Tokyo-to, Japan
  • 2010–2013
    • Shiga University of Medical Science
      • Molecular Neuroscience Research Center
      Ōtu, Shiga, Japan
  • 2005–2013
    • Saga University
      • Department of Biomolecular Sciences
      Сага Япония, Saga, Japan
  • 1989–2013
    • Osaka University
      • • Department of Disease Glycomics
      • • Research Institute for Microbial Diseases
      • • Division of Biochemistry
      • • Division of Molecular Regenerative Medicine
      • • Department of Integrated Medicine
      Ibaraki, Osaka-fu, Japan
  • 2012
    • Nippon Medical School
      • Department of Internal Medicine
      Sendai, Kagoshima-ken, Japan
  • 1992–2012
    • Osaka City University
      • • Department of Biochemistry
      • • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
  • 2011
    • Dalian Ocean University
      Lü-ta-shih, Liaoning, China
  • 2008–2011
    • Tohoku Pharmaceutical University
      Japan
    • Institute of Microbial Chemistry
      Edo, Tōkyō, Japan
    • Kyung Hee University Medical Center
      Sŏul, Seoul, South Korea
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
  • 2007–2010
    • Osaka Medical Center and Research Institute for Maternal and Child Health
      Izumi, Ōsaka, Japan
  • 2002–2010
    • Hyogo College of Medicine
      • Department of Biochemistry
      Nishinomiya, Hyogo-ken, Japan
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2003–2009
    • Sapporo Medical University
      • • Department of Biochemistry
      • • Division of Plastic and Reconstructive Surgery
      Sapporo, Hokkaidō, Japan
  • 2002–2009
    • Kyorin University
      • School of Medicine
      Edo, Tōkyō, Japan
  • 2005–2008
    • Kochi Medical School
      Kôti, Kōchi, Japan
  • 2004–2006
    • Korea Research Institute of Bioscience and Biotechnology KRIBB
      • Systemic Proteomics Research Center
      Ansan, Gyeonggi, South Korea
    • Kochi University
      Kôti, Kōchi, Japan
    • Fudan University
      • Department of Biochemistry
      Shanghai, Shanghai Shi, China
  • 2003–2006
    • Kuma Hospital
      Kōbe, Hyōgo, Japan
  • 1972–2005
    • Hokkaido University
      • • Department of Medical Oncology
      • • Laboratory of Biochemistry (School of Veterinary Medicine)
      • • Graduate School of Environmental Science
      • • Department of Medicine II
      Sapporo-shi, Hokkaido, Japan
  • 2001
    • Fukuoka University
      • Department of Pathology
      Hukuoka, Fukuoka, Japan
  • 2000
    • Nagoya University
      • Research Center of Health, Physical Fitness and Sports
      Nagoya-shi, Aichi-ken, Japan
  • 1998
    • St.Mary's Hospital (Fukuoka - Japan)
      Hukuoka, Fukuoka, Japan
  • 1992–1997
    • National Defense Medical College
      • Division of Hygiene
      Tokorozawa, Saitama-ken, Japan
  • 1996
    • Osaka Medical College
      • Department of Pediatrics
      Takatuki, Ōsaka, Japan
  • 1995
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Cornell University
      • Department of Biochemistry
      Ithaca, NY, United States
  • 1994–1995
    • Kurume University
      • • Division of Cell Biology
      • • Institute of Life Science
      Куруме, Fukuoka, Japan
    • Niigata University
      • Division of Neuropathology
      Niahi-niigata, Niigata, Japan
  • 1993
    • Nagasaki University Hospital
      Nagasaki, Nagasaki, Japan
  • 1990
    • Ube Industries, Ltd.
      Edo, Tōkyō, Japan
  • 1975–1986
    • Hokkaido University Hospital
      • Division of Internal Medicine II
      Sapporo, Hokkaidō, Japan
  • 1977
    • Hokkaido University of Education
      Sapporo, Hokkaidō, Japan