Yoshihiro Urade

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (430)1774.74 Total impact

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  • Michael Lazarus · Zhi-Li Huang · Yoshihiro Urade
    07/2015; DOI:10.1080/23328940.2015.1072658
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    ABSTRACT: Prostaglandin D2 (PGD2) is a major prostanoid secreted mainly by mast cells. Although PGD2 has been identified as a modulator of allergic inflammation, its precise role remains unclear. Here we investigate the role of PGD2 in food allergy. Oral administration of ovalbumin induces allergic responses in sensitized wild-type (WT) mice. Systemic gene deficiency of haematopoietic PGD synthase (H-PGDS(-/-)) exacerbates all of the manifestations accompanying severe mast cell hyperplasia in the intestine. Morphological studies show that c-kit/FcɛRI-positive WT mast cells strongly express H-PGDS. Transplantation of H-PGDS(-/-) mast cells also aggravates ovalbumin-induced mast cell hyperplasia and allergic symptoms in mast cell null mice. H-PGDS deficiency accelerates the production of SDF-1α and the activity of MMP-9 in the antigen-stimulated intestine. SDF-1α receptor blockade or MMP-9 inhibition relieves the exacerbated mast cell hyperplasia and manifestations observed in H-PGDS(-/-). Thus, PGD2 deficiency results in food antigen-induced mast cell hyperplasia.
    Nature Communications 07/2015; 6:7514. DOI:10.1038/ncomms8514 · 11.47 Impact Factor
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    ABSTRACT: Zinc is an essential trace element for humans and animals, being located, among other places, in the synaptic vesicles of cortical glutamatergic neurons and hippocampal mossy fibers in the brain. Extracellular zinc has the potential to interact with and modulate many different synaptic targets, including glutamate and GABA receptors. Because of the central role of these neurotransmitters in brain activity, we examined in this study the sleep-promoting activity of zinc by monitoring locomotor activity and electroencephalogram after its administration to mice. Zinc-containing yeast extract (40 and 80 mg/kg) dose dependently increased the total amount of non-rapid eye movement sleep and decreased the locomotor activity. However, this preparation did not change the amount of rapid eye movement sleep or show any adverse effects such as rebound of insomnia during a period of 24 h following the induction of sleep; whereas the extracts containing other divalent cations (manganese, iron, and copper) did not decrease the locomotor activity. This is the first evidence that zinc can induce sleep. Our data open the way to new types of food supplements designed to improve sleep. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Molecular Nutrition & Food Research 06/2015; DOI:10.1002/mnfr.201500082 · 4.60 Impact Factor
  • Biophysical Journal 01/2015; 108(2):510a. DOI:10.1016/j.bpj.2014.11.2792 · 3.97 Impact Factor
  • Biophysical Journal 01/2015; 108(2):513a. DOI:10.1016/j.bpj.2014.11.2813 · 3.97 Impact Factor
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    ABSTRACT: To test the hypothesis that lipocalin-type prostaglandin D synthase (L-PGDS), a marker of vascular epithelium disorders, may be a diagnostic for preeclampsia. Plasma and urine were collected from 36 preeclamptic and 94 non-symptomatic patients throughout their pregnancies. L-PGDS concentrations were determined by sandwich ELISA assay. Receiver operating characteristic (ROC) curve validated the cut-off point of the assay. The plasma and urinary L-PGDS concentrations were significantly higher in the preeclamptic than the non-symptomatic patients. L-PGDS concentrations in the urine of normal pregnant women were higher in the third trimester compared to earlier pregnancy, while plasma concentrations remained unchanged. Urinary L-PGDS levels were significantly higher in early onset of preeclampsia (onset <32 weeks gestation) compared with late onset and in the severe compared to mild forms of preeclampsia. ROC curve showed the cut-off point of 58.85μg/dl (sensitivity 76.5%, specificity 75.6%, positive predictive value (PPV) 46.4%, negative predictive value (NPV) 92.1% and area under curve (AUC) 0.82) in the plasma and 2.195μg/dl (sensitivity 84.6%, specificity 58.7%, PPV 33.8%, NPV 93.8% and AUC 0.76) in urine. Our results indicate the measurement of plasma and urinary concentrations of L-PGDS may be a potential diagnostic for preeclampsia. J. Takeda: None. K. Kinoshita: None. K. Matsuoka: None. S. Takeda: None. Y. Eguchi: None. H. Oda: None. N. Eguchi: None. Y. Urade: None. Copyright © 2014.
    01/2015; 5(1):77. DOI:10.1016/j.preghy.2014.10.155
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    ABSTRACT: When living organisms become sick as a result of a bacterial infection, a suite of brain-mediated responses occur, including fever, anorexia and sleepiness. Systemic administration of lipopolysaccharide (LPS), a common constituent of bacterial cell walls, increases body temperature and non-rapid eye movement (NREM) sleep in animals and induces the production of pro-inflammatory prostaglandins (PGs). Prostaglandin E2 (PGE2) is the principal mediator of fever, and both PGE2 and PGD2 regulate sleep-wake behavior. The extent to which PGE2 and PGD2 are involved in the effect of LPS on NREM sleep remains to be clarified. Therefore, we examined LPS-induced changes in body temperature and NREM sleep in mice with nervous system-specific knockouts (KO) for the PGE2 receptors, EP3 or EP4; in mice with total body KO of microsomal PGE synthase-1, or the PGD2 receptor DP; and in mice treated with the cyclooxygenase (COX) inhibitor meloxicam. We observed that LPS-induced NREM sleep was slightly attenuated in mice lacking EP4 receptors in the nervous system, but was not affected in any of the other KO mice or in mice pretreated with the COX inhibitor. These results suggest that the effect of LPS on NREM sleep is partially dependent on PGs and is likely mediated mainly by other pro-inflammatory substances. In addition, our data show that the main effect of LPS on body temperature is hypothermia in the absence of nervous system EP3 receptors or in the presence of a COX inhibitor. Copyright © 2014. Published by Elsevier Inc.
    Brain Behavior and Immunity 12/2014; 47. DOI:10.1016/j.bbi.2014.11.019 · 5.89 Impact Factor
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    ABSTRACT: Histaminergic neurons have been reported to play an important role in the regulation of sleep-wake behavior through the histamine H1 receptor (R, H1R). First generation H1R antagonists, such as doxepin and diphenhydramine, produce drowsiness in humans, and are occasionally used to treat insomnia. However, if H1R antagonists function via physically blocking the H1R remains unclear. In the current study, we used H1R knockout (KO) mice to investigate if the sleep-promoting effects of doxepin and diphenhydramine are dependent on blockade of the H1R. When doxepin was administered, non-rapid eye movement (NREM) sleep in wild type (WT) mice increased for 4 h, with an increase in the numbers of NREM sleep bouts of 256-512 s and 512-1024 s. These effects were not observed in the H1R KO mice. Furthermore, diphenhydramine increased NREM sleep for 6 h in WT, and not in the H1R KO mice after the injection. These results indicate that both doxepin at 15 mg/kg and diphenhydramine at 10 mg/kg induce NREM sleep through blockade of H1R. Copyright © 2014. Published by Elsevier Inc.
    Pharmacology Biochemistry and Behavior 12/2014; 129. DOI:10.1016/j.pbb.2014.12.002 · 2.78 Impact Factor
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    ABSTRACT: Neuregulin 1 type III is processed following regulated intramembrane proteolysis, which allows communication from the plasma membrane to the nucleus. We found that the intracellular domain of neuregulin 1 type III upregulated the prostaglandin D2 synthase (L-pgds, also known as Ptgds) gene, which, together with the G protein-coupled receptor Gpr44, forms a previously unknown pathway in PNS myelination. Neuronal L-PGDS is secreted and produces the PGD2 prostanoid, a ligand of Gpr44. We found that mice lacking L-PGDS were hypomyelinated. Consistent with this, specific inhibition of L-PGDS activity impaired in vitro myelination and caused myelin damage. Furthermore, in vivo ablation and in vitro knockdown of glial Gpr44 impaired myelination. Finally, we identified Nfatc4, a key transcription factor for myelination, as one of the downstream effectors of PGD2 activity in Schwann cells. Thus, L-PGDS and Gpr44 are previously unknown components of an axo-glial interaction that controls PNS myelination and possibly myelin maintenance.
    Nature Neuroscience 11/2014; 17(12). DOI:10.1038/nn.3857 · 16.10 Impact Factor
  • 19th International Congress of the World-Muscle-Society; 10/2014
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    ABSTRACT: Through intercellular signalling, the somatic compartment of the foetal testis is able to program primordial germ cells to undergo spermatogenesis. Fibroblast growth factor 9 and several members of the transforming growth factor β superfamily are involved in this process in the foetal testis, counteracting the induction of meiosis by retinoic acid and activating germinal mitotic arrest. Here, using in vitro and in vivo approaches, we show that prostaglandin D2 (PGD2), which is produced through both L-Pgds and H-Pgds enzymatic activities in the somatic and germ cell compartments of the foetal testis, plays a role in mitotic arrest in male germ cells by activating the expression and nuclear localization of the CDK inhibitor p21(Cip1) and by repressing pluripotency markers. We show that PGD2 acts through its Dp2 receptor, at least in part through direct effects in germ cells, and contributes to the proper differentiation of male germ cells through the upregulation of the master gene Nanos2. Our data identify PGD2 signalling as an early pathway that acts in both paracrine and autocrine manners, and contributes to the differentiation of germ cells in the foetal testis.
    Development 08/2014; 141(18). DOI:10.1242/dev.103408 · 6.46 Impact Factor
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    ABSTRACT: Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D2) caused more adenomas in ApcMin/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D2 (PGD2) binds to the prostaglandin D2 receptor known as PTGDR (or DP1). PGD2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD2. To assess, we produced ApcMin/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced ApcMin/+ mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in ApcMin/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. ApcMin/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD2 signals acting through PTGDR in suppression of intestinal tumors.
    Cancer Medicine 08/2014; 3(4). DOI:10.1002/cam4.251 · 2.50 Impact Factor
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    ABSTRACT: Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is the second major protein in human cerebrospinal fluid (CSF) and belongs to the lipocalin superfamily composed of various secretory lipophilic ligand transporter proteins. However, the endogenous ligand of L-PGDS has not yet been elucidated. In this study, we purified L-PGDS from the CSF of aneurysmal subarachnoid hemorrhage (SAH) patients. Lipocalin-type PG D synthase showed absorbance spectra with major peaks at 280 and 392 nm and a minor peak at around 660 nm. The absorbance at 392 nm of L-PGDS increased from 1 to 9 days and almost disappeared at 2 months after SAH, whereas the L-PGDS activity decreased from 1 to 7 days and recovered to normal at 2 months after SAH. These results indicate that some chromophore had accumulated in the CSF after SAH and bound to L-PGDS, thus inactivating it. Matrix assisted laser desorption ionization time-of-flight mass spectrometry of L-PGDS after digestion of it with endoproteinase Lys-C revealed that L-PGDS had covalently bound biliverdin, a by-product of heme breakdown. These results suggest that L-PGDS acted as a scavenger of biliverdin, which is a molecule not found in normal CSF. This is the first report of identification of a pathophysiologically important endogenous ligand for this lipocalin superfamily protein in humans.Journal of Cerebral Blood Flow & Metabolism advance online publication, 9 July 2014; doi:10.1038/jcbfm.2014.127.
    Journal of Cerebral Blood Flow & Metabolism 07/2014; 34(9). DOI:10.1038/jcbfm.2014.127 · 5.41 Impact Factor
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    ABSTRACT: The accurate and robust measurement of prostaglandins (PG) concentration could help to understand the many physiological functions. The present study revealed that liquid chromatography tandem mass spectrometry method for the PGs analysis can satisfy the requirements for both qualitative and quantitative performance as compared to competitive enzyme immunoassays.
    Journal of Bioscience and Bioengineering 07/2014; 118(1). DOI:10.1016/j.jbiosc.2013.12.022 · 1.88 Impact Factor
  • Ko Fujimori · Yoshihiro Urade
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    ABSTRACT: Adipogenesis is controlled by complex mechanisms, and transcription factors are involved in its regulation. PPARγ is a ligand-dependent transcription factor and the most important one for adipogenesis. Although prostaglandin (PG) D2 metabolites have been reported as being the ligands of PPARγ, the endogenous PPARγ ligand in adipocytes remains unclear. Here, we show the methods for the general analysis of adipocyte differentiation and the protocols for promoter analysis, fluorescence EMSA, and chromatin immunoprecipitation assay for the transcriptional regulation of the SREBP-1c-activated lipocalin-type PGD synthase gene in adipocytes. Moreover, we describe that PGD2 and its metabolites are involved in the regulation of adipogenesis through PPARγ-dependent and -independent mechanisms.
    Methods in molecular biology (Clifton, N.J.) 06/2014; 1164:177-96. DOI:10.1007/978-1-4939-0805-9_15 · 1.29 Impact Factor
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    ABSTRACT: Compared with prostaglandin E2, which has an established role in cancer, the role of the COX metabolite prostaglandin D2 (PGD2) in chronic inflammation leading to tumorigenesis is uncertain. In this study, we investigated the role of PGD2 in colitis and colitis-associated colon cancer (CAC) using genetically modified mice and an established model of inflammatory colon carcinogenesis. Systemic genetic deficiency in hematopoietic PGD synthase (H-PGDS) aggravated colitis and accelerated tumor formation in a manner associated with increased TNFα expression. Treatment with a TNFα receptor antagonist attenuated colitis regardless of genotype. Histologic analysis revealed that infiltrated mast cells strongly expressed H-PGDS in inflamed colons. Mast cell-specific H-PGDS deficiency also aggravated colitis and accelerated CAC. In contrast, treatment with a PGD2 receptor agonist inhibited colitis and CAC. Together, our results identified mast cell-derived PGD2 as an inhibitor of colitis and CAC, with implications for its potential use in preventing or treating colon cancer. Cancer Res; 74(11); 3011-9. ©2014 AACR.
    Cancer Research 06/2014; 74(11):3011-3019. DOI:10.1158/0008-5472.CAN-13-2792 · 9.33 Impact Factor
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    ABSTRACT: Background & Aims Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Proton pump inhibitor (PPI) therapy improves subjective but not objective sleep parameters in patients with GERD. This study aimed to investigate the association between GERD and sleep, and the effect of PPI on sleep by using a rat model of chronic acid reflux esophagitis. Methods Acid reflux esophagitis was induced by ligating the transitional region between the forestomach and the glandular portion and then wrapping the duodenum near the pylorus. Rats underwent surgery for implantation of electrodes for electroencephalogram and electromyogram recordings, and they were transferred to a soundproof recording chamber. Polygraphic recordings were scored by using 10-s epochs for wake, rapid eye movement sleep, and non-rapid eye movement (NREM) sleep. To examine the role of acid reflux, rats were subcutaneously administered a PPI, omeprazole, at a dose of 20 mg/kg once daily. Results Rats with reflux esophagitis presented with several erosions, ulcers, and mucosal thickening with basal hyperplasia and marked inflammatory infiltration. The reflux esophagitis group showed a 34.0% increase in wake (232.2±11.4 min and 173.3±7.4 min in the reflux esophagitis and control groups, respectively; p<0.01) accompanied by a reduction in NREM sleep during light period, an increase in sleep fragmentation, and more frequent stage transitions. The use of omeprazole significantly improved sleep disturbances caused by reflux esophagitis, and this effect was not observed when the PPI was withdrawn. Conclusions Acid reflux directly causes sleep disturbances in rats with chronic esophagitis.
    PLoS ONE 05/2014; 9(9):e106969. DOI:10.1371/journal.pone.0106969 · 3.23 Impact Factor
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    ABSTRACT: Idiopathic normal pressure hydrocephalus (iNPH) is a treatable cause of dementia, gait disturbance, and urinary incontinence in elderly patients with ventriculomegaly. Its unique morphological feature, called disproportionately enlarged subarachnoid-space hydrocephalus (DESH), may also be a diagnostic feature. Lipocalin-type prostaglandin D synthase (L-PGDS) is a major cerebrospinal fluid (CSF) protein produced by arachnoid cells, and its concentration in the CSF is reportedly decreased in iNPH. L-PGDS acts as a prostaglandin D2-producing enzyme and behaves as a chaperone to prevent the neurotoxic aggregation of amyloid beta (Abeta) implicated in Alzheimer's disease, a major comorbidity of iNPH. The aim of this study was to confirm the L-PGDS decrease in DESH-type iNPH and to clarify its relationship with clinico-radiological features or other CSF biomarkers. We evaluated 22 patients (age: 76.4 +/- 4.4 y; males: 10, females: 12) referred for ventriculomegaly without CSF pathway obstruction, and conducted a CSF tap test to determine the surgical indication. CSF concentrations of L-PGDS, Abeta42, Abeta40, and total tau (t-tau) protein were determined using enzyme-linked immunosorbent assays. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination, frontal assessment battery (FAB), and timed up and go test. The extent of DESH was approximated by the callosal angle, and the severity of parenchymal damage was evaluated by the age-related white matter change (ARWMC) score. L-PGDS and t-tau levels in CSF were significantly decreased in DESH patients compared to non-DESH patients (p = 0.013 and p = 0.003, respectively). L-PGDS and t-tau showed a significant positive correlation (Spearman r = 0.753, p < 0.001). Among the clinico-radiological profiles, L-PGDS levels correlated positively with age (Spearman r = 0.602, p = 0.004), callosal angle (Spearman r = 0.592, p = 0.004), and ARWMC scores (Spearman r = 0.652, p = 0.001), but were negatively correlated with FAB scores (Spearman r = 0.641, p = 0.004). Our data support the diagnostic value of L-PGDS as a CSF biomarker for iNPH and suggest a possible interaction between L-PGDS and tau protein. In addition, L-PGDS might work as a surrogate marker for DESH features, white matter damage, and frontal lobe dysfunction.
    Fluids and Barriers of the CNS 04/2014; 11(1):9. DOI:10.1186/2045-8118-11-9
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    ABSTRACT: An effective and safe treatment of insomnia in patients with neuropathic pain remains an unmet need. Melatonin and its analogs have been shown to have both analgesic and hypnotic effects; however, capacity of them on sleep disturbance with neuropathic pain as well as the precise mechanism is unclear. The present study evaluated effects of piromelatine, a novel melatonin receptor agonist, on sleep disturbance in a neuropathic pain-like condition as well as the underlying mechanisms. A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSL) was employed. The antinociceptive and hypnotic effects of piromelatine were evaluated by measurement of thermal hyperalgesia, mechanical allodynia, and electroencephalogram (EEG) recordings in PSL mice. Pharmacological approaches were used to clarify the mechanisms of action of piromelatine. PSL significantly lowered thermal and mechanical latencies and decreased non-rapid eye movement (NREM) sleep, and PSL mice exhibited sleep fragmentation. Treatment with 25, 50, or 100 mg/kg of piromelatine significantly prolonged thermal and mechanical latencies and increased NREM sleep. Moreover, the antinociceptive effect of piromelatine was prevented by melatonin antagonist luzindole, opioid receptor antagonist naloxone, or 5HT1A receptor antagonist WAY-100635. The hypnotic effect of piromelatine was blocked by luzindole but neither by naloxone nor WAY-100635. These data indicate that piromelatine is an effective treatment for both neuropathic pain and sleep disturbance in PSL mice. The antinociceptive effect of piromelatine is likely mediated by melatonin, opioid, and 5HT1A receptors; however, the hypnotic effect of piromelatine appears to be mediated by melatonin receptors.
    Psychopharmacology 04/2014; 231(20). DOI:10.1007/s00213-014-3530-5 · 3.88 Impact Factor

Publication Stats

12k Citations
1,774.74 Total Impact Points


  • 2013–2015
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
    • Fudan University
      • Department of Pharmacology
      Shanghai, Shanghai Shi, China
  • 1988–2015
    • Osaka Bioscience Institute
      Ōsaka, Ōsaka, Japan
  • 2014
    • Juntendo University
      • Faculty of Medicine
      Edo, Tōkyō, Japan
  • 1979–2012
    • Kyoto University
      • • Department of Dermatology
      • • Department of Medical Chemistry
      Kioto, Kyōto, Japan
  • 2010
    • Osaka University of Pharmaceutical Sciences
      • Laboratory of Biodefense and Regulation
      Takatuki, Ōsaka, Japan
  • 2009
    • Molecular Biology Institute of Barcelona
      Barcino, Catalonia, Spain
  • 2005
    • Osaka University
      Suika, Ōsaka, Japan
  • 2004
    • Gunma University
      • Institute for Molecular and Cellular Regulation
      Maebashi, Gunma, Japan
  • 2003
    • RIKEN
      Вако, Saitama, Japan
    • Waseda University
      • School of Human Sciences
      Tokyo, Tokyo-to, Japan
  • 2002
    • Mitsui Memorial Hospital
      Edo, Tōkyō, Japan
  • 2001
    • Dokkyo University
      Edo, Tōkyō, Japan
    • Kyorin University
      • School of Health Sciences
      Edo, Tōkyō, Japan
  • 1992–2001
    • The University of Tokyo
      • • School of Medicine
      • • Faculty and Graduate School of Agriculture and Life Sceince
      Tōkyō, Japan
    • Nutritional Laboratories International
      MSO, Montana, United States
  • 2000
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Pennsylvania State University
      • Department of Animal Science
      University Park, Maryland, United States
  • 1990–1991
    • Roche Institute of Molecular Biology
      Nutley, New Jersey, United States
  • 1985
    • Osaka Medical College
      Takatuki, Ōsaka, Japan