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  • 1.
    Alkhori, Liza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Öst, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    The corepressor Atrophin specifies odorant receptor expression in Drosophila2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 3, p. 1355-1364Article in journal (Refereed)
    Abstract [en]

    In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes.-Alkhori, L., Öst, A., Alenius, M. The corepressor Atrophin specifies odorant receptor expression in Drosophila.

  • 2. Alvarado-Kristensson, M
    et al.
    Pörn-Ares, MI
    Grethe, S
    Smith, D
    Zheng, Limin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Andersson, T
    p38 Mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis.2002In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 16, p. 129-131Article in journal (Refereed)
  • 3.
    Bengtson, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry.
    Zetterberg, H
    Påhlsson, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Larson, G
    EBV transformed B cells from an individual homozygously mutated (G329A) in the FUT7 gene do not roll on E- or P-selectins2003In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 17, no 5, p. A989-A989Conference paper (Other academic)
  • 4.
    Bett, Cyrus
    et al.
    University of Calif San Diego, USA .
    Fernandez-Borges, Natalia
    Centre Cooperat Research Biosci CIC bioGUNE, Spain .
    Kurt, Timothy D.
    University of Calif San Diego, USA .
    Lucero, Melanie
    University of Calif San Diego, USA .
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Castilla, Joaquin
    Centre Cooperat Research Biosci CIC bioGUNE, Spain Basque Fdn Science IkerBasque, Spain .
    Sigurdson, Christina J.
    University of Calif San Diego, USA.
    Structure of the beta 2-alpha 2 loop and interspecies prion transmission2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 7, p. 2868-2876Article in journal (Refereed)
    Abstract [en]

    Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The beta 2-alpha 2 loop region of endogenous prion protein, PrPC, has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar beta 2-alpha 2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the beta 2-alpha 2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered beta 2-alpha 2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrPC from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP.

  • 5.
    Gustavsson, Johanna
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Parpal, Santiago
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Margareta
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ramsing, Cecilia
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Thorn, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Borg, Marie
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindroth, Margaretha
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Holmgren Peterson, Kajsa
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Localization of the insulin receptor in caveolae of adipocyte plasma membrane1999In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 13, no 14, p. 1961-1971Article in journal (Refereed)
    Abstract [en]

    The insulin receptor is a transmembrane protein of the plasma membrane, where it recognizes extracellular insulin and transmits signals into the cellular signaling network. We report that insulin receptors are localized and signal in caveolae microdomains of adipocyte plasma membrane. Immunogold electron microscopy and immunofluorescence microscopy show that insulin receptors are restricted to caveolae and are colocalized with caveolin over the plasma membrane. Insulin receptor was enriched in a caveolae-enriched fraction of plasma membrane. By extraction with β-cyclodextrin or destruction with cholesterol oxidase, cholesterol reduction attenuated insulin receptor signaling to protein phosphorylation or glucose transport. Insulin signaling was regained by spontaneous recovery or by exogenous replenishment of cholesterol. β-Cyclodextrin treatment caused a nearly complete annihilation of caveolae invaginations as examined by electron microscopy. This suggests that the receptor is dependent on the caveolae environment for signaling. Insulin stimulation of cells prior to isolation of caveolae or insulin stimulation of the isolated caveolae fraction increased tyrosine phosphorylation of the insulin receptor in caveolae, demonstrating that insulin receptors in caveolae are functional. Our results indicate that insulin receptors are localized to caveolae in the plasma membrane of adipocytes, are signaling in caveolae, and are dependent on caveolae for signaling.

  • 6. Hedlund, M
    et al.
    Bengtson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry.
    Påhlsson, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Leffler, H
    Galectin mediated tethering and arrest of neutrophils under shear flow conditions2003In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 17, no 5, p. A990-A990Conference paper (Other academic)
  • 7.
    Järlestedt, Katarina
    et al.
    Perinatal Center, University of Gothenburg, Gothenburg, Sweden.
    Rousset, Catherine I
    Centre for the Developing Brain, King's College, London, UK.
    Ståhlberg, Anders
    Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Sourkova, Hana
    Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Atkins, Alison Lynn
    Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Thornton, Claire
    Centre for the Developing Brain, King's College, London, UK.
    Barnum, Scott R
    Department of Microbiology, University of Alabama, Birmingham, Alabama, USA.
    Wetsel, Rick A
    Research Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas–Houston, Houston, Texas, USA.
    Dragunow, Mike
    Department of Pharmacology and The National Research Centre for Growth and Development, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand .
    Pekny, Milos
    Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Mallard, Carina
    Perinatal Center, University of Gothenburg, Gothenburg, Sweden.
    Hagberg, Henrik
    Perinatal Center, Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Centre for the Developing Brain, King's College, London, UK.
    Pekna, Marcela
    Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxic-ischemic brain injury.2013In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 9, p. 3797-3804Article in journal (Refereed)
    Abstract [en]

    Complement is an essential component of inflammation that plays a role in ischemic brain injury. Recent reports demonstrate novel functions of complement in normal and diseased CNS, such as regulation of neurogenesis and synapse elimination. Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy. HI injury was induced at postnatal day 9 (P9), and loss of hippocampal tissue was determined on P31. We compared WT mice with transgenic mice expressing C3a under the control of glial fibrillary acidic protein promoter, which express biologically active C3a only in CNS and without the requirement of a priori complement activation. Further, we injected C3a peptide into the lateral cerebral ventricle of mice lacking the C3a receptor (C3aR) and WT mice and assessed HI-induced memory impairment 41 d later. We found that HI-induced tissue loss in C3a overexpressing mice was reduced by 50% compared with WT mice. C3a peptide injected 1 h after HI protected WT but not C3aR-deficient mice against HI-induced memory impairment. Thus, C3a acting through its canonical receptor ameliorates behavioral deficits after HI injury, and C3aR is a novel therapeutic target for the treatment of neonatal HI encephalopathy.

  • 8.
    Karlsson, Margareta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Thorn, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Parpal, Santiago
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Gustavsson, Johanna
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Insulin induces translocation of glucose transporter GLUT4 to plasma membrane caveolae in adipocytes2002In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 16, no 2, p. 249-251Article in journal (Refereed)
    Abstract [en]

    Insulin-stimulated glucose uptake in muscle and adipose tissue is the result of translocation of insulin-regulated glucose transporters (GLUT4) from intracellular vesicles to the plasma membrane. Here we report that GLUT4 in the plasma membrane of 3T3-L1 adipocytes were located predominantly in caveolae invaginations: by immunogold electron microscopy of plasma membranes, 88% of GLUT4 were localized to caveolae structures and this distribution within the plasma membrane was not affected by insulin. By immunofluorescence microscopy, a major part of GLUT 4 was colocalized with caveolin. The total amount of GLUT4 in the plasma membrane increased 2.2-fold in response to insulin as determined by immunogold electron or immunofluorescence microscopy. GLUT4 were enriched in caveolae fractions isolated without detergents from plasma membranes of rat adipocytes. In these fractions, GLUT4 were largely confined to caveolin-containing membranes of the caveolae preparation isolated from insulin-stimulated cells, determined by electron microscopy. Insulin increased the amount of GLUT4 2.7-fold in this caveolae fraction. Caveolae were purified further by immunoisolation with antibodies against caveolin. The amount of GLUT4 increased to the same extent in the immunopurified caveolae as in the cruder caveolae fractions from insulin-stimulated cells. We conclude that insulin induces translocation of GLUT4 to caveolae.

  • 9.
    Kumita, Janet R
    et al.
    University of Cambridge.
    Helmfors, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Williams, Jocy
    University of Cambridge.
    Luheshi, Leila M
    University of Cambridge.
    Menzer, Linda
    University of Liège.
    Dumoulin, Mireille
    University of Liège.
    Lomas, David A
    Cambridge Institute for Medical Research.
    Crowther, Damian C
    Cambridge Institute for Medical Research.
    Dobson, Christopher M
    University of Cambridge.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 1, p. 192-202Article in journal (Refereed)
    Abstract [en]

    We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic variants F57I and D67H were expressed in Drosophila melanogaster using the UAS-gal4 system and both the ubiquitous and retinal expression drivers Act5C-gal4 and gmr-gal4. The nontransgenic w(1118) Drosophila line was used as a control throughout. We utilized ELISA experiments to probe lysozyme protein levels, scanning electron microscopy for eye phenotype classification, and immunohistochemistry to detect the unfolded protein response (UPR) activation. We observed that expressing the destabilized F57I and D67H lysozymes triggers UPR activation, resulting in degradation of these variants, whereas the WT lysozyme is secreted into the fly hemolymph. Indeed, the level of WT was up to 17 times more abundant than the variant proteins. In addition, the F57I variant gave rise to a significant disruption of the eye development, and this correlated to pronounced UPR activation. These results support the concept that the onset of familial amyloid disease is linked to an inability of the UPR to degrade completely the amyloidogenic lysozymes prior to secretion, resulting in secretion of these destabilized variants, thereby leading to deposition and associated organ damage.-Kumita, J. R., Helmfors, L., Williams, J., Luheshi, L. M., Menzer, L., Dumoulin, M., Lomas, D. A., Crowther, D. C., Dobson, C. M., Brorsson, A.-C. Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster.

  • 10.
    Kågedal, Katarina
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Johansson, Uno
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    The lysosomal protease cathepsin D mediates apoptosis induced by oxidative stress2001In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 15, no 7, p. 1592-1594Article in journal (Refereed)
    Abstract [en]

    No abstract available.

  • 11.
    Lemberger, T.
    et al.
    German Cancer Research Center, Heidelberg, Germany, European Molecular Biology Organization, 69117 Heidelberg, Germany.
    Parkitna, J.R.
    German Cancer Research Center, Heidelberg, Germany.
    Chai, M.
    German Cancer Research Center, Heidelberg, Germany.
    Schutz, G.
    Schütz, G., German Cancer Research Center, Heidelberg, Germany, German Cancer Research Center, 69120 Heidelberg, Germany.
    Engblom, David
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    CREB has a context-dependent role in activity-regulated transcription and maintains neuronal cholesterol homeostasis2008In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 22, no 8, p. 2872-2879Article in journal (Refereed)
    Abstract [en]

    Induction of specific gene expression patterns in response to activity confers functional plasticity to neurons. A principal role in the regulation of these processes has been ascribed to the cAMP responsive element binding protein (CREB). Using genomewide expression profiling in mice lacking CREB in the forebrain, accompanied by deletion of the cAMP responsive element modulator gene (CREM), we here show that the role of these proteins in activity-induced gene expression is surprisingly selective and highly context dependent. Thus, only a very restricted subset of activity-induced genes (i.e., Gadd45b or Nr4a2) requires these proteins for their induction in the hippocampus after kainic acid administration, while they are required for most of the cocaine-induced expression changes in the striatum. Interestingly, in the absence of CREB, CREM is able to rescue activity-regulated transcription, which strengthens the notion of overlapping functions of the two proteins. In addition, we show that cholesterol metabolism is dysregulated in the brains of mutant mice, as reflected coordinated expression changes in genes involved in cholesterol synthesis and neuronal accumulation of cholesterol. These findings provide novel insights into the role of CREB and CREM in stimulus-dependent transcription and neuronal homeostasis. © FASEB.

  • 12.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Östblom, Mattias
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Xu, Lihua
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Hellsten, A.
    Leanderson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Liedberg, Bo
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Eaton, J.W.
    James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Cytocidal effects of atheromatous plaque components: The death zone revisited2006In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 20, no 13, p. 2281-2290Article in journal (Refereed)
    Abstract [en]

    Objective: Earlier we suggested that atheroma lesions constitute a "death zone" containing toxic materials that may cause dysfunction and demise of invading macrophages to prevent the removal of plaque materials. Here we have assessed the cytotoxic effects of nonfractionated gruel and insoluble (ceroid-like) material derived from advanced human atheroma. Methods and Results: The insoluble material within advanced atherosclerotic plaque was isolated following protease K digestion and extensive extraction with aqueous and organic solvents. FTIR, Raman, and atomic absorption spectroscopy suggested that, despite its fluorescent nature, this material closely resembled hydroxyapatite and dentin, but also contained a significant amount of iron and calcium. When added to J774 cells and human macrophages in culture, this insoluble substance was phagocytosed, and progressive cell death followed. However, an even more cytotoxic activity was found in the atheromatous "gruel" that contains abundant carbonyls/aldehydes. Cell death caused by both crude gruel and ceroid could be blocked by preincubating cells with the lipophilic iron chelator salicylaldehyde isonicotinoyl hydrazone, apoferritin, BAPTA/AM, or sodium borohydride, indicating that cellular iron, calcium, and reactive aldehyde(s) are responsible for the observed cytotoxicity. Conclusions: Toxic materials within atheromatous lesions include both ceroid and even more cytotoxic lipidaceous materials. The cytotoxic effects of these plaque components may help explain the persistence of atherosclerotic lesions. © FASEB.

  • 13.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Östblom, Mattias
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Xu, Lihua
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Hellsten, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery.
    Leanderson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Liedberg, Bo
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Eaton, John Wallace
    USA .
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Cytocidal effects of atheromatous plaque components: the death zone revisited.2006In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 20, p. 2281-2290Article in journal (Refereed)
    Abstract [en]

       

  • 14.
    Mirrasekhian, Elahe
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Johan L. Å.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Shionoya, Kiseko
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgren, Anders
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Zygmunt, Peter M.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, S-221 85 Lund, Sweden.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Högestätt, Edward D.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1–mediated hypothermia and is associated with prostaglandin inhibition in the brain2018In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860Article in journal (Refereed)
    Abstract [en]

    The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol?s propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E2 in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol?s antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E2, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.?Mirrasekhian, E., Nilsson, J. L. Å., Shionoya, K., Blomgren, A., Zygmunt, P. M., Engblom, D., Högestätt, E. D., Blomqvist, A. The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1?mediated hypothermia and is associated with prostaglandin inhibition in the brain.

  • 15.
    Morland, Cecilie
    et al.
    Department of Anatomy and Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Nordengen, Kaja
    Department of Anatomy and Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Larsson, Max
    Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Prolo, Laura M
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Farzampour, Zoya
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Reimer, Richard J
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Gundersen, Vidar
    Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Rikshospitalet Oslo, Oslo, Norway.
    Vesicular uptake and exocytosis of L-aspartate is independent of sialin.2013In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 3, p. 1264-1274Article in journal (Refereed)
    Abstract [en]

    The mechanism of release and the role of l-aspartate as a central neurotransmitter are controversial. A vesicular release mechanism for l-aspartate has been difficult to prove, as no vesicular l-aspartate transporter was identified until it was found that sialin could transport l-aspartate and l-glutamate when reconstituted into liposomes. We sought to clarify the release mechanism of l-aspartate and the role of sialin in this process by combining l-aspartate uptake studies in isolated synaptic vesicles with immunocyotchemical investigations of hippocampal slices. We found that radiolabeled l-aspartate was taken up into synaptic vesicles. The vesicular l-aspartate uptake, relative to the l-glutamate uptake, was twice as high in the hippocampus as in the whole brain, the striatum, and the entorhinal and frontal cortices and was not inhibited by l-glutamate. We further show that sialin is not essential for exocytosis of l-aspartate, as there was no difference in ATP-dependent l-aspartate uptake in synaptic vesicles from sialin-knockout and wild-type mice. In addition, expression of sialin in PC12 cells did not result in significant vesicle uptake of l-aspartate, and depolarization-induced depletion of l-aspartate from hippocampal nerve terminals was similar in hippocampal slices from sialin-knockout and wild-type mice. Further, there was no evidence for nonvesicular release of l-aspartate via volume-regulated anion channels or plasma membrane excitatory amino acid transporters. This suggests that l-aspartate is exocytotically released from nerve terminals after vesicular accumulation by a transporter other than sialin.

  • 16.
    Mrosek, Michael
    et al.
    Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland.
    Labeit, Dietmar
    Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany.
    Witt, Stephanie
    Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany.
    Heerklotz, Heiko
    Chemical Biophysics, Biozentrum, University of Basel, Basel, Switzerland.
    von Castelmur, Eleonore
    Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland.
    Labeit, Siegfried
    Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, Germany.
    Mayans, Olga
    Division of Structural Biology, Biozentrum, University of Basel, Basel, Switzerland.
    Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin.2007In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 21, no 7, p. 1383-1392Article in journal (Refereed)
    Abstract [en]

    Titin forms an intrasarcomeric filament system in vertebrate striated muscle, which has elastic and signaling properties and is thereby central to mechanotransduction. Near its C-terminus and directly preceding a kinase domain, titin contains a conserved pattern of Ig and FnIII modules (Ig(A168)-Ig(A169)-FnIII(A170), hereby A168-A170) that recruits the E3 ubiquitin-ligase MuRF-1 to the filament. This interaction is thought to regulate myofibril turnover and the trophic state of muscle. We have elucidated the crystal structure of A168-A170, characterized MuRF-1 variants by circular dichroism (CD) and SEC-MALS, and studied the interaction of both components by isothermal calorimetry, SPOTS blots, and pull-down assays. This has led to the identification of the molecular determinants of the binding. A168-A170 shows an extended, rigid architecture, which is characterized by a shallow surface groove that spans its full length and a distinct loop protrusion in its middle point. In MuRF-1, a C-terminal helical domain is sufficient to bind A168-A170 with high affinity. This helical region predictably docks into the surface groove of A168-A170. Furthermore, pull-down assays demonstrate that the loop protrusion in A168-A170 is a key mediator of MuRF-1 recognition. Our findings indicate that this region of titin could serve as a target to attempt therapeutic inhibition of MuRF-1-mediated muscle turnover, where binding of small molecules to its distinctive structural features could block MuRF-1 access.

  • 17.
    Neuzil, J.
    et al.
    Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany, Institute for Prevention of Cardiovascular Diseases, Pettenkoferstrasse 9, 80336 Munich, Germany.
    Weber, T.
    Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany.
    Schroder, A.
    Schröder, A., Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany.
    Lu, M.
    Medical Center North, Vanderbilt University, Nashville, TN, United States.
    Ostermann, G.
    Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany.
    Gellert, N.
    Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany.
    Mayne, G.C.
    Flinders University of South Australia, Adelaide, SA, Australia.
    Olejnicka, Beata
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Negre-Salvayre, A.
    Nègre-Salvayre, A., Biochemistry Department, INSERM, Toulouse, France.
    Sticha, M.
    Stícha, M., Faculty of Science, Charles University, Prague, Czech Republic.
    Coffey, R.J.
    Medical Center North, Vanderbilt University, Nashville, TN, United States.
    Weber, C.
    Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany, Institute for Prevention of Cardiovascular Diseases, Pettenkoferstrasse 9, 80336 Munich, Germany.
    Induction of cancer cell apoptosis by a-tocopheryl succinate: Molecular pathways and structural requirements2001In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 15, no 2, p. 403-415Article in journal (Refereed)
    Abstract [en]

    The vitamin E analog a-tocopheryl succinate (a-TOS) can induce apoptosis. We show that the proapoptotic activity of a-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented a-TOS-triggered apoptosis. More selective effectors indicated that a-TOS reduced PKCa isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCa inhibition in a-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCa overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of a-TOS-induced proapoptotic signals. Structural analogs revealed that a-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, a-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.

  • 18. Rattan, Sunil
    et al.
    Ghavami, Saeid
    Cunnington, Ryan H.
    Davies, Jared L.
    Bathe, Krista L.
    Yeganeh, Behzad
    Arora, Rakesh
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Freed, Darren H.
    Halayko, Andrew J.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada; Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada .
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Pierce, Grant N.
    Dixon, Ian M. C.
    Transfat-mediated apoptosis is regulated by autophagy in primary cardiac myofibroblasts2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Article in journal (Refereed)
  • 19.
    Rodriguez Parkitna, J
    et al.
    German Cancer Research Center, Heidelberg, Germany.
    Bilbao, A
    Central Institute of Mental Health,.
    Rieker, C
    German Cancer Research Center, Heidelberg, Germany.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Piechota, M
    Institute of Pharmacology of the Polish Academy of Sciences, Cracow, Poland.
    Nordheim, A
    Tübingen University, Tübingen, Germany.
    Spanagel, R
    Central Institute of Mental Health,.
    Schütz, G
    German Cancer Research Center, Heidelberg, Germany.
    Loss of the serum response factor in the dopaminesystem leads to hyperactivity2010In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 24, p. 2427-2435Article in journal (Refereed)
    Abstract [en]

    The serum response factor (SRF) is a key regulator of neural development and cellular plasticity, which enables it to act as a regulator of long-term adaptations in neurons. Here we performed a comprehensive analysis of SRF function in the murine dopamine system. We found that loss of SRF in dopaminoceptive, but not dopaminergic, neurons is responsible for the development of a hyperactivity syndrome, characterized by reduced body weight into adulthood, enhanced motor activity, and deficits in habituation processes. Most important, the hyperactivity also develops when the ablation of SRF is induced in adult animals. On the molecular level, the loss of SRF in dopaminoceptive cells is associated with altered expression of neuronal plasticity-related genes, in particular transcripts involved in calcium ion binding, formation of the cytoskeleton, and transcripts encoding neuropeptide precursors. Furthermore, abrogation of SRF causes specific deficits in activity-dependent transcription, especially a complete lack of psychostimulant-induced expression of the Egr   genes. We inferred that alterations in SRFdependent  gene expression underlie the observed hyperactive behavior. Thus, SRF depletion in dopaminoceptive neurons might trigger molecular mechanisms responsible for development of psychopathological conditions involving hyperactivity.

  • 20.
    Ruud, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Björk, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Tang, Yan-juan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Stroehle, Peter
    University of Cologne, Germany Max Planck Institute Neurol Research, Germany .
    Caesar, Robert
    University of Gothenburg, Sweden .
    Schwaninger, Markus
    Medical University of Lubeck, Germany .
    Wunderlich, Thomas
    University of Cologne, Germany Max Planck Institute Neurol Research, Germany .
    Backhed, Fredrik
    University of Gothenburg, Sweden .
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells2013In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, p. 1973-1980Article in journal (Refereed)
    Abstract [en]

    Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

  • 21.
    Stroh, C.
    et al.
    University of Münster, Germany and University of Düsseldorf, Germany.
    Cassens, U.
    University of Münster, Germany.
    Samraj, A. K.
    University of Münster, Germany and University of Düsseldorf, Germany .
    Sibrowski, W.
    University of Muenster, Germany.
    Schulze-Osthoff, Klaus
    University of Münster, Germany and University of Düsseldorf, Germany .
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, Germany.
    The role of caspases in cryoinjury: caspase inhibition strongly improves the recovery of cryopreserved hematopoietic and other cells2002In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 16, no 10, p. 1651-+Article in journal (Refereed)
    Abstract [en]

    Cryopreserved cells and tissues are increasingly used for stem cell transplantation and tissue engineering. However, their freezing, storage, and thawing is associated with severe damage, suggesting the need for better cryopreservation methods. Here, we show that activation of caspase-3 is induced during the freeze-thaw process. Moreover, we demonstrate that prevention of caspase activation by the caspase inhibitor zVAD-fmk strongly improves the recovery and survival of several cryopreserved cell types and hematopoietic progenitor cells. A short preincubation with the caspase inhibitor after thawing also enhances the colony-forming activity of hematopoietic progenitor cells up to threefold. Furthermore, overexpression of Bcl-2, but not the blockade of the death receptor signaling, confers protection, indicating that cryoinjury-associated cell death is mediated by a Bcl-2-controlled mitochondrial pathway. Thus, our data suggest the use of zVAD-fmk as an efficient cryoprotective agent. The addition of caspase inhibitors may be an important tool for the cryopreservation of living cells and advantageous in cell transplantation, tissue engineering, and other genetic technologies.

  • 22.
    Suuronen, Erik J.
    et al.
    University of Ottawa Eye Institute, Ottawa Health Research Institute-Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Nakamura, Masatsugu
    Santen Pharmaceutical Company Ltd., Ikoma-shi, Nara, Japan.
    Watsky, Mitchell A.
    Department of Physiology, University of Tennessee Health Science Centre, Memphis, Tennessee, USA.
    Stys, Peter K.
    Ottawa Health Research Institute, Division of Neuroscience, University of Ottawa, Ottawa, Canada;.
    Muller, Linda J.
    Department of Morphology, The Netherlands Ophthalmic Research Institute, Amsterdam, The Netherlands.
    Munger, Rejean E.
    Tokyo Dental College-Ichikawa General Hospital Cornea Centre, Ichikawa, Chiba, Japan.
    Shinozaki, Naoshi
    Tokyo Dental College-Ichikawa General Hospital Cornea Centre, Ichikawa, Chiba, Japan.
    Griffith, May
    University of Ottawa Eye Institute, Ottawa Health Research Institute-Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Innervated human corneal equivalents as in vitro models for nerve-target cell interactions2003In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 17, p. 170-+Article in journal (Refereed)
    Abstract [en]

    A sensory nerve supply is crucial for optimal tissue function. However, the mechanisms for successful innervation and the signaling pathways between nerves and their target tissue are not fully understood. Engineered tissue substitutes can provide controllable environments in which to study tissue innervation. We have therefore engineered human corneal substitutes that promote nerve in-growth in a pattern similar to in vivo re-innervation. We demonstrate that these nerves (a) are morphologically equivalent to natural corneal nerves; (b) make appropriate contact with target cells; (c) can generate action potentials; (d) respond to chemical and physical stimuli; and (e) play an important role in the overall functioning of the bioengineered tissue. This model can be used for studying the more general topics of nerve ingrowth or regeneration and the interaction between nerves and their target cells and, more specifically, the role of nerves in corneal function. This model could also be used as an in vitro alternative to animals for safety and efficacy testing of chemicals and drugs.

  • 23.
    Telang, S
    et al.
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Mahoney, J
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Law, I
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Lundqvist-Gustafsson, H
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Qian, M
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Iron dependent virulence in E. coli - A strain specific phenomenon2000In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 14, no 4, p. A280-A280Conference paper (Other academic)
  • 24.
    Zhang, Fei
    et al.
    Oregon Health and Science University, Portland, USA.
    Dai, Min
    Oregon Health and Science University, Portland, USA.
    Neng, Lingling
    Oregon Health and Science University, Portland, USA.
    Zhang, Jin Hui
    Oregon Health and Science University, Portland, USA.
    Zhi, Zhongwei
    University of Washington, Seattle, USA.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Shi, Xiaorui
    Oregon Health and Science University, Portland, USA.
    Perivascular macrophage-like melanocyte responsiveness to acoustic trauma--a salient feature of strial barrier associated hearing loss2013In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 9, p. 3730-3740Article in journal (Refereed)
    Abstract [en]

    Tissue perivascular resident macrophages (PVM/Ms), a hybrid cell type with characteristics of both macrophages and melanocytes, are critical for establishing and maintaining the endocochlear potential (EP) required for hearing. The PVM/Ms modulate expression of tight- and adherens-junction proteins in the endothelial barrier of the stria vascularis (intrastrial fluid-blood barrier) through secretion of a signaling molecule, pigment epithelium growth factor (PEDF). Here, we identify a significant link between abnormalities in PVM/Ms and endothelial barrier breakdown from acoustic trauma to the mouse ear. We find that acoustic trauma causes activation of PVM/Ms and physical detachment from capillary walls. Concurrent with the detachment, we find loosened tight junctions between endothelial cells and decreased production of tight- and adherens-junction protein, resulting in leakage of serum proteins from the damaged barrier. A key factor in the intrastrial fluid-blood barrier hyperpermeability exhibited in the mice is down-regulation of PVM/M modulated PEDF production. We demonstrate that delivery of PEDF to the damaged ear ameliorates hearing loss by restoring intrastrial fluid-blood barrier integrity. PEDF up-regulates expression of tight junction-associated proteins (ZO-1 and VE-cadherin) and PVM/M stabilizing neural cell adhesion molecule (NCAM-120). These studies point to the critical role PVM/Ms play in regulating intrastrial fluid-blood barrier integrity in healthy and noise-damaged ears.

  • 25.
    Zhang, Junhang
    et al.
    Karolinska Institute.
    Cao, R
    Karolinska Institute.
    Zhang, Y
    Shandong University.
    Jia, T
    Shandong University.
    Cao, Y
    Karolinska Institute.
    Wahlberg, Eric
    Karolinska Institute.
    Differential roles of PDGFR-(alpha) and PDGFR-(beta) in angiogenesis and vessel stability2009In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, p. 153-163Article in journal (Refereed)
    Abstract [en]

    Preclinical and clinical evaluations of individual proangiogenic/arteriogenic factors for the treatment of ischemic myocardium and skeletal muscle have produced unfulfilled promises. The establishment of functional and stable arterial vascular networks may require combinations of different angiogenic and arteriogenic factors. Using in vivo angiogenesis and ischemic hind-limb animal models, we have compared the angiogenic and therapeutic activities of fibroblast growth factor 2 (FGF-2) in combinations with PDGF-AA and PDGF-AB, two members of the platelet-derived growth factor (PDGF) family, with distinct receptor binding patterns. We show that both PDGF-AA/FGF-2 and PDGF-AB/FGF-2 in combinations synergistically induce angiogenesis in the mouse cornea. FGF-2 up-regulates PDGFR- and -β expression levels in the newly formed blood vessels. Interestingly, PDGF-AB/FGF-2, but not PDGF-AA/FGF-2, is able to stabilize the newly formed vasculature by recruiting pericytes, and an anti-PDGFR-β neutralizing antibody significantly blocks PDGF-AB/FGF-2-induced vessel stability. These findings demonstrate that PDGFR-β receptor is essential for vascular stability. Similarly, PDGF-AB/FGF-2 significantly induces stable collateral growth in the rat ischemic hind limb. The high number of collaterals induced by PDGF-AB/FGF-2 leads to dramatic improvement of the paw’s skin perfusion. Immunohistochemical analysis of the treated skeletal muscles confirms that a combination of PDGF-AB and FGF-2 significantly induces arteriogenesis in the ischemic tissue. A combination of PDGF-AB and FGF-2 would be optimal proangiogenic agents for the treatment of ischemic diseases.—Zhang, J., Cao, R., Zhang, Y., Jia, T., Cao, Y., Wahlberg, E. Differential roles of PDGFR- and PDGFR-β in angiogenesis and vessel stability.

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