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  • R‐flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice
    1. Katja Schmitz1,
    2. Natasja de Bruin2,,
    3. Philipp Bishay1,,
    4. Julia Männich1,
    5. Annett Häussler1,
    6. Christine Altmann1,
    7. Nerea Ferreirós1,
    8. Jörn Lötsch1,2,
    9. Alfred Ultsch3,
    10. Michael J Parnham2,
    11. Gerd Geisslinger1,2 and
    12. Irmgard Tegeder*,1,2
    1. 1Institute of Clinical Pharmacology Goethe‐University Hospital, Frankfurt am Main, Germany
    2. 2Fraunhofer Institute of Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (IME‐TMP), Frankfurt am Main, Germany
    3. 3DataBionics Research Group, University of Marburg, Marburg, Germany
    1. *Corresponding author. Tel: +49 69 6301 7621; Fax: +49 69 6301 7636; E‐mail: tegeder{at}em.uni-frankfurt.de
    1. These authors contributed equally to this work

    R‐flurbiprofen treatment of experimental autoimmune encephalomyelitis in mouse models of multiple sclerosis prevented and attenuated relapsing‐remitting and primary progressive EAE, suggesting that R‐flurbiprofen could restore motor functions and alleviate MS‐associated chronic pain in humans.

    Synopsis

    R‐flurbiprofen treatment of experimental autoimmune encephalomyelitis in mouse models of multiple sclerosis prevented and attenuated relapsing‐remitting and primary progressive EAE, suggesting that R‐flurbiprofen could restore motor functions and alleviate MS‐associated chronic pain in humans.

    • R‐flurbiprofen favored regulatory and inflammation‐resolving immune cells and reduced myelin and axon destruction

    • R‐flurbiprofen increased anti‐inflammatory endocannabinoids in the periphery and central nervous system and reduced pro‐inflammatory lipid signaling molecules

    • Effects are likely mediated through a multi‐targeted reduction of pro‐inflammatory gene transcription, anti‐oxidative neuroprotection and favoring of inflammation‐resolving lipid signaling molecules

    • endocannabinoids
    • multiple sclerosis
    • optic neuritis
    • pain
    • regulatory T cells
    • Received March 14, 2014.
    • Revision received August 28, 2014.
    • Accepted August 29, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Katja Schmitz, Natasja de Bruin, Philipp Bishay, Julia Männich, Annett Häussler, Christine Altmann, Nerea Ferreirós, Jörn Lötsch, Alfred Ultsch, Michael J Parnham, Gerd Geisslinger, Irmgard Tegeder
  • N‐WASP is required for Amphiphysin‐2/BIN1‐dependent nuclear positioning and triad organization in skeletal muscle and is involved in the pathophysiology of centronuclear myopathy
    1. Sestina Falcone*,1,28,
    2. William Roman18,
    3. Karim Hnia3,
    4. Vincent Gache1,2,
    5. Nathalie Didier18,
    6. Jeanne Lainé28,
    7. Frederic Auradé18,
    8. Isabelle Marty5,
    9. Ichizo Nishino6,
    10. Nicolas Charlet‐Berguerand3,
    11. Norma Beatriz Romero48,
    12. Giovanna Marazzi1,
    13. David Sassoon1,
    14. Jocelyn Laporte3 and
    15. Edgar R Gomes*,1,2,78
    1. 1Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France
    2. 2Institut de Myologie, Groupe Hospitalier Pitié‐Salpêtrière, Paris, France
    3. 3IGBMC‐CNRS, UMR 7104 INSERM U964, Illkirch, France
    4. 4Morphology Unit, Myology Institut Pitié Salpêtrière Hospital, Paris, France
    5. 5INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France
    6. 6National Center of Neurology and Psychiatry, Tokyo, Japan
    7. 7Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
    8. 8Sorbonne Universités UPMC ‐ INSERM UMRS 974, CNRS FRE 3617 Myology Research Center, Paris, France
    1. * Corresponding author. Tel: +33 1 40 77 96 31; E‐mail: sestinaf{at}gmail.com

      Corresponding author. Tel: +33 1 40 77 96 87; E‐mail: edgar.gomes{at}upmc.fr

    1. These authors contributed equally to this work

    Amphiphysin‐2/BIN1 is known to associate with centronuclear myopathy (CNM) and myotonic dystrophy. N‐WASP is found downstream of Amphiphysin‐2/BIN1 and aberrantly distributed in skeletal muscle of patients. Activation of N‐WASP could provide a therapeutic option for CNM.

    Synopsis

    Amphiphysin‐2/BIN1 is known to associate with centronuclear myopathy (CNM) and myotonic dystrophy. N‐WASP is found downstream of Amphiphysin‐2/BIN1 and aberrantly distributed in skeletal muscle of patients. Activation of N‐WASP could provide a therapeutic option for CNM.

    • Amphiphysin‐2/BIN1 interacts with N‐WASP in skeletal muscle.

    • Amphiphysin‐2/BIN1 and N‐WASP are required for peripheral nuclei positioning and triad formation.

    • Peripheral nuclear positioning requires microtubule/Map7/Kif5b‐dependent distribution of nuclei along the myofiber and is driven by actin and nesprins.

    • centronuclear myopathy
    • cytoskeleton
    • nuclear movement
    • triad formation
    • Received July 15, 2014.
    • Revision received August 19, 2014.
    • Accepted August 26, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Sestina Falcone, William Roman, Karim Hnia, Vincent Gache, Nathalie Didier, Jeanne Lainé, Frederic Auradé, Isabelle Marty, Ichizo Nishino, Nicolas Charlet‐Berguerand, Norma Beatriz Romero, Giovanna Marazzi, David Sassoon, Jocelyn Laporte, Edgar R Gomes
  • ZIPCO, a putative metal ion transporter, is crucial for Plasmodium liver‐stage development
    1. Tejram Sahu1,2,
    2. Bertrand Boisson1,3,
    3. Céline Lacroix1,4,
    4. Emmanuel Bischoff5,
    5. Quentin Richier1,
    6. Pauline Formaglio1,
    7. Sabine Thiberge1,
    8. Irina Dobrescu1,
    9. Robert Ménard1 and
    10. Patricia Baldacci*,1
    1. 1Institut Pasteur Unité de Biologie et Génétique du Paludisme, Paris Cedex 15, France
    2. 2Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA
    3. 3St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
    4. 4Institut de Biologie et Chimie des Protéines, Lyon Cedex 07, France
    5. 5Institut Pasteur Plateforme Puces à ADN Génopole, Paris Cedex 15, France
    1. *Corresponding author. Tel: +33 1 44 38 94 95; E‐mail: patricia.baldacci{at}pasteur.fr

    ZIPCO is a novel Plasmodium berghei ZIP family protein, which might be involved in the transport of iron and possibly zinc. Parasites lacking ZIPCO present a normal blood phase but display a major developmental block in the host liver, which can be rescued by iron and zinc supplementation.

    Synopsis

    ZIPCO is a novel Plasmodium berghei ZIP family protein, which might be involved in the transport of iron and possibly zinc. Parasites lacking ZIPCO present a normal blood phase but display a major developmental block in the host liver, which can be rescued by iron and zinc supplementation.

    • ZIPCO is a newly identified Plasmodium protein belonging to the ZRT, IRT‐like Protein (ZIP) family.

    • Plasmodium berghei parasites lacking ZIPCO have no defect during the blood phase of malaria but display a major developmental block in the host liver.

    • The growth defect is rescued by iron and zinc supplementation.

    • This is first time that a ZIP protein has been shown to be important for the Plasmodium life cycle.

    • iron
    • liver stage
    • Plasmodium
    • transporter
    • ZIP
    • Received January 16, 2014.
    • Revision received July 23, 2014.
    • Accepted July 24, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Tejram Sahu, Bertrand Boisson, Céline Lacroix, Emmanuel Bischoff, Quentin Richier, Pauline Formaglio, Sabine Thiberge, Irina Dobrescu, Robert Ménard, Patricia Baldacci
  • Tumor cell‐specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase
    1. Stefanie Peter1,
    2. Jennyfer Bultinck2,
    3. Kevin Myant3,
    4. Laura A Jaenicke1,
    5. Susanne Walz1,
    6. Judith Müller4,
    7. Michael Gmachl5,
    8. Matthias Treu5,
    9. Guido Boehmelt5,
    10. Carsten P Ade1,
    11. Werner Schmitz1,
    12. Armin Wiegering6,
    13. Christoph Otto6,
    14. Nikita Popov1,7,
    15. Owen Sansom3,
    16. Norbert Kraut5 and
    17. Martin Eilers*,1,7
    1. 1Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany
    2. 2Cytokine Receptor Lab, Department of Biochemistry, Ghent University, Ghent, Belgium
    3. 3CRUK Beatson Institute, Glasgow, UK
    4. 4Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
    5. 5Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
    6. 6Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital Würzburg, Würzburg, Germany
    7. 7Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
    1. *Corresponding author. Tel: +49 931 318 4111; E‐mail: martin.eilers{at}biozentrum.uni-wuerzburg.de

    New highly specific inhibitors of HUWE1 have been identified that can inhibit MYC function in a tumour cell‐specific manner, by preventing the HUWE1‐mediated block of a repressive complex of MYC with MIZ1 on MYC‐activated target genes.

    Synopsis

    New highly specific inhibitors of HUWE1 have been identified that can inhibit MYC function in a tumour cell‐specific manner, by preventing the HUWE1‐mediated block of a repressive complex of MYC with MIZ1 on MYC‐activated target genes.

    • HUWE1 is essential for growth of colorectal tumors in vivo and is globally required for expression of MYC target genes.

    • Small‐molecule inhibitors of HUWE1 inhibit expression of MYC target genes in a tumor‐cell specific manner.

    • Inhibition of HUWE1 stabilizes MIZ1 and induces global accumulation of MIZ1 on MYC‐bound target genes.

    • Accumulation of MIZ1 is required for repression of ribosomal protein genes upon HUWE1 inhibition.

    • colorectal cancer
    • HUWE1
    • MIZ1
    • MYC
    • ubiquitination
    • Received February 1, 2014.
    • Revision received July 30, 2014.
    • Accepted August 26, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Stefanie Peter, Jennyfer Bultinck, Kevin Myant, Laura A Jaenicke, Susanne Walz, Judith Müller, Michael Gmachl, Matthias Treu, Guido Boehmelt, Carsten P Ade, Werner Schmitz, Armin Wiegering, Christoph Otto, Nikita Popov, Owen Sansom, Norbert Kraut, Martin Eilers
  • MicroRNA mimicry blocks pulmonary fibrosis
    1. Rusty L Montgomery1,,
    2. Guoying Yu2,,
    3. Paul A Latimer1,
    4. Christianna Stack1,
    5. Kathryn Robinson1,
    6. Christina M Dalby1,
    7. Naftali Kaminski*,2 and
    8. Eva van Rooij*,1,3
    1. 1miRagen Therapeutics, Inc, Boulder, CO, USA
    2. 2Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA
    3. 3Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
    1. * Corresponding author. Tel: +1 203 7853508; E‐mail: naftali.kaminski{at}yale.edu

      Corresponding author. Tel: +31 30 2121800; E‐mail: e.vanrooij{at}hubrecht.eu

    1. Both authors contributed equally

    Therapeutic delivery of miR‐29 mimics during bleomycin‐induced pulmonary fibrosis in mice restores endogenous miR‐29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis.

    Synopsis

    Therapeutic delivery of miR‐29 mimics during bleomycin‐induced pulmonary fibrosis in mice restores endogenous miR‐29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis.

    • MicroRNA mimics can be used to increase levels of miRNAs in vivo in a time and dose‐dependent manner.

    • miR‐29 mimic does not affect target gene expression under basal conditions.

    • miR‐29 mimic can block and reverse aspects of bleomycin‐induced pulmonary fibrosis.

    • microRNA
    • mimic
    • miR‐29
    • pulmonary fibrosis
    • therapeutics
    • Received October 25, 2013.
    • Revision received August 13, 2014.
    • Accepted August 20, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Rusty L Montgomery, Guoying Yu, Paul A Latimer, Christianna Stack, Kathryn Robinson, Christina M Dalby, Naftali Kaminski, Eva van Rooij
  • TLR8 signaling enhances tumor immunity by preventing tumor‐induced T‐cell senescence
    1. Jian Ye1,
    2. Chunling Ma1,2,
    3. Eddy C Hsueh3,
    4. Jie Dou1,
    5. Wei Mo1,
    6. Shuai Liu1,
    7. Bing Han1,
    8. Yi Huang1,
    9. Yanping Zhang3,
    10. Mark A Varvares4,
    11. Daniel F Hoft1 and
    12. Guangyong Peng*,1
    1. 1Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA
    2. 2Department of Laboratory Medicine, Women & Children's Health Care Hospital of Linyi, Linyi, China
    3. 3Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
    4. 4Department of Otolaryngology‐Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
    1. *Corresponding author. Tel: +1 314 977 9064; Fax: +1 314 771 3816; E‐mail: gpeng{at}slu.edu

    This study identifies the induction of T‐cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.

    Synopsis

    This study identifies the induction of T‐cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.

    • Tumor cells convert naïve/effector T cells into senescent T cells with potent suppressive function.

    • Tumor‐derived cAMP is responsible for the tumor cell‐induced T‐cell senescence.

    • cAMP is directly transferred from tumor cells to targeted T cells through gap junctions inducing PKA‐LCK inhibitory signaling and senescence in T cells.

    • TLR8 signaling reverses tumor‐induced T‐cell senescence via down‐regulation of cAMP in tumor cells.

    • Activation of TLR8 signaling in tumor cells prevents tumor‐specific T‐cell senescence and enhances anti‐tumor immunity.

    • immunosenescence
    • regulatory T cells
    • toll‐like receptor
    • tumor immunity
    • tumor microenvironment
    • Received January 29, 2014.
    • Revision received August 12, 2014.
    • Accepted August 13, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Jian Ye, Chunling Ma, Eddy C Hsueh, Jie Dou, Wei Mo, Shuai Liu, Bing Han, Yi Huang, Yanping Zhang, Mark A Varvares, Daniel F Hoft, Guangyong Peng
  • Specific roles for dendritic cell subsets during initiation and progression of psoriasis
    1. Elisabeth Glitzner1,
    2. Ana Korosec1,
    3. Patrick M Brunner2,
    4. Barbara Drobits1,
    5. Nicole Amberg1,
    6. Helia B Schonthaler3,
    7. Tamara Kopp2,
    8. Erwin F Wagner3,
    9. Georg Stingl2,
    10. Martin Holcmann1 and
    11. Maria Sibilia*,1
    1. 1Department of Medicine I, Comprehensive Cancer Center Institute of Cancer Research Medical University of Vienna, Vienna, Austria
    2. 2Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria
    3. 3BBVA Foundation–CNIO Cancer Cell Biology Programme Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    1. *Corresponding author. Tel: +43 140160 57502; Fax: +43 140160 957502; E‐mail: maria.sibilia{at}meduniwien.ac.at

    Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti‐inflammatory IL‐10 and pro‐inflammatory IL‐23 axis.

    Synopsis

    Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti‐inflammatory IL‐10 and pro‐inflammatory IL‐23 axis.

    • Langerhans cells (LCs) are severely reduced and plasmacytoid DCs (pDCs) are increased in human psoriasis as well as in mouse models of psoriasis

    • Depletion of pDCs in mice prior to psoriasis induction results in disease amelioration whereas depletion during active disease has no effect

    • Depletion of LCs during active psoriasis results in disease aggravation whereas depletion before disease initiation has no effect

    • The anti‐inflammatory role of LCs is mediated by direct release of the immunosuppressive cytokine IL‐10 and by preventing excessive IL‐23 accumulation in the skin

    • pDC depletion results in reduced IL‐23 levels and therapeutic inhibition of IL‐23 receptor ameliorates disease symptoms

    • AP‐1
    • IL‐23
    • Langerhans cells
    • plasmacytoid dendritic cells
    • psoriasis
    • Received March 27, 2014.
    • Revision received August 12, 2014.
    • Accepted August 15, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Elisabeth Glitzner, Ana Korosec, Patrick M Brunner, Barbara Drobits, Nicole Amberg, Helia B Schonthaler, Tamara Kopp, Erwin F Wagner, Georg Stingl, Martin Holcmann, Maria Sibilia