VBP15, a novel anti‐inflammatory and membrane‐stabilizer, improves muscular dystrophy without side effects
Autor: | Christopher R. Heier, Edward M. Connor, Kathleen Tatem, Kanneboyina Nagaraju, Sarah Jordan, Luana Scheffer, Qing Yu, Tony Huynh, Michael E. Calhoun, Jack H. Van der Meulen, Olga Rodriguez, John M. McCall, Heather Gordish-Dressman, Erica K.M. Reeves, Sherry Dadgar, Eric P. Hoffman, Chris Albanese, Jesse M. Damsker, Arpana Sali, Brittany K. Miller, James L Quinn, Aditi Phadke, Blythe C. Dillingham, Jyoti K. Jaiswal |
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Rok vydání: | 2013 |
Předmět: |
Transcription
Genetic muscle T-Lymphocytes Duchenne muscular dystrophy Anti-Inflammatory Agents Pharmacology Muscular Dystrophies Myoblasts Mice 0302 clinical medicine Glucocorticoid receptor Protein Interaction Maps Muscular dystrophy Pregnadienediols Research Articles anti-inflammatory 0303 health sciences biology NF-kappa B 3. Good health Phenotype medicine.anatomical_structure dystrophy Prednisolone Molecular Medicine medicine.symptom Dystrophin mdx Immunosuppressive Agents Signal Transduction medicine.drug Inflammation Cell Line Necrosis 03 medical and health sciences Receptors Glucocorticoid medicine Animals 030304 developmental biology Lasers Cell Membrane Dystrophy Skeletal muscle medicine.disease Immunology Mice Inbred mdx biology.protein membrane injury 030217 neurology & neurosurgery |
Zdroj: | EMBO Molecular Medicine |
ISSN: | 1757-4684 1757-4676 |
Popis: | Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases. |
Databáze: | OpenAIRE |
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