9 results on '"Hesham M. Ismail"'
Search Results
2. OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease
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Alessandro Luciani, Marijana Samardzija, Leopoldo Staiano, Alkaly Gassama, Marine Berquez, Hesham M. Ismail, Christian Grimm, Robert L. Nussbaum, Maria Antonietta De Matteis, Olivier Devuyst, Beatrice Paola Festa, Irmgard Amrein, Olivier M. Dorchies, David P. Wolfer, Leonardo Scapozza, Festa, Beatrice Paola, Berquez, Marine, Gassama, Alkaly, Amrein, Irmgard, Ismail, Hesham M, Samardzija, Marijana, Staiano, Leopoldo, Luciani, Alessandro, Grimm, Christian, Nussbaum, Robert L, De Matteis, Maria Antonietta, Dorchies, Olivier M, Scapozza, Leonardo, Wolfer, David Paul, Devuyst, Olivier, and University of Zurich
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Phosphatidylinositol 4,5-Diphosphate ,0301 basic medicine ,10017 Institute of Anatomy ,Endocytic cycle ,030232 urology & nephrology ,Dent Disease ,Kidney ,10052 Institute of Physiology ,Kidney Tubules, Proximal ,Mice ,0302 clinical medicine ,Genetics(clinical) ,10064 Neuroscience Center Zurich ,Cells, Cultured ,Genetics (clinical) ,Mice, Knockout ,Dent's disease ,General Medicine ,LRP2 ,Endocytosis ,Low Density Lipoprotein Receptor-Related Protein-2 ,medicine.anatomical_structure ,10076 Center for Integrative Human Physiology ,General Article ,Locomotion ,10018 Ophthalmology Clinic ,2716 Genetics (clinical) ,Oculocerebrorenal syndrome ,610 Medicine & health ,Mice, Transgenic ,Endosomes ,Biology ,03 medical and health sciences ,1311 Genetics ,Chloride Channels ,1312 Molecular Biology ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,medicine.disease ,Actins ,Phosphoric Monoester Hydrolases ,Disease Models, Animal ,Oculocerebrorenal Syndrome ,030104 developmental biology ,Mutation ,Humanized mouse ,Cancer research ,570 Life sciences ,biology ,OCRL ,Lysosomes - Abstract
Mutations in OCRL encoding the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) disrupt phosphoinositide homeostasis along the endolysosomal pathway causing dysfunction of the cells lining the kidney proximal tubule (PT). The dysfunction can be isolated (Dent disease 2) or associated with congenital cataracts, central hypotonia and intellectual disability (Lowe syndrome). The mechanistic understanding of Dent disease 2/Lowe syndrome remains scarce due to limitations of animal models of OCRL deficiency. Here, we investigate the role of OCRL in Dent disease 2/Lowe syndrome by using OcrlY/− mice, where the lethal deletion of the paralogue Inpp5b was rescued by human INPP5B insertion, and primary culture of proximal tubule cells (mPTCs) derived from OcrlY/− kidneys. The OcrlY/− mice show muscular defects with dysfunctional locomotricity and present massive urinary losses of low-molecular-weight proteins and albumin, caused by selective impairment of receptor-mediated endocytosis in PT cells. The latter was due to accumulation of phosphatidylinositol 4,5–bisphosphate PI(4,5)P2 in endolysosomes, driving local hyper-polymerization of F-actin and impairing trafficking of the endocytic LRP2 receptor, as evidenced in OcrlY/− mPTCs. The OCRL deficiency was also associated with a disruption of the lysosomal dynamic and proteolytic activity. Partial convergence of disease-pathways and renal phenotypes observed in OcrlY/− and Clcn5Y/− mice suggest shared mechanisms in Dent diseases 1 and 2. These studies substantiate the first mouse model of Lowe syndrome and give insights into the role of OCRL in cellular trafficking of multiligand receptors. These insights open new avenues for therapeutic interventions in Lowe syndrome and Dent disease., Human Molecular Genetics, 28 (12), ISSN:0964-6906, ISSN:1460-2083
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- 2018
3. In silico and in vivo models for Qatari-specific classical homocystinuria as basis for development of novel therapies
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Gheyath K. Nasrallah, Sapna Gupta, Hesham M. Ismail, Valeria Di Giacomo, Beat Thöny, Henk J. Blom, Hatem Zayed, Warren D. Kruger, Nader Al-Dewik, Tawfeg Ben-Omran, Johannes Häberle, Nura A. Mohamed, Navaneethakrishnan Krishnamoorthy, University of Zurich, and Nasrallah, Gheyath K
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Protein Folding ,congenital, hereditary, and neonatal diseases and abnormalities ,2716 Genetics (clinical) ,In silico ,Mutant ,Mutation, Missense ,p.R336C mutation ,Cystathionine beta-Synthase ,Homocystinuria ,610 Medicine & health ,medicine.disease_cause ,Gene Expression Regulation, Enzymologic ,Article ,CBS ,Structure-Activity Relationship ,03 medical and health sciences ,Methionine ,1311 Genetics ,Protein-fragment complementation assay ,Enzyme Stability ,Genetics ,medicine ,Humans ,Missense mutation ,Computer Simulation ,Qatar ,Genetics (clinical) ,chemical chaperones ,030304 developmental biology ,0303 health sciences ,Mutation ,biology ,030305 genetics & heredity ,nutritional and metabolic diseases ,Hep G2 Cells ,medicine.disease ,Cystathionine beta synthase ,Protein Structure, Tertiary ,HEK293 Cells ,Biochemistry ,in silico ,10036 Medical Clinic ,biology.protein ,in vivo models ,Mutant Proteins ,Chemical chaperone ,Molecular Chaperones - Abstract
Homocystinuria is a rare inborn error of methionine metabolism caused by cystathionine β-synthase (CBS) deficiency. The prevalence of homocystinuria in Qatar is 1:1,800 births, mainly due to a founder Qatari missense mutation, c.1006C>T; p.R336C (p.Arg336Cys). We characterized the structure-function relationship of the p.R336C mutant protein, and investigated the effect of different chemical chaperones to restore p.R336C-CBS activity using three models: In silico, ΔCBS yeast, and CRISPR/Cas9 p.R336C knock-in HEK293T and HepG2 cell lines. Protein modeling suggested that the p.R336C induces severe conformational and structural changes, perhaps influencing CBS activity. Wildtype CBS, but not the p.R336C mutant, was able to restore the yeast growth in ΔCBS deficient yeast in a complementation assay. The p.R336C knock-in HEK293T and HepG2 cells decreased the level of CBS expression and reduce its structural stability; however, treatment of the p.R336C knock-in HEK293T cells with betaine, a chemical chaperone, restored the stability and tetrameric conformation of CBS, but not its activity. Collectively, these results indicate that the p.R336C mutation has a deleterious effect on CBS structure, stability, and activity, and using the chemical chaperones approach for treatment could be ineffective in restoring p.R336C CBS activity. This article is protected by copyright. All rights reserved. QNRF
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- 2018
4. Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy
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E. Gayi, Hesham M. Ismail, Laurent A. Decosterd, Leonardo Scapozza, M. Sierra, Jocelyn Laporte, Belinda S. Cowling, Xènia Massana Muñoz, Olivier M. Dorchies, Thomas Mercier, L. Neff, Université de Lausanne = University of Lausanne (UNIL), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lausanne University Hospital, and univOAK, Archive ouverte
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0301 basic medicine ,XLMTM ,Male ,Myotubularin ,General Physics and Astronomy ,Gene Expression ,Disease ,Dynamin II ,Mice ,Myofibrils ,Paralysis ,lcsh:Science ,skin and connective tissue diseases ,Excitation Contraction Coupling ,Class II Phosphatidylinositol 3-Kinases ,Mice, Knockout ,ddc:615 ,Multidisciplinary ,Protein Tyrosine Phosphatases, Non-Receptor ,Phenotype ,X-linked myotubular myopathy ,3. Good health ,Disease Progression ,Female ,medicine.symptom ,medicine.drug ,Myopathies, Structural, Congenital ,[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] ,Science ,Longevity ,Motor Activity ,Protective Agents ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Breast cancer ,medicine ,Animals ,Humans ,Muscle, Skeletal ,business.industry ,[SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT] ,General Chemistry ,medicine.disease ,Electric Stimulation ,DNM2 ,Disease Models, Animal ,Tamoxifen ,030104 developmental biology ,Cancer research ,lcsh:Q ,Genes, Lethal ,business - Abstract
X-linked myotubular myopathy (XLMTM, also known as XLCNM) is a severe congenital muscular disorder due to mutations in the myotubularin gene, MTM1. It is characterized by generalized hypotonia, leading to neonatal death of most patients. No specific treatment exists. Here, we show that tamoxifen, a well-known drug used against breast cancer, rescues the phenotype of Mtm1-deficient mice. Tamoxifen increases lifespan several-fold while improving overall motor function and preventing disease progression including lower limb paralysis. Tamoxifen corrects functional, histological and molecular hallmarks of XLMTM, with improved force output, myonuclei positioning, myofibrillar structure, triad number, and excitation-contraction coupling. Tamoxifen normalizes the expression level of the XLMTM disease modifiers DNM2 and PI3KC2B, likely contributing to the phenotypic rescue. Our findings demonstrate that tamoxifen is a promising candidate for clinical evaluation in XLMTM patients., X-linked myotubular myopathy (XLMTM) is a severe muscle disease with no effective treatment. Here, the authors show that tamoxifen, a drug used to treat breast cancer, rescues the pathology in a mouse model of the disease, at least in part by normalizing expression of the disease modifier proteins DNM2 and BIN1
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- 2018
5. Inhibition of iPLA2β and of stretch-activated channels by doxorubicin alters dystrophic muscle function
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M K Strosova, Leonardo Scapozza, Hesham M. Ismail, Remo Perozzo, Urs T. Ruegg, and Olivier M. Dorchies
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Pharmacology ,Voltage-dependent calcium channel ,Myogenesis ,Duchenne muscular dystrophy ,Aequorin ,Skeletal muscle ,Biology ,medicine.disease ,medicine.anatomical_structure ,Biochemistry ,polycyclic compounds ,medicine ,biology.protein ,medicine.symptom ,Intracellular ,Calcium signaling ,Muscle contraction - Abstract
Background and Purpose Chronic elevation in intracellular Ca2+ concentration participates in death of skeletal muscle from mdx mice, a model for Duchenne muscular dystrophy (DMD). Candidate pathways mediating this Ca2+ overload involve store-operated channels (SOCs) and stretch-activated channels (SACs), which are modulated by the Ca2+-independent form of PL A2 (iPLA2). We investigated the effect of doxorubicin (Dox), a chemotherapeutic agent reported to inhibit iPLA2 in other systems, on the activity of this enzyme and on the consequences on Ca2+ handling and muscle function in mdx mice. Experimental Approach Effects of Dox on iPLA2 activity, reactive oxygen species production and on Ca2+ influx were investigated in C2C12 and mdx myotubes. The mechanism of Dox-mediated iPLA2 inhibition was evaluated using purified 6x histidine-tagged enzyme. Aequorin technology was used to assess Ca2+ concentrations underneath the plasma membrane. Isolated muscles were exposed to fatigue protocols and eccentric contractions to evaluate the effects of Dox on muscle function. Key Results Dox at 1–30 μM inhibited iPLA2 activity in cells and in the purified enzyme. Dox also inhibited SAC- but not SOC-mediated Ca2+ influx in myotubes. Stimulated elevations of Ca2+ concentrations below the plasmalemma were also blocked. Exposure of excised muscle to Dox was not deleterious to force production and promoted recovery from eccentric contractions. Conclusions and Implications Dox showed efficacy against targets known to play a role in the pathology of DMD, namely iPLA2 and SAC. The potent SAC inhibitory effect of Dox is a novel finding that can explain partly the cardiomyopathy seen in chronic anthracycline treatment.
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- 2013
6. Repurposing the Selective Oestrogen Receptor Modulator Tamoxifen for the Treatment of Duchenne Muscular Dystrophy
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Olivier M. Dorchies, Leonardo Scapozza, E. Gayi, Hesham M. Ismail, Urs T. Ruegg, and L. Neff
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Male ,Selective Estrogen Receptor Modulators ,Duchenne muscular dystrophy ,0301 basic medicine ,Disease ,Bioinformatics ,Serm ,Mice ,03 medical and health sciences ,Breast cancer ,medicine ,Animals ,Humans ,Muscular dystrophy ,QD1-999 ,Repurposing ,business.industry ,General Medicine ,General Chemistry ,medicine.disease ,Muscular Dystrophy, Duchenne ,Tamoxifen ,Chemistry ,Drug repositioning ,030104 developmental biology ,Oestrogens ,Selective estrogen receptor modulator ,Female ,business ,medicine.drug - Abstract
Drug discovery is a long, expensive and risky process. Evaluating drugs that have already been proved safe for use in humans and testing them for a new indication greatly reduces the time and monetary costs involved in finding treatments for life-threatening conditions. Here tamoxifen, a drug that is used for the treatment of breast cancer, is investigated in a mouse model of Duchenne muscular dystrophy. Tamoxifen was efficacious in countering the symptoms of the disease without affecting the underlying genetic cause. Based on these results, tamoxifen has been tested in other forms of muscle disease with success. Drug repurposing may not only be a cost-effective manner for treating a variety of diseases, it may also help us uncover common mechanisms between conditions that were previously thought to be unrelated.
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- 2018
7. Diapocynin, a Dimer of the NADPH Oxidase Inhibitor Apocynin, Reduces ROS Production and Prevents Force Loss in Eccentrically Contracting Dystrophic Muscle
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Urs T. Ruegg, Olivier M. Dorchies, Leonardo Scapozza, and Hesham M. Ismail
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Pathology ,Heredity ,Genetic Linkage ,lcsh:Medicine ,Duchenne Muscular Dystrophy ,Biochemistry ,Antioxidants ,Dystrophin ,Mice ,chemistry.chemical_compound ,Drug Discovery ,Medicine and Health Sciences ,Muscular dystrophy ,lcsh:Science ,Musculoskeletal System ,Calcium signaling ,ddc:615 ,Multidisciplinary ,NADPH oxidase ,biology ,Myogenesis ,Neuromuscular Diseases ,3. Good health ,Cell biology ,Biphenyl compound ,Neurology ,Sex Linkage ,X-Linked Traits ,Anatomy ,medicine.symptom ,Muscle Contraction ,Research Article ,Muscle contraction ,Cell Physiology ,medicine.medical_specialty ,Drug Research and Development ,Genetics ,medicine ,Animals ,Calcium Signaling ,Muscle, Skeletal ,Clinical Genetics ,Pharmacology ,lcsh:R ,Biphenyl Compounds ,Acetophenones ,NADPH Oxidases ,Biology and Life Sciences ,Human Genetics ,Cell Biology ,medicine.disease ,Muscular Dystrophy, Duchenne ,Phospholipases A2 ,chemistry ,Diapocynin ,Apocynin ,Mice, Inbred mdx ,biology.protein ,lcsh:Q ,Reactive Oxygen Species - Abstract
Elevation of intracellular Ca2+, excessive ROS production and increased phospholipase A2 activity contribute to the pathology in dystrophin-deficient muscle. Moreover, Ca2+, ROS and phospholipase A2, in particular iPLA2, are thought to potentiate each other in positive feedback loops. NADPH oxidases (NOX) have been considered as a major source of ROS in muscle and have been reported to be overexpressed in muscles of mdx mice. We report here on our investigations regarding the effect of diapocynin, a dimer of the commonly used NOX inhibitor apocynin, on the activity of iPLA2, Ca2+ handling and ROS generation in dystrophic myotubes. We also examined the effects of diapocynin on force production and recovery ability of isolated EDL muscles exposed to eccentric contractions in vitro, a damaging procedure to which dystrophic muscle is extremely sensitive. In dystrophic myotubes, diapocynin inhibited ROS production, abolished iPLA2 activity and reduced Ca2+ influx through stretch-activated and store-operated channels, two major pathways responsible for excessive Ca2+ entry in dystrophic muscle. Diapocynin also prevented force loss induced by eccentric contractions of mdx muscle close to the value of wild-type muscle and reduced membrane damage as seen by Procion orange dye uptake. These findings support the central role played by NOX-ROS in the pathogenic cascade leading to muscular dystrophy and suggest diapocynin as an effective NOX inhibitor that might be helpful for future therapeutic approaches.
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- 2014
8. G.P.105
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E. Dahmane, Urs T. Ruegg, D. Picard, S. Tardy, Laurent A. Decosterd, J. Reutenauer-Patte, Leonardo Scapozza, Olivier M. Dorchies, and Hesham M. Ismail
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medicine.medical_specialty ,Fulvestrant ,business.industry ,Duchenne muscular dystrophy ,Estrogen receptor ,Alpha (ethology) ,medicine.disease ,Endocrinology ,stomatognathic system ,Neurology ,Selective estrogen receptor modulator ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Raloxifene ,Neurology (clinical) ,Toremifene ,skin and connective tissue diseases ,business ,hormones, hormone substitutes, and hormone antagonists ,Genetics (clinical) ,Tamoxifen ,medicine.drug - Abstract
We are investigating the effects of selective estrogen receptor modulators (SERMs) in mdx5Cv dystrophic mice (Dys), a model for Duchenne muscular dystrophy (DMD). SERMs display either pro-estrogenic or anti-estrogenic activities in a tissue-dependent manner. Tamoxifen (TAM), the most well characterised SERM, has been used for over 30 years to treat estrogen-sensitive breast cancer in both women and men and has been reported to be also well tolerated in pre-pubertal boys. In 2013, we published that oral treatment of Dys mice from 3 weeks of age for 15 months with TAM (10 mg/kg/day) improved muscle force and the structure of diaphragm and heart. TAM and its metabolites were present in nanomolar concentrations in plasma and muscles, suggesting signalling through high affinity targets, likely the estrogen receptors alpha and beta that were several-fold more abundant in dystrophic muscle than in normal ones. Next, we tested TAM in adult Dys mice in order to investigate its efficacy in the low-intensity chronic stage of the disease, which resembles most closely the DMD condition. TAM at doses as low as 0.1 mg/kg/day improved motor performance of active mice and enhanced the contractile characteristics of the triceps surae. At 3 mg/kg/day, TAM corrected most endpoints close to normal values. We are currently testing other SERMs (all at 3 mg/kg/day): the chlorinated TAM analogues clomiphene and toremifene, the 3-hydroxylated TAM derivative droloxifene, the second generation SERM unrelated to TAM raloxifene (RAL), and the pure anti-estrogen fulvestrant (Faslodex). Overall, the ranked efficacy was as follows: TAM > toremifene > clomiphene > droloxifene ≈ RAL > Faslodex. Our data as well as our current understanding of estrogenic signalling in dystrophic muscle suggests that TAM and other SERMs with pro-estrogenic activities on muscle might be beneficial for DMD and maybe also for other muscular dystrophies.
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- 2014
9. G.P.91
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Urs T. Ruegg, Leonardo Scapozza, Hesham M. Ismail, and Olivier M. Dorchies
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medicine.medical_specialty ,NADPH oxidase ,biology ,Duchenne muscular dystrophy ,Wild type ,Anatomy ,medicine.disease ,Pathogenesis ,chemistry.chemical_compound ,Endocrinology ,Neurology ,chemistry ,Diapocynin ,In vivo ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Apocynin ,medicine ,biology.protein ,Neurology (clinical) ,Genetics (clinical) ,Evans Blue - Abstract
Duchenne muscular dystrophy (DMD) is a severe X-linked muscular disease that causes premature death and for which no cure exists. We have shown previously that in vitro treatment of dystrophic myotubes and excised muscles with diapocynin, a dimer of the classically used NADPH oxidase inhibitor apocynin, ameliorated several molecular events involved in DMD pathogenesis, of which ROS production, phospholipase A2 activity, Ca 2+ influx and sarcolemmal integrity. Here, we report on the in vivo effects of diapocynin and apocynin in mdx 5Cv dystrophic mice, a model of DMD. Apocynin (50mg/kg/day) and diapocynin (10 and 100mg/kg/day) were given orally to mdx 5Cv mouse pups, first via the lactating mothers from post-natal day 14 to 28 and subsequently directly to the weaned pups till post-natal day 35±1 or 60±3. Diapocynin but not apocynin enhanced spontaneous locomotor activity, rescued voluntary wheel running capabilities, and ameliorated diaphragm structure of dystrophic mice. Diapocynin and apocynin were equally potent at increasing the resistance to fatigue of triceps surae muscles exposed to repeated isometric contractions in situ and at preserving sarcolemmal integrity as evidenced by Evans blue dye uptake. Furthermore, microarray analyses showed a tendency of the treatments to correct gene expression in dystrophic mice towards wild type controls. Although apocynin and diapocynin had beneficial effects in dystrophic mice, diapocynin was superior in improving locomotion.
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- 2014
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