Dissertations / Theses on the topic 'Muscle apoptosis'
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Siu, Parco Ming-fai. "The role of apoptosis in muscle remodeling." Morgantown, W. Va. : [West Virginia University Libraries], 2005. https://etd.wvu.edu/etd/controller.jsp?moduleName=documentdata&jsp%5FetdId=4040.
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Thesis (Ph. D.)--West Virginia University, 2005.Title from document title page. Document formatted into pages; contains xiv, 445 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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Fellows, Adam Lee. "FOXO3a in vascular smooth muscle cell apoptosis." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275687.
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FOXO3a is a pro-apoptotic transcription factor which shows increased activation in vascular smooth muscle cells (VSMCs) of advanced atherosclerotic plaques, specifically within the intimal layer. Since VSMC apoptosis plays a crucial role in the pathophysiology of atherosclerosis, we investigated the mechanisms underlying FOXO3a-mediated cell death in this particular cell type. We aimed to characterise a novel VSMC system (FOXO3aA3ERTM) and use these cells to validate MMP-13 and TIMP3 as new FOXO3a target genes. Also, we sought to determine the mechanisms of FOXO3aA3ERTM-mediated VSMC apoptosis, particularly regarding MMP-13 and TIMP3, potential MMP-13 substrates in the extracellular matrix and the precise apoptotic signalling involved. Furthermore, we aimed to investigate whether VSMC-specific activation of FOXO3aA3ERTM in mouse affects vascular remodelling during injury and whether this is reliant on MMP-13. Lastly, we aimed to address if endogenous FOXO3a upregulates MMP-13 in mouse and human VSMCs. Our laboratory has created a transgenic rat VSMC line which stably expresses an inducible FOXO3a mutant allele known as FOXO3aA3ERTM and previous microarray experiments identified matrix metalloproteinase 13 (MMP-13) as a potential novel FOXO3a target gene. Initially, we described several key features of the FOXO3aA3ERTM VSMCs used throughout this thesis, and subsequently demonstrated that MMP-13 is a bona fide target whose expression is rapidly upregulated upon FOXO3a activation, leading to markedly higher levels of protein, cleavage and proteolytic capacity. This induction of MMP-13 was responsible for the vast majority of FOXO3a-mediated apoptosis which was accompanied by prominent degradation of fibronectin, a glycoprotein found in the extracellular matrix. However, we could not identify a terminal apoptotic pathway. FOXO3a also downregulated the endogenous MMP inhibitor TIMP3, the recombinant protein of which reduced both MMP-13 proteolysis and FOXO3a-mediated apoptosis. Activation of FOXO3aA3ERTM in the VSMCs of medium and large arteries in mice resulted in heightened expression of MMP-13 in the vessel wall, which contributed to enhanced neointimal formation during carotid ligation. Finally, endogenous FOXO3a activation leads to increased MMP-13 expression in human VSMCs, but not mouse. Overall, we have shown that FOXO3a promotes VSMC apoptosis through MMP-13 both in vitro and in vivo, a novel pathway that has important implications for the pathogenesis and treatment of vascular disease.
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Sattiraju, Sandhya Ramani. "Apoptosis and necrosis drive muscle fiber loss in lipin1 deficient skeletal muscle." Wright State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1598626794423032.
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Smith, Sierra Marie. "FoxO1 Induces Apoptosis in Skeletal Myotubes." University of Toledo / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1270334870.
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PESSINA, PATRIZIA. "Necdin enhances muscle reconstitution of dystrophic muscle by mesoangioblast cells." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2009. http://hdl.handle.net/10281/7594.
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Improving stem cell therapy is a major goal for the treatment of muscle diseases, where
physiological muscle regeneration is progressively exhausted. Mesoangioblasts are vessel-associated stem cells that appear to be the most promising cell type for the cell therapy for muscular dystrophies because of their significant contribution to restoration of muscle structure and function in different muscular dystrophy model. Here we report that MAGE protein Necdin enhances muscle differentiation and regeneration by mesoangioblasts. Indeed, when Necdin is constitutively overexpressed, it accelerates their differentiation and fusion in vitro and it increases their efficacy to restore dystrophic phenotype of α-sarcoglycan mutant mouse. Moreover, Necdin confers a enhanced survival ability when mesoangioblasts are exposed to cytotoxic stimuli that mimic
inflammatory dystrophic environment. Taken together, these data demonstrate the pivotal role of Necdin in muscle reconstitution from which we could take advantage to boost therapeutic applications of mesoangioblasts.
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Koutsouki, Evgenia. "The role of cadherins in vascular smooth muscle cell apoptosis." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420910.
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Harford, Terri J. "Regulation of Apoptosis by the Muscle Regulatory Transcription Factor MyoD." Cleveland State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=csu1265812933.
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Storbeck, Christopher J. "Effects of the myotonic dystrophy mutation in muscle differentiation and apoptosis." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6194.
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Myotonic dystrophy (DM) is the most common inherited neuromuscular disorder of adult life. The genetic defect for DM was identified as an unstable CTG trinucleotide repeat found in the 3' untranslated region (UTR) of a serine threonine p&barbelow;rotein k&barbelow;inase, DMPK. Normal individuals possess 5--35 CTG repeats, typical adult DM patients have repeat sizes ranging from 80 to 1000 while cDM patients have from 1000 to several thousand CTG repeats. This discovery provided a molecular basis to account for large variability of penetrance and age of onset in DM. Work in our laboratory progressed from ascertaining mRNA levels in patient tissues to testing the hypothesis that overexpression of DMPK might cause features of DM. Transgenic mice expressed the human DMPK mRNA and protein in the appropriate tissues and had many features of DM including type I fibre atrophy, central nuclei and ringed fibres. Induction of expression resulted in about three fold higher levels of CTG 99 mRNA over CTG 11 mRNA at 48 hours post induction. Levels of cell death were assayed following induction and CTG 99 cell lines showed a marked level of cell death while CTG 11 cell lines did not. The presence of CTG repeats within mRNA therefore appears to be very problematic for the cell. Furthermore, we found that patient amniocytes and myoblasts are susceptible to staurosporine induced cell death. Taken together, this data suggests that myoblasts expressing the DMPK 3' UTR are prone to cell death in an expression level and repeat length dependent manner. In addition, patient cells were found to be susceptible in much the same way. These experiments also revealed that myogenin levels in vivo were reduced in transgenic embryos compared with wild type embryos suggesting that expression of the DMPK 3' UTR in vivo inhibits accumulation of myogenin and perhaps myogenesis. In adult mice there was consistent muscle atrophy in CTG 91 but not in CTG 11 mice despite much lower expression levels of the CTG 91 transgene. Together, these results indicate that expression of the DMPK 3' UTR by itself may inhibit myogenesis in vivo and contribute to pathological features of DM-like muscle atrophy. (Abstract shortened by UMI.)
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Leskinen, Markus. "Mast cell-mediated apoptosis of smooth muscle cells and endothelial cells." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/leskinen/.
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Pistilli, Emidio E. "The extrinsic apoptotic pathway in aged skeletal muscle roles of tumor necrosis factor-[alpha] and interleukin-15 /." Morgantown, W. Va. : [West Virginia University Libraries], 2006. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=4912.
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Thesis (Ph. D.)--West Virginia University, 2006.Title from document title page. Document formatted into pages; contains x, 189 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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Slimani, Lamia. "Mécanismes impliqués dans l'atrophie et la récupération musculaire après immobilisation chez le rat. : Rôle des altérations de la matrice extracellulaire." Thesis, Clermont-Ferrand 1, 2012. http://www.theses.fr/2012CLF1MM21/document.
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Le muscle squelettique est le réservoir principal d’acides aminés libres de l’organisme. Ainsi, l’atrophie musculaire induite par l’immobilisation peut entraîner un affaiblissement et un allongement des périodes de récupération générant des coûts de santé publique élevés. Une aggravation de l’atrophie caractérise de façon surprenante le muscle tibialis anterior (TA) après le déplâtrage, retardant la récupération. Mon objectif a été de comprendre les mécanismes à l’origine de l’aggravation de l’atrophie du TA pendant les phases précoces de récupération en étudiant i) la structure et le phénotype des muscles, ii) la composition de la matrice extracellulaire (MEC), iii) la protéolyse et l’apoptose, et iv) les processus de signalisation via les intégrines. Des rats ont été soumis à une immobilisation par plâtrage pendant 8 jours d’une des deux pattes arrière, l’autre servant de témoin, et placés en récupération pendant 10 jours. L’aggravation de l’atrophie du TA apparaît dès déplâtrage, corrélée avec i) une baisse de l’aire des fibres associée à leur déformation, ii) une redistribution des isoformes des chaines lourdes de myosines, iii) une augmentation de l’apoptose localisée dans le tissu conjonctif, iv) un épaississement de l’endomysium pendant la remobilisation, v) des adaptations au niveau des processus de remodelage des collagènes, et vi) une activation prononcée et persistante du système protéolytique ubiquitine-protéasome (UPS) et de l’apoptosome. Nous montrons également une élévation des niveaux ARNm dans le TA remobilisé vii) de la ténascine-C et de Sparc dès le déplâtrage, et viii) de marqueurs de l’autophagie à partir du moment où l’atrophie se stabilise. Enfin, nous montrons également une élévation des ARNm dans le TA immobilisé ix) des facteurs myogéniques, et x) des intégrines membranaires et de leurs partenaires pendant l’immobilisation et après le déplâtrage. En conclusion, mon travail de thèse a permis de montrer que l'aggravation de l’atrophie du TA est précoce, associée à un remodelage important de la structure et de la composition de la MEC et du phénotype des fibres musculaires, et pourrait résulter de l’augmentation persistante et prononcée de la voie UPS et de l’apoptose. Ce travail suggère que des modifications au niveau des molécules matricielles pendant la remobilisation pourraient influencer la signalisation dépendante des intégrines et la régénération musculaireSkeletal muscle is the main reservoir of body amino acids. Thus, muscle atrophy induced by immobilization can lead to a weakening and to a lengthening of recovery periods, leading to elevated healthcare costs. Surprisingly, a worsening of tibialis anterior (TA) muscle atrophy prevailed after cast removal and thus delayed recovery. The aim of my Ph.D was to understand mechanisms underlying the worsening of TA atrophy during early recovery by studying i) the muscle structure and phenotype, ii) the composition of the extracellular matrix (ECM), iii) proteolysis and apoptosis, and iv) the signaling pathways via integrins. Rats were subjected to hindlimb casting for 8 days of one hindllimb, the other leg served as control, and then were allowed to recover for 10 days. The worsening of TA atrophy appeared immediately after cast removal and correlated with i) a decrease in fiber crosssection area associated to fiber deformation, ii) a redistribution of myosin heavy chain isoforms, iii) an increase in apoptosis localized in the connective tissue, iv) a thickening of the endomysium during remobilization, v) some adaptations in collagen remodeling processes, and vi) a pronounced and sustained activation of the ubiquitin-proteasome proteolytic system (UPS) and of the apoptosome. We also showed an increase in the remobilized TA of mRNA levels vii) of tenascin-C and Sparc immediately after cast removal, and viii) of some autophagy markers, when atrophy stabilized. Finally, we showed an elevation of mRNA levels encoding ix) myogenic factors, and x) transmembrane integrins and their partners during TA immobilization and after cast removal. In conclusion, my Ph.D project showed that the worsening of the TA atrophy occurred early after cast removal, was associated with a significant remodeling of the structure and composition of the ECM and of the phenotype of muscle fibers, and may result from pronounced and sustained increase in the UPS and apoptosis. This work suggests that changes in the matricellular matrix molecules during remobilization could influence integrin-dependent signaling and muscle regeneration
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Maltais, Jean-Sébastien. "RAGE comme nouvelle cible thérapeutique prévenant le stress du réticulum endoplasmique et l’apoptose des cellules du muscle lisse vasculaire associés avec le diabète." Thèse, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/8804.
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Résumé : Les maladies cardiovasculaires représentent, par une large mesure, la première cause de morbidité et de mortalité chez les diabétiques. L’activation de RAGE par les produits de glycation avancée (AGE) générés en conditions hyperglycémiques est associée à une multitude de complications diabétiques vasculaires, notamment par une signalisation favorisant l’inflammation chronique ainsi que la mort des cellules formant les tissus et les organes exposés aux AGE. La surexpression de RAGE dans les cellules musculaires lisses des plaques athérosclérotiques vulnérables suggère que le récepteur pourrait contribuer à la survenue des accidents vasculaires. Nous avons donc émis l’hypothèse que l’activation de RAGE dans les cellules musculaires lisses était impliquée dans leur apoptose. Pour le vérifier, nous avons, dans un premier temps, mis au point une nouvelle méthode de détection sans marqueur basée sur le principe de la résonance des plasmons de surface (SPR) pour mesurer l’apoptose d’une monocouche cellulaire en temps réel et caractériser avec précision les paramètres cinétiques des phases d’initiation et d’exécution. Cet essai a permis de montrer que l’activation de RAGE induit l’apoptose dans plus de 75,6% des cellules musculaires lisses stimulées avec le CML-HSA pendant 20 heures. De surcroît, nous avons remarqué que l’activation de RAGE générait un fort stress du réticulum endoplasmique, indiqué par la formation d’un grand nombre de granules de stress ainsi que par l’augmentation de l’expression du marqueur de stress réticulaire HuR et de la caspase-9, deux importants régulateurs de l’apoptose induite par le stress réticulaire endoplasmique. Afin de vérifier le potentiel d’un antagoniste à bloquer l’activation du récepteur, nous avons ensuite synthétisé le peptide iRAGE dont la séquence est dérivée d’un site de liaison du CML-HSA ayant la particularité de posséder de nombreuses charges négatives à pH physiologique. Le prétraitement avec iRAGE s’est montré efficace pour prévenir l’activation de NF-κB, l’induction de l’apoptose et l’augmentation du stress réticulaire endoplasmique. Nous suggérons un modèle de fonctionnement par lequel iRAGE inhibe la signalisation de RAGE en empêchant la liaison des ligands multimériques et en stabilisant les récepteurs sous forme de monomères. À terme, la synthèse d’un antagoniste de RAGE utilisable en clinique pourrait constituer une avancée majeure dans la prévention des complications vasculaires et l’amélioration de la qualité de vie chez les diabétiques.Abstract : Cardiovascular diseases represent, to a large extent, the first cause of morbidity and mortality among people with diabetes. RAGE activation by advanced glycation end products (AGE) generated in hyperglycemic conditions is associated to a multitude of vascular diabetic complications, in particular by a signaling promoting chronic inflammation as well as death of cells forming tissues and organs exposed to AGE. Overexpression of RAGE in smooth muscle cells of vulnerable atheromatous plaques suggests the receptor could contribute to heart attacks and strokes. Therefore, we hypothesize that RAGE activation in smooth muscle cells is involved in apoptosis. To verify this hypothesis, we first designed a new label-free assay based of surface plasmon resonance (SPR) to measure apoptosis of a cell monolayer in real-time and to characterize precisely the kinetic parameters of the initiation and execution phases. This assay showed that RAGE activation induces apoptosis of more than 75.6% of smooth muscle cells stimulated with CML-HSA for 20 hours. Moreover, we noticed that RAGE activation generated strong endoplasmic reticular stress, indicated by the formation of a great number of stress granules as well as the increased expression of stress marker HuR and caspase-9, two important regulators of reticular stress-induced apoptosis. In order, to assess the potential of an antagonist to block RAGE activation, we then synthesized the iRAGE peptide whose sequence is derived from a binding site of CML-HSA that has the particularity of owning numerous negative charges at physiological pH. Pretreatment with iRAGE was successful to prevent activation of NF-κB, induction of apoptosis and generation of endoplasmic reticular stress. We suggest a model by which iRAGE inhibits RAGE signaling by hindering the binding of multimeric ligands and by stabilizing the receptors in a monomer state. Ultimately, the synthesis of a RAGE antagonist usable in clinic could constitute a major progress in the prevention of vascular complications and in the quality of life of people with diabetes.
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Mitchell, Lylieth Paula-Ann. "Vascular endothelial and smooth muscle cell apoptosis in vivo and in vitro." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq28795.pdf.
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Loro, Emanuele Loro. "Normal myogenesis and increased apoptosis in myotonic dystrophy type-1 muscle cells." Doctoral thesis, Università degli studi di Padova, 2010. http://hdl.handle.net/11577/3423200.
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Myotonic dystrophy type 1 (DM1) is caused by (CTG)n expansion in the 3’-untranslated region of DMPK gene. Mutant transcripts are retained in nuclear RNA foci, which sequester RNA binding proteins thereby misregulating their functions (i.e. splicing regulation). Controversy still surrounds the pathogenesis of the DM1 muscle distress, characterized by myotonia, weakness and wasting with distal muscle atrophy.
Eight primary human cell lines from adult-onset (DM1) and congenital (cDM1) patients, (CTG)n range 90-1800, were successfully differentiated into aneural-immature and contracting-innervated-mature myotubes. Morphological, immunohistochemical, RT-PCR and Western blotting analyses of several markers of myogenesis indicated that in vitro differentiation-maturation of DM1 myotubes was comparable to age-matched controls. In all pathological muscle cells, (CTG)n expansions were confirmed by long PCR and RNA fluorescence in-situ hybridization. Moreover, the DM1 myotubes displayed the splicing alteration of insulin receptor and MBNL1 genes associated to the DM1 phenotype.
Considerable myotube loss and atrophy of 15-day-differentiated DM1 myotubes indicated activated catabolic pathways, as confirmed by the presence of apoptotic (caspase-3 activation, cytochrome c release, chromatin fragmentation) and autophagic (P62/LC3) markers. Treatment with the pancaspase inhibitor Z-VAD significantly reduced the decrease in myonuclei number and in average width in15-day-differentiated DM1 myotubes. We thus propose that the muscle wasting typical in DM1 is due to impairment of muscle mass maintenance-regeneration, through premature apoptotic-autophagic activation, rather than altered myogenesis.La distrofia miotonica di tipo 1 (DM1) è causata dall'espansione (CTG)n nella regione trascritta ma non tradotta al 3' del gene DMPK. I trascritti mutati sono trattenuti in foci nucleari, i quali sequestrano diverse proteine leganti RNA spesso alterandone le funzioni (i.e. regolazione dello splicing). A livello del muscolo, i meccanismi patogenetici che portano a miotonia, debolezza e perdita di massa dei muscoli distali, non sono ad oggi chiari. Otto linee di mioblasti primari umani, ottenuti da biopsie di pazienti affetti da DM1 nelle forme adulta e congenita (range di espansione tra 90 e 1800 CTG), sono state differenziate ed innervate con successo, ottenendo miotubi in grado i contrarre. L'analisi morfologica e la quantificazione di diversi marker di miogenesi mediante RT-PCR e Western blotting, hanno indicato che il diferenziamento in vitro dei mioblasti primari DM1 è indistinguibile da quello ottenuto con mioblasti di controllo. In ciascuna linea DM1 è stata confermata l'espansione (CTG)n mediante long-PCR ed ibridizzazione in situ. Inoltre, nei miotubi DM1 è stato rilevata l'alterazione dello splicing del recettore per l'insulina e di MBNL1, caratteristica del fenotipo DM1. A 15 giorni di differenziamento, una considerevole perdita di miotubi DM1 ha suggerito l'attivazione di pathways catabolici, come confermato dalla presenza di marker di apoptosi (taglio proteolitico della caspasi 3, rilascio di citocromo c dai mitocondri, frammentazione della cromatina) e di autofagia (aumento dei livelli di LC3 lipidato e di P62). Il trattamento con l'inibitore delle caspasi Z-VAD si è dimostrato efficace nell'attenuare la riduzione del numero di mionuclei e del calibro medio dei miotubi a 15 giorni di differenziamento. Proponiamo quindi che la compromissione muscolare tipica della DM1 sia dovuta, più che ad un'alterata miogenesi, a problemi nei meccanismi di mantenimento/rigenerazione, che si esplicano attraverso la prematura attivazione di apoptosi e/o autofagia
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Gadde, Murali K. "Effects of aging on regulators of muscle apoptosis in the female F344BN rat." [Huntington, WV : Marshall University Libraries], 2009. http://www.marshall.edu/etd/descript.asp?ref=998.
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Enwere, Emeka K. "Regulation of Skeletal Muscle Formation and Regeneration by the Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20048.
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The inhibitor of apoptosis (IAP) proteins traditionally regulate programmed cell death by binding to and inhibiting caspases. Recent studies have uncovered a variety of alternate cellular roles for several IAP family members. The cellular inhibitor of apoptosis 1 (cIAP1) protein, for instance, regulates different axes of the NF-κB signalling pathway. Given the extensive functions of NF-κB signalling in muscle differentiation and regeneration, I asked if cIAP1 also plays critical roles in skeletal muscle myogenesis. In a primary myoblast cell-culture system, genetic and pharmacological approaches revealed that loss of cIAP1 dramatically increases the fusion of myoblasts into myotubes. NF-κB signalling occurs along a classical and an alternative pathway, both of which are highly active in cIAP1-/- myoblasts. Suppression of the alternative pathway attenuates myotube fusion in wildtype and cIAP1-/- myoblasts. Conversely, constitutive activation of the alternative pathway increases myoblast fusion in wildtype myoblasts. cIAP1-/- mice have greater muscle weight and size than wildtypes, as well as an increased number of muscle stem cells. These results identify cIAP1 as a regulator of myogenesis through its modulation of classical and alternative NF-κB signalling pathways.
Loss of the structural protein dystrophin in the mdx mouse model of Duchenne muscular dystrophy leads to chronic degeneration of skeletal muscle. The muscle pathology is strongly influenced by NF-κB signaling. Given the roles demonstrated for cIAP1 in cell culture and in vivo, I asked whether loss of cIAP1 would influence muscle pathology in the mdx mouse. To address this question, double-mutant mice were bred lacking both cIAP1 and dystrophin (cIAP1-/-;mdx). Histological analyses revealed that double-mutant mice exhibited reduced indications of damage on several measures, as compared to single-mutant (cIAP1+/+;mdx) controls. Unexpectedly, these reductions were seen in the “slow-twitch” soleus muscle but not in the “fast-twitch” extensor digitorum longus (EDL) muscle. The improvements in pathology of double-mutant solei were associated with reductions in muscle infiltration by CD68-expressing macrophages. Finally, the double-mutant mice exhibited improved endurance and resistance to damage during treadmill-running exercise. Taken together, these results suggest that loss of cIAP1, through its multiple regulatory functions, acts to improve myogenesis and increase muscle resistance to damage.
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Hazelett, Dennis J. "Gene expression during the segment-specific death of a muscle during insect metamorphosis /." view abstract or download file of text, 2005. http://wwwlib.umi.com/cr/uoregon/fullcit?p3164079.
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Thesis (Ph. D.)--University of Oregon, 2005.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 118-133). Also available for download via the World Wide Web; free to University of Oregon users.
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Granville, David James. "Biochemical mechanisms of endothelial and smooth muscle cell apoptosis induced by photodynamic therapy." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ61099.pdf.
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Schaub, Friedemann. "Fas/FADD-induced pro-inflammatory response in vascular smooth muscle cells /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/6345.
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Waltmann, Meaghan D. "Apolipoprotein E receptor 2 deficiency alters smooth muscle cell and macrophage characteristics to promote atherosclerotic lesion necrosis." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384851103.
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Zee, Michele Chi-Wai. "Steroid hormones and cell death : analysis of motorneuron and muscle fates during insect metamorphosis /." view abstract or download file of text, 2004. http://wwwlib.umi.com/cr/uoregon/fullcit?p3136456.
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Thesis (Ph. D.)--University of Oregon, 2004.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 99-113). Also available for download via the World Wide Web; free to University of Oregon users.
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Dishmon, Monja. "cFLIP regulates Fas-induced apoptosis and pro-inflammatory gene expression in human vascular smooth muscle cells /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/6341.
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Singh, François. "Skeletal muscle toxicity and statins : role of mitochondrial adaptations." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ050/document.
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Bien que les statines forment la classe d'hypolipidémiants la plus utilisée, une toxicité musculaire a été reportée, pouvant ainsi provoquer l’apparition d’une myopathie. Dans la première partie, nous avons montré chez l’Homme et l’animal que les statines inhibent directement la chaine respiratoire mitochondriale, et induisent la production de radicaux libres dérivés de l’oxygène (RLO), qui active les voies apoptotiques dans les muscles glycolytiques, alors que les muscles oxydatifs ne sont pas atteints. Nous avons ensuite montré in vitro que le stress réducteur peut engendrer une oxydation mitochondriale, pouvant conduire à une activation de la voie de biogenèse mitochondriale. De plus l’augmentation du contenu mitochondrial induite a permis de protéger les cellules contre l’apoptose induite par les statines. Enfin, nous avons montré in vivo que l’induction des voies de biogenèse mitochondriale est nécessaire à la tolérance des statines dans les muscles oxydatifs. En conclusion, le phénotype mitochondrial, tant au niveau quantitatif que qualitatif, semble être un facteur clé dans l’apparition de la myopathie aux statinesAlthough statins are the most prescribed class of lipid-lowering agents, adverse muscular toxicity has been reported, which can lead to the appearance of a myopathy. In the first part, we showed in Humans and animals that statins inhibit directly the mitochondrial respiratory chain, and induce the production of reactive oxygen species (ROS), that trigger apoptotic pathways in glycolytic skeletal muscles, whereas oxidative muscles are not impaired. We then showed in vitro that reductive stress can provoke mitochondrial oxidation, that could lead to an activation of mitochondrial biogenesis pathways. Moreover, the consequent increase in mitochondrial content enabled to protect cells against statin-induced apoptosis. Finally, we showed in vivo that the induction of mitochondrial biogenesis is necessary for statin tolerance in oxidative skeletal muscles. In conclusion, mitochondrial phenotype, both quantitatively and qualitatively, seems to be a key factor in the appearance of statin myopathy
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Tan, Yu Yin Nicole Medical Sciences Faculty of Medicine UNSW. "Gene expression during activation of smooth muscle cells." Publisher:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/43615.
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Cardiovascular disease, which involves the cardiac, cerebrovascular and peripheral vascular system, is the major cause of morbidity and mortality in the western world. Changes in the vascular microenvironment trigger cascades of molecular events involving altered signaling, transcription and translation of a gene. The aim of this thesis was to increase our understanding on the molecular regulation of activated vascular smooth muscle cells. The first study looking at PDGF-D expression provides new insights into the regulatory mechanisms controlling the phosphorylation of Sp1. Studies performed identified three amino acids in Sp1 (Thr668, Ser670 and Thr681) that is phosphorylated by PKC-zeta activated by AngII. In the second study, the translational regulatory role of a novel gene YrdC induced by injury was investigated. Current knowledge of translational regulators controlling altered gene expression is little and studies in this thesis shows a splice variant of YrdC playing an important role in controlling mRNA translation and thus protein synthesis in the context of injury. The final study investigated in this study was the increased expression of the apoptotic FasL by the activation of GATA6. Although FasL has been extensively studied over the years, this is the first study linking a GATA factor with FasL in any cell type and provides key insights into the transcriptional events underpinning FasL-dependent SMC apoptosis following exposure to AngII.
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D'Antoni, Michelle. "The effect of decorin and biglycan on human airway smooth muscle cell proliferation, apoptosis and attachment." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103624.
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Changes in extracellular matrix (ECM) deposition along with increases in airway smooth muscle (ASM) mass are characteristic features of airway remodeling which contribute to asthma pathophysiology. Modifications in ECM include increased collagen deposition and altered proteoglycans (PGs) levels. While biglycan, a small leucine-rich PG (SLRP), deposition is generally increased, changes in decorin, another SLRP, are more variable. The interaction between the cell and the surrounding ECM triggers numerous cellular responses, which modulate functions such as survival, proliferation and differentiation. Since decorin and biglycan are known to influence cell behaviour in various types of cells, we hypothesized that these molecules would affect human airway smooth muscle cell (HASMC) function. We sought to determine the effects of decorin and biglycan on HASMC proliferation, apoptosis and attachment, and to explore the putative mechanisms responsible for these effects. Collagen type I was used as a control.Culture on a decorin matrix caused a decrease in HASMC number, which was attributed to a decrease in proliferation and an increase in apoptosis. Culture on biglycan caused an initial decrease in cell number that was not sustained. Collagen caused a significant increase in cell number. Neither biglycan nor collagen caused changes in proliferation or apoptosis. Subsequent experiments showed that cell anchorage to decorin and biglycan matrices caused abnormal focal adhesion and cytoskeletal organization, as well as, increases in alpha2 integrin protein levels as compared to cells seeded on collagen or plastic. To assess integrin activation, focal adhesion kinase (FAK) protein levels and activation were measured. FAK levels were significantly decreased compared to cells cultured on plastic or collagen I, but activation levels were unchanged.These studies demonstrate that PGs have differential effects on HASMC growth. Whereas decorin reduces ASM proliferation and increases apoptosis, biglycan has no effect. Cell-matrix adhesions were irregular in HASMCs seeded on decorin or biglycan compared to cells on collagen I or plastic. Decreases in decorin in the asthmatic airway wall, as observed in fatal asthma cases, may permit more exuberant ASM hyperplasia, suggesting that decorin's presence could serve a protective role by modulating the increase in ASM mass in asthma.Les changements de composition de la matrice extracellulaire (MEC) ainsi que l'augmentation de la masse du muscle lisse des voies aériennes sont des caractéristiques du remodelage des voies aériennes qui contribuent à la physiopathologie de l'asthme. Les modifications de la MEC comprennent une augmentation du dépôt de collagène et un changement du niveau des protéoglycanes (PGs). Le dépôt de biglycane, un petit PG riche en leucine, est généralement plus élevé. Les changements d'expression de la décorine, un autre petit PG riche en leucine, sont, par contre, plus variables. L'interaction entre la cellule et la MEC qui l'entoure, déclenche de nombreuses réponses cellulaires, telles que la survie, la prolifération et la différenciation. Étant donné que la décorine et le biglycane peuvent influencer le comportement de différents types de cellules, nous avons émis l'hypothèse que ces molécules auraient aussi un effet sur la fonction des cellules musculaires lisses des voies aériennes. Nous avons cherché à déterminer les effets de la décorine et du biglycane sur la prolifération, l'apoptose et l'attachement des cellules musculaires lisses des voies aériennes. Nous avons aussi exploré les mécanismes putatifs qui seraient responsables de ces effets en utilisant le collagène de type I sera comme traitement de référence. La culture des cellules sur une matrice de décorine a provoqué une diminution du nombre cellules musculaires lisses des voies aériennes due à une diminution de la prolifération et à une augmentation de l'apoptose. La culture sur le biglycane a causé initialement une diminution du nombre de cellules, mais cette baise n'a pas été maintenue. Le collagène a provoqué une augmentation significative du nombre de cellules. Ni le biglycane ni le collagène n'ont induit des changements au niveau de la prolifération ou de l'apoptose. Des expériences ultérieures ont démontré que l'ancrage des cellules musculaires lisses des voies aériennes sur des matrices de décorine et de biglycane était anormal, ainsi que la formation d'adhésions focales et l'organisation du cytosquelette, en comparaison avec les cellules ensemencées sur du collagène ou du plastique. De plus, l'augmentation d'expression protéique de la sous-unité alpha2 d'intégrine a également été observée. Pour évaluer l'activation des intégrines, le niveau de protéine, ainsi que l'activation de la kinase des adhésions focales (FAK) ont été mesurés. En présence de décorine, l'expression protéique de FAK était significativement diminuée comparativement aux niveaux produits par les cellules ensemencées sur du plastique ou du collagène bien que le niveau d'activation était inchangé. Ces études démontrent que les PGs ont des effets distincts sur la croissance des cellules musculaires lisses des voies aériennes: la décorine a réduit la prolifération et a augmenté l'apoptose des cellules, tandis que le biglycane n'a pas modifié ces paramètres. Les adhésions cellules-matrice des cellules musculaires lisses des voies aériennes ensemencées sur la décorine ou le biglycane étaient irrégulières par rapport aux cellules sur le collagène de type I ou le plastique. La diminution de la quantité de décorine dans la paroi des voies aériennes observée dans les cas d'asthme fatal pourrait entraîner une hyperplasie plus prononcée des cellules musculaires lisses des voies aériennes. Ceci suggère que la présence de la décorine pourrait jouer un rôle protectif dans l'asthme, en modulant l'augmentation de la masse du muscle lisse des voies aériennes.
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Woolard, Jeanette. "Mechanisms of regression of vascular structure during antihypertensive therapy, hypoxia-induced apoptosis in vascular smooth muscle cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0002/MQ42706.pdf.
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Maddali, Kamala Kalyani. "A mandatory requirement of PKC-[delta] in testosterone regulated coronary smooth muscle cell differentiation, proliferation and apoptosis /." Free to MU Campus, others may purchase, 2005. http://proquest.umi.com/pqdweb?did=1232392431&sid=1&Fmt=2&clientId=45247&RQT=309&VName=PQD.
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Wang, Yenfeng. "The role of mast cells in foam cell formation, growth inhibition, and apoptosis of smooth muscle cells." Helsinki : University of Helsinki, 1999. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/wang/.
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Lima, Tãnia Marisa da Costa. "Molecular and functional changes in cardiac and skeletal muscle in HFpEF remodelling and reverse remodelling." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22238.
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Mestrado em BioquímicaA insuficiência cardíaca (IC) com fração de ejeção preservada (ICFEp) é uma síndrome com uma etiologia muito diversificada, cuja disfunção metabólica tem sido apontada como um importante mecanismo associado à sua severidade. A remodelagem do miocárdio, resulta de uma agressão ao coração que pode ser direta (isquemia, estenose aórtica, etc) ou indireta (diabetes, disfunção renal, etc). Quando esta agressão é atenuada, por tratamento farmacológico ou cirúrgico, o coração sofre uma remodelagem reversa (RR) e o miocárdio retoma à sua estrutura e função normais. Conhecer os mecanismos subjacentes ao padrão de remodelagem e RR do miocárdio irá certamente potenciar novas oportunidades de tratamento da ICFEp. Por ser uma síndrome multisistémica, os doentes com ICFEp apresentam frequentemente sinais e sintomas extra-cardíacos característicos do diagnóstico desta patologia, como é o caso da intolerância ao esforço. Assim este trabalho teve como objetivos implementar e caracterizar um modelo animal de ICFEp, bem como avaliar as alterações estruturais, funcionais e moleculares que ocorrem ao nível do músculo cardíaco e esquelético na remodelagem e RR. Os nossos resultados mostram que a implementação de um modelo animal que mimetiza o fenótipo de ICFEp foi bem-sucedida. De facto, os animais banding apresentaram uma marcada hipertrofia do ventrículo esquerdo (VE), disfunção diastólica com rigidez do miocárdio, alterações na regulação do cálcio e aumento do stress oxidativo. Observaram-se ainda alterações que sugerem um aumento da biogénese e da fissão mitocondrial bem como um aumento dos transportadores de glucose. Apesar do aumento da expressão da proteína desacopladora 1 (UCP-1), funcionalmente, as mitocôndrias apresentaram uma melhoria da sua função. A redução da performance física dos animais banding foi acompanhada de alterações estruturais ao nível do músculo-esquelético, assim como de uma alteração dos transportadores dos substratos metabólicos. Curiosamente, nos animais debanding, apesar da recuperação funcional, morfologicamente o miocárdio não normalizou totalmente. Adicionalmente, observou-se um aumento dos transportadores de ácidos gordos, acompanhado por uma diminuição do stress oxidativo e da apoptose no VE. Além disso, apesar da melhoria metabólica, as mitocôndrias do VE dos animais debanding mantém-se menores. Relativamente à capacidade aeróbica dos animais, observou-se uma melhoria após o debanding acompanhada por uma reversão da atrofia e a fibrose das fibras musculares, assim como da oxidação dos ácidos gordos. Este trabalho mostra evidências do envolvimento mitocondrial e metabólico na progressão da ICFEp, ao nível dos músculo-esquelético e cardíaco.
Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome with a diverse aetiology in which the metabolic dysfunction has been pointed out as an important mechanism that underlies the disease severity. Myocardial remodelling results from cardiac injury that can be direct (ischemia, aortic stenosis, etc) or indirect (diabetes, renal dysfunction, etc). When the deleterious stimulus is attenuated by pharmacological or surgical treatment, the heart enrols in a process called reverse remodelling (RR), and myocardial structure and function returns to normal. The knowledge of the molecular mechanism that underlie the RR process could represent an opportunity to develop novel therapeutic approaches and thus improve the treatment of HFpEF patients. As being a multi-systemic syndrome, HFpEF presents several extra-cardiac signals and symptoms typical of its diagnosis, such as effort intolerance. Thus, the aims of this work was to implement and characterize an animal model of cardiac remodelling and reverse remodelling of HFpEF and thus characterize structurally, functionally and molecularly the changes that occurs at the myocardium and at the skeletal muscle. Our results showed that we successfully implemented an animal model of HFpEF that presents an LV hypertrophic and increased stiffness. Additionally to LV diastolic dysfunction (DD) we also observed abnormalities on calcium and oxidative stress. In banding rats we denoted an increase of peroxisome proliferator-activated receptor-gamma coactivator alpha (PGC-1α) and downregulation of mitofusin (MNF1,2) as well as an augment of glucose transporters. Despite de increase of uncoupled protein 1 (UCP-1) expression, functionally we denoted an improvement of mitochondria respiration and membrane potential. The physical performance of banding animals was impaired and accomplished by structural changes at skeletal muscle level as well as at metabolic substrate transporters. Curiously, after afterload relief despite the functionally recovery, morphologically the myocardial reverse remodelling was incomplete. Moreover, regardless the metabolic transporters reversion the mitochondria continue smaller. After overload relief the rats showed an improvement on aerobic capacity as well as a reversion on skeletal muscle atrophy, fibrosis and an upregulation of FA oxidation. The present study shows clearly the involvement of mitochondria and metabolism on myocardial and skeletal muscle remodelling and RR.
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Unlu, Sebnem. "Role of isoprenylation in the control of cell proliferation and apoptosis in human vascular smooth muscle cells in culture." Thesis, Imperial College London, 2000. http://hdl.handle.net/10044/1/8577.
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Soutoudeh, Mohammad. "Use of a newly designed equi-biaxial stretch device to study stretch-induced apoptosis of vascular smooth muscle cells /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1998. http://wwwlib.umi.com/cr/ucsd/fullcit?p9913164.
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Marchildon, François. "The Role of CCAAT/Enhancer Binding Protein Beta (C/EBPβ) in Skeletal Muscle Satellite Cells after Injury and in Cancer Cachexia." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/33373.
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CCAAT/Enhancer Binding Proteins are a family of six bZIP transcription factors. C/EBPβ, the second member cloned, has been implicated in adipogenesis and osteogenesis, but the role of C/EBPβ in myogenesis remained undetermined. In adults, muscle-resident stem cells, called satellite cells (SCs), have the greatest propensity to regenerate the skeletal muscle. We found that C/EBPβ is expressed in SCs, and its expression progressively declines upon differentiation. Forcing the expression of C/EBPβ in myoblasts enhanced the expression of the SC marker Pax7, and repressed MyoD and the myogenic genes expression, resulting in the inhibition of myogenesis. Using a SC-specific conditional knockout (cKO) mouse model, we found that cKO myoblasts have decreased expression of Pax7, and we identified Pax7 as a direct target of C/EBPβ action. In vivo, excision of C/EBPβ resulted in muscle hypertrophy at the juvenile age, and adult cKO animals had enhanced muscle regeneration following BaCl2 muscle injury. Moreover, the number of Pax7+ cells in cKO animals decreased following BaCl2 injury. Upon performing a second injury into cKO animals, we demonstrate a decreased muscle fiber size and an exacerbation of the percentage number of SCs. While cKO animals repaired well a BaCl2 injury, regeneration failed in cKO animals following cardiotoxin (CTX) injury. We demonstrate that IL-1β expression is enhanced in muscle after CTX injury when compared to BaCl2, and we found that IL-1β can stimulate the expression of C/EBPβ in myoblasts. Ectopic C/EBPβ expression can protect myoblasts from apoptosis when triggered with thapsigargin, whereas cKO myoblasts are more sensitive to apoptosis. Using cancer cachexia as a model of chronic inflammation, we found that the expression of C/EBPβ is stimulated in the SCs of cachectic animals, and this correlated with a decrease in regenerative capacity. The severity of muscle wasting was not improved in cKO animals, but rather cKO SCs were lost to apoptosis. Together, this study establishes a protective role for C/EBPβ in muscle SCs in conditions of inflammation.
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Barrett, Brianna L. "MOLECULAR DISTINCTIONS REGULATING THE TEMPORAL EXPRESSION OF THE MYOD-RESPONSIVE GENES PUMA (RESPONSIBLE FOR APOPTOSIS) AND MYOGENIN (RESPONSIBLE FOR DIFFERENTIATION)." Cleveland State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=csu1557264097566887.
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Scholtes, Charlotte. "Étude des liens entre les acteurs de la dynamique mitochondriale et l'apoptose dans la dégénérescence musculaire dystrophinedépendante chez Caenorhabditis elegans." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1001.
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La forme des mitochondries change continuellement grâce aux actions combinées d'événements de fission et de fusion rendant le réseau mitochondrial très dynamique. Les processus mitochondriaux de fission et de fusion sont finement régulés par des GTPases de la famille des dynamines qui sont bien conservées entre les espèces. Chez C. elegans, la fission est régulée par DRP-1, la fusion de la membrane interne par EAT-3, homologue d’OPA1, et la fusion de la membrane externe par FZO-1, homologue de MFN1. Dans les cellules musculaires du nématode sauvage, les mitochondries tubulaires et circulaires sont dans des proportions égales et organisées le long du sarcomère. Cependant, durant la dégénérescence musculaire dystrophine-dépendante, une fragmentation du réseau mitochondrial dans les cellules musculaires apparaît. Or le rôle des acteurs de la dynamique mitochondriale dans les mécanismes moléculaires menant à la dégénérescence musculaire dystrophine-dépendante reste encore incompris. Nous avons trouvé que: (i) la dégénérescence musculaire dystrophine-dépendante s'accompagnait d'une augmentation drastique de la fragmentation mitochondriale qui peut être sauvée par des manipulations génétiques de la dynamique mitochondriale (ii) la perte de fonction du gène de fission drp-1 ou la surexpression des gènes de fusion eat-3 et fzo-1 provoquent une réduction de la dégénérescence musculaire et une mobilité améliorée des mutants dystrophiques (iii) les fonctions de DRP-1 dans l'apoptose et d’autres acteurs de l’apoptose sont importants pour la mort des cellules musculaires déficientes en dystrophine (iv) L’implication de DRP-1 dans l’apoptose est également importante pour la dégénérescence musculaire liée au vieillissement. En conclusion, nos résultats pointent vers un mécanisme impliquant la dynamique mitochondriale pour impacter la dégénérescence musculaire via l’apoptose chez Caenorhabditis elegansMitochondrial shape is continually changing thanks to the combined actions of fission and fusion events making the mitochondrial network very dynamic. The mitochondrial fission and fusion processes are finely regulated by GTPases of the family of dynamins that are well conserved between species. In C. elegans, fission is regulated by DRP-1, fusion of the inner membrane by EAT-3, homologue of OPA1, and fusion of the outer membrane by FZO-1, homologue of MFN1. In the muscle cells of wild nematode, tubular and circular mitochondria are in equal proportions and organized along the sarcomere. However, during dystrophin-dependent muscle degeneration, fragmentation of the mitochondrial network in muscle cells occurs. But the role of the actors of mitochondrial dynamics in the molecular mechanisms leading to dystrophin-dependent muscle degeneration is still misunderstood. We found that: (i) dystrophin-dependent muscle degeneration was accompanied by a drastic increase in mitochondrial fragmentation that can be saved by genetic manipulation of mitochondrial dynamics (ii) loss of function of the fission gene drp-1 or overexpression of the eat-3 and fzo-1 fusion genes causes a reduction in muscle degeneration and improved mobility of dystrophic mutants (iii) DRP-1 functions in apoptosis and other are important for the death of dystrophin-deficient muscle cells (iv) The involvement of DRP-1 in apoptosis is also important for age-dépendant muscle degeneration. In conclusion, our results point toward a mechanism involving mitochondrial dynamics to impact muscle degeneration via apoptosis in Caenorhabditis elegans
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Foster, Cerrone R., Laura L. Daniel, Christopher R. Daniels, Suman Dalal, Mahipal Singh, and Krishna Singh. "Deficiency of Ataxia Telangiectasia Mutated Kinase Modulates Cardiac Remodeling Following Myocardial Infarction: Involvement in Fibrosis and Apoptosis." Digital Commons @ East Tennessee State University, 2013. https://dc.etsu.edu/etsu-works/8570.
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Ataxia telangiectasia mutated kinase (ATM) is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI) as a model. Methods and Results: Left ventricular (LV) structure, function, apoptosis, fibrosis, and protein levels of apoptosisand fibrosis-related proteins were examined in wild-type (WT) and ATM heterozygous knockout (hKO) mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS) and ejection fraction (EF) in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.
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Andrianjafiniony, Tina. "Atrophie musculaire et récupération : homéostasie calcique, stress oxydant, apoptose et protéolyse musculaire." Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10171.
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L’exposition à une situation d’hypokinésie induit une atrophie fonctionnelle et phénotypique du musclesquelettique. Différents mécanismes sont suggérés contribuer à ce phénomène de plasticité musculaire,incluant en particulier des modifications de l’homéostasie calcique et de la production d’espèces réactivesde l’oxygène qui, en relation avec certains processus inflammatoires, activeraient des voies d’apoptose etde protéolyse musculaire. Le présent travail a porté un intérêt spécifique à ces phénomènes dans le cadrede l’atrophie musculaire induite par une hypokinésie ainsi que dans la récupération après cessation de ceprotocole. À l’aide d’approches cellulaires nous montrons que l’extrusion du calcium cytoplasmique estconsidérablement ralentie dans les fibres musculaires atrophiées. Cet effet, lié au moins en partie à unecontribution altérée des mitochondries, pourrait jouer un rôle dans l’activation de voies protéolytiquescalcium-dépendantes. Dans un deuxième temps, nous avons étudié l’évolution du niveau de stressoxydant et de l’expression de différentes cytokines ainsi que de marqueurs de la voie apoptotiquecaspase-dépendante et de la protéolyse musculaire au cours du phénomène de récupération après la fin del’hypokinésie. Les résultats montrent que le retour à la normale de la masse musculaire est facilité lors dela phase précoce (1-5 jours) de récupération via la modulation de l’apoptose mitochondriale et de laprotéolyse musculaire. Par contre le stress oxydant et la voie apoptotique impliquant TNF-a persistentjusqu’à 14 jours de récupération, alors que la masse musculaire est déjà reconstituéeExposure to hypokinesia induces a functional and phenotypic atrophy of skeletal muscle. Several types ofmechanisms have been suggested to contribute to this plasticity phenomenon, including changes inintracellular calcium handling and in production of reactive oxygen species which, together withinflammatory processes, would activate muscle apoptosis and proteolysis pathways. The present workspecifically focussed on these mechanisms within the framework of a model of hypokinesia-inducedatrophy and of recovery from this atrophy. Measurements on isolated muscle cells revealed that the rateof myoplasmic calcium extrusion was considerably reduced in atrophied muscle fibres. This effect whichappears to be, at least in part, related to an altered mitochondrial contribution, may play a pivotal role inthe activation of calcium-dependent proteolysis pathways. We then studied the time course of changes inoxidative stress as well as in the expression level of several cytokines and proteins specifically involvedin proteolysis and caspase-dependent apoptotic pathways, along the course of recovery from atrophy. Ourresults demonstrate that, at early stages (1-5 days) of recovery, muscle re-growth is mediated via themodulation of mitochondrial-driven apoptosis and muscle proteolysis. In contrast, oxidative stress and theTNF-a related apoptotic pathway remain activated until late stages (14 days) of recovery, at a time whenmuscle mass has already recovered
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Silva, Ramiro Hesiquio. "Avaliação de proteção celular a isquemia de retalhos musculares com soluções preservadoras de tecidos em modelo de ratos." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5158/tde-29092009-165603/.
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A transferência de retalhos livres e o reimplante de tecidos têm em comum a exposição dos tecidos à isquemia e tempos de reperfusão variáveis, que são importantes na determinação dos danos celulares estruturais e ultraestruturais, às vezes irreversíveis. O tempo de isquemia dificilmente pode ser controlado no período pré ou transoperatório, mas pode-se tentar prevenir ou diminuir as alterações celulares com soluções preservadoras, como, por exemplo, a da Universidade de Wisconsin, amplamente utilizada na prática clínica dos transplantes de tecidos. Porém a disponibilidade e o custo alto destas soluções dificultam seu uso rotineiro nos centros cirúrgicos. O presente trabalho propõe a utilização de solução de preservação (Solução Plástica-USP) que pode ser facilmente preparada com medicamentos accessíveis e baixo custo; a eficiência desta solução foi comparada com a da solução de Wisconsin. Os resultados demonstraram que não existe diferencia significativa entre a solução Plástica-USP, comparável à solução de Wisconsin; conferindo, ambas, um maior nível de proteção celular sobre os controles; beneficiando significativamente os resultados, e diminuindo assim os riscos de perdas do transplante a baixo custoThe free flaps transfer and reimplantation of tissue has in common the exposure of the tissue to ischemia and different time of reperfusion which are important for the determination of the extent of the cellular injury, being sometimes irreversible. In the pre and trans-surgical procedure the control of the ischemic period is difficult. Although efforts are made to prevent and decrease cellular changes using preservative solution, such as University of Wisconsin (UW) used in routine transplant of organs. The availability and high cost of this solution some time is one problem. The present study was made in a rat model that we have been reported in others works, we proposed the utilization of a preservation solution that we called Plastic Surgery-USP solution (PS-USP); witch can be easily prepared with accessible and low cost drugs. The efficiency of this PS-USP solution was compared to UW; our result showed that there is not significative difference in the protective effects of the PS-USP and UW solutions; both solutions were efficient considering cellular protection to ischemia/reperfusion injury, decreasing the risks of flap lost, with low cost and easy disposition
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Lejmi, Mrad Rim. "Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34260.
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Skeletal muscle atrophy is a debilitating condition caused by pathological conditions including cancer cachexia, disuse and denervation. Disuse atrophy is characterized by reduction in fiber size, fiber-type change and induction of markers of atrophy such as MuRF1 and Fn14. Recent studies have focused on understanding the fundamental role of signalling pathways and the proteolytic system in response to muscle atrophy. Unfortunately the exact mechanisms behind atrophy remain poorly understood. I recently demonstrated that cIAP1 and/or cIAP2 proteins are critical regulators of NF-kB activation, which has been shown to be involved in skeletal muscle atrophy. Here, I used genetic and pharmacological means to investigate the role of cIAP1 in a denervation-induced skeletal muscle atrophy model. Interestingly, I found that upon denervation loss of cIAP1 rescues muscle fiber size, prevents fiber-type changing and inhibits the expression of MuRF1 and Fn14. Moreover, treatment of mice with Smac mimetic compounds (SMC), a novel class of small molecule IAP antagonists, showed successful knockdown of cIAP1 in muscle and protects against denervation-induced muscle atrophy. Taken together, these data reveal that cIAP1 is both a novel mediator of skeletal muscle atrophy and an important therapeutic target.
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Schulz, Cathrin. "Tumour-selective apoptosis : identification of NMHCIIa as novel death receptor interactor regulating the response to TRAIL." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-01069133.
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The cytokine TRAIL is a promising cancer therapeutic candidate as it induces apoptosis selectively in transformed cells. TRAIL-induced clustering of its receptors (DR) is essential for the DISC complex formation, which induces cell death. The mechanism for TRAIL's tumour selective effect is largely unknown. We identified the cytoskeleton proteins non-muscle myosin heavy chain IIa, IIb (NMHCIIa, NMHCIIb), myosin regulatory light chain (MLC2) and ß-actin as novel DR-interactors. An initially weak and TRAIL-induced abrogation of NMHCII/DR interaction correlated with efficient DISC formation in tumour cells. In contrast, a robust NMHCII/DR interaction that was sustained upon TRAIL stimulus was accompanied by incomplete DISC arrangement. Weakening the NMHCII/DR interaction in normal cells using chemical inhibitors enhanced TRAIL-induced apoptosis. Intriguingly, siRNA-mediated NMHCIIa- but not NMHCIIb depletion potently released TRAIL resistance in normal cells and influenced DISC composition. Reduced NMHCII/DR interaction in transformed cells was characterised by diminished MLC2 phosphorylation and altered protein expression of upstream regulatory kinases. Our results suggest that normal cell resistance to TRAIL-apoptosis is based on the interaction of cytoskeleton components with DR that is impaired upon transformation. Since NMHCII function in cell adhesion and migration, it will be interesting to study possible roles of the interaction in cell detachment and altered TRAIL sensitivity; moreover this link may provide clues as to the cause of TRAIL resistance in some cancers.
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Ling, Shanhong. "Effects of estrogens on the vasculature in vitro cell culture studies." Monash University, Dept. of Medicine, 2003. http://arrow.monash.edu.au/hdl/1959.1/9345.
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Wismann, Jennifer Willoughby Darryn Scott. "Effects of 28 days of protein and amino acid supplementation and ankle immobilization on gastrocnemius muscle mass and strength and atrophy- and apoptosis-related gene expression in males." Waco, Tex. : Baylor University, 2008. http://hdl.handle.net/2104/5181.
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Alharthi, Sameer E. M. "The effect of mitogen-activated protein kinase phosphatase-2 (MKP-2) over-expression via infection with Adv.MKP-2 on human endothelial cell apoptosis and vascular smooth muscle cell proliferation." Thesis, University of Strathclyde, 2010. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=14479.
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Yadav, Prashant. "Understanding the Role of Phosphoinositide 3-Kinase and its Function as a Driving Force behind the ER Stress Response in Fibrostenotic Crohn’s Disease-affected Ileal Smooth Muscle Cells." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5511.
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Crohn’s disease (CD) affects about 780,000 people in the United States alone, and it is estimated that 6-15 per 100,000 persons will receive a diagnosis of this disease each year. There currently is no cure for Crohn’s disease, and available medical therapies simply serve to alleviate the inflammation. This does not help treat fibrostenosis that Crohn’s disease patients may develop, which can only be treated surgically. Finding alternatives to treat CD requires an understanding of mechanisms at the biochemical level. In this thesis, we attempted to gain a better understanding of certain pathways found to be active in Crohn’s disease-affected ileal smooth muscle cells. We found an upregulation of the ER stress pathway via expression of its surrogate, the GRP78 protein. We also showed evidence that the phosphoinositide 3-kinase (PI3K) pathway, a key proliferative pathway, is linked to ER stress in these cells, and is an upstream driving force of the ER stress response. Further research on the link between the PI3K and ER stress pathways needs to be conducted, and can potentially serve as a target for therapeutics to help reduce proliferation in fibrostenotic Crohn’s disease-affected ileal smooth muscle cells.
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Arnold, Ludovic Chazaud Bénédicte. "Rôle des macrophages dans la régénération du muscle strié squelettique." Créteil : Université de Paris-Val-de-Marne, 2007. http://doxa.scd.univ-paris12.fr:8080/theses-npd/th0357710.pdf.
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Kiskin, Fedir. "Developing an induced pluripotent stem cell model of pulmonary arterial hypertension to understand the contribution of BMPR2 mutations to disease-associated phenotypes in smooth muscle cells." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/285324.
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Mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) are the most common genetic cause of heritable pulmonary arterial hypertension (PAH). However, given the reduced penetrance of BMPR2 mutations in affected families, a major outstanding question is the identity of additional factors or pathways that are responsible for the manifestation of clinical disease. Furthermore, limited human tissue is available for study and usually only from patients with end-stage disease, making it difficult to understand how PAH is established and progresses. Alternative human models of PAH are therefore required. This thesis describes the characterisation of the first human iPSC-derived smooth muscle cell (iPSC-SMC) model of PAH and elucidates the role of BMPR2 deficiency in establishing PAH-associated phenotypes in iPSC-derived SMCs. To achieve this, I used CRISPR-Cas9 gene editing to generate wild-type and BMPR2+/- iPSC lines with isogenic backgrounds which were subsequently differentiated into lineage-specific iPSC-SMCs that displayed a gene expression profile and responses to BMP signalling akin to those present in distal pulmonary artery smooth muscle cells (PASMCs). Using these cells, I found that the introduction of a single BMPR2 mutation in iPSC-SMCs was sufficient to recapitulate the pro-proliferative and anti-apoptotic phenotype of patient-derived BMPR2+/- PASMCs. However, acquisition of the mitochondrial hyperpolarisation phenotype was enhanced by inflammatory signalling and required an interaction between BMPR2 mutations and environmental stimuli provided by exposure to serum over time. Furthermore, I showed that BMPR2+/- iPSC-SMCs had an altered differentiation state and were less contractile compared to wild-type iPSC-SMCs, phenotypes which have not been observed previously in PAH-derived PASMCs. Finally, RNA sequencing analysis identified genes that were differentially expressed between wild-type and BMPR2+/- iPSC-SMCs and may hence provide further insights into PAH pathobiology. The iPSC-SMC model described in this study will be useful for identifying additional factors involved in disease penetrance and for validating therapeutic approaches that target BMPR2.
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He, Wei. "Elucidating the Molecular and Cellular Mechanism Underlying Cancer Cachexia." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385054981.
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Moraes, Luis Henrique Rapucci. "A reinervação do músculo extensor longo dos dedos (EDL) de ratos (rattus norvegicus) seria influenciada pelo uso do laser de baixa potência e do tecido adiposo na técnica de tubulização?" Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/25/25142/tde-18082010-090713/.
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Lesões nervosas periféricas com alterações morfofuncionais são de grande importância clínica, porque pode prejudicar a função, comprometendo a sensibilidade e/ou a motricidade do órgão alvo. Quando o nervo é lesado, o indivíduo torna-se impossibilitado de realizar suas atividades, seja profissional ou pessoal, e a partir do acidente esta situação se agrava ainda mais, pois tem início uma trajetória de sofrimento e humilhações decorrentes do tipo de assistência que passa a receber, tendo em vista, ainda, a fragilidade emocional e o abatimento moral de que passa a ser vítima. Na tentativa de reparo de lesões graves de nervos periféricos, várias técnicas têm sido utilizada, mas algumas com prejuízos funcionais para outras área do corpo, como por exemplo, quando se usa outro nervo no enxerto. Considerando que enxertos venosos tem tido bons resultados na capacidade regenerativa das fibras nervosas, e como elas são encontradas em abundância e em locais de fácil acesso cirúrgico, pensou-se em verificar se o tecido adiposo e o laser de baixa potência alterariam os resultados da reinervação, por tubulização, em músculos de contração rápida (EDL). Para isso foi utilizado 84 ratos (Rattus norvegicus) da linhagem wistar, machos, que foram divididos em 12 grupos (oito experimentais e quatro controles). Nos grupos experimentais (GE) foi utilizada tubulização de veia preenchida, ou não de tecido adiposo (GEVV e GEVG, respectivamente), com e sem tratamento de laser (GEVVL e GEVGL, respectivamente). Os grupos controles (GC) receberam os nomes de positivos (GCP) quando os animais não sofreram intervenção cirúrgica, e negativos (GCN) quando os animais foram submetidos à desnervação do nervo ciático. Todos os grupos tiveram os seus animais sacrificados em dois períodos, 45 e 150 dias, após o início do experimento. A certificação da recuperação foi feita por meio da análise dos músculos inervados por ele (EDL), comparando-os com os respectivos grupos controles. Técnicas de microscopia, Imunofluorescência (MyoD e miogenina), apoptose (Tunel), morfométricas e análise funcional do ciático, foram empregadas nesta investigação. Os resultados mostraram que aos 45 dias pós desnervação os dados dos grupos experimentais estavam mais próximos do grupo controle negativo, mas aos 150 dias eles estavam mais próximos aos do grupo controle positivo. Baseado nos dados obtidos pode-se concluir que o uso de tecido adiposo e do laser de baixa potência na técnica de tubulização do nervo ciático interferem na recuperação do músculo EDL desnervado.The peripheral nerves injuries with morphofunctional alterations, have great clinical importance because could prejudice the function, committing the sensibility and/or the motricity of target organ. When nerve is damage, the individual becomes disabled to realize yours activities, either professional or personal, in the post accident periods, this situation aggravates each more, therefore initiate a trajectory of suffering and distressing despite of the kind of assistance that this person receives, in view of your emotional fragility and your moral discouragement that pass to be victim. In attempt to repair severe peripheral nerves lesions, many techniques had been used, but some present functional prejudices to other area of bodies, for example when other autologous nerve graft it is used. Considering that, vein graft had demonstrated good results in regenerative nerve fibers capacity, and the vein are found in abundance in many locals of chirurgic access, it thought in verify if the adipose tissue and low power laser could alter the reinnervation results, by tubulization technique, in fast twitch muscle (EDL). For this, was used 84 rats (Rattus norvegicus) wistar, male, divided in 12 groups (eight experimental and four controls). In the experimental groups (EG) was used tubulization by vein combined / or not with adipose tissue (EGV and EGVA, receptively), with or without laser treatment (EGVL and EGVAL, respectively). The controls groups (CG) was called of positives (CGP) when the animals did not subject to transaction nerve, and negatives (CGN) when the sciatic nerve was transaction in this animals. All groups had the animals scarified in two periods, 45 and 150 days post experiments beginning. The recuperation was notified by means of muscle innervated analysis (EDL), comparing with the respective controls groups. Microscope techniques, Immunofluorescence for (MyoD and Miogenin), apoptosis by (Tunel assay), morphometrics and sciatic functional analysis, were employed in this investigation. The results showed that in the 45 days post-dennervation, the data of experimental groups was nearest of negative control group (transaction sciatic nerve), but in the 150 days they was nearest to the positive control group. Based on this, could be conclude that the use of adipose tissue and low power laser used in the tubulization technique by vein in the sciatic nerve interfere in the recuperation of EDL muscle dennervated.
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Netherland, Courtney Denise. "Role of Type 2 Cannabinoid Receptor (CB2) in Atherosclerosis." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1392.
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Atherosclerosis is a macrophage-dominated nonresolving inflammatory disease of the arterial wall. Macrophage processes, including apoptosis, influence lesion development in atherosclerosis. Cannabinoids, compounds structurally related to Δ9-tetrahydrocannabinol (THC), the active ingredient in marijuana, exert their effects through cannabinoid receptors, CB1 and CB2. Cannabinoid treatment, THC or Win55,212-2, reduces atherosclerosis in ApoE-null mice by a mechanism thought to involve CB2. However, the exact role of CB2 in atherosclerosis remains unclear. We found that CB2-null macrophages are resistant to oxysterol/oxLDL-induced apoptosis leading us to hypothesize that CB2 may modulate macrophage apoptosis in atherosclerosis. To determine the functions of CB2 in atherosclerosis, we fed low density lipoprotein receptor-null (Ldlr-/-) and Ldlr-/- mice genetically deficient in CB2, an atherogenic diet for 8 and 12 weeks. CB2 deficiency did not significantly affect aortic root lesion area after 8 or 12 weeks; however, after 12 weeks, CB2-deficient lesions displayed increased lesional macrophage and smooth muscle cell (SMC) content and a ~2-fold reduction in lesional apoptosis. CB2-deficienct lesions also displayed reduced collagen content and elevated elastin fiber fragmentation that was associated with elevated levels of the extracellular matrix degrading enzyme, matrix metalloproteinase 9 (MMP9). These results demonstrate that although CB2 signaling does not affect atherosclerotic lesion size it does modulate lesional apoptosis, cellularity and ECM composition. Ldlr-/- and CB2-deficient Ldlr-/- mice were also subjected to daily treatments with Win55,212-2, a synthetic cannabinoid, over the last 2 weeks of an 8 week atherogenic diet to identify CB2-dependent and CB2-independent effects of cannabinoid receptor stimulation on atherosclerosis. Win55,212-2 did not affect hypercholesterolemia, aortic root lesion area, lesional macrophage infiltration, or ECM composition in either genotype but did significantly reduce total plasma triglyceride levels and lesional SMC content, independent of CB2. Surprisingly, lesional apoptosis was dose-dependently repressed by Win55,212-2 in Ldlr-/- mice by a CB2-dependent mechanism. All together, these results support the suggestion that CB2 may be a target for novel therapies aimed at modulating lesional apoptosis and cellularity to increase lesion stability and reduce the vulnerability to rupture.
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Neves, Dalvaci da Cunha Lira. "Quantificação das células estreladas ativadas / miofibroblastos e análise da apoptose das células do fígado durante a terapia celular na fibrose hepática em ratos." Universidade do Estado do Rio de Janeiro, 2011. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=3730.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorA fibrose hepática é o resultado de uma resposta cicatrizante frente a repetidas lesões no fígado, e é caracterizada pelo acúmulo excessivo de proteínas da matriz extracelular (MEC) no parênquima hepático, incluindo colágeno, fibronectina, elastina, laminina e proteoglicanos, com a participação de diferentes populações celulares do fígado. As principais células responsáveis pela síntese de proteínas da MEC na fibrose hepática são as células estreladas hepáticas ativadas e os miofibroblastos, que surgem após estímulo inflamatório e são caracterizadas pela expressão de alfa-actina de músculo liso (α-SMA). Sabe-se que durante a progressão da fibrose hepática, ocorre a morte de hepatócitos e sua substituição por células fibrogênicas α-SMA+. A apoptose dessas células fibrogênicas é de grande relevância para a regressão da fibrose e regeneração hepática. Nos últimos anos, a terapia com células tronco de medula óssea tem sido utilizada para estimular a regeneração hepática em diferentes modelos experimentais e protocolos clínicos. A fração mononuclear da medula óssea adulta possui duas populações de células-tronco importantes no tratamento de diversas doenças hepáticas: células-tronco hematopoiéticas e células-tronco mesenquimais. O objetivo deste estudo foi analisar a expressão de α-SMA e o processo de apoptose de células hepáticas durante a fibrose hepática induzida por ligadura do ducto biliar (LDB) e após o transplante de células mononucleares de medula óssea (CMMO). Os fígados foram coletados de ratos dos seguintes grupos: normal, 14 dias de LDB, 21 dias de LDB e animais que receberam CMMO após 14 dias de LDB, e foram analisados após 7 dias (totalizando 21 dias de LDB). Para quantificar a expressão de α-SMA por células fibrogênicas nos grupos experimentais, foi realizada imunoperoxidase para α-SMA, seguida de morfometria no programa Image Pro Plus. Para analisar a apoptose nas células hepáticas, foi realizada imunoperoxidase e Western Blotting (WB) para caspase-3 (proteína apoptótica) e imunofluorescência com dupla-marcação para caspase-3 e α-SMA, seguida de observação em microscópio confocal. Os resultados da quantificação de α-SMA por morfometria mostraram que a expressão de α-SMA aumentou significativamente 14 e 21 dias após a LDB. Entretanto, essa expressão diminuiu significativamente no grupo tratado com CMMO, que apresentou parênquima hepático mais preservado em relação ao grupo com 21 dias de LDB. Os resultados de imunoperoxidase, WB e microscopia confocal para expressão de caspase-3 demonstraram que essa proteína diminuiu nos animais fibróticos com 14 e 21 dias de LDB com relação ao grupo normal, e estava significativamente elevada no grupo tratado com CMMO. A análise por microscopia confocal demonstrou que algumas células coexpressaram α-SMA e caspase-3 nos animais tratados com CMMO, sugerindo a morte de células fibrogênicas e remodelamento do parênquima hepático.
Hepatic fibrosis is the result of a scarring response due to continued injury to the liver, and is featured by excessive accumulation of extracellular matrix (MEC) proteins in hepatic parenchyma. These proteins include collagen, fibronectin, elastin, laminin and proteoglicans, along with the participation of different cell populations within the liver. The main cells responsible for the synthesis of MEC proteins are activated hepatic stellate cells and myofibroblasts, which appear after inflammatory stimuli and are characterized by the expression of alpha-smooth muscle actin (α-SMA). It is known that hepatic fibrosis progression is accompanied by hepatocyte death and its substitution by α-SMA+ fibrogenic cells. Therefore, apoptosis of these fibrogenic cells is of main relevance to fibrosis regression and hepatic regeneration. In the later years, bone marrow stem cell therapy has been used to stimulate hepatic regeneration in different experimental models and clinical protocols. The adult bone marrow mononuclear fraction contains two stem cell populations particularly important in the treatment of diverse hepatic diseases: hematopoietic stem cells and mesenchymal stem cells. The aim of this study was to analyze α-SMA expression and the apoptotic process in hepatic cells during hepatic fibrosis induced by bile duct ligation (BDL) and after bone marrow mononuclear cell (BMMC) transplantation. Livers were collect from rats of the following groups: normal, 14 days of BDL, 21 days of BDL and rats that received BMMC 14 days after BDL and were analyzed after 7 days (total of 21 days of BDL). To quantify α-SMA expression by fibrogenic cells in the experimental groups, immunoperoxidase to α-SMA followed by morphometry in the Image Pro Plus software was performed. To analyze apoptosis in hepatic cells, immunoperoxidase and western blotting (WB) against caspase-3 (apoptotic protein) were used, along with double immunofluorescence against caspase-3 and α-SMA to confocal microscopy analysis. Results of α-SMA quantification by morphometry showed that α-SMA expression increased significantly 14 and 21 days after BDL. However, this expression was significantly decreased in the BMMC treated group, which presented a more preserved hepatic parenchyma in relation to the group with 21 days of BDL. Immunoperoxidase, WB and confocal microscopy results showed that caspase-3 is decreased in fibrotic livers with 14 and 21 days of BDL in comparison to normal group, and was significantly augmented in the BMMC treated group. Confocal microscopy analysis showed that were cells coexpressing α-SMA and caspase-3 in rats treated with BMMC, suggesting fibrogenic cells death and hepatic remodeling.
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Silina, Linda. "Targeting TYRO3 : A Novel Strategy to Radiosensitise Bladder Cancer Cells Review of Preclinical Studies to Improve Radiotherapy Response in Muscle-Invasive Bladder Cancer: Lessons and Perspectives TYRO3 Targeting as a Radiosensitizing Strategy in Bladder Cancer TYRO3 as a Molecular Target for Growth Inhibition and Apoptosis Induction in Bladder Cancer." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL024.
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Le cancer de la vessie est un problème majeur de santé publique. Il est le quatrième cancer le plus fréquent chez l’homme en termes d’incidence. 25% des cancers diagnostiqués sont des tumeurs envahissant le muscle (TVIM) présentant un mauvais pronostic. La cystectomie est le traitement standard de référence pour les TVIM, même si elle présente des inconvénients importants. La radiothérapie, associée à une chimiothérapie et à une résection transurétrale de la tumeur, émerge comme traitement conservateur alternatif. La chimiothérapie n’épargne pas les tissus sains et présentent de nombreux effets secondaires indésirables. Il est donc d’importance de découvrir de nouvelles stratégies de radiosensibilisation pour les tumeurs de la vessie. TYRO3 est un récepteur à activité tyrosine kinase de la famille TAM (qui comprend TYRO3, AXL et MERTK). TYRO3 est surexprimé dans de nombreux types de cancers et favorise la prolifération, la survie et la résistance des cellules tumorales à la chimiothérapie. De plus, la surexpression de TYRO3 a été associée à une diminution de la survie globale des patients. Cependant, le rôle de TYRO3 dans le cancer de la vessie n'a pas encore été étudié. Dans cette thèse, je me suis intéressée : (1) Au rôle de TYRO3 dans le cancer de la vessie; (2) A l'effet radiosensibilisant de la perte d’expression ou de l’inhibition de TYRO3 dans les cellules cancéreuses de la vessie; (3) A l'effet de l'inhibition ou de la perte d’expression de TYRO3 sur l’urothélium humain sain.Nous avons démontré que TYRO3 est surexprimé dans 50% des TVIM. De plus, nous avons mis en évidence que les cellules tumorales de vessie surexprimant TYRO3 développaient une dépendance à ce récepteur pour leur survie et leur croissance. Les résultats des données transcriptomiques suggèrent que la perte d’expression de TYRO3 induit des modifications importantes dans le contrôle du cycle cellulaire et de l’apoptose, ce qui laisse supposer que TYRO3 pourrait augmenter la sensibilité de ces tumeurs à la radiothérapie. La perte d’expression ou l’inhibition de TYRO3 dans les cellules dérivées de tumeur de vessie induit une radiosensibilisation significative des cellules traitées. A l’inverse, la surexpression de TYRO3 par transfection plasmidique sur des cellules exprimant peu TYRO3 induit une radiorésistance. En association avec le rayonnement, la perte d’expression de TYRO3 conduit à un arrêt du cycle cellulaire et à une persistance à 24h des foyers de réparation (détectés par immunofluorescence). Enfin, les travaux sur les cellules dérivées de l’urothélium sain ont montré que la perte d’expression de TYRO3 n'affectait pas leur viabilité suggérant que le ciblage de TYRO3 pourrait améliorer l'efficacité de la radiothérapie tout en épargnant les tissus normaux environnantsBladder cancer (BCa) is a major global health problem. It is the fourth most common cancer in men in industrialized countries. 25% of all diagnosed BCa are Muscle-invasive bladder cancers (MIBC) which have poor prognosis. Cystectomy is the standard treatment for MIBC, but for patients with comorbidities it presents significant drawbacks including increased risk of infection and impacted quality of life. Radiotherapy coupled with chemotherapy and tumor transurethral resection has emerged as a promising bladder sparing. Chemotherapy does not spare normal tissue and results in side effects. Therefore, it is of great interest to discover novel radiosensitisation strategies for bladder tumors.TYRO3 is a receptor tyrosine kinase of the TAM family (comprising TYRO3, AXL and MERTK) and is known to regulate diverse biological. TYRO3 is overexpressed in many types of cancer and promotes tumor cell proliferation, survival and resistance to chemotherapy. In addition, higher levels of TYRO3 expression have been associated with decreased overall survival in patients of diverse cancers. However, the role of TYRO3 in BCa has so far not been studied. In this thesis, I investigated:(1)The role of TYRO3 in BCa; (2) The radiosensitising effect of TYRO3 downregulation and inhibition in BCa cells; (3) The effect of TYRO3 downregulation and inhibition on normal human urothelial tissue.We first demonstrated that TYRO3 is overexpressed in 50% of MIBCs. TYRO3 overexpression conferred a TYRO3-dependance to bladder tumor cells for cell growth and viability. Transcriptomic analysis of TYRO3-downregulated cells suggested that TYRO3 signaling controlled cell cycle and protected from apoptosis, which indicated a potential to improve radiation response. TYRO3 downregulation lead to a significantly increased radiosensitivity of BCa cells and conversely, TYRO3-overexpression induced radioresistance. In combination with radiotherapy, TYRO3 dowregulation lead to a cell cycle arrest and a long term persistence of Ionizing Radiation-Induced Foci (IRIF). Finally, I demonstrated that TYRO3 downregulation and inhibition did not impact viability of normal human bladder cells suggesting that inhibiting TYRO3 could improve radiotherapy efficiency while sparing normal surrounding tissues