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Pesquisa : D12.776.157.125.050.110 [Categoria DeCS]
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[PMID]:29065150
[Au] Autor:Quattrocelli M; Capote J; Ohiri JC; Warner JL; Vo AH; Earley JU; Hadhazy M; Demonbreun AR; Spencer MJ; McNally EM
[Ad] Endereço:Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
[Ti] Título:Genetic modifiers of muscular dystrophy act on sarcolemmal resealing and recovery from injury.
[So] Source:PLoS Genet;13(10):e1007070, 2017 Oct.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Genetic disruption of the dystrophin complex produces muscular dystrophy characterized by a fragile muscle plasma membrane leading to excessive muscle degeneration. Two genetic modifiers of Duchenne Muscular Dystrophy implicate the transforming growth factor ß (TGFß) pathway, osteopontin encoded by the SPP1 gene and latent TGFß binding protein 4 (LTBP4). We now evaluated the functional effect of these modifiers in the context of muscle injury and repair to elucidate their mechanisms of action. We found that excess osteopontin exacerbated sarcolemmal injury, and correspondingly, that loss of osteopontin reduced injury extent both in isolated myofibers and in muscle in vivo. We found that ablation of osteopontin was associated with reduced expression of TGFß and TGFß-associated pathways. We identified that increased TGFß resulted in reduced expression of Anxa1 and Anxa6, genes encoding key components of the muscle sarcolemma resealing process. Genetic manipulation of Ltbp4 in dystrophic muscle also directly modulated sarcolemmal resealing, and Ltbp4 alleles acted in concert with Anxa6, a distinct modifier of muscular dystrophy. These data provide a model in which a feed forward loop of TGFß and osteopontin directly impacts the capacity of muscle to recover from injury, and identifies an intersection of genetic modifiers on muscular dystrophy.
[Mh] Termos MeSH primário: Genes Modificadores
Proteínas de Ligação a TGF-beta Latente/fisiologia
Músculo Esquelético/fisiologia
Distrofia Muscular Animal/genética
Osteopontina/metabolismo
[Mh] Termos MeSH secundário: Animais
Anexina A1/genética
Anexina A1/metabolismo
Anexina A6/genética
Anexina A6/metabolismo
Feminino
Regulação da Expressão Gênica
Masculino
Camundongos
Camundongos Endogâmicos DBA
Camundongos Knockout
Músculo Esquelético/lesões
Distrofia Muscular Animal/metabolismo
Distrofia Muscular Animal/patologia
Osteopontina/genética
Receptores de Fatores de Crescimento Transformadores beta/genética
Receptores de Fatores de Crescimento Transformadores beta/metabolismo
Recuperação de Função Fisiológica
Sarcolema/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A1); 0 (Annexin A6); 0 (LTBP-4 protein, mouse); 0 (Latent TGF-beta Binding Proteins); 0 (Receptors, Transforming Growth Factor beta); 0 (Spp1 protein, mouse); 0 (annexin A1, mouse); 106441-73-0 (Osteopontin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007070


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[PMID]:28881357
[Au] Autor:O'Sullivan D; Dowling P; Joyce H; McAuley E; McCann A; Henry M; McGovern B; Barham P; Kelleher FC; Murphy J; Kennedy S; Swan N; Moriarty M; Clynes M; Larkin A
[Ad] Endereço:National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
[Ti] Título:A novel inhibitory anti-invasive MAb isolated using phenotypic screening highlights AnxA6 as a functionally relevant target protein in pancreatic cancer.
[So] Source:Br J Cancer;117(9):1326-1335, 2017 Oct 24.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Discovery and validation of new antibody tractable targets is critical for the development of new antibody therapeutics to address unmet needs in oncology. METHODS: A highly invasive clonal variant of the MDA-MB-435S cell line was used to generate monoclonal antibodies (MAbs), which were screened for anti-invasive activity against aggressive cancer cells in vitro. The molecular target of selected inhibitory MAb 9E1 was identified using immunoprecipitation/liquid chromatography-tandem mass spectrometry. The potential anti-tumour effects of MAb 9E1 were investigated in vitro together with immunohistochemical analysis of the 9E1 target antigen in normal and cancer tissues. RESULTS: MAb 9E1 significantly decreases invasion in pancreatic, lung squamous and breast cancer cells and silencing of its target antigen, which was revealed as AnxA6, leads to markedly reduced invasive capacity of pancreatic and lung squamous cancer in vitro. IHC using MAb 9E1 revealed that AnxA6 exhibits a high prevalence of membrane immunoreactivity across aggressive tumour types with restricted expression observed in the majority of normal tissues. In pancreatic ductal adenocarcinoma, high AnxA6 IHC score correlated with the presence of tumour budding at the invasive front of tumours (P=0.082), the presence of perineural invasion (P= <0.0001) and showed a weak correlation with reduced survival (P=0.2242). CONCLUSIONS: This study highlights the use of phenotypic hybridoma screening as an effective strategy to select a novel function-blocking MAb, 9E1 with anti-cancer activity in vitro. Moreover, through characterisation of the 9E1 target antigen, AnxA6, our findings support further investigation of AnxA6 as a potential candidate target for antibody-mediated inhibition of pancreatic cancer.
[Mh] Termos MeSH primário: Anexina A6/metabolismo
Anticorpos Monoclonais/imunologia
Biomarcadores Tumorais/metabolismo
Neoplasias da Mama/metabolismo
Carcinoma Ductal Pancreático/metabolismo
Carcinoma de Células Escamosas/metabolismo
Neoplasias Pulmonares/metabolismo
Neoplasias Pancreáticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Anexina A6/antagonistas & inibidores
Anexina A6/imunologia
Neoplasias da Mama/imunologia
Neoplasias da Mama/patologia
Carcinoma Ductal Pancreático/imunologia
Carcinoma Ductal Pancreático/patologia
Carcinoma de Células Escamosas/imunologia
Carcinoma de Células Escamosas/patologia
Feminino
Seres Humanos
Neoplasias Pulmonares/imunologia
Neoplasias Pulmonares/patologia
Camundongos
Estadiamento de Neoplasias
Neoplasias Pancreáticas/imunologia
Neoplasias Pancreáticas/patologia
Prognóstico
Taxa de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A6); 0 (Antibodies, Monoclonal); 0 (Biomarkers, Tumor)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.306


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[PMID]:28712927
[Au] Autor:Cairns R; Alvarez-Guaita A; Martínez-Saludes I; Wason SJ; Hanh J; Nagarajan SR; Hosseini-Beheshti E; Monastyrskaya K; Hoy AJ; Buechler C; Enrich C; Rentero C; Grewal T
[Ad] Endereço:Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia.
[Ti] Título:Role of hepatic Annexin A6 in fatty acid-induced lipid droplet formation.
[So] Source:Exp Cell Res;358(2):397-410, 2017 Sep 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Annexin A6 (AnxA6) has been implicated in the regulation of endo-/exocytic pathways, cholesterol transport, and the formation of multifactorial signaling complexes in many different cell types. More recently, AnxA6 has also been linked to triglyceride storage in adipocytes. Here we investigated the potential role of AnxA6 in fatty acid (FA) - induced lipid droplet (LD) formation in hepatocytes. AnxA6 was associated with LD from rat liver and HuH7 hepatocytes. In oleic acid (OA) -loaded HuH7 cells, substantial amounts of AnxA6 bound to LD in a Ca -independent manner. Remarkably, stable or transient AnxA6 overexpression in HuH7 cells led to elevated LD numbers/size and neutral lipid staining under control conditions as well as after OA loading compared to controls. In contrast, overexpression of AnxA1, AnxA2 and AnxA8 did not impact on OA-induced lipid accumulation. On the other hand, incubation of AnxA6-depleted HuH7 cells or primary hepatocytes from AnxA6 KO-mice with OA led to reduced FA accumulation and LD numbers. Furthermore, morphological analysis of liver sections from A6-KO mice revealed significantly lower LD numbers compared to wildtype animals. Interestingly, pharmacological inhibition of cytoplasmic phospholipase A2α (cPLA α)-dependent LD formation was ineffective in AnxA6-depleted HuH7 cells. We conclude that cPLA α-dependent pathways contribute to the novel regulatory role of hepatic AnxA6 in LD formation.
[Mh] Termos MeSH primário: Anexina A6/metabolismo
Hepatócitos/metabolismo
Gotículas Lipídicas/metabolismo
Lipogênese/fisiologia
[Mh] Termos MeSH secundário: Animais
Transporte Biológico/fisiologia
Linhagem Celular
Seres Humanos
Fígado/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A6)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE


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[PMID]:28481224
[Au] Autor:Quattrocelli M; Barefield DY; Warner JL; Vo AH; Hadhazy M; Earley JU; Demonbreun AR; McNally EM
[Ti] Título:Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy.
[So] Source:J Clin Invest;127(6):2418-2432, 2017 Jun 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glucocorticoid steroids such as prednisone are prescribed for chronic muscle conditions such as Duchenne muscular dystrophy, where their use is associated with prolonged ambulation. The positive effects of chronic steroid treatment in muscular dystrophy are paradoxical because these steroids are also known to trigger muscle atrophy. Chronic steroid use usually involves once-daily dosing, although weekly dosing in children has been suggested for its reduced side effects on behavior. In this work, we tested steroid dosing in mice and found that a single pulse of glucocorticoid steroids improved sarcolemmal repair through increased expression of annexins A1 and A6, which mediate myofiber repair. This increased expression was dependent on glucocorticoid response elements upstream of annexins and was reinforced by the expression of forkhead box O1 (FOXO1). We compared weekly versus daily steroid treatment in mouse models of acute muscle injury and in muscular dystrophy and determined that both regimens provided comparable benefits in terms of annexin gene expression and muscle repair. However, daily dosing activated atrophic pathways, including F-box protein 32 (Fbxo32), which encodes atrogin-1. Conversely, weekly steroid treatment in mdx mice improved muscle function and histopathology and concomitantly induced the ergogenic transcription factor Krüppel-like factor 15 (Klf15) while decreasing Fbxo32. These findings suggest that intermittent, rather than daily, glucocorticoid steroid regimen promotes sarcolemmal repair and muscle recovery from injury while limiting atrophic remodeling.
[Mh] Termos MeSH primário: Glucocorticoides/administração & dosagem
Músculo Esquelético/efeitos dos fármacos
Prednisona/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Anexina A6/genética
Anexina A6/metabolismo
Células Cultivadas
Esquema de Medicação
Avaliação Pré-Clínica de Medicamentos
Expressão Gênica
Glucocorticoides/efeitos adversos
Masculino
Camundongos da Linhagem 129
Camundongos Endogâmicos DBA
Camundongos Endogâmicos mdx
Músculo Esquelético/fisiopatologia
Atrofia Muscular/induzido quimicamente
Distrofia Muscular de Duchenne/tratamento farmacológico
Prednisona/efeitos adversos
Ligação Proteica
Receptores de Glucocorticoides/metabolismo
Regeneração
Sarcolema/efeitos dos fármacos
Sarcolema/fisiologia
Ativação Transcricional/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A6); 0 (Glucocorticoids); 0 (Receptors, Glucocorticoid); VB0R961HZT (Prednisone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170509
[St] Status:MEDLINE


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[PMID]:28369848
[Au] Autor:Cui L; Rashdan NA; Zhu D; Milne EM; Ajuh P; Milne G; Helfrich MH; Lim K; Prasad S; Lerman DA; Vesey AT; Dweck MR; Jenkins WS; Newby DE; Farquharson C; Macrae VE
[Ad] Endereço:The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, United Kingdom.
[Ti] Título:End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.
[So] Source:J Cell Physiol;232(11):2985-2995, 2017 Nov.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Patients with end-stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4-fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8-fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP-1, and LAMP-2 and a concomitant up-regulation of the Annexin family of calcium-binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC-derived MVs (51.9-fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up-regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC-derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co-localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC-derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.
[Mh] Termos MeSH primário: Anexina A6/metabolismo
Estenose da Valva Aórtica/metabolismo
Valva Aórtica/metabolismo
Valva Aórtica/patologia
Calcinose/metabolismo
Matriz Extracelular/metabolismo
Vesículas Extracelulares/metabolismo
Hipercalcemia/etiologia
Falência Renal Crônica/complicações
[Mh] Termos MeSH secundário: Idoso
Fosfatase Alcalina/genética
Fosfatase Alcalina/metabolismo
Animais
Valva Aórtica/ultraestrutura
Estenose da Valva Aórtica/etiologia
Estenose da Valva Aórtica/genética
Estenose da Valva Aórtica/patologia
Calcinose/etiologia
Calcinose/genética
Calcinose/patologia
Cálcio/metabolismo
Células Cultivadas
Subunidade alfa 1 de Fator de Ligação ao Core/genética
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo
Matriz Extracelular/ultraestrutura
Vesículas Extracelulares/ultraestrutura
Feminino
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/metabolismo
Seres Humanos
Hipercalcemia/diagnóstico
Falência Renal Crônica/diagnóstico
Masculino
Microscopia Eletrônica de Transmissão
Mapas de Interação de Proteínas
Proteômica/métodos
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Ratos Sprague-Dawley
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A6); 0 (Core Binding Factor Alpha 1 Subunit); 0 (Homeodomain Proteins); 0 (MSX2 protein); 0 (RNA, Messenger); 0 (Runx2 protein, rat); EC 3.1.3.1 (Alkaline Phosphatase); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25935


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[PMID]:28315296
[Au] Autor:Shah A; Schiffmacher AT; Taneyhill LA
[Ad] Endereço:Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
[Ti] Título:Annexin A6 controls neuronal membrane dynamics throughout chick cranial sensory gangliogenesis.
[So] Source:Dev Biol;425(1):85-99, 2017 05 01.
[Is] ISSN:1095-564X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cranial sensory ganglia are components of the peripheral nervous system that possess a significant somatosensory role and include neurons within the trigeminal and epibranchial nerve bundles. Although it is well established that these ganglia arise from interactions between neural crest and neurogenic placode cells, the molecular basis of ganglia assembly is still poorly understood. Members of the Annexin protein superfamily play key roles in sensory nervous system development throughout metazoans. Annexin A6 is expressed in chick trigeminal and epibranchial placode cell-derived neuroblasts and neurons, but its function in cranial ganglia formation has not been elucidated. To this end, we interrogated the role of Annexin A6 using gene perturbation studies in the chick embryo. Our data reveal that placode cell-derived neuroblasts with reduced Annexin A6 levels ingress and migrate normally to the ganglionic anlage, where neural crest cell corridors correctly form around them. Strikingly, while Annexin A6-depleted placode cell-derived neurons still express mature neuronal markers, they fail to form two long processes, which are considered morphological features of mature neurons, and no longer innervate their designated targets due to the absence of this bipolar morphology. Moreover, overexpression of Annexin A6 causes some placode cell-derived neurons to form extra protrusions alongside these bipolar processes. These data demonstrate that the molecular program associated with neuronal maturation is distinct from that orchestrating changes in neuronal morphology, and, importantly, reveal Annexin A6 to be a key membrane scaffolding protein during sensory neuron membrane biogenesis. Collectively, our results provide novel insight into mechanisms underscoring morphological changes within placode cell-derived neurons that are essential for cranial gangliogenesis.
[Mh] Termos MeSH primário: Anexina A6/metabolismo
Proteínas Aviárias/metabolismo
Membrana Celular/metabolismo
Gânglios Sensitivos/metabolismo
Células Receptoras Sensoriais/metabolismo
Crânio/inervação
[Mh] Termos MeSH secundário: Processamento Alternativo
Animais
Anexina A6/genética
Proteínas Aviárias/genética
Sequência de Bases
Embrião de Galinha
Galinhas
Gânglios Sensitivos/citologia
Gânglios Sensitivos/embriologia
Regulação da Expressão Gênica no Desenvolvimento
Técnicas de Silenciamento de Genes
Immunoblotting
Microscopia Confocal
Células-Tronco Neurais/citologia
Células-Tronco Neurais/metabolismo
Células Receptoras Sensoriais/citologia
Homologia de Sequência do Ácido Nucleico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Annexin A6); 0 (Avian Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170319
[St] Status:MEDLINE


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[PMID]:27984093
[Au] Autor:Enrich C; Rentero C; Grewal T
[Ad] Endereço:Departament de Biomedicina, Unitat de Biologia Cellular, Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain. Electronic address: enrich@ub.edu.
[Ti] Título:Annexin A6 in the liver: From the endocytic compartment to cellular physiology.
[So] Source:Biochim Biophys Acta;1864(6):933-946, 2017 06.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Annexin A6 (AnxA6) belongs to the conserved annexin family - a group of Ca -dependent membrane binding proteins. AnxA6 is the largest of all annexins and highly expressed in smooth muscle, hepatocytes, endothelial cells and cardiomyocytes. Upon activation, AnxA6 binds to negatively charged phospholipids in a wide range of intracellular localizations, in particular the plasma membrane, late endosomes/pre-lysosomes, but also synaptic vesicles and sarcolemma. In these cellular sites, AnxA6 is believed to contribute to the organization of membrane microdomains, such as cholesterol-rich lipid rafts and confer multiple regulatory functions, ranging from vesicle fusion, endocytosis and exocytosis to programmed cell death and muscle contraction. Growing evidence supports that Ca and Ca -binding proteins control endocytosis and autophagy. Their regulatory role seems to operate at the level of the signalling pathways that initiate autophagy or at later stages, when autophagosomes fuse with endolysosomal compartments. The convergence of the autophagic and endocytic vesicles to lysosomes shares several features that depend on Ca originating from lysosomes/late endosomes and seems to depend on proteins that are subsequently activated by this cation. However, the involvement of Ca and its effector proteins in these autophagic and endocytic stages still remains poorly understood. Although AnxA6 makes up almost 0.25% of total protein in the liver, little is known about its function in hepatocytes. Within the endocytic route, we identified AnxA6 in endosomes and autophagosomes of hepatocytes. Hence, AnxA6 and possibly other annexins might represent new Ca effectors that regulate converging steps of autophagy and endocytic trafficking in hepatocytes. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
[Mh] Termos MeSH primário: Anexina A6/metabolismo
Compartimento Celular
Endocitose
Fígado/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Linhagem Celular Tumoral
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Annexin A6)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE


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[PMID]:27783649
[Au] Autor:Dismuke WM; Klingeborn M; Stamer WD
[Ad] Endereço:Department of Ophthalmology, Duke University, Durham, North Carolina, United States of America.
[Ti] Título:Mechanism of Fibronectin Binding to Human Trabecular Meshwork Exosomes and Its Modulation by Dexamethasone.
[So] Source:PLoS One;11(10):e0165326, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Exosomes are emerging as important mediators of cell-matrix interactions by means of specific adhesion proteins. Changes in the tissue-specific exosomal protein expression may underlie pathological conditions whereby extracellular matrix turnover and homeostasis is disrupted. Ocular hypertension due to extracellular matrix accumulation in the trabecular meshwork is a hallmark of glucocorticoid-induced glaucoma. In the trabecular meshwork, exosomal fibronectin mediates cell matrix interactions at cellular structures called "invadosomes". Trabecular meshwork cells use invadosomes to turn over their surrounding matrix and maintain passageways for flow of aqueous humor. In this study, we observed that human trabecular meshwork explants treated with dexamethasone released exosomes with significantly reduced amounts of fibronectin bound per exosome. Further, we found that exosome-fibronectin binding is heparan sulfate-dependent, consistent with our observation that trabecular meshwork exosomes are enriched in the heparin/heparan sulfate binding annexins A2 and A6. In this way, dexamethasone-treated explants released exosomes with a significant reduction in annexin A2 and A6 per exosome. Interestingly, we did not detect exosomal matrix metalloproteinases, but we identified abundant dipeptidyl peptidase 4, a serine protease whose activity was reduced on exosomes isolated from dexamethasone-treated explants. Together, our findings demonstrate mechanistically how corticosteroid-induced alterations in exosomal adhesion cargo and properties can account for the pathological matrix accumulation seen in many glaucoma patients.
[Mh] Termos MeSH primário: Dexametasona/farmacologia
Exossomos/efeitos dos fármacos
Fibronectinas/metabolismo
[Mh] Termos MeSH secundário: Anexina A2/química
Anexina A2/metabolismo
Anexina A6/química
Anexina A6/metabolismo
Anti-Inflamatórios/farmacologia
Células Cultivadas
Meios de Cultura Livres de Soro/química
Exossomos/química
Exossomos/metabolismo
Matriz Extracelular/metabolismo
Fibronectinas/química
Heparitina Sulfato/química
Heparitina Sulfato/metabolismo
Seres Humanos
Nanopartículas/química
Nanopartículas/metabolismo
Ligação Proteica
Malha Trabecular/citologia
Malha Trabecular/efeitos dos fármacos
Malha Trabecular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A2); 0 (Annexin A6); 0 (Anti-Inflammatory Agents); 0 (Culture Media, Serum-Free); 0 (Fibronectins); 7S5I7G3JQL (Dexamethasone); 9050-30-0 (Heparitin Sulfate)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161027
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0165326


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[PMID]:27701147
[Au] Autor:Leca J; Martinez S; Lac S; Nigri J; Secq V; Rubis M; Bressy C; Sergé A; Lavaut MN; Dusetti N; Loncle C; Roques J; Pietrasz D; Bousquet C; Garcia S; Granjeaud S; Ouaissi M; Bachet JB; Brun C; Iovanna JL; Zimmermann P; Vasseur S; Tomasini R
[Ti] Título:Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness.
[So] Source:J Clin Invest;126(11):4140-4156, 2016 Nov 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk. Formation of the ANXA6/LRP1/TSP1 complex was restricted to cancer-associated fibroblasts (CAFs) and required physiopathologic culture conditions that improved tumor cell survival and migration. Increased PDA aggressiveness was dependent on tumor cell-mediated uptake of CAF-derived ANXA6+ EVs carrying the ANXA6/LRP1/TSP1 complex. Depletion of ANXA6 in CAFs impaired complex formation and subsequently impaired PDA and metastasis occurrence, while injection of CAF-derived ANXA6+ EVs enhanced tumorigenesis. We found that the presence of ANXA6+ EVs in serum was restricted to PDA patients and represents a potential biomarker for PDA grade. These findings suggest that CAF-tumor cell crosstalk supported by ANXA6+ EVs is predictive of PDA aggressiveness, highlighting a therapeutic target and potential biomarker for PDA.
[Mh] Termos MeSH primário: Anexina A6/metabolismo
Biomarcadores Tumorais/metabolismo
Carcinoma Ductal Pancreático/metabolismo
Micropartículas Derivadas de Células/metabolismo
Fibroblastos/metabolismo
Proteínas de Neoplasias/metabolismo
Neoplasias Pancreáticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo
Carcinoma Ductal Pancreático/patologia
Comunicação Celular
Micropartículas Derivadas de Células/patologia
Feminino
Fibroblastos/patologia
Seres Humanos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Masculino
Camundongos
Camundongos Nus
Neoplasias Pancreáticas/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A6); 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors); 0 (Biomarkers, Tumor); 0 (LRP1 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Neoplasm Proteins); 0 (SPZ1 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE


  10 / 321 MEDLINE  
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[PMID]:27334756
[Au] Autor:Meier EM; Rein-Fischboeck L; Pohl R; Wanninger J; Hoy AJ; Grewal T; Eisinger K; Krautbauer S; Liebisch G; Weiss TS; Buechler C
[Ad] Endereço:Department of Internal Medicine I, Regensburg University Hospital, Regensburg, 93042, Germany.
[Ti] Título:Annexin A6 protein is downregulated in human hepatocellular carcinoma.
[So] Source:Mol Cell Biochem;418(1-2):81-90, 2016 Jul.
[Is] ISSN:1573-4919
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Annexin A6 (AnxA6) is a lipid-binding protein highly expressed in the liver, regulating cholesterol homeostasis and signaling pathways with a role in liver physiology. Here, we analyzed whether hepatic AnxA6 levels are affected by pathological conditions that are associated with liver dysfunction and liver injury. AnxA6 levels in the fatty liver of mice fed a high-fat diet, in ob/ob and db/db animals and in human fatty liver are comparable to controls. Similarly, AnxA6 levels appear unaffected in murine nonalcoholic steatohepatitis and human liver fibrosis. Accordingly, adiponectin, lysophosphatidylcholine, palmitate, and TGFbeta, all of which have a role in liver injury, do not affect AnxA6 expression in human hepatocytes. Likewise, adiponectin and IL8 do not alter AnxA6 levels in primary human hepatic stellate cells. However, in hepatic tumors of 18 patients, AnxA6 protein levels are substantially reduced compared to nontumorous tissues. AnxA6 mRNA is even increased in the tumors suggesting that posttranscriptional mechanisms are involved herein. Lipidomic analysis shows trends toward elevated cholesteryl ester and sphingomyelin in the tumor samples, yet the ratio of tumor to nontumorous AnxA6 does not correlate with these lipids. The current study shows that AnxA6 is specifically reduced in human hepatocellular carcinoma suggesting a role of this protein in hepatocarcinogenesis.
[Mh] Termos MeSH primário: Anexina A6/biossíntese
Carcinoma Hepatocelular/metabolismo
Regulação para Baixo
Regulação Neoplásica da Expressão Gênica
Neoplasias Hepáticas/metabolismo
Proteínas de Neoplasias/biossíntese
[Mh] Termos MeSH secundário: Anexina A6/genética
Carcinoma Hepatocelular/genética
Carcinoma Hepatocelular/patologia
Células Hep G2
Seres Humanos
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/patologia
Proteínas de Neoplasias/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A6); 0 (Neoplasm Proteins)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160624
[St] Status:MEDLINE
[do] DOI:10.1007/s11010-016-2735-9



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