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[PMID]:29317209
[Au] Autor:Gong Y; Zhu Y; Zhu B; Si X; Heng D; Tang Y; Sun X; Lin L
[Ad] Endereço:Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
[Ti] Título:LncRNA MALAT1 is up-regulated in diabetic gastroparesis and involved in high-glucose-induced cellular processes in human gastric smooth muscle cells.
[So] Source:Biochem Biophys Res Commun;496(2):401-406, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent years, widespread long non-coding RNAs (lncRNAs) were identified and known as regulator of gene expression. Diabetic gastroparesis (DGP) is one of the most common chronic complications of diabetes mellitus. There was no research reported the role of lncRNAs in DGP. In this study, we firstly established a rat model of DGP by STZ injection. Then, we detected the expression of MALAT1 and found that expression of MALAT1 was up-regulated in rat model of DGP, comparing to the control group (P < .01). Furthermore, we revealed that MALAT1 expression was increased in the samples from diabetic patients with DGP symptoms, in comparison with the control. In addition, we demonstrated that the inhibition of MALAT1 increased the expression of α-SMA and SM myosin heavy chains, reduced the cell viability, inhibited the potential of cell migration and induced cell apoptosis in human gastric smooth muscle cells (SMCs). Ultimately, we found that the regulation of MALAT1 expression modulated the function of high-glucose stimulation in human gastric SMCs. Therefore, our study firstly indicated that MALAT1 was up-regulated in DGP and played an important role in the pathogenesis of DGP.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/genética
Neuropatias Diabéticas/genética
Gastroparesia/genética
Miócitos de Músculo Liso/metabolismo
RNA Longo não Codificante/genética
Estômago/metabolismo
[Mh] Termos MeSH secundário: Actinas/genética
Actinas/metabolismo
Animais
Apoptose/efeitos dos fármacos
Apoptose/genética
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Diabetes Mellitus Experimental/induzido quimicamente
Diabetes Mellitus Experimental/complicações
Diabetes Mellitus Experimental/metabolismo
Neuropatias Diabéticas/induzido quimicamente
Neuropatias Diabéticas/complicações
Neuropatias Diabéticas/metabolismo
Esvaziamento Gástrico
Gastroparesia/induzido quimicamente
Gastroparesia/complicações
Gastroparesia/metabolismo
Regulação da Expressão Gênica
Glucose/farmacologia
Seres Humanos
Masculino
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/patologia
Cadeias Pesadas de Miosina/genética
Cadeias Pesadas de Miosina/metabolismo
Cultura Primária de Células
RNA Longo não Codificante/metabolismo
Ratos
Ratos Sprague-Dawley
Transdução de Sinais
Estômago/efeitos dos fármacos
Estômago/patologia
Estreptozocina
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ACTA2 protein, human); 0 (Actins); 0 (MALAT1 long non-coding RNA, human); 0 (RNA, Long Noncoding); 5W494URQ81 (Streptozocin); EC 3.6.4.1 (Myosin Heavy Chains); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


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[PMID]:29200148
[Au] Autor:Aoki T; Kunishima S; Yamashita Y; Minamitani K; Ota S
[Ad] Endereço:Department of Pediatrics, Teikyo University Chiba Medical Center, Chiba.
[Ti] Título:Macrothrombocytopenia With Congenital Bilateral Cataracts: A Phenotype of MYH9 Disorder With Exon 24 Indel Mutations.
[So] Source:J Pediatr Hematol Oncol;40(1):76-78, 2018 Jan.
[Is] ISSN:1536-3678
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:MYH9 disorder is characterized by large platelets and granulocyte inclusion bodies, and can be complicated with young-adult onsets of nephropathy, sensorineural hearing loss, and cataracts. Congenital cataracts in patients with MYH9 disorder is rare, and their etiology has not been elucidated. We report a 3-year-old patient with MYH9 disorder who had a p.E1066_A1072del mutation and developed cataracts congenitally. A review of the literature reveals that patients with an MYH9 exon 24 indel mutation, including p.E1066_A1072del, are susceptible to developing congenital cataracts and should be followed closely for other nonhematological complications.
[Mh] Termos MeSH primário: Catarata/congênito
Granulócitos/ultraestrutura
Mutação INDEL
Proteínas Motores Moleculares/genética
Cadeias Pesadas de Miosina/genética
Trombocitopenia/complicações
[Mh] Termos MeSH secundário: Plaquetas/patologia
Catarata/genética
Pré-Escolar
Éxons
Granulócitos/patologia
Perda Auditiva Neurossensorial
Seres Humanos
Corpos de Inclusão/patologia
Fenótipo
Trombocitopenia/congênito
Trombocitopenia/etiologia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MYH9 protein, human); 0 (Molecular Motor Proteins); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180112
[Lr] Data última revisão:
180112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1097/MPH.0000000000000998


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[PMID]:29224747
[Au] Autor:Talebi F; Mardasi FG; Asl JM; Sayahi M
[Ad] Endereço:Ahvaz Welfare Organization, Ahvaz, Iran.
[Ti] Título:Next-generation sequencing identifies three novel missense variants in ILDR1 and MYO6 genes in an Iranian family with hearing loss with review of the literature.
[So] Source:Int J Pediatr Otorhinolaryngol;103:103-108, 2017 Dec.
[Is] ISSN:1872-8464
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Hearing impairment is the most common sensorineural disorder and is genetically heterogeneous. Identification of the pathogenic mutations underlying hearing impairment is difficult, since causative mutations in 127 different genes have so far been reported. METHODS: In this study, we performed Next-generation sequencing (NGS) in 2 individuals from a consanguineous family with hearing loss. RESULTS: Three novel mutations in known deafness genes were identified in the family; MYO6-p.R928C and -p.D1223N in heterozygous state and ILDR1-p.Y143C in homozygous state. Sanger sequencing confirmed co-segregation of the three mutations with deafness in the family. The identified mutation in ILDR1 gene is located in the immunoglobulin-type domain of the ILDR1 protein and the detected mutations in MY06 are located in the tail domain of the MYO6 protein. The mutations are predicted to be pathogenic by SIFT, PolyPhen and Mutation Taster. CONCLUSIONS: Our results suggest that either the homozygous ILDR1-p.Y143C mutation might be the pathogenic variant for ARNSHL or heterozygous MYO6- p.R928C, -p.D1223N might be involved in these patient's disorder due to compound heterozygousity. To our knowledge, this is the first ILDR1 and MYO6 mutations recognized in the southwest Iran. Our data expands the spectrum of mutations in ILDR1 and MYO6 genes.
[Mh] Termos MeSH primário: Perda Auditiva/genética
Cadeias Pesadas de Miosina/genética
Receptores de Superfície Celular/genética
[Mh] Termos MeSH secundário: Feminino
Heterogeneidade Genética
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Seres Humanos
Irã (Geográfico)
Masculino
Mutação
Linhagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (ILDR1 protein, human); 0 (Receptors, Cell Surface); 0 (myosin VI); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


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[PMID]:29203562
[Au] Autor:Hartupee J; Szalai GD; Wang W; Ma X; Diwan A; Mann DL
[Ad] Endereço:From the Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO (J.H., X.M., A.D., D.L.M.); John Cochran VA Medical Center, St. Louis, MO (A.D.); and Winters Center for Heart Failure Research, Section of Cardiology, Department of Medicine, Baylor Col
[Ti] Título:Impaired Protein Quality Control During Left Ventricular Remodeling in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor.
[So] Source:Circ Heart Fail;10(12), 2017 Dec.
[Is] ISSN:1941-3297
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sustained inflammation in the heart is sufficient to provoke left ventricular dysfunction and left ventricular remodeling. Although inflammation has been linked to many of the biological changes responsible for adverse left ventricular remodeling, the relationship between inflammation and protein quality control in the heart is not well understood. METHODS AND RESULTS: To study the relationship between chronic inflammation and protein quality control, we used a mouse model of dilated cardiomyopathy driven by cardiac restricted overexpression of TNF (tumor necrosis factor; -sTNF). -sTNF mice develop protein aggregates containing ubiquitin-tagged proteins within cardiac myocytes related to proteasome dysfunction and impaired autophagy. The 26S proteasome was dysfunctional despite normal function of the core 20S subunit. We found an accumulation of autophagy substrates in -sTNF mice, which were also seen in tissue from patients with end-stage heart failure. Moreover, there was evidence of impaired autophagosome clearance after chloroquine administration in these mice indicative of impaired autophagic flux. Finally, there was increased mammalian target of rapamycin complex 1 (mTORC1) activation, which has been linked to inhibition of both the proteasome and autophagy. CONCLUSIONS: -sTNF mice with sustained inflammatory signaling develop proteasome dysfunction and impaired autophagic flux that is associated with enhanced mTORC1 activation.
[Mh] Termos MeSH primário: Cardiomiopatia Dilatada/enzimologia
Ventrículos do Coração/enzimologia
Mediadores da Inflamação/metabolismo
Miócitos Cardíacos/enzimologia
Complexo de Endopeptidases do Proteassoma/metabolismo
Fator de Necrose Tumoral alfa/metabolismo
Disfunção Ventricular Esquerda/enzimologia
Função Ventricular Esquerda
Remodelação Ventricular
[Mh] Termos MeSH secundário: Animais
Autofagossomos/enzimologia
Autofagossomos/patologia
Autofagia
Cardiomiopatia Dilatada/genética
Cardiomiopatia Dilatada/patologia
Cardiomiopatia Dilatada/fisiopatologia
Modelos Animais de Doenças
Predisposição Genética para Doença
Insuficiência Cardíaca/enzimologia
Insuficiência Cardíaca/patologia
Ventrículos do Coração/patologia
Ventrículos do Coração/fisiopatologia
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
Camundongos Transgênicos
Miócitos Cardíacos/patologia
Cadeias Pesadas de Miosina/genética
Fenótipo
Regiões Promotoras Genéticas
Agregados Proteicos
Agregação Patológica de Proteínas
Fatores de Tempo
Fator de Necrose Tumoral alfa/genética
Ubiquitinação
Regulação para Cima
Disfunção Ventricular Esquerda/genética
Disfunção Ventricular Esquerda/patologia
Disfunção Ventricular Esquerda/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Inflammation Mediators); 0 (Myh6 protein, mouse); 0 (Protein Aggregates); 0 (Tumor Necrosis Factor-alpha); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.4.99.- (ATP dependent 26S protease); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE


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[PMID]:28471487
[Au] Autor:Hwang SY; Kang YJ; Sung B; Jang JY; Hwang NL; Oh HJ; Ahn YR; Kim HJ; Shin JH; Yoo MA; Kim CM; Chung HY; Kim ND
[Ad] Endereço:Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
[Ti] Título:Folic acid is necessary for proliferation and differentiation of C2C12 myoblasts.
[So] Source:J Cell Physiol;233(2):736-747, 2018 Feb.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Folic acid, a water soluble B vitamin, plays an important role in cellular metabolic activities, such as functioning as a cofactor in one-carbon metabolism for DNA and RNA synthesis as well as nucleotide and amino acid biosynthesis in the body. A lack of dietary folic acid can lead to folic acid deficiency and result in several health problems, including macrocytic anemia, elevated plasma homocysteine, cardiovascular disease, birth defects, carcinogenesis, muscle weakness, and walking difficulty. However, the effect of folic acid deficiency on skeletal muscle development and its molecular mechanisms are unknown. We, therefore, investigated the effect of folic acid deficiency on myogenesis in skeletal muscle cells and found that folic acid deficiency induced proliferation inhibition and cell cycle breaking as well as cellular senescence in C2C12 myoblasts, implying that folic acid deficiency influences skeletal muscle development. Folic acid deficiency also inhibited differentiation of C2C12 myoblasts and induced deregulation of the cell cycle exit and many cell cycle regulatory genes. It inhibited expression of muscle-specific marker MyHC as well as myogenic regulatory factor (myogenin). Moreover, immunocytochemistry and Western blot analyses revealed that DNA damage was more increased in folic acid-deficient medium-treated differentiating C2C12 cells. Furthermore, we found that folic acid resupplementation reverses the effect on the cell cycle and senescence in folic acid-deficient C2C12 myoblasts but does not reverse the differentiation of C2C12 cells. Altogether, the study results suggest that folic acid is necessary for normal development of skeletal muscle cells.
[Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Deficiência de Ácido Fólico/tratamento farmacológico
Ácido Fólico/farmacologia
Desenvolvimento Muscular/efeitos dos fármacos
Mioblastos Esqueléticos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Ciclo Celular/efeitos dos fármacos
Linhagem Celular
Senescência Celular/efeitos dos fármacos
Dano ao DNA
Deficiência de Ácido Fólico/metabolismo
Deficiência de Ácido Fólico/patologia
Camundongos
Mioblastos Esqueléticos/metabolismo
Mioblastos Esqueléticos/patologia
Miogenina/metabolismo
Cadeias Pesadas de Miosina/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Myog protein, mouse); 0 (Myogenin); 935E97BOY8 (Folic Acid); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25989


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[PMID]:28991257
[Au] Autor:Jin SC; Homsy J; Zaidi S; Lu Q; Morton S; DePalma SR; Zeng X; Qi H; Chang W; Sierant MC; Hung WC; Haider S; Zhang J; Knight J; Bjornson RD; Castaldi C; Tikhonoa IR; Bilguvar K; Mane SM; Sanders SJ; Mital S; Russell MW; Gaynor JW; Deanfield J; Giardini A; Porter GA; Srivastava D; Lo CW; Shen Y; Watkins WS; Yandell M; Yost HJ; Tristani-Firouzi M; Newburger JW; Roberts AE; Kim R; Zhao H; Kaltman JR; Goldmuntz E; Chung WK; Seidman JG; Gelb BD; Seidman CE; Lifton RP; Brueckner M
[Ad] Endereço:Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
[Ti] Título:Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.
[So] Source:Nat Genet;49(11):1593-1601, 2017 Nov.
[Is] ISSN:1546-1718
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
[Mh] Termos MeSH primário: Transtorno Autístico/genética
Miosinas Cardíacas/genética
Predisposição Genética para Doença
Fator 1 de Diferenciação de Crescimento/genética
Cardiopatias Congênitas/genética
Cadeias Pesadas de Miosina/genética
Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
[Mh] Termos MeSH secundário: Adulto
Transtorno Autístico/patologia
Estudos de Casos e Controles
Criança
Exoma
Feminino
Expressão Gênica
Estudo de Associação Genômica Ampla
Cardiopatias Congênitas/patologia
Heterozigoto
Sequenciamento de Nucleotídeos em Larga Escala
Homozigoto
Seres Humanos
Masculino
Mutação
Linhagem
Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GDF1 protein, human); 0 (Growth Differentiation Factor 1); 0 (MYH6 protein, human); EC 2.7.10.1 (FLT4 protein, human); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-3); EC 3.6.1.- (Cardiac Myosins); EC 3.6.4.1 (Myosin Heavy Chains)
[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:171010
[St] Status:MEDLINE
[do] DOI:10.1038/ng.3970


  7 / 6312 MEDLINE  
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[PMID]:28927399
[Au] Autor:Bánfai Z; Hadzsiev K; Pál E; Komlósi K; Melegh M; Balikó L; Melegh B
[Ad] Endereço:Department of Medical Genetics, University of Pécs, Szigeti út 12, Pécs, H-7624, Hungary.
[Ti] Título:Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report.
[So] Source:BMC Med Genet;18(1):105, 2017 Sep 19.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Defects of the slow myosin heavy chain isoform coding MYH7 gene primarily cause skeletal myopathies including Laing Distal Myopathy, Myosin Storage Myopathy and are also responsible for cardiomyopathies. Scapuloperoneal and limb-girdle muscle weakness, congenital fiber type disproportion, multi-minicore disease were also reported in connection of MYH7. Pathogeneses of the defects in the head and proximal rod region of the protein are well described. However, the C-terminal mutations of the MYH7 gene are less known. Moreover, only two articles describe the phenotypic impact of the elongated mature protein product caused by termination signal loss. CASE PRESENTATION: Here we present a male patient with an unusual phenotypic variant of early-onset and predominant involvement of neck muscles with muscle biopsy indicating myopathy and sarcoplasmic storage material. Cardiomyopathic involvements could not be observed. Sequencing of MYH7 gene revealed a stop-loss mutation on the 3-prime end of the rod region, which causes the elongation of the mature protein. CONCLUSIONS: The elongated protein likely disrupts the functions of the sarcomere by multiple functional abnormalities. This elongation could also affect the thick filament degradation leading to protein deposition and accumulation in the sarcomere, resulting in the severe myopathy of certain axial muscles. The phenotypic expression of the detected novel MYH7 genotype could strengthen and further expand our knowledge about mutations affecting the structure of MyHCI by termination signal loss in the MYH7 gene.
[Mh] Termos MeSH primário: Miosinas Cardíacas/genética
Variação Genética
Doenças Musculares/congênito
Cadeias Pesadas de Miosina/genética
[Mh] Termos MeSH secundário: Miopatias Distais/diagnóstico por imagem
Miopatias Distais/genética
Predisposição Genética para Doença
Seres Humanos
Masculino
Meia-Idade
Músculo Esquelético/patologia
Doenças Musculares/diagnóstico por imagem
Doenças Musculares/genética
Mutação
Miopatias Congênitas Estruturais/diagnóstico por imagem
Miopatias Congênitas Estruturais/genética
Oftalmoplegia/diagnóstico por imagem
Oftalmoplegia/genética
Fenótipo
Canal de Liberação de Cálcio do Receptor de Rianodina/deficiência
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MYH7 protein, human); 0 (Ryanodine Receptor Calcium Release Channel); EC 3.6.1.- (Cardiac Myosins); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0463-y


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[PMID]:28899987
[Au] Autor:Li Y; Zhu G; Paolocci N; Zhang P; Takahashi C; Okumus N; Heravi A; Keceli G; Ramirez-Correa G; Kass DA; Murphy AM
[Ad] Endereço:From the Division of Cardiology, Department of Pediatrics (Y.L., N.O., A.H., G.R.-C., A.M.M.), Division of Cardiology, Department of Medicine (G.Z., N.P., C.T., G.K., D.A.K.), Department of Pharmacology and Molecular Sciences, Department of Biomedical Engineering (D.A.K.), and Deparment of Ophthalmo
[Ti] Título:Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.
[So] Source:Circ Heart Fail;10(9), 2017 Sep.
[Is] ISSN:1941-3297
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown. METHODS AND RESULTS: To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific α-myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or ß-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts. CONCLUSIONS: Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI.
[Mh] Termos MeSH primário: Insuficiência Cardíaca/metabolismo
Hemodinâmica
Contração Miocárdica
Traumatismo por Reperfusão Miocárdica/metabolismo
Troponina I/metabolismo
Função Ventricular Esquerda
[Mh] Termos MeSH secundário: Agonistas Adrenérgicos beta/farmacologia
Animais
Calpaína/metabolismo
Modelos Animais de Doenças
Predisposição Genética para Doença
Insuficiência Cardíaca/genética
Insuficiência Cardíaca/fisiopatologia
Hemodinâmica/efeitos dos fármacos
Preparação de Coração Isolado
Masculino
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Mutação
Contração Miocárdica/efeitos dos fármacos
Traumatismo por Reperfusão Miocárdica/genética
Traumatismo por Reperfusão Miocárdica/fisiopatologia
Traumatismo por Reperfusão Miocárdica/prevenção & controle
Miofibrilas/metabolismo
Cadeias Pesadas de Miosina/genética
Fenótipo
Fosforilação
Regiões Promotoras Genéticas
Domínios Proteicos
Estabilidade Proteica
Proteólise
Recuperação de Função Fisiológica
Serina
Fatores de Tempo
Troponina I/genética
Função Ventricular Esquerda/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic beta-Agonists); 0 (Myh6 protein, mouse); 0 (Troponin I); 452VLY9402 (Serine); EC 3.4.22.- (Calpain); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170914
[St] Status:MEDLINE


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[PMID]:28867487
[Au] Autor:Rotty JD; Brighton HE; Craig SL; Asokan SB; Cheng N; Ting JP; Bear JE
[Ad] Endereço:UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
[Ti] Título:Arp2/3 Complex Is Required for Macrophage Integrin Functions but Is Dispensable for FcR Phagocytosis and In Vivo Motility.
[So] Source:Dev Cell;42(5):498-513.e6, 2017 Sep 11.
[Is] ISSN:1878-1551
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Arp2/3 complex nucleates branched actin, forming networks involved in lamellipodial protrusion, phagocytosis, and cell adhesion. We derived primary bone marrow macrophages lacking Arp2/3 complex (Arpc2 ) and directly tested its role in macrophage functions. Despite protrusion and actin assembly defects, Arpc2 macrophages competently phagocytose via FcR and chemotax toward CSF and CX3CL1. However, CR3 phagocytosis and fibronectin haptotaxis, both integrin-dependent processes, are disrupted. Integrin-responsive actin assembly and αM/ß2 integrin localization are compromised in Arpc2 cells. Using an in vivo system to observe endogenous monocytes migrating toward full-thickness ear wounds we found that Arpc2 monocytes maintain cell speeds and directionality similar to control. Our work reveals that the Arp2/3 complex is not a general requirement for phagocytosis or chemotaxis but is a critical driver of integrin-dependent processes. We demonstrate further that cells lacking Arp2/3 complex function in vivo remain capable of executing important physiological responses that require rapid directional motility.
[Mh] Termos MeSH primário: Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo
Movimento Celular
Integrinas/metabolismo
Macrófagos/citologia
Macrófagos/metabolismo
Fagocitose
Receptores Fc/metabolismo
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Movimento Celular/efeitos dos fármacos
Forma Celular/efeitos dos fármacos
Quimiocina CX3CL1/farmacologia
Quimiotaxia/efeitos dos fármacos
Fatores Estimuladores de Colônias/farmacologia
Feminino
Fibronectinas/farmacologia
Ligantes
Antígeno de Macrófago 1/metabolismo
Macrófagos/efeitos dos fármacos
Macrófagos/ultraestrutura
Masculino
Camundongos Endogâmicos C57BL
Cadeias Pesadas de Miosina/metabolismo
Fagocitose/efeitos dos fármacos
Fenótipo
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actin-Related Protein 2-3 Complex); 0 (Actins); 0 (Chemokine CX3CL1); 0 (Colony-Stimulating Factors); 0 (Fibronectins); 0 (Integrins); 0 (Ligands); 0 (Macrophage-1 Antigen); 0 (Receptors, Fc); 0 (Receptors, G-Protein-Coupled); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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Texto completo
[PMID]:28832620
[Au] Autor:Seki Y; Miyasaka Y; Suzuki S; Wada K; Yasuda SP; Matsuoka K; Ohshiba Y; Endo K; Ishii R; Shitara H; Kitajiri SI; Nakagata N; Takebayashi H; Kikkawa Y
[Ad] Endereço:Mammalian Genetics Project, Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
[Ti] Título:A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear hair cells.
[So] Source:PLoS One;12(8):e0183477, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:An unconventional myosin encoded by the myosin VI gene (MYO6) contributes to hearing loss in humans. Homozygous mutations of MYO6 result in nonsyndromic profound congenital hearing loss, DFNB37. Kumamoto shaker/waltzer (ksv) mice harbor spontaneous mutations, and homozygous mutants exhibit congenital defects in balance and hearing caused by fusion of the stereocilia. We identified a Myo6c.1381G>A mutation that was found to be a p.E461K mutation leading to alternative splicing errors in Myo6 mRNA in ksv mutants. An analysis of the mRNA and protein expression in animals harboring this mutation suggested that most of the abnormal alternatively spliced isoforms of MYO6 are degraded in ksv mice. In the hair cells of ksv/ksv homozygotes, the MYO6 protein levels were significantly decreased in the cytoplasm, including in the cuticular plates. MYO6 and stereociliary taper-specific proteins were mislocalized along the entire length of the stereocilia of ksv/ksv mice, thus suggesting that MYO6 attached to taper-specific proteins at the stereociliary base. Histological analysis of the cochlear hair cells showed that the stereociliary fusion in the ksv/ksv mutants, developed through fusion between stereociliary bundles, raised cuticular plate membranes in the cochlear hair cells and resulted in incorporation of the bundles into the sheaths of the cuticular plates. Interestingly, the expression of the stereociliary rootlet-specific TRIO and F-actin binding protein (TRIOBP) was altered in ksv/ksv mice. The abnormal expression of TRIOBP suggested that the rootlets in the hair cells of ksv/ksv mice had excessive growth. Hence, these data indicated that decreased MYO6 levels in ksv/ksv mutants disrupt actin networks in the apical region of hair cells, thereby maintaining the normal structure of the cuticular plates and rootlets, and additionally provided a cellular basis for stereociliary fusion in Myo6 mutants.
[Mh] Termos MeSH primário: Actinas/metabolismo
Processamento Alternativo
Células Ciliadas Auditivas Internas/metabolismo
Mutação
Cadeias Pesadas de Miosina/genética
[Mh] Termos MeSH secundário: Animais
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (myosin VI); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183477



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