Base de dados : MEDLINE
Pesquisa : D08.811.277.656.675.374.102.500.844 [Categoria DeCS]
Referências encontradas : 362 [refinar]
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[PMID]:29241192
[Au] Autor:Mao G; Wu P; Zhang Z; Zhang Z; Liao W; Li Y; Kang Y
[Ad] Endereço:Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
[Ti] Título:MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1ß-Induced Catabolism in Human Articular Chondrocytes.
[So] Source:Cell Physiol Biochem;44(1):38-52, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) are secreted enzymes belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family that play significant roles in the progression of osteoarthritis (OA). Here, we aimed to determine whether the expression of ADAMTS-4/5 in chondrogenesis and inflammation is regulated by microRNA-92a-3p (miR-92a-3p). METHODS: MiR-92a-3p and ADAMTS-4/5 expressions were determined by quantitative polymerase chain reaction (qPCR). To investigate the repressive effect of miR-92a-3p on ADAMTS-4/5 expression, chondrogenic human mesenchymal stem cells (hMSCs) and human chondrocytes were transfected with mature miR-92a-3p or an antisense inhibitor (anti-miR-92a-3p), respectively. ADAMTS-4/5 protein production was quantified by enzyme-linked immunosorbent assay (ELISA), and miR-92a-3p involvement in IL-1ß-mediated catabolic effects was examined by immunoblotting. The roles of activated MAP kinases (MAPK) and nuclear factor (NF)-κB were evaluated by using specific inhibitors. Interaction between miR-92a-3p and its putative binding site in the 3'-untranslated region (3'-UTR) of ADAMTS-4/5 mRNA was confirmed by luciferase reporter assay. RESULTS: miR-92a-3p expression was elevated in chondrogenic hMSCs, with significantly lower expression in OA cartilage than in normal cartilage. Stimulation with IL-1ß significantly reduced miR-92a-3p expression in primary human chondrocytes (PHCs). Transfection of chondrocytes with miR-92a-3p downregulated IL-1ß-induced ADAMTS-4/5 expression, and the activity of a reporter construct containing the 3'-UTR of human ADAMTS-4/5 mRNA. MiR-92a-3p expression was suppressed upon IL-1ß-induced activation of MAPK and NF-κB in chondrocytes. CONCLUSION: MiR-92a-3p is an important regulator of ADAMTS-4/5 in human chondrocytes and may contribute to the development of OA.
[Mh] Termos MeSH primário: Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/metabolismo
Condrogênese/efeitos dos fármacos
Condrogênese/genética
Interleucina-1beta/farmacologia
MicroRNAs/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS4/antagonistas & inibidores
Proteína ADAMTS4/genética
Proteína ADAMTS5/antagonistas & inibidores
Proteína ADAMTS5/genética
Adulto
Idoso
Antagomirs/metabolismo
Células da Medula Óssea/citologia
Cartilagem Articular/metabolismo
Cartilagem Articular/patologia
Células Cultivadas
Condrócitos/citologia
Condrócitos/efeitos dos fármacos
Condrócitos/metabolismo
Feminino
Expressão Gênica/efeitos dos fármacos
Seres Humanos
Masculino
Células Mesenquimais Estromais/citologia
Células Mesenquimais Estromais/efeitos dos fármacos
Células Mesenquimais Estromais/metabolismo
MicroRNAs/antagonistas & inibidores
MicroRNAs/genética
Meia-Idade
Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores
Proteínas Quinases Ativadas por Mitógeno/metabolismo
NF-kappa B/antagonistas & inibidores
NF-kappa B/metabolismo
Osteoartrite do Joelho/genética
Osteoartrite do Joelho/metabolismo
Osteoartrite do Joelho/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antagomirs); 0 (Interleukin-1beta); 0 (MIRN92 microRNA, human); 0 (MicroRNAs); 0 (NF-kappa B); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.82 (ADAMTS4 Protein)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE
[do] DOI:10.1159/000484579


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[PMID]:28464560
[Au] Autor:Wilkinson DJ; Habgood A; Lamb HK; Thompson P; Hawkins AR; Désilets A; Leduc R; Steinmetzer T; Hammami M; Lee MS; Craik CS; Watson S; Lin H; Milner JM; Rowan AD
[Ad] Endereço:Newcastle University, Newcastle upon Tyne, UK.
[Ti] Título:Matriptase Induction of Metalloproteinase-Dependent Aggrecanolysis In Vitro and In Vivo: Promotion of Osteoarthritic Cartilage Damage by Multiple Mechanisms.
[So] Source:Arthritis Rheumatol;69(8):1601-1611, 2017 08.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA. METHODS: Aggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction. Murine OA was induced by surgical destabilization of the medial meniscus, and matriptase inhibitors were administered via osmotic minipump or intraarticular injection. Cartilage damage was scored histologically and aggrecan cleavage was visualized immunohistochemically using specific neoepitope antibodies. RESULTS: The addition of soluble recombinant matriptase promoted a time-dependent release of aggrecan (and collagen) from OA cartilage, which was sensitive to metalloproteinase inhibition and protease-activated receptor 2 antagonism. Although engineered human (normal) cartilage discs failed to release aggrecan following matriptase addition, both matrix metalloproteinase- and aggrecanase-mediated cleavages of aggrecan were detected in human OA cartilage. Additionally, while matriptase did not directly degrade aggrecan, it promoted the accumulation of low-density lipoprotein receptor-related protein 1 (LRP-1) in conditioned media of the OA cartilage explants. Matriptase inhibition via neutralizing antibody or small molecule inhibitor significantly reduced cartilage damage scores in murine OA, which was associated with reduced generation of metalloproteinase-mediated aggrecan cleavage. CONCLUSION: Matriptase potently induces the release of metalloproteinase-generated aggrecan fragments as well as soluble LRP-1 from OA cartilage. Therapeutic targeting of matriptase proteolytic activity reduces metalloproteinase activity, further suggesting that this serine proteinase may have potential as a disease-modifying therapy in OA.
[Mh] Termos MeSH primário: Agrecanas/efeitos dos fármacos
Cartilagem Articular/efeitos dos fármacos
Osteoartrite do Joelho/metabolismo
Serina Endopeptidases/farmacologia
[Mh] Termos MeSH secundário: Proteína ADAMTS4/efeitos dos fármacos
Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/efeitos dos fármacos
Proteína ADAMTS5/metabolismo
Idoso
Idoso de 80 Anos ou mais
Agrecanas/metabolismo
Animais
Anticorpos Neutralizantes/farmacologia
Western Blotting
Cartilagem Articular/metabolismo
Cartilagem Articular/patologia
Endopeptidases/efeitos dos fármacos
Endopeptidases/metabolismo
Feminino
Perfilação da Expressão Gênica
Seres Humanos
Imuno-Histoquímica
Técnicas In Vitro
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/efeitos dos fármacos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Masculino
Metaloproteinases da Matriz/efeitos dos fármacos
Metaloproteinases da Matriz/metabolismo
Proteínas de Membrana/antagonistas & inibidores
Proteínas de Membrana/metabolismo
Meniscos Tibiais/cirurgia
Camundongos
Meia-Idade
Osteoartrite do Joelho/patologia
Reação em Cadeia da Polimerase em Tempo Real
Proteínas Recombinantes/farmacologia
Serina Endopeptidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aggrecans); 0 (Antibodies, Neutralizing); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Membrane Proteins); 0 (Recombinant Proteins); EC 3.4.- (Endopeptidases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.109 (ST14 protein, human); EC 3.4.21.109 (St14 protein, mouse); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (Matrix Metalloproteinases); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.4.99.- (aggrecanase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180119
[Lr] Data última revisão:
180119
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/art.40133


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[PMID]:28613895
[Au] Autor:Durham TB; Marimuthu J; Toth JL; Liu C; Adams L; Mudra DR; Swearingen C; Lin C; Chambers MG; Thirunavukkarasu K; Wiley MR
[Ad] Endereço:Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
[Ti] Título:A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose.
[So] Source:J Med Chem;60(13):5933-5939, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC is 5 mg q.d.
[Mh] Termos MeSH primário: Proteína ADAMTS4/antagonistas & inibidores
Proteína ADAMTS5/antagonistas & inibidores
Inibidores Enzimáticos/química
Inibidores Enzimáticos/uso terapêutico
Hidantoínas/química
Hidantoínas/uso terapêutico
Osteoartrite/tratamento farmacológico
[Mh] Termos MeSH secundário: Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/metabolismo
Agrecanas/metabolismo
Animais
Inibidores Enzimáticos/sangue
Inibidores Enzimáticos/farmacologia
Seres Humanos
Hidantoínas/sangue
Hidantoínas/farmacologia
Masculino
Simulação de Acoplamento Molecular
Osteoartrite/enzimologia
Osteoartrite/metabolismo
Ratos
Ratos Endogâmicos Lew
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aggrecans); 0 (Enzyme Inhibitors); 0 (Hydantoins); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.82 (ADAMTS4 Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00650


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[PMID]:28389425
[Au] Autor:Elayyan J; Lee EJ; Gabay O; Smith CA; Qiq O; Reich E; Mobasheri A; Henrotin Y; Kimber SJ; Dvir-Ginzberg M
[Ad] Endereço:Laboratory of Cartilage Biology, Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
[Ti] Título:LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes.
[So] Source:FASEB J;31(7):3116-3125, 2017 Jul.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study, we assessed the role of SIRT1 in LEF1-mediated MMP13 gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1ß, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-1ß challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1 presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.-Elayyan, J., Lee, E.-J., Gabay, O., Smith, C. A., Qiq, O., Reich, E., Mobasheri, A., Henrotin, Y., Kimber, S. J., Dvir-Ginzberg, M. LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes.
[Mh] Termos MeSH primário: Condrócitos/metabolismo
Regulação da Expressão Gênica/fisiologia
Fator 1 de Ligação ao Facilitador Linfoide/metabolismo
Metaloproteinase 13 da Matriz/metabolismo
Sirtuína 1/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS4/genética
Proteína ADAMTS4/metabolismo
Animais
Cartilagem Articular
Seres Humanos
Interleucina-1beta/genética
Interleucina-1beta/metabolismo
Fator 1 de Ligação ao Facilitador Linfoide/genética
Metaloproteinase 13 da Matriz/genética
Metaloproteinase 3 da Matriz/genética
Metaloproteinase 3 da Matriz/metabolismo
Metaloproteinase 8 da Matriz/genética
Metaloproteinase 8 da Matriz/metabolismo
Camundongos
Camundongos Knockout
Osteoartrite/metabolismo
Sirtuína 1/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-1beta); 0 (Lymphoid Enhancer-Binding Factor 1); EC 3.4.24.- (Matrix Metalloproteinase 13); EC 3.4.24.17 (MMP3 protein, human); EC 3.4.24.17 (Matrix Metalloproteinase 3); EC 3.4.24.34 (MMP8 protein, human); EC 3.4.24.34 (Matrix Metalloproteinase 8); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.5.1.- (Sirtuin 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170409
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601253R


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[PMID]:28323982
[Au] Autor:Gueye NA; Mead TJ; Koch CD; Biscotti CV; Falcone T; Apte SS
[Ad] Endereço:Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
[Ti] Título:Versican Proteolysis by ADAMTS Proteases and Its Influence on Sex Steroid Receptor Expression in Uterine Leiomyoma.
[So] Source:J Clin Endocrinol Metab;102(5):1631-1641, 2017 May 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Leiomyomas have abundant extracellular matrix (ECM), with upregulation of versican, a large proteoglycan. Objective: We investigated ADAMTS (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs) protease-mediated versican cleavage in myometrium and leiomyoma and the effect of versican knockdown in leiomyoma cells. Design: We used quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and RNA in situ hybridization for analysis of myometrium, leiomyoma and immortalized myometrium and leiomyoma cells. Short interfering RNA (siRNA) was used to knockdown versican in leiomyoma cells. Setting: This study was performed in an academic laboratory. Patients: Study subjects were women with symptomatic or asymptomatic leiomyoma. Main Outcome Measures: We quantified messenger RNAs (mRNAs) for versican splice variants. We identified ADAMTS-cleaved versican in myometrium and leiomyoma and ADAMTS messenger RNAs and examined the effect of VCAN siRNA on smooth muscle differentiation and expression of estrogen and progesterone receptors. Results: The women in the symptomatic group (n = 7) had larger leiomyoma (P = 0.01), heavy menstrual bleeding (P < 0.01), and lower hemoglobin levels (P = 0.02) compared with the asymptomatic group (n = 7), but were similar in age and menopausal status. Versican V0 and V1 isoforms were upregulated in the leiomyomas of symptomatic versus asymptomatic women (P = 0.03 and P = 0.04, respectively). Abundant cleaved versican was detected in leiomyoma and myometrium, as well as in myometrial and leiomyoma cell lines. ADAMTS4 (P = 0.03) and ADAMTS15 (P = 0.04) were upregulated in symptomatic leiomyomas. VCAN siRNA did not effect cell proliferation, apoptosis, or smooth muscle markers, but reduced ESR1 and PR-A expression (P = 0.001 and P = 0.002, respectively). Conclusions: Versican in myometrium, leiomyomas and in the corresponding immortalized cells is cleaved by ADAMTS proteases. VCAN siRNA suppresses production of estrogen receptor 1 and progesterone receptor-A. These findings have implications for leiomyoma growth.
[Mh] Termos MeSH primário: Proteínas ADAMTS/genética
Proteína ADAMTS4/genética
Receptor alfa de Estrogênio/genética
Leiomioma/metabolismo
RNA Mensageiro/metabolismo
Receptores de Progesterona/genética
Neoplasias Uterinas/metabolismo
Versicanas/metabolismo
[Mh] Termos MeSH secundário: Proteínas ADAMTS/metabolismo
Proteína ADAMTS4/metabolismo
Adulto
Apoptose/genética
Doenças Assintomáticas
Western Blotting
Linhagem Celular Tumoral
Proliferação Celular/genética
Receptor alfa de Estrogênio/metabolismo
Matriz Extracelular/metabolismo
Feminino
Técnicas de Silenciamento de Genes
Hemoglobinas/metabolismo
Seres Humanos
Imuno-Histoquímica
Hibridização In Situ
Leiomioma/patologia
Menorragia/etiologia
Meia-Idade
Miométrio/metabolismo
Isoformas de Proteínas/genética
Proteólise
RNA Interferente Pequeno
Receptores de Progesterona/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Carga Tumoral
Regulação para Cima
Neoplasias Uterinas/patologia
Versicanas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Estrogen Receptor alpha); 0 (Hemoglobins); 0 (Protein Isoforms); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Receptors, Progesterone); 0 (VCAN protein, human); 0 (estrogen receptor alpha, human); 0 (progesterone receptor A); 126968-45-4 (Versicans); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTS15 protein, human); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.4.24.82 (ADAMTS4 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-3527


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[PMID]:28207788
[Au] Autor:Mern DS; Tschugg A; Hartmann S; Thomé C
[Ad] Endereço:Department of Neurosurgery, Innsbruck Medical University, Innsbruck, Austria.
[Ti] Título:Self-complementary adeno-associated virus serotype 6 mediated knockdown of ADAMTS4 induces long-term and effective enhancement of aggrecan in degenerative human nucleus pulposus cells: A new therapeutic approach for intervertebral disc disorders.
[So] Source:PLoS One;12(2):e0172181, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inhibition of intervertebral disc (IVD) degeneration, which is often accompanied by painful inflammatory and immunopathological processes, is challenging. Current IVD gene therapeutic approaches are based on adenoviral gene delivery systems, which are limited by immune reactions to their viral proteins. Their applications in IVDs near to sensitive neural structure could provoke toxicity and immunological side-effects with neurological deficits. Self-complementary adeno-associated virus (scAAV) vectors, which do not express any viral gene and are not linked with any known disease in humans, are attractive therapeutic gene delivery vectors in degenerative IVDs. However, scAAV-based silencing of catabolic or inflammatory factor has not yet been investigated in human IVD cells. Therefore, we used scAAV6, the most suitable serotype for transduction of human nucleus pulposus (NP) cells, to knockdown the major catabolic gene (ADAMTS4) of IVD degeneration. IVD degeneration grades were determined by preoperative magnetic resonance imaging. Lumbar NP tissues of degeneration grade III were removed from 12 patients by nucleotomy. NP cells were isolated and cultured with low-glucose. Titre of recombinant scAAV6 vectors targeting ADAMTS4, transduction efficiencies, transduction units, cell viabilities and expression levels of target genes were analysed using quantitative PCR, fluorescence microscopy, fluorescence-activated cell sorting, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assays, quantitative reverse transcription PCR, western blot and enzyme-linked immunosorbent assays during 48 days of post-transduction. Transduction efficiencies between 98.2% and 37.4% and transduction units between 611 and 245 TU/cell were verified during 48 days of post-transduction (p<0.001). scAAV6-mediated knockdown of ADAMTS4 with maximum 87.7% and minimum 40.1% was confirmed on day 8 and 48 with enhanced the level of aggrecan 48.5% and 30.2% respectively (p<0.001). scAAV6-mediated knockdown of ADAMTS4 showed no impact on cell viability and expression levels of other inflammatory catabolic proteins. Thus, our results are promising and may help to design long-term and less immunogenic gene therapeutic approaches in IVD disorders, which usually need prolonged therapeutic period between weeks and months.
[Mh] Termos MeSH primário: Proteína ADAMTS4/antagonistas & inibidores
Agrecanas/metabolismo
Dependovirus/genética
Terapia Genética
Degeneração do Disco Intervertebral/terapia
Núcleo Pulposo/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS4/genética
Adulto
Células Cultivadas
Feminino
Vetores Genéticos/administração & dosagem
Seres Humanos
Degeneração do Disco Intervertebral/genética
Degeneração do Disco Intervertebral/patologia
Masculino
Meia-Idade
Núcleo Pulposo/patologia
Sorogrupo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aggrecans); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.4.24.82 (ADAMTS4 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172181


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[PMID]:28099917
[Au] Autor:Fontanil T; Álvarez-Teijeiro S; Villaronga MÁ; Mohamedi Y; Solares L; Moncada-Pazos A; Vega JA; García-Suárez O; Pérez-Basterrechea M; García-Pedrero JM; Obaya AJ; Cal S
[Ad] Endereço:Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Asturias Spain.
[Ti] Título:Cleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells.
[So] Source:Oncotarget;8(8):13716-13729, 2017 Feb 21.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibulin-2 participates in the assembly of extracellular matrix components through interactions with multiple ligands and promotes contacts between cells and their surrounding environment. Consequently, identification of processes that could lead to an altered Fibulin-2 could have a major impact not only in the maintenance of tissue architecture and morphogenesis but also in pathological situations including cancer. Herein, we have investigated the ability of the secreted metalloproteases ADAMTS-4 and ADAMTS-5 to digest Fibulin-2. Using in vitro approaches and cultured breast cancer cell lines we demonstrate that Fibulin-2 is a better substrate for ADAMTS-5 than it is for ADAMTS-4. Moreover, Fibulin-2 degradation is associated to an enhancement of the invasive potential of T47D, MCF-7 and SK-BR-3 cells. We have also found that conditioned medium from MCF-7 cells that simultaneously overexpress Fibulin-2 and ADAMTS-5 significantly induced the migratory and invasive ability of normal breast fibroblasts using 3D collagen matrices. Immunohistochemical analysis highlights the close proximity or partial overlap of both Fibulin-2 and ADAMTS-5 in breast tumor samples. Additionally, proteolytic products derived from a potential degradation of Fibulin-2 by ADAMTS-5 were also identified in these samples. Finally, we also show that the cleavage of Fibulin-2 by ADAMTS-5 is counteracted by ADAMTS-12, a metalloprotease that interacts with Fibulin-2. Overall, our results provide direct evidence indicating that Fibulin-2 is a novel substrate of ADAMTS-5 and that this proteolysis could alter the cellular microenvironment affecting the balance between protumor and antitumor effects associated to both Fibulin-2 and the ADAMTSs metalloproteases.
[Mh] Termos MeSH primário: Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/metabolismo
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Proteínas de Ligação ao Cálcio/metabolismo
Proteínas da Matriz Extracelular/metabolismo
[Mh] Termos MeSH secundário: Neoplasias da Mama/enzimologia
Carcinogênese
Linhagem Celular Tumoral
Feminino
Fibroblastos/patologia
Seres Humanos
Células MCF-7
Esferoides Celulares
Transfecção
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium-Binding Proteins); 0 (Extracellular Matrix Proteins); 0 (fibulin 2); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (ADAMTS5 protein, human); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.4.24.82 (ADAMTS4 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14627


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[PMID]:28081267
[Au] Autor:Perera RS; Dissanayake PH; Senarath U; Wijayaratne LS; Karunanayake AL; Dissanayake VH
[Ad] Endereço:Department of Allied Health Sciences, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.
[Ti] Título:Single Nucleotide Variants of Candidate Genes in Aggrecan Metabolic Pathway Are Associated with Lumbar Disc Degeneration and Modic Changes.
[So] Source:PLoS One;12(1):e0169835, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Lumbar disc degeneration (LDD) is genetically determined and severity of LDD is associated with Modic changes. Aggrecan is a major proteoglycan in the intervertebral disc and end plate. Progressive reduction of aggrecan is a main feature of LDD and Modic changes. OBJECTIVES: The study investigated the associations of single nucleotide variants (SNVs) of candidate genes in the aggrecan metabolic pathway with the severity of LDD and Modic changes. In-silico functional analysis of significant SNVs was also assessed. METHODS: A descriptive cross sectional study was carried out on 106 patients with chronic mechanical low back pain. T1, T2 sagittal lumbar MRI scans were used to assess the severity of LDD and Modic changes. 62 SNVs in ten candidate genes (ACAN, IL1A, IL1B, IL6, MMP3, ADAMTS4, ADAMTS5, TIMP1, TIMP2 and TIMP3) were genotyped on Sequenom MassARRAY iPLEX platform. Multiple linear regression analysis was carried out using PLINK 1.9 in accordance with additive genetic model. In-silico functional analysis was carried out using Provean, SIFT, PolyPhen and Mutation Taster. RESULTS: Mean age was 52.42±9.42 years. 74 (69.8%) were females. The rs2856836, rs1304037, rs17561 and rs1800587 variants of the IL1A gene were associated with the severity of LDD and Modic changes. The rs41270041 variant of the ADAMTS4 gene and the rs226794 variant of the ADAMTS5 gene were associated with severity of LDD while the rs34884997 variant of the ADAMTS4 gene, the rs55933916 variant of the ADAMTS5 gene and the rs9862 variant of the TIMP3 gene were associated with severity of Modic changes. The rs17561 variant of the IL1A gene was predicted as pathogenic by the PolyPhen prediction tool. CONCLUSIONS: SNVs of candidate genes in ACAN metabolic pathway are associated with severity of LDD and Modic changes in patients with chronic mechanical low back pain. Predictions of in-silico functional analysis of significant SNVs are inconsistent.
[Mh] Termos MeSH primário: Proteína ADAMTS4/genética
Proteína ADAMTS5/genética
Agrecanas/genética
Dor Crônica/genética
Interleucina-1alfa/genética
Degeneração do Disco Intervertebral/genética
Deslocamento do Disco Intervertebral/genética
Dor Lombar/genética
Polimorfismo de Nucleotídeo Único
Inibidor Tecidual de Metaloproteinase-3/genética
[Mh] Termos MeSH secundário: Adulto
Dor Crônica/diagnóstico por imagem
Feminino
Seres Humanos
Degeneração do Disco Intervertebral/diagnóstico por imagem
Deslocamento do Disco Intervertebral/diagnóstico por imagem
Dor Lombar/diagnóstico por imagem
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (ACAN protein, human); 0 (Aggrecans); 0 (IL1A protein, human); 0 (Interleukin-1alpha); 0 (TIMP3 protein, human); 0 (Tissue Inhibitor of Metalloproteinase-3); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (ADAMTS5 protein, human); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.4.24.82 (ADAMTS4 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170113
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0169835


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[PMID]:27982477
[Au] Autor:Gaucherand L; Falk BA; Evanko SP; Workman G; Chan CK; Wight TN
[Ad] Endereço:Matrix Biology Program, Benaroya Research Institute, Seattle, Washington.
[Ti] Título:Crosstalk Between T Lymphocytes and Lung Fibroblasts: Generation of a Hyaluronan-Enriched Extracellular Matrix Adhesive for Monocytes.
[So] Source:J Cell Biochem;118(8):2118-2130, 2017 Aug.
[Is] ISSN:1097-4644
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In immunity and inflammation, T cells are often associated with stromal mesenchymal cells such as fibroblasts. Hyaluronan and proteins that associate with hyaluronan such as versican and tumor necrosis factor-inducible gene-6 (TSG-6) are extracellular matrix (ECM) components that promote leukocyte adhesion, accumulation, and activation. However, the factors responsible for producing this specialized ECM and its impact on inflammatory events are not well understood. In this study, we explored the role of T cells in stimulating lung fibroblasts to produce an ECM that impacts monocyte adhesion. We found that CD3/CD28-activated human CD4+ T cells when co-cultured with human lung fibroblasts stimulated the expression of mRNA for hyaluronan synthase 2 (HAS2) and decreased the expression of hyaluronidase 2 (HYAL2). This led to an increase in the deposition of hyaluronan that formed cable-like structures within the ECM. Co-culturing activated T cells with fibroblasts also led to increased expression and accumulation of TSG-6. Surprisingly, addition of activated CD4+ T cells to the fibroblasts reduced the expression of mRNA for versican, and increased the expression of enzymes that degrade versican, such as ADAMTS4 and ADAMTS9 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif) leading to a decrease in versican in the ECM of the co-cultures. Furthermore, addition of human monocytes to these co-cultures resulted in elevated monocyte adhesion to the cable-like structures in the ECM when compared to controls. These results illustrate the importance of crosstalk between T cells and fibroblasts in promoting the generation of a matrix that is adhesive for monocytes. J. Cell. Biochem. 118: 2118-2130, 2017. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Matriz Extracelular/imunologia
Fibroblastos/imunologia
Ácido Hialurônico/biossíntese
Monócitos/imunologia
Versicanas/biossíntese
[Mh] Termos MeSH secundário: Proteína ADAMTS4/genética
Proteína ADAMTS4/imunologia
Proteína ADAMTS9/genética
Proteína ADAMTS9/imunologia
Linfócitos T CD4-Positivos/citologia
Adesão Celular
Moléculas de Adesão Celular/genética
Moléculas de Adesão Celular/imunologia
Comunicação Celular
Técnicas de Cocultura
Matriz Extracelular/metabolismo
Fibroblastos/citologia
Proteínas Ligadas por GPI/genética
Proteínas Ligadas por GPI/imunologia
Regulação da Expressão Gênica
Glucuronosiltransferase/genética
Glucuronosiltransferase/imunologia
Seres Humanos
Hialuronan Sintases
Ácido Hialurônico/imunologia
Hialuronoglucosaminidase/genética
Hialuronoglucosaminidase/imunologia
Pulmão/citologia
Pulmão/imunologia
Ativação Linfocitária
Monócitos/citologia
Cultura Primária de Células
Transdução de Sinais
Versicanas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Adhesion Molecules); 0 (GPI-Linked Proteins); 0 (TNFAIP6 protein, human); 126968-45-4 (Versicans); 9004-61-9 (Hyaluronic Acid); EC 2.4.1.17 (Glucuronosyltransferase); EC 2.4.1.212 (HAS2 protein, human); EC 2.4.1.212 (Hyaluronan Synthases); EC 3.2.1.25 (Hyal2 protein, human); EC 3.2.1.35 (Hyaluronoglucosaminidase); EC 3.4.24.- (ADAMTS9 Protein); EC 3.4.24.- (ADAMTS9 protein, human); EC 3.4.24.82 (ADAMTS4 Protein)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE
[do] DOI:10.1002/jcb.25842


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[PMID]:27844209
[Au] Autor:Karakose M; Caliskan M; Arslan MS; Demirci T; Karakose S; Cakal E
[Ad] Endereço:Department of Endocrinology and Metabolism, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey. meliakarakose@yahoo.com.
[Ti] Título:The impact of parathyroidectomy on serum ADAMTS1, ADAMTS4 levels, insulin resistance, and subclinical cardiovascular disease in primary hyperparathyroidism.
[So] Source:Endocrine;55(1):283-288, 2017 Jan.
[Is] ISSN:1559-0100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Primary hyperparathyroidism has been associated with increased incidence of morbidity and mortality of the cardiovascular system. The etiopathogenetic mechanisms underlying this association are still not completely clear. Accumulating evidence suggested that a disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS) has a role in the development of inflammation and atherosclerosis. In this study, we aimed to determine whether there is a change in serum levels of ADAMTS1, ADAMTS4, carotid intima-media thickness, and cardiovascular risk score after the surgery and also whether there is a relationship between ADAMTS levels and cardiovascular risk score in hypercalcemic primary hyperparathyroidism patients. METHODS: The study included the 48 consecutive newly diagnosed patients with primary hyperparathyroidism. The patients were evaluated before and six months after parathyroidectomy. The Framingham score is used to calculate cardiovascular risk. Serum ADAMTS levels were determined by a human enzyme-linked immunoassay in all subjects. RESULTS: The fasting glucose, fasting insulin levels and HOMA values were decreased significantly in all patients after surgery compared to the pretreatment values (p < 0.05). ADAMTS1, ADAMTS4, and carotid intima-media thickness levels were significantly lower after surgical correction of primary hyperparathyroidism compared to the preoperative values (p < 0.05). cardiovascular risk score was decreased after parathyroidectomy however, the difference were not statistical significant (p > 0.05). There were statistically significant relationship between cardiovascular risk score and waist/hip ratio, calcium, LDL-cholesterol, carotid intima-media thickness, ADAMTS4 values. CONCLUSION: Based on the results of the present study, fasting glucose, fasting insulin levels, ADAMTS1, ADAMTS4, and carotid intima-media thickness might be an additional parameters during the management of patients with primary hyperparathyroidism, since these factors might improve after surgery.
[Mh] Termos MeSH primário: Proteína ADAMTS1/sangue
Proteína ADAMTS4/sangue
Doenças Cardiovasculares/sangue
Hiperparatireoidismo Primário/cirurgia
Resistência à Insulina/fisiologia
[Mh] Termos MeSH secundário: Adulto
Glicemia
Espessura Intima-Media Carotídea
Feminino
Seres Humanos
Hiperparatireoidismo Primário/sangue
Masculino
Meia-Idade
Hormônio Paratireóideo/sangue
Paratireoidectomia
Fatores de Risco
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Parathyroid Hormone); EC 3.4.24.- (ADAMTS1 Protein); EC 3.4.24.82 (ADAMTS4 Protein)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161116
[St] Status:MEDLINE
[do] DOI:10.1007/s12020-016-1175-3



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