Base de dados : MEDLINE
Pesquisa : D12.776.526.100 [Categoria DeCS]
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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]:28724630
[Au] Autor:Aarnio-Peterson M; Zhao P; Yu SH; Christian C; Flanagan-Steet H; Wells L; Steet R
[Ad] Endereço:From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
[Ti] Título:Altered Met receptor phosphorylation and LRP1-mediated uptake in cells lacking carbohydrate-dependent lysosomal targeting.
[So] Source:J Biol Chem;292(36):15094-15104, 2017 Sep 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acid hydrolases utilize a carbohydrate-dependent mechanism for lysosomal targeting. These hydrolases acquire a mannose 6-phosphate tag by the action of the GlcNAc-1-phosphotransferase enzyme, allowing them to bind receptors and traffic to endosomes. Loss of GlcNAc-1-phosphotransferase results in hydrolase hypersecretion and profound lysosomal storage. Little, however, is known about how these cellular phenotypes affect the trafficking, activity, and localization of surface glycoproteins. To address this question, we profiled the abundance of surface glycoproteins in WT and CRISPR-mediated HeLa cells and identified changes in numerous glycoproteins, including the uptake receptor LRP1 and multiple receptor tyrosine kinases. Decreased cell surface LRP1 in cells corresponded with a reduction in its steady-state level and less amyloid-ß-40 (Aß40) peptide uptake. cells displayed elevated activation of several kinases including Met receptor. We found increased Met phosphorylation within both the kinase and the docking domains and observed that lower concentrations of pervanadate were needed to cause an increase in phospho-Met in cells. Together, these data suggested a decrease in the activity of the receptor and non-receptor protein-tyrosine phosphatases that down-regulate Met phosphorylation. cells exhibited elevated levels of reactive oxygen species, known to inactivate cell surface and cytosolic phosphatases by oxidation of active site cysteine residues. Consistent with this mode of action, peroxide treatment of parental HeLa cells elevated phospho-Met levels whereas antioxidant treatment of cells reduced phospho-Met levels. Collectively, these findings identify new mechanisms whereby impaired lysosomal targeting can impact the activity and recycling of receptors.
[Mh] Termos MeSH primário: Carboidratos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Lisossomos/metabolismo
Proteínas Proto-Oncogênicas c-met/metabolismo
Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
[Mh] Termos MeSH secundário: Células HeLa
Seres Humanos
Fosforilação
Proteínas Proto-Oncogênicas c-met/química
Transferases (Outros Grupos de Fosfato Substituídos)/deficiência
Transferases (Outros Grupos de Fosfato Substituídos)/genética
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carbohydrates); 0 (LRP1 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-1); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups)); EC 2.7.8.15 (GNPTAB protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.790139


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[PMID]:28684538
[Au] Autor:Mantuano E; Azmoon P; Brifault C; Banki MA; Gilder AS; Campana WM; Gonias SL
[Ad] Endereço:Department of Pathology, University of California, San Diego, La Jolla, CA.
[Ti] Título:Tissue-type plasminogen activator regulates macrophage activation and innate immunity.
[So] Source:Blood;130(11):1364-1374, 2017 Sep 14.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tissue-type plasminogen activator (tPA) is the major intravascular activator of fibrinolysis and a ligand for receptors involved in cell signaling. In cultured macrophages, tPA inhibits the response to lipopolysaccharide (LPS) by a pathway that apparently requires low-density lipoprotein receptor-related protein-1 (LRP1). Herein, we show that the mechanism by which tPA neutralizes LPS involves rapid reversal of IκBα phosphorylation. tPA independently induced transient IκBα phosphorylation and extracellular signal-regulated kinase 1/2 (ERK1/2) activation in macrophages; however, these events did not trigger inflammatory mediator expression. The tPA signaling response was distinguished from the signature of signaling events elicited by proinflammatory LRP1 ligands, such as receptor-associated protein (RAP), which included sustained IκBα phosphorylation and activation of all 3 MAP kinases (ERK1/2, c-Jun kinase, and p38 MAP kinase). Enzymatically active and inactive tPA demonstrated similar immune modulatory activity. Intravascular administration of enzymatically inactive tPA in mice blocked the toxicity of LPS. In mice not treated with exogenous tPA, the plasma concentration of endogenous tPA increased 3-fold in response to LPS, to 116 ± 15 pM, but remained below the approximate threshold for eliciting anti-inflammatory cell signaling in macrophages (∼2.0 nM). This threshold is readily achieved in patients when tPA is administered therapeutically for stroke. In addition to LRP1, we demonstrate that the -methyl-D-aspartic acid receptor (NMDA-R) is expressed by macrophages and essential for anti-inflammatory cell signaling and regulation of cytokine expression by tPA. The NMDA-R and Toll-like receptor-4 were not required for proinflammatory RAP signaling. By mediating the tPA response in macrophages, the NMDA-R provides a pathway by which the fibrinolysis system may regulate innate immunity.
[Mh] Termos MeSH primário: Imunidade Inata/efeitos dos fármacos
Ativação de Macrófagos/efeitos dos fármacos
Ativador de Plasminogênio Tecidual/farmacologia
[Mh] Termos MeSH secundário: Animais
Células da Medula Óssea/efeitos dos fármacos
Células da Medula Óssea/patologia
Seres Humanos
Inflamação/imunologia
Inflamação/patologia
Ligantes
Lipopolissacarídeos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Fosforilação/efeitos dos fármacos
Receptores de N-Metil-D-Aspartato/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Lipopolysaccharides); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Receptors, N-Methyl-D-Aspartate); EC 3.4.21.68 (Tissue Plasminogen Activator)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171008
[Lr] Data última revisão:
171008
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-04-780205


  4 / 1499 MEDLINE  
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[PMID]:28662213
[Au] Autor:Kolb M; Kurz S; Schäfer A; Huse K; Dietz A; Wichmann G; Birkenmeier G
[Ad] Endereço:Clinic of Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Leipzig, Germany.
[Ti] Título:Verification and characterization of an alternative low density lipoprotein receptor-related protein 1 splice variant.
[So] Source:PLoS One;12(6):e0180354, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Low density lipoprotein (LDL) receptor-related protein 1 (LRP1) is a ubiquitously expressed multi-ligand endocytosis receptor implicated in a wide range of signalling, among others in tumour biology. Tumour-associated genomic mutations of the LRP1 gene are described, but nothing is known about cancer-associated expression of LRP1 splice variants Therefore, the focus of this study was on an annotated truncated LRP1 splice variant (BC072015.1; NCBI GenBank), referred to as smLRP1, which was initially identified in prostate and lung carcinoma. METHODS: Using PCR and quantitative PCR, the expression of LRP1 and smLRP1 in different human tissues and tumour cell lines was screened and compared on tumour biopsies of head and neck squamous cell carcinoma (HNSCC). Using a recently developed anti-smLRP1 antibody, the expression of the putative LRP1 protein isoform in tumour cell lines in Western blot and immunofluorescence staining was further investigated. RESULTS: The alternative transcript smLRP1 is ubiquitously expressed in 12 human cell lines of different origin and 22 tissues which is similar to LRP1. A shift in expression of smLRP1 relative to LRP1 towards smLRP1 was observed in most tumour cell lines compared to healthy tissue. The expression of LRP1 as well as smLRP1 is decreased in HNSCC cell lines in comparison to healthy mucosa. In vitro results were checked using primary HNSCC. Furthermore, the expression of the protein isoform smLRP1 (32 kDa) was confirmed in human tumour cell lines. CONCLUSIONS: Similar to LRP1, the truncated splice variant smLRP1 is ubiquitously expressed in healthy human tissues, but altered in tumours pointing to a potential role of smLRP1 in cancer. Comparative results suggest a shift in expression in favour of smLRP1 in tumour cells that warrant further evaluation. The protein isoform is suggested to be secreted.
[Mh] Termos MeSH primário: Processamento Alternativo
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Carcinoma de Células Escamosas/patologia
Linhagem Celular Tumoral
Neoplasias de Cabeça e Pescoço/patologia
Seres Humanos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Low Density Lipoprotein Receptor-Related Protein-1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180354


  5 / 1499 MEDLINE  
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[PMID]:28580688
[Au] Autor:Panezai J; Bergdahl E; Sundqvist KG
[Ad] Endereço:Division of Periodontology, Department of Dental Medicine, Karolinska Institute at Karolinska University Hospital, Stockholm, Sweden.
[Ti] Título:T-cell regulation through a basic suppressive mechanism targeting low-density lipoprotein receptor-related protein 1.
[So] Source:Immunology;152(2):308-327, 2017 Oct.
[Is] ISSN:1365-2567
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cell adhesion is generally considered to depend on positive regulation through ligation of integrins and cytokine receptors. However, here we show that T-cell adhesion, and notably also T-cell receptor (TCR) -induced activation, are subject to constant suppression through shedding of low-density lipoprotein receptor-related protein 1 (LRP1). The broad-spectrum metalloprotease inhibitor GM6001 abrogated shedding, so inducing prominent cell surface expression of LRP1 while enhancing TCR-induced activation and adhesion to ß and ß integrin ligands, hence arresting the cells. Integrin ligands also inhibited shedding but the effect was less potent than that of GM6001. Unlike GM6001, integrin ligands also induced cell surface expression of full-length thrombospondin-1 (TSP170) and TSP130, which associated with LRP1, and TSP110, which did not associate with LRP1. Cell surface expression of LRP1 and TSP130 were induced exclusively in adhering cells, expression of TSP110 preferentially in non-adhering cells and expression of TSP170 correlated with T-cell motility. The pro-adhesive chemokine CXCL12 also inhibited LRP1 shedding and induced surface expression of TSP170 and TSP130 while inhibiting TSP110. Exogenous TSP-1 and ligation of CD28 inhibited shedding although less effectively than GM6001, and the inhibition through CD28 was independent of TSP-1. Small interfering RNA silencing experiments confirmed involvement of LRP1 and TSP-1 in integrin-dependent adhesion and TCR-induced activation. Hence, the poor LRP1 expression in T cells depends on shedding. Integrin ligands and CXCL12 antagonize shedding through a TSP-1-dependent pathway and ligation of CD28 antagonizes shedding independent of TSP-1. The disappearance of LRP1 from the cell surface may provide basic immunosuppression at the T-cell level.
[Mh] Termos MeSH primário: Adesão Celular
Movimento Celular
Tolerância Imunológica
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Ativação Linfocitária
Linfócitos T/metabolismo
[Mh] Termos MeSH secundário: Antígenos CD18/imunologia
Antígenos CD18/metabolismo
Antígenos CD28/imunologia
Antígenos CD28/metabolismo
Adesão Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Quimiocina CXCL12/farmacologia
Dipeptídeos/farmacologia
Seres Humanos
Tolerância Imunológica/efeitos dos fármacos
Integrina beta1/imunologia
Integrina beta1/metabolismo
Ligantes
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/imunologia
Ativação Linfocitária/efeitos dos fármacos
Inibidores de Metaloproteinases de Matriz/farmacologia
Fragmentos de Peptídeos/imunologia
Fragmentos de Peptídeos/metabolismo
Interferência de RNA
Receptores de Antígenos de Linfócitos T/imunologia
Receptores de Antígenos de Linfócitos T/metabolismo
Transdução de Sinais
Linfócitos T/efeitos dos fármacos
Linfócitos T/imunologia
Trombospondina 1/genética
Trombospondina 1/imunologia
Trombospondina 1/metabolismo
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD18 Antigens); 0 (CD28 Antigens); 0 (Chemokine CXCL12); 0 (Dipeptides); 0 (Integrin beta1); 0 (LRP1 protein, human); 0 (Ligands); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Matrix Metalloproteinase Inhibitors); 0 (N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide); 0 (Peptide Fragments); 0 (Receptors, Antigen, T-Cell); 0 (Thrombospondin 1); 0 (thrombospondin-1, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170606
[St] Status:MEDLINE
[do] DOI:10.1111/imm.12770


  6 / 1499 MEDLINE  
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[PMID]:28552561
[Au] Autor:Wujak L; Hesse C; Sewald K; Jonigk D; Braubach P; Warnecke G; Fieguth HG; Braun A; Lochnit G; Markart P; Schaefer L; Wygrecka M
[Ad] Endereço:Department of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany.
[Ti] Título:FXII promotes proteolytic processing of the LRP1 ectodomain.
[So] Source:Biochim Biophys Acta;1861(8):2088-2098, 2017 08.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Factor XII (FXII) is a serine protease that is involved in activation of the intrinsic blood coagulation, the kallikrein-kinin system and the complement cascade. Although the binding of FXII to the cell surface has been demonstrated, the consequence of this event for proteolytic processing of membrane-anchored proteins has never been described. METHODS: The effect of FXII on the proteolytic processing of the low-density lipoprotein receptor-related protein 1 (LRP1) ectodomain was tested in human primary lung fibroblasts (hLF), alveolar macrophages (hAM) and in human precision cut lung slices (hPCLS). The identity of generated LRP1 fragments was confirmed by MALDI-TOF-MS. Activity of FXII and gelatinases was measured by S-2302 hydrolysis and zymography, respectively. RESULTS: Here, we demonstrate a new function of FXII, namely its ability to process LRP1 extracellular domain. Incubation of hLF, hAM, or hPCLS with FXII resulted in the accumulation of LRP1 ectodomain fragments in conditioned media. This effect was independent of metalloproteases and required FXII proteolytic activity. Binding of FXII to hLF surface induced its conversion to FXIIa and protected FXIIa against inactivation by a broad spectrum of serine protease inhibitors. Preincubation of hLF with collagenase I impaired FXII activation and, in consequence, LRP1 cleavage. FXII-triggered LRP1 processing was associated with the accumulation of gelatinases (MMP-2 and MMP-9) in conditioned media. CONCLUSIONS: FXII controls LRP1 levels and function at the plasma membrane by modulating processing of its ectodomain. GENERAL SIGNIFICANCE: FXII-dependent proteolytic processing of LRP1 may exacerbate extracellular proteolysis and thus promote pathological tissue remodeling.
[Mh] Termos MeSH primário: Fator XII/farmacologia
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
[Mh] Termos MeSH secundário: Gelatinases/metabolismo
Seres Humanos
Domínios Proteicos
Proteólise
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (LRP1 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 9001-30-3 (Factor XII); EC 3.4.24.- (Gelatinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE


  7 / 1499 MEDLINE  
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[PMID]:28495363
[Au] Autor:Fu T; Guan Y; Xu J; Wang Y
[Ad] Endereço:Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, People's Republic of China.
[Ti] Título:APP, APLP2 and LRP1 interact with PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo.
[So] Source:Biochim Biophys Acta;1862(9):883-889, 2017 09.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that post-transcriptionally regulates the levels of hepatic low-density lipoprotein receptors (LDLRs). PCSK9 binds to the extracellular domain of the LDLR, and the PCSK9-LDLR complex is internalized through canonical clathrin-dependent endocytosis and then delivered to lysosomes for degradation. The mechanism by which PCSK9 blocks recycling of the LDLR has not been fully defined. Previous reports showed that amyloid precursor-like protein 2 (APLP2) interacts with PCSK9, but its role in PCSK9-mediated LDLR degradation remains controversial. Here we found that amyloid precursor protein (APP), APLP2 and LDL receptor-related protein 1 (LRP1) interact with PCSK9. To test whether any of these proteins are required for PCSK9-mediated LDLR degradation, we examined the effects of disrupting these proteins in mice. Infusion of PCSK9 into App , Aplp2 , Aplp2-depleted App , or liver-specific Lrp1 mice resulted in similar reductions in the levels of hepatic LDLR as seen in wild-type (WT) mice. Infusion of PCSK9 into WT mice also had no effect on the levels of hepatic APP, APLP2 or LRP1. Thus, APP, APLP2 and LRP1 are not required for PCSK9-mediated LDLR degradation and are not regulated by PCSK9 in vivo.
[Mh] Termos MeSH primário: Precursor de Proteína beta-Amiloide/metabolismo
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Pró-Proteína Convertase 9/metabolismo
Receptores de LDL/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Endocitose/fisiologia
Hepatócitos/metabolismo
Hepatócitos/fisiologia
Seres Humanos
Lipoproteínas LDL/metabolismo
Fígado/metabolismo
Fígado/fisiologia
Lisossomos/metabolismo
Lisossomos/fisiologia
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (Lipoproteins, LDL); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Receptors, LDL); EC 3.4.21.- (Proprotein Convertase 9)
[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:170513
[St] Status:MEDLINE


  8 / 1499 MEDLINE  
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[PMID]:28322979
[Au] Autor:Pérez-Hernández M; Fernández-Valle ME; Rubio-Araiz A; Vidal R; Gutiérrez-López MD; O'Shea E; Colado MI
[Ad] Endereço:Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain; Red de Trastornos Adictivos del Instituto de Salud Carlos III, 28029 Madrid, Spain.
[Ti] Título:3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces edema due to BBB disruption induced by MMP-9 activation in rat hippocampus.
[So] Source:Neuropharmacology;118:157-166, 2017 May 15.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The recreational drug of abuse, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier (BBB) integrity in rats through an early P2X receptor-mediated event which induces MMP-9 activity. Increased BBB permeability often causes plasma proteins and water to access cerebral tissue leading to vasogenic edema formation. The current study was performed to examine the effect of a single neurotoxic dose of MDMA (12.5 mg/kg, i.p.) on in vivo edema development associated with changes in the expression of the perivascular astrocytic water channel, AQP4, as well as in the expression of the tight-junction (TJ) protein, claudin-5 and Evans Blue dye extravasation in the hippocampus of adult male Dark Agouti rats. We also evaluated the ability of the MMP-9 inhibitor, SB-3CT (25 mg/kg, i.p.), to prevent these changes in order to validate the involvement of MMP-9 activation in MDMA-induced BBB disruption. The results show that MDMA produces edema of short duration temporally associated with changes in AQP4 expression and a reduction in claudin-5 expression, changes which are prevented by SB-3CT. In addition, MDMA induces a short-term increase in both tPA activity and expression, a serine-protease which is involved in BBB disruption and upregulation of MMP-9 expression. In conclusion, this study provides evidence enough to conclude that MDMA induces edema of short duration due to BBB disruption mediated by MMP-9 activation.
[Mh] Termos MeSH primário: Barreira Hematoencefálica/fisiopatologia
Edema Encefálico/induzido quimicamente
Regulação da Expressão Gênica/efeitos dos fármacos
Alucinógenos/toxicidade
Metaloproteinase 9 da Matriz/metabolismo
N-Metil-3,4-Metilenodioxianfetamina/toxicidade
[Mh] Termos MeSH secundário: Animais
Aquaporina 4/metabolismo
Barreira Hematoencefálica/diagnóstico por imagem
Barreira Hematoencefálica/efeitos dos fármacos
Edema Encefálico/diagnóstico por imagem
Edema Encefálico/patologia
Claudina-5/metabolismo
Modelos Animais de Doenças
Inibidores Enzimáticos/farmacologia
Proteína Glial Fibrilar Ácida/metabolismo
Compostos Heterocíclicos com 1 Anel/farmacologia
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Imagem por Ressonância Magnética
Masculino
Permeabilidade/efeitos dos fármacos
Plasminogênio/metabolismo
Ratos
Sulfonas/farmacologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aqp4 protein, rat); 0 (Aquaporin 4); 0 (Claudin-5); 0 (Enzyme Inhibitors); 0 (Glial Fibrillary Acidic Protein); 0 (Hallucinogens); 0 (Heterocyclic Compounds, 1-Ring); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (SB 3CT compound); 0 (Sulfones); 9001-91-6 (Plasminogen); EC 3.4.24.35 (Matrix Metalloproteinase 9); KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE


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[PMID]:28304302
[Au] Autor:Wei M; Zhao B; Huo K; Deng Y; Shang S; Liu J; Li Y; Ma L; Jiang Y; Dang L; Chen C; Wei S; Zhang J; Yang H; Gao F; Qu Q
[Ad] Endereço:Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
[Ti] Título:Sleep Deprivation Induced Plasma Amyloid-ß Transport Disturbance in Healthy Young Adults.
[So] Source:J Alzheimers Dis;57(3):899-906, 2017.
[Is] ISSN:1875-8908
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sleep is an important physiological process and beneficial in the removal of brain metabolites and functional recovery. Prior studies have shown that sleep disorders are significant risk factors for Alzheimer's disease (AD). OBJECTIVE: The present study was designed to characterize the effect of short-term total sleep deprivation (TSD) on plasma amyloid-ß (Aß) concentrations. METHODS: A clinical trial was conducted between March 1, 2016, and April 1, 2016. Twenty volunteers (age 27.3±3.4 years) with normal cognitive function and sleeping habits were recruited from the local population. Participants underwent 24 h of TSD. Periprocedural blood samples were collected to compare the changes of plasma Aß42, Aß40, low-density lipoprotein receptor-related protein (sLRP-1), soluble receptors for advanced glycation end products (sRAGE), and serum superoxide dismutase (SOD) and malonaldehyde (MDA). RESULTS: TSD increased morning plasma Aß40 levels by 32.6% (p < 0.001) and decreased the Aß42/Aß40 ratio by 19.3% (p < 0.001). A positive relationship was found between TSD duration and plasma Aß40 level (r = 0.51, p < 0.001) and Aß40/Aß42 ratio (r = 0.25, p = 0.003). Plasma concentrations of sLRP1 (p = 0.018) and sRAGE (p = 0.001) decreased significantly after TSD. Aß40 and Aß42 plasma concentrations correlated with plasma levels of sLRP1 and sRAGE. Serum SOD decreased after TSD (p = 0.005), whereas serum MDA was increased (p = 0.001). CONCLUSION: Sleep deprivation can lead to an elevation of plasma Aß40 and decrease of the Aß42/Aß40 ratio. The underlying mechanisms may be related to increased oxidative stress and impaired peripheral Aß clearance as pathomechanisms of AD.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/sangue
Fragmentos de Peptídeos/sangue
Privação do Sono/sangue
[Mh] Termos MeSH secundário: Adulto
Feminino
Seres Humanos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/sangue
Masculino
Malondialdeído/sangue
Receptor para Produtos Finais de Glicação Avançada/sangue
Superóxido Dismutase/sangue
Fatores de Tempo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AGER protein, human); 0 (Amyloid beta-Peptides); 0 (LRP1 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Peptide Fragments); 0 (Receptor for Advanced Glycation End Products); 0 (amyloid beta-protein (1-40)); 0 (amyloid beta-protein (1-42)); 4Y8F71G49Q (Malondialdehyde); EC 1.15.1.1 (Superoxide Dismutase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.3233/JAD-161213


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[PMID]:28235248
[Au] Autor:Yamamoto K; Santamaria S; Botkjaer KA; Dudhia J; Troeberg L; Itoh Y; Murphy G; Nagase H
[Ad] Endereço:University of Oxford, Oxford, UK.
[Ti] Título:Inhibition of Shedding of Low-Density Lipoprotein Receptor-Related Protein 1 Reverses Cartilage Matrix Degradation in Osteoarthritis.
[So] Source:Arthritis Rheumatol;69(6):1246-1256, 2017 Jun.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The aggrecanase ADAMTS-5 and the collagenase matrix metalloproteinase 13 (MMP-13) are constitutively secreted by chondrocytes in normal cartilage, but rapidly endocytosed via the cell surface endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP-1) and subsequently degraded. This endocytic system is impaired in osteoarthritic (OA) cartilage due to increased ectodomain shedding of LRP-1. The aim of this study was to identify the LRP-1 sheddase(s) in human cartilage and to test whether inhibition of LRP-1 shedding prevents cartilage degradation in OA. METHODS: Cell-associated LRP-1 and soluble LRP-1 (sLRP-1) released from human cartilage explants and chondrocytes were measured by Western blot analysis. LRP-1 sheddases were identified by proteinase inhibitor profiling and gene silencing with small interfering RNAs. Specific monoclonal antibodies were used to selectively inhibit the sheddases. Degradation of aggrecan and collagen in human OA cartilage was measured by Western blot analysis using an antibody against an aggrecan neoepitope and a hydroxyproline assay, respectively. RESULTS: Shedding of LRP-1 was increased in OA cartilage compared with normal tissue. Shed sLRP-1 bound to ADAMTS-5 and MMP-13 and prevented their endocytosis without interfering with their proteolytic activities. Two membrane-bound metalloproteinases, ADAM-17 and MMP-14, were identified as the LRP-1 sheddases in cartilage. Inhibition of their activities restored the endocytic capacity of chondrocytes and reduced degradation of aggrecan and collagen in OA cartilage. CONCLUSION: Shedding of LRP-1 is a key link to OA progression. Local inhibition of LRP-1 sheddase activities of ADAM-17 and MMP-14 is a unique way to reverse matrix degradation in OA cartilage and could be effective as a therapeutic approach.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Colagenases/efeitos dos fármacos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/efeitos dos fármacos
Osteoartrite/tratamento farmacológico
Proteólise/efeitos dos fármacos
[Mh] Termos MeSH secundário: Proteína ADAM17/análise
Proteína ADAM17/metabolismo
Proteína ADAMTS5/metabolismo
Adolescente
Adulto
Agrecanas/efeitos dos fármacos
Cartilagem Articular/metabolismo
Criança
Condrócitos/fisiologia
Colágeno/efeitos dos fármacos
Endocitose/efeitos dos fármacos
Feminino
Seres Humanos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia
Masculino
Metaloproteinase 13 da Matriz/metabolismo
Metaloproteinase 14 da Matriz/análise
Metaloproteinase 14 da Matriz/metabolismo
Meia-Idade
Osteoartrite/fisiopatologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aggrecans); 0 (Antibodies, Monoclonal); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 9007-34-5 (Collagen); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (Collagenases); EC 3.4.24.- (MMP13 protein, human); EC 3.4.24.- (Matrix Metalloproteinase 13); EC 3.4.24.80 (MMP14 protein, human); EC 3.4.24.80 (Matrix Metalloproteinase 14); EC 3.4.24.86 (ADAM17 Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1002/art.40080



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