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Pesquisa : D12.644.276.100.050 [Categoria DeCS]
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[PMID]:28456825
[Au] Autor:Lu Q; Lu L; Chen W; Lu P
[Ad] Endereço:Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
[Ti] Título:Expression of angiopoietin-like protein 8 correlates with VEGF in patients with proliferative diabetic retinopathy.
[So] Source:Graefes Arch Clin Exp Ophthalmol;255(8):1515-1523, 2017 Aug.
[Is] ISSN:1435-702X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To investigate the vitreous and serum levels of angiopoietin-like protein 8 (ANGPTL-8) and vascular endothelial growth factor (VEGF) in patients with proliferative diabetic retinopathy (PDR). The serum levels of these factors were also analyzed in patients with diabetes and no diabetic retinopathy (NDR) and with non-proliferative diabetic retinopathy (NPDR), to detect the possible correlation between the ANGPTL-8 levels and hyperlipidemia. METHODS: Vitreous samples were obtained from 28 patients with PDR and from 12 patients without diabetes and with idiopathic macular hole (IMH). Serum samples were also obtained from 26 patients with NDR and 22 patients with NPDR. ANGPTL-8 levels and other factors were determined using an enzyme-linked immunosorbent assay. RESULTS: The ANGPTL-8 and VEGF levels in the vitreous and serum of the patients with PDR were higher than those in the patients with IMH, and were significantly correlated. The vitreous and serum ANGPTL-8 levels were more correlated with the triglyceride and low-density lipoprotein cholesterol levels than with the high-density lipoprotein cholesterol or total cholesterol levels in the patients with PDR. CONCLUSIONS: The vitreous and serum ANGPTL-8 levels were both upregulated in patients with PDR. There was an association between the elevation in the ANGPTL-8 levels and angiogenic and hyperlipidemic factors in the patients with PDR. These results suggest that ANGPTL-8 is a potential new diagnostic marker and therapeutic target for PDR treatment.
[Mh] Termos MeSH primário: Proteínas Semelhantes a Angiopoietina/biossíntese
Retinopatia Diabética/metabolismo
Hormônios Peptídicos/biossíntese
Neovascularização Retiniana/metabolismo
Fator A de Crescimento do Endotélio Vascular/metabolismo
Corpo Vítreo/metabolismo
[Mh] Termos MeSH secundário: Biomarcadores/metabolismo
Retinopatia Diabética/complicações
Retinopatia Diabética/diagnóstico
Ensaio de Imunoadsorção Enzimática
Feminino
Seres Humanos
Masculino
Meia-Idade
Neovascularização Retiniana/complicações
Neovascularização Retiniana/diagnóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPTL8 protein, human); 0 (Angiopoietin-like Proteins); 0 (Biomarkers); 0 (Peptide Hormones); 0 (Vascular Endothelial Growth Factor A)
[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:170501
[St] Status:MEDLINE
[do] DOI:10.1007/s00417-017-3676-z


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[PMID]:28946139
[Au] Autor:Yang S; Zhang J; Wang S; Shi J; Zhao X
[Ti] Título:Knockdown of Angiopoietin-Like Protein 2 Ameliorates Diabetic Nephropathy by Inhibiting TLR4.
[So] Source:Cell Physiol Biochem;43(2):685-696, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Angiopoietin-like protein 2 (ANGPTL2) was reported to be implicated in the pathogenesis of inflammatory disease. Its role in diabetic nephropathy (DN) remained illdefined. METHODS: qRT-PCR and western blot analysis were performed to detect the expressions of ANGPTL2 or TLR4 in streptozotocin (STZ)-induced DN rats and HG-stimulated podocytes. The renal injury index including 24-h proteinuria, blood glucose level, serum creatinine and blood urea nitrogen were measured in DN rats using corresponding commercial kits. The effect of ANGPTL2 knockdown on the secretion or expression of inflammatory cytokines was detected by ELISA or qRT-PCR analysis. The effect of ANGPTL2 knockdown on extracellular matrix (ECM) accumulation was determined by testing TGF-ß1, Collagen-IV, fibronectin (FN) and PTEN expression via western blot. RESULTS: ANGPTL2 and TLR4 were both highly expressed in DN rats compared with control group. ANGPTL2 knockdown alleviated renal injury in STZ-induced DN rat model. ANGPTL2 knockdown also suppressed inflammatory cytokines (IL-6, TNF-α, MCP-1, IL-1ß) expression and ECM accumulation (TGF-ß1, Collagen-IV, FN, PTEN) in HG-induced podocytes. Moreover, ANGPTL2 knockdown led to a significant decrease of TLR4 expression in both DN rat and cell model. Furthermore, TAK-242 treatment exacerbated the inhibitory effect of ANGPTL2 knockdown on inflammatory cytokines expression and ECM accumulation in HG-induced podocytes. CONCLUSION: ANGPTL2 knockdown ameliorates DN by inhibiting TLR4 expression, an observation contributing to a better understanding of DN pathogenesis.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/genética
Diabetes Mellitus Experimental/complicações
Nefropatias Diabéticas/genética
Nefropatias Diabéticas/terapia
Rim/patologia
Receptor 4 Toll-Like/genética
[Mh] Termos MeSH secundário: Proteínas Semelhantes a Angiopoietina
Animais
Células Cultivadas
Citocinas/análise
Nefropatias Diabéticas/patologia
Técnicas de Silenciamento de Genes
Terapia Genética
Rim/metabolismo
Masculino
Podócitos/metabolismo
Podócitos/patologia
Ratos
Ratos Sprague-Dawley
Receptor 4 Toll-Like/análise
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Angiopoietin-like Proteins); 0 (Angptl2 protein, rat); 0 (Cytokines); 0 (Tlr4 protein, rat); 0 (Toll-Like Receptor 4)
[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:170926
[St] Status:MEDLINE
[do] DOI:10.1159/000480654


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[PMID]:28934245
[Au] Autor:Ohno T; Yamamoto G; Hayashi JI; Nishida E; Goto H; Sasaki Y; Kikuchi T; Fukuda M; Hasegawa Y; Mogi M; Mitani A
[Ad] Endereço:Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
[Ti] Título:Angiopoietin-like protein 2 regulates Porphyromonas gingivalis lipopolysaccharide-induced inflammatory response in human gingival epithelial cells.
[So] Source:PLoS One;12(9):e0184825, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Angiopoietin-like protein 2 (ANGPTL2) maintains tissue homeostasis by inducing inflammation and angiogenesis. It is produced in infiltrating immune cells or resident cells, such as adipocytes, vascular endothelial cells, and tumor cells. We hypothesized that ANGPTL2 might play an important role as a unique mediator in both systemic and periodontal disease. We demonstrated an increased ANGPTL2 concentration in gingival crevicular fluid from chronic periodontitis patients. Porphyromonas gingivalis lipopolysaccharide (LPS) treatment strongly induced ANGPTL2 mRNA and protein levels in Ca9-22 human gingival epithelial cells. Recombinant human ANGPTL2 increased interleukin 1ß (IL-1ß), IL-8, and tumor necrosis factor-α (TNF-α) mRNA and protein levels in Ca9-22 cells. Small-interfering (si)RNA-mediated ANGPTL2 knockdown in Ca9-22 cells reduced IL-1ß, IL-8 and TNF-α mRNA and protein levels compared with control siRNA (p<0.01) in P. gingivalis LPS-stimulated Ca9-22 cells. Antibodies against integrin α5ß1, an ANGPTL receptor, blocked induction of these inflammatory cytokines in P. gingivalis LPS-treated Ca9-22 cells, suggesting that secreted ANGPTL induces inflammatory cytokines in gingival epithelial cells via an autocrine loop. The classic sequential cascade of P. gingivalis LPS → inflammatory cytokine induction is well established. However, in the current study, we reveal a novel cascade comprising sequential P. gingivalis LPS → ANGPTL2 → integrin α5ß1 → inflammatory cytokine induction, which might be responsible for inducing potent periodontal disorganization activity in gingival epithelial cells. Via this pathway, ANGPTL2 functions in the pathogenesis of periodontitis and contributes to prolonging chronic inflammation in patients with systemic disease.
[Mh] Termos MeSH primário: Angiopoietinas/metabolismo
Gengiva/imunologia
Lipopolissacarídeos/metabolismo
Periodontite/imunologia
Porphyromonas gingivalis/metabolismo
[Mh] Termos MeSH secundário: Proteínas Semelhantes a Angiopoietina
Angiopoietinas/administração & dosagem
Angiopoietinas/antagonistas & inibidores
Angiopoietinas/genética
Linhagem Celular
Citocinas/metabolismo
Células Epiteliais/imunologia
Células Epiteliais/microbiologia
Gengiva/microbiologia
Seres Humanos
Integrina alfa5beta1/antagonistas & inibidores
Integrina alfa5beta1/metabolismo
Periodontite/microbiologia
RNA Mensageiro/metabolismo
Proteínas Recombinantes/administração & dosagem
Proteínas Recombinantes/metabolismo
Receptor 2 Toll-Like/antagonistas & inibidores
Receptor 2 Toll-Like/genética
Receptor 2 Toll-Like/metabolismo
Receptor 4 Toll-Like/antagonistas & inibidores
Receptor 4 Toll-Like/genética
Receptor 4 Toll-Like/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPTL2 protein, human); 0 (Angiopoietin-like Proteins); 0 (Angiopoietins); 0 (Cytokines); 0 (Integrin alpha5beta1); 0 (Lipopolysaccharides); 0 (RNA, Messenger); 0 (Recombinant Proteins); 0 (TLR2 protein, human); 0 (TLR4 protein, human); 0 (Toll-Like Receptor 2); 0 (Toll-Like Receptor 4)
[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:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184825


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[PMID]:28754390
[Au] Autor:Piché ME; Thorin-Trescases N; Auclair A; Marceau S; Martin J; Fortier A; Thorin E; Poirier P
[Ad] Endereço:Quebec Heart and Lung Institute, Quebec City, Quebec, Canada; Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
[Ti] Título:Bariatric Surgery-Induced Lower Angiopoietin-Like 2 Protein Is Associated With Improved Cardiometabolic Profile.
[So] Source:Can J Cardiol;33(8):1044-1051, 2017 Aug.
[Is] ISSN:1916-7075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Plasma angiopoietin-like 2 (Angptl2), a proinflammatory protein, has been associated with obesity and diabetes. Whether weight loss induced by bariatric surgery and associated improvement of the cardiometabolic risk profile influence circulating Angptl2 levels is unknown. We tested whether biliopancreatic diversion with duodenal switch (BPD-DS) surgery alters plasma Angptl2 concentrations. METHODS: Severely obese patients (n = 73; body mass index: 49.8 ± 7.1) underwent BPD-DS. Plasma levels of Angptl2 and metabolic biomarkers were obtained acutely (days 1 and 5) and at 6 and 12 months after surgery, and compared with results in an age- and sex-matched control group (n = 33) remaining on the waiting list. RESULTS: Preoperative Angptl2 levels were high (median: 12.3 ng/mL) and correlated with metabolic and anthropometric parameters. A significant (P < 0.01) increase in Angptl2 levels, fasting glucose, insulin, and interleukin-6 levels was observed acutely postoperatively (day 1) followed by a progressive decline from day 5. Besides weight loss, Angptl2 levels were decreased at the 12-month follow-up (11.5 ± 4.7 vs 14.0 ± 4.0 ng/mL, P < 0.0001), but not at the 6-month time point. Long-term changes in plasma Angptl2 levels showed significant positive correlations with changes in fasting glucose, insulin resistance, and tumour necrosis factor-α levels, and negative correlation with changes in leptin concentration (P < 0.05). No significant correlation was observed between changes in anthropometric parameters and Angptl2. CONCLUSIONS: Plasma Angptl2 levels decreased after BPD-DS in severely obese patients; no changes occurred in control participants. Lowered circulating levels of the inflammatory factor Angptl2 because of BPD-DS were closely related to favourable changes in glucose-insulin homeostasis and inflammatory profiles.
[Mh] Termos MeSH primário: Angiopoietinas/sangue
Cirurgia Bariátrica
Doenças Cardiovasculares/epidemiologia
Obesidade Mórbida/cirurgia
Medição de Risco
[Mh] Termos MeSH secundário: Adulto
Proteínas Semelhantes a Angiopoietina
Biomarcadores/sangue
Índice de Massa Corporal
Doenças Cardiovasculares/etiologia
Doenças Cardiovasculares/prevenção & controle
Feminino
Seres Humanos
Incidência
Masculino
Meia-Idade
Obesidade Mórbida/sangue
Obesidade Mórbida/complicações
Quebeque/epidemiologia
Fatores de Risco
Taxa de Sobrevida/tendências
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPTL2 protein, human); 0 (Angiopoietin-like Proteins); 0 (Angiopoietins); 0 (Biomarkers)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170730
[St] Status:MEDLINE


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[PMID]:28723334
[Au] Autor:Gaudet D; Gipe DA; Pordy R; Ahmad Z; Cuchel M; Shah PK; Chyu KY; Sasiela WJ; Chan KC; Brisson D; Khoury E; Banerjee P; Gusarova V; Gromada J; Stahl N; Yancopoulos GD; Hovingh GK
[Ad] Endereço:Université de Montréal, Chicoutimi, QC, Canada.
[Ti] Título:ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia.
[So] Source:N Engl J Med;377(3):296-297, 2017 07 20.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Angiopoietinas/antagonistas & inibidores
Anticorpos Monoclonais/uso terapêutico
LDL-Colesterol/sangue
Hiperlipoproteinemia Tipo II/tratamento farmacológico
[Mh] Termos MeSH secundário: Proteínas Semelhantes a Angiopoietina
Genótipo
Seres Humanos
Hiperlipoproteinemia Tipo II/sangue
Hiperlipoproteinemia Tipo II/genética
Receptores de LDL/efeitos dos fármacos
Receptores de LDL/genética
Receptores de LDL/metabolismo
[Pt] Tipo de publicação:CLINICAL TRIAL; LETTER
[Nm] Nome de substância:
0 (ANGPTL3 protein, human); 0 (Angiopoietin-like Proteins); 0 (Angiopoietins); 0 (Antibodies, Monoclonal); 0 (Cholesterol, LDL); 0 (Receptors, LDL); 0 (evinacumab)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1705994


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[PMID]:28633452
[Au] Autor:Fazio S; Minnier J; Shapiro MD; Tsimikas S; Tarugi P; Averna MR; Arca M; Tavori H
[Ad] Endereço:Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon 97239.
[Ti] Título:Threshold Effects of Circulating Angiopoietin-Like 3 Levels on Plasma Lipoproteins.
[So] Source:J Clin Endocrinol Metab;102(9):3340-3348, 2017 Sep 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function gene mutations results in familial combined hypobetalipoproteinemia type 2 (FHBL2) in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low-density lipoprotein (LDL) phenotype in carriers of ANGPTL3 mutations is unexplained. Objective: To determine whether reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to determine whether proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in determining low LDL levels in this condition. Design: We studied subjects from 19 families with ANGPTL3 mutations and subjects with familial combined hypobetalipoproteinemia type 1 (FHBL1) due to truncated apolipoprotein B (apoB) species. Results: First, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels but only when the latter was <25% of normal (<60 ng/dL). Second, the very low-density lipoprotein particle concentration correlated strongly with plasma ANGPTL3 when the latter was <58% of normal. Third, both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9 and higher levels of its furin-cleaved form. Finally, LDL-bound PCSK9 is protected from cleavage by furin and binds to the LDL receptor more strongly than apoB-free PCSK9. Conclusions: Our results suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on a threshold of plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues.
[Mh] Termos MeSH primário: Angiopoietinas/genética
Apolipoproteínas B/sangue
Predisposição Genética para Doença
Hipobetalipoproteinemias/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Proteínas Semelhantes a Angiopoietina
Western Blotting
Estudos de Coortes
Feminino
Heterozigoto
Seres Humanos
Hipobetalipoproteinemias/sangue
Hipobetalipoproteinemias/fisiopatologia
Modelos Lineares
Lipoproteínas HDL/sangue
Lipoproteínas LDL/sangue
Masculino
Meia-Idade
Análise Multivariada
Mutação
Linhagem
Fenótipo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPTL3 protein, human); 0 (Angiopoietin-like Proteins); 0 (Angiopoietins); 0 (Apolipoproteins B); 0 (Lipoproteins, HDL); 0 (Lipoproteins, LDL)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-4043


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[PMID]:28538136
[Au] Autor:Dewey FE; Gusarova V; Dunbar RL; O'Dushlaine C; Schurmann C; Gottesman O; McCarthy S; Van Hout CV; Bruse S; Dansky HM; Leader JB; Murray MF; Ritchie MD; Kirchner HL; Habegger L; Lopez A; Penn J; Zhao A; Shao W; Stahl N; Murphy AJ; Hamon S; Bouzelmat A; Zhang R; Shumel B; Pordy R; Gipe D; Herman GA; Sheu WHH; Lee IT; Liang KW; Guo X; Rotter JI; Chen YI; Kraus WE; Shah SH; Damrauer S; Small A; Rader DJ; Wulff AB; Nordestgaard BG; Tybjærg-Hansen A; van den Hoek AM; Princen HMG; Ledbetter DH; Carey DJ; Overton JD; Reid JG; Sasiela WJ; Banerjee P
[Ad] Endereço:From Regeneron Genetics Center (F.E.D., C.O., C.S., O.G., S.M., C.V.V.H., S.B., L.H., A.L., J.P., N.S., A.J.M., J.D.O., J.G.R., A.R.S., I.B.B., T.M.T., G.D.Y., S.J.M., A. Baras) and Regeneron Pharmaceuticals (V.G., H.M.D., A.Z., W.S., N.S., A.J.M., S.H., A. Bouzelmat, R.Z., B.S., R.P., D.G., G.A.H.,
[Ti] Título:Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.
[So] Source:N Engl J Med;377(3):211-221, 2017 07 20.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).
[Mh] Termos MeSH primário: Angiopoietinas/antagonistas & inibidores
Anticorpos Monoclonais/administração & dosagem
Aterosclerose/tratamento farmacológico
Doença da Artéria Coronariana/genética
Dislipidemias/tratamento farmacológico
Lipídeos/sangue
Mutação
[Mh] Termos MeSH secundário: Idoso
Proteínas Semelhantes a Angiopoietina
Angiopoietinas/genética
Animais
Anticorpos Monoclonais/efeitos adversos
Anticorpos Monoclonais/farmacologia
Aterosclerose/metabolismo
Doenças Cardiovasculares/prevenção & controle
Doença da Artéria Coronariana/metabolismo
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Método Duplo-Cego
Dislipidemias/sangue
Feminino
Seres Humanos
Metabolismo dos Lipídeos/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos
Meia-Idade
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (ANGPTL3 protein, human); 0 (Angiopoietin-like Proteins); 0 (Angiopoietins); 0 (Angptl3 protein, mouse); 0 (Antibodies, Monoclonal); 0 (Lipids); 0 (evinacumab)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170525
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1612790


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[PMID]:28538111
[Au] Autor:Graham MJ; Lee RG; Brandt TA; Tai LJ; Fu W; Peralta R; Yu R; Hurh E; Paz E; McEvoy BW; Baker BF; Pham NC; Digenio A; Hughes SG; Geary RS; Witztum JL; Crooke RM; Tsimikas S
[Ad] Endereço:From Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
[Ti] Título:Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.
[So] Source:N Engl J Med;377(3):222-232, 2017 07 20.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins. METHODS: We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins. RESULTS: The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events. CONCLUSIONS: Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).
[Mh] Termos MeSH primário: Angiopoietinas/antagonistas & inibidores
Aterosclerose/tratamento farmacológico
Doença da Artéria Coronariana/genética
Dislipidemias/tratamento farmacológico
Lipídeos/sangue
Oligonucleotídeos Antissenso/uso terapêutico
Oligonucleotídeos/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Proteínas Semelhantes a Angiopoietina
Angiopoietinas/genética
Animais
Aterosclerose/metabolismo
Aterosclerose/prevenção & controle
Doença da Artéria Coronariana/metabolismo
Modelos Animais de Doenças
Método Duplo-Cego
Dislipidemias/sangue
Feminino
Seres Humanos
Metabolismo dos Lipídeos/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos
Meia-Idade
Oligonucleotídeos/farmacologia
Oligonucleotídeos Antissenso/farmacologia
RNA Mensageiro/antagonistas & inibidores
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (ANGPTL3 protein, human); 0 (Angiopoietin-like Proteins); 0 (Angiopoietins); 0 (Angptl3 protein, mouse); 0 (IONIS-ANGPTL3-LRx); 0 (Lipids); 0 (Oligonucleotides); 0 (Oligonucleotides, Antisense); 0 (RNA, Messenger)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170525
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1701329


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[PMID]:28528274
[Au] Autor:Mysore R; Liebisch G; Zhou Y; Olkkonen VM; Nidhina Haridas PA
[Ad] Endereço:Minerva Foundation Institute for Medical Research, Helsinki, Finland.
[Ti] Título:Angiopoietin-like 8 (Angptl8) controls adipocyte lipolysis and phospholipid composition.
[So] Source:Chem Phys Lipids;207(Pt B):246-252, 2017 Oct.
[Is] ISSN:1873-2941
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Angiopoietin-like 8 (Angptl8) inhibits lipolysis in the circulation together with Angplt3 and controls post-prandial fat storage in white adipose tissue (WAT). It is strongly induced by insulin in vivo in WAT and in vitro in adipocytes. In this study we addressed the function of Angptl8 in adipocytes by its stable lentivirus-mediated knock-down in 3T3-L1 cells, followed by analyses of triglyceride (TG) storage, lipid droplet (LD) morphology, the cellular lipidome, lipolysis, and gene expression. Depletion of Angptl8 did not drastically affect the adipocyte differentiation of 3T3-L1 cells but resulted in a moderate (18-19%) reduction of stored TGs. The lipidome analysis revealed a reduction of alkyl- phosphatidylcholines (PCs) and phosphatidylethanolamine (PE) plasmalogens, as well as saturated PCs and PEs. Importantly, the Angptl8 depleted cells displayed enhanced lipolysis as measured by release of non-esterified fatty acids (NEFAs). Consistently, mRNAs encoding Angptl4 and Leptin, which facilitate lipolysis, as well as Cpt1a, Cpt1b, and Pgc-1α involved in FA oxidation, were elevated. The Angptl8 mRNA itself was suppressed by pharmacologic treatments inducing lipolysis: stimulation with the ß-adrenergic agonist isoproterenol or with the adenylate cyclase activator forskolin. To conclude, knock-down of Angptl8 in adipocytes suggests that the protein acts to inhibit intracellular lipolysis, analogous to its activity in the circulation. Depletion of Angptl8 results in an altered cellular phospholipid composition. The findings identify Angptl8 as a central insulin-regulated controller of adipocyte lipid metabolism.
[Mh] Termos MeSH primário: Adipócitos/metabolismo
Angiopoietinas/metabolismo
Lipólise
Fosfolipídeos/metabolismo
[Mh] Termos MeSH secundário: Células 3T3-L1
Proteínas Semelhantes a Angiopoietina
Angiopoietinas/deficiência
Animais
Células Cultivadas
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPTL8 protein, mouse); 0 (Angiopoietin-like Proteins); 0 (Angiopoietins); 0 (Phospholipids)
[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:170522
[St] Status:MEDLINE


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[PMID]:28385496
[Au] Autor:Stitziel NO; Khera AV; Wang X; Bierhals AJ; Vourakis AC; Sperry AE; Natarajan P; Klarin D; Emdin CA; Zekavat SM; Nomura A; Erdmann J; Schunkert H; Samani NJ; Kraus WE; Shah SH; Yu B; Boerwinkle E; Rader DJ; Gupta N; Frossard PM; Rasheed A; Danesh J; Lander ES; Gabriel S; Saleheen D; Musunuru K; Kathiresan S; PROMIS and Myocardial Infarction Genetics Consortium Investigators
[Ad] Endereço:Cardiovascular Division, Department of Medicine, Department of Genetics, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Electronic address: nstitziel@wustl.edu.
[Ti] Título:ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.
[So] Source:J Am Coll Cardiol;69(16):2054-2063, 2017 Apr 25.
[Is] ISSN:1558-3597
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD. METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.
[Mh] Termos MeSH primário: Angiopoietinas/deficiência
Doença da Artéria Coronariana/genética
[Mh] Termos MeSH secundário: Adulto
Proteínas Semelhantes a Angiopoietina
Angiopoietinas/sangue
Angiopoietinas/genética
Animais
Aterosclerose/genética
Estudos de Casos e Controles
Feminino
Seres Humanos
Lipídeos/sangue
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Meia-Idade
Mutação de Sentido Incorreto
Infarto do Miocárdio/sangue
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPTL3 protein, human); 0 (Angiopoietin-like Proteins); 0 (Angiopoietins); 0 (Lipids)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE



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