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[PMID]:28216625
[Au] Autor:Baretella O; Chung SK; Xu A; Vanhoutte PM
[Ad] Endereço:Department of Pharmacology & Pharmacy, the University of Hong Kong, Hong Kong SAR, China.
[Ti] Título:Endothelial overexpression of endothelin-1 modulates aortic, carotid, iliac and renal arterial responses in obese mice.
[So] Source:Acta Pharmacol Sin;38(4):498-512, 2017 Apr.
[Is] ISSN:1745-7254
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Endothelin-1 (ET-1) is essential for mammalian development and life, but it has also been implicated in increased cardiovascular risk under pathophysiological conditions. The aim of this study was to determine the impact of endothelial overexpression of the prepro-endothelin-1 gene on endothelium-dependent and endothelium-independent responses in the conduit and renal arteries of lean and obese mice. Obesity was induced by high-fat-diet (HFD) consumption in mice with Tie-1 promoter-driven, endothelium-specific overexpression of the prepro-endothelin-1 gene (TET ) and in wild-type (WT) littermates on a C57BL/6N background. Isometric tension was measured in rings (with endothelium) of the aorta (A), carotid (CA) and iliac (IA) arteries as well as the main (MRA) and segmental renal (SRA) arteries; all experiments were conducted in the absence or presence of L-NAME and/or the COX inhibitor meclofenamate. The release of prostacyclin and thromboxane A2 was measured by ELISA. In the MRA, TET per se increased contractions to endothelin-1, but the response was decreased in SRA in response to serotonin; there were also improved relaxations to acetylcholine but not insulin in the SRA in the presence of L-NAME. HFD per se augmented the contractions to endothelin-1 (MRA) and to the thromboxane prostanoid (TP) receptor agonist U46619 (CA, MRA) as well as facilitated relaxations to isoproterenol (A). The combination of HFD and TET overexpression increased the contractions of MRA and SRA to vasoconstrictors but not in the presence of meclofenamate; this combination also augmented further relaxations to isoproterenol in the A. Contractions to endothelin-1 in the IA were prevented by endothelin-A receptor antagonist BQ-123 but only attenuated in obese mice by BQ-788. The COX-1 inhibitor FR122047 abolished the contractions of CA to acetylcholine. The release of prostacyclin during the latter condition was augmented in samples from obese TET mice and abolished by FR122047. These findings suggest that endothelial TET overexpression in lean animals has minimal effects on vascular responsiveness. However, if comorbid with obesity, endothelin-1-modulated, prostanoid-mediated renal arterial dysfunction becomes apparent.
[Mh] Termos MeSH primário: Artérias/metabolismo
Células Endoteliais/metabolismo
Endotelina-1/metabolismo
Obesidade/fisiopatologia
[Mh] Termos MeSH secundário: Acetilcolina/farmacologia
Animais
Aorta/metabolismo
Aorta/fisiopatologia
Artérias/fisiopatologia
Artérias Carótidas/metabolismo
Artérias Carótidas/fisiopatologia
Ciclo-Oxigenase 1
Dieta Hiperlipídica/efeitos adversos
Antagonistas do Receptor de Endotelina A/farmacologia
Artéria Ilíaca/metabolismo
Artéria Ilíaca/fisiopatologia
Masculino
Proteínas de Membrana/antagonistas & inibidores
Camundongos Transgênicos
Contração Muscular
Relaxamento Muscular
Músculo Liso Vascular/fisiopatologia
Óxido Nítrico Sintase/antagonistas & inibidores
Obesidade/etiologia
Obesidade/metabolismo
Receptores de Tromboxanos/metabolismo
Artéria Renal/metabolismo
Artéria Renal/fisiopatologia
Tromboxano A2/metabolismo
Vasoconstritores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endothelin A Receptor Antagonists); 0 (Endothelin-1); 0 (Membrane Proteins); 0 (Receptors, Thromboxane); 0 (Vasoconstrictor Agents); 57576-52-0 (Thromboxane A2); EC 1.14.13.39 (Nitric Oxide Synthase); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (Ptgs1 protein, mouse); N9YNS0M02X (Acetylcholine)
[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:170221
[St] Status:MEDLINE
[do] DOI:10.1038/aps.2016.138


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[PMID]:27845050
[Au] Autor:Capra V; Mauri M; Guzzi F; Busnelli M; Accomazzo MR; Gaussem P; Nisar SP; Mundell SJ; Parenti M; Rovati GE
[Ad] Endereço:Department of Pharmacological and Biomolecular Sciences, University of Milan, Milano, Italy; Department of Health Science, University of Milan, Milano, Italy. Electronic address: Valerie.Capra@unimi.it.
[Ti] Título:Impaired thromboxane receptor dimerization reduces signaling efficiency: A potential mechanism for reduced platelet function in vivo.
[So] Source:Biochem Pharmacol;124:43-56, 2017 Jan 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Thromboxane A is a potent mediator of inflammation and platelet aggregation exerting its effects through the activation of a G protein-coupled receptor (GPCR), termed TP. Although the existence of dimers/oligomers in Class A GPCRs is widely accepted, their functional significance still remains controversial. Recently, we have shown that TPα and TPß homo-/hetero-dimers interact through an interface of residues in transmembrane domain 1 (TM1) whose disruption impairs dimer formation. Here, biochemical and pharmacological characterization of this dimer deficient mutant (DDM) in living cells indicates a significant impairment in its response to agonists. Interestingly, two single loss-of-function TPα variants, namely W29C and N42S recently identified in two heterozygous patients affected by bleeding disorders, match some of the residues mutated in our DDM. These two naturally occurring variants display a reduced potency to TP agonists and are characterized by impaired dimer formation in transfected HEK-293T cells. These findings provide proofs that lack of homo-dimer formation is a crucial process for reduced TPα function in vivo, and might represent one molecular mechanism through which platelet TPα receptor dysfunction affects the patient(s) carrying these mutations.
[Mh] Termos MeSH primário: Plaquetas/fisiologia
Receptores de Tromboxanos/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Dimerização
Relação Dose-Resposta a Droga
Células HEK293
Seres Humanos
Ligantes
Mutação
Receptores de Tromboxanos/agonistas
Receptores de Tromboxanos/antagonistas & inibidores
Receptores de Tromboxanos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, Thromboxane)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161116
[St] Status:MEDLINE


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[PMID]:27683007
[Au] Autor:Onetti Y; Dantas AP; Pérez B; McNeish AJ; Vila E; Jiménez-Altayó F
[Ad] Endereço:Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
[Ti] Título:Peroxynitrite formed during a transient episode of brain ischaemia increases endothelium-derived hyperpolarization-type dilations in thromboxane/prostaglandin receptor-stimulated rat cerebral arteries.
[So] Source:Acta Physiol (Oxf);220(1):150-166, 2017 May.
[Is] ISSN:1748-1716
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: Increased thromboxane A and peroxynitrite are hallmarks of cerebral ischaemia/reperfusion (I/R). Stimulation of thromboxane/prostaglandin receptors (TP) attenuates endothelium-derived hyperpolarization (EDH). We investigated whether EDH-type middle cerebral artery (MCA) relaxations following TP stimulation are altered after I/R and the influence of peroxynitrite. METHODS: Vascular function was determined by wire myography after TP stimulation with the thromboxane A mimetic 9,11-dideoxy-9α, 11α -methano-epoxy prostaglandin F2α (U46619) in MCA of Sprague Dawley rats subjected to MCA occlusion (90 min)/reperfusion (24 h) or sham operation, and in non-operated (control) rats. Some rats were treated with saline or the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) (20 mg kg ). Protein expression was evaluated in MCA and in human microvascular endothelial cells submitted to hypoxia (overnight)/reoxygenation (24 h) (H/R) using immunofluorescence and immunoblotting. RESULTS: In U46619-pre-constricted MCA, EDH-type relaxation by the proteinase-activated receptor 2 agonist serine-leucine-isoleucine-glycine-arginine-leucine-NH (SLIGRL) was greater in I/R than sham rats due to an increased contribution of small-conductance calcium-activated potassium channels (SK ), which was confirmed by the enlarged relaxation to the SK activator N-cyclohexyl-N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine. I/R and H/R induced endothelial protein tyrosine nitration and filamentous-actin disruption. In control MCA, either cytochalasin D or peroxynitrite disrupted endothelial filamentous-actin and augmented EDH-type relaxation. Furthermore, peroxynitrite decomposition during I/R prevented the increase in EDH-type responses. CONCLUSION: Following TP stimulation in MCA, EDH-type relaxation to SLIGRL is greater after I/R due to endothelial filamentous-actin disruption by peroxynitrite, which prevents TP-induced block of SK input to EDH. These results reveal a novel mechanism whereby peroxynitrite could promote post-ischaemic brain injury.
[Mh] Termos MeSH primário: Endotélio Vascular/fisiopatologia
Infarto da Artéria Cerebral Média/fisiopatologia
Ácido Peroxinitroso/metabolismo
Traumatismo por Reperfusão/fisiopatologia
Vasodilatação/fisiologia
[Mh] Termos MeSH secundário: Animais
Western Blotting
Linhagem Celular
Modelos Animais de Doenças
Endotélio Vascular/metabolismo
Imunofluorescência
Seres Humanos
Infarto da Artéria Cerebral Média/metabolismo
Ataque Isquêmico Transitório/metabolismo
Ataque Isquêmico Transitório/fisiopatologia
Masculino
Artéria Cerebral Média
Oligopeptídeos/farmacologia
Ratos
Ratos Sprague-Dawley
Receptores de Prostaglandina/metabolismo
Receptores de Tromboxanos/metabolismo
Traumatismo por Reperfusão/metabolismo
Vasodilatação/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oligopeptides); 0 (Receptors, Prostaglandin); 0 (Receptors, Thromboxane); 0 (seryl-leucyl-isoleucyl-glycyl-arginyl-leucine); 14691-52-2 (Peroxynitrous Acid)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160930
[St] Status:MEDLINE
[do] DOI:10.1111/apha.12809


  4 / 1597 MEDLINE  
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[PMID]:26666460
[Au] Autor:Siangjong L; Goldman DH; Kriska T; Gauthier KM; Smyth EM; Puli N; Kumar G; Falck JR; Campbell WB
[Ad] Endereço:Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
[Ti] Título:Vascular hepoxilin and trioxilins mediate vasorelaxation through TP receptor inhibition in mouse arteries.
[So] Source:Acta Physiol (Oxf);219(1):188-201, 2017 Jan.
[Is] ISSN:1748-1716
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: 12/15-lipoxygenase (12/15-LO) metabolizes arachidonic acid (AA) into several vasoactive eicosanoids. In mouse arteries, we previously characterized the enzyme's 15-LO metabolites 12(S)-hydroxyeicosatetraenoic acid (HETE), 15-HETE, hydroxyepoxyeicosatrienoic acids (HEETAs) and 11,12,15-trihydroxyeicosatrienoic acids (11,12,15-THETAs) as endothelium-derived relaxing factors. However, the observed 12-LO metabolites remained uncharacterized. The purpose of this study was to determine the structure and biological functions of eicosanoids generated by the enzyme's 12-LO activity. METHODS: Metabolites extracted from aortas of C57BL/6 male mice were separated using a series of reverse and normal phase chromatographic steps and identified as hepoxilin A , trioxilin A and trioxilin C by mass spectrometry. Activities of these natural compounds were tested on isometric tension and intracellular calcium release. The role of thromboxane (TP) receptor was determined in HEK293 cells overexpressing TPα receptor (TPα -HEK). RESULTS: All identified vascular 12-LO metabolites were biologically active. In mouse mesenteric arteries, trioxilin A , C and hepoxilin A (3 µm) relaxed arteries constricted with the thromboxane mimetic, U46619-constricted arteries (maximum relaxations of 78.9 ± 3.2, 29.7 ± 4.6, 82.2 ± 5.0 and 88.0 ± 2.4% respectively), but not phenylephrine-constricted arteries. In TPα-HEK cells, trioxilin A , C and hepoxilin A (10 µm) inhibited U46619 (10 nM)-induced increases in intracellular calcium by 53.0 ± 7.2%, 32.8 ± 5.0% and 37.9 ± 13.5% respectively. In contrast, trioxilin B and hepoxilin B were not synthesized in arteries and exhibited little biological activity. CONCLUSION: Trioxilin A and C and hepoxilin A are endogenous vascular relaxing factors. They are not endothelium-derived hyperpolarizing factors but mediate vascular relaxation by inhibiting TP agonist-induced increases in intracellular calcium. Thus, they regulate vascular homeostasis by acting as endogenous TP antagonists.
[Mh] Termos MeSH primário: Ácido 8,11,14-Eicosatrienoico/análogos & derivados
Aorta/metabolismo
Artérias Mesentéricas/metabolismo
Receptores de Tromboxanos/metabolismo
Vasodilatação/efeitos dos fármacos
Vasodilatadores/farmacologia
[Mh] Termos MeSH secundário: Ácido 8,11,14-Eicosatrienoico/metabolismo
Ácido 8,11,14-Eicosatrienoico/farmacologia
Animais
Células HEK293
Seres Humanos
Masculino
Artérias Mesentéricas/efeitos dos fármacos
Camundongos
Camundongos Endogâmicos C57BL
Receptores de Tromboxanos/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Thromboxane); 0 (Vasodilator Agents); 68860-46-8 (8,11,12-trihydroxy-5,9,14-eicosatrienoic acid); 7324-41-6 (8,11,14-Eicosatrienoic Acid); 85589-24-8 (8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151216
[St] Status:MEDLINE
[do] DOI:10.1111/apha.12642


  5 / 1597 MEDLINE  
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[PMID]:27174823
[Au] Autor:Nijoukubo D; Tanaka Y; Okuno Y; Yin G; Kitazawa T; Peterson RE; Kubota A; Teraoka H
[Ad] Endereço:School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
[Ti] Título:Protective effect of prostacyclin against pre-cardiac edema caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin and a thromboxane receptor agonist in developing zebrafish.
[So] Source:Chemosphere;156:111-117, 2016 Aug.
[Is] ISSN:1879-1298
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The role of prostaglandin pathways has been suggested in some toxicological responses to dioxins. Cyclooxygenase type 2b (COX2b), thromboxane synthase, and the thromboxane receptor (TP) pathway have been implicated in mediating 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced pre-cardiac edema in developing zebrafish at 55 h post fertilization (hpf). Pre-cardiac edema refers to edema located in a small cavity between the heart and body wall of zebrafish eleutheroembryos. In the present study, we assessed the role of prostacyclin, which counteracts some biological effects of thromboxane, in TCDD-induced pre-cardiac edema. Pre-cardiac edema induced by TCDD exposure (0.5 and 1 ppb) beginning at 24 hpf was markedly inhibited by exposure to beraprost (5 and 10 µM), a prostacyclin receptor (IP) agonist, beginning at 33 hpf. The preventive effect of beraprost was reduced by exposure to CAY10441 (10 µM), an IP antagonist starting at 33 hpf. Knockdowns of the IP receptor (IP-KD) with two different morpholinos caused edema by themselves and enhanced pre-cardiac edema caused by the low concentration of TCDD (0.5 ppb). On the other hand, short exposure beginning at 48 hpf to U46619 (7.5-30 µM), a thromboxane receptor agonist caused pre-cardiac edema, which was inhibited by exposure beginning at 48 hpf to both ICI-192,605 (24 µM), a TP antagonist, and beraprost. Expression of prostacyclin synthase was increased from fertilization, plateaued by 48 hpf, and was maintained until at least 96 hpf. Overall, the results demonstrate a preventive effect of prostacyclin on TCDD-induced pre-cardiac edema in developing zebrafish.
[Mh] Termos MeSH primário: Edema Cardíaco/prevenção & controle
Edema/prevenção & controle
Epoprostenol/farmacologia
Dibenzodioxinas Policloradas/toxicidade
Receptores de Tromboxanos/agonistas
Peixe-Zebra/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Animais
Anti-Hipertensivos/farmacologia
Ciclo-Oxigenase 2/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Edema/induzido quimicamente
Edema Cardíaco/induzido quimicamente
Embrião não Mamífero/citologia
Embrião não Mamífero/efeitos dos fármacos
Poluentes Ambientais/toxicidade
Epoprostenol/análogos & derivados
Oxirredutases Intramoleculares/metabolismo
Inibidores da Agregação de Plaquetas/farmacologia
Proteínas de Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antihypertensive Agents); 0 (Environmental Pollutants); 0 (Platelet Aggregation Inhibitors); 0 (Polychlorinated Dibenzodioxins); 0 (Receptors, Thromboxane); 0 (Zebrafish Proteins); 35E3NJJ4O6 (beraprost); 9035-51-2 (Cytochrome P-450 Enzyme System); DCR9Z582X0 (Epoprostenol); EC 1.14.99.1 (Cyclooxygenase 2); EC 5.3.- (Intramolecular Oxidoreductases); EC 5.3.99.4 (prostacyclin synthetase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160514
[St] Status:MEDLINE


  6 / 1597 MEDLINE  
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[PMID]:27019366
[Au] Autor:Romero M; Leon-Gomez E; Lobysheva I; Rath G; Dogné JM; Feron O; Dessy C
[Ad] Endereço:Pole of Pharmacology and Therapeutics (FATH), Institute of Experimental & Clinical Research (IREC), Université Catholique de Louvain (UCL) Medical School, Brussels, Belgium.
[Ti] Título:Effects of BM-573 on Endothelial Dependent Relaxation and Increased Blood Pressure at Early Stages of Atherosclerosis.
[So] Source:PLoS One;11(3):e0152579, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Endothelial dysfunction is considered to be an early event in atherosclerosis and plays a pivotal role in the development, progression and clinical complications of atherosclerosis. Previous studies have shown the beneficial effects of combined inhibition of thromboxane synthase and antagonism of thromboxane receptors by BM-573 on atherosclerosis; however our knowledge about the beneficial effects of BM-573 on endothelial function and increased blood pressure related to early stage of atherosclerosis is limited. In the present study, we investigated the effects of short-term (3 µM, 1 hour) and chronic (10 mg/L, 8 weeks) treatments with BM-573 on vasodilatory function, nitric oxide (NO) bioavailability, oxidative stress and systolic blood pressure in 15 weeks old apolipoprotein E-deficient (ApoE-KO) mice. ApoE-KO mice showed a reduced endothelium-derived relaxation. In addition, NO bioavailability was reduced and oxidative stress and blood pressure were increased in ApoE-KO mice versus wild-type mice. BM-573 treatments were able to improve the relaxation profile in ApoE-KO mice. Short-term effects of BM-573 were mainly mediated by an increased phosphorylation of both eNOS and Akt, whereas BM-573 in vivo treatment also reduced oxidative stress and restored NO bioavailability. In addition, chronic administration of BM-573 reduced systolic blood pressure in ApoE-KO mice. In conclusion, pharmacological modulation of TxA2 biosynthesis and biological activities by dual TP antagonism/TxAS inhibition with BM-573, already known to prevent plaque formation, has the potential to correct vasodilatory dysfunction at the early stages of atherosclerosis.
[Mh] Termos MeSH primário: Aterosclerose/tratamento farmacológico
Compostos de Sulfonilureia/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Apolipoproteínas E/deficiência
Apolipoproteínas E/genética
Aterosclerose/patologia
Pressão Sanguínea/efeitos dos fármacos
Ciclo-Oxigenase 1/genética
Ciclo-Oxigenase 1/metabolismo
Ciclo-Oxigenase 2/genética
Ciclo-Oxigenase 2/metabolismo
Modelos Animais de Doenças
Endotélio Vascular/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo III/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-akt/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Receptores de Tromboxanos/antagonistas & inibidores
Receptores de Tromboxanos/metabolismo
Compostos de Sulfonilureia/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea); 0 (Reactive Oxygen Species); 0 (Receptors, Thromboxane); 0 (Sulfonylurea Compounds); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.14.13.39 (Nos3 protein, mouse); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (Cyclooxygenase 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160406
[Lr] Data última revisão:
160406
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160329
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0152579


  7 / 1597 MEDLINE  
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[PMID]:26774228
[Au] Autor:Vidal-Gómez X; Novella S; Pérez-Monzó I; Garabito M; Dantas AP; Segarra G; Hermenegildo C; Medina P
[Ad] Endereço:Department of Physiology, University of Valencia, Valencia, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain.
[Ti] Título:Decreased bioavailability of nitric oxide in aorta from ovariectomized senescent mice. Role of cyclooxygenase.
[So] Source:Exp Gerontol;76:1-8, 2016 Apr.
[Is] ISSN:1873-6815
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:This study investigates the effects of aging and/or ovariectomy on vascular reactivity to thromboxane A2 (TXA2) receptor stimulation with U46619, and the modulation by nitric oxide (NO) and cyclooxygenase (COX) in aorta from female senescence-accelerated mice (SAMP8) and from senescence resistant mice (SAMR1). Five-month-old female SAMR1 and SAMP8 were divided into three groups: sham-operated, ovariectomized and ovariectomized plus estradiol. Twenty-eight days after surgery, thoracic aortic rings were mounted for isometric recording of tension and concentration-response curves for U46619 (10(-10)-3 × 10(-7) M) were performed in the absence and in the presence of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) and/or COX inhibitor indomethacin (10(-5)M). Vascular superoxide production was detected by dihydroethidium staining on sections of thoracic aorta. NO bioavailability in response to U46619 was suppressed by estrogen withdrawn in young and senescent mice and was restored by the administration of estradiol. In the presence of indomethacin, contractions to U46619 decreased in all groups indicating an aging- and estrogen-dependent modulation of contractile prostanoids. The simultaneous incubation of L-NAME and indomethacin did not change the maximal responses and sensitivities to TXA2 in any group in comparison with untreated aortic segments. The superoxide generation induced by TXA2 was greater in aorta from SAMP8 than in SAMR1. Moreover, in ovariectomized groups superoxide production was further increased and treatment with 17ß-estradiol reverted the effects of the ovariectomy. Inhibition of COX with indomethacin prevented the U46619-induced increase in superoxide formation. Our results indicate that NO bioavailability in response to TP receptor activation is both estrogen- and aging-dependent. TXA2 induced contractions are partially mediated by COX activation. Both aging and ovariectomy enhanced COX-dependent component of the TXA2-induced contraction. It is noteworthy that in the absence of estrogen, COX inhibition induces an increase of NO bioavailability. Therefore, in senescent female mice with an experimental menopause, TP-receptor stimulation is responsible for COX activation and enhanced superoxide generation, which may result in reduced NO bioavailability. These effects were reversed by estrogen administration.
[Mh] Termos MeSH primário: Envelhecimento/metabolismo
Aorta Torácica/enzimologia
Menopausa/metabolismo
Óxido Nítrico/metabolismo
Ovariectomia
Prostaglandina-Endoperóxido Sintases/metabolismo
Vasoconstrição
[Mh] Termos MeSH secundário: Fatores Etários
Animais
Aorta Torácica/efeitos dos fármacos
Inibidores de Ciclo-Oxigenase/farmacologia
Relação Dose-Resposta a Droga
Regulação para Baixo
Ativação Enzimática
Estradiol/farmacologia
Terapia de Reposição de Estrogênios
Feminino
Camundongos
Óxido Nítrico Sintase/antagonistas & inibidores
Óxido Nítrico Sintase/metabolismo
Estresse Oxidativo
Receptores de Tromboxanos/agonistas
Receptores de Tromboxanos/metabolismo
Transdução de Sinais
Superóxidos/metabolismo
Tromboxano A2/farmacologia
Vasoconstrição/efeitos dos fármacos
Vasoconstritores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclooxygenase Inhibitors); 0 (Receptors, Thromboxane); 0 (Vasoconstrictor Agents); 11062-77-4 (Superoxides); 31C4KY9ESH (Nitric Oxide); 4TI98Z838E (Estradiol); 57576-52-0 (Thromboxane A2); EC 1.14.13.39 (Nitric Oxide Synthase); EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160118
[St] Status:MEDLINE


  8 / 1597 MEDLINE  
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[PMID]:26640151
[Au] Autor:van Jaarsveld MT; Houthuijzen JM; Voest EE
[Ad] Endereço:Department of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands.
[Ti] Título:Molecular mechanisms of target recognition by lipid GPCRs: relevance for cancer.
[So] Source:Oncogene;35(31):4021-35, 2016 Aug 04.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Over the past decade the importance of lipids for cancer cell metabolism and cancer-related processes such as proliferation, metastasis and chemotherapy resistance has become more apparent. The mechanisms by which lipid signals are transduced are poorly understood, but frequently involve G-protein Coupled Receptors (GPCRs), which can be explored as druggable targets. Here, we discuss how GPCRs recognize four classes of cancer-relevant lipids (lysophospholipids, phospholipids, fatty acids and eicosanoids). We compare the ligand-binding properties of >50 lipid receptors, we examine how their dysregulation contributes to tumorigenesis and how they may be therapeutically exploited.
[Mh] Termos MeSH primário: Lipídeos/fisiologia
Neoplasias/metabolismo
Receptores Acoplados a Proteínas-G/fisiologia
[Mh] Termos MeSH secundário: Animais
Eicosanoides/metabolismo
Endocanabinoides/fisiologia
Ácidos Graxos/metabolismo
Seres Humanos
Lisofosfolipídeos/química
Lisofosfolipídeos/fisiologia
Neoplasias/etiologia
Receptores de Leucotrienos/fisiologia
Receptores de Lisofosfolipídeos/fisiologia
Receptores de Tromboxanos/fisiologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Eicosanoids); 0 (Endocannabinoids); 0 (Fatty Acids); 0 (Lipids); 0 (Lysophospholipids); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Leukotriene); 0 (Receptors, Lysophospholipid); 0 (Receptors, Thromboxane)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151208
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2015.467


  9 / 1597 MEDLINE  
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[PMID]:26621246
[Au] Autor:Hoxha M; Buccellati C; Capra V; Garella D; Cena C; Rolando B; Fruttero R; Carnevali S; Sala A; Rovati GE; Bertinaria M
[Ad] Endereço:Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
[Ti] Título:In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition.
[So] Source:Pharmacol Res;103:132-43, 2016 Jan.
[Is] ISSN:1096-1186
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Patients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atherosclerosis) that require effective management of chronic pain may take advantage from new non-steroidal anti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activity and reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with a cardioprotective component involving antagonism of thromboxane A2 prostanoid (TP) receptor. METHODS: New compounds were obtained modulating the structure of the most potent coxib, lumiracoxib, to obtain novel multitarget NSAIDs endowed with balanced coxib and TP receptor antagonist properties. Antagonist activity at TP receptor (pA2) was evaluated for all compounds in human platelets and in an heterologous expression system by measuring prevention of aggregation and Gq-dependent production of intracellular inositol phosphate induced by the stable thromboxane A2 (TXA2) agonist U46619. COX-1 and COX-2 inhibitory activities were assessed in human washed platelets and lympho-monocytes suspension, respectively. COX selectivity was determined from dose-response curves by calculating a ratio (COX-2/COX-1) of IC50 values. RESULTS: The tetrazole derivative 18 and the trifluoromethan sulfonamido-isoster 20 were the more active antagonists at TP receptor, preventing human platelet aggregation and intracellular signalling, with pA2 values statistically higher from that of lumiracoxib. Comparative data regarding COX-2/COX-1 selectivity showed that while compounds 18 and 7 were rather potent and selective COX-2 inhibitor, compound 20 was somehow less potent and selective for COX-2. CONCLUSION: These results indicate that compounds 18 and 20 are two novel combined TP receptor antagonists and COX-2 inhibitors characterized by a fairly balanced COX-2 inhibitor activity and TP receptor antagonism and that they may represent a first optimization of the original structure to improve their multitarget activity.
[Mh] Termos MeSH primário: Inibidores de Ciclo-Oxigenase 2/farmacologia
Receptores de Tromboxanos/antagonistas & inibidores
[Mh] Termos MeSH secundário: Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia
Adolescente
Adulto
Plaquetas/efeitos dos fármacos
Plaquetas/metabolismo
Ciclo-Oxigenase 1/metabolismo
Ciclo-Oxigenase 2/metabolismo
Diclofenaco/análogos & derivados
Diclofenaco/farmacologia
Feminino
Células HEK293
Seres Humanos
Masculino
Meia-Idade
Naftalenos/farmacologia
Naproxeno/farmacologia
Propionatos/farmacologia
Receptores de Tromboxanos/genética
Receptores de Tromboxanos/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclooxygenase 2 Inhibitors); 0 (Naphthalenes); 0 (Propionates); 0 (Receptors, Thromboxane); 144O8QL0L1 (Diclofenac); 57Y76R9ATQ (Naproxen); 76898-47-0 (15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid); A6WX9391D8 (terutroban); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (PTGS1 protein, human); EC 1.14.99.1 (PTGS2 protein, human); V91T9204HU (lumiracoxib)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151202
[St] Status:MEDLINE


  10 / 1597 MEDLINE  
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[PMID]:26460717
[Au] Autor:Signorello MG; Leoncini G
[Ad] Endereço:Department of Pharmacy, Biochemistry Lab, University of Genoa, Viale Benedetto XV 3, 16132, Genova, Italy.
[Ti] Título:Regulation of cAMP Intracellular Levels in Human Platelets Stimulated by 2-Arachidonoylglycerol.
[So] Source:J Cell Biochem;117(5):1240-9, 2016 May.
[Is] ISSN:1097-4644
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We demonstrated that in human platelets the endocannabinoid 2-arachidonoylglycerol (2-AG) decreased dose- and time-dependently cAMP intracellular levels. No effect on cAMP decrease induced by 2-AG was observed in the presence of the adenylate cyclase inhibitor SQ22536 as well in platelets pretreated with the thromboxane A2 receptor antagonist, SQ29548 or with aspirin, inhibitor of arachidonic acid metabolism through the cyclooxygenase pathway. An almost complete recovering of cAMP level was measured in platelets pretreated with the specific inhibitor of phosphodiesterase (PDE) 3A, milrinone. In platelets pretreated with LY294002 or MK2206, inhibitors of PI3K/AKT pathway, and with U73122, inhibitor of phospholipase C pathway, only a partial prevention was shown. cAMP intracellular level depends on synthesis by adenylate cyclase and hydrolysis by PDEs. In 2-AG-stimulated platelets adenylate cyclase activity seems to be unchanged. In contrast PDEs appear to be involved. In particular PDE3A was specifically activated, as milrinone reversed cAMP reduction by 2-AG. 2-AG enhanced PDE3A activity through its phosphorylation. The PI3K/AKT pathway and PKC participate to this PDE3A phosphorylation/activation mechanism as it was greatly inhibited by platelet pretreatment with LY294002, MK2206, U73122, or the PKC specific inhibitor GF109203X. Taken together these data suggest that 2-AG potentiates its power of platelet agonist reducing cAMP intracellular level.
[Mh] Termos MeSH primário: Ácidos Araquidônicos/farmacologia
Plaquetas/efeitos dos fármacos
AMP Cíclico/metabolismo
Endocanabinoides/farmacologia
Glicerídeos/farmacologia
[Mh] Termos MeSH secundário: Adenina/análogos & derivados
Adenina/farmacologia
Inibidores de Adenilil Ciclase/farmacologia
Adenilil Ciclases/metabolismo
Plaquetas/citologia
Plaquetas/metabolismo
Agonistas de Receptores de Canabinoides/farmacologia
Células Cultivadas
Cromonas/farmacologia
Relação Dose-Resposta a Droga
Estrenos/farmacologia
Seres Humanos
Hidrazinas/farmacologia
Immunoblotting
Indóis/farmacologia
Espaço Intracelular/efeitos dos fármacos
Espaço Intracelular/metabolismo
Maleimidas/farmacologia
Milrinona/farmacologia
Morfolinas/farmacologia
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Fosfatidilinositol 3-Quinases/metabolismo
Inibidores da Fosfodiesterase 3/farmacologia
Agregação Plaquetária/efeitos dos fármacos
Proteína Quinase C/antagonistas & inibidores
Proteína Quinase C/metabolismo
Pirrolidinonas/farmacologia
Receptores de Tromboxanos/antagonistas & inibidores
Receptores de Tromboxanos/metabolismo
Fosfolipases Tipo C/antagonistas & inibidores
Fosfolipases Tipo C/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 0 (Arachidonic Acids); 0 (Cannabinoid Receptor Agonists); 0 (Chromones); 0 (Endocannabinoids); 0 (Estrenes); 0 (Glycerides); 0 (Hydrazines); 0 (Indoles); 0 (Maleimides); 0 (Morpholines); 0 (Phosphodiesterase 3 Inhibitors); 0 (Pyrrolidinones); 0 (Receptors, Thromboxane); 112648-68-7 (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione); 17318-31-9 (9-(tetrahydro-2-furyl)-adenine); 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one); 8D239QDW64 (glyceryl 2-arachidonate); 98299-61-7 (SQ 29548); E0399OZS9N (Cyclic AMP); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.13 (Protein Kinase C); EC 3.1.4.- (Type C Phospholipases); EC 4.6.1.1 (Adenylyl Cyclases); JAC85A2161 (Adenine); JU9YAX04C7 (Milrinone); L79H6N0V6C (bisindolylmaleimide I)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151014
[St] Status:MEDLINE
[do] DOI:10.1002/jcb.25408



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