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Pesquisa : D08.811.277.352.100.680.750.937.750 [Categoria DeCS]
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[PMID]:28856929
[Au] Autor:Alasmary FAS; Alnahdi FS; Ben Bacha A; El-Araby AM; Moubayed N; Alafeefy AM; El-Araby ME
[Ad] Endereço:a Chemistry Department, College of Science , King Saud University , Riyadh , Saudi Arabia.
[Ti] Título:New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase.
[So] Source:J Enzyme Inhib Med Chem;32(1):1143-1151, 2017 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N'-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a-f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a-f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b-d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC = 9.99 ± 0.18 µM); which is comparable to quercetin (IC = 9.93 ± 0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC > 200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Fosfolipases A2 Secretórias/antagonistas & inibidores
Quinoxalinas/farmacologia
alfa-Glucosidases/metabolismo
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Fosfolipases A2 Secretórias/metabolismo
Quinoxalinas/síntese química
Quinoxalinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Quinoxalines); EC 3.1.1.4 (Phospholipases A2, Secretory); EC 3.2.1.20 (alpha-Glucosidases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1363743


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[PMID]:28433579
[Au] Autor:Zweitzig DR; Tibbe AG; Kopnitsky MJ; Cichonski K; Terstappen LWMM
[Ad] Endereço:ZEUS Scientific Inc., 200 Evans Way, Branchburg, NJ 08876, United States. Electronic address: dzweitzig@zeusscientific.com.
[Ti] Título:Distinguishing septic from normal donors by detection of sPLA2-IIA from human plasma using a microsieve-based immunoassay.
[So] Source:J Immunol Methods;447:86-91, 2017 Aug.
[Is] ISSN:1872-7905
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Bloodstream infections that progress to septic shock are responsible for hundreds of thousands of deaths each year, and are associated with significant healthcare costs. Recent studies have shown that a member of the secreted phospholipase protein family, termed sPLA2-IIA, may play a role during the innate immune response to bacterial infections, and is elevated in the plasma of septic patients. In this report, the feasibility of a simple microsieve-based sPLA2-IIA detection immunoassay was explored. Microsieves containing 5µm pores were covalently coupled with a sPLA2-IIA-specific monoclonal antibody at 0.1, 1.0, and 10µg/mL and then assayed with plasma-based positive and negative controls to determine the optimal coating concentration. Recombinant sPLA2-IIA was then serially diluted to a final concentration of 200, 100, 50, 25, 12.5, and 6.25ng/mL and tested alongside a non-spiked sample to estimate the detection limit of the prototype assay. Recombinant sPLA2-IIA was also spiked into serum, EDTA-plasma, and Lithium-Heparin plasma, in an effort to evaluate assay performance when analyzing these sample matrices. The preliminary limit of detection studies suggests that the microsieve assay is able to distinguish approximately 6-12ng/mL of sPLA2-IIA from a non-spiked sample. When compared to an immunoassay diluent, the microsieve assay also yielded acceptable percent recoveries for each of the three sample matrices spiked with clinically significant levels of sPLA2-IIA. The sPLA2-IIA microsieve assay prototype also clearly distinguished five samples from septic patients from five normal donor samples, and the results were in good agreement with a comparator ELISA test system (R =0.9347).
[Mh] Termos MeSH primário: Ensaios Enzimáticos Clínicos
Imunoensaio
Fosfolipases A2 Secretórias/sangue
Sepse/diagnóstico
[Mh] Termos MeSH secundário: Anticorpos Monoclonais
Ensaio de Imunoadsorção Enzimática/métodos
Estudos de Viabilidade
Seres Humanos
Imunidade Inata
Imunoensaio/instrumentação
Imunoensaio/métodos
Masculino
Fosfolipases A2 Secretórias/química
Fosfolipases A2 Secretórias/imunologia
Fosfolipases A2 Secretórias/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); EC 3.1.1.4 (Phospholipases A2, Secretory)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170424
[St] Status:MEDLINE


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[PMID]:28249041
[Au] Autor:Martín R; Cordova C; Gutiérrez B; Hernández M; Nieto ML
[Ad] Endereço:Instituto de Biología y Genética Molecular (IBGM), CSIC-UVa, Valladolid, Spain.
[Ti] Título:A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells.
[So] Source:PLoS One;12(3):e0170675, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.
[Mh] Termos MeSH primário: Astrocitoma/metabolismo
Movimento Celular
Proliferação Celular
Regulação Enzimológica da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Leptina/metabolismo
Sistema de Sinalização das MAP Quinases
Fosfolipases A2 Secretórias/biossíntese
Ativação Transcricional
[Mh] Termos MeSH secundário: Animais
Astrocitoma/genética
Astrocitoma/patologia
Linhagem Celular Tumoral
MAP Quinases Reguladas por Sinal Extracelular/genética
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Seres Humanos
Leptina/genética
Leptina/farmacologia
Camundongos
Fosfolipases A2 Secretórias/genética
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Proto-Oncogênicas pp60(c-src)/genética
Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo
Receptor do Fator de Crescimento Epidérmico/genética
Receptor do Fator de Crescimento Epidérmico/metabolismo
Receptores para Leptina/biossíntese
Receptores para Leptina/genética
Proteínas Quinases S6 Ribossômicas 70-kDa/genética
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Leptin); 0 (Receptors, Leptin); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src)); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.1.1.4 (Phospholipases A2, Secretory)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170302
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0170675


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[PMID]:28201868
[Au] Autor:Fouladi F; Steffen KJ; Mallik S
[Ad] Endereço:Department of Pharmaceutical Sciences, North Dakota State University , Fargo, North Dakota 58108, United States.
[Ti] Título:Enzyme-Responsive Liposomes for the Delivery of Anticancer Drugs.
[So] Source:Bioconjug Chem;28(4):857-868, 2017 Apr 19.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Liposomes are nanocarriers that deliver the payloads at the target site, leading to therapeutic drug concentrations at the diseased site and reduced toxic effects in healthy tissues. Several approaches have been used to enhance the ability of the nanocarrier to target the specific tissues, including ligand-targeted liposomes and stimuli-responsive liposomes. Ligand-targeted liposomes exhibit higher uptake by the target tissue due to the targeting ligand attached to the surface, while the stimuli-responsive liposomes do not release their cargo unless they expose to an endogenous or exogenous stimulant at the target site. In this review, we mainly focus on the liposomes that are responsive to pathologically increased levels of enzymes at the target site. Enzyme-responsive liposomes release their cargo upon contact with the enzyme through several destabilization mechanisms: (1) structural perturbation in the lipid bilayer, (2) removal of a shielding polymer from the surface and increased cellular uptake, (3) cleavage of a lipopeptide or lipopolymer incorporated in the bilayer, and (4) activation of a prodrug in the liposomes.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Biocatálise
Preparações de Ação Retardada/metabolismo
Lipossomos/metabolismo
[Mh] Termos MeSH secundário: Animais
Catepsina B/metabolismo
Preparações de Ação Retardada/química
Sistemas de Liberação de Medicamentos/métodos
Seres Humanos
Lipopeptídeos/química
Lipopeptídeos/metabolismo
Lipossomos/química
Metaloproteinases da Matriz/metabolismo
Neoplasias/tratamento farmacológico
Elastase Pancreática/metabolismo
Fosfolipases A2 Secretórias/metabolismo
Polímeros/química
Polímeros/metabolismo
Pró-Fármacos/administração & dosagem
Antígeno Prostático Específico/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Delayed-Action Preparations); 0 (Lipopeptides); 0 (Liposomes); 0 (Polymers); 0 (Prodrugs); EC 3.1.1.4 (Phospholipases A2, Secretory); EC 3.4.21.36 (Pancreatic Elastase); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator); EC 3.4.21.77 (Prostate-Specific Antigen); EC 3.4.22.1 (Cathepsin B); EC 3.4.24.- (Matrix Metalloproteinases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170715
[Lr] Data última revisão:
170715
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.6b00736


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[PMID]:28123160
[Au] Autor:Xie Q; Zhang D
[Ad] Endereço:Department of Cardiology, The First Hospital of Xiamen University.
[Ti] Título:Effects of Statins and Xuezhikang on the Expression of Secretory Phospholipase A2, Group IIA in Rat Vascular Smooth Muscle Cells.
[So] Source:Int Heart J;58(1):115-124, 2017 Feb 07.
[Is] ISSN:1349-3299
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Atherosclerosis is a multifactorial vascular disease characterized by formation of inflammatory lesions. Secretory phospholipase A2, group IIA (sPLA2-IIA) is involved in this process and plays a critical role. However, the exact role of sPLA2-IIA in cardiovascular inflammation is more complicated and remains unclear. Furthermore, both statins and Xuezhikang (XZK) are widely used in the prevention and treatment of cardiovascular disease risk because of their pleiotropic effects on the cardiovascular system. However, their effects on sPLA2-IIA are still controversial. We investigated the regulation of sPLA2-IIA by rat thoracic aorta smooth muscle cells (VSMCs) in culture. Cells were first incubated with IL-1ß alone to induce expression of sPLA2-IIA and then treated with several concentrations of statins or XZK for different times in the absence or presence of IL-1ß. We tested the expression of sPLA2-IIA, including sPLA2-IIA mRNA, protein, as well as activity. We found that statins or IL-1ß increase the expression of sPLA2-IIA in VSMCs and the effect is based on a synergetic relationship between them. However, for the first time, we observed that XZK effectively reduces sPLA2-IIA expression in IL-1ß-treated VSMCs. Our findings may shine a new light on the clinical use of XZK and statins in the prevention and treatment of atherosclerosis-related thrombosis.
[Mh] Termos MeSH primário: Medicamentos de Ervas Chinesas/farmacologia
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
Músculo Liso Vascular/enzimologia
Miócitos de Músculo Liso/efeitos dos fármacos
Fosfolipases A2 Secretórias/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Interleucina-1beta/metabolismo
Masculino
Músculo Liso Vascular/citologia
Miócitos de Músculo Liso/enzimologia
Ratos Sprague-Dawley
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drugs, Chinese Herbal); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Interleukin-1beta); 0 (xuezhikang); EC 3.1.1.4 (Phospholipases A2, Secretory)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170327
[Lr] Data última revisão:
170327
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170127
[St] Status:MEDLINE
[do] DOI:10.1536/ihj.16-163


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[PMID]:28063498
[Au] Autor:Ghomashchi F; Brglez V; Payré C; Jeammet L; Bezzine S; Gelb MH; Lambeau G
[Ad] Endereço:University of Washington, Seattle, WA, United States.
[Ti] Título:Preparation of the Full Set of Recombinant Mouse- and Human-Secreted Phospholipases A .
[So] Source:Methods Enzymol;583:35-69, 2017.
[Is] ISSN:1557-7988
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A family of 14-20kDa, disulfide-rich, calcium-dependent secreted phospholipases A (sPLA s) that release fatty acids from the sn-2 position of glycerophospholipids can be found in mammals. They have a diverse array of tissue distribution and biological functions. In this chapter we provide detailed protocols for production of nearly all of the mouse and human sPLA s mainly by expression in bacteria and in vitro refolding or by expression in insect cells. High-resolution mass spectrometry and enzymatic assays were, respectively, used to show that all disulfides are formed and that the enzymes are active, strongly suggesting that each sPLA was prepared in the structurally native form. The availability of these proteins has allowed kinetic studies to be carried out, to prepare highly selective antisera, to screen for selective inhibitors, to study receptor binding, and to study the action of each enzyme on mammalian cell membranes and their in vivo biological roles.
[Mh] Termos MeSH primário: Expressão Gênica
Fosfolipases A2 Secretórias/metabolismo
Fosfolipídeos/metabolismo
Proteínas Recombinantes de Fusão/metabolismo
[Mh] Termos MeSH secundário: Animais
Baculoviridae/genética
Baculoviridae/metabolismo
Clonagem Molecular
Dissulfetos/química
Ensaios Enzimáticos
Escherichia coli/genética
Escherichia coli/metabolismo
Fator Xa/química
Glutationa Transferase/genética
Glutationa Transferase/metabolismo
Células HEK293
Seres Humanos
Hidrólise
Corpos de Inclusão/química
Isoenzimas/genética
Isoenzimas/metabolismo
Cinética
Camundongos
Fosfolipases A2 Secretórias/química
Fosfolipases A2 Secretórias/genética
Fosfolipídeos/química
Redobramento de Proteína
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/genética
Células Sf9
Spodoptera
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Disulfides); 0 (Isoenzymes); 0 (Phospholipids); 0 (Recombinant Fusion Proteins); EC 2.5.1.18 (Glutathione Transferase); EC 3.1.1.4 (Phospholipases A2, Secretory); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170109
[St] Status:MEDLINE


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[PMID]:28063492
[Au] Autor:Tatulian SA
[Ad] Endereço:College of Sciences, University of Central Florida, Orlando, FL, United States. Electronic address: statulia@ucf.edu.
[Ti] Título:Interfacial Enzymes: Membrane Binding, Orientation, Membrane Insertion, and Activity.
[So] Source:Methods Enzymol;583:197-230, 2017.
[Is] ISSN:1557-7988
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Most interfacial enzymes undergo activation upon membrane binding. Interfacial activation is determined not only by the binding strength but also by the specific mode of protein-membrane interactions, including the angular orientation and membrane insertion of the enzymes. This chapter describes biophysical techniques to quantitatively evaluate membrane binding, orientation, membrane insertion, and activity of secreted phospholipase A (PLA ) and lipoxygenase (LO) enzymes. Procedures for recombinant production and purification of human pancreatic PLA and human 5-lipoxygenase (5-LO) are also presented. Several methods for measurements of membrane binding of peripheral proteins are described, i.e., fluorescence resonance energy transfer (FRET) from tryptophan or tyrosine residues of the protein to a fluorescent lipid in vesicles, changes in fluorescence of an environment-sensitive fluorescent lipid upon binding of proteins to membranes, and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. These methods produce the apparent binding constant, the protein-to-lipid binding stoichiometry, and the Hill cooperativity coefficient. Experimental procedures for segmental isotope labeling of proteins and determination of the orientation of membrane-bound proteins by polarized ATR-FTIR spectroscopy are described. Furthermore, evaluation of membrane insertion of peripheral proteins by a fluorescence quenching technique is outlined. Combination of the orientation and membrane insertion provides a unique configuration of the protein-membrane complex and hence elucidates certain details of the enzyme function, such as the modes of acquisition of a membrane-residing substrate and product release. Finally, assays for determination of the activities of secreted PLA , soybean LO, and human 5-LO are described.
[Mh] Termos MeSH primário: Araquidonato 5-Lipoxigenase/metabolismo
Membrana Celular/enzimologia
Ensaios Enzimáticos
Lipídeos de Membrana/metabolismo
Fosfolipases A2 Secretórias/metabolismo
[Mh] Termos MeSH secundário: Araquidonato 5-Lipoxigenase/química
Araquidonato 5-Lipoxigenase/genética
Membrana Celular/química
Clonagem Molecular
Escherichia coli/genética
Escherichia coli/metabolismo
Transferência Ressonante de Energia de Fluorescência
Expressão Gênica
Seres Humanos
Marcação por Isótopo/métodos
Lipídeos de Membrana/química
Modelos Moleculares
Pâncreas/química
Pâncreas/enzimologia
Fosfolipases A2 Secretórias/química
Fosfolipases A2 Secretórias/genética
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Feijão de Soja/química
Feijão de Soja/enzimologia
Espectroscopia de Infravermelho com Transformada de Fourier
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Membrane Lipids); 0 (Recombinant Proteins); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); EC 3.1.1.4 (Phospholipases A2, Secretory)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170109
[St] Status:MEDLINE


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[PMID]:28063487
[Au] Autor:Yamamoto K; Miki Y; Sato H; Murase R; Taketomi Y; Murakami M
[Ad] Endereço:Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima, Japan; PRIME, Japan Agency for Medical Research and Development, Tokyo, Japan.
[Ti] Título:Secreted Phospholipase A Specificity on Natural Membrane Phospholipids.
[So] Source:Methods Enzymol;583:101-117, 2017.
[Is] ISSN:1557-7988
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The secreted phospholipase A (sPLA ) family contains 10 catalytically active isoforms. Current in vitro biochemical studies have shown that individual sPLA s have distinct substrate selectivity in terms of the polar head groups or sn-2 fatty acids of their substrate phospholipids. Importantly, transgenic or knockout mice for distinct sPLA s display nonoverlapping phenotypes, arguing that they do act on different phospholipid substrates and mobilize unique lipid metabolites in vivo. In an effort to comprehensively understand lipid metabolism driven by individual sPLA s under pathophysiological conditions, we took advantages of mass spectrometric lipidomics technology to monitor the spatiotemporal changes in phospholipids (substrates) and products (fatty acids, lysophospholipids, and their metabolites) in tissues or cells of sPLA -transgenic or knockout mice. The in vivo lipidomic data were compared with the in vitro activity of recombinant sPLA s toward phospholipid mixtures extracted from the target tissues, cells, or extracellular membrane components on which sPLA s may intrinsically act. These approaches reveal that the overall tendency in in vitro assays using natural membranes is recapitulated in several in vivo systems, often with even more selective patterns of hydrolysis. In this chapter, we will summarize current understanding of the in vivo substrate specificity of sPLA s toward natural membrane phospholipids.
[Mh] Termos MeSH primário: Metabolismo dos Lipídeos/fisiologia
Lipídeos de Membrana/metabolismo
Fosfolipases A2 Secretórias/metabolismo
Fosfolipídeos/metabolismo
[Mh] Termos MeSH secundário: Tecido Adiposo/química
Tecido Adiposo/enzimologia
Animais
Ácido Araquidônico/isolamento & purificação
Ácido Araquidônico/metabolismo
Linhagem Celular
Colo/química
Colo/enzimologia
Ácidos Docosa-Hexaenoicos/isolamento & purificação
Ácidos Docosa-Hexaenoicos/metabolismo
Epiderme/química
Epiderme/enzimologia
Hidrólise
Isoenzimas/deficiência
Isoenzimas/genética
Isoenzimas/metabolismo
Ácido Linoleico/isolamento & purificação
Ácido Linoleico/metabolismo
Linfonodos/química
Linfonodos/enzimologia
Lisofosfolipídeos/isolamento & purificação
Lisofosfolipídeos/metabolismo
Masculino
Camundongos
Camundongos Transgênicos
Ácido Oleico/isolamento & purificação
Ácido Oleico/metabolismo
Especificidade de Órgãos
Fosfolipases A2 Secretórias/deficiência
Fosfolipases A2 Secretórias/genética
Espectrometria de Massas por Ionização por Electrospray
Espermatozoides/química
Espermatozoides/enzimologia
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoenzymes); 0 (Lysophospholipids); 0 (Membrane Lipids); 0 (Phospholipids); 25167-62-8 (Docosahexaenoic Acids); 27YG812J1I (Arachidonic Acid); 2UMI9U37CP (Oleic Acid); 9KJL21T0QJ (Linoleic Acid); EC 3.1.1.4 (Phospholipases A2, Secretory)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170109
[St] Status:MEDLINE


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[PMID]:27894770
[Au] Autor:Keshavarz A; Zelaya L; Singh J; Ranganathan R; Hajdu J
[Ad] Endereço:Department of Chemistry and Biochemistry, California State University, Northridge, CA 91330-8268, USA. Electronic address: akeshavarz@ucmerced.edu.
[Ti] Título:Activity-based targeting of secretory phospholipase A enzymes: A fatty-acid-binding-protein assisted approach.
[So] Source:Chem Phys Lipids;202:38-48, 2017 Jan.
[Is] ISSN:1873-2941
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Syntheses and enzymological characterization of fluorogenic substrate probes targeting secretory phospholipase A (sPLA ) for detection and quantitative assays are presented. Three fluorogenic phosphatidylcholine analogs PC-1, PC-2, and PC-3 each containing the duo of 7-mercapto-4-methyl-coumarin fluorophore and 2,4-dinitroanaline quencher on either tail were synthesized from (R)-3-amino-1,2-propanediol and R-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol. These small reporter groups are advantageous in preserving natural membrane integrity. Phosphocholine was incorporated into the sn-3 position of the glycerol backbone. Acyl amino group at the sn-1 position in PC-1 and PC-2 is meant to block sPLA . The sn-1 and sn-2 positions of the glycerol backbone in PC-1 have a quencher terminated 12-carbon chain and fluorophore terminated 11-carbon chain respectively. PC-2 has a quencher terminated 3-carbon chain at the sn-2 and chain terminating fluorescent reporter at the sn-1 positions. PC-3 resembles PC-1 except for an ester instead of amide at the sn-1 position, because of which it is more similar to natural phospholipids than PC-1. It was designed to elucidate the effect of replacing the ester group with amide by comparing its hydrolysis rate with that of PC-1. Design principles apply to synthesis of other labeled phospholipids. Enzymological characterization using bee-venom sPLA was performed by a fatty-acid-binding-protein fluorescence assay and by pH-Stat method in which the amount of fatty acid released by hydrolysis is given by the amount of base required to maintain a constant pH of 8.0. Hydrolytic activity toward PC-1 and PC-3 were each about 238±25µmol/mg/min and 537µmol/mg/min on unmodified phospholipid. Ester to amide change did not affect hydrolysis rates. Activity toward PC-2 was about 45-µmol/mg/min. PC-1 and PC-3 show potential for targeted real-time spectrophotometric assay of sPLA .
[Mh] Termos MeSH primário: Ácidos Graxos/metabolismo
Corantes Fluorescentes/análise
Corantes Fluorescentes/química
Fosfatidilcolinas/química
Fosfolipases A2 Secretórias/análise
Fosfolipases A2 Secretórias/metabolismo
[Mh] Termos MeSH secundário: Ativação Enzimática
Ácidos Graxos/química
Estrutura Molecular
Fosfatidilcolinas/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Fluorescent Dyes); 0 (Phosphatidylcholines); EC 3.1.1.4 (Phospholipases A2, Secretory)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170504
[Lr] Data última revisão:
170504
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161130
[St] Status:MEDLINE


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[PMID]:27856457
[Au] Autor:Verbeek R; Boyer M; Boekholdt SM; Hovingh GK; Kastelein JJ; Wareham N; Khaw KT; Arsenault BJ
[Ad] Endereço:From the Department of Vascular Medicine (R.V., G.K.H., J.J.P.K.) and Department of Cardiology (S.M.B.), Academic Medical Centre, Amsterdam, The Netherlands; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Canada (M.B., B.J.A.); Department of Medicine, Fac
[Ti] Título:Carriers of the PCSK9 R46L Variant Are Characterized by an Antiatherogenic Lipoprotein Profile Assessed by Nuclear Magnetic Resonance Spectroscopy-Brief Report.
[So] Source:Arterioscler Thromb Vasc Biol;37(1):43-48, 2017 Jan.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Carriers of the PCSK9 (proprotein convertase subtilisin/kexin 9) R46L genetic variant (rs11591147) are characterized by low levels of low-density lipoprotein cholesterol and a decreased risk of cardiovascular disease. We studied the impact of the R46L variant on lipoprotein size and composition. APPROACH AND RESULTS: Lipoprotein size and composition were measured by nuclear magnetic resonance spectroscopy in 2373 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. After adjusting for age, sex, and cardiovascular disease status, carriers of the R46L variant (n=77) were characterized by lower concentrations of very low-density lipoprotein particles (85.8±26.2 versus 99.0±33.3 nmol/L; P<0.001), low-density lipoprotein particles (1479.7±396.8 versus 1662.9±458.3 nmol/L; P<0.001), and lipoprotein(a) (11.1 [7.2-28.6] versus 12.4 [6.7-29.1] mg/dL; P<0.001) compared with noncarriers. Total high-density lipoprotein particle and very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particle sizes were comparable in carriers and noncarriers. Carriers were characterized by lower secretory phospholipase A2 (4.2±0.9 versus 4.6±1.3 nmol/mL/min; P=0.004) and lipoprotein-associated phospholipase A2 activity (47.5±14.1 versus 52.4±16.2 nmol/mL/min; P=0.02) compared with noncarriers. CONCLUSIONS: Results of this study suggest that carriers of the PCSK9 R46L genetic variant have lower very low-density lipoprotein and low-density lipoprotein particle concentrations, lower lipoprotein(a) levels, and lower secretory phospholipase A2 and lipoprotein-associated phospholipase A2 activity compared with noncarriers.
[Mh] Termos MeSH primário: Aterosclerose/prevenção & controle
Heterozigoto
Lipoproteínas/sangue
Espectroscopia de Ressonância Magnética
Polimorfismo de Nucleotídeo Único
Pró-Proteína Convertase 9/genética
[Mh] Termos MeSH secundário: 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue
Idoso
Aterosclerose/sangue
Aterosclerose/enzimologia
Aterosclerose/genética
Biomarcadores/sangue
Estudos de Casos e Controles
Inglaterra
Feminino
Seres Humanos
Lipoproteína(a)/sangue
Lipoproteínas LDL/sangue
Lipoproteínas VLDL/sangue
Masculino
Meia-Idade
Tamanho da Partícula
Fenótipo
Fosfolipases A2 Secretórias/sangue
Estudos Prospectivos
Fatores de Proteção
Medição de Risco
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Lipoprotein(a)); 0 (Lipoproteins); 0 (Lipoproteins, LDL); 0 (Lipoproteins, VLDL); EC 3.1.1.4 (Phospholipases A2, Secretory); EC 3.1.1.47 (1-Alkyl-2-acetylglycerophosphocholine Esterase); EC 3.1.1.47 (PLA2G7 protein, human); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161119
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.116.307995



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