Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Chemistry ; 25(61): 13837, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31691398

RESUMO

Invited for the cover of this issue is the group of Gérard Coquerel at Université de Rouen Normandie. The image depicts a pyramid-like tetrahedron of the quaternary phase diagram showing where symmetry breaking can take place. Read the full text of the article at 10.1002/chem.201903338.

2.
Chemistry ; 25(61): 13890-13898, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31393026

RESUMO

A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2 O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second-order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate-forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes.

3.
Health Qual Life Outcomes ; 17(1): 86, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118046

RESUMO

BACKGROUND AND AIMS: Patients with age -related hearing loss (ARHL) and their natural caregivers have to confront a disability that produces progressive lifestyle changes. There is an interest in studying the ability of patients and their caregivers to cope with the difficulties that affect quality of life (QoL). In a sample of patient-caregiver dyads in the specific context of ARHL, we examine whether the QoL of patients and caregivers is influenced by the coping processes they use from a specific actor-partner interdependence model (APIM). METHODS: This cross-sectional study involved dyads with patients having a diagnosis of ARHL. The self-reported data included QoL (WHOQoL-BREF) and coping strategies (BriefCope). The APIM was used to test the dyadic effects of coping strategies on QoL. RESULTS: A total of 448 dyads were included; the patients and caregivers were love partners for 59% of the dyads. Coping strategies, such as social support, avoidance, problem solving, and positive thinking, exhibited evidence of actor effects (degree to which the individual's coping strategies are associated with their own QoL). Effects on the partner (degree to which the individual's coping strategies are associated with the QoL of the other member of the dyad) were found, i.e., when the patients mobilized their coping strategy based on social support and problem-solving, their caregivers reported higher environmental QoL. CONCLUSION: This study emphasizes that the QoL for patients and their caregivers was directly related to the coping strategies they used. This finding suggests that targeted interventions should be offered to help patients and their relatives to implement more effective coping strategies.


Assuntos
Adaptação Psicológica , Cuidadores/psicologia , Perda Auditiva/psicologia , Qualidade de Vida/psicologia , Adulto , Idoso , Envelhecimento/fisiologia , Estudos Transversais , Feminino , Perda Auditiva/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato , Apoio Social
5.
BMC Public Health ; 18(1): 1087, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30170577

RESUMO

BACKGROUND: In 2009, the World Health Organization's Commission on Social Determinants of Health set out its recommendations for action, which included establishing equity from early childhood onwards by enabling all children and their mothers to benefit from a comprehensive package of quality programmes. In order to address social inequalities in health, it is recommended that action be taken from early childhood, and actions providing support for parenting are an effective lever in this respect. The aim of this review of systematic reviews is to analyse, on the one hand, the components and characteristics of effective interventions in parenting support and, on the other, the extent to which the reviews took into account social inequalities in health. METHODS: A total of 796 reviews were selected from peer-reviewed journals published between 2009 and 2016 in French or English. Of these, 21 reviews responding to the AMSTAR and selected ROBIS criteria were retained. These were analysed in relation to the consideration they gave to social inequalities in health according to PRISMA-equity. RESULTS: The reviews confirmed that parenting support programmes improved infants' sleep, increased mothers' self-esteem and reduced mothers' anger, anxiety and stress levels. The mainly authors noted that the contexts in which the interventions had taken place were described either scantly or not at all, making it difficult to evaluate them. Only half of the reviews had addressed the question of social inequalities in health. In particular, there had been little research conducted on the relational aspect and the social link. CONCLUSION: In terms of addressing social inequalities in perinatal health, the approach remains both modest and reductive. Understanding how, for whom and in what conditions interventions operate is one way of optimising their results. Further research is needed to study the interactions between the interventions and their contexts.


Assuntos
Disparidades nos Níveis de Saúde , Mães/psicologia , Poder Familiar/psicologia , Apoio Social , Feminino , Humanos , Lactente , Literatura de Revisão como Assunto , Determinantes Sociais da Saúde , Fatores Socioeconômicos
9.
Bull Cancer ; 103(11): 928-934, 2016 Nov.
Artigo em Francês | MEDLINE | ID: mdl-27810142

RESUMO

INTRODUCTION: Breast cancer surgery is suitable for outpatient practice. Indeed, this is a planned surgery with short operative time. Objective was to evaluate the recognized success indicators in day surgery: rate of conversion into conventional hospitalization, rate of complications and re-hospitalizations the month following surgery. METHODS: Consecutive cases of breast cancer patients operated in day surgery were prospectively entered into the Day Surgery database between 25 November 2012 and 31 December 2013. Patient characteristics and tumor pathology, preoperative procedures and type of surgery were collected. Statistical analysis was performed. RESULTS: Three hundred and ninety-six consecutive patients were included. The mean age was 54 years [25-84], we performed 382 conservative breast surgery (98.2%), 238 sentinel node (60.1%) and 40 axillary lymphadenectomy (10.1%). Thirty-nine scheduled for outpatient surgery were hospitalized in conventional surgery being a conversion rate of 9.8%, 95% CI [6.9-12.7] with 24 patients because of a drainage (61.5%). We have observed 15 complications in the month after the surgery (3.7%, 95% CI [1.8-5.6]), and 5 rehospitalization in the month following surgery (1.2%, IC 95% [0.1-2.3]). CONCLUSION: Postoperative complication and readmissions are very low (<5%) after breast ambulatory surgery. This confirms its feasibility and safety in a breast cancer center. Adaptating anaesthetic methods to ambulatory care and preparing patient going home with an axillary drain are necessary to reduce rate of conversion to hospitalisation.


Assuntos
Procedimentos Cirúrgicos Ambulatórios , Neoplasias da Mama/cirurgia , Carcinoma in Situ/cirurgia , Carcinoma Ductal de Mama/cirurgia , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Ambulatórios/efeitos adversos , Procedimentos Cirúrgicos Ambulatórios/estatística & dados numéricos , Estudos de Viabilidade , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Excisão de Linfonodo/estatística & dados numéricos , Mastectomia Segmentar/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Prospectivos , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Fatores de Tempo
10.
Cardiovasc Res ; 105(1): 55-64, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25411381

RESUMO

AIMS: Stimulation of ß-adrenergic receptors (ß-AR) increases cAMP production and contributes to the pathogenesis of cardiac hypertrophy and failure through poorly understood mechanisms. We previously demonstrated that Exchange protein directly activated by cAMP 1 (Epac1)-induced hypertrophy in primary cardiomyocytes. Among the mechanisms triggered by cardiac stress, autophagy has been highlighted as a protective or harmful response. Here, we investigate whether Epac1 promotes cardiac autophagy and how altered autophagy has an impact on Epac1-induced cardiomyocyte hypertrophy. METHODS AND RESULTS: We reported that direct stimulation of Epac1 with the agonist, Sp-8-(4-chlorophenylthio)-2'-O-methyl-cAMP (Sp-8-pCPT) promoted autophagy activation in neonatal cardiomyocytes. Stimulation of ß-AR with isoprenaline (ISO) mimicked the effect of Epac1 on autophagy markers. Conversely, the induction of autophagy flux following ISO treatment was prevented in cardiomyocytes pre-treated with a selective inhibitor of Epac1, CE3F4. Importantly, we found that Epac1 deletion in mice protected against ß-AR-induced cardiac remodelling and prevented the induction of autophagy. The signalling mechanisms underlying Epac1-induced autophagy involved a Ca(2+)/calmodulin-dependent kinase kinase ß (CaMKKß)/AMP-dependent protein kinase (AMPK) pathway. Finally, we provided evidence that pharmacological inhibition of autophagy using 3-methyladenine (3-MA) or down-regulation of autophagy-related protein 5 (Atg5) significantly potentiated Epac1-promoted cardiomyocyte hypertrophy. CONCLUSION: Altogether, these findings demonstrate that autophagy is an adaptive response to antagonize Epac1-promoted cardiomyocyte hypertrophy.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Crescimento Celular , Células Cultivadas , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/agonistas , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Quinolinas/farmacologia , Ratos , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Tionucleotídeos/farmacologia
11.
Circulation ; 131(4): 390-400; discussion 400, 2015 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-25369805

RESUMO

BACKGROUND: Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood. METHODS AND RESULTS: Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin(-/-)) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice; P<0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented transverse aortic constriction-induced cardiac hypertrophy with preserved fractional shortening (39.9±1.2% versus 25.9±2.6% in control plus transverse aortic constriction mice; P<0.0001). Carabin also conferred protection against adrenergic receptor-induced hypertrophy in isolated cardiomyocytes. Mechanistically, Carabin carries out a tripartite suppressive function. Indeed, Carabin, through its calcineurin-interacting site and Ras/Rab GTPase-activating protein domain, functions as an endogenous inhibitor of calcineurin and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca(2+)/calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras-GTPase-activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin. CONCLUSIONS: Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca(2+)/calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure.


Assuntos
Calcineurina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/prevenção & controle , Proteínas Ativadoras de GTPase/biossíntese , Genes ras/fisiologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Ratos , Transdução de Sinais/fisiologia
12.
FASEB J ; 28(11): 4617-28, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25103224

RESUMO

Cigarette smoke (CS) induces inflammatory responses characterized by increase of immune cells and cytokine release. Remodeling processes, such as mucus hypersecretion and extracellular matrix protein production, are also directly or indirectly induced by CS. Recently, we showed that activation of the exchange protein directly activated by cAMP (Epac) attenuates CS extract-induced interleukin (IL)-8 release from cultured airway smooth muscle cells. Using an acute, short-term model of CS exposure, we now studied the role of Epac1, Epac2, and the Epac effector phospholipase-Cε (PLCε) in airway inflammation and remodeling in vivo. Compared to wild-type mice exposed to CS, the number of total inflammatory cells, macrophages, and neutrophils and total IL-6 release was lower in Epac2(-/-) mice, which was also the case for neutrophils and IL-6 in PLCε(-/-) mice. Taken together, Epac2, acting partly via PLCε, but not Epac1, enhances CS-induced airway inflammation in vivo. In total lung homogenates of Epac1(-/-) mice, MUC5AC and matrix remodeling parameters (transforming growth factor-ß1, collagen I, and fibronectin) were increased at baseline. Our findings suggest that Epac1 primarily is capable of inhibiting remodeling processes, whereas Epac2 primarily increases inflammatory processes in vivo.


Assuntos
Remodelação das Vias Aéreas/fisiologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fumaça/efeitos adversos , Remodelação das Vias Aéreas/genética , Animais , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Inflamação/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout
13.
Cell Signal ; 25(4): 970-80, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23266473

RESUMO

ß1 and ß2 adrenergic receptors (ßARs) are highly homologous but fulfill distinct physiological and pathophysiological roles. Here we show that both ßAR subtypes activate the cAMP-binding protein Epac1, but they differentially affect its signaling. The distinct effects of ßARs on Epac1 downstream effectors, the small G proteins Rap1 and H-Ras, involve different modes of interaction of Epac1 with the scaffolding protein ß-arrestin2 and the cAMP-specific phosphodiesterase (PDE) variant PDE4D5. We found that ß-arrestin2 acts as a scaffold for Epac1 and is necessary for Epac1 coupling to H-Ras. Accordingly, knockdown of ß-arrestin2 prevented Epac1-induced histone deacetylase 4 (HDAC4) nuclear export and cardiac myocyte hypertrophy upon ß1AR activation. Moreover, Epac1 competed with PDE4D5 for interaction with ß-arrestin2 following ß2AR activation. Dissociation of the PDE4D5-ß-arrestin2 complex allowed the recruitment of Epac1 to ß2AR and induced a switch from ß2AR non-hypertrophic signaling to a ß1AR-like pro-hypertrophic signaling cascade. These findings have implications for understanding the molecular basis of cardiac myocyte remodeling and other cellular processes in which ßAR subtypes exert opposing effects.


Assuntos
Arrestinas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Animais , Arrestinas/antagonistas & inibidores , Arrestinas/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Transferência Ressonante de Energia de Fluorescência , Células HEK293 , Humanos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Transdução de Sinais , beta-Arrestinas
14.
Biochem Soc Trans ; 40(1): 51-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22260665

RESUMO

Epacs (exchange proteins directly activated by cAMP) are guanine-nucleotide-exchange factors for the Ras-like small GTPases Rap1 and Rap2. Epacs were discovered in 1998 as new sensors for the second messenger cAMP acting in parallel to PKA (protein kinase A). As cAMP regulates many important physiological functions in brain and heart, the existence of Epacs raises many questions regarding their role in these tissues. The present review focuses on the biological roles and signalling pathways of Epacs in neurons and cardiac myocytes. We discuss the potential involvement of Epacs in the manifestation of cardiac and central diseases such as cardiac hypertrophy and memory disorders.


Assuntos
Encéfalo/metabolismo , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Diferenciação Celular , Proliferação de Células , Doenças do Sistema Nervoso Central/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Coração/fisiopatologia , Cardiopatias/metabolismo , Humanos , Miocárdio/metabolismo , Miocárdio/patologia
15.
J Mol Cell Cardiol ; 52(1): 283-91, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22056318

RESUMO

Epac is a guanine nucleotide exchange protein that is directly activated by cAMP, but whose cardiac cellular functions remain unclear. It is important to understand cardiac Epac signaling, because it is activated in parallel to classical cAMP-dependent signaling via protein kinase A. In addition to activating contraction, Ca(2+) is a key cardiac transcription regulator (excitation-transcription coupling). It is unknown how myocyte Ca(2+) signals are decoded in cardiac myocytes to control nuclear transcription. We examine Epac actions on cytosolic ([Ca(2+)](i)) and intranuclear ([Ca(2+)](n)) Ca(2+) homeostasis, focusing on whether Epac alters [Ca(2+)](n) and activates a prohypertrophic program in cardiomyocytes. Adult rat cardiomyocytes, loaded with fluo-3 were viewed by confocal microscopy during electrical field stimulation at 1Hz. Acute Epac activation by 8-pCPT increased Ca(2+) sparks and diastolic [Ca(2+)](i), but decreased systolic [Ca(2+)](i). The effects on diastolic [Ca(2+)](i) and Ca(2+) spark frequency were dependent on phospholipase C (PLC), inositol 1,4,5 triphosphate receptor (IP(3)R) and CaMKII activation. Interestingly, Epac preferentially increased [Ca(2+)](n) during both diastole and systole, correlating with the perinuclear expression pattern of Epac. Moreover, Epac activation induced histone deacetylase 5 (HDAC5) nuclear export, with consequent activation of the prohypertrophic transcription factor MEF2. These data provide the first evidence that the cAMP-binding protein Epac modulates cardiac nuclear Ca(2+) signaling by increasing [Ca(2+)](n) through PLC, IP(3)R and CaMKII activation, and initiates a prohypertrophic program via HDAC5 nuclear export and subsequent activation of the transcription factor MEF2.


Assuntos
Cálcio/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Sinalização do Cálcio , Núcleo Celular/metabolismo , Diástole , Ratos , Ratos Wistar , Sístole
16.
Sci Total Environ ; 409(20): 4480-3, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21794896

RESUMO

Indoor aldehydes may result from ozone-initiated chemistry, mainly documented by experimental studies. As part of an environmental investigation included in the PARIS birth cohort, the aim of this study was to examine ozone contribution to airborne aldehyde formation in Paris homes. Formaldehyde, acetaldehyde and hexaldehyde levels, as well as styrene, nitrogen dioxide and nicotine concentrations, comfort parameters and carbon dioxide levels, were measured twice during the first year of life of the babies. Ambient ozone concentrations were collected from the closest background station of the regional air monitoring network. Traffic-related nitrogen oxide concentrations in front of the dwellings were estimated by an air pollution dispersion model. Home characteristics and families' way of life were described by questionnaires. Stepwise multiple linear regression models were used to link aldehyde levels with ambient ozone concentrations and a few aldehyde precursors involved in oxidation reactions, adjusting for other indoor aldehyde sources, comfort parameters and traffic-related nitrogen oxides. A 4 and 11% increase in formaldehyde and hexaldehyde levels was pointed out when 8-hour ozone concentrations increased by 20 µg/m(3). The influence of potential precursors such as indoor styrene level and frequent use of air fresheners, containing unsaturated volatile organic compounds as terpenes, was also found. Thus, our results suggest that ambient ozone can significantly impact indoor air quality, especially with regard to formaldehyde and hexaldehyde levels.


Assuntos
Poluição do Ar em Ambientes Fechados/análise , Aldeídos/análise , Monitoramento Ambiental/métodos , Habitação , Ozônio/análise , Poluentes Atmosféricos/análise , Habitação/normas , Paris , Emissões de Veículos/análise
17.
Curr Heart Fail Rep ; 8(3): 159-67, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21594764

RESUMO

Cyclic adenosine 3',5'-monophosphate (cAMP) mediates the biological effects of various hormones and neurotransmitters. Stimulation of cardiac ß-adrenergic receptors (ß-AR) via catecholamines leads to activation of adenylyl cyclases and increases cAMP production to enhance myocardial function. Because many other receptors signaling through cAMP generation exist in cardiac myocytes, a central question is how different hormones induce distinct cellular responses through the same second messenger. A large body of evidence suggests that the localization and compartmentalization of ß-AR/cAMP signaling affects the net outcome of biological functions. Spatiotemporal dynamics of cAMP action is achieved by various proteins, including protein kinase A (PKA), phosphodiesterases, and scaffolding proteins such as A-kinase-anchoring proteins. In addition, the discovery of the cAMP target Epac (exchange proteins directly activated by cAMP), which functions in a PKA-independent manner, represents a novel mechanism for governing cAMP-signaling specificity. Aberrant cAMP signaling through dysregulation of ß-AR/cAMP compartmentalization may contribute to cardiac remodeling and heart failure.


Assuntos
AMP Cíclico/fisiologia , Insuficiência Cardíaca/fisiopatologia , Miócitos Cardíacos/metabolismo , Receptores Adrenérgicos beta/fisiologia , Sistemas do Segundo Mensageiro/fisiologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Insuficiência Cardíaca/metabolismo , Humanos , Diester Fosfórico Hidrolases/fisiologia , Receptores Adrenérgicos beta/metabolismo , Receptores CCR10/fisiologia , Transdução de Sinais/fisiologia
18.
Cell Signal ; 23(8): 1257-66, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21402149

RESUMO

Epac proteins respond to the second messenger cyclic AMP (cAMP) and are activated by Gs coupled receptors. They act as specific guanine nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2 of the Ras family. A plethora of studies using 8-pCPT-2'-O-Me-cAMP, an Epac agonist, has revealed the importance of these multi-domain proteins in the control of key cellular functions such as cell division, migration, growth and secretion. Epac and protein kinase A (PKA) may act independently but are often associated with the same biological process, in which they fulfill either synergistic or opposite effects. In addition, compelling evidence is now accumulating about the formation of molecular complexes in distinct cellular compartments that influence Epac signaling and cellular function. Epac is spatially and temporally regulated by scaffold protein and its effectors are interconnected with other signaling pathways. Pathophysiological changes in Epac signaling may underlie certain diseases.


Assuntos
AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Transdução de Sinais , Proteínas rap de Ligação ao GTP/metabolismo , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Receptores Acoplados a Proteínas-G/metabolismo
19.
Malar J ; 9: 294, 2010 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-20974009

RESUMO

BACKGROUND: The use of malaria rapid diagnostic tests (RDTs) has been widely advocated to improve Plasmodium falciparum diagnosis, especially in settings where quality microscopy is not available. RDTs based on the detection of histidine-rich protein 2 (HRP-2) can remain positive for several weeks after an infection is cured, due to the persistence of HRP-2 antigens. As a result, test specificity may vary between age groups with different prevalence of P. falciparum infection. METHODS: A community-based cross-sectional survey, carried out in southern Tanzania in July and August 2004, evaluated the performance of the Paracheck Pf in comparison with microscopy (number of P. falciparum parasites/200 leucocytes). A sample of 598 individuals living in an area of intense malaria transmission had demographic data collected before an RDT was performed. HRP-2 test sensitivity, specificity, positive and negative predictive values were calculated and compared between distinct age groups, using microscopy as "gold standard". RESULTS: The overall malaria prevalence was 34.3% according to microscopy and 57.2% according to the HRP-2 test. The HRP-2 test had a sensitivity of 96.1%, a specificity of 63.1%, a positive predictive value of 57.6% and a negative predictive value of 96.9%. The test sensitivity was higher (ranging from 98% to 100%) amongst people less than 25 years of age, but decreased to 81.3% in older adults. The HRP-2 test specificity varied between age groups, ranging from 25% among children of five to nine years of age, to 73% among adults aged 25 or more. The test positive predictive value increased with malaria prevalence, while the negative predictive value was consistently high across age groups. CONCLUSIONS: These results suggest that the performance of HRP-2 tests in areas of intense malaria transmission varies by age and the prevalence of P. falciparum infection. The particularly low specificity among children will lead to the over-estimation of malaria infection prevalence in this group.


Assuntos
Antígenos de Protozoários/análise , Testes Diagnósticos de Rotina/métodos , Malária Falciparum/diagnóstico , Parasitologia/métodos , Plasmodium falciparum/isolamento & purificação , Proteínas de Protozoários/análise , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microscopia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Tanzânia , Adulto Jovem
20.
Cell Signal ; 22(10): 1459-68, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20576488

RESUMO

Epac (Exchange protein directly activated by cAMP) is a sensor for cAMP and represents a novel mechanism for governing cAMP signalling. Epac is a guanine nucleotide exchange factor (GEF) for the Ras family of small GTPases, Rap. Previous studies demonstrated that, in response to a prolonged beta-adrenergic stimulation Epac induced cardiac myocyte hypertrophy. The aim of our study was to further characterize Epac downstream effectors involved in cardiac myocyte growth. Here, we found that Epac led to the activation of the small G protein H-Ras in primary neonatal cardiac myocytes. A Rap GTPase activating protein (RapGAP) partially inhibited Epac-induced H-Ras activation. Interestingly, we found that H-Ras activation involved the GEF domain of Epac. However, Epac did not directly induce exchange activity on this small GTPase protein. Instead, the effect of Epac on H-Ras activation was dependent on a signalling cascade involving phospholipase C (PLC)/inositol 1,3,5 triphosphate receptor (IP3R) and an increase intracellular calcium. In addition, we found that Epac activation induced histone deacetylase type 4 (HDAC4) translocation. Whereas HDAC5 alone was unresponsive to Epac, it became responsive to Epac in the presence of HDAC4 in COS cells. Consistent with its effect on HDAC cytoplasmic shuttle, Epac activation also increased the prohypertrophic transcription factor MEF2 in a CaMKII dependent manner in primary cardiac myocytes. Thus, our data show that Epac activates a prohypertrophic signalling pathway which involves PLC, H-Ras, CaMKII and HDAC nuclear export.


Assuntos
Núcleo Celular/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Histona Desacetilases/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Transporte Ativo do Núcleo Celular , Animais , Cálcio/metabolismo , Cardiomegalia/metabolismo , Domínio Catalítico , Células Cultivadas , Fatores de Troca do Nucleotídeo Guanina/química , Humanos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Fatores de Transcrição MEF2 , Miócitos Cardíacos/enzimologia , Fatores de Regulação Miogênica/metabolismo , Fatores de Transcrição NFATC/metabolismo , Ratos , Fosfolipases Tipo C/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA