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Abstract Background: Implantable cardiac defibrillators (ICDs) therapy for primary prevention (PP) of sudden cardiac arrest (SCA) is well-established but underutilized globally. The Improve SCA study has identified a cohort of patients called 1.5 primary prevention (1.5PP), based on PP patients with the presence of documented risk factors: non-sustained ventricular tachycardia, frequent premature ventricular contractions, left ventricular ejection fraction < 25%, and pre-syncope or syncope. Objective: This study evaluated the cost-effectiveness of ICD therapy compared to no ICD among 1.5PP patients in the Brazilian public healthcare system. Methods: Modified inputs to a published Markov model were applied to compare costs and outcomes of ICD therapy to no ICD therapy from the Brazilian payer's perspective. Mortality and utility estimates were obtained from the IMPROVE SCA trial. Additional effectiveness inputs were sourced from the literature. Cost inputs were obtained from the Brazilian Unified Health System and the Ministry of Health. Costs were discounted at 4.7%; quality-adjusted life years (QALYs) were discounted at 1.45%. This study applied a willingness-to-pay (WTP) value of three times Brazil's gross domestic product (GDP) in 2017, R$105,723 (Brazilian Real). Results: The total discounted lifetime costs for ICD therapy were R$100,920 compared to R$43,866 for no ICD therapy. Total discounted QALYs for ICD therapy and no ICD therapy were 9.85 and 7.15, respectively. The incremental cost effectiveness ratio was R$21,156 per QALY and less than the R$105,723 WTP threshold. Results from sensitivity analyses were consistent with base case results. Conclusions: ICD therapy compared to no ICD therapy is cost-effective in the 1.5PP population in Brazil. (Int J Cardiovasc Sci. 2021; [online].ahead print, PP.0-0)
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Programmed cell death is regulated by the balance between activating and inhibitory signals. Here, we have identified RECS1 (responsive to centrifugal force and shear stress 1) [also known as TMBIM1 (transmembrane BAX inhibitor motif containing 1)] as a proapoptotic member of the TMBIM family. In contrast to other proteins of the TMBIM family, RECS1 expression induces cell death through the canonical mitochondrial apoptosis pathway. Unbiased screening indicated that RECS1 sensitizes cells to lysosomal perturbations. RECS1 localizes to lysosomes, where it regulates their acidification and calcium content, triggering lysosomal membrane permeabilization. Structural modeling and electrophysiological studies indicated that RECS1 is a pH-regulated calcium channel, an activity that is essential to trigger cell death. RECS1 also sensitizes whole animals to stress in vivo in Drosophila melanogaster and zebrafish models. Our results unveil an unanticipated function for RECS1 as a proapoptotic component of the TMBIM family that ignites cell death programs at lysosomes.
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Influenza A virus (IAV) activates ZBP1-initiated RIPK3-dependent parallel pathways of necroptosis and apoptosis in infected cells. Although mice deficient in both pathways fail to control IAV and succumb to lethal respiratory infection, RIPK3-mediated apoptosis by itself can limit IAV, without need for necroptosis. However, whether necroptosis, conventionally considered a fail-safe cell death mechanism to apoptosis, can restrict IAV-or indeed any virus-in the absence of apoptosis is not known. Here, we use mice selectively deficient in IAV-activated apoptosis to show that necroptosis drives robust antiviral immune responses and promotes effective virus clearance from infected lungs when apoptosis is absent. We also demonstrate that apoptosis and necroptosis are mutually exclusive fates in IAV-infected cells. Thus, necroptosis is an independent, "stand-alone" cell death mechanism that fully compensates for the absence of apoptosis in antiviral host defense.
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Caspase 8/genética , Interações entre Hospedeiro e Microrganismos/genética , Vírus da Influenza A/imunologia , Necroptose/genética , Infecções por Orthomyxoviridae/imunologia , Imunidade Adaptativa , Animais , Apoptose/genética , Apoptose/imunologia , Caspase 8/metabolismo , Feminino , Técnicas de Introdução de Genes , Interações entre Hospedeiro e Microrganismos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Necroptose/imunologia , Infecções por Orthomyxoviridae/virologia , Proteínas de Ligação a RNA/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismoRESUMO
Resumen Objetivo: medir el impacto de la terapia de resincronización cardiaca en términos de variables ecocardiográficas en pacientes de países latinoamericanos. Método: se realizó un estudio prospectivo, multicéntrico, intervencionista, en el que los pacientes elegibles fueron llevados, por primera vez, a implante de un dispositivo de resincronización cardiaca. El objetivo primario fue valorar los cambios del tamaño y la función del ventrículo izquierdo por medio de un ecocardiograma previo al implante del dispositivo y en el sexto mes. Los objetivos secundarios evaluados fueron hospitalizaciones, cambios en la clase funcional, mortalidad, calidad de vida y un score compuesto clínico basado en estos factores de evaluación global del paciente. Resultados: para cumplir el objetivo primario se analizaron datos de 75 sujetos. La edad promedio fue de 63,7 años; 21.3% fueron mujeres y 30.7% tuvieron cardiopatía isquémica. Al sexto mes de seguimiento las mediciones de volumen de fin de diástole y sístole del ventrículo izquierdo disminuyeron en promedio 37.6 ml y 37.8 ml, respectivamente. La fracción de eyección del ventrículo izquierdo en promedio se incrementó un 11%. El puntaje compuesto clínico mostró mejoría en el 86.4% de los pacientes en el sexto mes postimplante del resincronizador. Conclusiones: se observó remodelado inverso del ventrículo izquierdo y mejoría en el estado clínico de los pacientes con insuficiencia cardiaca y disfunción sistólica del ventrículo izquierdo que recibieron terapia de resincronización cardiaca en el ámbito de la práctica clínica de rutina.
Abstract Objective: To measure the impact of cardiac resynchronisation therapy in terms of cardiac ultrasound variables in patients from Latin-American countries. Method: A prospective, multicentre, interventionist study was conducted, in which the eligible patients were those that had a cardiac resynchronisation device implanted for the first time. The primary objective was to assess the changes in size and left ventricular function by means of a cardiac ultrasound carried out prior to implanting the device and in the sixth month. The secondary objectives evaluated were hospital admissions, change in functional class, mortality, quality of life, and an overall assessment of the patient using a combined clinical score based on these factors. Results: A total of 75 subjects were analysed in order to complete the primary objective. The mean age was 63.7 years; 21.3% were female, and 30.7% had ischaemic heart disease. At the sixth month, the left ventricular end-diastolic and systolic volume decreased by a mean of 37.6 ml and 37.8 ml, respectively. The left ventricular ejection fraction increased by a mean of 11%. The combined clinical score showed an improvement in 86.4% of the patients in the sixth month after the implantation of the synchronisation device. Conclusions: A reverse remodelling of the left ventricle was observed, as well as an improvement in the clinical stage of patients with heart failure and left ventricular systolic dysfunction that received cardiac resynchronisation treatment in the setting of routine clinical practice.
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Humanos , Feminino , Pessoa de Meia-Idade , Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca , Terapêutica , Ecocardiografia , MortalidadeRESUMO
In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article.
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Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a signalling network known as the unfolded protein response (UPR). Here, we identified filamin A as a major binding partner of the ER stress transducer IRE1α. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1α controls actin cytoskeleton dynamics and affects cell migration upstream of filamin A. The regulation of cytoskeleton dynamics by IRE1α is independent of its canonical role as a UPR mediator, serving instead as a scaffold that recruits and regulates filamin A. Targeting IRE1α expression in mice affected normal brain development, generating a phenotype resembling periventricular heterotopia, a disease linked to the loss of function of filamin A. IRE1α also modulated cell movement and cytoskeleton dynamics in fly and zebrafish models. This study unveils an unanticipated biological function of IRE1α in cell migration, whereby filamin A operates as an interphase between the UPR and the actin cytoskeleton.
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Citoesqueleto de Actina/metabolismo , Movimento Celular , Endorribonucleases/metabolismo , Fibroblastos/metabolismo , Filaminas/metabolismo , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Endorribonucleases/deficiência , Endorribonucleases/genética , Evolução Molecular , Feminino , Filaminas/genética , Células HEK293 , Humanos , Cinética , Masculino , Camundongos , Camundongos Knockout , Neurônios/patologia , Heterotopia Nodular Periventricular/genética , Heterotopia Nodular Periventricular/metabolismo , Heterotopia Nodular Periventricular/patologia , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Resposta a Proteínas não Dobradas , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
INTRODUCTION: Abnormalities of autonomic function have been reported in patients with chronic obstructive pulmonary disease (COPD). Our objectives were to identify determinants of abnormal heart rate recovery at 1 min (HRR1) following completion of the 6-min walk test (6MWT) in COPD and to establish whether abnormal HRR1 predicts acute exacerbations (AECOPD). METHODS: Hundred one COPD patients (FEV1 (SD) 53 (19) % predicted) were prospectively recruited in a multi-center study. HRR1 after the 6MWT was evaluated as the difference between heart rate at the end of the test and 1 min into the recovery (HRR1). Linear and logistic regression was used to identify predictors of HRR1 and AECOPD, respectively. The best HRR1 cut-off point to predict AECOPD was selected using the receiver operating characteristics (ROC) curves. The follow-up period was 12 months. RESULTS: Distance covered during the 6MWT (m) and DLco (% predicted) were independently associated with HRR1 (r 2 = 0.51, p = 0.001). Among several potential covariates, HRR1 emerged as the most significant predictor of AECOPD (Odds ratio [OR], 0.91 per beat of recovery; 95% confidence interval [CI], 0.85-0.97; p = 0.02). The ROC analysis indicated that subjects with HRR1 less than 14 beats (AUC, 0.71 [CI] 0.60-0.80; p = 0.0001) were more likely to suffer an exacerbation during the follow-up period (for HRR1, p = 0.004 [log-rank test]). CONCLUSIONS: HRR1 after the 6MWT is an independent predictor factor for AECOPD. Further studies are warranted to examine the physiological mechanisms associating a delayed HRR and acute exacerbations in COPD patients.
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Tolerância ao Exercício , Frequência Cardíaca , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Teste de Caminhada , Idoso , Área Sob a Curva , Colômbia , Progressão da Doença , Europa (Continente) , Feminino , Volume Expiratório Forçado , Humanos , Estimativa de Kaplan-Meier , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , New South Wales , Razão de Chances , Valor Preditivo dos Testes , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Curva ROC , Recuperação de Função Fisiológica , Fatores de TempoRESUMO
En las últimas décadas ha crecido el estudio los mecanismos involucrados en el comportamiento social, gran parte de estas indagaciones se han realizado desde una aproximación de la neurociencia social cognitiva, la cual se basa en un modelo representacional del procesamiento de información. No obstante, esta aproximación ha sido ampliamente criticada por desconocer la participación del cuerpo, la dinámica afectiva, el contexto social, el cambio durante el desarrollo y suponer un procesamiento modular endógeno. En este sentido, este artículo presenta un modelo neurodinámico de la cognición social (CS), comprendiéndola desde una aproximación enactiva, situada, relacional y sistémica. Desde este modelo se describen los principales cambios en esperados la actividad cerebral durante las interacciones sociales en tiempo real y durante la ontogenia. Se concluye resaltando los desafíos y oportunidades que este tipo de aproximaciones puede proporcionar a la neurociencia y psicología social del futuro.
In recent decades it has seen a growing interest to study the mechanisms involved in social behavior, much of these inquiries fall within social cognitive neuroscience approach, which is based on a representational model of information processing. However, this approach has been widely criticized for ignoring the body participation, emotional dynamics, social context, developmental changes and assuming an endogenous modular processing. In this regard, this article presents a neurodynamic model of social cognition, which understand social process from an enactive, embodied, situated, relational and systemic perspective. This model let us described the main expected changes in brain activity during ongoing social interactions and ontogeny. The conclusion highlights the challenges and opportunities that this kind of approach can provide for a coming neuroscience and social psychology.
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BACKGROUND: Autonomic modulation is a valuable therapeutic option for the management of ventricular arrhythmias. Bilateral cardiac sympathetic denervation (BCSD) has shown promising results in the acute, intermediate, and long-term management of polymorphic and monomorphic ventricular tachycardia (VT) in patients with structural heart disease. Cardiomyopathy (CM) due to Chagas disease (CD), and associated VT, is thought to be in part due to autonomic neuronal destruction and dysfunction. OBJECTIVE: The purpose of this study was to assess whether BCSD is a safe and effective treatment modality in patients with CD and VT storm or refractory VT. METHODS: A retrospective analysis of data from patients with chagasic CM who underwent BCSD between 2009 and 2015 at 2 international centers was performed. RESULTS: Of 75 patients who underwent BCSD for VT storm or refractory VT in the setting of CM, 7 (9.3%) patients had CD as the etiology of CM. All patients had monomorphic VT. Median follow-up was 7 months (range 1-46 months). All patients either underwent previous unsuccessful catheter ablation or were not candidates for ablation. The median number of implantable cardioverter-defibrillator (ICD) shocks 1 month before BCSD was 4 (range 2-30) and decreased to 0 (range 0-2) during available follow-up after BCSD. When antitachycardia pacing therapies were included in the analysis, the median number of ICD therapies (shocks + antitachycardia pacing) still decreased to 1 (range 0-3). CONCLUSION: In patients with chagasic CM presenting with refractory monomorphic VT, early evidence suggests that BCSD reduces appropriate ICD therapy and may represent a valuable treatment option.
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Cardiomiopatia Chagásica , Simpatectomia , Taquicardia Ventricular/prevenção & controle , California/epidemiologia , Cardiomiopatia Chagásica/complicações , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/fisiopatologia , Colômbia/epidemiologia , Feminino , Seguimentos , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Simpatectomia/efeitos adversos , Simpatectomia/métodos , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia , Resultado do TratamentoRESUMO
Adaptation to endoplasmic reticulum (ER) stress depends on the activation of the unfolded protein response (UPR) stress sensor inositol-requiring enzyme 1α (IRE1α), which functions as an endoribonuclease that splices the mRNA of the transcription factor XBP-1 (X-box-binding protein-1). Through a global proteomic approach we identified the BCL-2 family member PUMA as a novel IRE1α interactor. Immun oprecipitation experiments confirmed this interaction and further detected the association of IRE1α with BIM, another BH3-only protein. BIM and PUMA double-knockout cells failed to maintain sustained XBP-1 mRNA splicing after prolonged ER stress, resulting in early inactivation. Mutation in the BH3 domain of BIM abrogated the physical interaction with IRE1α, inhibiting its effects on XBP-1 mRNA splicing. Unexpectedly, this regulation required BCL-2 and was antagonized by BAD or the BH3 domain mimetic ABT-737. The modulation of IRE1α RNAse activity by BH3-only proteins was recapitulated in a cell-free system suggesting a direct regulation. Moreover, BH3-only proteins controlled XBP-1 mRNA splicing in vivo and affected the ER stress-regulated secretion of antibodies by primary B cells. We conclude that a subset of BCL-2 family members participates in a new UPR-regulatory network, thus assuming apoptosis-unrelated functions.
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Proteínas Reguladoras de Apoptose/metabolismo , Endorribonucleases/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Resposta a Proteínas não Dobradas , Animais , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Técnicas de Inativação de Genes , Imunoprecipitação , Proteínas de Membrana/genética , Camundongos , Ligação Proteica , Mapeamento de Interação de Proteínas , Proteoma/análise , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Augmented expression of protein kinase CK2 is associated with hyperproliferation and resistance to apoptosis in cancer cells. Effects of CK2 are at least partially linked to signaling via the Wnt/ß-catenin pathway, which is dramatically enhanced in colon cancer. Cyclooxygenase-2 (COX-2), a Wnt/ß-catenin target gene, has been associated with enhanced cancer progression and metastasis. However, the possibility that a connection may exist between CK2 and COX-2 has not been explored previously. Here we investigated changes in COX-2 expression and activity upon CK2 modulation and evaluated how these changes affected cell viability. COX-2 expression and cell viability decreased upon selective inhibition of COX-2 with SC-791 or CK2 with 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), both in human colon (HT29-ATCC, HT29-US, DLD-1) and breast (ZR-75) cancer cells, as well as in human embryonic kidney (HEK-293T) cells. On the other hand, ectopic CK2α expression promoted up-regulation of COX-2 by activating the Wnt/ß-catenin pathway in HEK-293T cells. Noteworthy, over-expression of either CK2α, ß-catenin or COX-2, as well as supplementation of the medium with prostaglandin E2 (PGE2), all were individually sufficient to overcome limitations in cell viability triggered by CK2 inhibition either upon addition of DMAT or over-expression of a dominant negative CK2α variant. Altogether, these findings provide new insight to the role of CK2 in cancer by up-regulating COX-2 expression and thereby PGE2 production.
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Caseína Quinase II/fisiologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Regulação para Cima/fisiologia , Apoptose , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , beta Catenina/metabolismoRESUMO
Augmented expression of cyclooxygenase-2 (COX-2) and enhanced production of prostaglandin E(2) (PGE(2)) are associated with increased tumor cell survival and malignancy. Caveolin-1 is a scaffold protein that has been proposed to function as a tumor suppressor in human cancer cells, although mechanisms underlying this ability remain controversial. Intriguingly, the possibility that caveolin-1 regulates the expression of COX-2 has not been explored. Here we show that augmented caveolin-1 expression in cells with low basal levels of this protein, such as human colon cancer (HT29, DLD-1), breast cancer (ZR75), and embryonic kidney (HEK293T) cells reduced COX-2 mRNA and protein levels and beta-catenin-Tcf/Lef and COX-2 gene reporter activity, as well as the production of PGE(2) and cell proliferation. Moreover, COX-2 overexpression or PGE(2) supplementation increased levels of the inhibitor of apoptosis protein survivin by a transcriptional mechanism, as determined by PCR analysis, survivin gene reporter assays and Western blotting. Furthermore, addition of PGE(2) to the medium prevented effects attributed to caveolin-1-mediated inhibition of beta-catenin-Tcf/Lef-dependent transcription. Finally, PGE(2) reduced the coimmunoprecipitation of caveolin-1 with beta-catenin and their colocalization at the plasma membrane. Thus, by reducing COX-2 expression, caveolin-1 interrupts a feedback amplification loop involving PGE(2)-induced signaling events linked to beta-catenin/Tcf/Lef-dependent transcription of tumor survival genes including cox-2 itself and survivin.
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Caveolina 1/metabolismo , Ciclo-Oxigenase 2/genética , Dinoprostona/biossíntese , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Transcrição Gênica , beta Catenina/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose , Proteínas Associadas aos Microtúbulos/genética , Modelos Biológicos , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Survivina , Transcrição Gênica/efeitos dos fármacosRESUMO
La investigación en comprensión emocional ha privilegiado el estudio de los antecedentes y ha desatendido el que atañe al conocimiento sobre las consecuencias de las emociones. Se diseñó una tarea para niños de dos rangos de edad (4 a 5 y 5 a 6 años) con dos historias (valencias positivay negativa). Se midió la concordancia entre valencias (consecuencia-historias), y la calidad de las justificaciones sobre la elección de la consecuencia. Se encontró que la concordancia cambia en función de la edad, la valencia de las historias y las justificaciones a la elección de la consecuencia; las justificaciones dependen de la edad; existe una relación estrecha entre el desarrollo de la comprensión de las consecuencias y la regulación emocional.
Research about emotional understanding has privileged the study of antecedents, but has missed the study of knowledge of the consequences of emotions. We created a task for children of two ages (4 to 5 and 5 to 6 years) with two stories (positive and negative valences). We assessed the valences concordance (consequence-stories), and the justification quality on the consequence election. We found that concordance changes in function of age, story valence and justifications; justifications depend on age; there is a close relation between the developmentof understanding of emotional consequences and emotional regulation.
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Humanos , Emoções , Estresse Psicológico/psicologiaRESUMO
Caveolin-1 reportedly acts as a tumor suppressor and promotes events associated with tumor progression, including metastasis. The molecular mechanisms underlying such radical differences in function are not understood. Recently, we showed that caveolin-1 inhibits expression of the inhibitor of apoptosis protein survivin via a transcriptional mechanism involving the beta-catenin-Tcf/Lef pathway. Surprisingly, while caveolin-1 expression decreased survivin mRNA and protein levels in HT29(ATCC) human colon cancer cells, this was not the case in metastatic HT29(US) cells. Survivin down-regulation was paralleled by coimmunoprecipitation and colocalization of caveolin-1 with beta-catenin in HT29(ATCC) but not HT29(US) cells. Unlike HT29(ATCC) cells, HT29(US) cells expressed small amounts of E-cadherin that accumulated in intracellular patches rather than at the cell surface. Re-expression of E-cadherin in HT29(US) cells restored the ability of caveolin-1 to down-regulate beta-catenin-Tcf/Lef-dependent transcription and survivin expression, as seen in HT29(ATCC) cells. In addition, coimmunoprecipitation and colocalization between caveolin-1 and beta-catenin increased upon E-cadherin expression in HT29(US) cells. In human embryonic kidney HEK293T and HT29(US) cells, caveolin-1 and E-cadherin cooperated in suppressing beta-catenin-Tcf/Lef-dependent transcription as well as survivin expression. Finally, mouse melanoma B16-F10 cells, another metastatic cell model with low endogenous caveolin-1 and E-cadherin levels, were characterized. In these cells, caveolin-1-mediated down-regulation of survivin in the presence of E-cadherin coincided with increased apoptosis. Thus, the absence of E-cadherin severely compromises the ability of caveolin-1 to develop activities potentially relevant to its role as a tumor suppressor.
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Caderinas/metabolismo , Caveolina 1/metabolismo , Regulação para Baixo/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição TCF/metabolismo , beta Catenina/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Células Clonais , Cães , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Imunoprecipitação , Proteínas Inibidoras de Apoptose , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Survivina , Transcrição GênicaRESUMO
Caveolin-1 is suggested to act as a tumor suppressor. We tested the hypothesis that caveolin-1 does so by repression of survivin, an Inhibitor of apoptosis protein that regulates cell-cycle progression as well as apoptosis and is commonly overexpressed in human cancers. Ectopic expression of caveolin-1 in HEK293T and ZR75 cells or siRNA-mediated silencing of caveolin-1 in NIH3T3 cells caused downregulation or upregulation of survivin mRNA and protein, respectively. Survivin downregulation in HEK293T cells was paralleled by reduced cell proliferation, increases in G0-G1 and decreases in G2-M phase of the cell cycle. In addition, apoptosis was evident, as judged by several criteria. Importantly, expression of green fluorescent protein-survivin in caveolin-1-transfected HEK293T cells restored cell proliferation and viability. In addition, expression of caveolin-1 inhibited transcriptional activity of a survivin promoter construct in a beta-catenin-Tcf/Lef-dependent manner. Furthermore, in HEK293T cells caveolin-1 associated with beta-catenin and inhibited Tcf/Lef-dependent transcription. Similar results were obtained upon caveolin-1 expression in DLD1 cells, where APC mutation leads to constitutive activation of beta-catenin-Tcf/Lef-mediated transcription of survivin. Taken together, these results suggest that anti-proliferative and pro-apoptotic properties of caveolin-1 may be attributed to reduced survivin expression via a mechanism involving diminished beta-catenin-Tcf/Lef-dependent transcription.
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Caveolina 1/metabolismo , Morte Celular/fisiologia , Proliferação de Células , Regulação da Expressão Gênica , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Caveolina 1/genética , Ciclo Celular/fisiologia , Linhagem Celular , Humanos , Proteínas Inibidoras de Apoptose , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/fisiologia , Survivina , Fatores de Transcrição TCF/metabolismo , Transcrição Gênica , Proteínas Wnt/metabolismoRESUMO
Chronic ethanol consumption leads to cell injury in virtually every tissue. Tumor necrosis factor-alpha (TNF-alpha) constitutes a major factor in the development of alcohol-induced liver injury. In alcohol-dependent subjects, elevated levels of plasma TNF-alpha are strongly predictive of mortality. Binding of TNF-alpha to TNF-alpha receptor-1 (TNF-R1) activates death domain pathways, leading to necrosis and apoptosis in most tissues, and it also increases the expression of intercellular adhesion molecules (i.e., ICAM-1), which promote inflammation. We determined whether ethanol exposure leads to increases in cellular TNF-R1. We incubated HepG2 human hepatoma cells and H4-II-E-C3 rat hepatoma cells with 25, 50, and 100 mM ethanol for various intervals of time up to 48 h. Human colonic adenocarcinoma cells (Caco-2 cells) and neonatal rat primary cardiomyocytes were also incubated with different concentrations of ethanol. Levels of TNF-R1 were measured either by a sandwich enzyme-linked immunosorbent assay (ELISA) method or by determining the extracellular transmembrane domain of TNF-R1 by an intact-cell ELISA method. Ethanol exposure for 48 h increased TNF-R1 levels in human hepatoma cells in a dose-dependent manner. Levels increased significantly by 164% at 50 mM and by 240% at 100 mM ethanol. Effects were time dependent and did not reach a plateau at 48 h. Similar increases in TNF-R1 were also observed in rat hepatoma cells (90% at 50 mM and 230% at 100 mM ethanol). Under similar conditions, Caco-2 cells showed a significant 80% increase in TNF-R1 levels at 200 mM ethanol, a concentration found in intestine. Neonatal rat primary cardiomyocytes showed TNF-R1 increases of 36% at 50 mM and 44% at 100 mM ethanol. These results indicate that exposure of different cell types to pharmacologic concentrations of ethanol increases TNF-R1 levels and may augment TNF-alpha-mediated cell injury in different tissues.
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Etanol/farmacologia , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Receptores Tipo I de Fatores de Necrose Tumoral/biossíntese , Regulação para Cima/efeitos dos fármacos , Animais , Células CACO-2 , Linhagem Celular Tumoral , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Fígado/citologia , Fígado/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
El presente informe describe los hallazgos clínicos y polisomnográficos en una mujer con antecedentes de síndrome de Guillain-Barré que refería hipersomnia diurna relacionada con moviminetos periódicos del sueño.