RESUMO
Synucleins are a family of small, soluble proteins mainly expressed in neural tissue and in certain tumors. Since their discovery, tens of thousands of scientific reports have been published about this family of proteins as they are associated with severe human diseases. Although the physiological function of these proteins is still elusive, their relationship with neurodegeneration and cancer has been clearly described over the years. In this review, we summarize data connecting synucleins and cancer, going from the structural description of these molecules to their involvement in tumor-related processes, and discuss the putative use of these proteins as cancer molecular biomarkers.
Assuntos
Neoplasias , alfa-Sinucleína , Humanos , alfa-Sinucleína/genética , Neoplasias/genéticaRESUMO
Objetivo. Desarrollar y poner a punto la técnica de dispersión de la cromatina espermática (SCD) para evaluar el grado de fragmentación del ADN en semen. Materiales y métodos. Se incluyeron 57 pacientes normozoospérmicos (OMS 2010), los cuales fueron invitados a participar del estudio luego de firmar los consentimientos correspondientes. Se evaluó el grado de fragmentación mediante técnica de SCD, de manera objetiva y subjetiva, en muestras sometidas a estrés oxidativo con H2O2 y seleccionadas mediante swim up o gradiente de densidad, así como congeladas y descongeladas. Resultados. La evaluación objetiva demuestra que la menor fragmentación se asociaría a un mayor tamaño del halo por definición, aunque se observa un aumento (p<0,05) en el tamaño del núcleo. El tratamiento oxidante (>100μM de H2O2) aumenta el índice de fragmentación de forma dosis-dependiente sin afectar la viabilidad ni la motilidad espermática. Las técnicas de selección de espermatozoides mótiles evaluadas (swim up o gradiente de densidad) disminuyen el índice de fragmentación, aunque se observa cierta susceptibilidad individual. La congelación directa a -20°C permite diferir la realización del test, independientemente del tipo de muestra. Conclusión. La evaluación subjetiva de la técnica SCD es suficiente para su uso en el laboratorio clínico, siempre que se evalúe la relación halo/núcleo para la clasificación. La utilización del tratamiento oxidante permite introducir un control positivo de daño para la puesta a punto de la técnica. La selección espermática mediante técnicas de uso habitual en reproducción asistida disminuye el índice de fragmentación, observándose cierta susceptibilidad individual. La técnica SCD puede ser diferida mediante congelamiento de la muestra, lo que permite un ahorro de insumos, reactivos y tiempo de procesamiento (AU)
Objective. To develop the sperm chromatin dispersion test (SCD) for evaluating the DNA fragmentation in semen. Materials and methods. 57 normozoospermic (WHO 2010) patients were invited to participate in the study after signing the consents. DNA fragmentation was evaluated by SCD, objectively and subjectively, after oxidative stress with H2O2 and also in motile selected samples (swim up or density gradient), as well as in frozen and thawed samples. Results. The objective assessment showed that minor fragmentation is associated to a larger halo size by definition, but also a significant increase in the size of the nucleus is observed. Oxidizing treatment (>100μM of H2O2) increases the fragmentation index in a dose-depend way without affecting sperm viability and motility. Different techniques of motile sperm selection (swim up or density gradients) decrease the fragmentation index with an individual susceptibility. Regardless of the sample (semen, suspension or post swim up direct freezing to -20°C allows to delay the test. Conclusion. Subjective evaluation of the SCD test is sufficient for the clinical laboratory, evaluating the relation halo/nucleoid for the classification. To set up the SCD a dose-response curve with oxidizing treatment is required as a positive control of damage. The use of sperm selection methods used in assisted reproduction, decreases the fragmentation index, however individual susceptibility was observed. The SCD could be delayed by freezing the sample which allows saving of reagents and processing time (AU)
Assuntos
Humanos , Masculino , Cromatina Sexual/isolamento & purificação , Cromatina/isolamento & purificação , Espermatozoides/fisiologia , Peróxido de Hidrogênio/administração & dosagem , Peróxido de Hidrogênio/análise , Fragmentação do DNA , Estresse Oxidativo/genética , Análise do Sêmen/instrumentação , Análise do Sêmen/métodos , Intervalos de Confiança , Estresse Oxidativo/fisiologiaRESUMO
BACKGROUND: Domperidone is widely prescribed in patients with gastrointestinal disorders but some cardiac adverse effects have been recently reported. AIM: To evaluate the risk of QT prolongation, ventricular arrhythmias and sudden cardiac death associated with the use of oral domperidone in adults without cancer. MATERIAL AND METHODS: Systematic searches in MEDLINE, LILACS, SciELO, the Cochrane Library and regulatory agencies websites were performed, followed by a manual search of cited references. The search strategy consisted of combining free and indexed text words without any date or language restriction. RESULTS: Three case-control studies met the inclusion criteria; none of them evaluated QT interval prolongation. With low risk of bias, each study quantified the risk of ventricular arrhythmia or sudden cardiac death (VA/SCD). The odds ratios for these events in these studies were 4.7 (95% confidence interval (CI): 1.4-16), 1.59 (95% CI: 1.28-1.98) and 11.02 (95% CI: 2.02-62.3) respectively. A significantly increased risk was observed in patients older than 60 years of age or receiving doses > 30 mg/day. CONCLUSIONS: Heterogeneity between selected studies did not allow the computation of a summary measure. However, evidence was found that an increased risk of VA/SCD is associated with the use of oral domperidone in adults.
Assuntos
Antieméticos/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Morte Súbita Cardíaca/etiologia , Domperidona/efeitos adversos , Adulto , Feminino , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/tratamento farmacológico , Razão de Chances , Fatores de Risco , Vômito/tratamento farmacológicoRESUMO
Background: Domperidone is widely prescribed in patients with gastrointestinal disorders but some cardiac adverse effects have been recently reported. Aim: To evaluate the risk of QT prolongation, ventricular arrhythmias and sudden cardiac death associated with the use of oral domperidone in adults without cancer. Material and Methods: Systematic searches in MEDLINE, LILACS, SciELO, the Cochrane Library and regulatory agencies websites were performed, followed by a manual search of cited references. The search strategy consisted of combining free and indexed text words without any date or language restriction. Results: Three case-control studies met the inclusion criteria; none of them evaluated QT interval prolongation. With low risk of bias, each study quantified the risk of ventricular arrhythmia or sudden cardiac death (VA/SCD). The odds ratios for these events in these studies were 4.7 (95% confidence interval (CI): 1.4-16), 1.59 (95% CI: 1.28-1.98) and 11.02 (95% CI: 2.02-62.3) respectively. A significantly increased risk was observed in patients older than 60 years of age or receiving doses > 30 mg/day. Conclusions: Heterogeneity between selected studies did not allow the computation of a summary measure. However, evidence was found that an increased risk of VA/SCD is associated with the use of oral domperidone in adults.
Assuntos
Animais , Feminino , Humanos , Camundongos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Diterpenos/administração & dosagem , Compostos de Epóxi/administração & dosagem , Paclitaxel/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Diterpenos/química , Sinergismo Farmacológico , Compostos de Epóxi/química , Lactonas/administração & dosagem , Lactonas/química , Camundongos Nus , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacos , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A short and efficient methodology for the synthesis of chiral dioxa-caged compounds from levoglucosenone, a biomass-derived enone, is herein presented. The key transformation, that involves a cascade 3-step cationic cyclization, was efficiently carried out in high yields and selectivities by Montmorillonite K-10 catalysis. The usefulness of K-10 in related semi-pinacol rearrangements to obtain pyran-3-ones is also shown. Interesting differences in the reactivity pattern was found for epimeric alcohols, and the origins of these findings were determined by DFT calculations.
Assuntos
Bentonita/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Glucose/análogos & derivados , Configuração de Carboidratos , Catálise , Técnicas de Química Sintética , Glucose/síntese química , Glucose/química , Modelos Moleculares , EstereoisomerismoRESUMO
AIMS: To assess the association of the use of domperidone in infants with QTc interval prolongation and proarrhythmic events. METHODS: A systematic search of the scientific literature was conducted without any date or language restriction. The electronic database MEDLINE and the sources LILACS, ScIELO and Cochrane library were consulted. RESULTS: From the twelve identified studies, eight were excluded because they did not meet the inclusion criteria. One case report and three pilot studies were selected. Rocha et al (2005) reported the case of an infant (age 3 months) with QTc interval = 463 ms after being treated during one month with 1.8 mg/kg/day of oral domperidone. Djeddi et al (2008) administered an average dose of 1.3 mg/kg/day to 31 neonates; QTc interval prolongation > 30 ms was observed in nine neonates. Hegar et al (2009) studied 10 infants (mean age 5.6 months) who received 0.8 mg/ kg/day of oral domperidone; QTc interval prolongation was not observed. Günlemez et al (2010) enrolled 40 premature infants who were administered 1 mg/kg/day of oral domperidone; the QTc interval increased to above 450 ms in two infants. CONCLUSIONS: Although evidence that orally administrated domperidone in infants produces prolongation of QTc interval was found, further studies are needed in order to quantify the risk associated with the drug in that population. We suggest that heath professionals should conduct ECGs to infants treated with domperidone and inform the pharmacovigilance system the occurrence of any case of adverse event.
Objetivo: Determinar si existe evidencia de prolongación del intervalo QTc y efectos proarrítmicos asociados al uso de domperidona oral en infantes. Método: Se realizó una revisión sistemática de la literatura científica consultando la base de datos electrónica MEDLINE y las fuentes LILACS, ScIELO y Biblioteca Cochrane a través de la Biblioteca Virtual de Salud, sin límite de fecha ni de idioma. Resultados: De los estudios identificados se excluyeron ocho por no cumplir con los criterios de inclusión, quedando seleccionados un reporte de caso y tres estudios pilotos. Rocha et al (2005) reportan el caso de un niño de 3 meses con intervalo QTc=463 mseg tras un mes de tratamiento con 1,8 mg/kg/día de domperidona oral. Djeddi et al (2008) administraron una dosis promedio de 1,3 mg/kg/día a 31 neonatos, observando prolongación del intervalo QTc>30 mseg en nueve. Hegar et al (2009) estudiaron a 10 niños con edad media de 5,6 meses tratados con 0,8 mg/kg/día y no observaron prolongación del intervalo QTc. Gunlemez et al (2010) incluyeron en su estudio a 40 infantes prematuros a quienes administraron 1 mg/kg/día de domperidona oral, en dos de ellos el intervalo QTc aumentó por encima de 450 mseg. Conclusiones: Aunque se encontró evidencia de prolongación del intervalo QTc en infantes tratados con domperidona oral, se necesitan más estudios para cuantificar el riesgo asociado a la droga en esta población. Se sugiere a los profesionales de la salud realizar un monitoreo electrocardiográfico de los infantes tratados con domperidona e informar al sistema de farmacovigilancia los casos de ocurrencia de eventos adversos.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Domperidona/efeitos adversos , Antagonistas de Dopamina/efeitos adversos , Fibrilação Atrial/induzido quimicamente , Cisaprida/farmacologia , Cisaprida/uso terapêutico , Contraindicações , Citocromo P-450 CYP3A/fisiologia , Domperidona/farmacocinética , Domperidona/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Interações Medicamentosas , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/induzido quimicamente , Síndrome do QT Longo/induzido quimicamente , Projetos Piloto , Estudos ProspectivosRESUMO
Objetivo: Determinar si existe evidencia de prolongación del intervalo QTc y efectos proarrítmicos asociados al uso de domperidonaoral en infantes. Método: Se realizó una revisión sistemática de la literatura científica consultando la base de datos electrónica MEDLINEy las fuentes LILACS, ScIELO y Biblioteca Cochrane a través de la Biblioteca Virtual de Salud, sin límite de fecha ni de idioma. Resultados: De los estudios identificados se excluyeron ocho por no cumplir con los criterios de inclusión, quedando seleccionados un reporte de caso y tres estudios pilotos. Rocha etal (2005) reportan el caso de un niño de 3 meses con intervalo QTc=463 mseg tras un mes de tratamiento con 1,8 mg/kg/díade domperidona oral. Djeddi et al (2008) administraron unadosis promedio de 1,3 mg/kg/día a 31 neonatos, observando prolongación del intervalo QTc>30 mseg en nueve. Hegar et al (2009) estudiaron a 10 niños con edad media de 5,6 meses tratados con 0,8 mg/kg/día y no observaron prolongación del intervalo QTc. Gunlemez et al (2010) incluyeron en su estudio a 40 infantes prematuros a quienes administraron 1 mg/kg/día de domperidona oral, en dos de ellos el intervalo QTc aumentó por encima de 450 mseg. Conclusiones: Aunque se encontró evidencia de prolongación del intervalo QTc en infantes tratados con domperidona oral, se necesitan más estudios para cuantificar el riesgo asociado a la droga en esta población. Se sugiere a los profesionales de la salud realizar un monitoreo electrocardiográfico de los infantes tratados con domperidona e informar al sistema de farmacovigilancia los casos de ocurrencia de eventos adversos
Aims: To assess the association of the use of domperidone in infants with QTc interval prolongation and proarrhythmic events. Methods: A systematic search of the scientific literature was conducted without any date or language restriction. The electronic database MEDLINE and the sources LILACS, ScIELO and Cochrane library were consulted. Results: From the twelve identified studies, eight were excluded because they did not meet the inclusion criteria. One case report and three pilot studies were selected. Rocha et al (2005) reported the case of an infant (age 3 months) with QTc interval = 463ms after being treated during one month with 1.8 mg/kg/day of oral domperidone. Djeddi et al (2008) administered an average dose of 1.3 mg/kg/day to 31 neonates; QTc interval prolongation > 30 ms was observed in nine neonates. Hegar et al (2009) studied 10 infants (mean age 5.6 months) who received 0.8 mg/ kg/day of oral domperidone; QTc interval prolongation was not observed. Günlemez et al (2010) enrolled 40 premature infants who were administered 1 mg/kg/day of oral domperidone; the QTc interval increased to above 450 ms in two infants. Conclusions: Although evidence that orally administrated domperidone in infants produces prolongation of QTc interval was found, further studies are needed in order to quantify the risk associated with the drug in that population. We suggest that heath professionals should conduct ECGs to infants treated with domperidone and inform the pharmacovigilance system the occurrence of any case of adverse event
