Retinoic acid downregulates thiol antioxidant defences and homologous recombination while promotes A549 cells sensitization to cisplatin

Recent studies have investigated the use of retinoic acid (RA) molecule in combined chemotherapies to cancer cells as an attempt to increase treatment efficiency and circumvent cell resistance. Positive results were obtained in clinical trials from lung cancer patients treated with RA and cisplatin. Meanwhile, the signalling process that results from the interaction of both molecules remains unclear. One of the pathways that RA is able to modulate is the activity of NRF2 transcription factor, which is highly associated with tumour progression and resistance. Therefore, the aim of this work was to investigate molecular mechanism of RA and cisplatin co-treatment in A549 cells, focusing in NRF2 pathway. To this end, we investigated NRF2 and NRF2-target genes expression, cellular redox status, cisplatin-induced apoptosis, autophagy and DNA repair through homologous recombination. RA demonstrated to have an inhibitory effect over NRF2 activation, which regulates the expression of thiol antioxidants enzymes. Moreover, RA increased reactive species production associated with increased oxidation of thiol groups within the cells. The expression of proteins associated with DNA repair through homologous recombination was also suppressed by RA pre-treatment. All combined, these effects appear to create a more sensitive cellular environment to cisplatin treatment, increasing apoptosis frequency. Interestingly, autophagy was also increased by combination therapy, suggesting a resistance mechanism by A549 cells. In conclusion, these results provided new information about molecular mechanisms of RA and cisplatin treatment contributing to chemotherapy optimization

Biomarcadores de estrés oxidativo como indicadores pronósticos de severidad en pacientes con dengue

There is evidence for the role of oxidative stress in severe dengue pathogenesis. However, previous observational studies presents certain methodological limitations, which may affect its internal and external validity. This study was a case-control analysis of patients with severe dengue and dengue with warning signs, to evaluate the serum protein carbonyls-PCOs and lipid hydroperoxides-LOOHs levels and activities of superoxide dismutases-SODs (MnSOD, Cu/ZnSOD and total SOD), as potential prognosis indicators of severity in dengue patients, using binary logistic regression analysis and strategy of double cross-validation. Therefore, the study population was subdivided into a derivation group (pediatric patients, Barranquilla-Colombia) and an external validation group (children and adults patients, National Institute of Health of Peru). PCOs was the only oxidative stress markers that showed a strongest association with the severity of dengue, both in children and adults. In the derivation group, the optimal cut-off point was estimated at 5.29 nmol/mg of protein, and in the external validation group, it was 5.77 nmol/mg of protein. The prognostic models based on these two diagnostic thresholds showed a high discriminatory capacity of dengue severity, external reproducibility, geographic transportability, and typical characteristics of diagnostic validity and safety of screening tests.Existe evidencia del papel del estrés oxidativo en la patogénesis grave del dengue. Sin embargo, estudios observacionales previos presentan ciertas limitaciones metodológicas, que pueden afectar su validez interna y externa. Este estudio fue un análisis de casos y controles de pacientes con dengue severo y dengue con signos de advertencia, para evaluar la proteína sérica carbonilo-PCO y los niveles de hidroperóxidos de lípidos-LOOH y las actividades de superóxido dismutasas-SOD (MnSOD, Cu / ZnSOD y SOD total) , como posibles indicadores de pronóstico de severidad en pacientes con dengue, mediante análisis de regresión logística binaria y estrategia de doble validación cruzada. Por lo tanto, la población de estudio se subdividió en un grupo de derivación (pacientes pediátricos, Barranquilla-Colombia) y un grupo de validación externa (pacientes niños y adultos, Instituto Nacional de Salud del Perú). Los PCO fueron los únicos marcadores de estrés oxidativo que mostraron una asociación más fuerte con la gravedad del dengue, tanto en niños como en adultos. En el grupo de derivación, el punto de corte óptimo se estimó en 5,29 nmol / mg de proteína, y en el grupo de validación externa fue de 5,77 nmol / mg de proteína. Los modelos de pronóstico basados ​​en estos dos umbrales diagnósticos mostraron una alta capacidad discriminatoria de la gravedad del dengue, la reproducibilidad externa, la transportabilidad geográfica y las características típicas de la validez diagnóstica y la seguridad de las pruebas de detección