RESUMEN
Inflammation contributes to development and progression in a variety of cancers, including cervical cancer, which is the second leading cause of cancer deaths in women worldwide. In this study, we examined the anti-inflammatory effects of imperatorin, a psoralen-type furanocoumarin from the fruits of Angelica dahurica, in tumor necrosis factor-α (TNF-α)-stimulated HeLa cells by investigating its impact on the production and expression of cytokines and the major signal-transduction pathways. We found this compound significantly inhibited the TNF-α-induced expression of NF-κB target genes, such as COX-2, cyclin D1, MMP-9, VEGF, IL-6 and Bcl-xL in a concentration-dependent manner. Further analysis revealed that imperatorin was a potent inhibitor of NF-κB activation by the suppression of TNF-α-induced IKKα/ß phosphorylation, IκB phosphorylation and degradation, and NF-κB p65 nuclear translocation. We also demonstrated that imperatorin downregulated TNF-α-induced activation of PI3K/Akt. Furthermore, our findings show that imperatorin inhibits TNF-α-induced ROS generation. Taken together, imperatorin can blunt inflammation by inhibiting the ROS-mediated activation of the PI3K/Akt/NF-κB pathway.
Asunto(s)
Furocumarinas/administración & dosificación , Inflamación/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Angelica/química , Femenino , Frutas/química , Furocumarinas/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Inflamación/genética , Inflamación/patología , FN-kappa B/genética , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinasas/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
Previous studies have shown that up-regulation of transforming growth factor ß1 results in neuroprotective effects. However, the role of the transforming growth factor ß1 downstream molecule, SMAD2/3, following ischemia/reperfusion remains unclear. Here, we investigated the neuroprotective effects of SMAD2/3 by analyzing the relationships between SMAD2/3 expression and cell apoptosis and inflammation in the brain of a rat model of cerebral ischemia/reperfusion. Levels of SMAD2/3 mRNA were up-regulated in the ischemic penumbra 6 hours after cerebral ischemia/reperfusion, reached a peak after 72 hours and were then decreased at 7 days. Phosphorylated SMAD2/3 protein levels at the aforementioned time points were consistent with the mRNA levels. Over-expression of SMAD3 in the brains of the ischemia/reperfusion model rats via delivery of an adeno-associated virus containing the SMAD3 gene could reduce tumor necrosis factor-α and interleukin-1ß mRNA levels, down-regulate expression of the pro-apoptotic gene, capase-3, and up-regulate expression of the anti-apoptotic protein, Bcl-2. The SMAD3 protein level was negatively correlated with cell apoptosis. These findings indicate that SMAD3 exhibits neuroprotective effects on the brain after ischemia/reperfusion through anti-inflammatory and anti-apoptotic pathways.
