Centro Regional Of Investigaciones Biomedicas

Albacete, Spain

Centro Regional Of Investigaciones Biomedicas

Albacete, Spain
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Cuenca-Lopez M.D.,University of Castilla - La Mancha | Brea D.,University of Santiago de Compostela | Segura T.,Servicio de Neurologia | Anton-Martinez D.,Complejo Hospitalario Universitario Of Albacete | And 5 more authors.
Revista de Neurologia | Year: 2010

Introduction. The immune central nervous system (CNS) innate immune cells including microglia and macrophages play integral roles in receiving and propagating inflammatory signals. Inflammation is generally a beneficial response of an organism to infection but, when prolonged or inappropriate, it can be detrimental. Neuronal loss in acute (e.g. stroke and head injury) and chronic (e.g. multiple sclerosis and Alzheimer's disease) CNS diseases has been associated with inflammatory processes systemically and in the brain. Development. Herein we review the processes that participate in the activation of the immune system and the starting of inflammatory response after stroke, where neuronal necrotic cell death has been described. We addressed the relevance of the innate inflammatory cells that are on the CNS, as microglia and macrophages, which have an important role in receiving and spreading inflammatory signals. In addition, the inflammatory response is characterized by an increase in the levels of expression of inflammatory mediators, which regulate adhesion molecules, and increase the permeability of the blood-brain barrier. It has also been described that inflammation promotes the rapid over-expression and activation of a variety of genes, and it has been postulated that transcription factors should be studied for their potential use in therapeutics and repair. Transcriptional activation can be a double-edged sword since depending on the individual transcription factor it can induce the expression of either neuroprotective or neurotoxic genes. Conclusion. In summary, a better understanding of the different molecules mediating the immune response will allow the design of new pharmacological tools that could improve stroke treatment. © 2010 Revista de Neurología.


Cuenca-Lopez M.D.,University of Castilla - La Mancha | Brea D.,University of Santiago de Compostela | Galindo M.F.,Universitario Of Albacete | Anton-Martinez D.,University of Castilla - La Mancha | And 7 more authors.
Revista de Neurologia | Year: 2010

Introduction. After cerebral ischemia, necrotic cell death occurs specially for neurons, mainly due to the privation of oxygen and glucose. Cell necrosis triggers the activation of the immune system followed by an inflammatory response. This reaction is characterized by the activation of astrocytes and microglia together with the infiltration of peripheral immune cells. Development. Both, microglia and inflammatory cells, including circulating peripheral inflammatory cells, get activated and release a plethora of inflammatory mediators, cytokines, chemokines, etc. Such released factors induce the overexpression of adhesion molecules, increasing the blood brain barrier permeability, thus favoring even more inflammatory cell infiltration. In the end, this contributes to increase brain damage. Inflammatory response is nevertheless necessary in order to eliminate cellular debris from both apoptotic and necrotic cells. It seems to be also implicated in the initiation of certain mechanisms responsible for brain repair and plasticity. As a result, the inflammatory response is a coordinated effort. Activation of inflammation triggers an immunosuppressant and anti-inflammatory response. A high rate of infections in patients suffering from stroke, together with increased serum levels of anti-inflammatory molecules in these patients, support this statement. The anti-inflammatory response could be interpreted as the organism attempting to control the heightened inflammatory response that occurs after cerebral ischemia. On the other hand, following an ischemic event, there are several new cerebral epitopes that get exposed to the immune system, which would never have been exposed under normal physiological conditions. Conclusion. Therefore immunosuppression after an ischemic accident hinders the development of auto-immune responses. © 2010 Revista de Neurología.


Ruiz-Garcia A.,Centro Regional Of Investigaciones Biomedicas | Monsalve E.,Centro Regional Of Investigaciones Biomedicas | Novellasdemunt L.,University of Barcelona | Navarro-Sabate A.,University of Barcelona | And 7 more authors.
Journal of Biological Chemistry | Year: 2011

Macrophages activated through Toll receptor triggering increase the expression of the A2A and A2B adenosine receptors. In this study, we show that adenosine receptor activation enhances LPS-induced pfkfb3 expression, resulting in an increase of the key glycolytic allosteric regulator fructose 2,6-bisphosphate and the glycolytic flux. Using shRNA and differential expression of A2A and A2B receptors, we demonstrate that the A2A receptor mediates, in part, the induction of pfkfb3 by LPS, whereas the A2B receptor, with lower adenosine affinity, cooperates when high adenosine levels are present. pfkfb3 promoter sequence deletion analysis, site-directed mutagenesis, and inhibition by shRNAs demonstrated that HIF1α is a key transcription factor driving pfkfb3 expression following macrophage activation by LPS, whereas synergic induction of pfkfb3 expression observed with the A2 receptor agonists seems to depend on Sp1 activity. Furthermore, levels of phospho-AMP kinase also increase, arguing for increased PFKFB3 activity by phosphorylation in long term LPS-activated macrophages. Taken together, our results show that, in macrophages, endogenously generated adenosine cooperates with bacterial components to increase PFKFB3 isozyme activity, resulting in greater fructose 2,6-bisphosphate accumulation. This process enhances the glycolytic flux and favors ATP generation helping to develop and maintain the long term defensive and reparative functions of the macrophages. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


Galan-Moya E.M.,Centro Regional Of Investigaciones Biomedicas | de la Cruz-Morcillo M.A.,Centro Regional Of Investigaciones Biomedicas | Valero M.L.,Centro Regional Of Investigaciones Biomedicas | Callejas-Valera J.L.,Centro Regional Of Investigaciones Biomedicas | And 6 more authors.
PLoS ONE | Year: 2011

The p38 MAPK signaling pathway has been proposed as a critical mediator of the therapeutic effect of several antitumor agents, including cisplatin. Here, we found that sensitivity to cisplatin, in a system of 7 non-small cell lung carcinoma derived cell lines, correlated with high levels of MKK6 and marked activation of p38 MAPK. However, knockdown of MKK6 modified neither the response to cisplatin nor the activation of p38 MAPK. Deeper studies showed that resistant cell lines also displayed higher basal levels of MKK3. Interestingly, MKK3 knockdown significantly decreased p38 phosphorylation upon cisplatin exposure and consequently reduced the response to the drug. Indeed, cisplatin poorly activated MKK3 in resistant cells, while in sensitive cell lines MKK3 showed the opposite pattern in response to the drug. Our data also demonstrate that the low levels of MKK6 expressed in resistant cell lines are the consequence of high basal activity of p38 MAPK mediated by the elevated levels of MKK3. This finding supports the existence of a regulatory mechanism between both MAPK kinases through their MAPK. Furthermore, our results were also mirrored in head and neck carcinoma derived cell lines, suggesting our observations boast a potential universal characteristic in cancer resistance of cisplatin. Altogether, our work provides evidence that MKK3 is the major determinant of p38 MAPK activation in response to cisplatin and, hence, the resistance associated with this MAPK. Therefore, these data suggest that the balance between both MKK3 and MKK6 could be a novel mechanism which explains the cellular response to cisplatin. © 2011 Galan-Moya et al.


PubMed | Centro Regional Of Investigaciones Biomedicas
Type: Journal Article | Journal: PloS one | Year: 2011

The p38 MAPK signaling pathway has been proposed as a critical mediator of the therapeutic effect of several antitumor agents, including cisplatin. Here, we found that sensitivity to cisplatin, in a system of 7 non-small cell lung carcinoma derived cell lines, correlated with high levels of MKK6 and marked activation of p38 MAPK. However, knockdown of MKK6 modified neither the response to cisplatin nor the activation of p38 MAPK. Deeper studies showed that resistant cell lines also displayed higher basal levels of MKK3. Interestingly, MKK3 knockdown significantly decreased p38 phosphorylation upon cisplatin exposure and consequently reduced the response to the drug. Indeed, cisplatin poorly activated MKK3 in resistant cells, while in sensitive cell lines MKK3 showed the opposite pattern in response to the drug. Our data also demonstrate that the low levels of MKK6 expressed in resistant cell lines are the consequence of high basal activity of p38 MAPK mediated by the elevated levels of MKK3. This finding supports the existence of a regulatory mechanism between both MAPK kinases through their MAPK. Furthermore, our results were also mirrored in head and neck carcinoma derived cell lines, suggesting our observations boast a potential universal characteristic in cancer resistance of cisplatin. Altogether, our work provides evidence that MKK3 is the major determinant of p38 MAPK activation in response to cisplatin and, hence, the resistance associated with this MAPK. Therefore, these data suggest that the balance between both MKK3 and MKK6 could be a novel mechanism which explains the cellular response to cisplatin.

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