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Husi H.,University of Glasgow | Sanchez-Nino M.D.,Institute Investigacion Sanitaria IDIPAZ | Delles C.,University of Glasgow | Mullen W.,University of Glasgow | And 5 more authors.
BMC Systems Biology | Year: 2013

Background: Acute kidney injury (AKI) is a frequent condition in hospitalised patients undergoing major surgery or the critically ill and is associated with increased mortality. Based on the volume of the published literature addressing this condition, reporting both supporting as well as conflicting molecular evidence, it is apparent that a comprehensive analysis strategy is required to understand and fully delineate molecular events and pathways which can be used to describe disease induction and progression as well as lead to a more targeted approach in intervention therapies.Results: We used a Systems Biology approach coupled with a de-novo high-resolution proteomic analysis of kidney cortex samples from a mouse model of folic acid-induced AKI (12 animals in total) and show comprehensive mapping of signalling cascades, gene activation events and metabolite interference by mapping high-resolution proteomic datasets onto a de-novo hypothesis-free dataspace. The findings support the involvement of the glutamatergic signalling system in AKI, induced by over-activation of the N-methyl-D-aspartate (NMDA)-receptor leading to apoptosis and necrosis by Ca2+-influx, calpain and caspase activation, and co-occurring reactive oxygen species (ROS) production to DNA fragmentation and NAD-rundown. The specific over-activation of the NMDA receptor may be triggered by the p53-induced protein kinase Dapk1, which is a known non-reversible cell death inducer in a neurological context. The pathway mapping is consistent with the involvement of the Renin-Angiotensin Aldosterone System (RAAS), corticoid and TNFα signalling, leading to ROS production and gene activation through NFκB, PPARγ, SMAD and HIF1α trans-activation, as well as p53 signalling cascade activation. Key elements of the RAAS-glutamatergic axis were assembled as a novel hypothetical pathway and validated by immunohistochemistry.Conclusions: This study shows to our knowledge for the first time in a molecular signal transduction pathway map how AKI is induced, progresses through specific signalling cascades that may lead to end-effects such as apoptosis and necrosis by uncoupling of the NMDA receptor. Our results can potentially pave the way for a targeted pharmacological intervention in disease progression or induction. © 2013 Husi et al.; licensee BioMed Central Ltd. Source

Puertolas J.A.,University of Zaragoza | Vadillo J.L.,University of Zaragoza | Sanchez-Salcedo S.,Complutense University of Madrid | Sanchez-Salcedo S.,CIBER ISCIII | And 5 more authors.
Journal of Materials Science: Materials in Medicine | Year: 2012

The mechanical properties of bioceramic conformed pieces based on micelle-templated silica (MTS) such as SBA15, MCM41 and MCM48 as well as MTS/ agarose systems have been evaluated under static and cyclic compressive tests. The MTS pieces exhibited a brittle behaviour. Agarose, a biocompatible and biodegradable hydrogel, has been used to shape ceramic-agarose pieces following a low temperature shaping method. Agarose conferred toughness, ductility and a rubbery consistency up to a 60% strain in ceramic MTS/agarose systems leading to a maximum strength of 10-50 MPa, without losing their initial cylindrical structure. This combination of ceramic and organic matrix contributes to avoiding the inherent brittleness of the bioceramic and enhances the compression resistance of hydrogel. The presence of mechanical hysteresis, permanent deformation after the first cycle and recovery of the master monotonous curve of MTS/agarose systems indicate a Mullins-like effect similar to that found in carbon-filled rubber systems. We report this type of mechanical behaviour, the Mullins effect, for the first time in MTS bioceramics and MTS bioceramic/agarose systems. © 2011 Springer Science+Business Media, LLC. Source

Garcia-Rodriguez B.,Spanish University for Distance Education (UNED) | Garcia-Rodriguez B.,Institute Investigacion Sanitaria IDIPAZ | Casares-Guillen C.T.,Spanish University for Distance Education (UNED) | Molina J.A.,Hospital 12 de Octubre | And 4 more authors.
Revista de Neurologia | Year: 2011

Introduction. Previous research has shown that correct identification of emotional facial expressions (EFE) depends on the cognitive resources that are available. In this study, we examine whether the capacity to identify EFE in a dual task paradigm is affected in Parkinson's disease (PD). Aim. To investigate the interference generated by introducing a secondary task in EFE processing during the encoding and recovery of the facial expression in non-medicated PD patients. Subjects and methods. A total of 14 patients with de novo PD and 28 healthy adults identified 24 EFE under two conditions: simultaneous encoding along with a secondary task and introduction of the secondary task between the time that spans the encoding of the primary task and the response time latency. Results. Results showed that identification of EFE by patients with PD was significantly worse than by healthy adults in the simultaneous encoding condition. In contrast, no differences were found when the interference of the secondary task took place in the phase involving recovery of information of the primary task. Conclusions. Patients with PD only display specific deficits in processing EFE when the task consumes high levels of the resources required for divided attention, as occurs in everyday situations. © 2011 Revista de Neurología. Source

de la Cueva A.,Institute Investigaciones Biomedicas | de la Cueva A.,IMDEA Madrid Institute for Advanced Studies | Ramirez de Molina A.,Institute Investigaciones Biomedicas | Ramirez de Molina A.,IMDEA Madrid Institute for Advanced Studies | And 8 more authors.
PLoS ONE | Year: 2013

Background:Colorectal cancer (CRC) is the third major cause of cancer related deaths in the world. 5-fluorouracil (5-FU) is widely used for the treatment of colorectal cancer but as a single-agent renders low response rates. Choline kinase alpha (ChoKα), an enzyme that plays a role in cell proliferation and transformation, has been reported overexpressed in many different tumors, including colorectal tumors. ChoKα inhibitors have recently entered clinical trials as a novel antitumor strategy.Methodology/Principal Findings:ChoKα specific inhibitors, MN58b and TCD-717, have demonstrated a potent antitumoral activity both in vitro and in vivo against several tumor-derived cell line xenografts including CRC-derived cell lines. The effect of ChoKα inhibitors in combination with 5-FU as a new alternative for the treatment of colon tumors has been investigated both in vitro in CRC-tumour derived cell lines, and in vivo in mouse xenografts models. The effects on thymidilate synthase (TS) and thymidine kinase (TK1) levels, two enzymes known to play an essential role in the mechanism of action of 5-FU, were analyzed by western blotting and quantitative PCR analysis. The combination of 5-FU with ChoKα inhibitors resulted in a synergistic effect in vitro in three different human colon cancer cell lines, and in vivo against human colon xenografts in nude mice. ChoKα inhibitors modulate the expression levels of TS and TK1 through inhibition of E2F production, providing a rational for its mechanism of action.Conclusion/Significance:Our data suggest that both drugs in combination display a synergistic antitumoral effect due to ChoKα inhibitors-driven modulation of the metabolization of 5-FU. The clinical relevance of these findings is strongly supported since TCD-717 has recently entered Phase I clinical trials against solid tumors. © 2013 de la Cueva et al. Source

Pifl C.,Medical University of Vienna | Hornykiewicz O.,Medical University of Vienna | Blesa J.,University of Navarra | Blesa J.,Charles III University of Madrid | And 6 more authors.
Journal of Neurochemistry | Year: 2013

We recently found severe noradrenaline deficits throughout the thalamus of patients with Parkinson's disease [C. Pifl, S. J. Kish and O. Hornykiewicz Mov Disord. 27, 2012, 1618.]. As this noradrenaline loss was especially severe in nuclei of the motor thalamus normally transmitting basal ganglia motor output to the cortex, we hypothesized that this noradrenaline loss aggravates the motor disorder of Parkinson's disease. Here, we analysed noradrenaline, dopamine and serotonin in motor (ventrolateral and ventroanterior) and non-motor (mediodorsal, centromedian, ventroposterior lateral and reticular) thalamic nuclei in MPTP-treated monkeys who were always asymptomatic; who recovered from mild parkinsonism; and monkeys with stable, either moderate or severe parkinsonism. We found that only the symptomatic parkinsonian animals had significant noradrenaline losses specifically in the motor thalamus, with the ventroanterior motor nucleus being affected only in the severe parkinsonian animals. In contrast, the striatal dopamine loss was identical in both the mild and severe symptom groups. MPTP-treatment had no significant effect on noradrenaline in non-motor thalamic nuclei or dopamine and serotonin in any thalamic subregion. We conclude that in the MPTP primate model, loss of noradrenaline in the motor thalamus may also contribute to the clinical expression of the parkinsonian motor disorder, corroborating experimentally our hypothesis on the role of thalamic noradrenaline deficit in Parkinson's disease. Parkinson patients and animals with experimentally reduced thalamic noradrenaline exhibit pathological thalamic discharge patterns. In Parkinson's disease, motor thalamic noradrenaline is profoundly reduced. MPTP-induced parkinsonian monkeys had in addition to basal ganglia dopamine loss noradrenaline losses specifically in the motor thalamus, with the ventroanterior motor nucleus being affected only in severe parkinsonism. Thus, noradrenaline, specifically in the thalamus, appears to be an important player in the pathophysiology of Parkinson's disease. Read the Editorial Highlight for this article on doi: 10.1111/jnc.12167. © 2013 International Society for Neurochemistry. Source

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