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Garcia-Matas S.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | De Vera N.,Institute Dinvestigacions Biomediques Of Barcelona Iibb | Aznar A.O.,Hospital Universitari Vall dHebron | Marimon J.M.,University of Barcelona | And 4 more authors.
Journal of Alzheimer's Disease | Year: 2010

Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease. Age is the main risk factor for sporadic AD, which is the most prevalent type. Amyloid-β peptide (Aβ) neurotoxicity is the proposed first step in a cascade of deleterious events leading to AD pathology and dementia. Glial cells play an important role in these changes. Astrocytes provide vital support to neurons and modulate functional synapses. Therefore, the toxic effects of Aβ on astrocytes might promote neurodegenerative changes that lead to AD. Aging reduces astrocyte antioxidant defenses and induces oxidative stress. We studied the effects of Aβ {42} on cultures of human astrocytes in the presence or absence of the following pro-oxidant agents: buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, and FeSO{4}, which liberates redox active iron. Pro-oxidant conditions potentiated Aβ toxicity, as shown by the generation of free radicals, inflammatory changes, and apoptosis. Similar treatments were assessed in rats in vivo. A combination of Aβ {40} and Aβ {42} or Aβ {42} alone was infused intracerebroventricularly for 4 weeks. Other animal groups were also infused with BSO and FeSO{4}. A long-term analysis that ended 4 months later showed greater cognitive impairment in the Morris water maze task, which was induced by Aβ plus pro-oxidant agent treatments. Pro-oxidant agents also potentiated brain tissue pathology. This was demonstrated in histological studies that showed highly increased astrocyte reactivity in AD-vulnerable areas, Aβ deposits, and oxidative damage of AD-sensitive hippocampal neurons. To increase our understanding of AD, experimental models should be used that mimic age-related brain changes, in which age-related oxidative stress potentiates the effects of Aβ. © 2010 - IOS Press and the authors. Source


Villegas E.,Hospital Clinic | Estruch R.,Hospital Clinic | Estruch R.,CIBER ISCIII | Mengod G.,IIBB | Cortes R.,IIBB
Addiction Biology | Year: 2011

Specific binding of [ 3H]MK801 to N-methyl-D-aspartate (NMDA) receptors in the frontal cortex and hippocampus (CA1 and gyrus dentatus) was measured by receptor autoradiography in 16 Caucasian chronic alcohol consumers free of clinical manifestations of alcoholism, and compared with 16 Caucasian control subjects. Binding densities were not significantly different between heavy and moderate drinkers, neither between alcohol consumers that were abstinent or non-abstinent before death, nor between ethanol drinkers and controls. Continued alcohol consumption, in the absence of hepatic, neurologic or psychiatric disorders related to alcoholism, does not alter the binding properties of NMDA receptors in the brain areas studied. © 2010 Society for the Study of Addiction. Source


Martinez-Boubeta C.,ICMAB CSIC | Martinez-Boubeta C.,University of Barcelona | Balcells L.,ICMAB CSIC | Cristofol R.,IIBB | And 12 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2010

A one-step process for the production of nanoparticles presenting advanced magnetic properties can be achieved using vapor condensation. In this article, we report on the fabrication of Fe particles covered by a uniform MgO epitaxial shell. MgO has a lower surface energy than Fe, which results in a core-shell crystal formation. The particles satisfy a few of technical requirements for the practical use in real clinics, such as a high biocompatibility in living cells in-vitro, an injection through blood vessels without any clothing problems in murine model, a high absorption rate for magnetic hyperthermia at small particle concentration, and the potential to be used as contrast agent in the field of diagnostic magnetic imaging. They are also able to be used in drug delivery and magnetic-activated cell sorting. From the Clinical Editor: In this paper, the authors report on the synthesis of Fe particles covered by a uniform MgO epitaxial shell resulting in a core-shell crystal formation. The particles are proven to be useful as contrast agents for magnetic resonance imaging and have the potential to be useful as heating mediators for cancer therapy through hyperthermia. They also might be used in drug delivery and magnetic-activated cell sorting. © 2010 Elsevier Inc. All rights reserved. Source


Slevin M.,Manchester Metropolitan University | Slevin M.,Research Center Cardiovascular | Matou-Nasri S.,Manchester Metropolitan University | Turu M.,Research Center Cardiovascular | And 10 more authors.
Brain Pathology | Year: 2010

Native C-reactive protein (nCRP) is a pentameric oligo-protein and an acute phase reactant whose serum expression is increased in patients with inflammatory disease. We have identified by immunohistochemistry, significant expression of a tissue-binding insoluble modified version or monomeric form of CRP (mCRP) associated with angiogenic microvessels in peri-infarcted regions of patients studied with acute ischaemic stroke. mCRP, but not nCRP was expressed in the cytoplasm and nucleus of damaged neurons. mCRP co-localized with CD105, a marker of angiogenesis in regions of revascularisation. In vitro investigations demonstrated that mCRP was preferentially expressed in human brain microvessel endothelial cells following oxygen-glucose deprivation and mCRP (but not column purified nCRP) associated with the endothelial cell surface, and was angiogenic to vascular endothelial cells, stimulating migration and tube formation in matrigel more strongly than fibroblast growth factor-2. The mechanism of signal transduction was not through the CD16 receptor. Western blotting showed that mCRP stimulated phosphorylation of the key down-stream mitogenic signalling protein ERK12. Pharmacological inhibition of ERK12 phosphorylation blocked the angiogenic effects of mCRP. We propose that mCRP may contribute to the neovascularization process and because of its abundant presence, be important in modulating angiogenesis in both acute stroke and later during neuro-recovery. © 2009 International Society of Neuropathology. Source


Loncle C.,Aix - Marseille University | Bonjoch L.,IIBB | Folch-Puy E.,IIBB | Lopez-Millan M.B.,Aix - Marseille University | And 9 more authors.
Cancer Research | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering "druggable" molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3β, a wellknown mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiologic role for REG3β during pancreatitis and PDAC initiation. © 2015 AACR. Source

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