Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas

Barcelona, Spain

Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas

Barcelona, Spain
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Rojas S.,Institute dAlta Tecnologia | Martin A.,CIC Biomagune | Pareto D.,Institute dAlta Tecnologia | Herance J.R.,Institute dAlta Tecnologia | And 7 more authors.
Neuroscience | Year: 2011

Background and purpose: Positron emission tomography (PET) studies in humans have used 11C-flumazenil (FMZ) to assess neuronal viability after stroke. Here we aimed to study whether 11C-FMZ binding was sensitive to neuronal damage in the acute phase following ischemia/reperfusion in the rat brain. Experimental procedures: Transient (2 h followed by reperfusion) and permanent intraluminal middle cerebral artery occlusion was carried out. 11C-FMZ binding was studied by PET up to 24 h after the onset of ischemia. Tissue infarction was evaluated post-mortem at 24 h. Immunohistochemistry against a neuronal nuclei specific protein (NeuN) was performed to assess neuronal injury. Results: No decrease in 11C-FMZ binding was detected in the ipsilateral cortex up to 24 h post-ischemia in the model of transient occlusion despite the fact that rats developed cortical and striatal infarction, and neuronal injury was clearly apparent at this time. In contrast, 11C-FMZ binding was significantly depressed in the ipsilateral cortex at 24 h following permanent ischemia. Conclusions: This finding evidences that 11C-FMZ binding is not sensitive to neuronal damage on the acute phase of ischemia/reperfusion in the rat brain. © 2011 IBRO.


Bonjoch L.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Gironella M.,Institute dInvestigacions Biomediques August Pi i Sunyer IDIBAPS | Iovanna J.L.,Aix - Marseille University | Closa D.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas
Scientific Reports | Year: 2017

Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-sized membrane vesicles containing proteins and nucleic acids, which act as intercellular messengers. They play an important role in a variety of physiological processes, as well as in pathological situations such as inflammation or cancer. Here, we show that in the case of pancreatic ductal adenocarcinoma (PDAC), the healthy pancreatic tissue surrounding the tumor releases REG3β, a lectin that binds to the glycoproteins present in the surface of EVs, thus interfering with their uptake and internalization by target cells. In vitro, the disruption of the signaling mediated by EVs due to the presence of REG3β, prevents the EV-induced phenotypic switch in macrophages, inhibits the increased cell migration of cancer cells and reverses a number of metabolomic changes promoted by EVs. In vivo, the uptake of REG3β+ EVs by tumor cells is significantly impaired. Furthermore, it results in an increase of circulating REG3β+ EVs in blood of pancreatic cancer patients. Our findings highlight the effect of a lectin released by the healthy pancreatic tissue surrounding the tumor in modulating the EV-mediated interactions between different cell types in PDAC. © 2017 The Author(s).


Zaouali M.A.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Bardag-Gorce F.,University of California at Los Angeles | Carbonell T.,University of Barcelona | Oliva J.,University of California at Los Angeles | And 6 more authors.
Experimental and Molecular Pathology | Year: 2013

Background: The dramatic shortage of organs leads to consider the steatotic livers for transplantation although their poor tolerance against ischemia reperfusion injury (IRI). Ubiquitin proteasome system (UPS) inhibition during hypothermia prolongs myocardial graft preservation. The role of UPS in the liver IRI is not fully understood. Bortezomib (BRZ) treatment at non-toxic doses of rats fed alcohol chronically has shown protective effects by increasing liver antioxidant enzymes. We evaluated and compared both proteasome inhibitors BRZ and MG132 in addition to University of Wisconsin preservation solution (UW) at low and non-toxic dose for fatty liver graft protection against cold IRI. Experimental: Steatotic and non-steatotic livers have been stored in UW enriched with BRZ (100. nM) or MG132 (25 μM), for 24. h at 4 °C and then subjected to 2-h normothermic reperfusion (37 °C). Liver injury (AST/ALT), hepatic function (bile output; vascular resistance), mitochondrial damage (GLDH), oxidative stress (MDA), nitric oxide (NO) (e-NOS activity; nitrates/nitrites), proteasome chymotrypsin-like activity (ChT), and UPS (19S and 20S5 beta) protein levels have been measured. Results: ChT was inhibited when BRZ and MG132 were added to UW. Both inhibitors prevented liver injury (AST/ALT), when compared to UW alone. BRZ increased bile production more efficiently than MG132. Only BRZ decreased vascular resistance in fatty livers, which correlated with an increase in NO generation (through e-NOS activation) and AMPK phosphorylation. GLDH and MDA were also prevented by BRZ. In addition, BRZ inhibited adiponectin, IL-1, and TNF alpha, only in steatotic livers. Conclusion: MG132 and BRZ, administrated at low and non toxic doses, are very efficient to protect fatty liver grafts against cold IRI. The benefits of BRZ are more effective than those of MG132. This evidenced for the first time the potential use of UPS inhibitors for the preservation of marginal liver grafts and for future applications in the prevention of IRI. © 2013 Elsevier Inc.


Padrissa-Altes S.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Zaouali M.A.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Bartrons R.,University of Barcelona | Rosello-Catafau J.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Rosello-Catafau J.,Institute dInvestigacions Biomediques August Pi i Sunyer
Clinical Science | Year: 2012

In the present Hypothesis article, we summarize and present data from the literature that support our hypothesis on the potential mechanisms by which UPS (ubiquitin-proteasome system) inhibitors reduce I/R (ischaemia/reperfusion) injury in the liver. I/R is the main cause of primary liver failure and, consequently, minimizing the detrimental effects of this process could increase the number of suitable transplantation grafts and also enhance the survival rate of patients after liver transplantation. A potential strategy to reduce I/R injury is the use of UPS inhibitors either as additives to preservation solutions or as drugs administered to patients. However, there is still controversy over whether the use of UPS inhibitors is beneficial or deleterious with regard to liver injury. From our experience and the few studies that have investigated the role of UPS in hepatic I/R, we believe that the use of UPS inhibitors is a potential strategy to reduce I/R injury in liver transplantation and graft preservation. We hypothesize that one of the main mechanisms of action of UPS inhibitors may be the up-regulation of AMPK (AMP-activated protein kinase) activity and the consequent down-regulation of mTOR (mammalian target of rapamycin), which may finally influence autophagy and preserve the energy state of the cell. © 2012 The Author(s).


Puig J.,Hospital Universitari Dr Josep Trueta | Puig J.,University of Barcelona | Pedraza S.,Hospital Universitari Dr Josep Trueta | Demchuk A.,University of Calgary | And 9 more authors.
American Journal of Neuroradiology | Year: 2012

BACKGROUND AND PURPOSE: Little is known about the factors that determine recanalization after intravenous thrombolysis. We assessed the value of thrombus Hounsfield unit quantification as a predictive marker of stroke subtype and MCA recanalization after intravenous rtPA treatment. MATERIALS AND METHODS: NCCT scans and CTA were performed on patients with MCA acute stroke within 4.5 hours of symptom onset. Demographics, stroke severity, vessel hyperattenuation, occlusion site, thrombus length, and time to thrombolysis were recorded. Stroke origin was categorized as LAA, cardioembolic, or indeterminate according to TOAST criteria. Two blinded neuroradiologists calculated the Hounsfield unit values for the thrombus and contralateral MCA segment. We used ROC curves to determine the rHU cutoff point to discriminate patients with successful recanalization from those without. We assessed the accuracy (sensitivity, specificity, and positive and negative predictive values) of rHU in the prediction of recanalization. RESULTS: Of 87 consecutive patients, 45 received intravenous rtPA and only 15 (33.3%) patients had acute recanalization. rHU values and stroke mechanism were the highest predictive factors of recanalization. The Matthews correlation coefficient was highest for rHU (0.901). The sensitivity, specificity, and positive and negative predictive values for lack of recanalization after intravenous rtPA for rHU ≤ 1.382 were 100%, 86.67%, 93.75%, and 100%, respectively. LAA thrombi had lower rHU than cardioembolic and indeterminate stroke thrombi (P = .004). CONCLUSIONS: The Hounsfield unit thrombus measurement ratio can predict recanalization with intravenous rtPA and may have clinical utility for endovascular treatment decision making.


Puig J.,Hospital Universitari Dr Josep Trueta | Puig J.,Autonomous University of Barcelona | Pedraza S.,Hospital Universitari Dr Josep Trueta | Blasco G.,Hospital Universitari Dr Josep Trueta | And 8 more authors.
American Journal of Neuroradiology | Year: 2011

BACKGROUND AND PURPOSE: Early prediction of motor outcome is of interest in stroke management. We aimed to determine whether lesion location at DTT is predictive of motor outcome after acute stroke and whether this information improves the predictive accuracy of the clinical scores. MATERIALS AND METHODS: We evaluated 60 consecutive patients within 12 hours of middle cerebral artery stroke onset. We used DTT to evaluate CST involvement in the motor cortex and premotor cortex, centrum semiovale, corona radiata, and PLIC and in combinations of these regions at admission, at day 3, and at day 30. Severity of limb weakness was assessed by using the motor subindex scores of the National Institutes of Health Stroke Scale (5a, 5b, 6a, 6b). We calculated volumes of infarct and fractional anisotropy values in the CST of the pons. RESULTS: Acute damage to the PLIC was the best predictor associated with poor motor outcome, axonal damage, and clinical severity at admission (P < .001). There was no significant correlation between acute infarct volume and motor outcome at day 90 (P = .176, r = 0.485). The sensitivity, specificity, and positive and negative predictive values of acute CST involvement at the level of the PLIC for motor outcome at day 90 were 73.7%, 100%, 100%, and 89.1%, respectively. In the acute stage, DTT predicted motor outcome at day 90 better than the clinical scores (R2 = 75.50, F = 80.09, P < .001). CONCLUSIONS: In the acute setting, DTT is promising for stroke mapping to predict motor outcome. Acute CST damage at the level of the PLIC is a significant predictor of unfavorable motor outcome. Copyright © 2011 by the American Society of Neuroradiology.


Gresa-Arribas N.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Vieitez C.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Dentesano G.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Serratosa J.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | And 2 more authors.
PLoS ONE | Year: 2012

Neuron-microglia co-cultures treated with pro-inflammatory agents are a useful tool to study neuroinflammation in vitro, where to test the potential neuroprotective effect of anti-inflammatory compounds. However, a great diversity of experimental conditions can be found in the literature, making difficult to select the working conditions when considering this approach for the first time. We compared the use of neuron-primary microglia and neuron-BV2 cells (a microglial cell line) co-cultures, using different neuron:microglia ratios, treatments and time post-treatment to induce glial activation and derived neurotoxicity. We show that each model requires different experimental conditions, but that both neuron-BV2 and neuron-primary microglia LPS/IFN-γ-treated co-cultures are good to study the potential neuroprotective effect of anti-inflammatory agents. The contribution of different pro-inflammatory parameters in the neurotoxicity induced by reactive microglial cells was determined. IL-10 pre-treatment completely inhibited LPS/IFN-γ-induced TNF-α and IL-6 release, and COX-2 expression both in BV2 and primary microglial cultures, but not NO production and iNOS expression. However, LPS/IFN-γ induced neurotoxicity was not inhibited in IL-10 pre-treated co-cultures. The inhibition of NO production using the specific iNOS inhibitor 1400 W totally abolished the neurotoxic effect of LPS/IFN-γ, suggesting a major role for NO in the neurotoxic effect of activated microglia. Consequently, among the anti-inflammatory agents, special attention should be paid to compounds that inhibit NO production. © 2012 Gresa-Arribas et al.


Mahfoudh-Boussaid A.,University of Monastir | Tka K.H.A.,University of Monastir | Zaouali M.A.,University of Monastir | Rosello-Catafau J.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Ben Abdennebi H.,University of Monastir
Renal Failure | Year: 2014

Renal ischemia reperfusion (I/R) injury, which occurs during renal surgery or transplantation, is the major cause of acute renal failure. Trimetazidine (TMZ), an anti-ischemic drug, protects kidney against the deleterious effects of I/R. However its protective mechanism remains unclear. The aim of this study is to examine the relevance of Akt, endothelial nitric oxide synthase (eNOS), and hypoxia inducible factor-1α (HIF-1α) on TMZ induced protection of kidneys against I/R injury. Wistar rats were subjected to 60 min of warm renal ischemia followed by 120 min of reperfusion, or to intraperitoneal injection of TMZ (3 mg/kg) 30 min before ischemia. In sham operated group renal pedicles were only dissected. Compared to I/R, TMZ treatment decreased lactate dehydrogenase (845 ± 13 vs. 1028 ± 30 U/L). In addition, creatinine clearance and sodium reabsorption rates reached 105 ± 12 versus 31 ± 11 μL/min/g kidney weight and 95 ± 1 versus 68 ± 5%, respectively. Besides, we noted a decrease in malondialdehyde concentration (0.33 ± 0.01 vs. 0.59 ± 0.03 nmol/mg of protein) and an increase in glutathione concentration (2.6 ± 0.2 vs. 0.93 ± 0.16 μg GSH/mg of protein), glutathione peroxidase (95 ± 4 vs. 61 ± 3 μg GSH/min/mg of protein), and superoxide dismutase (25 ± 3 vs. 11 ± 2 U/mg of protein) and catalase (91 ± 12 vs. 38 ± 9 μmol/min/mg of protein) activities. Parallely, we noted a significant increase in p-Akt, eNOS, nitrite and nitrate (18 ± 2 vs. 8 ± 0.1 pomL/mg of protein), HIF-1α (333 ± 48 vs. 177 ± 14 μg/mg of protein) and heme oxygenase-1 (HO-1) levels regarding I/R. TMZ treatment improves renal tolerance to warm I/R. Such protection implicates an activation of Akt/eNOS signaling pathway, HIF-1α stabilization and HO-1 activation. © 2014 Informa Healthcare USA, Inc. All rights reserved.


Mahfoudh-Boussaid A.,University of Monastir | Zaouali M.A.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Hadj-Ayed K.,University of Monastir | Miled A.-H.,University of Monastir | And 3 more authors.
Journal of Biomedical Science | Year: 2012

Background: Although recent studies indicate that renal ischemic preconditioning (IPC) protects the kidney from ischemia-reperfusion (I/R) injury, the precise protective mechanism remains unclear. In the current study, we investigated whether early IPC could upregulate hypoxia inducible transcription factor-1 (HIF-1) expression and could reduce endoplasmic reticulum (ER) stress after renal I/R and whether pharmacological inhibition of nitric oxide (NO) production would abolish these protective effects. Methods. Kidneys of Wistar rats were subjected to 60 min of warm ischemia followed by 120 min of reperfusion (I/R group), or to 2 preceding cycles of 5 min ischemia and 5 min reperfusion (IPC group), or to intravenously injection of NG-nitro-L- arginine methylester (L-NAME, 5 mg/kg) 5 min before IPC (L-NAME+IPC group). The results of these experimental groups were compared to those of a sham-operated group. Sodium reabsorption rate, creatinine clearance, plasma lactate dehydrogenase (LDH) activity, tissues concentrations of malonedialdehyde (MDA), HIF-1 and nitrite/nitrate were determined. In addition, Western blot analyses were performed to identify the amounts of Akt, endothelial nitric oxide synthase (eNOS) and ER stress parameters. Results: IPC decreased cytolysis, lipid peroxidation and improved renal function. Parallely, IPC enhanced Akt phosphorylation, eNOS, nitrite/nitrate and HIF-1 levels as compared to I/R group. Moreover, our results showed that IPC increased the relative amounts of glucose-regulated protein 78 (GRP78) and decreased those of RNA activated protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 4 (ATF4) and TNF-receptor-associated factor 2 (TRAF2) as judged to I/R group. However, pre treatment with L-NAME abolished these beneficial effects of IPC against renal I/R insults. Conclusion: These findings suggest that early IPC protects kidney against renal I/R injury via reducing oxidative and ER stresses. These effects are associated with phosphorylation of Akt, eNOS activation and NO production contributing thus to HIF-1 stabilization. The beneficial impact of IPC was abolished when NO production is inhibited before IPC application. © 2012 Mahfoudh-Boussaid et al; licensee BioMed Central Ltd.


Tabka D.,University of Monastir | Bejaoui M.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | Javellaud J.,French Institute of Health and Medical Research | Rosello-Catafau J.,Institute Dinvestigacions Biomediques Of Barcelona Consejo Superior Of Investigaciones Cientificas | And 2 more authors.
World Journal of Gastroenterology | Year: 2015

AIM: To compare Institut Georges Lopez (IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury (IRI). METHODS: Two experimental models were used. In the first one, acetylcholine-induced endotheliumdependent relaxation (EDR) was measured in isolated ring preparations of rat hepatic arteries preserved or not in IGL-1 or Celsior solutions (24 h at 4 °C). To determine nitric oxide (NO) and cyclooxygenase EDR, hepatic arteries were incubated with L-NG-nitroarginine methyl ester (L-NAME), an inhibitor of endothelium nitric oxide synthase (eNOS), or with L-NAME plus indomethacin, an inhibitor of cyclooxygenase. In the second experiment, rat livers were cold-stored in IGL-1 or Celsior solutions for 24 h at 4 °C and then perfused "ex vivo " for 2 h at 37 °C. Liver injury was assessed by transaminase measurements, liver function by bile production and bromosulfophthalein clearance, oxidative stress by malondialdehyde levels and catalase activity and alterations in cell signaling pathways by pAkt, pAMPK, eNOS and MAPKs proteins level. RESULTS: After cold storage for 24 h with either Celsior or IGL-1, EDR was only slightly altered. In freshly isolated arteries, EDR was exclusively mediated by NO. However, cold-stored arteries showed NOand COX-dependent relaxation. The decrease in NO-dependent relaxation after cold storage was significantly more marked with Celsior. The second study indicated that IGL-1 solution obtained better liver preservation and protection against IRI than Celsior. Liver injury was reduced, function was improved and there was less oxidative stress. IGL-1 solution activated Akt and AMPK, which was concomitant with increased eNOS expression and nitrite/nitrate levels. Furthermore, MAPKs kinases were regulated in livers preserved with IGL-1 solution since reductions in p-p38, p-ERK and p-JNK protein levels were observed. CONCLUSION: IGL-1 solution preserved NO-dependent relaxation better than Celsior storage solution and enhanced liver graft preservation. © The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

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