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1.
Neurobiol Dis ; 62: 521-32, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24184799

RESUMEN

Although Alzheimer's disease (AD) is usually sporadic, in a small proportion of cases it is familial and can be linked to mutations in ß-amyloid precursor protein (APP). Unlike the other genetic defects, the mutation [alanine-673→valine-673] (A673V) causes the disease only in the homozygous condition with enhanced amyloid ß (Aß) production and aggregation; heterozygous carriers remain unaffected. It is not clear how misfolding and aggregation of Aß is affected in vivo by this mutation and whether this correlates with its toxic effects. No animal models over-expressing the A673V-APP gene or alanine-2-valine (A2V) mutated human Aß protein are currently available. Using the invertebrate Caenorhabditis elegans, we generated the first transgenic animal model to express the human Aß1-40 wild-type (WT) in neurons or possess the A2V mutation (Aß1-40A2V). Insertion of an Aß-mutated gene into this nematode reproduced the homozygous state of the human pathology. Functional and biochemical characteristics found in the A2V strain were compared to those of transgenic C. elegans expressing Aß1-40WT. The expression of both WT and A2V Aß1-40 specifically reduced the nematode's lifespan, causing behavioral defects and neurotransmission impairment which were worse in A2V worms. Mutant animals were more resistant than WT to paralysis induced by the cholinergic agonist levamisole, indicating that the locomotor defect was specifically linked to postsynaptic dysfunctions. The toxicity caused by the mutated protein was associated with a high propensity to form oligomeric assemblies which accumulate in the neurons, suggesting this to be the central event involved in the postsynaptic damage and early onset of the disease in homozygous human A673V carriers.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/toxicidad , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/genética , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans , Humanos , Locomoción/efectos de los fármacos , Mutación , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética
2.
Pharmacol Res ; 73: 35-43, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23644256

RESUMEN

BACKGROUND: Co-administration of ibuprofen (IBU) and isosorbide dinitrate (ISDN) provides synergistic beneficial effects on dystrophic skeletal muscle. Whether this treatment has also cardioprotective effects in this disease was still unknown. AIMS: To evaluate the effects of co-administration of IBU and ISDN (a) on left ventricular (LV) structure and function, and (b) on cardiac inflammatory response and fibrosis in mdx mice. METHODS: Three groups of mice were studied: mdx mice treated with IBU (50 mg kg⁻¹)+ISDN (30 mg kg⁻¹) administered daily in the diet, mdx mice that received standard diet without drugs and wild type aged-matched mice. Animals were analysed after 10-11 months of treatment. Structural and functional parameters were evaluated by echocardiography while histological analyses were performed to evaluate inflammatory response, collagen deposition, cardiomyocyte number and area. RESULTS: Treatment for 10-11 months with IBU+ISDN preserved LV wall thickness and LV mass. Drug treatment also preserved the total number of cardiomyocytes in the LV and attenuated the increase in cardiomyocyte size, when compared to untreated mdx mice. Moreover, a trend towards a decreased number of inflammatory cells, a reduced LV myocardial interstitial fibrosis and an enhanced global LV function response to stress was observed in treated mdx mice. CONCLUSIONS: Treatment for 10-11 months with IBU+ISDN is effective in preventing the alterations in LV morphology of mdx mice while not reaching statistical significance on LV function and cardiac inflammation.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Ibuprofeno/administración & dosificación , Dinitrato de Isosorbide/administración & dosificación , Distrofia Muscular de Duchenne/tratamiento farmacológico , Donantes de Óxido Nítrico/administración & dosificación , Animales , Gasto Cardíaco , Ratones , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Duchenne/fisiopatología , Miocardio/patología , Volumen Sistólico , Función Ventricular Izquierda/efectos de los fármacos
3.
Cancer Res ; 82(7): 1423-1434, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35131872

RESUMEN

Ovarian cancer is the deadliest gynecologic cancer, and novel therapeutic options are crucial to improve overall survival. Here we provide evidence that impairment of oxidative phosphorylation (OXPHOS) can help control ovarian cancer progression, and this benefit correlates with expression of the two mitochondrial master regulators PGC1α and PGC1ß. In orthotopic patient-derived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC1α and PGC1ß (PGC1α/ß) fostered a unique transcriptional signature, leading to increased mitochondrial abundance, enhanced tricarboxylic acid cycling, and elevated cellular respiration that ultimately conferred vulnerability to OXPHOS inhibition. Treatment with the respiratory chain complex I inhibitor IACS-010759 caused mitochondrial swelling and ATP depletion that consequently delayed malignant progression and prolonged the lifespan of high PGC1α/ß-expressing OC-PDX-bearing mice. Conversely, low PGC1α/ß OC-PDXs were not affected by IACS-010759, thus pinpointing a selective antitumor effect of OXPHOS inhibition. The clinical relevance of these findings was substantiated by analysis of ovarian cancer patient datasets, which showed that 25% of all cases displayed high PGC1α/ß expression along with an activated mitochondrial gene program. This study endorses the use of OXPHOS inhibitors to manage ovarian cancer and identifies the high expression of both PGC1α and ß as biomarkers to refine the selection of patients likely to benefit most from this therapy. SIGNIFICANCE: OXPHOS inhibition in ovarian cancer can exploit the metabolic vulnerabilities conferred by high PGC1α/ß expression and offers an effective approach to manage patients on the basis of PGC1α/ß expression.


Asunto(s)
Neoplasias Ováricas , Fosforilación Oxidativa , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas de Unión al ARN , Animales , Femenino , Humanos , Ratones , Mitocondrias/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Oxidación-Reducción , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas de Unión al ARN/metabolismo
4.
Am J Physiol Renal Physiol ; 301(5): F1114-23, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21816757

RESUMEN

Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin-converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here, we assessed whether combination therapy with an ACE inhibitor and ET(A) receptor antagonist provided reno- and cardioprotection in rats with overt type 2 diabetes. Four groups of Zucker diabetic fatty (ZDF) rats were treated orally from 4 (when proteinuric) to 8 mo with vehicle, ramipril (1 mg/kg), sitaxsentan (60 mg/kg), and ramipril plus sitaxsentan. Lean rats served as controls. Combined therapy ameliorated proteinuria and glomerulosclerosis mostly as a result of the action of ramipril. Simultaneous blockade of ANG II and ET-1 pathways normalized renal monocyte chemoattractant protein-1 and interstitial inflammation. Cardiomyocyte loss, volume enlargement, and capillary rarefaction were prominent abnormalities of ZDF myocardium. Myocyte volume was reduced by ramipril and sitaxsentan, which also ameliorated heart capillary density. Drug combination restored myocardial structure and reestablished an adequate capillary network in the presence of increased cardiac expression of VEGF/VEGFR-1, and significant reduction of oxidative stress. In conclusion, in type 2 diabetes concomitant blockade of ANG II synthesis and ET-1 biological activity through an ET(A) receptor antagonist led to substantial albeit not complete renoprotection, almost due to the ACE inhibitor. The drug combination also showed cardioprotective properties, which however, were mainly dependent on the contribution of the ET(A) receptor antagonist through the action of VEGF.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Diabetes Mellitus Tipo 2/patología , Antagonistas de los Receptores de la Endotelina A , Corazón/efectos de los fármacos , Riñón/patología , Miocardio/patología , Animales , Glucemia/metabolismo , Peso Corporal/fisiología , Recuento de Células , Colágeno Tipo III/metabolismo , Diabetes Mellitus Tipo 2/genética , Endotelina-1/metabolismo , Hemodinámica/efectos de los fármacos , Inmunohistoquímica , Riñón/efectos de los fármacos , Riñón/metabolismo , Pruebas de Función Renal , Masculino , Células Musculares/efectos de los fármacos , Miocardio/metabolismo , Ratas , Ratas Zucker , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Sobrevida , Tirosina/análogos & derivados , Tirosina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
5.
Neurobiol Dis ; 43(2): 507-15, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21575722

RESUMEN

Pharmacological blockade of NR2B-containing N-methyl-d-aspartate receptors (NMDARs) during epileptogenesis reduces neurodegeneration provoked in the rodent hippocampus by status epilepticus. The functional consequences of NMDAR activation are crucially influenced by their synaptic vs extrasynaptic localization, and both NMDAR function and localization are dependent on the presence of the NR2B subunit and its phosphorylation state. We investigated whether changes in NR2B subunit phosphorylation, and alterations in its neuronal membrane localization and cellular expression occur during epileptogenesis, and if these changes are involved in neuronal cell loss. We also explored NR2B subunit changes both in the acute phase of status epilepticus and in the chronic phase of spontaneous seizures which encompass the epileptogenesis phase. Levels of Tyr1472 phosphorylated NR2B subunit decreased in the post-synaptic membranes from rat hippocampus during epileptogenesis induced by electrical status epilepticus. This effect was concomitant with a reduced interaction between NR2B and post-synaptic density (PSD)-95 protein, and was associated with decreased CREB phosphorylation. This evidence suggests an extra-synaptic localization of NR2B subunit in epileptogenesis. Accordingly, electron microscopy showed increased NR2B both in extra-synaptic and pre-synaptic neuronal compartments, and a concomitant decrease of this subunit in PSD, thus indicating a shift in NR2B membrane localization. De novo expression of NR2B in activated astrocytes was also found in epileptogenesis indicating ectopic receptor expression in glia. The NR2B phosphorylation changes detected at completion of status epilepticus, and interictally in the chronic phase of spontaneous seizures, are predictive of receptor translocation from synaptic to extrasynaptic sites. Pharmacological blockade of NR2B-containing NMDARs by ifenprodil administration during epileptogenesis significantly reduced pyramidal cell loss in the hippocampus, showing that the observed post-translational and cellular changes of NR2B subunit contribute to excitotoxicity. Therefore, pharmacological targeting of misplaced NR2B-containing NMDARs, or prevention of these NMDAR changes, should be considered to block excitotoxicity which develops after various pro-epileptogenic brain injuries.


Asunto(s)
Epilepsia/metabolismo , Hipocampo/metabolismo , Neurotoxinas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Técnicas de Cultivo de Órganos , Fosforilación/fisiología , Subunidades de Proteína/metabolismo , Subunidades de Proteína/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Membranas Sinápticas/metabolismo , Transmisión Sináptica/fisiología
6.
Neurobiol Dis ; 40(2): 424-31, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20637283

RESUMEN

The accumulation and deposition of amyloid beta (Aß) peptide in extracellular dense plaques in the brain is a key phase in Alzheimer's disease (AD). Small oligomeric forms of Aß are responsible for the toxicity and the early cognitive impairment observed in patients before the amyloid plaque deposits appear. It is essential for the development of an efficient cure for AD to identify compounds that interfere with Aß aggregation, counteracting the molecular mechanisms involved in conversion of the monomeric amyloid protein into oligomeric and fibrillar forms. Tetracyclines have been proposed for AD therapy, although their effects on the aggregation of Aß protein, particularly their ability to interact in vivo with the Aß oligomers and/or aggregates, remain to be understood. Using transgenic Caenorhabditis elegans as a simplified invertebrate model of AD, we evaluated the ability of tetracyclines to interfere with the sequence of events leading to Aß proteotoxicity. The drugs directly interact with the Aß assemblies in vivo and reduce Aß oligomer deposition, protecting C. elegans from oxidative stress and the onset of the paralysis phenotype. These effects were specific, dose-related and not linked to any antibiotic activity, suggesting that the drugs might offer an effective therapeutic strategy to target soluble Aß aggregates.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Tetraciclina/farmacología , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Caenorhabditis elegans , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores de la Síntesis de la Proteína/administración & dosificación , Tetraciclina/administración & dosificación
7.
MethodsX ; 7: 100771, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31993338

RESUMEN

The identification of new treatments for primary pulmonary arterial hypertension (PAH) is a critical unmet need since there is no a definitive cure for this disease yet. Due to the complexity of PAH, a wide set of methods are necessary to assess the response to a pharmacological intervention. Thus, a rigorous protocol is crucial when experimental studies are designed. In the present experimental protocol, a stepwise approach was followed in a monocrotaline-induced PAH model in the rat, moving from the dose finding study of treatment compounds to the recognition of the onset of disease manifestation, in order to identify when to start a curative treatment. A complete multidimensional evaluation of treatment effects represented the last step. The primary study endpoint was the change in right ventricular systolic pressure after 14 days of treatment; echocardiographic and biohumoral markers together with heart and pulmonary arterial morphometric parameters were considered as secondary efficacy and/or safety endpoints and for the evaluation of the biologic coherence in the different results.

8.
J Am Heart Assoc ; 9(24): e016494, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33289464

RESUMEN

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4-hour post-resuscitation ventilation with: 70% nitrogen-30% oxygen (control); 50% Ar-20% nitrogen-30% oxygen (Ar 50%); and 70% Ar-30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety-six-hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group (P<0.0001). Histology showed less neuronal degeneration in the cortex (P<0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus (P=0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation (P<0.05), were present in Ar-treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release (P<0.01). Conclusions Post-resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no-flow duration. Benefits are greater after Ar 70% than Ar 50%.


Asunto(s)
Argón/farmacología , Reanimación Cardiopulmonar/métodos , Paro Cardíaco/terapia , Recuperación de la Función/efectos de los fármacos , Ventilación/métodos , Animales , Argón/administración & dosificación , Biomarcadores/sangre , Encéfalo/patología , Encéfalo/ultraestructura , Lesiones Encefálicas/sangre , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/fisiopatología , Reanimación Cardiopulmonar/estadística & datos numéricos , Estudios de Casos y Controles , Hemodinámica/efectos de los fármacos , Masculino , Modelos Animales , Fármacos Neuroprotectores/farmacología , Nitrógeno/administración & dosificación , Oxígeno/administración & dosificación , Recuperación de la Función/fisiología , Seguridad , Análisis de Supervivencia , Porcinos , Resultado del Tratamiento
9.
Circulation ; 117(8): 1055-64, 2008 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-18268142

RESUMEN

BACKGROUND: Despite widespread clinical use as a prognostic marker in ischemic heart disorders, the actual pathogenetic role of the short pentraxin, C-reactive protein, has not undergone stringent genetic testing because of evolutionary divergence between mouse and humans. The long pentraxin PTX3 is conserved in evolution, is expressed in the heart under inflammatory conditions, and is a candidate prognostic marker in acute myocardial infarction. It was therefore important to assess whether PTX3 plays a pathogenetic role in acute myocardial infarction. METHODS AND RESULTS: In a model of acute myocardial infarction caused by coronary artery ligation and reperfusion, tissue mRNA expression and circulating levels of PTX3 increased. The interleukin-1R-MyD88 pathway plays a pivotal role in the induction of PTX3 transcript after ischemia. ptx3-deficient mice showed exacerbated heart damage (33% larger infarcts in null mice; P=0.0047). Increased myocardial damage in ptx3-deficient mice was associated with a greater no-reflow area, increased neutrophil infiltration, decreased number of capillaries, and increased number of apoptotic cardiomyocytes. In addition, ptx3-deficient mice with acute myocardial infarction showed higher circulating levels of interleukin-6 and increased C3 deposition in lesional tissue. The phenotype was reversed by exogenous PTX3. CONCLUSIONS: Thus, PTX3 plays a nonredundant, regulatory, cardioprotective role in acute myocardial infarction in mice. Our results suggest that modulation of the complement cascade contributes to the cardioprotective function of PTX3.


Asunto(s)
Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Animales , Complemento C3/metabolismo , Modelos Animales de Enfermedad , Interleucina-1 , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Infarto del Miocardio/inmunología , Daño por Reperfusión Miocárdica/inmunología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Neutrófilos/inmunología , Fenotipo , Pronóstico , ARN Mensajero/metabolismo
10.
Eur J Pharmacol ; 865: 172777, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31697933

RESUMEN

Novel pharmacological approaches are needed to improve outcomes of patients with idiopathic pulmonary hypertension. Rho-associated protein kinase (ROCK) inhibitors have shown beneficial effects in preclinical models of pulmonary arterial hypertension (PAH), because of their role in the regulation of pulmonary artery vasoconstrictor tone and remodeling. We compared a ROCK inhibitor, Y-27632, for the first time with the dual endothelin receptor antagonist, macitentan, in a monocrotaline-induced rat pulmonary hypertension model. Different methods (echocardiography, hemodynamics, histology of right ventricle and pulmonary vessels, and circulating biomarkers) showed consistently that 100 mg/kg daily of Y-27632 and 10 mg/kg daily of macitentan slowed the progression of PAH both at the functional and structural levels. Treatments started on day 14 after monocrotaline injection and lasted 14 days. The findings of all experimental methods show that the selective ROCK inhibitor Y-27632 has more pronounced effects than macitentan, but a major limitation to its use is its marked peripheral vasodilating action.


Asunto(s)
Amidas/uso terapéutico , Antagonistas de los Receptores de Endotelina/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Ventrículos Cardíacos/patología , Hemodinámica/efectos de los fármacos , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Masculino , Monocrotalina , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Ratas Wistar
11.
J Agric Food Chem ; 66(26): 6860-6868, 2018 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-29877708

RESUMEN

There is growing concern about the presence of nanoparticles (NPs) in titanium dioxide (TiO2) as food additive (E171). To realistically estimate the number and the amount of TiO2 NPs ingested with food, we applied a transmission electron microscopy method combined with inductively coupled plasma optical emission spectrometry. Different percentages of TiO2 NPs (6-18%) were detected in E171 from various suppliers. In the eight chewing gums analyzed as food prototypes, TiO2 NPs were absent in one sample and ranged 0.01-0.66 mg/gum, corresponding to 7-568 billion NPs/gum, in the other seven. We estimated that the mass-based TiO2 NPs ingested with chewing gums by the European population ranged from 0.28 to 112.40 µg/kg b.w./day, and children ingested more nanosized titanium than adolescents and adults. Although this level may appear negligible it corresponds to 0.1-84 billion TiO2 NPs/kg b.w/day, raising important questions regarding their potential accumulation in the body, possibly causing long-term effects on consumers' health.


Asunto(s)
Goma de Mascar/análisis , Aditivos Alimentarios/análisis , Nanopartículas/análisis , Titanio/análisis , Humanos , Microscopía Electrónica de Transmisión , Tamaño de la Partícula
12.
Shock ; 49(2): 205-212, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28562475

RESUMEN

INTRODUCTION: The study investigated the effect of untreated cardiac arrest (CA), that is, "no-flow" time, on postresuscitation myocardial and neurological injury, and survival in a pig model to identify an optimal duration that adequately reflects the most frequent clinical scenario. METHODS: An established model of myocardial infarction followed by CA and cardiopulmonary resuscitation was used. Twenty-two pigs were subjected to three no-flow durations: short (8-10 min), intermediate (12-13 min), and long (14-15 min). Left ventricular ejection fraction (LVEF) was assessed together with thermodilution cardiac output (CO) and high sensitivity cardiac troponin T (hs-cTnT). Neurological impairment was evaluated by neurological scores, serum neuron specific enolase (NSE), and histopathology. RESULTS: More than 60% of animals survived when the duration of CA was ≤13 min, compared to only 20% for a duration ≥14 min. Neuronal degeneration and neurological scores showed a trend toward a worse recovery for longer no-flow durations. No animals achieved a good neurological recovery for a no-flow ≥14 min, in comparison to a 56% for a duration ≤13 min (P = 0.043). Serum NSE levels significantly correlated with the no-flow duration (r = 0.892). Longer durations of CA were characterized by lower LVEF and CO compared to shorter durations (P < 0.05). The longer was the no-flow time, the higher was the number of defibrillations delivered (P = 0.043). The defibrillations delivered significantly correlated with LVEF and plasma hs-cTnT. CONCLUSIONS: Longer no-flow durations caused greater postresuscitation myocardial and neurological dysfunction and reduced survival. An untreated CA of 12-13 min may be an optimal choice for a clinically relevant model.


Asunto(s)
Paro Cardíaco/patología , Animales , Reanimación Cardiopulmonar , Modelos Animales de Enfermedad , Paro Cardíaco/terapia , Masculino , Porcinos
13.
Life Sci ; 81(12): 951-9, 2007 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-17825849

RESUMEN

Diabetes aggravates the clinical severity and represents an additional independent risk factor of hypertension. Since both diseases separately concur to cardiomyocyte apoptosis, a mechanism at least partly involving unbalanced oxidative stress, we investigated whether the combination of diabetes and hypertension potentiated cardiac cell death in experimental models, compared to either disease alone. We also evaluated the short-term effects of different drugs in these models. Streptozotocin-induced diabetic normotensive (WKY) or hypertensive (SHR) rats were treated for one week with a DA(2)/alpha(2) agonist (CHF-1024), a selective beta1 adrenergic blocker (metoprolol), an angiotensin II-receptor blocker (valsartan) or a radical scavenger (tempol). In separate experiments, isolated cardiomyocytes were cultured in high glucose medium (25 mM) containing the same drugs. Although the number of apoptotic cardiomyocytes and the myocardial density of oxygen radicals were higher in non diabetic hypertensive than in normotensive controls, diabetes raised these variables to comparable absolute levels in both strains. All drugs except metoprolol significantly reduced apoptosis and oxidative stress in the diabetic animals of both strains and in the isolated myocytes cultured with high glucose. In conclusion, hypertensive rat is no more susceptible than its normotensive control to acute apoptosis induced by diabetes. Oxidative stress might be considered the common trigger for cardiac myocyte apoptosis in both conditions.


Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Apoptosis/efectos de los fármacos , Complicaciones de la Diabetes/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Hipertensión/tratamiento farmacológico , Metoprolol/farmacología , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Tetrazoles/farmacología , Valina/análogos & derivados , Animales , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/patología , Hipertensión/metabolismo , Hipertensión/patología , Masculino , Metoprolol/uso terapéutico , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Estreptozocina , Tetrazoles/uso terapéutico , Valina/farmacología , Valina/uso terapéutico , Valsartán
14.
J Card Fail ; 12(5): 375-80, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16762801

RESUMEN

BACKGROUND: Endothelin is elevated in heart failure and contributes to neurohormonal activation, hemodynamic deterioration, and cardiovascular remodeling. Here, we examined its prognostic value in a large population of patients with chronic heart failure. METHODS AND RESULTS: Big endothelin-1 (Big ET-1) and 4 other neurohormones were measured at study entry in 2359 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) and their concentrations related to outcome over a median follow-up of 23 months. Baseline concentration of Big ET-1 (median 0.80 pmol/L) was proportional to severity of disease (New York Heart Association class, left ventricular structure and function). High circulating concentrations of brain natriuretic peptide (BNP), creatinine and bilirubin, advanced New York Heart Association class, elevated body mass index, and the presence of atrial fibrillation were independently associated to higher concentrations of Big ET-1. Big ET-1 (ranking second just behind BNP among neurohormonal factors) was an independent predictor of outcome defined as all-cause mortality (hazard ratio 1.49, 95% CI 1.20-1.84, P = .0003) or the combined endpoint of mortality and morbidity (hazard ratio 1.43, 95% CI 1.20-1.69, P < .0001) and provided incremental prognostic value compared with BNP. CONCLUSIONS: In a large population of patients with symptomatic heart failure, the circulating concentration of Big ET-1, a precursor of the paracrine and bioactive peptide ET-1, was an independent marker of mortality and morbidity. In this setting, BNP remained the strongest neurohormonal prognostic factor.


Asunto(s)
Gasto Cardíaco Bajo/sangre , Gasto Cardíaco Bajo/mortalidad , Endotelina-1/sangre , Anciano , Gasto Cardíaco Bajo/fisiopatología , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Péptido Natriurético Encefálico/sangre , Concentración Osmolar , Pronóstico , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad
15.
Circ Res ; 95(9): 911-21, 2004 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-15472116

RESUMEN

Cardiac myocytes have been traditionally regarded as terminally differentiated cells that adapt to increased work and compensate for disease exclusively through hypertrophy. However, in the past few years, compelling evidence has accumulated suggesting that the heart has regenerative potential. Recent studies have even surmised the existence of resident cardiac stem cells, endothelial cells generating cardiomyocytes by cell contact or extracardiac progenitors for cardiomyocytes, but these findings are still controversial. We describe the isolation of undifferentiated cells that grow as self-adherent clusters (that we have termed "cardiospheres") from subcultures of postnatal atrial or ventricular human biopsy specimens and from murine hearts. These cells are clonogenic, express stem and endothelial progenitor cell antigens/markers, and appear to have the properties of adult cardiac stem cells. They are capable of long-term self-renewal and can differentiate in vitro and after ectopic (dorsal subcutaneous connective tissue) or orthotopic (myocardial infarction) transplantation in SCID beige mouse to yield the major specialized cell types of the heart: myocytes (ie, cells demonstrating contractile activity and/or showing cardiomyocyte markers) and vascular cells (ie, cells with endothelial or smooth muscle markers).


Asunto(s)
Separación Celular/métodos , Miocardio/citología , Miocitos Cardíacos/citología , Células Madre/citología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Agregación Celular , Diferenciación Celular , División Celular , Células Cultivadas/citología , Niño , Preescolar , Células Clonales/citología , Técnicas de Cocultivo , Citometría de Flujo , Genes Reporteros , Humanos , Inmunofenotipificación , Lactante , Recién Nacido , Ratones , Ratones Mutantes , Ratones SCID , Ratones Transgénicos , Persona de Mediana Edad , Contracción Miocárdica , Infarto del Miocardio/terapia , Organoides/citología , Ratas , Trasplante de Células Madre
16.
Life Sci ; 79(2): 121-9, 2006 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-16445948

RESUMEN

Blockade of the renin-angiotensin system (RAS) reduces cardiovascular morbidity and mortality in diabetic patients. Ang II-mediated generation of reactive oxygen species (ROS) has been suggested to be involved in several diabetic complications. We investigated whether the inhibition of Ang II production with an ACE inhibitor (ACEi) reduces oxidative stress and limits structural cardiovascular remodeling in a rat model of streptozotocin (STZ)-induced diabetes. Diabetic rats were treated for 7 weeks with an ACEi (lisinopril, 5 mg/kg/d), an antioxidant (N-acetyl-l-cysteine (NAC), 0.5 g/kg/d) and their combination. At sacrifice, ROS in the myocardium and thoracic aorta, LV myocyte number and size and aorta morphology were determined by quantitative histological methods. Superoxide and hydroxyl radical content, detected by dihydroethidium (DHE) and 8-hydroxydeoxyguanosine (8-OHdG), were 6.7 and 4.5-fold, respectively, higher in diabetic myocardium than in non-diabetic controls (p<0.001). The amount of superoxide was 5-fold higher in the thoracic aorta of diabetic rats compared to controls (p<0.001). Diabetes caused a modest increase in myocyte volume (+13%, p<0.01), a reduction of LV myocyte number (-43%, p<0.001), an accumulation of collagen around coronary arterioles (1.9-fold increase, p<0.01) and a decrease in arterial elastin/collagen ratio (-63%, p<0.001) compared to controls. Treatment with the ACEi attenuated ROS formation and prevented phenotypic changes in the heart (cardiomyocyte hypertrophy, perivascular fibrosis) and in the aorta of diabetic rats to the same extent as NAC. The absence of an additive effect, suggests a common mechanism of action, through the reduction of oxidative stress.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Sistema Cardiovascular/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Estrés Oxidativo/efectos de los fármacos , Angiotensina II/biosíntesis , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Peso Corporal/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Elastina/metabolismo , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Fibrosis , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Hemodinámica/efectos de los fármacos , Masculino , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Superóxidos/metabolismo
17.
Circulation ; 106(19): 2454-8, 2002 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-12417542

RESUMEN

BACKGROUND: Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly related to severity of and are independent predictors of outcome in heart failure. The long-term effects of angiotensin receptor blockers on BNP and NE in heart failure patients are not known. METHODS AND RESULTS: Both BNP and NE were measured in 4284 patients randomized to valsartan or placebo in the Valsartan Heart Failure Trial (Val-HeFT) at baseline and 4, 12, and 24 months after randomization. The effects of valsartan were tested by ANCOVA, controlling for baseline values and concomitant ACE inhibitors and/or beta-blockers. BNP and NE concentrations were similar at baseline in the 2 groups and were decreased by valsartan starting at 4 months and up to 24 months. BNP increased over time in the placebo group. At the end point, least-squares mean (+/-SEM) BNP increased from baseline by 23+/-5 pg/mL in the placebo group (n=1979) but decreased by 21+/-5 pg/mL (n=1940) in the valsartan group (P<0.0001). NE increased by 41+/-6 pg/mL (n=1979) and 12+/-6 pg/mL (n=1941) for placebo and valsartan, respectively (P=0.0003). Concomitant therapy with both ACE inhibitors and beta-blockers significantly reduced the effect of valsartan on BNP but not on NE (P for interaction=0.0223 and 0.2289, respectively). CONCLUSIONS: In Val-HeFT, the largest neurohormone study in patients with symptomatic chronic heart failure, BNP and NE rose over time in the placebo group. Valsartan caused sustained reduction in BNP and attenuated the increase in NE over the course of the study. These neurohormone effects of valsartan are consistent with the clinical benefits reported in Val-HeFT.


Asunto(s)
Antihipertensivos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Péptido Natriurético Encefálico/sangre , Norepinefrina/sangre , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Valina/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Enfermedad Crónica , Método Doble Ciego , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/sangre , Humanos , Masculino , Persona de Mediana Edad , Neurotransmisores/sangre , Tasa de Supervivencia , Tiempo , Valsartán
18.
Mol Neurobiol ; 45(2): 247-57, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22399241

RESUMEN

Neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal storage diseases characterized by neurological impairment and blindness. NCLs are almost always due to single mutations in different genes (CLN1-CLN8). Ubiquitous accumulation of undigested material and of a hydrophobic inner mitochondrial membrane protein, the subunit c of mitochondrial ATP synthase, has been described. Although protein mutation(s) in the endoplasmic reticulum-lysosomes axis can modify the trafficking and the recycling of different molecules, one of the upstream targets in these diseases may be represented by the balance of gene expression. To understand if and how neurons modify the levels of important genes during the first phases of the disease, it is important to characterize the mechanisms of neurodegeneration. Due to the impossibility of performing this analysis in humans, alternative models of investigation are required. In this study, a mouse model of human NCL8, the mnd mouse has been employed. The mnd mice recapitulate many clinical and histopathological features described in NCL8 patients. In this study, we found an altered expression of different genes in both central and peripheral organs associated with lipopigment accumulation. This is a preliminary approach, which could also be of interest in providing new diagnostic tools for NCLs.


Asunto(s)
Sistema Nervioso Central/metabolismo , Regulación de la Expresión Génica/fisiología , Lipofuscina/genética , Lipofuscina/metabolismo , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Animales , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Lipofuscina/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Distribución Tisular/genética , Distribución Tisular/fisiología
19.
Toxicol Lett ; 202(3): 226-36, 2011 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-21354282

RESUMEN

2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD) causes abnormalities during heart development. Cardiomyocytes derived from embryonic stem (ES) cells are a robust model for the study of early cardiomyogenesis. Here, we evaluated the effects of TCDD at key stages during the differentiation of mouse ES cells into cardiomyocytes analysing: (i) the transcription of lineage differentiation (Brachyury, Nkx-2.5, Actc-1), cardiac-specific (Alpk3, cTnT, cTnI, cTnC) and detoxification phase I (Cyp1A1, Cyp1A2 and Cyp1B1) and phase II (Nqo1, Gsta1 and Ugt1a6) genes; (ii) the global gene expression; (iii) the ultrastructure of ES-derived cardiomyocytes; (iv) level of ATP production and (v) the immunolocalisation of sarcomeric α-actinin, ß-myosin heavy chain and cTnT proteins. We show that TCDD affects the differentiation of ES cells into cardiomyocytes at several levels: (1) induces the expression of phase I genes; (2) down-regulates a group of heart-specific genes, some involved in the oxidative phosphorylation pathway; (3) reduces the efficiency of differentiation; (4) alters the arrangement of mitochondria, that show twisted and disrupted cristae, and of some sarcomeres, with misalignement or disarrangement of the myofibrillar organisation and (5) reduces ATP production. This study provides novel evidences that TCDD impairs cardiomyocyte differentiation. Sarcomeres and mitochondria could be a target for dioxin toxicity, their disruption representing a possible mechanism developing cardiac injury.


Asunto(s)
Cuerpos Embrioides/efectos de los fármacos , Células Madre Embrionarias/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Miocitos Cardíacos/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Teratógenos/toxicidad , Adenosina Trifosfato/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Regulación hacia Abajo/efectos de los fármacos , Cuerpos Embrioides/citología , Cuerpos Embrioides/metabolismo , Células Madre Embrionarias/fisiología , Enzimas/genética , Enzimas/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Fase I de la Desintoxicación Metabólica/genética , Fase II de la Desintoxicación Metabólica/genética , Ratones , Microscopía Electrónica de Transmisión , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , Análisis de Secuencia por Matrices de Oligonucleótidos , Transcripción Genética/efectos de los fármacos
20.
J Alzheimers Dis ; 21(4): 1367-81, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21504138

RESUMEN

Synaptic dysfunction is an early event in the development of Alzheimer's disease (AD) and relates closely to the cognitive impairment characterizing this neurodegenerative process. A causative association has been proposed, largely on the basis of in vitro studies, between memory decline, soluble amyloid-ß (Aß) oligomers and alterations of glutamatergic neurotransmission. We aimed here to characterize in vivo N-methyl-D-aspartate receptor (NMDAR)-mediated signaling, at an early stage of AD, before extracellular amyloid plaques are deposited. We assessed the functional link between cognitive abilities and NMDAR-mediated pharmacological responses of six-month-old AßPP23 transgenic mice (AßPP23tg), overexpressing the human amyloid-ß protein precursor carrying the Swedish double mutation. We found evidence of cognitive impairments in these mice, indicated by deficits in the delayed-non-matching-to-place task. Alterations of NMDAR-mediated signaling in this mouse model were confirmed by the reduced sensitivity of motor-activation and working memory to pharmacological inhibition of NMDAR activity. At the molecular level, AßPP23tg mice show hippocampal alterations in the trafficking of synaptic NMDAR subunits NR2A and NR2B and at an ultrastructural analysis show Aß oligomers intracellularly localized in the synaptic compartments. Importantly, the behavioral and biochemical alterations of NMDAR signaling are associated with the inhibition of long-term synaptic potentiation and inversion of metaplasticity at CA1 synapses in hippocampal slices from AßPP23tg mice. These results indicate a general impairment of synaptic function and learning and memory in young AßPP23tg mice with Aß oligomers but no amyloid plaques.


Asunto(s)
Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Trastornos del Conocimiento/genética , Plasticidad Neuronal , Fragmentos de Péptidos/genética , Placa Amiloide/genética , Sinapsis/genética , Animales , Conducta Animal/fisiología , Trastornos del Conocimiento/fisiopatología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal/genética , Placa Amiloide/patología , Sinapsis/patología
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