Oxidative Stress: A Pathogenic Mechanism for Niemann-Pick Type C Disease

Niemann-Pick type C (NPC) disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of oxidative stress markers in the serumof NPC patients. Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage. Another possible source of reactive species in NPC is the diminished activity of different antioxidant enzymes. Moreover, because NPC is mainly caused by the accumulation of free cholesterol, oxidized cholesterol derivatives produced by oxidative stress may contribute to the pathogenesis of the disease

Role of the Wnt receptor Frizzled-1 in presynaptic differentiation and function

<p>Abstract</p> <p>Background</p> <p>The <it>Wnt </it>signaling pathway regulates several fundamental developmental processes and recently has been shown to be involved in different aspects of synaptic differentiation and plasticity. Some <it>Wnt </it>signaling components are localized at central synapses, and it is thus possible that this pathway could be activated at the synapse.</p> <p>Results</p> <p>We examined the distribution of the <it>Wnt </it>receptor Frizzled-1 in cultured hippocampal neurons and determined that this receptor is located at synaptic contacts co-localizing with presynaptic proteins. Frizzled-1 was found in functional synapses detected with FM1-43 staining and in synaptic terminals from adult rat brain. Interestingly, overexpression of Frizzled-1 increased the number of clusters of Bassoon, a component of the active zone, while treatment with the extracellular cysteine-rich domain (CRD) of Frizzled-1 decreased Bassoon clustering, suggesting a role for this receptor in presynaptic differentiation. Consistent with this, treatment with the Frizzled-1 ligand <it>Wnt-3a </it>induced presynaptic protein clustering and increased functional presynaptic recycling sites, and these effects were prevented by co-treatment with the CRD of Frizzled-1. Moreover, in synaptically mature neurons <it>Wnt-3a </it>was able to modulate the kinetics of neurotransmitter release.</p> <p>Conclusion</p> <p>Our results indicate that the activation of the <it>Wnt </it>pathway through Frizzled-1 occurs at the presynaptic level, and suggest that the synaptic effects of the <it>Wnt </it>signaling pathway could be modulated by local activation through synaptic Frizzled receptors.</p

Synaptic Clustering of PSD-95 Is Regulated by c-Abl through Tyrosine Phosphorylation

The c-Abl tyrosine kinase is present in mouse brain synapses, but its precise synaptic function is unknown. We found that c-Abl levels in the rat hippocampus increase postnatally, with expression peaking at the first postnatal week. In 14 d in vitro hippocampal neuron cultures, c-Abl localizes primarily to the postsynaptic compartment, in which it colocalizes with the postsynaptic scaffold protein postsynaptic density protein-95 (PSD-95) in apposition to presynaptic markers. c-Abl associates with PSD-95, and chemical or genetic inhibition of c-Abl kinase activity reduces PSD-95 tyrosine phosphorylation, leading to reduced PSD-95 clustering and reduced synapses in treated neurons. c-Abl can phosphorylate PSD-95 on tyrosine 533, and mutation of this residue reduces the ability of PSD-95 to cluster at postsynaptic sites. Our results indicate that c-Abl regulates synapse formation by mediating tyrosine phosphorylation and clustering of PSD-95

Lysosomal vitamin E accumulation in Niemann–Pick type C disease

AbstractNiemann–Pick C disease (NPC) is a neuro-visceral lysosomal storage disorder mainly caused by genetic defects in the NPC1 gene. As a result of loss of NPC1 function large quantities of free cholesterol and other lipids accumulate within late endosomes and lysosomes. In NPC livers and brains, the buildup of lipids correlates with oxidative damage; however the molecular mechanisms that trigger it remain unknown. Here we study potential alterations in vitamin E (α-tocopherol, α-TOH), the most potent endogenous antioxidant, in liver tissue and neurons from NPC1 mice. We found increased levels of α-TOH in NPC cells. We observed accumulation and entrapment of α-TOH in NPC neurons, mainly in the late endocytic pathway. Accordingly, α-TOH levels were increased in cerebellum of NPC1 mice. Also, we found decreased mRNA levels of the α-TOH transporter, α-Tocopherol Transfer Protein (α-TTP), in the cerebellum of NPC1 mice. Finally, by subcellular fractionation studies we detected a significant increase in the hepatic α-TOH content in purified lysosomes from NPC1 mice. In conclusion, these results suggest that NPC cells cannot transport vitamin E correctly leading to α-TOH buildup in the endosomal/lysosomal system. This may result in a decreased bioavailability and impaired antioxidant function of vitamin E in NPC, contributing to the disease pathogenesis

Carbonic anhydrase inhibitors reduce cardiac dysfunction after sustained coronary artery ligation in rats

Background Two potent carbonic anhydrase (CA) inhibitors with widely differing membrane permeability, poorly diffusible benzolamide (BZ), and highly diffusible ethoxzolamide (ETZ) were assessed to determine whether they can reduce cardiac dysfunction in rats subjected to coronary artery ligation (CAL)-induced myocardial infarction. Methods and results Rats with evidence of heart failure (HF) at 32 weeks following a permanent left anterior coronary artery occlusion were treated with placebo, BZ, or ETZ (4 mg kg�day−1) for 4 weeks at which time left ventricular function and structure were evaluated. Lung weight/body weight (LW/BW) ratio increased in CAL rats by 17�1% vs. control, suggesting pulmonary edema. There was a trend for BZ and ETZ to ameliorate the increase in LW/BW by almost 50% (9�5% and 9�8%, respectively, versus CAL) (P=.16, NS). Echocardiographic assessment showed decreased left ventricular midwall shortening in HF rats, 21�1% vs. control 32�1%, which was improved by BZ to 29�1% and ETZ to 27�1%, and reduced endocardial shortening in HF rats 38�3% vs. control 62�1%, partially restored by BZ and ETZ to ~50%. Expression of the hypoxia-inducible membrane-associated CAIX isoform increased by ~60% in HF rat hearts, and this effect was blocked by ETZ. Conclusions We conclude that CAL-induced myocardial interstitial fibrosis and associated decline in left ventricular function were diminished with BZ or ETZ treatment. The reductions in cardiac remodeling in HF with both ETZ and BZ CA inhibitors suggest that inhibition of a membrane-bound CA appears to be the critical site for this protection.Fil: Vargas, Lorena Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Pinilla, Oscar Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Diaz, Romina Gisel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Sepúlveda, Diana Elizabeth. Universidad Favaloro. Facultad de Medicina. Departamento de Ciencias Básicas de la Patología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Swenson, Erik R.. University of Washington. School of Medicine; Estados UnidosFil: Perez, Nestor Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Alvarez, Bernardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentin

Structural and magnetic behavior of ferrogels obtained by freezing thawing of polyvinyl alcohol/poly (acrylic acid) (PAA)-coated iron oxide nanoparticles

Superparamagnetic ferrogels with high swelling ability and potential applications as solvent absorbers and stimuli-responsive drug delivery devices were obtained by a non-toxic and environmentally friendly route based on dispersion of poly(acrylic acid)-coated iron oxide nanoparticles (PAA-coated NPs) in poly(vinyl alcohol) (PVA) solutions followed by freezing–thawing. Presence of carboxylate groups arising from the PAA coating allowed hydrogen bonding formation between NPs and PVA and enabled the synthesis of optically homogenous, superparamagnetic materials formed by a homogenous distribution of NPs diffuse clusters in the PVA matrix. The addition of PAA-coated NPs produced a remarkable increase in crystallinity degree, thermal degradation and swelling percentage respect to the neat matrix, which demonstrates that ferrogels with improved properties can be obtained by this procedure. Thereafter, combination of a cryogenic technique with the use of non-toxic components and magnetic NPs coated by a pH sensitive polymer makes these ferrogels very promising for applications in the biomedical field.Fil: Moscoso Londoño, Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Tecnologías y Ciencias de la Ingeniería; Argentina. Universidad de Buenos Aires. Facultad de Ingenieria. Departamento de Fisica. Laboratorio de Sólidos Amorfos; ArgentinaFil: Gonzalez, Jimena Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación en Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de Mar del Plata; ArgentinaFil: Muraca, D.. Universidade Estadual de Campinas. Instituto de Física ’Gleb Wataghin’. Laboratorio de Materiais e Baixas Temperaturas; Brasil;Fil: Hoppe, Cristina Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación en Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de Mar del Plata; ArgentinaFil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación en Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de Mar del Plata; ArgentinaFil: López Quintela, A.. Universidad de Santiago de Compostela; España;Fil: Socolovsky, Leandro Martin. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto D/tec.y Cs.de la Ing.;Fil: Pirota, K. R.. Universidade Estadual de Campinas. Instituto de Física ’Gleb Wataghin’. Laboratorio de Materiais e Baixas Temperaturas; Brasil

Control de la corte penal internacional frente a la ley de justicia y paz

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Magnetic properties study of iron-oxide nanoparticles/PVA ferrogels with potential biomedical applications

A study of the magnetic behavior of maghemite nanoparticles (NPs) in polyvinyl alcohol (PVA) polymer matrices prepared by physical cross-linking is reported. The magnetic nanocomposites (ferrogels) were obtained by the in situ co-precipitation of iron salts in the presence of PVA polymer, and subsequently subjected to freezing-thawing cycles. The magnetic behavior of these ferrogels was compared with that of similar systems synthesized using the glutaraldehyde. This type of chemical cross-linking agents presents several disadvantages due to the presence of residual toxic molecules in the gel, which are undesirable for biological applications. Characteristic particle size determined by several techniques are in the range 7.9-9.3 nm. The iron oxidation state in the NPs was studied by X-ray absorption spectroscopy. Mössbauer measurements showed that the NP magnetic moments present collective magnetic excitations and superparamagnetic relaxations. The blocking and irreversibility temperatures of the NPs in the ferrogels, and the magnetic anisotropy constant, were obtained from magnetic measurements. An empirical model including two magnetic contributions (large NPs slightly departed from thermodynamic equilibrium below 200 K, and small NPs at thermodynamic equilibrium) was used to fit the experimental magnetization curves. A deviation from the superparamagnetic regime was observed. This deviation was explained on the basis of an interacting superparamagnetic model. From this model, relevant magnetic and structural properties were obtained, such as the magnitude order of the dipolar interaction energy, the NPs magnetic moment, and the number of NPs per ferrogel mass unit. This study contributes to the understanding of the basic physics of a new class of materials that could emerge from the PVA-based magnetic ferrogels.Fil: Mendoza Zélis, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto de Física La Plata; Argentina; Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina;Fil: Muraca, D.. Universidade Estadual de Campinas. Gleb Wataghin Physics Institute; Brasil;Fil: Gonzalez, Jimena Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación en Ciencia y Tecnología de Materiales (i); Argentina; Universidad Nacional de Lomas de Zamora. Facultad de Ingenieria; Argentina;Fil: Pasquevich, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto de Física La Plata; Argentina; Universidad Nacional de La Plata. Facultad de Ingenieria; Argentina;Fil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación en Ciencia y Tecnología de Materiales (i); Argentina; Universidad Nacional de Mar del Plata. Facultad de Ingenieria; Argentina;Fil: Pirota, K. R.. Universidade Estadual de Campinas. Gleb Wataghin Physics Institute; Brasil;Fil: Sanchez, Francisco Homero. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto de Física La Plata; Argentina; Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina

Ibero-American Consensus on Low- and No-Calorie Sweeteners: Safety, Nutritional Aspects and Benefits in Food and Beverages

International scientific experts in food, nutrition, dietetics, endocrinology, physical activity, paediatrics, nursing, toxicology and public health met in Lisbon on 2-4 July 2017 to develop a Consensus on the use of low- and no-calorie sweeteners (LNCS) as substitutes for sugars and other caloric sweeteners. LNCS are food additives that are broadly used as sugar substitutes to sweeten foods and beverages with the addition of fewer or no calories. They are also used in medicines, health-care products, such as toothpaste, and food supplements. The goal of this Consensus was to provide a useful, evidence-based, point of reference to assist in efforts to reduce free sugars consumption in line with current international public health recommendations. Participating experts in the Lisbon Consensus analysed and evaluated the evidence in relation to the role of LNCS in food safety, their regulation and the nutritional and dietary aspects of their use in foods and beverages. The conclusions of this Consensus were: (1) LNCS are some of the most extensively evaluated dietary constituents, and their safety has been reviewed and confirmed by regulatory bodies globally including the World Health Organisation, the US Food and Drug Administration and the European Food Safety Authority; (2) Consumer education, which is based on the most robust scientific evidence and regulatory processes, on the use of products containing LNCS should be strengthened in a comprehensive and objective way; (3) The use of LNCS in weight reduction programmes that involve replacing caloric sweeteners with LNCS in the context of structured diet plans may favour sustainable weight reduction. Furthermore, their use in diabetes management programmes may contribute to a better glycaemic control in patients, albeit with modest results. LNCS also provide dental health benefits when used in place of free sugars; (4) It is proposed that foods and beverages with LNCS could be included in dietary guidelines as alternative options to products sweetened with free sugars; (5) Continued education of health professionals is required, since they are a key source of information on issues related to food and health for both the general population and patients. With this in mind, the publication of position statements and consensus documents in the academic literature are extremely desirable