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Hypertension is the most prevalent modifiable risk factor for stroke and is associated with worse functional outcomes. Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid (SAHA) modulates gene expression and has emerged as a promising therapeutic approach to reduce ischaemic brain injury. Here, we have tested the therapeutic potential of SAHA administered during reperfusion in adult male spontaneously hypertensive (SHR) rats subjected to transient middle cerebral artery occlusion (tMCAO; 90â¯min occlusion/24â¯h reperfusion). Animals received a single dose of SAHA (50â¯mg/kg) or vehicle i.p. at 1, 4, or 6â¯h after reperfusion onset. The time-course of brain histone H3 acetylation was studied. After tMCAO, drug brain penetrance and beneficial effects on behavioural outcomes, infarct volume, oedema, angiogenesis, blood-brain barrier integrity, cerebral artery oxidative stress and remodelling, and brain and vascular inflammation were evaluated. SAHA increased brain histone H3 acetylation from 1 to 6â¯h after injection, reaching the ischaemic brain administered during reperfusion. Treatment given at 4â¯h after reperfusion onset improved neurological score, reduced infarct volume and oedema, attenuated microglial activation, prevented exacerbated MCA angiogenic sprouting and blood-brain barrier breakdown, normalised MCA oxidative stress and remodelling, and modulated brain and cerebrovascular cytokine expression. Overall, we demonstrate that SAHA administered during early reperfusion exerts robust brain and vascular protection after tMCAO in hypertensive rats. These findings are aligned with previous research in ischaemic normotensive mice and help pave the way to optimise the design of clinical trials assessing the effectiveness and safety of SAHA in ischaemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Masculino , Ratas , Animales , Ratones , Vorinostat/farmacología , Vorinostat/uso terapéutico , Histona Desacetilasas , Ratas Endogámicas SHR , Isquemia Encefálica/tratamiento farmacológico , Histonas , Accidente Cerebrovascular/tratamiento farmacológico , Encéfalo , Infarto , EdemaRESUMEN
AIMS: Transient receptor potential vanilloid 2 (TRPV2) channels are expressed in both smooth muscle and endothelial cells and participate in vascular mechanotransduction and sensing of high temperatures and lipids. Nevertheless, the impact of TRPV2 channel activation by agonists on the coordinated and cell-type specific modulation of vasoreactivity is unknown. MAIN METHODS: Aorta from 2- to 4-months-old male Oncins France 1 mice was dissected and mounted in tissue baths for isometric tension measurements. TRPV2 channel expression was assessed by immunofluorescence and western blot in mice aortas and in cultured A7r5 rat aortic smooth muscle cells. KEY FINDINGS: TRPV2 channels were expressed in all three mouse aorta layers. Activation of TRPV2 channels with probenecid evoked endothelium-dependent relaxations through a mechanism that involved activation of smooth muscle Kir and Kv channels. In addition, TRPV2 channel inhibition with tranilast increased endothelium-independent relaxations to probenecid and this effect was abrogated by the KATP channel blocker glibenclamide, revealing that smooth muscle TRPV2 channels induce negative feedback on probenecid relaxations mediated via KATP channel inhibition. Exposure to the NO donor sodium nitroprusside increased TRPV2 channel translocation to the plasma membrane in cultured smooth muscle cells and enhanced negative feedback on probenecid relaxations. SIGNIFICANCE: In conclusion, we present the first evidence that TRPV2 channels may modulate vascular tone through a balance of opposed inputs from the endothelium and the smooth muscle leading to net vasodilation. The fact that TRPV2 channel-induced activity can be amplified by NO emphasizes the pathophysiological relevance of these findings.
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Células Endoteliales , Probenecid , Ratones , Ratas , Masculino , Animales , Probenecid/farmacología , Mecanotransducción Celular , Aorta/metabolismo , Vasodilatación , Adenosina Trifosfato/metabolismo , Endotelio Vascular/fisiologíaRESUMEN
Key events in postnatal brain development, such as neuronal migration, synaptogenesis, and myelination, shape the adult brain. These events are reflected in changes in gray and white matter (GM and WM) occurring during this period. Therefore, precise knowledge of GM and WM composition in perinatal brain development is crucial to characterizing brain formation as well as the neurodevelopmental disruption observed in diseases such as autism and schizophrenia. In this study, we combined histochemical and immunohistochemical staining with biochemical and biophysical analyses using Fourier transform infrared (IR) microspectroscopy (µFTIR) to better understand the chemical changes during postnatal developmental myelination. For this purpose, we analyzed the GM and WM in the mouse brain and cerebellum (strain C57BL/6) from postnatal day 0 (P0) to day P28 and established presumed correlations between staining and IR data. IR spectra allowed the (i) quantification of lipid and protein content through the CH2/amide I ratio, (ii) determination of chemical characteristics of lipids, such as the presence of unsaturated bonds in the carbonate chain or carbonyls from ester groups in the polar head, and (iii) determination of the protein secondary structure (α-helix and intramolecular ß-sheets). The results indicate that the increase in the CH2/amide I ratio calculated from the µFTIR data correlates well with lipid histochemical staining. IR data indicated a change in the lipid composition in WM since carbonyl and unsaturated olefinic groups do not increase when lipids accumulate during myelination. Our correlation analysis between IR data and immunohistochemical staining of myelin-associated proteins revealed that myelin oligodendrocyte protein correlated well with lipid accumulation, while myelin basic protein appeared before lipid modifications, which indicated that myelin-associated proteins and lipid deposition were not synchronic. These events were related to a decrease in the intramolecular ß/α protein ratio. Our results indicate that lipids and proteins in WM substantially change their composition due to primary myelination, and according to results obtained from staining, these modifications are better described by lipid histochemical staining than by immunohistochemistry against myelin-related proteins. In conclusion, µFTIR can be a useful technique to study WM during perinatal development and provide detailed information about alterations in the chemical composition related to neurodevelopmental diseases.
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Sustancia Blanca , Ratones , Animales , Embarazo , Femenino , Sustancia Blanca/metabolismo , Ratones Endogámicos C57BL , Encéfalo/metabolismo , Corteza Cerebral , LípidosRESUMEN
Demyelinating disorders show impaired remyelination due to failure in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-forming oligodendrocytes, a process driven by microglia-OPC crosstalk. Through conducting a transcriptomic analysis of microarray studies on the demyelination-remyelination cuprizone model and using human samples of multiple sclerosis (MS), we identified molecules involved in this crosstalk. Differentially expressed genes (DEGs) of specific regions/cell types were detected in GEO transcriptomic raw data after cuprizone treatment and in MS samples, followed by functional analysis with GO terms and WikiPathways. Additionally, microglia-OPC crosstalk between microglia ligands, OPC receptors and target genes was examined with the NicheNet model. We identified 108 and 166 DEGs in the demyelinated corpus callosum (CC) at 2 and 4 weeks of cuprizone treatment; 427 and 355 DEGs in the remyelinated (4 weeks of cuprizone treatment + 14 days of normal diet) compared to 2- and 4-week demyelinated CC; 252 DEGs in MS samples and 2730 and 12 DEGs in OPC and microglia of 4-week demyelinated CC. At this time point, we found 95 common DEGs in the CC and OPCs, and one common DEG in microglia and OPCs, mostly associated with myelin and lipid metabolism. Crosstalk analysis identified 47 microglia ligands, 43 OPC receptors and 115 OPC target genes, all differentially expressed in cuprizone-treated samples and associated with myelination. Our differential expression pipeline identified demyelination/remyelination transcriptomic biomarkers in studies using diverse platforms and cell types/tissues. Cellular crosstalk analysis yielded novel markers of microglia ligands, OPC receptors and target genes.
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Enfermedades Desmielinizantes , Esclerosis Múltiple , Células Precursoras de Oligodendrocitos , Remielinización , Ratones , Animales , Humanos , Células Precursoras de Oligodendrocitos/metabolismo , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/metabolismo , Ratones Endogámicos C57BL , Remielinización/genética , Cuprizona/toxicidad , Oligodendroglía/metabolismo , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Diferenciación Celular/genética , Microglía/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Modelos Animales de EnfermedadRESUMEN
Transient potential receptor vanilloid 2 (TRPV2) is widely expressed through the nervous system and specifically found in neuronal subpopulations and some glial cells. TRPV2 is known to be sensitized by methionine oxidation, which results from inflammation. Here we aim to characterize the expression and regulation of TRPV2 in myelination pathologies, such as hypomyelination and demyelination. We validated the interaction between TRPV2 and its putative interactor Opalin, an oligodendrocyte marker, in mixed glial cultures under pro- and anti-inflammatory conditions. Then, we characterized TRPV2 time-course expression in experimental animal models of hypomyelination (jimpy mice) and de-/remyelination (cuprizone intoxication and experimental autoimmune encephalomyelitis (EAE)). TRPV2 showed upregulation associated with remyelination, inflammation in cuprizone and EAE models, and downregulation in hypomyelinated jimpy mice. TRPV2 expression was altered in human samples of multiple sclerosis (MS) patients. Additionally, we analyzed the expression of methionine sulfoxide reductase A (MSRA), an enzyme that reduces oxidated methionines in TRPV2, which we found increased in inflammatory conditions. These results suggest that TRPV2 may be a key player in myelination in accordance with the recapitulation hypothesis, and that it may become an interesting clinical target in the treatment of demyelination disorders.
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Encefalomielitis Autoinmune Experimental , Remielinización , Animales , Canales de Calcio/metabolismo , Sistema Nervioso Central/metabolismo , Cuprizona/toxicidad , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Humanos , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismoRESUMEN
Determination of microglial phagocytosis of myelin has acquired importance in the study of demyelinating diseases. One strategy to determine microglial phagocytosis capacity consists of assaying microglia with fluorescently labeled myelin; however, most approaches are performed in cell culture, where microglia usually show important phenotypic differences compared with in vivo conditions. In this article we describe an adapted flow cytometry protocol to assay myelin phagocytosis by microglia obtained directly from in vivo tissue of the central nervous system. Key steps for a first analysis of phagocytic microglia are provided. Additionally, we describe how to fluorescently label myelin using a pH-sensitive tag, pHrodo™ Green STP Ester. © 2021 Wiley Periodicals LLC. Basic Protocol: Assay for determination of myelin phagocytosis by microglia/macrophages using flow cytometry Support Protocol 1: Conjugation of isolated and purified myelin with pHrodo Green STP Ester Support Protocol 2: Quantification of phagocytic cell number by flow cytometry.
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Microglía , Vaina de Mielina , Citometría de Flujo , Macrófagos , FagocitosisRESUMEN
Microglia are the main immune cells of the central nervous system (CNS), and they are devoted to the active surveillance of the CNS during homeostasis and disease. In the last years, the microglial receptor Triggering Receptor Expressed on Myeloid cells-2 (TREM2) has been defined to mediate several microglial functions, including phagocytosis, survival, proliferation, and migration, and to be a key regulator of a new common microglial signature induced under neurodegenerative conditions and aging, also known as disease-associated microglia (DAM). Although microglial TREM2 has been mainly studied in chronic neurodegenerative diseases, few studies address its regulation and functions in acute inflammatory injuries. In this context, the present work aims to study the regulation of TREM2 and its functions after reparative axonal injuries, using two-well established animal models of anterograde and retrograde neuronal degeneration: the perforant pathway transection (PPT) and the facial nerve axotomy (FNA). Our results indicate the appearance of a subpopulation of microglia expressing TREM2 after both anterograde and retrograde axonal injury. TREM2+ microglia were not directly related to proliferation, instead, they were associated with specific recognition and/or phagocytosis of myelin and degenerating neurons, as assessed by immunohistochemistry and flow cytometry. Characterization of TREM2+ microglia showed expression of CD16/32, CD68, and occasional Galectin-3. However, specific singularities within each model were observed in P2RY12 expression, which was only downregulated after PPT, and in ApoE, where de novo expression was detected only in TREM2+ microglia after FNA. Finally, we report that the pro-inflammatory or anti-inflammatory cytokine microenvironment, which may affect phagocytosis, did not directly modify the induction of TREM2+ subpopulation in any injury model, although it changed TREM2 levels due to modification of the microglial activation pattern. In conclusion, we describe a unique TREM2+ microglial subpopulation induced after axonal injury, which is directly associated with phagocytosis of specific cell remnants and show different phenotypes, depending on the microglial activation status and the degree of tissue injury.
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Microglia are considered to be the resident macrophages of the CNS and main effector of immune brain function. Due to their essential role in the regulation of neuroinflammatory response, microglia constitute an important target for neurological diseases, such as multiple sclerosis, Alzheimer's or Parkinson's disease. The communication between neurons and microglia contributes to a proper maintenance of homeostasis in the CNS. Research developed in the last decade has demonstrated that this interaction is mediated by "Off-signals" - molecules exerting immune inhibition - and "On signals" - molecules triggering immune activation. Among "Off signals", molecular pair CD200 and its CD200R receptor, expressed mainly in the membrane of neurons and microglia, respectively, have centered our attention due to its unexplored and powerful immunoregulatory functions. In this review, we will offer an updated global view of the CD200-CD200R role in the microglia-neuron crosstalk during homeostasis and neuroinflammation. Specifically, the effects of CD200-CD200R in the inhibition of pro-inflammatory microglial activation will be explained, and their involvement in other functions such as homeostasis preservation, tissue repair, and brain aging, among others, will be pointed out. In addition, we will depict the effects of CD200-CD200R uncoupling in the etiopathogenesis of autoimmune and neurodegenerative diseases. Finally, we will explore how to translate the scientific evidence of CD200-CD200R interaction into possible clinical therapeutic strategies to tackle neuroinflammatory CNS diseases.
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Antígenos CD/metabolismo , Enfermedades del Sistema Nervioso Central/patología , Inflamación/fisiopatología , Receptores de Orexina/metabolismo , Animales , Enfermedades Autoinmunes/patología , Encéfalo/citología , Encéfalo/patología , Comunicación Celular/fisiología , Sistema Nervioso Central/citología , Sistema Nervioso Central/patología , Homeostasis , Humanos , Inmunomodulación , Microglía/citología , Microglía/patología , Enfermedades Neurodegenerativas/patologíaRESUMEN
Lafora disease (LD), the most devastating adolescence-onset epilepsy, is caused by mutations in the EPM2A or EPM2B genes, which encode the proteins laforin and malin, respectively. Loss of function of one of these proteins, which are involved in the regulation of glycogen synthesis, induces the accumulation of polyglucosan bodies (PGBs)-known as Lafora bodies (LBs) and associated with neurons-in the brain. Ageing and some neurodegenerative conditions lead to the appearance of another type of PGB called corpora amylacea, which are associated with astrocytes and contain neo-epitopes that can be recognized by natural antibodies. Here we studied the PGBs in the cerebral cortex and hippocampus of malin knockout mice, a mouse model of LD. These animals presented not only LBs associated with neurons but also a significant number of PGBs associated with astrocytes. These astrocytic PGBs were also increased in mice from senescence-accelerated mouse-prone 8 (SAMP8) strain and mice with overexpression of Protein Targeting to Glycogen (PTGOE ), indicating that they are not exclusive of LD. The astrocytic PGBs, but not neuronal LBs, contained neo-epitopes that are recognized by natural antibodies. The astrocytic PGBs appeared predominantly in the hippocampus but were also present in some cortical brain regions, while neuronal LBs were found mainly in the brain cortex and the pyramidal layer of hippocampal regions CA2 and CA3. Our results indicate that astrocytes, contrary to current belief, are involved in the etiopathogenesis of LD.
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Astrocitos/metabolismo , Corteza Cerebral/metabolismo , Glucanos/metabolismo , Cuerpos de Inclusión/metabolismo , Enfermedad de Lafora/metabolismo , Neuronas/metabolismo , Animales , Astrocitos/patología , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Cuerpos de Inclusión/patología , Enfermedad de Lafora/patología , Ratones Transgénicos , Neuronas/patologíaRESUMEN
Low physical activity (PA), or sedentary lifestyle, is associated with the development of several chronic diseases. We aimed to investigate current prevalence of sedentariness and its association with diabetes and other cardiovascular risk factors. PA was evaluated in a population-based, cross-sectional, randomly sampled study conducted in 2009-2010 in Spain. International Physical Activity Questionnaire (SF-IPAQ) was used to assess PA. 4991 individuals (median age 50 years, 57% women) were studied. Prevalence of sedentariness was 32.3% for men and 39% for women (p < 0.0001). Sex differences were particularly notable (age*sex interaction, p = 0.0024) at early and older ages. Sedentary individuals had higher BMI (28 vs. 27 kg/m2) and obesity prevalence (37 vs. 26%). Low PA was present in 44, 43, and 38% of individuals with known diabetes (KDM), prediabetes/unknown-diabetes (PREDM/UKDM), and normal glucose regulation (p = 0.0014), respectively. No difference between KDM and PREDM/UKDM (p = 0.72) was found. Variables independently associated (p < 0.05) with sedentariness were age, sex, BMI, central obesity, Mediterranean diet adherence, smoking habit, HDL-cholesterol, triglycerides and dyslipidemia. Low PA is on the rise in Spain, especially among women. Sedentariness is associated with several cardiovascular risk factors and may be responsible for the increasing prevalence of obesity and diabetes in this country.
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Enfermedades Cardiovasculares/etiología , Diabetes Mellitus/etiología , Ejercicio Físico , Conducta Sedentaria , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Diabetes Mellitus/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Obesidad/etiología , Prevalencia , Factores de Riesgo , Factores Sexuales , España/epidemiología , Adulto JovenRESUMEN
Brain ageing in mice leads to the progressive appearance and expansion of degenerative granular structures frequently referred as "PAS granules" because of their positive staining with periodic acid-Schiff (PAS). PAS granules are present mainly in the hippocampus, although they have also been described in other brain areas such as piriform and entorhinal cortices, and have been observed in other mammals than mice, like rats and monkeys. PAS granules have been identified as a wide range of brain deposits related to numerous neurodegenerative diseases, such as amyloid deposits, neurofibrillary tangles, Lafora bodies, corpora amylacea and polyglucosan bodies, and these identifications have generated controversy and particular theories about them. We have recently reported the presence of a neo-epitope in mice hippocampal PAS granules and the existence of natural IgM auto-antibodies directed against the neo-epitope in the plasma of the animals. The significance of the neo-epitope and the autoantibodies is discussed in this review. Moreover, we observed that the IgM anti-neo-epitope is frequently present as a contaminant in numerous commercial antibodies and is responsible of a considerable amount of false positive immunostainings, which may produce misinterpretations in the identification of the granules. Now that this point has been clarified, this article reviews and reconsiders the nature and physiopathological significance of these degenerative granules. Moreover, we suggest that neo-epitopes may turn into a useful brain-ageing biomarker and that autoimmunity could become a new focus in the study of age-related degenerative processes.
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Envejecimiento , Epítopos/inmunología , Hipocampo , Enfermedades Neurodegenerativas , Ácido Peryódico/inmunología , Placa Amiloide , Envejecimiento/inmunología , Envejecimiento/patología , Animales , Autoinmunidad , Hipocampo/inmunología , Hipocampo/patología , Humanos , Inmunohistoquímica , Ratones , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/fisiopatología , Placa Amiloide/inmunología , Placa Amiloide/fisiopatologíaRESUMEN
BACKGROUND: Degenerative granular structures appear progressively with age in the hippocampus of most mouse strains. We recently reported that these granules contain a neo-epitope that is recognised by IgM antibodies present as contaminants in many commercial antibodies obtained from mouse ascites and mouse or rabbit serum. We hypothesise that these anti-neo-epitope IgMs are in fact natural auto-antibodies that are generated spontaneously during the foetal stage without previous contact with external antigens and whose repertoire and reactivity pattern have been determined through evolution, being remarkably stable within species and even between species. FINDINGS: In the present work we found that mice from the ICR-CD1, BALB/C and SAMP8 strains have anti-neo-epitope IgM antibodies in their plasma at all ages tested and even when maintained under specific opportunistic pathogen-free conditions. Moreover, we determined that these anti-neo-epitope IgMs are also present in rabbit, goat and rat serum. We also found that, in each mouse that presented hippocampal granules, the anti-neo-epitope IgMs contained in its plasma recognised the neo-epitopes in its own granules. CONCLUSIONS: This study led to the conclusion that anti-neo-epitope IgMs are widespread natural auto-antibodies contained in the plasma of mice and other species. The presence of these natural auto-antibodies not only explains why they are frequently found as contaminants in commercial antibodies, but also paves the way for a new approach to a treatment and diagnosis of pathological brain processes based on natural IgMs and neo-epitopes.
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Receptor-mediated transcytosis has been widely studied as a possible strategy to transport neurotherapeutics across the blood-brain barrier (BBB). Monoclonal antibodies directed against the transferrin receptor (TfR) have been proposed as potential carrier candidates. A better understanding of the mechanisms involved in their cellular uptake and intracellular trafficking is required and could critically contribute to the improvement of delivery methods. Accordingly, we studied here the trafficking of gold nanoparticles (AuNPs) coated with the 8D3 anti-transferrin receptor antibody at the mouse BBB. 8D3-AuNPs were intravenously administered to mice and allowed to recirculate for a range of times, from 10 min to 24 h, before brain extraction and analysis by transmission electron microscope techniques. Our results indicated a TfR-mediated and clathrin-dependent internalization process by which 8D3-AuNPs internalize individually in vesicles. These vesicles then follow at least two different routes. On one hand, most vesicles enter intracellular processes of vesicular fusion and rearrangement in which the AuNPs end up accumulating in late endosomes, multivesicular bodies or lysosomes, which present a high AuNP content. On the other hand, a small percentage of the vesicles follow a different route in which they fuse with the abluminal membrane and open to the basal membrane. In these cases, the 8D3-AuNPs remain attached to the abluminal membrane, which suggests an endosomal escape, but not dissociation from TfR. Altogether, although receptor-mediated transport continues to be one of the most promising strategies to overcome the BBB, different optimization approaches need to be developed for efficient drug delivery.
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Anticuerpos Monoclonales/administración & dosificación , Barrera Hematoencefálica , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos , Oro/química , Nanopartículas del Metal/química , Receptores de Transferrina/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Masculino , Ratones , Ratones Endogámicos ICR , Transporte de Proteínas , Distribución TisularRESUMEN
OBJECTIVE: The aim of this study was to examine possible associations between ambient temperature and obesity in the Spanish population using an ecological focus. METHODS: The Di@bet.es study is a national, cross-sectional, population-based survey of cardiometabolic risk factors and their association with lifestyle. SAMPLE: 5,061 subjects in 100 clusters. VARIABLES: Clinical, demographic and lifestyle survey, physical examination, and blood sampling. The mean annual temperature (°C) for each study site was collected from the Spanish National Meteorology Agency (1971-2000). RESULTS: The prevalence rates of obesity in the different geographical areas divided according to mean annual temperature quartiles were 26.9% in quartile 1 (10.4-14.5°C), 30.5% in quartile 2 (14.5-15.5°C), 32% in quartile 3 (15.5-17.8°C), and 33.6% in quartile 4 (17.8-21.3°C) (P = 0.003). Logistic regression analyses including multiple socio-demographic (age, gender, educational level, marital status) and lifestyle (physical activity, Mediterranean diet score, smoking) variables showed that, as compared with quartile 1, the odd ratios for obesity were 1.20 (1.01-1.42), 1.35 (1.12-1.61), and 1.38 (1.14-1.67) in quartiles 2, 3, and 4, respectively (P = 0.001 for difference, P < 0.001 for trend). CONCLUSIONS: Our study reports an association between ambient temperature and obesity in the Spanish population controlled for known confounders.
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Obesidad/epidemiología , Temperatura , Adolescente , Adulto , Anciano , Estudios Transversales , Dieta Mediterránea , Ambiente , Femenino , Humanos , Estilo de Vida , Masculino , Estado Civil , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , España/epidemiología , Adulto JovenRESUMEN
Clusters of pathological granular structures appear and progressively increase in number with age in the hippocampus of several mice strains, markedly in the senescence-accelerated mouse prone 8 mice. In the present work, we performed an ultrastructural study of these granules paying special attention to the first stages of their formation, which have not been previously explored. The analysis of the immature granules allowed concluding that granules are not simple accumulations of molecular waste but the result of a degenerative process involving principally astrocytic processes, although nearby neuronal structures can be also affected. The granule generation includes the instability of the plasmatic membranes and the appearance of abnormal membranous structures that form intracellular bubbles or blebs of variable sizes and irregular shapes. These structures and some organelles degenerate producing some membranous fragments, and an assembly process of the resulting fragments generates the dense-core nucleus of the mature granule. Moreover, we found out that the neo-epitope recently described in the mature granules and localised abundantly in the membranous fragments of their dense-core nucleus emerges in the first stages of the granule formation. On the other hand, with this study, we increase the evidences that each cluster of granules is formed by the granules comprised in one astrocyte. A better knowledge of the causes of the granule formation and the function of the neo-epitope will help in both the interpretation of the physiological significance of the granules and their contribution to the degenerating processes in aging brain.
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Envejecimiento , Astrocitos/ultraestructura , Hipocampo/patología , Enfermedades Neurodegenerativas/patología , Neurópilo/ultraestructura , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inmunohistoquímica , Ratones , Microscopía Confocal , Microscopía Electrónica de TransmisiónRESUMEN
BACKGROUND AND AIM: Prevalence rates of "metabolically healthy obese" (MHO) subjects vary depending on the criteria used. This study examined the prevalence and characteristics of MHO subjects and metabolically abnormal normal-weight subjects and compared the findings with the NHANES 1999-2004 study. The aims of the present study were, first, to determine the prevalence rates of MHO and MNHNO subjects using the same criteria as those of the National Health and Nutrition Examination Survey (NHANES) (1999-2004) study, and second to compare the prevalence and correlates of obese subjects who are resistant to the development of adiposity-associated cardiometabolic abnormalities (CA) and normal-weight individuals who display cardiometabolic risk factor clustering between the Spanish and the US populations. METHODS AND RESULTS: Di@bet.es study is a national, cross-sectional population-based survey of 5728 adults conducted in 2009-2010. Clinical, metabolic, sociodemographic, and anthropometric data and information about lifestyle habits, such as physical activity, smoking habit, alcohol intake and food consumption, were collected. Subjects were classified according to their body mass index (BMI) (normal-weight, <25 kg/m(2); overweight, 25-29.9 kg/m(2); and obese, >30 kg/m(2)). CA included elevated blood pressure; elevated levels of triglycerides, fasting glucose, and high-sensitivity C-reactive protein (hs-CRP); and elevated homeostasis model assessment of insulin resistance (HOMA-IR) value and low high-density lipoprotein cholesterol (HDL-c) level. Two phenotypes were defined: metabolically healthy phenotype (0-1 CA) and metabolically abnormal phenotype (≥2 CA). The prevalence of metabolically abnormal normal-weight phenotype was slightly lower in the Spanish population (6.5% vs. 8.1%). The prevalence of metabolically healthy overweight and MHO subjects was 20.9% and 7.0%, respectively, while in NHANES study it was 17.9% and 9.7%, respectively. Cigarette smoking was associated with CA in each phenotype, while moderate physical activity and moderate alcohol intake were associated with being metabolically healthy. Olive oil intake was negatively associated with the prevalence of CA. CONCLUSIONS: Smoking, physical activity level, and alcohol intake contribute to the explanation of the prevalence of CA in the Spanish population, as in the US population. However in Spain, olive oil intake contributes significantly to the explanation of the variance in the prevalence of CA.
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Enfermedades Cardiovasculares/epidemiología , Conducta Alimentaria , Estilo de Vida , Síndrome Metabólico/epidemiología , Obesidad/epidemiología , Adolescente , Adulto , Anciano , Glucemia , Índice de Masa Corporal , Peso Corporal , Proteína C-Reactiva/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Estudios Transversales , Dieta , Femenino , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Actividad Motora , Encuestas Nutricionales , Estado Nutricional , Fenotipo , Prevalencia , Factores Socioeconómicos , España/epidemiología , Triglicéridos/sangre , Estados Unidos/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: Dyslipidemia is a significant contributor to the elevated CVD risk observed in type 2 diabetes mellitus. We assessed the prevalence of dyslipidemia and its association with glucose metabolism status in a representative sample of the adult population in Spain and the percentage of subjects at guideline-recommended LDL-C goals. MATERIAL AND METHODS: The di@bet.es study is a national, cross-sectional population-based survey of 5728 adults. RESULTS: A total of 4776 subjects were studied. Dyslipidemia was diagnosed in 56.8% of subjects; only 13.2% of subjects were treated with lipid lowering drugs. Lipid abnormalities were found in 56.8% of Spanish adults: 23.3% with high LDL-C, 21.5% high TG, 35.8% high non-HDL-C, and 17.2% low HDL-C. Most normal subjects showed an LDL-C ≤ 3.36 mmol/l. Pre-diabetics presented similar proportion when considering a goal of 3.36 mmol/l, but only 35% of them reached an LDL-C goal ≤ 2.6 mmol/l. Finally, 45.3% of diabetics had an LDL-C ≤ 2.6 mmol/l, and only 11.3% achieved an LDL-C ≤ 1.8 mmol/l. CONCLUSIONS: Our study demonstrates a high prevalence of dyslipidemia in the adult Spanish population, and a low use of lipid-lowering drugs. Moreover, the number of subjects achieving their corresponding LDL-C goal is small, particularly in subjects at high cardiovascular risk, such as diabetics.
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LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Dislipidemias/epidemiología , Glucosa/metabolismo , Adolescente , Adulto , Anciano , Enfermedades Cardiovasculares/etiología , HDL-Colesterol/sangre , Estudios Transversales , Dislipidemias/complicaciones , Dislipidemias/tratamiento farmacológico , Femenino , Humanos , Hipolipemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Estado Prediabético/sangre , Prevalencia , Factores de Riesgo , España/epidemiología , Adulto JovenRESUMEN
Clustered pathological granules related to a degenerative process appear and increase progressively with age in the hippocampus of numerous mouse strains. We describe herein the presence of a neo-epitope of carbohydrate nature in these granules, which is not present in other brain areas and thus constitutes a new marker of these degenerative structures. We also found that this epitope is recognised by a contaminant IgM present in several antibodies obtained from mouse ascites and from both mouse and rabbit sera. These findings entail the need to revise the high number of components that are thought to be present in the granules, such as the controversial ß-amyloid peptides described in the granules of senescence-accelerated mouse prone-8 (SAMP8) mice. Characterisation of the composition of SAMP8 granules, taking into account the presence of the neo-epitope and the contaminant IgM, showed that granules do not contain either ß-amyloid peptides or tau protein. The presence of the neo-epitope in the granules but not in other brain areas opens up a new direction in the study of the neurodegenerative processes associated with age. The SAMP8 strain, in which the progression of the granules is enhanced, may be a useful model for this purpose.
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Envejecimiento/patología , Péptidos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Proteínas tau/metabolismo , Animales , Anticuerpos/metabolismo , Ascitis/metabolismo , Modelos Animales de Enfermedad , Pruebas de Hemaglutinación , Hipocampo/patología , Procesamiento de Imagen Asistido por Computador , Inmunoglobulina M/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos , Microscopía Confocal , Microscopía Electrónica , Microscopía FluorescenteRESUMEN
Neurogenesis persists in the adult brain as a form of plasticity due to the existence of neural stem cells (NSCs). Alterations in neurogenesis have been found in transgenic Alzheimer's disease (AD) mouse models, but NSC activity and neurogenesis in sporadic AD models remains to be examined. We herein describe a remarkable increase in NSC proliferation in the forebrain of SAMP8, a non-transgenic mouse strain that recapitulates the transition from healthy aging to AD. The increase in proliferation is transient, precedes AD-like symptoms such as amyloid beta 1-42 [Aß(1-42)] increase or gliosis, and is followed by a steep decline at later stages. Interestingly, in vitro studies indicate that secreted Aß(1-42) and PI3K signaling may account for the early boost in NSC proliferation. Our results highlight the role of soluble Aß(1-42) peptide and PI3K in the autocrine regulation of NSCs, and further suggest that over-proliferation of NSCs before the appearance of AD pathology may underlie neurogenic failure during the age-related progression of the disease. These findings have implications for therapeutic approaches based on neurogenesis in AD.