RESUMEN
Most organs rely on stem cells to maintain homeostasis during post-embryonic life. Typically, stem cells of independent lineages work coordinately within mature organs to ensure proper ratios of cell types. Little is known, however, on how these different stem cells locate to forming organs during development. Here we show that neuromasts of the posterior lateral line in medaka are composed of two independent life-long lineages with different embryonic origins. Clonal analysis and 4D imaging revealed a hierarchical organisation with instructing and responding roles: an inner, neural lineage induces the formation of an outer, border cell lineage (nBC) from the skin epithelium. Our results demonstrate that the neural lineage is necessary and sufficient to generate nBCs highlighting self-organisation principles at the level of the entire embryo. We hypothesise that induction of surrounding tissues plays a major role during the establishment of vertebrate stem cell niches.
Asunto(s)
Células-Madre Neurales/fisiología , Organogénesis , Oryzias/embriología , Piel/citología , Nicho de Células Madre , AnimalesRESUMEN
The aim of this randomized controlled trial was to determine the effects of 8-week exercise-intervention on cognition and related serum biochemical markers in nonagenarians. We also studied the effects of a 4-week training cessation ('detraining') period on our study variables. Participants were randomly allocated to a standard-care (control) or intervention (exercise) group [n=20 (16 women)/group]. The intervention focused on supervised, light-to-moderate-intensity aerobic and resistance exercises (mainly leg press), and included 3 weekly sessions. Cognitive status was determined by the mini-mental state examination and geriatric depression scale. We analysed proteins with reported relation with mechanisms behind cognition changes such as serum levels of angiotensin converting enzyme, amyloid-precursor protein, epidermal growth factor, brain-derived neural factor and tumor necrosis factor. No significant change (P>0.05) in any of the variables studied was found following the exercise intervention compared with the standard-care group. Similarly, no significant changes (P>0.05) were observed following the detraining period compared with the standard-care group. Overall changes after the exercise intervention in serum biomarkers were not associated with changes in functional capacity and cognitive measures. An 8-week exercise intervention focusing on resistance exercises neither benefits cognitive function nor affects the levels of the serum proteins analysed in nonagenarians.
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Envejecimiento/sangre , Envejecimiento/psicología , Proteínas Sanguíneas/metabolismo , Cognición/fisiología , Entrenamiento de Fuerza , Anciano de 80 o más Años , Precursor de Proteína beta-Amiloide/sangre , Biomarcadores/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor de Crecimiento Epidérmico/sangre , Femenino , Humanos , Masculino , Fuerza Muscular/fisiología , Peptidil-Dipeptidasa A/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
It is becoming evident that chronic exposure to glucocorticoids might not only result in insulin resistance or cognitive deficits, but also is considered as a risk factor for pathologies such as depression or Alzheimer's disease. In the present study, in vivo experiments using a non-invasive method of chronic administration of corticosterone in drinking water demonstrated that chronic corticosterone administration led to cognitive impairment in the novel object recognition test and insulin resistance, as shown by significant increases in plasma insulin levels and the homeostatic model assessment index, and decreased insulin receptor phosphorylation. Corticosterone treatment induced an increased expression of stress-activated c-Jun N-terminal kinase (JNK) in the hippocampus, accompanied by decreases in glycogen synthase kinase 3ß, increases in pTau levels and increased neuronal cell death (caspase-3 activity). All these effects were reversed by the administration of a JNK1 inhibitor or by the mineralocorticoid receptor antagonist spironolactone. It is suggested that the mineralocorticoid receptors and JNK-mediated pathways are involved in the interaction of glucocorticoid-insulin resistance and the development of relevant cellular processes for Alzheimer's disease.
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Trastornos del Conocimiento/inducido químicamente , Corticosterona/administración & dosificación , Resistencia a la Insulina , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animales , Corticosterona/efectos adversos , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: Atherosclerosis is a chronic inflammatory process. Poly(ADP-ribose) polymerase-1 (PARP), a nuclear enzyme linked to DNA repair, has been shown to be involved in atherogenesis; however, the effects on dendritic cells, T cells and serum auto-antibody levels are not fully understood. METHODS: Male Apoe-/- mice on a western diet were treated with the PARP inhibitor INO-1001 (n = 15), while the control group (n = 15) received 5% glucose solution for 10 weeks. RESULTS: Inhibition of PARP markedly reduced atherosclerotic lesion development (p = 0.001). Immunohistochemistry and mRNA analysis revealed a reduced inflammatory compound inside the lesion. Focusing on dendritic cells, INO-1001 reduced number of cells (p = 0.04), grade of activation, represented by Il12 (p = 0.04) and Cd83 (p = 0.03), and grade of attraction, represented by Mip3α (p = 0.02) in the plaque. Furthermore, INO-1001 decreased number of T lymphocyte (p = 0.003) in the lesion and grade of activation after stimulation with oxLDL in vitro. Moreover, serum IgM antibody levels to oxLDL were significantly lower in INO-1001 treated mice (p = 0.03). CONCLUSIONS: Functional blockade of PARP by INO-1001 reduces atherosclerotic lesion development. The anti-atherogenic effect is beside already known mechanisms also moderated due to modulation of DC and T cell invasion and activation, DC attraction as well as IgM antibody levels to oxLDL.
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Aterosclerosis/enzimología , Autoanticuerpos/química , Células Dendríticas/enzimología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Linfocitos T/enzimología , Animales , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Reparación del ADN , Células Dendríticas/citología , Inmunohistoquímica/métodos , Inflamación , Lipoproteínas LDL/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Poli(ADP-Ribosa) Polimerasas/genética , ARN/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/metabolismo , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Processes of restenosis, following arterial injury, are complex involving different cell types producing various cytokines and enzymes. Among those enzymes, smooth muscle cell-derived matrix metalloproteinases (MMPs) are thought to take part in cell migration, degrading of extracellular matrix, and neointima formation. MMP-9, also known as gelatinase B, is expressed immediately after vascular injury and its expression and activity can be inhibited by statins. Using an established in vivo model of vascular injury, we investigated the effect of the HMG-CoA reductase inhibitor rosuvastatin on MMP-9 expression and neointima formation. MATERIALS AND METHODS: 14-week old male Sprague Dawley rats underwent balloon injury of the common carotid artery. Half of the animals received rosuvastatin (20 mg/kg body weight/day) via oral gavage, beginning 3 days prior to injury. Gelatinase activity and neointima formation were analyzed 3 days and 14 days after balloon injury, respectively. 14 days after vascular injury, proliferative activity was assessed by staining for Ki67. RESULTS: After 14 days, animals in the rosuvastatin group showed a decrease in total neointima formation (0.194±0.01 mm2 versus 0.124±0.02 mm2, p<0.05) as well as a reduced intima/media ratio (1.26±0.1 versus 0.75±0.09, p<0.05). Balloon injury resulted in increased activity of MMP-9 3 days after intervention for both rosuvastatin treated animals and controls with no significant difference observed between the groups. There was a trend towards a reduction in the number of Ki67-positive cells 14 days after injury. CONCLUSIONS: Rosuvastatin attenuates neointima formation without affecting early MMP-9 activity in a rat model of vascular injury.
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Arterias Carótidas/patología , Cateterismo/efectos adversos , Fluorobencenos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neointima/prevención & control , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Masculino , Metaloproteinasa 9 de la Matriz/análisis , Ratas , Ratas Sprague-Dawley , Rosuvastatina CálcicaRESUMEN
OBJECTIVE: LIGHT (TNFSF 14) belongs to the tumor necrosis factor superfamily and is expressed by activated T cells as well as various types of antigen presenting cells. LIGHT binds to its cellular receptors TR2 and LTbetaR and has a co-stimulatory role in T cell activation. Here, we compared the relative expression of LIGHT in different immune cells and the biological activity of immune cell-derived LIGHT on endothelial cells. METHODS AND RESULTS: Surface expression of LIGHT and mRNA production by PBMC and isolated T cells (CD4+ or CD8+) significantly increased after stimulation with PMA (Phorbolester-12- Myristat-13-Acetat)+ionomycin. No LIGHT expression on PMA stimulated monocytes or monocytic-like THP-1 cells could be detected; differentiation of monocytes and THP-1 cells into macrophages, however, resulted in up-regulation of LIGHT. Supernatants of stimulated T cells contained higher concentrations of soluble LIGHT than macrophage supernatants normalized to cell numbers; release of soluble LIGHT was found to be dependent on metalloproteinase activity. Size determination of released soluble LIGHT by size exclusion chromatography revealed a molecular mass of approximately 60 kDa, suggesting a trimeric form. Released soluble LIGHT induced expression of proinflammatory antigens ICAM-1, tissue factor and IL-8 in human endothelial cells and caused apoptosis of IFN-g pretreated endothelial cells. Soluble LIGHT was detected at low levels in sera of healthy controls and was significantly enhanced in sera of patients with chronic hepatitis C and rheumatoid arthritis (24.93+/-9.41 vs. 129.53+/-49.14 and 172.13+/-77.64; p<0.0005). CONCLUSION: These findings suggest that among immune cells activated T lymphocytes are the main source of soluble LIGHT with released amounts of soluble LIGHT markedly higher compared to platelets. Immune cell-derived membrane-bound and soluble trimeric LIGHT is biologically active, inducing proinflammatory changes in endothelial cells. Enhanced plasma levels of soluble LIGHT in patients with chronic infections suggest a role of LIGHT in systemic inflammatory activation.
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Endotelio Vascular/metabolismo , Leucocitos Mononucleares/inmunología , Macrófagos/inmunología , Linfocitos T/inmunología , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Adolescente , Adulto , Anciano , Artritis Reumatoide/sangre , Diferenciación Celular , Células Cultivadas , Combinación de Medicamentos , Endotelio Vascular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Femenino , Expresión Génica/efectos de los fármacos , Hepatitis C Crónica/sangre , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-8/metabolismo , Ionomicina/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Macrófagos/efectos de los fármacos , Persona de Mediana Edad , Peso Molecular , ARN Mensajero/metabolismo , Linfocitos T/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Tromboplastina/metabolismo , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Venas Umbilicales/citología , Regulación hacia Arriba , Adulto JovenRESUMEN
The treatment of endocarditis remains a challenge for physicians, even in times of modern antibiotic treatment. Depending on its cause, endocarditis can either be of infectious or non-infectious origin. Infective endocarditis is caused by bacterial (or fungal) pathogens, and the clinical course is critically dependent on the virulence factors of the specific microorganisms involved. Therefore, the clinical type of endocarditis can be divided into an acute and more aggressive form and a subacute form (endocarditis lenta). Much of our knowledge regarding the pathogenesis of infective endocarditis is based on studies of the virulence of Staphylococcus aureus, which has become the most frequent cause of infective endocarditis nowadays. However, independently of the underlying cause of endocarditis (infectious or noninfectious), the pathogenesis involves the damage and disturbance of endothelial function and the formation of associated "vegetation". Surprisingly little is known about the specific role of the endothelium in the pathogenesis of endocarditis. This review will thus give insights into current knowledge of the pathogenesis of endocarditis with a focus on the role of the endothelium.
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Células Endoteliales/metabolismo , Endotelio/metabolismo , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismo , Factores de Virulencia/metabolismo , Enfermedad Aguda , Animales , Endocarditis Bacteriana Subaguda , Células Endoteliales/microbiología , Células Endoteliales/patología , Endotelio/microbiología , Endotelio/patología , Humanos , Micosis/metabolismo , Micosis/microbiología , Micosis/patología , Infecciones Estafilocócicas/patología , Staphylococcus aureus/patogenicidadRESUMEN
BACKGROUND AND PURPOSE: The beneficial effect of 5-HT6 receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT6 receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits. EXPERIMENTAL APPROACH: The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046. KEY RESULTS: Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046. CONCLUSIONS AND IMPLICATIONS: These data suggest a potential therapeutic role of 5-HT6 receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer's disease and schizophrenia.
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Trastornos del Conocimiento/tratamiento farmacológico , Aprendizaje por Laberinto/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Tiofenos/farmacología , Animales , Inhibidores de la Colinesterasa/farmacología , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Esquema de Medicación , Quimioterapia Combinada , Galantamina/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Serotonina/metabolismo , Escopolamina/farmacología , Antagonistas de la Serotonina/administración & dosificación , Sulfonamidas/administración & dosificación , Tiofenos/administración & dosificación , Bostezo/efectos de los fármacosRESUMEN
RATIONALE: Many studies support the validity of the chronic mild stress (CMS) model of depression in rodents. However, most of them focus on analysis of reactivity to rewards during the CMS and/or depressive-like behavior shortly after stress. In this study, we investigate acute and long-term effects of CMS and antidepressant treatment on depressive, anxiety-like behavior and learning. MATERIALS AND METHODS: Mice (C57BL/6) were exposed to CMS for 6 weeks and anhedonia was evaluated by weekly monitoring of sucrose intake. Paroxetine (10 mg kg(-1)day(-1) i.p.) or saline were administered the last 3 weeks of CMS and continued for 2 weeks thereafter. Behavioral tests were performed over the last week of CMS (acute effects) and 1 month later (long-term effects). RESULTS: Mice exposed to CMS displayed both acute and long-term decreased sucrose intake, increased immobility in the forced swimming test (FST) and impaired memory in the novel object recognition test. It is interesting to note that a correlation was found between the cognitive deficits and the helpless behavior in the FST induced by CMS. During the CMS procedure, paroxetine treatment reverted partially recognition memory impairment but failed to prevent the increased immobility in the FST. Moreover, it decreased on its own sucrose intake. Importantly, the long-term effects of CMS were partially prevented by chronic paroxetine. CONCLUSIONS: CMS leads to a long-term altered behavioral profile that could be partially reverted by chronic antidepressant treatment. This study brings novel features regarding the long-term effects of CMS and on the predictive validity of this depression animal model.
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Antidepresivos de Segunda Generación/farmacología , Ansiedad/psicología , Depresión/psicología , Recuerdo Mental/efectos de los fármacos , Paroxetina/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Estrés Psicológico/complicaciones , Animales , Ingestión de Líquidos/efectos de los fármacos , Reacción de Fuga/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Miedo/efectos de los fármacos , Desamparo Adquirido , Inyecciones Intraperitoneales , Cuidados a Largo Plazo , Masculino , Ratones , Motivación , Actividad Motora , Reconocimiento Visual de Modelos/efectos de los fármacos , Sacarosa/administración & dosificación , Gusto/efectos de los fármacosRESUMEN
Neuropsychiatric symptoms seen in Alzheimer's disease (AD) are not simply a consequence of neurodegeneration, but probably result from differential neurotransmitter alterations, which some patients are more at risk of than others. Therefore, the hypothesis of this study is that an imbalance between the cholinergic and serotonergic systems is related to cognitive symptoms and psychological syndromes of dementia (BPSD) in patients with AD. Cholinergic and serotonergic functions were assessed in post-mortem frontal and temporal cortex from 22 AD patients who had been prospectively assessed with the Mini-Mental State examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD including aggressive behavior, overactivity, depression and psychosis. Not only cholinergic deficits, but also the cholinacetyltransferase/serotonin ratio significantly correlated with final MMSE score both in frontal and temporal cortex. In addition, decreases in cholinergic function correlated with the aggressive behavior factor, supporting a dual role for the cholinergic system in cognitive and non-cognitive disturbances associated to AD. The serotonergic system showed a significant correlation with overactivity and psychosis. The ratio of serotonin to acetylcholinesterase levels was also correlated with the psychotic factor at least in women. It is concluded that an imbalance between cholinergic-serotonergic systems may be responsible for the cognitive impairment associated to AD. Moreover, the major findings of this study are the relationships between neurochemical markers of both cholinergic and serotonergic systems and non-cognitive behavioral disturbances in patients with dementia.
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Acetilcolina/farmacología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Trastornos del Conocimiento/etiología , Serotonina/farmacología , Anciano , Anciano de 80 o más Años , Agresión , Enfermedad de Alzheimer/complicaciones , Estudios de Casos y Controles , Depresión/etiología , Femenino , Lóbulo Frontal/fisiología , Humanos , Masculino , Escala del Estado Mental , Escalas de Valoración Psiquiátrica , Trastornos Psicóticos/etiología , Lóbulo Temporal/fisiologíaRESUMEN
Expression of cytokeratins (CK) is considered a hallmark of the state of epithelial differentiation. CK also occur in certain vascular smooth muscle cells (VSMC), inferring an association with a less differentiated phenotype. Recently, CK posttranslational modification was shown to occur in epithelial cells in stress, mitosis or apoptosis. The aim of this study was to determine potential CK phosphorylation patterns in human VSMC. Tissue samples of normal peripheral and coronary arteries, atherosclerotic lesions and umbilical cord vessels were evaluated by immunofluorescence microscopy applying antibodies specific for cytokeratins 8 and 18, specific cytokeratin phosphorylation sites, Ki-67-antigen as a proliferation marker and nick end labeling (TUNEL) to detect apoptosis. All samples contained cytokeratin-positive VSMC but diverse phosphorylation patterns. The C-terminal serine 431 of cytokeratin 8 (CK8Ser-431) was phosphorylated in the vast majority of CK-expressing VSMC of coronary artery lesions. Only a subset of these cells demonstrated phosphorylation of CK18Ser-33 or, to an even lesser extent, CK8Ser-73. DNA fragmentation occurred predominantly in samples containing cells with phosphorylated CK8Ser-431 domains. In contrast, occluded peripheral lesions exhibited little or no phosphorylation. Neonatal VSMC in umbilical cord vessels contain abundant phosphorylated CK domains, again predominantly CK8Ser-431, but also CK18Ser-33. Again, only single cells were found to be proliferating or to contain DNA fragmentation. Thus, abundant CK phosphorylation in VSMC of atherosclerotic lesions suggests a specific functional response to cell stress and a possible relation to apoptosis.
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Enfermedad de la Arteria Coronaria/metabolismo , Queratinas/metabolismo , Músculo Liso Vascular/metabolismo , Cordón Umbilical/irrigación sanguínea , Aorta/metabolismo , Aorta/patología , Vasos Sanguíneos/metabolismo , Puente de Arteria Coronaria , Enfermedad de la Arteria Coronaria/patología , Arteria Femoral/metabolismo , Arteria Femoral/patología , Humanos , Músculo Liso Vascular/patología , Fosforilación , Vena Safena/metabolismo , Vena Safena/patología , Vena Safena/trasplanteRESUMEN
Phenotypic modulation of smooth muscle cells (SMC) is a key event during the development of atherosclerotic and restenotic lesions. During this process, the composition of the cytoskeleton is substantially altered, with changes predominantly in actin expression reflecting a shift from smooth muscle alpha-actin to the non-muscle beta-isoform. We now demonstrate that yet another actin isoform, cardiac alpha-actin, is synthesized, de novo, in SMC of various atherosclerotic lesions. Using a highly specific monoclonal antibody against cardiac alpha-actin, we analyzed and compared the accumulation of this actin isoform in diverse SMC by immunofluorescence microscopy and immunoblotting. As expected, cardiac alpha-actin was present in human myocardium but not in healthy SMC of adult aorta, coronary arteries, trabeculae of the spleen, colon, stomach or skeletal muscle. Interestingly, the presence of cardiac alpha-actin was detected in umbilical cord vessels, human myometrium, in atherosclerotic coronary lesions and atherosclerotic lesions from peripheral vascular disease. The distribution of cardiac alpha-actin often paralleled that of cytokeratins 8 and 18, intermediate filament proteins typically found in dedifferentiated SMC. Taken together, the data presented here illustrate the expression of cardiac alpha-actin to be limited to either fetal vessels or those vessels or tissue having suffered damage or atrophy, outside its 'native' environment in the heart. The demonstration of cardiac alpha-actin in SMC of umbilical cord vessels and in atherosclerotic lesions but not in apparently healthy vessels supports the notion that SMC in atherosclerotic lesions exhibit a dedifferentiated phenotype.