RESUMEN
The methane-rich areas, the Loki's Castle vent field and the Jan Mayen vent field at the Arctic Mid Ocean Ridge (AMOR), host abundant niches for anaerobic methane-oxidizers, which are predominantly filled by members of the ANME-1. In this study, we used a metagenomic-based approach that revealed the presence of phylogenetic and functional different ANME-1 subgroups at AMOR, with heterogeneous distribution. Based on a common analysis of ANME-1 genomes from AMOR and other geographic locations, we observed that AMOR subgroups clustered with a vent-specific ANME-1 group that occurs solely at vents, and with a generalist ANME-1 group, with a mixed environmental origin. Generalist ANME-1 are enriched in genes coding for stress response and defense strategies, suggesting functional diversity among AMOR subgroups. ANME-1 encode a conserved energy metabolism, indicating strong adaptation to sulfate-methane-rich sediments in marine systems, which does not however prevent global dispersion. A deep branching family named Ca. Veteromethanophagaceae was identified. The basal position of vent-related ANME-1 in phylogenomic trees suggests that ANME-1 originated at hydrothermal vents. The heterogeneous and variable physicochemical conditions present in diffuse venting areas of hydrothermal fields could have favored the diversification of ANME-1 into lineages that can tolerate geochemical and environmental variations.
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Respiraderos Hidrotermales , Regiones Árticas , Sedimentos Geológicos , Metano/metabolismo , Filogenia , SulfatosRESUMEN
BACKGROUND AND PURPOSE: Although useful as a rapid-acting antidepressant drug, ketamine is known to induce psychotomimetic effects, which may interfere with its therapeutic use. Cannabidiol (CBD) is a non-psychostimulant compound from Cannabis sativa, which has shown promising antidepressant effects without inducing hyperlocomotion. AMPA receptor activation is involved in the antidepressant effect induced by ketamine, but its relevance for the effects of CBD is not known. Moreover, given that CBD has antipsychotic and antidepressant properties, it is unknown whether adding CBD to ketamine could potentiate the antidepressant properties of ketamine while also attenuating its psychostimulant effects. EXPERIMENTAL APPROACH: S-Ketamine (2.5, 3, 5, 10, 30 mg/kg) and cannabidiol (3, 10, 30 mg/kg) were administered alone or in combination to male Swiss mice. Independent groups received NBQX (AMPA receptor antagonist) 5 min before administration of CBD or S-ketamine. The antidepressant-like effect was assessed in the forced swimming test (FST), and the open field test (OFT) evaluated the psychostimulant effect. KEY RESULTS: CBD induced significant dose-dependent antidepressant effects without causing hyperlocomotion in the OFT. S-ketamine produced an antidepressant effect associated with hyperlocomotion in the higher dose. NBQX inhibited the antidepressant effect of both ketamine and CBD. Pretreatment with CBD (10 mg/kg) attenuated the ketamine-induced hyperlocomotion while preserving its antidepressant effect. CONCLUSION: AND IMPLICATIONS: Similar to ketamine, the antidepressant-like effect elicited by CBD involves AMPA receptor activation. Additionally, CBD prevents the hyperlocomotion induced by S-ketamine without affecting its antidepressant-like effect. Our findings suggest that CBD and ketamine's combined administration can be a promising therapeutic strategy for achieving an appropriate antidepressant effect without unwanted side-effects. This article is part of the special issue on 'Cannabinoids'.
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Antidepresivos/administración & dosificación , Cannabidiol/administración & dosificación , Depresión/tratamiento farmacológico , Ketamina/administración & dosificación , Actividad Motora/efectos de los fármacos , Animales , Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Cannabidiol/uso terapéutico , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Ketamina/uso terapéutico , Masculino , RatonesRESUMEN
Altered endocannabinoid (eCB) signalling is suggested as an important contributor to the pathophysiology of depression. To further elucidate this, we conducted a study using a genetic rat model of depression, the Flinders Sensitive Line (FSL), and their controls, the Flinders Resistant Line (FRL) rats. Plasma, right and left prefrontal cortex, and hippocampus were isolated from FSL and FRL rats. We analyzed each region for the eCB anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels by liquid chromatography/multiple reaction monitoring (LC/MRM), mRNA and protein levels of the cannabinoid type 1 receptor (CB1R), fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) by real time qPCR and Western blotting. Content of 2-AG was lower in the left side of the hippocampus and prefrontal cortex in FSL rats compared to FRL rats. Inversely, levels of AEA were higher in right hippocampus than in left hippocampus. In plasma, AEA levels were increased and 2-AG decreased. Cannabinoid receptor 1 (Cnr1), Faah and Magl mRNA levels were prominently decreased in right prefrontal cortex of FSL rats as compared to FRL rats. Protein expression of CB1R and FAAH were decreased in left hippocampus. In summary, our data suggest a decreased eCB signalling in the FSL rats, which could contribute to the depressive-like behaviour. Interestingly, the altered eCB system activity appear to be hemisphere-specific in the limbic regions. Our study support the existing literature and showed altered eCB system activity in this particular animal model of depression.
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Depresión/metabolismo , Endocannabinoides/metabolismo , Hipocampo/metabolismo , Corteza Prefrontal/metabolismo , Animales , Cerebro/metabolismo , Depresión/genética , Masculino , Ratas , Ratas Transgénicas , Especificidad de la EspecieRESUMEN
Probiotic administration to rodents is typically achieved using oral gavage or water bottles, but both approaches may compromise animal welfare, bacterial viability, dosing accuracy, or ease of administration. Oral gavage dosing may induce stress, especially when given daily over several weeks, and cannot be performed by inexperienced personnel. Delivery in water bottles does not take multiple co-housed animals into account, leading to inaccurate dosing of individual rats. Moreover, slow consumption of the solutions over several hours may lead to variability in bacterial stability, and potential leftovers or clogging of the bottle further threaten the reliability of this method. To date, no method has been described that can provide non-stressful precise dosing of probiotics or prebiotics in individual rats. In accordance with the 3R principles (replace, reduce, refine), we propose syringe-feeding as a refinement method for simple yet accurate administration of probiotics. Animals hereby voluntarily consume the solution directly from a syringe held into their home cage, thereby enabling controlled dosing of individual animals. This method requires a short training phase of approximately 3 days, but is very fast thereafter, only taking seconds per rat. Since studies using probiotics are usually long-term experiments, we consider syringe-feeding the most appropriate probiotic delivery mode available to date.
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Administración Oral , Sistemas de Liberación de Medicamentos/métodos , Ciencia de los Animales de Laboratorio/métodos , Probióticos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estrés Psicológico/psicología , JeringasRESUMEN
BACKGROUND/OBJECTIVES: The current world-wide obesity epidemic partially results from a vicious circle whereby maternal obesity during pregnancy predisposes the offspring for accelerated weight gain and development of metabolic syndrome. Here we investigate whether low-grade inflammation, characteristic of the obese state, provides a causal role for this disastrous fetal programming in mice. METHODS: We exposed pregnant and lactating C57BL/6JBom female mice to either high-fat diet (HFD), or continuous infusion of lipopolysaccharide (LPS), a potent trigger of innate immunity, and studied offspring phenotypes. RESULTS: Both maternal LPS or HFD treatments rendered the offspring hyperphagic and inept of coping with a HFD challenge during adulthood, increasing their adiposity and weight gain. The metabolic effects were more pronounced in female offspring, while exposed male offspring mounted a larger inflammatory response to HFD at adulthood. CONCLUSIONS: This supports our hypothesis and highlights the programming potential of inflammation in obese pregnancies.
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Dieta Alta en Grasa/efectos adversos , Desarrollo Fetal/fisiología , Inflamación/fisiopatología , Resistencia a la Insulina/fisiología , Obesidad/fisiopatología , Aumento de Peso/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal , Fenómenos Fisiologicos de la Nutrición Prenatal/fisiologíaRESUMEN
Behavioural stress has shown to strongly affect neurotransmission within the neocortex. In this study, we analysed the effect of an acute stress model on density and distribution of neurotransmitter-containing vesicles within medial prefrontal cortex. Serial section transmission electron microscopy was employed to compare two groups of male rats: (1) rats subjected to foot-shock stress and (2) rats with sham stress as control group. Two-dimensional (2D) density measures are common in microscopic images and are estimated by following a 2D path in-section. However, this method ignores the slant of the active zone and thickness of the section. In fact, the active zone is a surface in three-dimension (3D) and the 2D measures do not accurately reflect the geometric configuration unless the active zone is perpendicular to the sectioning angle. We investigated synaptic vesicle density as a function of distance from the active zone in 3D. We reconstructed a 3D dataset by estimating the thickness of all sections and by registering all the image sections into a common coordinate system. Finally, we estimated the density as the average number of vesicles per area and volume and modelled the synaptic vesicle distribution by fitting a one-dimensional parametrized distribution that took into account the location uncertainty due to section thickness. Our results showed a clear structural difference in synaptic vesicle density and distribution between stressed and control group with improved separation by 3D measures in comparison to the 2D measures. Our results showed that acute foot-shock stress exposure significantly affected both the spatial distribution and density of the synaptic vesicles within the presynaptic terminal.
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Biometría/métodos , Imagenología Tridimensional/métodos , Microscopía Electrónica de Transmisión/métodos , Corteza Prefrontal/patología , Estrés Psicológico , Vesículas Sinápticas/ultraestructura , Animales , Modelos Animales de Enfermedad , Masculino , RatasRESUMEN
Elevation of the proinflammatory cytokine IL-6 has been implicated in depression; however, the mechanisms remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression post-transcriptionally. The lethal-7 (let-7) miRNA family was suggested to be involved in the inflammation process and IL-6 was shown to be one of its targets. In the present study, we report elevation of Il6 in the prefrontal cortex (PFC) of a genetic rat model of depression, the Flinders Sensitive Line (FSL) compared to the control Flinders Resistant Line. This elevation was associated with an overexpression of LIN28B and downregulation of let-7 miRNAs, the former an RNA-binding protein that selectively represses let-7 synthesis. Also DROSHA, a key enzyme in miRNA biogenesis was downregulated in FSL. Running was previously shown to have an antidepressant-like effect in the FSL rat. We found that running reduced Il6 levels and selectively increased let-7i and miR-98 expression in the PFC of FSL, although there were no differences in LIN28B and DROSHA expression. Pri-let-7i was upregulated in the running FSL group, which associated with increased histone H4 acetylation. In conclusion, the disturbance of let-7 family biogenesis may underlie increased proinflammatory markers in the depressed FSL rats while physical activity could reduce their expression, possibly through regulating primary miRNA expression via epigenetic mechanisms.
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Depresión/genética , Interleucina-6/genética , MicroARNs/genética , Corteza Prefrontal/metabolismo , Animales , Modelos Animales de Enfermedad , Interleucina-6/metabolismo , Masculino , MicroARNs/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasa III/metabolismoRESUMEN
The immunological checkpoints of programmed death 1 and its ligand (PD-L1) are currently in focus as novel therapeutic targets in renal cell carcinoma (RCC). The aim of this study was to evaluate the prognostic association of PD-L1 expression in clear cell (cc) RCC with clinical parameters, tumor aggressiveness and overall survival (OS). Patients who underwent renal surgery due to RCC between 1994 and 2003 were retrospectively evaluated. Tumor specimens were analyzed for PD-L1 expression by immunohistochemistry. One hundred and seventy-seven ccRCC patients were eligible for analysis, in which 140 (79.1 %) were negative and 37 (20.9 %) were positive for PD-L1 expression. PD-L1 positivity was associated with female gender (p = 0.001), lymph node metastasis (p = 0.004), distant metastasis (p = 0.002), higher AJCC stage (p = 0.004), as well as advanced disease (pT3/4 and/or N+ and/or M1) (p < 0.001). Kaplan-Meier analysis revealed a significantly diminished 5- and 10-year overall survival of 46.7 and 28.3 % for PD-L1(+) compared to PD-L1(-) tumors with 66 and 53.4 % (p = 0.005), respectively. Univariate analysis showed a significant negative association of OS with PD-L1 positivity [p = 0.005; HR: 2 (95 % CI 1.2-3.3)], even though PD-L1 positivity only tends to predict independently the OS using multivariate analyses [p = 0.066; HR: 1.6 (95 % CI 0.98-2.7)]. PD-L1 expression in ccRCC is associated with parameters of aggressiveness, as well as with poor OS, even though PD-L1 status was not identified as a significant independent prognostic parameter. However, further studies in larger cohorts are warranted.
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Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/análisis , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de Matrices TisularesRESUMEN
Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.
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Astrocitos , Estimulación Encefálica Profunda , Depresión/fisiopatología , Depresión/terapia , Corteza Prefrontal/fisiopatología , Animales , Masculino , Ratas , Ratas Sprague-DawleyAsunto(s)
Corticosterona/metabolismo , Lóbulo Frontal/patología , Ácido Glutámico/metabolismo , Terminales Presinápticos/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Animales , Corticosterona/farmacología , Técnicas In Vitro , Terminales Presinápticos/efectos de los fármacosRESUMEN
Stress and glucocorticoids alter glutamatergic transmission, and the outcome of stress may range from plasticity enhancing effects to noxious, maladaptive changes. We have previously demonstrated that acute stress rapidly increases glutamate release in prefrontal and frontal cortex via glucocorticoid receptor and accumulation of presynaptic SNARE complex. Here we compared the ex vivo effects of acute stress on glutamate release with those of in vitro application of corticosterone, to analyze whether acute effect of stress on glutamatergic transmission is mediated by local synaptic action of corticosterone. We found that acute stress increases both the readily releasable pool (RRP) of vesicles and depolarization-evoked glutamate release, while application in vitro of corticosterone rapidly increases the RRP, an effect dependent on synaptic receptors for the hormone, but does not induce glutamate release for up to 20 min. These findings indicate that corticosterone mediates the enhancement of glutamate release induced by acute stress, and the rapid non-genomic action of the hormone is necessary but not sufficient for this effect.
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Corticosterona/metabolismo , Lóbulo Frontal/patología , Neuronas/patología , Terminales Presinápticos/metabolismo , Estrés Psicológico/patología , Análisis de Varianza , Animales , Ácido Aspártico/metabolismo , Corticosterona/farmacología , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Técnicas In Vitro , Masculino , Neuronas/metabolismo , Terminales Presinápticos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estrés Psicológico/etiología , Sinapsinas/metabolismo , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismo , Sinaptosomas/metabolismo , Tritio/farmacocinéticaRESUMEN
BACKGROUND: Numerous studies have shown a positive correlation between elevated C-reactive protein (CRP) and systemic spread of malignancies. The goal of the current study was to assess the predictive significance of preoperative CRP in patients undergoing radical cystectomy (RC). MATERIAL AND METHODS: Preoperative CRP values were measured in 194 patients undergoing RC because of urothelial carcinoma between 1996 and 2005. Elevated CRP level was defined as ≥ 5 mg/l. RESULTS: Preoperative increased CRP values were detected in 89 (45.9%) patients and these patients were more likely to have advanced tumor stages (pT3-4), positive resection margins and positive lymph nodes. Advanced urinary diversions were more common in patients with normal CRP values. In multivariate analysis, CRP was identified as an independent prognostic indicator for poor cancer-specific survival. CONCLUSION: The results confirm previous reports that showed a prognostic significance of preoperative CRP elevation.
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Biomarcadores de Tumor/sangre , Proteína C-Reactiva/análisis , Cistectomía/mortalidad , Cuidados Preoperatorios/estadística & datos numéricos , Neoplasias de la Vejiga Urinaria/sangre , Neoplasias de la Vejiga Urinaria/mortalidad , Anciano , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Cuidados Preoperatorios/métodos , Cuidados Preoperatorios/mortalidad , Prevalencia , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Sensibilidad y Especificidad , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Neuropeptide Y (NPY) has been implicated in depression, emotional processing and stress response. Part of this evidence originates from human single-nucleotide polymorphism (SNP) studies. In the present study, we report that a SNP in the rat Npy promoter (C/T; rs105431668) affects in vitro transcription and DNA-protein interactions. Genotyping studies showed that the C-allele of rs105431668 is present in a genetic rat model of depression (Flinders sensitive line; FSL), while the SNP's T-allele is present in its controls (Flinders resistant line; FRL). In vivo experiments revealed binding of a transcription factor (CREB2) and a histone acetyltransferase (Ep300) only at the SNP locus of the FRL. Accordingly, the FRL had increased hippocampal levels of Npy mRNA and H3K18 acetylation; a gene-activating histone modification maintained by Ep300. Next, based on previous studies showing antidepressant-like effects of physical activity in the FSL, we hypothesized that physical activity may affect Npy's epigenetic status. In line with this assumption, physical activity was associated with increased levels of Npy mRNA and H3K18 acetylation. Physical activity was also associated with reduced mRNA levels of a histone deacetylase (Hdac5). Conclusively, the rat rs105431668 appears to be a functional Npy SNP that may underlie depression-like characteristics. In addition, the achieved epigenetic reprogramming of Npy provides molecular support for the putative effectiveness of physical activity as a non-pharmacological antidepressant.
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Depresión/genética , Epigénesis Genética/fisiología , Actividad Motora/fisiología , Neuropéptido Y/genética , Polimorfismo de Nucleótido Simple/genética , Animales , Decepción , Depresión/fisiopatología , Modelos Animales de Enfermedad , Expresión Génica/genética , Expresión Génica/fisiología , Genotipo , Hipocampo/química , Hipocampo/fisiología , Neuropéptido Y/análisis , Neuropéptido Y/fisiología , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genética , Regiones Promotoras Genéticas/fisiología , Ratas , Factores de Transcripción/fisiologíaRESUMEN
Dietary protein restriction in pregnant females reduces offspring birth weight and increases the risk of developing obesity, type 2 diabetes and cardiovascular disease. Despite these grave consequences, few studies have addressed the effects of preconceptional maternal malnutrition. Here we investigate how a preconceptional low-protein (LP) diet affects offspring body mass and insulin-regulated glucose metabolism. Ten-week-old female mice (C57BL/6JBom) received either an LP or isocaloric control diet (8% and 22% crude protein, respectively) for 10 weeks before conception, but were thereafter fed standard laboratory chow (22.5% crude protein) during pregnancy, lactation and offspring growth. When the offspring were 10 weeks old, they were subjected to an intraperitoneal glucose tolerance test (GTT), and sacrificed after a 5-day recovery period to determine visceral organ mass. Body mass of LP male offspring was significantly lower at weaning compared with controls. A similar, nonsignificant, tendency was observed for LP female offspring. These differences in body mass disappeared within 1 week after weaning, a consequence of catch-up growth in LP offspring. GTTs of 10-week-old offspring revealed enhanced insulin sensitivity in LP offspring of both sexes. No differences were found in body mass, food intake or absolute size of visceral organs of adult offspring. Our results indicate that maternal protein restriction imposed before pregnancy produces effects similar to postconceptional malnutrition, namely, low birth weight, catch-up growth and enhanced insulin sensitivity at young adulthood. This could imply an increased risk of offspring developing lifestyle-acquired diseases during adulthood.
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Dieta con Restricción de Proteínas , Glucosa/metabolismo , Efectos Tardíos de la Exposición Prenatal , Animales , Tamaño Corporal , Femenino , Insulina/sangre , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Ratones Endogámicos C57BL , Tamaño de los Órganos , EmbarazoRESUMEN
1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist [EC(50) = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.
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Ansiolíticos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Piperazinas/uso terapéutico , Sulfuros/uso terapéutico , Animales , Monoaminas Biogénicas/análisis , Citalopram/farmacología , Humanos , Masculino , Ondansetrón/farmacología , Piperazinas/farmacocinética , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1B/metabolismo , Receptores de Serotonina/metabolismo , Reflejo/efectos de los fármacos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Sulfuros/farmacocinética , Sulfuros/farmacología , Vocalización Animal/efectos de los fármacos , VortioxetinaRESUMEN
The aim of this study was to investigate whether the previously reported effect of chronic restraint stress (CRS) on hippocampal neuron morphology and spine density is paralleled by a similar change in the expression levels of synaptic scaffolding proteins. Adult male Wistar rats were subjected either to CRS (6 h/day) for 21 days or to control conditions. The resulting brains were divided and one hemisphere was impregnated with Golgi-Cox before coronal sectioning and autometallographic development. Neurons from CA1, CA3b, CA3c, and dentate gyrus (DG) area were reconstructed and subjected to Sholl analysis and spine density estimation. The contralateral hippocampus was used for quantitative real-time polymerase chain reaction and protein analysis of genes associated with spine density and morphology (the synaptic scaffolding proteins: Spinophilin, Homer1-3, and Shank1-3). In the CA3c area, CRS decreased the number of apical dendrites and their total length, whereas CA1 and DG spine density were significantly increased. Analysis of the contralateral hippocampal homogenate displayed an increased gene expression of Spinophilin, Homer1, Shank1, and Shank2 and increased protein expression of Spinophilin and Homer1 in the CRS animals. In conclusion, CRS influences hippocampal neuroplasticity by modulation of dendrite branching pattern and spine density paralleled by increased expression levels of synaptic scaffolding proteins.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Espinas Dendríticas/patología , Guanilato-Quinasas/metabolismo , Hipocampo/citología , Plasticidad Neuronal/fisiología , Estrés Fisiológico , Animales , Giro Dentado/citología , Masculino , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVES: Papillary renal cell carcinoma (pRCC) represents the largest subgroup of non-clear-cell kidney cancer. In this retrospective multicenter study, we assessed tumor characteristics and long-term prognosis of patients with pRCC in comparison with conventional clear-cell cancer (ccRCC). METHODS: We evaluated 2,804 patients who had undergone renal surgery for pRCC or ccRCC between 1990 and 2006. The mean follow-up was 65 months. RESULTS: Both pRCC and ccRCC groups were comparable concerning age, tumor grade and the incidence of regional lymph node metastasis at diagnosis. The percentage of male patients was higher in pRCC than in ccRCC (76.0% vs. 63.6%), pRCC patients suffered less often from advanced tumors (22.3% vs. 38.1%), visceral metastasis at diagnosis (8.1% vs. 14.5%) and died less frequently due to RCC progression (16.3% vs. 29.6%). Applying multivariable analyses pRCC was found to be an independent predictor of a favorable clinical course for patients with organ-confined RCC. In contrast in advanced disease papillary histology was significantly associated with a poor prognosis and early tumour-related death. CONCLUSIONS: pRCC seem to be stratified into two different prognostic groups. Localized pRCC has a significantly better prognosis than ccRCC. In contrast, advanced pRCC is characterized by a worse clinical outcome. Whether these two different pRCC cohorts are consistent with the recently defined types 1 and 2 pRCC subtypes or are characterized by other typical genetic alterations, which would lead to a novel pRCC subclassification is currently under investigation within the German Renal Cancer Network.
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Carcinoma de Células Renales/mortalidad , Neoplasias Renales/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
OBJECTIVES: Obesity increases the risk of developing renal cell carcinoma (RCC). We assessed whether different body mass index (BMI) levels and the body surface area (BSA) at the time of surgery had an effect on aggressiveness and long-term prognosis of RCC. METHODS: The study included 1,595 RCC patients with complete information about their BMI who had undergone surgery for renal cell cancer at the University Hospitals in Hannover (MHH) and Marburg between 1990 and 2005. The mean follow-up was 5.0 years. RESULTS: A higher BMI and a higher than average BSA were significantly associated with younger age. A high BMI value was additionally related to a lower tumor grade, the clear cell histological subtype, and metastasis at the time of diagnosis. Overweight patients had a significantly lower risk of cancer-related death; their median 5-year tumor-specific survival rate was 76.9% (BMI>30) and 72.6% (BMI 25-30) as opposed to 63.5% for patients with a BMI below 25 (p<0.001). However, the positive correlation between a high BMI and tumor-specific survival could be confirmed in multivariable analyses for localized clear cell RCC only. CONCLUSION: We identified BMI as an independent prognostic marker of improved cancer-specific survival in patients with RCC, particularly with organ-confined clear cell cancer.
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Índice de Masa Corporal , Carcinoma de Células Renales/mortalidad , Neoplasias Renales/mortalidad , Obesidad/mortalidad , Sobrepeso/mortalidad , Neoplasias Abdominales/mortalidad , Neoplasias Abdominales/patología , Neoplasias Abdominales/secundario , Adulto , Anciano , Anciano de 80 o más Años , Superficie Corporal , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Comorbilidad , Femenino , Alemania , Humanos , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Obesidad/patología , Obesidad/cirugía , Sobrepeso/patología , Sobrepeso/cirugía , Pronóstico , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
An increasing number of scientific studies indicate that maternal stress during pregnancy influences fetal development of the nervous system and thereby the behavioural phenotype. We have previously reported attenuated prepulse inhibition (PPI) of the startle reaction in adult female rats derived from dams exposed to chronic mild stress (CMS) during gestation. In humans, decreased PPI has been reported to be associated with anxiety. Because of its potential translational value across species, the modulation of startle reactivity may be a useful tool in examining altered emotional reactivity following prenatal insults. The present study aimed at investigating whether prenatally stressed male offspring would display altered startle phenotype. Stress was induced by maternal gestational exposure to alternating procedures, i.e. CMS. At the age of 3 months, half of the offspring were blood sampled under restraint. At the age of 6 months, i.e. three months later, all animals were tested in the acoustic startle and the light enhanced startle (LES) paradigm. Control and CMS male offspring showed similar basal startle and LES levels. Maternal gestational exposure to the relatively mild, variable paradigm of stressors affected the PPI response pattern in male rats. In prenatally manipulated males, the PPI response differed statistically significantly, depending on prior exposure to an episode of postnatal acute stress (blood sampling under restraint). In contrast, the PPI response in control males was unaffected by this postnatal experience. The present work supports the hypothesis that the maternal environment is a long-term determinant of phenotypic differences in sensitivity to stressors.
Asunto(s)
Efectos Tardíos de la Exposición Prenatal , Reflejo de Sobresalto/fisiología , Estrés Psicológico , Animales , Femenino , Masculino , Embarazo , Ratas , Ratas WistarRESUMEN
Depressive disorders represent a major public health problem worldwide. The limitations of current antidepressant drugs have warranted on-going research to identify pharmacological agents and strategies that offer a greater therapeutic efficacy. The NMDA/L-arginine nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade is an important signaling pathway that is also implicated in the regulation of depression. In animal models detecting antidepressant activity, distinct NO synthase inhibitors display antidepressant-like action. Therefore, the aim of current study was to evaluate whether pretreatment with L-arginine (precursor of NO) could counteract antidepressant-like effects of distinct antidepressant classes in the mouse forced swimming test (FST), and whether these drugs are able to modulate the nitric oxide synthesis in the brain. We found in the FST that pretreatment with L-arginine (500 mg/kg) counteracted the antidepressant-like effect of imipramine (IMI, 15 mg/kg) and venlafaxine (VENL, 6 mg/kg), but not the effects of bupropion (BUPR, 20mg/kg) or fluoxetine (FLX, 20mg/kg). Increasing the dose of L-Arg to 1000 mg/kg attenuated the antidepressant-like effects of BUPR, but did not modify the action of FLX. L-Arginine was devoid of any locomotor effects on the animals. The effect of antidepressants on brain NO metabolism paralleled their behavioral action in case of IMI and VENL which decreased the nitrite+nitrate concentration in the brain. BUPR and FLX did not have any effect on brain nitrite+nitrate concentration. These results support the idea that some antidepressants are able to inhibit nitric oxide synthesis in the brain, an effect which could be mechanistically related to the ability of L-arginine to counteract their antidepressant-like effects.