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Extracellular vesicles (EVs) are membrane-delimited vesicular bodies carrying different molecules, classified according to their size, density, cargo, and origin. Research on this topic has been actively growing through the years, as EVs are associated with critical pathological processes such as neurodegenerative diseases and cancer. Despite that, studies exploring the physiological functions of EVs are sparse, with particular emphasis on their role in organismal development, initial cell differentiation, and morphogenesis. In this review, we explore the topic of EVs from a developmental perspective, discussing their role in the earliest cell-fate decisions and neural tissue morphogenesis. We focus on the function of EVs through development to highlight possible conserved or novel processes that can impact disease progression. Specifically, we take advantage of what was learned about their role in development so far to discuss EVs impact on glioblastoma, a particular brain tumor of stem-cell origin and poor prognosis, and how their function can be hijacked to improve current therapies.
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Vesículas Extracelulares , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Vesículas Extracelulares/patología , Comunicación Celular , Células Madre , Diferenciación CelularRESUMEN
BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor that exhibits resistance to current treatment, making the identification of novel therapeutic targets essential. In this context, cellular prion protein (PrPC) stands out as a potential candidate for new therapies. Encoded by the PRNP gene, PrPC can present increased expression levels in GBM, impacting cell proliferation, growth, migration, invasion and stemness. Nevertheless, the exact molecular mechanisms through which PRNP/PrPC modulates key aspects of GBM biology remain elusive. METHODS: To elucidate the implications of PRNP/PrPC in the biology of this cancer, we analyzed publicly available RNA sequencing (RNA-seq) data of patient-derived GBMs from four independent studies. First, we ranked samples profiled by bulk RNA-seq as PRNPhigh and PRNPlow and compared their transcriptomic landscape. Then, we analyzed PRNP+ and PRNP- GBM cells profiled by single-cell RNA-seq to further understand the molecular context within which PRNP/PrPC might function in this tumor. We explored an additional proteomics dataset, applying similar comparative approaches, to corroborate our findings. RESULTS: Functional profiling revealed that vesicular dynamics signatures are strongly correlated with PRNP/PrPC levels in GBM. We found a panel of 73 genes, enriched in vesicle-related pathways, whose expression levels are increased in PRNPhigh/PRNP+ cells across all RNA-seq datasets. Vesicle-associated genes, ANXA1, RAB31, DSTN and SYPL1, were found to be upregulated in vitro in an in-house collection of patient-derived GBM. Moreover, proteome analysis of patient-derived samples reinforces the findings of enhanced vesicle biogenesis, processing and trafficking in PRNPhigh/PRNP+ GBM cells. CONCLUSIONS: Together, our findings shed light on a novel role for PrPC as a potential modulator of vesicle biology in GBM, which is pivotal for intercellular communication and cancer maintenance. We also introduce GBMdiscovery, a novel user-friendly tool that allows the investigation of specific genes in GBM biology.
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Glioblastoma , Priones , Humanos , Expresión Génica , Perfilación de la Expresión Génica , Glioblastoma/genética , Glioblastoma/patología , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Priones/genética , Priones/metabolismo , Proteínas de Unión al GTP rab/genética , Sinaptofisina/metabolismoRESUMEN
The phytoalexin Resveratrol (3,5,4'-trihydroxystilbene; RSV) has been related to numerous beneficial effects on health by its cytoprotection and chemoprevention activities. Liver fibrosis is characterized by the extracellular matrix accumulation after hepatic injury and can lead to cirrhosis. Hepatic stellate cells (HSC) play a crucial role during fibrogenesis and liver wound healing by changing their quiescent phenotype to an activated phenotype for protecting healthy areas from damaged areas. Strategies on promoting the activated HSC death, the quiescence return or the cellular activation stimuli decrease play an important role on reducing liver fibrosis. Here, we evaluated the RSV effects on some markers of activation in GRX, an HSC model. We further evaluated the RSV influence in the ability of GRX on releasing inflammatory mediators. RSV at 1 and 10 µM did not alter the protein content of α-SMA, collagen I and GFAP; but 50 µM increased the content of these activation-related proteins. Also, RSV did not change the myofibroblast-like morphology of GRX. Interestingly, RSV at 10 and 50 µM decreased the GRX migration and collagen-I gel contraction. Finally, we showed that RSV triggered the increase in the TNF-α and IL-10 content in culture media of GRX while the opposite occurred for the IL-6 content. Altogether, these results suggested that RSV did not decrease the activation state of GRX and oppositely, triggered a pro-activation effect at the 50 µM concentration. However, despite the increase of TNF- α in culture media, these results on IL-6 and IL-10 secretion were in accordance with the anti-inflammatory role of RSV in our model.
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Antioxidantes/farmacología , Citocinas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Resveratrol/farmacología , Animales , Línea Celular , Proliferación Celular , Células Estrelladas Hepáticas/inmunología , Células Estrelladas Hepáticas/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Cirrosis Hepática/inmunología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Ratones , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismoRESUMEN
Alzheimer's disease is a neurodegenerative disorder characterized by extracellular deposition of amyloid-ß (Aß) peptide and hyperphosphorylation of Tau protein, which ultimately leads to the formation of intracellular neurofibrillary tangles and cell death. Increasing evidence indicates that genistein, a soy isoflavone, has neuroprotective effects against Aß-induced toxicity. However, the molecular mechanisms involved in its neuroprotection are not well understood. In this study, we have established a neuronal damage model using retinoic-acid differentiated SH-SY5Y cells treated with different concentrations of Aß25-35 to investigate the effect of genistein against Aß-induced cell death and the possible involvement of protein kinase B (PKB, also termed Akt), glycogen synthase kinase 3ß (GSK-3ß), and Tau as an underlying mechanism to this neuroprotection. Differentiated SH-SY5Y cells were pre-treated for 24 hr with genistein (1 and 10 nM) and exposed to Aß25-35 (25 µM), and we found that genistein partially inhibited Aß induced cell death, primarily apoptosis. Furthermore, the protective effect of genistein was associated with the inhibition of Aß-induced Akt inactivation and Tau hyperphosphorylation. These findings reinforce the neuroprotective effects of genistein against Aß toxicity and provide evidence that its mechanism may involve regulation of Akt and Tau proteins.
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Péptidos beta-Amiloides/toxicidad , Genisteína/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Neuronas/fisiología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas tau/efectos de los fármacos , Proteínas tau/metabolismoRESUMEN
The mobility of cellular prion protein (PrPC) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its cell function. PrPC works in concert with several partners to organize signaling platforms implicated in various cellular processes. The scaffold property of PrPC is able to gather a molecular repertoire to create heterogeneous membrane domains that favor endocytic events. Dynamic trafficking of PrPC through multiple pathways, in a well-orchestrated mechanism of intra and extracellular vesicular transport, defines its functional plasticity, and also assists the conversion and spreading of its infectious isoform associated with neurodegenerative diseases. In this review, we highlight how PrPC traffics across intra- and extracellular compartments and the consequences of this dynamic transport in governing cell functions and contributing to prion disease pathogenesis.
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Enfermedades Neurodegenerativas/metabolismo , Proteínas PrPC/metabolismo , Enfermedades por Prión/metabolismo , Transducción de Señal , Animales , Membrana Celular/metabolismo , Humanos , Microdominios de Membrana/metabolismo , Modelos Biológicos , Transporte de ProteínasRESUMEN
Cell motility is a central process involved in fundamental biological phenomena during embryonic development, wound healing, immune surveillance, and cancer spreading. Cell movement is complex and dynamic and requires the coordinated activity of cytoskeletal, membrane, adhesion and extracellular proteins. Cellular prion protein (PrPC) has been implicated in distinct aspects of cell motility, including axonal growth, transendothelial migration, epithelial-mesenchymal transition, formation of lamellipodia, and tumor migration and invasion. The preferential location of PrPC on cell membrane favors its function as a pivotal molecule in cell motile phenotype, being able to serve as a scaffold protein for extracellular matrix proteins, cell surface receptors, and cytoskeletal multiprotein complexes to modulate their activities in cellular movement. Evidence points to PrPC mediating interactions of multiple key elements of cell motility at the intra- and extracellular levels, such as integrins and matrix proteins, also regulating cell adhesion molecule stability and cell adhesion cytoskeleton dynamics. Understanding the molecular mechanisms that govern cell motility is critical for tissue homeostasis, since uncontrolled cell movement results in pathological conditions such as developmental diseases and tumor dissemination. In this review, we discuss the relevant contribution of PrPC in several aspects of cell motility, unveiling new insights into both PrPC function and mechanism in a multifaceted manner either in physiological or pathological contexts.
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Movimiento Celular/fisiología , Proteínas Priónicas/metabolismo , Animales , Adhesión Celular/fisiología , Membrana Celular/metabolismo , Membrana Celular/fisiología , Citoesqueleto/metabolismo , Citoesqueleto/fisiología , HumanosRESUMEN
Heat shock proteins (HSPs) are evolutionary conserved proteins that work as molecular chaperones and perform broad and crucial roles in proteostasis, an important process to preserve the integrity of proteins in different cell types, in health and disease. Their function in cancer is an important aspect to be considered for a better understanding of disease development and progression. Glioblastoma (GBM) is the most frequent and lethal brain cancer, with no effective therapies. In recent years, HSPs have been considered as possible targets for GBM therapy due their importance in different mechanisms that govern GBM malignance. In this review, we address current evidence on the role of several HSPs in the biology of GBMs, and how these molecules have been considered in different treatments in the context of this disease, including their activities in glioblastoma stem-like cells (GSCs), a small subpopulation able to drive GBM growth. Additionally, we highlight recent works that approach other classes of chaperones, such as histone and mitochondrial chaperones, as important molecules for GBM aggressiveness. Herein, we provide new insights into how HSPs and their partners play pivotal roles in GBM biology and may open new therapeutic avenues for GBM based on proteostasis machinery.
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Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas de Choque Térmico/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Proteínas de Choque Térmico/efectos de los fármacos , Humanos , Terapia Molecular DirigidaRESUMEN
Chemical coding of stomatogastric nervous system (STNS) and enteric nervous system (ENS) of midgut and hindgut in the snail Megalobulimus abbreviatus was investigated using histochemistry, histofluorescence, and immunohistochemistry. The gastrointestinal plexuses, constituted by intrinsic neurons and fibers originating from the subesophageal ganglia and/or STNS, showed intense acetylcholinesterase (AChE) and nicotinamide adenine dinucleotide diaphorase (NADPHd) activity. The enteric neurons and fibers with AChE activity are scattered in the submucosa and between both muscular layers of gastrointestinal tract, whereas NADPHd neurons and fibers are more abundant between muscular layers than in the submucosa. Catecholaminergic nerve fibers and varicosities are found mainly within the submucosa across the mid- and hindgut. Serotoninand FMRFamide-immunoreactive neurons and fibers originating from the STNS are distributed in the submucosa of the intestine and rectum. FMRFamide-immunoreactive neurons and fibers are present in the mucosa, submucosa, and muscular layers of mid- and hindgut. The neuron-like intraepithelial cells exhibited AChE activity, a few NADPHd activity, and immunoreactivity for serotonin and FMRFamide. Intense glial fibrillary acidic protein (GFAP) immunoreaction is found throughout the intestine plexuses and in the STNS ganglia. The GFAP immunoreaction in intramural plexuses suggests the presence of glial cells as an important component of ENS in this pulmonate snail.
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Caracoles/fisiología , Animales , Tracto Gastrointestinal/inervación , Tracto Gastrointestinal/fisiología , Inmunohistoquímica , Fenómenos Fisiológicos del Sistema Nervioso , Neuronas/fisiologíaRESUMEN
The most common cause of spinal cord injury are high impact trauma, which often result in some motor impairment, sensory or autonomic a greater or lesser extent in the distal areas the level of trauma. In terms of survival and complications due to sequelae, veterinary patients have a poor prognosis unfavorable. Therefore justified the study of experimental models of spinal cord injury production that could provide more support to research potential treatments for spinal cord injuries in medicine and veterinary medicine. Preclinical studies of acute spinal cord injury require an experimental animal model easily reproducible. The most common experimental animal model is the rat, and several techniques for producing a spinal cord injury. The objective of this study was to describe and evaluate the effectiveness of acute spinal cord injury production technique through inflation of Fogarty(r) catheter using rabbits as an experimental model because it is a species that has fewer conclusive publications and contemplating. The main requirements of a model as low cost, handling convenience, reproducibility and uniformity. The technique was adequate for performing preclinical studies in neuro-traumatology area, effectively leading to degeneration and necrosis of the nervous tissue fostering the emergence of acute paraplegia.
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Catéteres , Modelos Animales de Enfermedad , Compresión de la Médula Espinal/etiología , Animales , Espacio Epidural , Conejos , Reproducibilidad de los ResultadosRESUMEN
We describe the morphology and innervation of the midgut and hindgut of the giant land snail Megalobulimus abbreviatus for the first time. The midgut (stomach and intestine) and hindgut (rectum and anus) are innervated by the subesophageal ganglia, through the gastrointestinal branch (originated from the visceral nerve) and the rectum-anal nerve, respectively. Backfilling through these nerves revealed neuronal bodies, mainly in the right parietal and visceral ganglia. The enteric plexuses of the midgut and hindgut are formed by extensive axonal networks and several neuronal somata arranged in clusters or as isolated cells. The gastrointestinal branch and the rectum-anal nerve directly innervate the enteric plexuses of the intestine and the hindgut, respectively. However, the outer wall of the stomach has a stomatogastric nervous system, which consists of four ganglia: stomatogastric, gastric, cardic, and pyloric. Fibers of the gastrointestinal branch project to these ganglia. Anterograde tracing from stomatogastric system ganglia revealed that the enteric plexus of the stomach is innervated only by these peripheral ganglia. Anterograde tracing of the gastrointestinal branch did not result in labeling in the enteric plexus of the stomach. Therefore, the midgut and hindgut of M. abbreviatus is controlled by an intrinsic innervation, constituted by the submucous and myenteric plexuses, which are innervated directly by neurons from the subesophageal ganglia or indirectly via the stomatogastric nervous system (for the stomach).
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Tracto Gastrointestinal/anatomía & histología , Tracto Gastrointestinal/inervación , Gastrópodos/anatomía & histología , Animales , NeuronasRESUMEN
OBJECTIVE: The aim of this study was to evaluate the influence of the incorporation of chlorhexidine-hexametaphosphate nanoparticles (CHX-HMP NPs) on antibacterial, cytotoxic and physicochemical properties of AH Plus (AH), MTA Fillapex (MTA) and Pulp Canal Sealer (PCS). METHODS: The NPs were synthesized and characterized by Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), zeta potential, Atomic Force Microscopy (AFM) and Energy-Dispersive X-ray Spectroscopy (EDS). The incorporation was made by weight, 2% and 5% of NPs. The antimicrobial activity, cytotoxicity, flow, radiopacity, setting time, solubility and pH were evaluated. The statistical analysis was performed by two-way analysis of variance test and Tukey post hoc test (P < 0.05). RESULTS: SEM analysis showed the tendency for CHX-HMP NPs to cluster, the effective mean diameter measured by DLS: 169.39 nm and the zeta potential: -10.18 mV. The NPs were individually measured by AFM: 22.99-52.75 nm. EDS analysis identified the presence of C, N, O, Na, P, Cl. After incorporation: The Direct Contact Test showed an increase in the antimicrobial action of AH, PCS and MTA; the sealers showed a decrease in flow and at 24 h of immersion also an increase in solubility, but did not affect the radiopacity of the samples; AH setting time increased and MTA did not reach setting under any of the conditions tested. All samples showed a decrease in pH value as the immersion time progressed. SIGNIFICANCE: The incorporation of NPs can improve the antimicrobial performance of endodontic sealers without impairing other biological and physicochemical properties.
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Nanopartículas , Materiales de Obturación del Conducto Radicular , Antibacterianos/farmacología , Compuestos de Calcio , Clorhexidina/farmacología , Cavidad Pulpar , Combinación de Medicamentos , Resinas Epoxi , Ensayo de Materiales , Fosfatos , SilicatosRESUMEN
OBJECTIVE: Follicular lesions of the thyroid with papillary carcinoma nuclear characteristics are classified as infiltrative follicular variant of papillary thyroid carcinoma-FVPTC (IFVPTC), encapsulated/well demarcated FVPTC with tumour capsular invasion (IEFVPTC), and the newly described category "non-invasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) formerly known as non-invasive encapsulated FVPTC. This study evaluated whether computerized image analysis can detect nuclear differences between these three tumour subtypes. METHODS: Slides with histological material from 15 cases of NIFTP and 33 cases of FVPTC subtypes (22 IEFVPTC, and 11 IFVPTC) were analyzed using the Image J image processing program. Tumour cells were compared for both nuclear morphometry and chromatin textural characteristics. RESULTS: Nuclei from NIFTP and IFVPTC tumours differed in terms of chromatin textural features (grey intensity): mean (92.37 ± 21.01 vs 72.99 ± 14.73, p = 0.02), median (84.93 ± 21.17 vs 65.18 ± 17.08, p = 0.02), standard deviation (47.77 ± 9.55 vs 39.39 ± 7.18; p = 0.02), and coefficient of variation of standard deviation (19.96 ± 4.01 vs 24.75 ± 3.31; p = 0.003). No differences were found in relation to IEFVPTC. CONCLUSION: Computerized image analysis revealed differences in nuclear texture between NIFTP and IFVPTC, but not for IEFVPTC.
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Adenocarcinoma Folicular , Carcinoma Papilar Folicular , Carcinoma Papilar , Neoplasias de la Tiroides , Adenocarcinoma Folicular/diagnóstico por imagen , Adenocarcinoma Folicular/genética , Cromatina , Humanos , Estudios Retrospectivos , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/genéticaRESUMEN
OBJECTIVES: To investigate the expression levels of surface markers of activation (CD38 and HLA-DR), inhibition (PD-1, TIGIT and CD57) and co-stimulation (CD28 and CD127) on CD4+ T cells of children/adolescents with vertical HIV infection (HI patients) and HIV-uninfected (HU) controls vaccinated with the meningococcal C conjugate vaccine (MCC). METHODS: HI patients (n=12), aged 8-17 years, were immunized with two MCC injections, while HU controls (n=9), aged 5.3-10.7 years, received a single MCC dose (as per national recommendation at the time of this study, a single MCC vaccine dose should be given for healthy children and youth aged 1-18 years). The HI patients were categorized according to the combined antiretroviral therapy (cART) treatment. Blood samples were obtained before vaccination, after priming, and after the administration of a booster dose of vaccine to determine the serum bactericidal antibody (SBA) titers and the expression levels of surface markers on CD4+ T cells by flow cytometry. The levels of serum cytokines, IL-4 and CXCL-13 were also measured using Luminex kits. RESULTS: The co-expression of the TIGIT-HLA-DR-CD38 molecules increased in the CD4+ T cells of HI patients/no-cART who also showed a lower frequency of CD127+CD28+ CD4+ T cells than HI patients/cART and HU group subjects. There were significant negative correlations between the frequency of exhausted CD4+ T cells and the SBA response. IL-4 levels were higher in HI patients/cART and positively correlated with SBA titers but negatively associated with the expression of exhaustion markers. Moreover, the CXCL-13 levels were positively correlated with the exhausted CD4+ T cells. CONCLUSION: The results of our study suggest that the co-expression of exhaustion markers and/or loss of co-stimulatory molecules influence the SBA response in HI patients.
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Infecciones por VIH , Vacunas Meningococicas , Adolescente , Formación de Anticuerpos , Linfocitos T CD4-Positivos , Niño , HumanosRESUMEN
BACKGROUND: Thyroid nodules diagnosed as 'atypia of undetermined significance/follicular lesion of undetermined significance' (AUS/FLUS) or 'follicular neoplasm/suspected follicular neoplasm' (FN/SFN), according to Bethesda's classification, represent a challenge in clinical practice. Computerized analysis of nuclear images (CANI) could be a useful tool for these cases. Our aim was to evaluate the ability of CANI to correctly classify AUS/FLUS and FN/SFN thyroid nodules for malignancy. METHODS: We studied 101 nodules cytologically classified as AUS/FLUS (n = 68) or FN/SFN (n = 33) from 97 thyroidectomy patients. Slides with cytological material were submitted for manual selection and analysis of the follicular cell nuclei for morphometric and texture parameters using ImageJ software. The histologically benign and malignant lesions were compared for such parameters which were then evaluated for the capacity to predict malignancy using the classification and regression trees gini model. The intraclass coefficient of correlation was used to evaluate method reproducibility. RESULTS: In AUS/FLUS nodule analysis, the benign and malignant nodules differed for entropy (P < 0.05), while the FN/SFN nodules differed for fractal analysis, coefficient of variation (CV) of roughness, and CV-entropy (P < 0.05). Considering the AUS/FLUS and FN/SFN nodules separately, it correctly classified 90.0 and 100.0% malignant nodules, with a correct global classification of 94.1 and 97%, respectively. We observed that reproducibility was substantially or nearly complete (0.61-0.93) in 10 of the 12 nuclear parameters evaluated. CONCLUSION: CANI demonstrated a high capacity for correctly classifying AUS/FLUS and FN/SFN thyroid nodules for malignancy. This could be a useful method to help increase diagnostic accuracy in the indeterminate thyroid cytology.
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OBJECTIVE: Reactive oxygen species play an important role in the pathogenesis of chronic kidney disease (CKD). Physical exercise was suggested as a useful approach to diminish impaired oxidative defense mechanisms. This study sought to observe the effects of physical training before the induction of renal lesions on oxidative stress parameters in animals induced for CKD. METHODS: Twenty-four male Wistar rats were divided into four groups (n = 6): sham, sham plus exercise, CKD, and CKD plus exercise. Exercise groups performed physical training on a treadmill for 8 weeks (up to 1 km/h for 50 min/day, 5 days/week). Forty-eight hours after the final exercise session, a surgical reduction of renal mass was performed (5/6 nephrectomized). Thirty days later, blood samples were collected to determine serum creatinine and urea concentrations, and the right kidney was surgically removed and stored at -70 degrees C for later analysis of superoxide production, antioxidant enzymes (superoxide dismutase and catalase), and oxidative damage of lipids (thiobarbituric acid reactive susbstances level) and proteins (carbonyl groups and sulfhydryl content). RESULTS: A significant increase occurred in creatinine and urea levels, superoxide production, antioxidant enzymes, and oxidative damage in the CKD group, compared with sham-treated animals (P < .05). Physical training prevented superoxide production, and decreased the oxidative damage in the CKD group (P < .05), but did not increase the effect of antioxidants. CONCLUSION: Physical training before induction of a renal lesion is capable of improving oxidative damage parameters and oxidant production, without altering renal function and the antioxidant defense system.
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Fallo Renal Crónico/fisiopatología , Estrés Oxidativo/fisiología , Esfuerzo Físico/fisiología , Animales , Catalasa/metabolismo , Creatinina/sangre , Modelos Animales de Enfermedad , Riñón/enzimología , Riñón/metabolismo , Riñón/cirugía , Fallo Renal Crónico/etiología , Peroxidación de Lípido , Masculino , Ratas , Ratas Wistar , Arteria Renal/cirugía , Superóxido Dismutasa/metabolismo , Superóxidos/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Urea/sangreRESUMEN
Tumor cells can employ epithelial-mesenchymal transition (EMT) or autophagy in reaction to microenvironmental stress. Importantly, EMT and autophagy negatively regulate each other, are able to interconvert, and both have been shown to contribute to drug-resistance in glioblastoma (GBM). EMT has been considered one of the mechanisms that confer invasive properties to GBM cells. Autophagy, on the other hand, may show dual roles as either a GBM-promoter or GBM-suppressor, depending on microenvironmental cues. The Wingless (WNT) signaling pathway regulates a plethora of developmental and biological processes such as cellular proliferation, adhesion and motility. As such, GBM demonstrates deregulation of WNT signaling in favor of tumor initiation, proliferation and invasion. In EMT, WNT signaling promotes induction and stabilization of different EMT activators. WNT activity also represses autophagy, while nutrient deprivation induces ß-catenin degradation via autophagic machinery. Due to the importance of the WNT pathway to GBM, and the role of WNT signaling in EMT and autophagy, in this review we highlight the effects of the WNT signaling in the regulation of both processes in GBM, and discuss how the crosstalk between EMT and autophagy may ultimately affect tumor biology.
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Several studies have demonstrated the antitumor effect of doxazosin, an α1-adrenergic blocker, against glioma and breast, bladder and prostate cancers. Doxazosin is also being evaluated as a treatment for posttraumatic stress disorder (PTSD) and alcoholism, and α1-adrenergic blockers have been linked to neuroprotection in neurodegenerative disorders, such as Alzheimer's Disease (AD). Cancer and AD have an inverse relationship in many aspects, with several factors that contribute to apoptosis inhibition and proliferation being increased in cancers but decreased in AD. Neuroblastoma (NB) is a pediatric tumor derived from embryonic neural-crest cells, with an overall cure rate of 40%, despite aggressive treatment. Thus, due to the need of new therapeutic strategies against NB and neurodegenerative disorders and the inverse relationship between these diseases, we investigated whether doxazosin may serve as an antitumor and neuroprotective agent. We analyzed the drug's effects on undifferentiated and retinoic acid-differentiated SH-SY5Y human NB cells and on an in vitro model of organotypic hippocampal cultures exposed to amyloid-ß. Doxazosin showed antitumor effect on undifferentiated NB cells by induction of apoptosis, necrosis, cell cycle arrest and decrease of p-EGFRTyr1048 levels. On differentiated cells, doxazosin was less cytotoxic and increased p-EGFRTyr1048, p-AktSer473 and p-GSK-3ßSer9 levels. Moreover, the drug was able to protect hippocampal slices from amyloid-ß toxicity through prevention of GSK-3ß activation and of Tau hyperphosphorylation. Therefore, our results show that doxazosin has antitumor activity against undifferentiated NB and is neuroprotective on an in vitro model of Alzheimer's disease.
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Enfermedad de Alzheimer/metabolismo , Antineoplásicos/farmacología , Doxazosina/farmacología , Neuroblastoma/metabolismo , Fármacos Neuroprotectores/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Doxazosina/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Masculino , Neuroblastoma/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Técnicas de Cultivo de Órganos , Ratas , Ratas WistarRESUMEN
Since 2006, meningococcal serogroup C (MenC) conjugate (MCC) vaccines have been supplied by the Brazilian government for HIV-infected children under 13 years old. For measuring protection against MenC, the serum bactericidal antibody (SBA) assay is the method of choice. The characterization of T follicular helper cells (TFH) cells has been an area of intensive study because of their significance in multiple human diseases and in vaccinology. The objective of this study was to characterize the phenotype of peripheral TFH cells and B cells and how they associated with each other and with SBA levels induced by vaccination as well as with serum cytokine levels of HIV-infected and non-infected children and adolescents. We found that CD27-IgD-CD21-CD38+ (exhausted B cells) as well as short-lived plasmablasts (CD27+IgD-CD21-CD38+) are increased in cART treated HIV patients and negatively associated with MCC vaccine induced SBA levels. Baseline frequency of activated peripheral TFH cells was a negative correlate for SBA response to MCC vaccine but positively correlated with circulating plasmablast frequency. Baseline IL4-levels positively associated with SBA response but showed a negative correlation with activated peripheral TFH cells frequency. The increased frequency of activated peripheral TFH cells found in non-responders to the vaccine implies that higher activation/differentiation of CD4 T cells within the lymph node is not necessarily associated with induction of vaccine responses.
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Linfocitos B/inmunología , Infecciones por VIH/inmunología , VIH-1/fisiología , Meningitis Bacterianas/inmunología , Vacunas Meningococicas/inmunología , Neisseria meningitidis Serogrupo C/fisiología , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Anticuerpos Antibacterianos/sangre , Circulación Sanguínea , Niño , Preescolar , Estudios de Cohortes , Resistencia a la Enfermedad , Femenino , Centro Germinal/inmunología , Humanos , Interleucina-4/sangre , Activación de Linfocitos , Masculino , Estudios Prospectivos , VacunaciónRESUMEN
BACKGROUND: Computerized image analysis seems to represent a promising diagnostic possibility for thyroid tumors. Our aim was to evaluate the discriminatory diagnostic efficiency of computerized image analysis of cell nuclei from histological materials of follicular tumors. METHODS: We studied paraffin-embedded materials from 42 follicular adenomas (FA), 47 follicular variants of papillary carcinomas (FVPC) and 20 follicular carcinomas (FC) by the software ImageJ. Based on the nuclear morphometry and chromatin texture, the samples were classified as FA, FC or FVPC using the Classification and Regression Trees method. RESULTS: We observed high diagnostic sensitivity and specificity rates (FVPC: 89.4% and 100%; FC: 95.0% and 92.1%; FA: 90.5 and 95.5%, respectively). When the tumors were compared by pairs (FC vs FA, FVPC vs FA), 100% of the cases were classified correctly. CONCLUSION: The computerized image analysis of nuclear features showed to be a useful diagnostic support tool for the histological differentiation between follicular adenomas, follicular variants of papillary carcinomas and follicular carcinomas.
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PURPOSE: To investigate the efficacy of allogeneic mesenchymal stem-cells and autologous mononuclear cells to promote sensorimotor recovery and tissue rescue. METHODS: Female rabbits were submitted to the epidural balloon inflation method and the intravenous cells administrations were made after 8 hours or seven days after injury induction. Sensorimotor evaluation of the hindlimbs was performed, and the euthanasia was made thirty days after the treatment. Spinal cords were stained with hematoxylin and eosin. RESULTS: Both therapies given 8 hours after the injury promoted the sensorimotor recovery after a week. Only the group treated after a week with mononuclear cells showed no significant recovery at post-injury day 14. In the days 21 and 28, all treatments promoted significant recovery. Histopathological analysis showed no difference among the experimental groups. Our results showed that both bone marrow-derived cell types promoted significant sensorimotor recovery after injury, and the treatment made at least a week after injury is efficient. CONCLUSION: The possibilities of therapy with bone marrow-derived cells are large, increasing the therapeutic arsenal for the treatment of spinal cord injury.