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OBJECTIVE: The aim of this study was to analyze the factors associated with elder abuse according to the levels of social determinants. METHODOLOGY: This is a quantitative and multicentric study, with a cross-sectional cut. It was developed in two teaching hospitals in Paraíba, Brazil, with 323 older adults, from July 2019 to February 2020. Data were collected using the Hwalek-Sengstock Elder Abuse Screening Test and Conflict Tactics Scale-1 and then analyzed using descriptive and inferential statistics. RESULTS: There was a significant association between risk for violence and female gender (p = 0.004), residing with grandchildren (p = 0.025), and having four or more comorbidities (p < 0.00). Physical violence was associated with income (p = 0.048). A positive correlation was observed between the number of comorbidities and the risk for violence score (p < 0.001), psychological violence (p = 0.004), and physical violence (p = 0.005). The probability of presenting a risk to violence increased by 2.08 times for women, 1.03 times for those who were illiterate, and 7.03 times for those with four or more comorbidities. CONCLUSION: The social determinants of health that integrate the macrosystem, such as income and number of comorbidities, correlate with situations of violence.
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Plants used in traditional medicine offer an affordable new alternative in tissue repair therapy. This study aimed to evaluate the effectiveness of the 5% Rhizophora mangle cream compared to the 5% dexpanthenol cream in healing open surgical wounds on the upper eyelid. A total of 18 patients were submitted to the experiment and divided into 2 groups with 9 patients each who used topically and daily 5% dexpanthenol cream (control group) or 5% R.mangle cream (intervention group) for 7 days. Clinical, morphometric and histomorphometric analyses of wounds and surgical procedures for skin removal were performed. In the morphometric analysis, all wounds treated with R.mangle and dexpanthenol creams showed complete macroscopic scars, without inflammatory signs and infection free. The skin hydration values in pre and post application periods of the cream were 43.82 ± 43.93 and 62.12 ± 67.40 respectively. The histomorphometric study showed lower values of epithelium distance in R. mangle group and higher in dexpanthenol group with significant difference between groups (p < 0.05). The R.mangle 5% cream proved to be effective in healing wounds of human upper eyelid skin with a significant improvement in epithelization compared to dexpanthenol 5% cream.
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Ácido Pantoténico/análogos & derivados , Rhizophoraceae , Cicatrización de Heridas , Humanos , Brasil , Párpados/cirugíaRESUMEN
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease that affects the central nervous system (CNS), varying from relatively benign to severely disabling. Although the roles of several cytokines and chemokines in MS are well established, their roles in MS lesions and evolution remain a matter of debate. Soluble CD40L (sCD40L) is a ligand that induces lymphocyte proinflammatory activity by stimulating the activation and maturation of B cells, promoting isotype switching and affinity hypermutation. Circulating sCD40L levels reflect activation of the CD40-CD40L complex. The interaction between CD40 and CD40L is of fundamental importance, suggesting their role in MS pathogenesis. Interleukin-31 (IL-31) is a proinflammatory cytokine that plays a role in allergies, autoimmune diseases, and is a major factor in several chronic inflammatory diseases. IL-31 triggers the JAK-STAT pathway in several different cell types, to induce proliferation and tissue remodeling in fibroblasts, epithelial cells, and endothelial cells. Some studies have described a correlation between these two cytokines and decreased serum levels of sCD40L and IL-31 after MS treatment, accompanied by a lower inflammatory response. In this review, we emphasize the possible correlation and positive feedback between IL31 and sCD40L in the MS proinflammatory response. We also describe the justification for this hypothesis and whether it is possible to investigate these cytokines as biomarkers of MS.
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Ligando de CD40 , Esclerosis Múltiple , Humanos , Ligando de CD40/metabolismo , Células Endoteliales/metabolismo , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Biomarcadores , Interleucinas , CitocinasRESUMEN
Mesenchymal stem cells comprise a natural reservoir of undifferentiated cells within adult tissues. Given their self-renewal, multipotency, regenerative potential and immunomodulatory properties, MSCs have been reported as a promising cell therapy for the treatment of different diseases, including neurodegenerative and autoimmune diseases. In this study, we investigated the immunomodulatory properties of human tubal mesenchymal stem cells (htMSCs) using the EAE model. htMSCs were able to suppress dendritic cells activation downregulating antigen presentation-related molecules, such as MHCII, CD80 and CD86, while impairing IFN-γ and IL-17 and increasing IL-10 and IL-4 secretion. It further correlated with milder disease scores when compared to the control group due to fewer leukocytes infiltrating the CNS, specially Th1 and Th17 lymphocytes, associated with increased IL-10 secreting Tr1 cells. Conversely, microglia were less activated and infiltrating mononuclear cells secreted higher levels of IL-4 and IL-10 and expressed reduced chemokine receptors as CCR4, CCR6 and CCR8. qPCR of the spinal cords revealed upregulation of indoleamine-2,3-dioxygenase (IDO) and brain derived neurotrophic factor (BDNF). Taken together, here evidenced the potential of htMSCs as an alternative for the treatment of inflammatory, autoimmune or neurodegenerative diseases.
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Encefalomielitis Autoinmune Experimental , Células Madre Mesenquimatosas , Adulto , Animales , Sistema Nervioso Central , Encefalomielitis Autoinmune Experimental/terapia , Trompas Uterinas , Femenino , Humanos , Interleucina-10 , Interleucina-4RESUMEN
OBJECTIVE: To verify the prevalence of violence among elderly community members and its relationship with nutritional status and sociodemographic characteristics. METHOD: Cross-sectional and analytical study developed with 159 community elderly registered at a Family Health Unit in Recife/Pernambuco between March 2016 and March 2017. The Brazil Old Age Schedule, Conflict Tactics Scales and Mini Nutritional Assessment were used as data collection instruments. Data received descriptive and inferential statistical treatment. RESULTS: Among the elderly classified as with violence, there was a predominance of psychological violence (64.3%), and the majority were at risk for malnutrition (54.3%). There was an association between 'having a partner' and psychological (48.1%; p=0.02) and physical (48.1%; p=0.03) violence. Logistic regression demonstrated that being in a relationship or being malnourished increases the likelihood of suffering psychological violence (OR=2.63; OR=3.67), just as not being working increases the likelihood of physical violence (OR=5.61). CONCLUSION: Violence was negatively related to the nutritional status of elderly community members.
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Estado Nutricional , Violencia , Anciano , Brasil/epidemiología , Estudios Transversales , Humanos , PrevalenciaRESUMEN
MicroRNAs (miRNAs) are a family of non-translated small ribonucleic acids (RNAs) measuring 21-25 nucleotides in length that play various roles in multiple sclerosis (MS). By regulating gene expression via either mediating translational repression or cleavage of the target RNA, miRNAs can alter the expression of transcripts in different cells, such as B lymphocytes, also known as B cells. They are crucial in the pathogenesis of MS; however, they have not been extensively studied during the treatment of some drugs such as natalizumab (NTZ). NTZ is a humanized immunoglobulin G4 antibody antagonist for integrin alpha 4 (α4) used in the treatment of MS. The drug reduces the homing of lymphocytes to inflammation sites. Integrin α4 expression on the cell surface of B cells is related to MS severity, indicating a critical component in the pathogenesis of the disease. NTZ plays an important role in modifying the gene expression in B cells and the levels of miRNAs in the treatment of MS. In this review, we have described changes in gene expression in B cells and the levels of miRNAs during NTZ therapy in MS and its relapse. Studies using the experimental autoimmune encephalomyelitis (EAE) model and those involving patients with MS have described changes in the levels of microRNAs in the regulation of proteins affected by specific miRNAs, gene expression in B cells, and certain functions of B cells as well as their subpopulations. Therefore, there is a possibility that some miRNAs could be studied at different stages of MS during NTZ treatment, and these specific miRNAs can be tested as markers of therapeutic response to this drug in future studies. Physiopathology, gene expression in B cells and their subpopulations can help understand this complex puzzle involving miRNAs and the therapeutic response of patients with MS.
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Cellular therapy with mesenchymal stem cells (MSCs) is a huge challenge for scientists, as little translational relevance has been achieved. However, many studies using MSCs have proved their suppressive and regenerative capacity. Thus, there is still a need for a better understanding of MSCs biology and the establishment of newer protocols, or to test unexplored tissue sources. Here, we demonstrate that murine endometrial-derived MSCs (meMSCs) suppress Experimental Autoimmune Encephalomyelitis (EAE). MSC-treated animals had milder disease, with a significant reduction in Th1 and Th17 lymphocytes in the lymph nodes and in the central nervous system (CNS). This was associated with increased Il27 and Cyp1a1 expression, and presence of IL-10-secreting T CD4+ cells. At EAE peak, animals had reduced CNS infiltrating cells, histopathology and demyelination. qPCR analysis evidenced the down-regulation of several pro-inflammatory genes and up-regulation of indoleamine-2,3-dioxygenase (IDO). Consistently, co-culturing of WT and IDO-/- meMSCs with T CD4+ cells evidenced the necessity of IDO on the suppression of encephalitogenic lymphocytes, and IDO-/- meMSCs were not able to suppress EAE. In addition, WT meMSCs stimulated with IL-17A and IFN-γ increased IDO expression and secretion of kynurenines in vitro, indicating a negative feedback loop. Pathogenic cytokines were increased when CD4+ T cells from AhR-/- mice were co-cultured with WT meMSC. In summary, our research evidences the suppressive activity of the unexplored meMSCs population, and shows the mechanism depends on IDO-kynurenines-Aryl hydrocarbon receptor (AhR) axis. To our knowledge this is the first report evidencing that the therapeutic potential of meMSCs relying on IDO expression.
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Encefalomielitis Autoinmune Experimental/terapia , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Trasplante de Células Madre Mesenquimatosas , Animales , Encefalomielitis Autoinmune Experimental/enzimología , Encefalomielitis Autoinmune Experimental/inmunología , Endometrio/citología , Femenino , Activación de Linfocitos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Ratones Endogámicos C57BL , Linfocitos T/metabolismoRESUMEN
The embryonic stage is the most vulnerable period for congenital abnormalities. Due to its prolonged developmental course, the central nervous system (CNS) is susceptible to numerous genetic, epigenetic, and environmental influences. During embryo implantation, the CNS is more vulnerable to external influences such as environmental tobacco smoke (ETS), increasing the risk for delayed fetal growth, sudden infant death syndrome, and immune system abnormalities. This study aimed to evaluate the effects of in utero exposure to ETS on neuroinflammation in the offspring of pregnant mice challenged or not with lipopolysaccharide (LPS). After the confirmation of mating by the presence of the vaginal plug until offspring birth, pregnant C57BL/6 mice were exposed to either 3R4F cigarettes smoke (Kentucky University) or compressed air, twice a day (1h each), for 21 days. Enhanced glial cell and mixed cell cultures were prepared from 3-day-old mouse pups. After cell maturation, both cells were stimulated with LPS or saline. To inhibit microglia activation, minocycline was added to the mixed cell culture media 24 h before LPS challenge. To verify the influence of in utero exposure to ETS on the development of neuroinflammatory events in adulthood, a different set of 8-week-old animals was submitted to the Autoimmune Experimental Encephalomyelitis (EAE) model. The results indicate that cells from LPS-challenged pups exposed to ETS in utero presented high levels of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNFα) and decreased cell viability. Such a proinflammatory environment could modulate fetal programming by an increase in microglia and astrocytes miRNA155. This scenario may lead to the more severe EAE observed in pups exposed to ETS in utero.
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ABSTRACT Objective: To verify the prevalence of violence among elderly community members and its relationship with nutritional status and sociodemographic characteristics. Method: Cross-sectional and analytical study developed with 159 community elderly registered at a Family Health Unit in Recife/Pernambuco between March 2016 and March 2017. The Brazil Old Age Schedule, Conflict Tactics Scales and Mini Nutritional Assessment were used as data collection instruments. Data received descriptive and inferential statistical treatment. Results: Among the elderly classified as with violence, there was a predominance of psychological violence (64.3%), and the majority were at risk for malnutrition (54.3%). There was an association between 'having a partner' and psychological (48.1%; p=0.02) and physical (48.1%; p=0.03) violence. Logistic regression demonstrated that being in a relationship or being malnourished increases the likelihood of suffering psychological violence (OR=2.63; OR=3.67), just as not being working increases the likelihood of physical violence (OR=5.61). Conclusion: Violence was negatively related to the nutritional status of elderly community members.
RESUMEN Objetivo: Verificar la prevalencia de violencia entre ancianos de la comunidad y su relación con el estado nutricional y las características sociodemográficas. Método: Estudio transversal and analítico realizado con 159 ancianos de la comunidad registrados en una unidad de salud familiar en Recife/Pernambuco. Se utilizó el Brazil Old Age Schedule; Conflict Tactics Scales y Mini Nutritional Assessment como instrumentos de recolección. Los datos recibieron tratamiento estadístico descriptivo e inferencial. Resultados: Entre los ancianos clasificados con violencia, predominaba la violencia psicológica (64,3%), y la mayoría de ellos están en riesgo de desnutrición (54,3%). Hubo una asociación entre 'tener pareja' y violencia psicológica (48,1%; p=0,02) y física (48,1%; p=0,03). La regresión logística demostró que estar en una relación o estar desnutrido aumenta la probabilidad de sufrir violencia psicológica (OR=2,63; OR=3,67), así como, no estar trabajando aumenta la probabilidad de violencia física (OR=5,61). Conclusión: La violencia se relacionó negativamente con el estado nutricional de los ancianos de la comunidad.
RESUMO Objetivo: Verificar a prevalência da violência entre idosos comunitários e sua relação com o estado nutricional e características sociodemográficas. Método: Estudo transversal, desenvolvido com 159 idosos comunitários cadastrados em Unidade de Saúde da Família em Recife/Pernambuco entre março de 2016 e março de 2017. Foram utilizados Brazil Old Age Schedule, Conflict Tactics Scales e Mini Nutritional Assessment como instrumentos de coleta. Os dados receberam tratamento estatístico descritivo e inferencial. Resultados: Dentre os idosos considerados com violência, houve predomínio da violência psicológica (64,3%), e a maioria possuía risco para desnutrição (54,3%). Verificou-se associação entre 'ter um companheiro' e a violência psicológica (48,1%; p=0,02) e física (48,1%; p=0,03). A regressão logística demonstrou que ter um companheiro ou estar desnutrido aumenta a probabilidade de sofrer violência psicológica (OR=2,63; OR=3,67), assim como não estar trabalhando aumenta a probabilidade de violência física (OR=5,61). Conclusões: A violência se relacionou negativamente ao estado nutricional dos idosos comunitários.
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Zika virus (ZIKV) is a mosquito-borne Flavivirus structurally and antigenically related to Dengue virus (DENV). Zika virus has been associated with congenital anomalies and most ZIKV outbreaks have occurred in endemic areas of DENV. The present study investigated the effects of prior DENV serotype 1 (DENV1) immunity in immunocompetent female Swiss mice on gestational ZIKV infection in offspring. Physical/reflex development, locomotor activity, anxiety, visual acuity, and brain-derived neurotrophic factor (BDNF) levels were evaluated in offspring during infancy and adolescence. Anti-DENV1 and anti-ZIKV antibodies were detected in sera of the progenitors, whereas no ZIKV genomes were detected in the offspring brain. Pups from dams with only DENV1 immunity presented alterations of physical/reflex development. Pups from all infected dams exhibited time-related impairments in locomotor activity and anxiolytic-like behavior. Offspring from DENV/ZIKV-infected dams exhibited impairments in visual acuity during infancy but not during adolescence, which was consistent with morphometric analysis of the optic nerve. Pups from DENV1-, ZIKV-, and DENV/ZIKV-infected dams exhibited a decrease in BDNF levels during infancy and an increase during adolescence in distinct brain regions. In summary, we found no influence of prior DENV1 immunity on gestational ZIKV infection in offspring, with the exception of alterations of early visual parameters, and an increase in BDNF levels in the hippocampus during adolescence.
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Conducta Animal , Dengue/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/psicología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/psicología , Animales , Encéfalo/inmunología , Encéfalo/virología , Factor Neurotrófico Derivado del Encéfalo/inmunología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Femenino , Masculino , Aprendizaje por Laberinto , Ratones , EmbarazoRESUMEN
The psychostimulant drug modafinil has been used for many years for the treatment of sleep disorders. Recent studies have indicated that modafinil has immunomodulatory properties in the central nervous system (CNS) and peripheral immune cells. Thus, our aim was to determine the effects of in vivo therapeutic treatment with modafinil on the severity of clinical symptoms and immune response during the acute phase of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis. Modafinil treatment, given after the onset of symptoms, resulted in an improvement of EAE symptoms and motor impairment, which was correlated with reduced cellular infiltrate and a decreased percentage of T helper (Th) 1 cells in the CNS. The spinal cord analysis revealed that modafinil treatment decreased interferon (IFN)-γ and interleukin (IL)-6 protein levels and down regulated genes related to Th1 immunity, such as IFN-γ and TBX21, without affecting Th17-related genes. Our research indicates that therapeutic modafinil treatment has anti-inflammatory properties in an EAE model by inhibiting brain Th1 response, and may be useful as adjuvant treatment for multiple sclerosis.
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Estimulantes del Sistema Nervioso Central/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Modafinilo/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Citocinas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Ratones Endogámicos C57BL , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunologíaRESUMEN
Multiple sclerosis (MS) is an autoimmune and neuroinflammatory disease characterized by demyelination of the Central Nervous System. Immune cells activation and release of pro-inflammatory cytokines play a crucial role in the disease modulation, decisively contributing to the neurodegeneration observed in MS and the experimental autoimmune encephalomyelitis (EAE), the widely used MS animal model. Synthetic glucocorticoids, commonly used to treat the MS attacks, have controversial effects on neuroinflammation and cognition. We sought to verify the influence of dexamethasone (DEX) on the EAE progression and on EAE-induced cognitive deficits. In myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced EAE female mice, treated once with DEX (50 mg/kg) or not, on the day of immunization, DEX decreased EAE-induced motor clinical scores, infiltrating cells in the spinal cord and delayed serum corticosterone peak. At the asymptomatic phase (8-day post-immunization), DEX did not protected from the EAE-induced memory consolidation deficits, which were accompanied by increased glucocorticoid receptor (GR) activity and decreased EGR-1 expression in the hippocampus. Blunting hippocampal GR genomic activation with DnGR vectors prevented DEX effects on EAE-induced memory impairment. These data suggest that, although DEX improves clinical signs, it decreases cognitive and memory capacity by diminishing neuronal activity and potentiating some aspects of neuroinflammation in EAE.
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Antiinflamatorios/administración & dosificación , Dexametasona/administración & dosificación , Encefalomielitis Autoinmune Experimental/complicaciones , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Trastornos Motores/etiología , Trastornos Motores/prevención & control , Animales , Antiinflamatorios/farmacocinética , Corticosterona/sangre , Dexametasona/farmacocinética , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/diagnóstico , Técnica del Anticuerpo Fluorescente , Hipocampo/metabolismo , Hipocampo/patología , Ratones , Ratones Endogámicos C57BL , Trastornos Motores/fisiopatología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/tratamiento farmacológico , Receptores de Glucocorticoides/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patologíaRESUMEN
Stem cells from human exfoliated deciduous teeth (SHED) have great therapeutic potential and here, by the first time, we evaluated their immunomodulatory effect on experimental model of autoimmune encephalomyelitis (EAE). Specifically, we investigated the effect of SHED administration on clinical signs and cellular patterns in EAE model using Foxp3 GFP + transgenic mice (C57Bl/6-Foxp3GFP). The results showed that SHED infusion ameliorated EAE clinical score with reduced number of infiltrating IFN-γ+CD8+, IL-4+CD8+, IFN-γ+CD4+ and IL-4+CD4+ T cells into the central nervous system (CNS). In addition, we observed that SHED promoted a significant increase in CD4+FOXP3+ T cells population in the spleen of EAE-affected animals. Taken together, our results provide strong evidence that SHED can modulate peripherally the CD4+ T cell responses suggesting that SHED would be explored as part of cellular therapy in autoimmune diseases associated with CNS.
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Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Encefalomielitis Autoinmune Experimental , Trasplante de Células Madre , Células Madre , Diente Primario/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/terapia , Xenoinjertos , Humanos , Ratones , Ratones Transgénicos , Células Madre/inmunología , Células Madre/patología , Diente Primario/patologíaRESUMEN
Our understanding of how thymocytes differentiate into many subtypes has been increased progressively in its complexity. At early life, the thymus provides a suitable microenvironment with specific combination of stromal cells, growth factors, cytokines, and chemokines to induce the bone marrow lymphoid progenitor T-cell precursors into single-positive CD4(+) and CD8(+) T effectors and CD4(+)CD25(+) T-regulatory cells (Tregs). At postthymic compartments, the CD4(+) T-cells acquire distinct phenotypes which include the classical T-helper 1 (Th1), T-helper 2 (Th2), T-helper 9 (Th9), T-helper 17 (Th17), follicular helper T-cell (Tfh), and induced T-regulatory cells (iTregs), such as the regulatory type 1 cells (Tr1) and transforming growth factor-ß- (TGF-ß-) producing CD4(+) T-cells (Th3). Tregs represent only a small fraction, 5-10% in mice and 1-2% in humans, of the overall CD4(+) T-cells in lymphoid tissues but are essential for immunoregulatory circuits mediating the inhibition and expansion of all lineages of T-cells. In this paper, we first provide an overview of the major cell-intrinsic developmental programs that regulate T-cell lineage fates in thymus and periphery. Next, we introduce the SV40 immortomouse as a relevant mice model for implementation of new approaches to investigate thymus organogenesis, CD4 and CD8 development, and thymus cells tumorogenesis.
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Linfocitos T CD4-Positivos/citología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Tejido Linfoide/citología , Ratones , Células TH1/citología , Células TH1/inmunología , Células Th17/citología , Células Th17/inmunología , Células Th2/citología , Células Th2/inmunología , Timocitos/citología , Timocitos/inmunologíaRESUMEN
Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.
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Modelos Animales de Enfermedad , Microcefalia/virología , Virus Zika/patogenicidad , Animales , Apoptosis , Autofagia , Encéfalo/patología , Encéfalo/virología , Brasil/epidemiología , Proliferación Celular , Femenino , Retardo del Crecimiento Fetal/patología , Retardo del Crecimiento Fetal/virología , Feto/virología , Ratones , Microcefalia/epidemiología , Microcefalia/etiología , Microcefalia/patología , Células-Madre Neurales/patología , Células-Madre Neurales/virología , Organoides/patología , Organoides/virología , Placenta/virología , Embarazo , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/epidemiología , Infección por el Virus Zika/patología , Infección por el Virus Zika/virologíaRESUMEN
Leishmania (L.) amazonensis [L. (L.) amazonensis] is widely distributed in Brazil and its symptomatic infections usually lead to few localized lesions and sometimes to diffuse cutaneous form, with nodules throughout the body, anergy to parasite antigens and poor therapeutic response. The variability of these manifestations draws attention to the need for studies on the pathophysiology of infection by this species. In this study, we analysed the course and immunological aspects of L. (L.) amazonensis infection in BALB/c and C57BL/6 strains, both susceptible, but displaying different clinical courses, and athymic BALB/c nude, to illustrate the role of T cell dependent responses. We analysed footpad thickness and parasite burden by in vivo imaging. Furthermore, we evaluated the cellular profile and cytokine production in lymph nodes and the inflammatory infiltrates of lesions. Nude mice showed delayed lesion development and less inflammatory cells in lesions, but higher parasite burden than BALB/c and C57BL/6. BALB/c and C57BL/6 mice had similar parasite burdens, lesion sizes and infiltrates until 6 weeks after infection, and after that C57BL/6 mice controlled the infection. Small differences in parasite numbers were observed in C57BL/6 macrophages in vitro, indicating that in vivo milieu accounts for most differences in infection. We believe our results shed light on the role of host immune system in the course of L. (L.) amazonensis infection by comparing three mouse strains that differ in parasitaemia and inflammatory cells.
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Interacciones Huésped-Parásitos/inmunología , Leishmaniasis Cutánea/inmunología , Animales , Citocinas/inmunología , Leishmania/inmunología , Ganglios Linfáticos/citología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Carga de Parásitos , Especificidad de la EspecieRESUMEN
Cigarette smoke-induced chronic obstructive pulmonary disease is a very debilitating disease, with a very high prevalence worldwide, which results in a expressive economic and social burden. Therefore, new therapeutic approaches to treat these patients are of unquestionable relevance. The use of mesenchymal stromal cells (MSCs) is an innovative and yet accessible approach for pulmonary acute and chronic diseases, mainly due to its important immunoregulatory, anti-fibrogenic, anti-apoptotic and pro-angiogenic. Besides, the use of adjuvant therapies, whose aim is to boost or synergize with their function should be tested. Low level laser (LLL) therapy is a relatively new and promising approach, with very low cost, no invasiveness and no side effects. Here, we aimed to study the effectiveness of human tube derived MSCs (htMSCs) cell therapy associated with a 30mW/3J-660 nm LLL irradiation in experimental cigarette smoke-induced chronic obstructive pulmonary disease. Thus, C57BL/6 mice were exposed to cigarette smoke for 75 days (twice a day) and all experiments were performed on day 76. Experimental groups receive htMSCS either intraperitoneally or intranasally and/or LLL irradiation either alone or in association. We show that co-therapy greatly reduces lung inflammation, lowering the cellular infiltrate and pro-inflammatory cytokine secretion (IL-1ß, IL-6, TNF-α and KC), which were followed by decreased mucus production, collagen accumulation and tissue damage. These findings seemed to be secondary to the reduction of both NF-κB and NF-AT activation in lung tissues with a concomitant increase in IL-10. In summary, our data suggests that the concomitant use of MSCs + LLLT may be a promising therapeutic approach for lung inflammatory diseases as COPD.
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Células Madre Mesenquimatosas/metabolismo , Nicotiana/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Fumar/efectos adversos , Adulto , Animales , Líquido del Lavado Bronquioalveolar/química , Células Cultivadas , Femenino , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Terapia por Luz de Baja Intensidad/métodos , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Neumonía/inducido químicamente , Neumonía/metabolismo , Humo/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Experimental autoimmune uveitis (EAU) is a well established model for immune-mediated organ-specific disease. Our group has recently shown that the M. leprae Hsp65 aggravated the uveitis in mice; in the present study, we evaluated the action of M. leprae K(409)A mutant protein and the synthetic peptides Leader pep and K(409)A pep (covering amino acids residues 352-371 of WT and K(409)A proteins of M. leprae Hsp65, resp.) on the pathogenesis of EAU. Mice received the 161-180 IRBP peptide and B. pertussis toxin followed by the intraperitoneal inoculation of K(409)A protein or the Leader pep or K(409)A pep. The Leader pep aggravated the disease, but mice receiving the K(409)A pep did not develop the disease and presented an increase in IL-10 levels by spleen cells and a decrease in the percentage of CD4+ IFN-γ+ T cells. Moreover, animals receiving the Leader pep presented the highest scores of the disease associated with increase percentage of CD4+ IFN-γ+ T cells. These results would contribute to understanding of the pathogenesis of EAU and support the concept that immune responses to Hsp are of potential importance in exacerbating, perpetuating, or even controlling organ-restricted autoimmune diseases, and it is discussed the irreversibility of autoimmune syndromes.
RESUMEN
OBJECTIVES: FTY720 modulates CD4+T cells by the augmentation of regulatory T cell activity, secretion of suppressive cytokines and suppression of IL-17 secretion by Th17 cells. To further understand the process of graft rejection/acceptance, we evaluated skin allograft survival and associated events after FTY720 treatment. METHODS: F1 mice (C57BL/6xBALB/c) and C57BL/6 mice were used as donors for and recipients of skin transplantation, respectively. The recipients were transplanted and either not treated or treated with FTY720 by gavage for 21 days to evaluate the allograft survival. In another set of experiments, the immunological evaluation was performed five days post-transplantation. The spleens, axillary lymph nodes and skin allografts of the recipient mice were harvested for phenotyping (flow cytometry), gene expression (real-time PCR) and cytokine (Bio-Plex) analysis. RESULTS: The FTY720 treatment significantly increased skin allograft survival, reduced the number of cells in the lymph nodes and decreased the percentage of Tregs at this site in the C57BL/6 recipients. Moreover, the treatment reduced the number of graft-infiltrating cells and the percentage of CD4+ graft-infiltrating cells. The cytokine analysis (splenocytes) showed decreased levels of IL-10, IL-6 and IL-17 in the FTY720-treated mice. We also observed a decrease in the IL-10, IL-6 and IL-23 mRNA levels, as well as an increase in the IL-27 mRNA levels, in the splenocytes of the treated group. The FTY720-treated mice exhibited increased mRNA levels of IL-10, IL-27 and IL-23 in the skin graft. CONCLUSIONS: Our results demonstrated prolonged but not indefinite skin allograft survival by FTY720 treatment. This finding indicates that the drug did not prevent the imbalance between Tr1 and Th17 cells in the graft that led to rejection.
Asunto(s)
Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Glicoles de Propileno/uso terapéutico , Trasplante de Piel/inmunología , Esfingosina/análogos & derivados , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Citocinas/metabolismo , Femenino , Clorhidrato de Fingolimod , Citometría de Flujo , Rechazo de Injerto/inmunología , Supervivencia de Injerto/inmunología , Interleucinas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Esfingosina/uso terapéutico , Linfocitos T Reguladores/inmunología , Células Th17/inmunologíaRESUMEN
OBJECTIVES: FTY720 modulates CD4+T cells by the augmentation of regulatory T cell activity, secretion of suppressive cytokines and suppression of IL-17 secretion by Th17 cells. To further understand the process of graft rejection/acceptance, we evaluated skin allograft survival and associated events after FTY720 treatment. METHODS: F1 mice (C57BL/6xBALB/c) and C57BL/6 mice were used as donors for and recipients of skin transplantation, respectively. The recipients were transplanted and either not treated or treated with FTY720 by gavage for 21 days to evaluate the allograft survival. In another set of experiments, the immunological evaluation was performed five days post-transplantation. The spleens, axillary lymph nodes and skin allografts of the recipient mice were harvested for phenotyping (flow cytometry), gene expression (real-time PCR) and cytokine (Bio-Plex) analysis. RESULTS: The FTY720 treatment significantly increased skin allograft survival, reduced the number of cells in the lymph nodes and decreased the percentage of Tregs at this site in the C57BL/6 recipients. Moreover, the treatment reduced the number of graft-infiltrating cells and the percentage of CD4+ graft-infiltrating cells. The cytokine analysis (splenocytes) showed decreased levels of IL-10, IL-6 and IL-17 in the FTY720-treated mice. We also observed a decrease in the IL-10, IL-6 and IL-23 mRNA levels, as well as an increase in the IL-27 mRNA levels, in the splenocytes of the treated group. The FTY720-treated mice exhibited increased mRNA levels of IL-10, IL-27 and IL-23 in the skin graft. CONCLUSIONS: Our results demonstrated prolonged but not indefinite skin allograft survival by FTY720 treatment. This finding indicates that the drug did not prevent the imbalance between Tr1 and Th17 cells in the graft that led to rejection.