RESUMO
Multiple sclerosis is a severe demyelinating disease mediated by cells of the innate and adaptive immune system, especially pathogenic T lymphocytes that produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). Although the factors and molecules that drive the genesis of these cells are not completely known, some were discovered and shown to promote the development of such cells, such as dietary factors. In this regard, iron, the most abundant chemical element on Earth, has been implicated in the development of pathogenic T lymphocytes and in MS development via its effects on neurons and glia. Therefore, the aim of this paper is to revise the state-of-art regarding the role of iron metabolism in cells of key importance to MS pathophysiology, such as pathogenic CD4+ T cells and CNS resident cells. Harnessing the knowledge of iron metabolism may aid in the discovery of new molecular targets and in the development of new drugs that tackle MS and other diseases that share similar pathophysiology.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Humanos , Esclerose Múltipla/etiologia , Esclerose Múltipla/terapia , Linfócitos T , CitocinasRESUMO
Obesity-induced insulin resistance (OIR) has been associated with an increased prevalence of neurodegenerative disorders such as multiple sclerosis. Obesity results in increased blood-brain barrier (BBB) permeability, specifically in the hypothalamic regions associated with the control of caloric intake. In obesity, the chronic state of low-grade inflammation has been implicated in several chronic autoimmune inflammatory disorders. However, the mechanisms that connect the inflammatory profile of obesity with the severity of experimental autoimmune encephalomyelitis (EAE) are poorly defined. In this study, we show that obese mice are more susceptible to EAE, presenting a worse clinical score with more severe pathological changes in the spinal cord when compared with control mice. Analysis of immune infiltrates at the peak of the disease shows that high-fat diet (HFD)- and control (chow)-fed groups do not present any difference in innate or adaptive immune cell compartments, indicating the increased severity occurs prior to disease onset. In the setting of worsening EAE in HFD-fed mice, we observed spinal cord lesions in myelinated regions and (blood brain barrier) BBB disruption. We also found higher levels of pro-inflammatory monocytes, macrophages, and IFN-γ+CD4+ T cells in the HFD-fed group compared to chow-fed animals. Altogether, our results indicate that OIR promotes BBB disruption, allowing the infiltration of monocytes/macrophages and activation of resident microglia, ultimately promoting CNS inflammation and exacerbation of EAE.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Esclerose Múltipla/patologia , Barreira Hematoencefálica/patologia , Inflamação/patologia , Permeabilidade , Obesidade/complicações , Camundongos Endogâmicos C57BLRESUMO
Numerous studies relate the onset and severity of multiple sclerosis (MS) with viral infections. Herpes simplex virus type 1 (HSV-1), which is neurotropic and highly prevalent in the brain of healthy individuals, has been proposed to relate to MS. Here, we review and discuss the reported connections between HSV-1 and MS.
Assuntos
Infecções por Vírus Epstein-Barr , Herpes Simples , Herpesvirus Humano 1 , Esclerose Múltipla , Viroses , Humanos , DNA ViralRESUMO
Dysregulated microglia and astrocytes have been associated with progressive neurodegeneration in multiple sclerosis (MS), highlighting the need for strategies that additionally target intrinsic inflammation in the central nervous system (CNS). The objective of the present study was to investigate the glial response in experimental autoimmune encephalomyelitis (EAE)-induced mice treated with a combination of dimethyl fumarate (DMF) and pregabalin (PGB). For that, 28 C57BL/6J mice were randomly assigned to the five experimental groups: naïve, EAE, EAE-DMF, EAE-PGB, and EAE-DMF + PGB. Pharmacological treatments were initiated with the beginning of clinical signs, and all animals were euthanized at 28 dpi for the lumbar spinal cord evaluation. The results demonstrated a stronger attenuation of the clinical presentation by the combined approach. DMF alone promoted the downregulation of Iba-1 (microglia/macrophages marker) in the ventral horn compared with the non-treated EAE animals (P < 0.05). PGB treatment was associated with reduced Iba-1 immunofluorescence in both the dorsal (P < 0.05) and ventral horn (P < 0.05) compared to EAE vehicle-treated counterparts. However, the combined approach reduced the Iba-1 marker in the dorsal (P < 0.05) and ventral (P < 0.01) horns compared to non-treated EAE animals and further reduced Iba-1 in the ventral horn compared to each drug-alone approach (P < 0.05). In addition, the combination of DMF and PGB reduced activated astrocytes (GFAP) in both the dorsal and ventral horns of the spinal cord to a naïve-like level and upregulated Nrf-2 expression. Taken together, the data herein suggest robust attenuation of the glial response in EAE mice treated with DMF and PGB.
RESUMO
Multiple sclerosis (MS) is a highly disabling, progressive neurodegenerative disease with no curative treatment available. Although significant progress has been made in understanding how MS develops, there remain aspects of disease pathogenesis that are yet to be fully elucidated. In this regard, studies have shown that dysfunctional adenosinergic signaling plays a pivotal role, as patients with MS have altered levels adenosine (ADO), adenosine receptors and proteins involved in the generation and termination of ADO signaling, such as CD39 and adenosine deaminase (ADA). We have therefore performed a literature review regarding the involvement of the adenosinergic system in the development of MS and propose mechanisms by which the modulation of this system can support drug development and repurposing.
Assuntos
Esclerose Múltipla , Doenças Neurodegenerativas , Receptores Purinérgicos P1 , Adenosina/imunologia , Adenosina Desaminase/imunologia , Apirase/imunologia , Humanos , Esclerose Múltipla/etiologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/terapia , Receptores Purinérgicos P1/imunologia , Transdução de SinaisRESUMO
In times of crisis, prophets tend to emerge in different realms including that of religion. This paper undertakes a Jungian analysis of the phenomenon presented between spiritual leader Osho and his disciples in the 1970s and 1980s, as an example of the risks entailed in the type of group process where leader and followers inadvertently identify with the collective archetypes of prophet and follower. Psychosocial situations that predispose the appearance of prophets are analysed, and cases of collective suicides in recent decades are recalled. The paper also highlights the intervention of another psychological phenomenon: the conflict between the ethics of individuals versus that of groups, since large groups produce a decrease in responsibility and individual ethics.
Dans les périodes de crise, des prophètes ont tendance à faire leur apparition dans différents domaines, dont celui de la religion. Cet article entreprend une analyse Jungienne du phénomène que présentent le leader spirituel Osho et ses disciples dans les années 70 et 80, en tant qu'exemple des risques inhérents à ce genre de processus de groupe dans lequel leader et adeptes s'identifient par inadvertance aux archétypes collectifs de prophète et d'adepte. L'article analyse des situations psychosociales qui prédisposent à l'apparition de prophètes, et revisite des cas de suicides collectifs dans les décennies récentes. L'article souligne aussi l'intervention d'un autre phénomène psychologique: le conflit qui oppose l'éthique des individus à l'éthique des groupes, puisque les grands groupes produisent une diminution de responsabilité et d'éthique individuelle.
En tiempo de crisis, los profetas tienden a emerger en ámbitos diversos, incluyendo también el de la religión. El presente trabajo desarrolla un análisis Junguiano del fenómeno ocurrido entre el líder espiritual Osho y sus discípulos en las décadas del 70 y 80, como ejemplo del riesgo que conllevan ciertos procesos en un grupo en el cual líder y seguidores se identifican inadvertidamente con los arquetipos de profeta y seguidor del inconsciente colectivo. Se analizan situaciones psicosociales que predisponen la aparición de profetas, y se recuerdan casos de suicidios colectivos de las décadas recientes. El trabajo destaca también la intervención de otro fenómeno psicológico: el conflicto entre la ética del individuo versus la del grupo, debido a que grupos extensos producen una disminución de la responsabilidad y de la ética individual.
Em tempos de crise, os profetas tendem a surgir em diferentes reinos, incluindo o da religião. Este artigo empreende uma análise junguiana do fenômeno apresentado entre o líder espiritual Osho e seus discípulos nas décadas de 1970 e 1980, como um exemplo dos riscos envolvidos no tipo de processo grupal em que líder e seguidores se identificam inadvertidamente com os arquétipos coletivos de profeta e seguidor. Situações psicossociais que predispõem ao aparecimento de profetas são analisadas, e casos de suicídios coletivos nas últimas décadas são lembrados. O artigo também destaca a intervenção de outro fenômeno psicológico: o conflito entre a ética dos indivíduos versus a dos grupos, já que grandes grupos produzem uma diminuição na responsabilidade e na ética individual.
Assuntos
Suicídio , Humanos , Comportamento SocialRESUMO
Epigenetics is the study of how signals from the environment can change gene expression through the creation of molecules and chemical bonds that can last a lifetime and, therefore, determine the phenotype (the characteristics of the individual resulting from the interaction of their genotype [genes] with their environment). Research in this field began at McGill University, Canada, where it was observed that rats' mothers who were more nurturing raised more resilient pups. Since then, many studies have been carried out with animals and humans, showing the link between epigenetic changes and the experience of the great mother archetype - with potential consequences for the emotional life of the individual and for society.
L'épigénétique est l'étude de comment les signaux provenant de l'environnement peuvent changer l'expression des gènes, par la création de molécules et de liens chimiques qui peuvent durer toute la vie et qui, de ce fait, déterminent le phénotype. La recherche dans ce domaine a commencé à l'université McGill au Canada: il y a été observé que les mères de rats plus maternelles élevaient des jeunes plus résilients. Depuis, de nombreuses études ont été menées avec des animaux et des humains, montrant le lien entre les changements épigénétiques et l'expérience de l'archétype de la grande mère, avec des conséquences potentielles pour la vie émotionnelle de l'individu et pour la société.
La epigenética es el estudio de cómo señales del medio ambiente pueden modificar la expresión genética, a través de la creación de moléculas y enlaces químicos que pueden durar toda la vida y, por lo tanto, determinar el fenotipo. Las investigaciones en este campo comenzaron en la Universidad McGill, en Canadá, donde fue observado que las madres de ratas que fueron más nutricias criaban crías más resilientes. Desde entonces, se han llevado a cabo muchos estudios con animales y humanos, mostrando el vínculo entre los cambios epigenéticos y la experiencia del arquetipo de la Gran Madre - con consecuencias potenciales para la vida emocional del individuo y de la sociedad.
A epigenética é o estudo de como o ambiente pode interferir na expressão gênica, através de moléculas e ligações químicas que podem durar por toda a vida e, portanto, determinar o fenótipo. Todas as pesquisas começaram na universidade McGill, onde observou-se que ratas mais cuidadosas, maior comportamento de limpar e lamber os filhotes, acabavam por desenvolver filhotes com mais resiliência. Desde então muitas pesquisas foram realizadas com animais e seres humanos evidenciando a ligação entre epigenética e a experiência dentro do arquétipo da grande mãe e suas potenciais consequências para com os aspectos emocionais do indivíduo e da sociedade.
Assuntos
Epigênese Genética , Mães , Animais , Feminino , Humanos , RatosRESUMO
This paper explores the images related to Carnival in the texts of early Brazilian modernist writers, who wanted to minimize the feeling of inauthenticity due to the systematic emulation of European aesthetic matrices. This critique of Brazilian 'nationalist' complexes was manifested in cultural forms which were unlinked from academic approaches, but were instead expressed in the registers of the popular songbook - sung-poems in which Carnival-related images abounded. In the analysis of this set of poems, the paper outlines the emerging of a poetry of 'masking', raising the hypothesis that these poets had invented a tradition that aimed for a native originality, having the celebration of Carnival and its mythical variants as its literary motivation. During the 1930's, Carnival-related images became rare in written poetry, establishing the sung poems as their permanent ground. With Orfeu da Conceição, in 1956, Vinicius de Moraes converged these two elements, dissolving the remaining boundaries that set them apart. This paper explores the images of Carnival and the mask, and attempts to unmask the characteristics of a form of Brazilian culture, including, in particular, its racism.
Cet article étudie les images en lien avec le Carnaval dans les textes d'auteurs Brésiliens modernistes, auteurs qui ont voulu minimiser les sentiments d'inauthenticité dus à l'imitation systématique des matrices esthétiques Européennes. Cette critique des complexes Brésiliens 'nationalistes' s'est révélée dans des formes culturelles qui ne sont pas liées aux approches universitaires mais furent plutôt exprimées dans les registres de chansons populaires - les poèmes chantés dans lesquels les images en lien avec le Carnaval sont abondantes. Par l'analyse de cette série de poèmes, l'article souligne l'émergence d'une poésie du masquage, soulevant l'hypothèse que ces poètes inventèrent une tradition qui vise l'originalité indigène, et qui trouve dans la célébration du Carnaval et ses variantes mythiques une motivation littéraire. Dans les années 30, les images liées au Carnaval sont devenues rares dans la poésie écrite, ce qui instaure les poèmes chantés comme leur terrain permanent. Avec Orfeu da Conceiçao, en 1956, Vinicius de Moraes a fait converger ces deux éléments, faisant fondre les dernières barrières qui les maintenaient séparés. Cet article étudie les images du Carnaval et du masque et vise à démasquer les caractéristiques d'une forme de culture Brésilienne, en incluant tout particulièrement son racisme.
El presente trabajo explora las imágenes relacionadas al Carnaval en los textos de los escritores modernos brasileros, quienes quisieron minimizar el sentimiento de inautenticidad debido a la emulación sistemática de las matrices estéticas europeas. Esta crítica de los complejos 'nacionalistas' brasileros se manifestó a través de formas culturales, que, a diferencias de los abordajes académicos, se expresaban a través de los cancioneros populares - poemas-cantados en los que abundan imágenes vinculadas al Carnaval. A través del análisis de estos poemas, el trabajo describe la emergencia de una poesía del 'enmascaramiento', creando la hipótesis de que estos poetas han inventado una tradición que persiguió la originalidad nativa, teniendo como su motivación para la escritura la celebración del Carnaval y sus variantes míticas. Durante la década del 30, las imágenes relativas al Carnaval eran raras en la poesía escrita, estableciendo su suelo permanente en los cancioneros. Con Orfeu da Conceição, en 1956, Vinicius de Moraes hizo converger estos dos elementos, disolviendo los límites restantes que los separaban. El presente trabajo explora las imágenes de Carnaval y sus máscaras, y los intentos de desenmascarar las características de una forma cultural brasilera, incluyendo particularmente, su racismo.
Este artigo explora as imagens relacionadas ao Carnaval nos textos dos primeiros escritores modernistas brasileiros, que queriam minimizar o sentimento de inautenticidade devido à emulação sistemática das matrizes estéticas europeias. Essa crítica aos complexos "nacionalistas" brasileiros se manifestou em formas culturais que estavam desvinculadas das abordagens acadêmicas, mas foram expressas nos registros do cancioneiro popular - poemas cantados nos quais imagens relacionadas ao Carnaval abundavam. Na análise desse conjunto de poemas, o artigo descreve o surgimento de uma poesia de "mascaramento", levantando a hipótese de que esses poetas inventaram uma tradição que visava uma originalidade nativa, tendo a celebração do Carnaval e suas variantes míticas como sua motivação literária. Durante a década de 1930, imagens relacionadas ao Carnaval se tornaram raras na poesia escrita, estabelecendo os poemas cantados como seu terreno permanente. Com Orfeu da Conceição, em 1956, Vinicius de Moraes convergiu esses dois elementos, dissolvendo os limites restantes que os diferenciavam. Este artigo explora as imagens do Carnaval e da máscara e tenta desmascarar as características de uma forma de cultura brasileira, incluindo, em particular, seu racismo.
Assuntos
Racismo , Canto , Brasil , Emoções , HumanosRESUMO
Metabolites produced by the gut microbiota have been shown to play an important role in numerous inflammatory, neuropsychiatric, and neurodegenerative diseases. Specifically, microbial metabolites have been implicated in the modulation of innate and adaptive immunity, especially in the generation of regulatory T cells (Tregs), which are key regulators of multiple sclerosis (MS) pathogenesis. Furthermore, they affect processes relevant to MS pathophysiology, such as inflammation and demyelination, which makes them attractive molecules to be explored as therapeutics in MS. In this review, we discuss the importance of these metabolites as factors contributing to disease pathogenesis and as therapeutic targets in MS. Establishing an improved understanding of these gut-microbiota derived metabolites may provide new avenues for the treatment of MS.
RESUMO
TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Interferon beta-1b/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Peptídeos/uso terapêuticoRESUMO
Development and implementation of effective protected area management to reduce deforestation depend in part on identifying factors contributing to forest loss and areas at risk of conversion, but standard land-use-change modeling may not fully capture contextual factors that are not easily quantified. To better understand deforestation and agricultural expansion in Amazonian protected areas, we combined quantitative land-use-change modeling with qualitative discourse analysis in a case study of Brazil's Jamanxim National Forest. We modeled land-use change from 2008 to 2018 and projected deforestation through 2028. We used variables identified in a review of studies that modeled land-use change in the Amazon (e.g., variables related to agricultural suitability and economic accessibility) and from a critical discourse analysis that examined documents produced by different actors (e.g., government agencies and conservation nonprofit organizations) at various spatial scales. As measured by analysis of variance, McFadden's adjusted pseudo R2 , and quantity and allocation disagreement, we found that including variables in the model identified as important to deforestation dynamics through the qualitative discourse analysis (e.g., the proportion of unallocated public land, distance to proposed infrastructure developments, and density of recent fires) alongside more traditional variables (e.g., elevation, distance to roads, and protection status) improved the predictive ability of these models. Models that included discourse analysis variables and traditional variables explained up to 19.3% more of the observed variation in deforestation probability than a model that included only traditional variables and 4.1% more variation than a model with only discourse analysis variables. Our approach of integrating qualitative and quantitative methods in land-use-change modeling provides a framework for future interdisciplinary work in land-use change.
El desarrollo y la implementación de la gestión efectiva de las áreas protegidas para reducir la deforestación dependen parcialmente de la identificación de los factores que contribuyen a la pérdida del bosque y de las áreas en riesgo de ser convertidas, pero el modelado estándar del cambio de uso de suelo puede no capturar completamente los factores contextuales que no se cuantifican fácilmente. Combinamos el modelado cuantitativo del cambio de uso de suelo con el análisis cualitativo del discurso en un estudio de caso del Bosque Nacional Jamanxim de Brasil para entender de mejor manera la deforestación y la expansión agrícola en las áreas protegidas del Amazonas. Modelamos el cambio de uso de suelo entre 2008 y 2018 y lo proyectamos hasta 2028. Usamos las variables identificadas en una revisión de estudios que modelaron el cambio de uso de suelo en el Amazonas (p. ej.: variables relacionadas con la idoneidad agrícola y la accesibilidad económica) y en el análisis crítico del discurso que examinó documentos producidos por diferentes actores (p. ej.: agencias gubernamentales y organizaciones sin fines de lucro para la conservación) a varias escalas espaciales. Conforme a las medidas del análisis de varianza, la pseudo-R2 ajustada de McFadden y el desacuerdo en la cantidad y la asignación, descubrimos que la inclusión dentro del modelo de las variables identificadas como importantes para las dinámicas de deforestación mediante el análisis cualitativo del discurso (p. ej.: la proporción de terrenos públicos sin asignar, la distancia hacia los desarrollos propuestos de infraestructura y la densidad de incendios recientes) junto con variables más tradicionales (p. ej.: elevación, distancia a las carreteras y estado de protección) mejoró la habilidad predictiva de dichos modelos. Los modelos que incluyeron la mezcla de variables explicaron hasta 19.3% más de la variación observada en la probabilidad de deforestación que un modelo que solamente incluyó las variables tradicionales y 4.1% más variación que un modelo con las variables del análisis del discurso. Nuestra estrategia de integrar los métodos cualitativos y cuantitativos dentro del modelado del cambio de uso de suelo proporciona un marco para futuros trabajos interdisciplinarios sobre el cambio de uso de suelo.
Assuntos
Conservação dos Recursos Naturais , Incêndios , Florestas , Agricultura , BrasilRESUMO
RATIONALE: The FDA-approved Dimethyl Fumarate (DMF) as an oral drug for Multiple Sclerosis (MS) treatment based on its immunomodulatory activities. However, it also caused severe adverse effects mainly related to the gastrointestinal system. OBJECTIVE: Investigated the potential effects of solid lipid nanoparticles (SLNs) containing DMF, administered by inhalation on the clinical signs, central nervous system (CNS) inflammatory response, and lung function changes in mice with experimental autoimmune encephalomyelitis (EAE). MATERIALS AND METHODS: EAE was induced using MOG35-55 peptide in female C57BL/6J mice and the mice were treated via inhalation with DMF-encapsulated SLN (CTRL/SLN/DMF and EAE/SLN/DMF), empty SLN (CTRL/SLN and EAE/SLN), or saline solution (CTRL/saline and EAE/saline), every 72 h during 21 days. RESULTS: After 21 days post-induction, EAE mice treated with DMF-loaded SLN, when compared with EAE/saline and EAE/SLN, showed decreased clinical score and weight loss, reduction in brain and spinal cord injury and inflammation, also related to the increased influx of Foxp3+ cells into the spinal cord and lung tissues. Moreover, our data revealed that EAE mice showed signs of respiratory disease, marked by increased vascular permeability, leukocyte influx, production of TNF-α and IL-17, perivascular and peribronchial inflammation, with pulmonary mechanical dysfunction associated with loss of respiratory volumes and elasticity, which DMF-encapsulated reverted in SLN nebulization. CONCLUSION: Our study suggests that inhalation of DMF-encapsulated SLN is an effective therapeutic protocol that reduces not only the CNS inflammatory process and disability progression, characteristic of EAE disease, but also protects mice from lung inflammation and pulmonary dysfunction.
Assuntos
Fumarato de Dimetilo/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Lipossomos/administração & dosagem , Nanopartículas/administração & dosagem , Pneumonia/tratamento farmacológico , Administração por Inalação , Animais , Modelos Animais de Doenças , Feminino , Imunossupressores/administração & dosagem , Camundongos Endogâmicos C57BL , Esclerose MúltiplaRESUMO
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.
Assuntos
Encefalomielite Autoimune Experimental , Células-Tronco Mesenquimais , Adulto , Animais , Sistema Nervoso Central , Encefalomielite Autoimune Experimental/terapia , Tubas Uterinas , Feminino , Humanos , Interleucina-10 , Interleucina-4RESUMO
TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.
RESUMO
Resumen La presente revisión sistemática tuvo como objetivo identificar y analizar las propiedades psicométricas de los instrumentos de alimentación emocional (AE) actualmente validados en México. La búsqueda de los test se realizó con base a los criterios PRISMA en tres bases de datos: Pubmed, Science Direct y Redalyc. Fueron identificados dos instrumentos: El Cuestionario sobre la Conducta Alimentaria Relacionada con las Emociones y el Estrés (EADES) y la Escala de Alimentación Emocional (EAE). El método de validez empleado en ambas escalas fue el análisis factorial exploratorio y de confiabilidad el alpha de Cronbach (α = .91 en el EADES y α =.94 en la EAE). Se concluye que el empleo de estas escalas podría estar en función de la definición conceptual y operacional de la AE que considera cada una, con el fin de retomar la que mejor se adecúe a los objetivos del estudio. Asimismo, se sugiere dar continuidad a la consolidación de las propiedades psicométricas de ambas escalas, a través de ampliar a otras poblaciones (clínicas, de diferentes etapas etarias y residentes de distintas zonas del país) así como emplear los actuales indicadores psicométricos sugeridos (entre ellos el AFC y cálculo del coeficiente omega).
Abstract The objective of this systematic review was to identify and analyze the psychometric properties of the emotional eating (EE) tests currently validated in Mexico. The search was performed according to PRISMA criteria in three databases: Pubmed, Science Direct and Redalyc. Two instruments were identified: The Eating and Appraisal Due to Emotions and Stress Questionnaire (EADES) and the Emotional Eating Scale (EAE). The validity method used in both scales was the exploratory factor analysis and reliability of Cronbach's alpha (α = .91 in the EADES and α = .94 in the EES). It is concluded that the use of these scales could be based on the conceptual and operational definition of the EE that each one considers, in order to retake the one that best suits the objectives of the study. In the same way, it's suggested to give continuity to the consolidation of the psychometric properties of both scales, through expanding to other populations (clinics, of different age groups and residents of different areas of the country) as well as using the currently suggested psychometric indicators (among them the CFA and the calculation omega's coefficient).
RESUMO
Multiple sclerosis (MS) is currently thought to arise by interactions between genetic susceptibility and environmental factors. Infections in general trigger autoimmune responses causing clinical manifestations of disease. However, as a result of regulatory T (Treg)- and regulatory B (Breg)-cell induction, helminth infections tend to dampen disease activity. IL-35, the newest member of the IL-12 family, is an inhibitory cytokine composed of an EBI3ß chain subunit, and an IL-12p35 subunit. The aim of this study was to investigate the role of IL-35 during parasite infections occurring in individuals with MS. Numbers of IL-35-producing Breg cells are higher in CSF from helminth-infected than from uninfected MS subjects, a finding associated with decreased MRI disease activity. Interestingly, stimulation of CD19+ B cells with IL-35 promotes conversion of these cells to Breg cells producing both IL-35 and IL-10. Coculture of B cells from helminth-infected MS patients inhibits proliferation of Th1 and Th17 myelin peptide-specific T cells, as well as production of IFN-γ and IL-17. Following activation, CD4+ CD25+ Treg cells significantly upregulate expression of EBI3 and IL-12p35 mRNA. Furthermore, CD4+ CD25- T cells activated in the presence of IL-35 induce a population of cells with regulatory function, known as iTR35. Finally, B cells from normal individuals cultured in vitro in the presence of the helminth antigen SEA increase expression of the transcription BATF, IRF4 and IRF8, acquiring a pattern similar to that of IL-35 Breg cells. These data highlight the important immunoregulatory effects of IL-35 on both Breg and Treg cells, observed in helminth-infected MS subjects.
Assuntos
Linfócitos B Reguladores/imunologia , Helmintíase/imunologia , Interleucinas/metabolismo , Esclerose Múltipla/complicações , Linfócitos T Reguladores/imunologia , Adulto , Animais , Linfócitos B Reguladores/metabolismo , Feminino , Helmintíase/parasitologia , Helmintos/imunologia , Helmintos/isolamento & purificação , Interações Hospedeiro-Parasita , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th17/imunologiaRESUMO
Multiple Sclerosis (MS) is a neuroinflammatory and chronic Central Nervous System (CNS) disease that affects millions of people worldwide. The search for more promising drugs for the treatment of MS has led to studies on Sildenafil, a phosphodiesterase type 5 Inhibitor (PDE5I) that has been shown to possess neuroprotective effects in the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. We have previously shown that Sildenafil improves the clinical score of EAE mice via modulation of apoptotic pathways, but other signaling pathways were not previously covered. Therefore, the aim of the present study was to further investigate the effects of Sildenafil treatment on autophagy and nitrosative stress signaling pathways in EAE. 24 female C57BL/6 mice were divided into the following groups: (A) Control - received only water; (B) EAE - EAE untreated mice; (C) SILD - EAE mice treated with 25mg/kg of Sildenafil s.c. The results showed that EAE mice presented a pro-nitrosative profile characterized by high tissue nitrite levels, lowered levels of p-eNOS and high levels of iNOS. Furthermore, decreased levels of LC3, beclin-1 and ATG5, suggests impaired autophagy, and decreased levels of AMPK in the spinal cord were also detected in EAE mice. Surprisingly, treatment with Sildenafil inhibited nitrosative stress and augmented the levels of LC3, beclin-1, ATG5, p-CREB and BDNF and decreased mTOR levels, as well as augmented p-AMPK. In conclusion, we propose that Sildenafil alleviates EAE by activating autophagy via the eNOS-NO-AMPK-mTOR-LC3-beclin1-ATG5 and eNOS-NO-AMPK-mTOR-CREB-BDNF pathways in the spinal cord.
Assuntos
Autofagia/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Medula Espinal/efeitos dos fármacos , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Estresse Nitrosativo/efeitos dos fármacosRESUMO
Invasive species have major impacts on biodiversity and are one of the primary causes of amphibian decline and extinction. Unlike other top ant invaders that negatively affect larger fauna via chemical defensive compounds, the Argentine ant (Linepithema humile) does not have a functional sting. Nonetheless, it deploys defensive compounds against competitors and adversaries. We estimated levels of ant aggression toward 3 native terrestrial amphibians by challenging juveniles in field ant trails and in lab ant foraging arenas. We measured the composition and quantities of toxin in L. humile by analyzing pygidial glands and whole-body contents. We examined the mechanisms of toxicity in juvenile amphibians by quantifying the toxin in amphibian tissues, searching for histological damages, and calculating toxic doses for each amphibian species. To determine the potential scope of the threat to amphibians, we used global databases to estimate the number, ranges, and conservation status of terrestrial amphibian species with ranges that overlap those of L. humile. Juvenile amphibians co-occurring spatially and temporally with L. humile die when they encounter L. humile on an ant trail. In the lab, when a juvenile amphibian came in contact with L. humile the ants reacted quickly to spray pygidial-gland venom onto the juveniles. Iridomyrmecin was the toxic compound in the spray. Following absorption, it accumulated in brain, kidney, and liver tissue. Toxic dose for amphibian was species dependent. Worldwide, an estimated 817 terrestrial amphibian species overlap in range with L. humile, and 6.2% of them are classified as threatened. Our findings highlight the high potential of L. humile venom to negatively affect amphibian juveniles and provide a basis for exploring the largely overlooked impacts this ant has in its wide invasive range.
Efectos del Veneno de la Hormiga Argentina sobre los Anfibios Terrestres Resumen Las especies invasoras tienen un impacto importante sobre la biodiversidad y son una de las causas principales del declive y extinción de los anfibios. A diferencia de otras hormigas super-invasoras que afectan negativamente a animales más grandes por medio de compuestos químicos de defensa, la hormiga argentina (Linepithema humile) no tiene unaguijón funcional. Sin embargo, esta hormiga despliega compuestos defensivos contra sus competidores y adversarios. Estimamos los niveles de agresión de las hormigas hacia tres anfibios terrestres nativos exponiendo a los anfibios juveniles en pistas de hormigas en el campo y en las arenas de forrajeo de las hormigas en el laboratorio. Medimos la composición y las cantidades de toxina que presenta L. humile por medio del análisis de las glándulas pigidiales y el contenido en el cuerpo completo. Examinamos los mecanismos de la toxicidad en los anfibios juveniles cuantificando la toxina en el tejido del anfibio, buscando daños histológicos y calculando las dosis tóxicas para cada especie de anfibio. Para determinar el alcance potencial de la amenaza para los anfibios usamos bases de datos mundiales para estimar el número, distribución y estado de conservación de las especies terrestres de anfibios con distribuciones que se solapan con la de L. humile. Los anfibios juveniles que co-ocurren temporal y espacialmente con L. humile mueren al encontrarse con esta especie de hormiga en sus pistas. En el laboratorio, cuando un anfibio juvenil entró en contacto con L. humile, las hormigas reaccionaron rápidamente rociando a estos juveniles con veneno proveniente de las glándulas pigidiales. La iridomyrmecina fue el compuesto tóxico que encontramos en las glándulas pigidiales. Después de ser absorbida por la piel del anfibio, se acumuló en el cerebro, los riñones y el hígado. La dosis tóxica para los anfibios depende de la especie. A nivel mundial, se estima que 817 especies de anfibios terrestres tienen una distribución que se solapa con la de L. humile, y el 6.2% de estas especies se encuentran clasificadas como amenazadas. Nuestros hallazgos resaltan el potencial alto del veneno de L. humile para tener efectos negativos sobre los anfibios juveniles y también proporcionan una base para la exploración de los impactos de esta hormiga en su amplio rango invasivo, los cuales generalmente son ignorados.
Assuntos
Venenos de Formiga , Formigas , Anfíbios , Animais , Comportamento Animal , Conservação dos Recursos NaturaisRESUMO
While Treg cells are responsible for self-tolerance and immune homeostasis, pathogenic autoreactive Th17 cells produce pro-inflammatory cytokines that lead to tissue damage associated with autoimmunity, as observed in multiple sclerosis. Therefore, the immunological balance between Th17 and Treg cells may represent a promising option for immune therapy. Statin drugs are used to treat dyslipidemia; however, besides their effects on preventing cardiovascular diseases, statins also have anti-inflammatory effects. Here, we investigated the role of pitavastatin on experimental autoimmune encephalomyelitis (EAE) and the differentiation of Treg and Th17 cells. EAE was induced by immunizing C57BL/6 mice with MOG35-55. EAE severity was determined by analyzing the clinical score and inflammatory parameters in the spinal cord. Naive CD4 T cells were cultured under Treg and Th17-skewing conditions in vitro in the presence of pitavastatin. We found that pitavastatin decreased EAE development, which was accompanied by a reduction of all parameters investigated. Pitavastatin also reduced the expression of IBA1 and pSTAT3 (Y705 and S727) in the spinal cords of EAE mice. Interestingly, the reduction of Th17 cell frequency in the draining lymph nodes of EAE mice treated with pitavastatin was followed by an increase of Treg cells. Indeed, pitavastatin directly affects T cell differentiation in vitro by decreasing Th17 and increasing Treg cell differentiation. Mechanistically, pitavastatin effects are dependent on mevalonate synthesis. Thus, our data show the potential anti-inflammatory effect of pitavastatin on the pathogenesis of the experimental neuroinflammation by modulating the Th17/Treg axis.
Assuntos
Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Encefalomielite Autoimune Experimental/prevenção & controle , Ácido Mevalônico/metabolismo , Quinolinas/farmacologia , Medula Espinal/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Mediadores da Inflamação/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Medula Espinal/imunologia , Medula Espinal/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Solieria filiformis has been reported to have molecules with various biological activities. In this study we used environmentally friendly extraction methods, such as enzyme-assisted extraction (EAE), as a first step to obtain bioactive compounds from this species. Five combinations of protease (PRO) and carbohydrase (AMG) were utilized (1:0, 0:1, 2:1, 1:1, 1:2 PRO:AMG) to obtain Water Soluble Enzymatic Hydrolysates (WSEHs). Extraction yields, biochemical and structural characterization, as well as in vitro activity against Herpes simplex virus type 1 (HSV-1) and antioxidant capacities were determined. All PRO:AMG combinations significantly improved yields. EAE yielded heterogeneous extracts rich in iota-carrageenan and phenols, as confirmed by FTIR spectra. The highest antiherpetic activity (EC50 4.5 ± 0.4 µg mL-1) was found in the WSEHs obtained under 2:1 PRO:AMG. At this combination high antioxidant capacity was also obtained for ABTS (2,2'-Azino-Bis-3-ethylbenzoThiazoline-6-Sulfonic acid) radical scavenging activity and Ferric Reducing Antioxidant Power (FRAP). These could probably play a synergistic role associated to the strong antiviral activity obtained. These results suggest that 2:1 PRO:AMG could be effective in promoting the hydrolytic breakdown of high MW polysaccharides, contributing to the improvement of WSEHs bioactivity. Although Solieria filiformis WSEHs showed promising results, further research, including separation and purification techniques are needed.