RESUMO

Astrocytes are the most abundant type of glial cell in the central nervous system. Upon injury and inflammation, astrocytes become reactive and undergo morphological and functional changes. Depending on their phenotypic classification as A1 or A2, reactive astrocytes contribute to both neurotoxic and neuroprotective responses, respectively. However, this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries. Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles, which emphasizes the heterogeneous nature of their reactivity. Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types, releasing cytokines, and influencing the immune response. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior, as evidenced by in silico , in vitro , and in vivo results. In astrocytes, inflammatory cues trigger a cascade of molecular events, where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses. Here, we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation. We highlight the involvement of various signaling pathways that regulate astrocyte reactivity, including the PI3K/AKT/mammalian target of rapamycin (mTOR), α v ß 3 integrin/PI3K/AKT/connexin 43, and Notch/PI3K/AKT pathways. While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage, evidence suggests that activating this pathway could also yield beneficial outcomes. This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation. The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior. The findings should then be validated using in vivo models to ensure real-life relevance. The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage, although further studies are required to fully comprehend its role due to varying factors such as different cell types, astrocyte responses to inflammation, and disease contexts. Specific strategies are clearly necessary to address these variables effectively.

RESUMO

BACKGROUND: In response to brain injury or inflammation, astrocytes undergo hypertrophy, proliferate, and migrate to the damaged zone. These changes, collectively known as "astrogliosis", initially protect the brain; however, astrogliosis can also cause neuronal dysfunction. Additionally, these astrocytes undergo intracellular changes involving alterations in the expression and localization of many proteins, including αvß3 integrin. Our previous reports indicate that Thy-1, a neuronal glycoprotein, binds to this integrin inducing Connexin43 (Cx43) hemichannel (HC) opening, ATP release, and astrocyte migration. Despite such insight, important links and molecular events leading to astrogliosis remain to be defined. METHODS: Using bioinformatics approaches, we analyzed different Gene Expression Omnibus datasets to identify changes occurring in reactive astrocytes as compared to astrocytes from the normal mouse brain. In silico analysis was validated by both qRT-PCR and immunoblotting using reactive astrocyte cultures from the normal rat brain treated with TNF and from the brain of a hSOD1G93A transgenic mouse model. We evaluated the phosphorylation of Cx43 serine residue 373 (S373) by AKT and ATP release as a functional assay for HC opening. In vivo experiments were also performed with an AKT inhibitor (AKTi). RESULTS: The bioinformatics analysis revealed that genes of the PI3K/AKT signaling pathway were among the most significantly altered in reactive astrocytes. mRNA and protein levels of PI3K, AKT, as well as Cx43, were elevated in reactive astrocytes from normal rats and from hSOD1G93A transgenic mice, as compared to controls. In vitro, reactive astrocytes stimulated with Thy-1 responded by activating AKT, which phosphorylated S373Cx43. Increased pS373Cx43 augmented the release of ATP to the extracellular medium and AKTi inhibited these Thy-1-induced responses. Furthermore, in an in vivo model of inflammation (brain damage), AKTi decreased the levels of astrocyte reactivity markers and S373Cx43 phosphorylation. CONCLUSIONS: Here, we identify changes in the PI3K/AKT molecular signaling network and show how they participate in astrogliosis by regulating the HC protein Cx43. Moreover, because HC opening and ATP release are important in astrocyte reactivity, the phosphorylation of Cx43 by AKT and the associated increase in ATP release identify a potential therapeutic window of opportunity to limit the adverse effects of astrogliosis.

Assuntos

Lesões Encefálicas , Conexina 43 , Animais , Camundongos , Ratos , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Astrócitos/metabolismo , Lesões Encefálicas/metabolismo , Conexina 43/metabolismo , Gliose/metabolismo , Inflamação/metabolismo , Integrina beta3/genética , Integrina beta3/metabolismo , Integrina beta3/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima , Antígenos Thy-1/metabolismo , Integrina alfa5/metabolismo

RESUMO

Appendicular neoplasms are rare tumors, with an incidence of less than 0.05% among all gastrointestinal tumors. This work presents the case of a 52-year-old patient who manifested colicky pain in the right iliac fossa. Laboratory test results with bandemia and hyperbilirubinemia. Abdominal tomography with an acute appendicular inflammatory process, for which the patient was admitted for surgery. A dependent tumor of the cecum and appendicular region is observed, which compromises the ileocecal valve. The histopathological diagnosis was "low-grade appendiceal mucinous neoplasm." Appendiceal tumors are often incidental findings due to their low frequency; however, their possibility should not be dismissed.

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Las neoplasias apendiculares son tumores raros, con una incidencia menor al 0.05% de todos los tumores gastrointestinales. Presentamos el caso de paciente de 52 años, quien acude por dolor cólico en fosa iliaca derecha. Estudios de laboratorio con bandemia e hiperbilirrubinemia. Tomografía abdominal con proceso inflamatorio apendicular agudo por lo que se ingresa a cirugía. Se observa tumoración dependiente de ciego y región apendicular que compromete válvula ileocecal. El diagnóstico histopatológico fue "neoplasia mucinosa apendicular de bajo grado. Los tumores de apéndice son a menudo hallazgos incidentales por su baja frecuencia, sin embargo, su posibilidad no debe descartarse.

Assuntos

Neoplasias Gastrointestinais , Neoplasias Císticas, Mucinosas e Serosas , Humanos , Pessoa de Meia-Idade

RESUMO

Background: Studies have shown elevated blood lead levels (BLL) in residents of remote communities in the Amazon, yet sources of lead exposure are not fully understood, such as lead ammunition consumed in wild game. Methods: Data was collected during two cross-sectional studies that enrolled 307 individuals in 26 communities. Regression models with community random effects were used to evaluate risk factors for BLLs, including diet, water source, smoking, sex, age, and indigenous status. The All-Ages Lead Model (AALM) from the Environmental Protection Agency (EPA) was used to estimate background and dose from wild game consumption. Findings: Indigenous status and wild game consumption were associated with increased BLLs. Indigenous participants had 2.52 µg/dL (95% CI: 1.95-3.24) higher BLLs compared to non-indigenous. Eating wild game was associated with a 1.41 µg/dL (95% CI: 1.20-1.70) increase in BLLs. Two or more portions per serving were associated with increased BLLs of 1.66 µg/dL (95% CI: 1.10-2.57), compared to smaller servings. Using the AALM, we estimate background lead exposures to be 20 µg/day with consumption of wild game contributing 500 µg/meal. Lastly, we found a strong association between BLLs and mercury exposure. Interpretation: Consumption of wild game hunted with lead ammunition may pose a common source of lead exposure in the Amazon. Communities that rely on wild game and wild fish may face a dual burden of exposure to lead and mercury, respectively.

RESUMO

We explored sex-biased effects of the primary stress glucocorticoid hormone corticosterone on the miRNA expression profile in the rat hippocampus. Adult adrenalectomized (ADX) female and male rats received a single corticosterone (10 mg/kg) or vehicle injection, and after 6 h, hippocampi were collected for miRNA, mRNA, and Western blot analyses. miRNA profiling microarrays showed a basal sex-biased miRNA profile in ADX rat hippocampi. Additionally, acute corticosterone administration triggered a sex-biased differential expression of miRNAs derived from genes located in several chromosomes and clusters on the X and 6 chromosomes. Putative promoter analysis unveiled that most corticosterone-responsive miRNA genes contained motifs for either direct or indirect glucocorticoid actions in both sexes. The evaluation of transcription factors indicated that almost 50% of miRNA genes sensitive to corticosterone in both sexes was under glucocorticoid receptor regulation. Transcription factor-miRNA regulatory network analyses identified several transcription factors that regulate, activate, or repress miRNA expression. Validated target mRNA analysis of corticosterone-responsive miRNAs showed a more complex miRNA-mRNA interaction network in males compared to females. Enrichment analysis revealed that several hippocampal-relevant pathways were affected in both sexes, such as neurogenesis and neurotrophin signaling. The evaluation of selected miRNA targets from these pathways displayed a strong sex difference in the hippocampus of ADX-vehicle rats. Corticosterone treatment did not change the levels of the miRNA targets and their corresponding tested proteins. Our data indicate that corticosterone exerts a sex-biased effect on hippocampal miRNA expression, which may engage in sculpting the basal sex differences observed at higher levels of hippocampal functioning.

Assuntos

Corticosterona , MicroRNAs , Adrenalectomia , Animais , Corticosterona/farmacologia , Feminino , Hipocampo/metabolismo , Masculino , MicroRNAs/genética , Ratos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo

RESUMO

Several lines of evidence suggest that antidepressant drugs may act by modulating neuroplasticity pathways in key brain areas like the hippocampus. We have reported that chronic treatment with fasudil, a Rho-associated protein kinase inhibitor, prevents both chronic stress-induced depressive-like behavior and morphological changes in CA1 area. Here, we examined the ability of fasudil to (i) prevent stress-altered behaviors, (ii) influence the levels/phosphorylation of glutamatergic receptors and (iii) modulate signaling pathways relevant to antidepressant actions. 89 adult male Sprague-Dawley rats received intraperitoneal fasudil injections (10 mg/kg/day) or saline vehicle for 18 days. Some of these animals were daily restraint-stressed from day 5-18 (2.5 h/day). 24 hr after treatments, rats were either evaluated for behavioral tests (active avoidance, anxiety-like behavior and object location) or euthanized for western blot analyses of hippocampal whole extract and synaptoneurosome-enriched fractions. We report that fasudil prevents stress-induced impairments in active avoidance, anxiety-like behavior and novel location preference, with no effect in unstressed rats. Chronic stress reduced phosphorylations of ERK-2 and CREB, and decreased levels of GluA1 and GluN2A in whole hippocampus, without any effect of fasudil. However, fasudil decreased synaptic GluA1 Ser831 phosphorylation in stressed animals. Additionally, fasudil prevented stress-decreased phosphorylation of GSK-3ß at Ser9, in parallel with an activation of the mTORC1/4E-BP1 axis, both in hippocampal synaptoneurosomes, suggesting the activation of the AKT pathway. Our study provides evidence that chronic fasudil treatment prevents chronic stress-altered behaviors, which correlated with molecular modifications of antidepressant-relevant signaling pathways in hippocampal synaptoneurosomes.

RESUMO

Cancer cell adhesion to the vascular endothelium is an important step in tumor metastasis. Thy-1 (CD90), a cell adhesion molecule expressed in activated endothelial cells, has been implicated in melanoma metastasis by binding to integrins present in cancer cells. However, the signaling pathway(s) triggered by this Thy-1-Integrin interaction in cancer cells remains to be defined. Our previously reported data indicate that Ca2+-dependent hemichannel opening, as well as the P2X7 receptor, are key players in Thy-1-αVß3 Integrin-induced migration of reactive astrocytes. Thus, we investigated whether this signaling pathway is activated in MDA-MB-231 breast cancer cells and in B16F10 melanoma cells when stimulated with Thy-1. In both cancer cell types, Thy-1 induced a rapid increase in intracellular Ca2+, ATP release, as well as cell migration and invasion. Connexin and Pannexin inhibitors decreased cell migration, implicating a requirement for hemichannel opening in Thy-1-induced cell migration. In addition, cell migration and invasion were precluded when the P2X7 receptor was pharmacologically blocked. Moreover, the ability of breast cancer and melanoma cells to transmigrate through an activated endothelial monolayer was significantly decreased when the ß3 Integrin was silenced in these cancer cells. Importantly, melanoma cells with silenced ß3 Integrin were unable to metastasize to the lung in a preclinical mouse model. Thus, our results suggest that the Ca2+/hemichannel/ATP/P2X7 receptor-signaling axis triggered by the Thy-1-αVß3 Integrin interaction is important for cancer cell migration, invasion and transvasation. These findings open up the possibility of therapeutically targeting the Thy-1-Integrin signaling pathway to prevent metastasis.

RESUMO

Autism is a neurodevelopmental disorder characterized by a deep deficit in language and social interaction, accompanied by restricted, stereotyped and repetitive behaviors. The use of genetic autism animal models has revealed that the alteration of the mechanisms controlling the formation and maturation of neural circuits are points of convergence for the physiopathological pathways in several types of autism. Brain Derived Neurotrophic Factor (BDNF), a key multifunctional regulator of brain development, has been related to autism in several ways. However, its precise role is still elusive, in part, due to its extremely complex posttranscriptional regulation. In order to contribute to this topic, we treated prenatal rats with Valproate, a well-validated model of autism, to analyze BDNF levels in the hippocampus of juvenile rats. Valproate-treated rats exhibited an autism-like behavioral profile, characterized by a deficit in social interaction, anxiety-like behavior and repetitive behavior. In situ hybridization (ISH) experiments revealed that Valproate reduced BDNF mRNA, especially long-3'UTR-containing transcripts, in specific areas of the dentate gyrus (DG) and CA3 regions. At the same time, Valproate reduced BDNF immunoreactivity in the suprapyramidal and lucidum layers of CA3, but improved hippocampus-dependent spatial learning. The molecular changes reported here may help to explain the cognitive and behavioral signs of autism and reinforce BDNF as a potential molecular target for this neurodevelopmental disorder.

RESUMO

Astrocytes have long been considered the supportive cells of the central nervous system, but during the last decades, they have gained much more attention because of their active participation in the modulation of neuronal function. For example, after brain damage, astrocytes become reactive and undergo characteristic morphological and molecular changes, such as hypertrophy and increase in the expression of glial fibrillary acidic protein (GFAP), in a process known as astrogliosis. After severe damage, astrocytes migrate to the lesion site and proliferate, which leads to the formation of a glial scar. At this scar-forming stage, astrocytes secrete many factors, such as extracellular matrix proteins, cytokines, growth factors and chondroitin sulfate proteoglycans, stop migrating, and the process is irreversible. Although reactive gliosis is a normal physiological response that can protect brain cells from further damage, it also has detrimental effects on neuronal survival, by creating a hostile and non-permissive environment for axonal repair. The transformation of astrocytes from reactive to scar-forming astrocytes highlights migration as a relevant regulator of glial scar formation, and further emphasizes the importance of efficient communication between astrocytes in order to orchestrate cell migration. The coordination between astrocytes occurs mainly through Connexin (Cx) channels, in the form of direct cell-cell contact (gap junctions, GJs) or contact between the extracellular matrix and the astrocytes (hemichannels, HCs). Reactive astrocytes increase the expression levels of several proteins involved in astrocyte migration, such as αvß3 Integrin, Syndecan-4 proteoglycan, the purinergic receptor P2X7, Pannexin1, and Cx43 HCs. Evidence has indicated that Cx43 HCs play a role in regulating astrocyte migration through the release of small molecules to the extracellular space, which then activate receptors in the same or adjacent cells to continue the signaling cascades required for astrocyte migration. In this review, we describe the communication of astrocytes through Cxs, the role of Cxs in inflammation and astrocyte migration, and discuss the molecular mechanisms that regulate Cx43 HCs, which may provide a therapeutic window of opportunity to control astrogliosis and the progression of neurodegenerative diseases.

RESUMO

Fourteen fungal entomopathogenic strains were isolated from soil samples and infected field-collected fall armyworm larvae, in Guanajuato, Mexico. Isolates were identified by morphology and internal transcribed spacers sequencing. Isolates Ma22, Ma41, and Mr8 showed 99% identity with reference strains (RS) of Metarhizium anisopliae. Isolates Bb9, Bb19, Bb21, Bb40, Bb27, Bb23, and Bb39 showed identity between 99 and 100% with RS of Beauveria bassiana. Isolates Nr1, Nr2, Nr3, and Nr4 showed identity between 98 and 100% with RS of Nomuraea rileyi. Qualitative selection used one concentration (1 × 108 conidia/ml) on fall armyworm eggs and neonate larvae. Strains Ma22, Ma41, and Mr8 showed 100%, and strains Bb39, Bb23, Bb9, Bb40, Bb19, and Bb21 showed 92, 89.2, 87.6, 82.8, 58, and 38% egg mortality, respectively. Bioassays on neonate larvae showed 100% mortality with strains Ma22, Ma41, Mr8, and Bb9. Strains Bb39, Bb19, Bb27, Bb23, Bb21, and Bb40 showed 74, 60, 54, 53, 28, and 19% mortality, respectively. Bioassay estimated LC50s for strains Ma41 at 7.4 × 104, Mr8 at 8.9 × 104, and Ma22 at 10 × 104 conidia/ml, on fall armyworm eggs. LC50s on neonate larvae were estimated at 2.8 × 105, 16 × 105, 26 × 105, and 36 × 105 conidia/ml for strains Ma41, Bb9, Ma22, and Mr8, respectively. Virulence genes mad1 and mad2 were found in Mr8, Ma22, and Ma41, whereas the gen gmact was found only in the strain Ma22. Genes hyd1 and hyd2 were identified in Bb9, Bb19, Bb21, and Bb27. No correlation was observed between the virulence gene detection and the estimated LC50s. Strain Ma41 showed the highest potential to be developed as a bioinsecticide.

Assuntos

Metarhizium/patogenicidade , Mariposas , Controle Biológico de Vetores , Animais , Genes Fúngicos , Larva , Metarhizium/genética , Metarhizium/isolamento & purificação , Óvulo

RESUMO

Several studies have shown that a single exposure to stress may improve or impair learning and memory processes, depending on the timing in which the stress event occurs with relation to the acquisition phase. However, to date there is no information about the molecular changes that occur at the synapse during the stress-induced memory modification and after a recovery period. In particular, there are no studies that have evaluated-at the same time-the temporality of stress and stress recovery period in hippocampal short-term memory and the effects on dendritic spine morphology, along with variations in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. The aim of our study was to take a multidimensional approach to investigate concomitant behavioral, morphological and molecular changes induced by a single restraint stress exposure (2.5 h) and a recovery period of 6 and 24 h in rats. We found that acute stress elicited a reduced preference to explore an object placed in a novel position (a hippocampal-dependent task). These changes were accompanied by increased activity of LIM kinase I (LIMK; an actin-remodeling protein) and increased levels of NR2A subunits of NMDA receptors. After 6 h of recovery from stress, rats showed similar preference to explore an object placed in a novel or familiar position, but density of immature spines increased in secondary CA1 apical dendrites, along with a transient rise in GluA2 AMPA receptor subunits. After 24 h of recovery from stress, the animals showed a preference to explore an object placed in a novel position, which was accompanied by a normalization of NMDA and AMPA receptor subunits to control values. Our data suggest that acute stress produces reversible molecular and behavioral changes 24 h after stress, allowing a full reestablishment of hippocampal-related memory. Further studies need to be conducted to deepen our understanding of these changes and their reciprocal interactions.Adaptive stress responses are a promising avenue to develop interventions aiming at restoring hippocampal function impaired by repetitive stress exposure.

RESUMO

El hemotórax es una patología que de no ser diagnosticada y tratada a tiempo amenaza la vida del paciente, "los traumas torácicos son el 25% de los tipos de trauma en los pacientes politraumatizados" (Greenfield, 2011).Por lo tanto, es de suma importancia realizar un adecuado examen físico primario y secundario, para así poder descartar lesiones que ameriten una actitud resolutiva de emergencia; asimismo, el diagnóstico es clínico y radiológico, siempre tomando en consideración la condición global del paciente. Lo anterior, para elegir el método más práctico, rápido y fidedigno para apoyar el diagnóstico clínico; el tratamiento con sello de tórax es el manejo de elección inicial, el cual dependiendo de la evolución clínica del paciente seguirá una serie de métodos para realizar la completa evacuación del mismo y evitar, en la medida de lo posible, las complicaciones. Además, es de gran interés realizar un tratamiento rápido y eficaz para evitar que el líquido se coagule, lo cual puede producir un empiema o fibrotórax. Por esta razón, todos los proveedores de la salud, en especial los médicos encargados de emergencias y los cirujanos deben tener en mente el probable desarrollo de un hemotórax en pacientes quienes sufran síntomas inexplicables de hipovolemia, específicamente en politraumatizados, por esto se debe conocer a profundidad las características de esta patología.

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Hemothorax is a disease in which if not diagnosed and treated in time, threatens the patient's life. Thoracic traumas account for 25% of trauma in politraumatized patients (Greenfield, 2011), it is paramount to perform an adequate first and secondary physical examination, so we can rule out any problems that merit an emergency operative attitude. The diagnosis is clinical and radiological, taking always into consideration the overall condition of the patient, to choose the most convenient treatment, the fastest and most reliable method to support the clinical diagnosis. The chest tube is the initial choice method, depending on the clinical evolution of the patient a number of other methods can be perform in order to complete the evacuation of the collection and avoid as much as possible the complications; it is very important to make a fast and effective treatment to prevent the liquid from clotting, which can cause empyema or fibrothorax. All health providers and more the physicians in charge of the emergency department and the surgeons, should keep in mind the likely development of a hemothorax in patients suffering unexplained symptoms of hypovolemia in trauma cases, that is why is important to know in depth the characteristics of this disease.

Assuntos

Humanos , Hemotórax , Hipovolemia

RESUMO

Th17 cells, a recently described subtype of CD4+ effector lymphocytes, have been linked to cell-mediated autoimmune and inflammatory diseases as well as to cardiovascular diseases. However, the participation of IL-17A in myocardial ischemic injury has not been clearly defined. We therefore conducted the present study to evaluate IL-17A and Th17-related cytokine levels in a rat model of myocardial infarction (MI). MI was induced in male Sprague Dawley rats by coronary artery ligation. Controls were sham-operated (Sh) or non-operated (C). Blood and samples from the left ventricle (LV) were collected at weeks 1 and 4 post-MI. At week 1, MI animals exhibited increased IL-6, IL-23 and TGF-ß mRNA levels with no apparent change in IL-17 mRNA or protein levels in whole LV. Only TGF-ß mRNA remained elevated at week 4 post-MI. However, further analysis revealed that IL-17A mRNA and protein levels as well as IL-6 and IL-23 mRNA were indeed increased in the infarcted region, though not in the remote non infarcted region of the LV, except for IL-23 mRNA. The increased expression of IL-17A and Th17-related cytokines in the infarcted region of LV, suggests that this proinflammatory pathway might play a role in early stages of post MI cardiac remodelling.

Assuntos

Ventrículos do Coração/metabolismo , Interleucina-17/metabolismo , Infarto do Miocárdio/metabolismo , Células Th17/metabolismo , Animais , Modelos Animais de Doenças , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley

RESUMO

Th17 cells, a recently described subtype of CD4+ effector lymphocytes, have been linked to cell-mediated autoimmune and inflammatory diseases as well as to cardiovascular diseases. However, the participation of IL-17A in myocardial ischemic injury has not been clearly defined. We therefore conducted the present study to evaluate IL-17A and Th17-related cytokine levels in a rat model of myocardial infarction (MI). MI was induced in male Sprague Dawley rats by coronary artery ligation. Controls were sham-operated (Sh) or non-operated (C). Blood and samples from the left ventricle (LV) were collected at weeks 1 and 4 post-MI. At week 1, MI animals exhibited increased IL-6, IL-23 and TGF-β mRNA levels with no apparent change in IL-17 mRNA or protein levels in whole LV. Only TGF-β mRNA remained elevated at week 4 post-MI. However, further analysis revealed that IL-17A mRNA and protein levels as well as IL-6 and IL-23 mRNA were indeed increased in the infarcted region, though not in the remote non infarcted region of the LV, except for IL-23 mRNA. The increased expression of IL-17A and Th17-related cytokines in the infarcted region of LV, suggests that this proinflammatory pathway might play a role in early stages of post MI cardiac remodelling.

Assuntos

Animais , Masculino , Ratos , Ventrículos do Coração/metabolismo , /metabolismo , Infarto do Miocárdio/metabolismo , /metabolismo , Modelos Animais de Doenças , Ratos Sprague-Dawley , RNA Mensageiro/metabolismo

RESUMO

Clustering of alphavbeta3 integrin after interaction with the RGD-like integrin-binding sequence present in neuronal Thy-1 triggers formation of focal adhesions and stress fibers in astrocytes via RhoA activation. A putative heparin-binding domain is present in Thy-1, raising the possibility that this membrane protein stimulates astrocyte adhesion via engagement of an integrin and the proteoglycan syndecan-4. Indeed, heparin, heparitinase treatment and mutation of the Thy-1 heparin-binding site each inhibited Thy-1-induced RhoA activation, as well as formation of focal adhesions and stress fibers in DI TNC(1) astrocytes. These responses required both syndecan-4 binding and signaling, as evidenced by silencing syndecan-4 expression and by overexpressing a syndecan-4 mutant lacking the intracellular domain, respectively. Furthermore, lack of RhoA activation and astrocyte responses in the presence of a PKC inhibitor or a dominant-negative form of PKCalpha implicated PKCalpha and RhoA activation in these events. Therefore, combined interaction of the astrocyte alphavbeta3-integrin-syndecan-4 receptor pair with Thy-1, promotes adhesion to the underlying matrix via PKCalpha- and RhoA-dependent pathways. Importantly, signaling events triggered by such receptor cooperation are shown here to be the consequence of cell-cell rather than cell-matrix interactions. These observations are likely to be of widespread biological relevance because Thy-1-integrin binding is reportedly relevant to melanoma invasion, monocyte transmigration through endothelial cells and host defense mechanisms.

Assuntos

Astrócitos/metabolismo , Integrina alfaVbeta3/metabolismo , Neurônios/metabolismo , Proteína Quinase C-alfa/metabolismo , Sindecana-4/metabolismo , Antígenos Thy-1/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Sequência de Aminoácidos , Animais , Astrócitos/química , Adesão Celular , Linhagem Celular , Ativação Enzimática , Humanos , Integrina alfaVbeta3/genética , Dados de Sequência Molecular , Neurônios/química , Ligação Proteica , Proteína Quinase C-alfa/genética , Estrutura Terciária de Proteína , Ratos , Alinhamento de Sequência , Transdução de Sinais , Sindecana-4/genética , Antígenos Thy-1/química , Antígenos Thy-1/genética , Proteína rhoA de Ligação ao GTP/genética

RESUMO

This article focuses on the relationship and mutual influence of astrology and other so-called occult sciences within the context of seventeenth-century New Spain. By presenting some case studies of inquisitorial trials against astrologers, it explores the interrelation between astrological and physiognomical ideas and practices in order to shed some light on the moral dimension of these natural philosophical fields of knowledge. During the early modern period, both astrology and physiognomy were regarded as tools for self-understanding and the understanding of others by means of interpretation of natural signs. Thus their history is key for understanding the shaping of the boundaries between the natural and the moral realms.

Assuntos

Astrologia , Fisiognomia , Astrologia/história , Astrologia/psicologia , História do Século XVII , México , Religião e Ciência

RESUMO

Thy-1, a cell adhesion molecule abundantly expressed in mammalian neurons, binds to a beta(3)-containing integrin on astrocytes and thereby stimulates the assembly of focal adhesions and stress fibers. Such events lead to morphological changes in astrocytes that resemble those occurring upon injury in the brain. Extracellular matrix proteins, typical integrin ligands, bind to integrins and promote receptor clustering as well as signal transduction events that involve small G proteins and cytoskeletal changes. Here we investigated the possibility that the cell surface protein Thy-1, when interacting with a beta(3)-containing integrin on astrocytes, could trigger signaling events similar to those generated by extracellular matrix proteins. DI-TNC(1) astrocytes were stimulated with Thy-1-Fc immobilized on beads, and increased RhoA activity was confirmed using an affinity precipitation assay. The effect of various inhibitors on the cellular response was also studied. The presence of Y-27632, an inhibitor of Rho kinase (p160ROCK), a key downstream effector of RhoA, significantly reduced focal adhesion and stress fiber formation induced by Thy-1. Similar effects were obtained when astrocytes were treated with C3 transferase, an inhibitor of RhoA. Alternatively, astrocytes were transfected with an expression vector encoding fusion proteins of enhanced green fluorescent protein with either the Rho-binding domain of Rhotekin, which blocks RhoA function, or the dominant-negative N19RhoA mutant. In both cases, Thy-1-induced focal adhesion formation was inhibited. Furthermore, we observed that RhoA activity after stimulation with soluble Thy-1-Fc molecule was augmented upon further cross-linking using protein A-Sepharose beads. The same was shown by cross-linking beta(3)-containing integrin with anti-beta(3) antibodies. Together, these results indicate that Thy-1-mediated astrocyte stimulation depended on beta(3) integrin clustering and the resulting increase in RhoA activity.

Assuntos

Astrócitos/metabolismo , Integrinas/química , Antígenos Thy-1/metabolismo , Proteína rhoA de Ligação ao GTP/química , Amidas/farmacologia , Animais , Adesão Celular , Linhagem Celular , Matriz Extracelular/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Adesões Focais , Genes Dominantes , Integrinas/metabolismo , Ligantes , Microscopia de Fluorescência , Ligação Proteica , Piridinas/farmacologia , Ratos , Proteínas Recombinantes/química , Fatores de Tempo

RESUMO

Thy-1 is an abundant neuronal glycoprotein in mammals. Despite such prevalence, Thy-1 function remains largely obscure in the absence of a defined ligand. Recently described evidence that Thy-1 interacts with beta 3 integrin on astrocytes will be discussed. Thy-1 binding to beta 3 integrin triggers tyrosine phosphorylation of focal adhesion proteins in astrocytes, thereby promoting focal adhesion formation, cell attachment and spreading. Thy-1 has been reported to modulate neurite outgrowth by triggering a cellular response in neurons. However, our data indicate that Thy-1 can also initiate signaling events that promote adhesion of adjacent astrocytes to the underlying surface. Preliminary results suggest that morphological changes observed in the actin cytoskeleton of astrocytes as a consequence of Thy-1 binding is mediated by small GTPases from the Rho family. Our findings argue that Thy-1 functions in a bimodal fashion, as a receptor on neuronal cells and as a ligand for beta 3 integrin receptor on astrocytes. Since Thy-1 is implicated in the inhibition of neurite outgrowth, signaling events in astrocytes are likely to play an important role in this process.

Assuntos

Astrócitos/fisiologia , Integrina beta3/fisiologia , Neurônios/fisiologia , Transdução de Sinais/fisiologia , Antígenos Thy-1/fisiologia , Animais , Humanos , Receptores de Vitronectina/fisiologia , Proteínas rho de Ligação ao GTP/fisiologia

Assuntos

Publicidade , Indústria da Beleza , Publicações Periódicas como Assunto , Opinião Pública , Estereotipagem , Saúde da Mulher , Publicidade/economia , Publicidade/história , Publicidade/legislação & jurisprudência , Atitude Frente a Saúde/etnologia , Beleza , Indústria da Beleza/economia , Indústria da Beleza/educação , Indústria da Beleza/história , Indústria da Beleza/legislação & jurisprudência , Saúde , História do Século XX , México/etnologia , Publicações Periódicas como Assunto/economia , Publicações Periódicas como Assunto/história , Publicações Periódicas como Assunto/legislação & jurisprudência , Mulheres/educação , Mulheres/história , Mulheres/psicologia , Saúde da Mulher/economia , Saúde da Mulher/etnologia , Saúde da Mulher/história , Saúde da Mulher/legislação & jurisprudência

RESUMO

Thy-1 is an abundant neuronal glycoprotein in mammals. Despite such prevalence, Thy-1 function remains largely obscure in the absence of a defined ligand. Recently described evidence that Thy-1 interacts with beta 3 integrin on astrocytes will be discussed. Thy-1 binding to beta 3 integrin triggers tyrosine phosphorylation of focal adhesion proteins in astrocytes, thereby promoting focal adhesion formation, cell attachment and spreading. Thy-1 has been reported to modulate neurite outgrowth by triggering a cellular response in neurons. However, our data indicate that Thy-1 can also initiate signaling events that promote adhesion of adjacent astrocytes to the underlying surface. Preliminary results suggest that morphological changes observed in the actin cytoskeleton of astrocytes as a consequence of Thy-1 binding is mediated by small GTPases from the Rho family. Our findings argue that Thy-1 functions in a bimodal fashion, as a receptor on neuronal cells and as a ligand for beta 3 integrin receptor on astrocytes. Since Thy-1 is implicated in the inhibition of neurite outgrowth, signaling events in astrocytes are likely to play an important role in this process

Assuntos

Humanos , Animais , Antígenos Thy-1 , Astrócitos , Glicoproteínas da Membrana de Plaquetas , Transdução de Sinais , Antígenos Thy-1 , Astrócitos , Glicoproteínas da Membrana de Plaquetas , Receptores de Vitronectina , Proteínas rho de Ligação ao GTP