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1.
Int J Mol Sci ; 25(7)2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38612763

RESUMO

Idiopathic intellectual disability (IID) encompasses the cases of intellectual disability (ID) without a known cause and represents approximately 50% of all cases. Neural progenitor cells (NPCs) from the olfactory neuroepithelium (NEO) contain the same information as the cells found in the brain, but they are more accessible. Some miRNAs have been identified and associated with ID of known etiology. However, in idiopathic ID, the effect of miRNAs is poorly understood. The aim of this study was to determine the miRNAs regulating the expression of mRNAs that may be involved in development of IID. Expression profiles were obtained using NPC-NEO cells from IID patients and healthy controls by microarray. A total of 796 miRNAs and 28,869 mRNAs were analyzed. Several miRNAs were overexpressed in the IID patients compared to controls. miR-25 had the greatest expression. In silico analysis showed that ROBO2 was the target for miR-25, with the highest specificity and being the most down-regulated. In vitro assay showed an increase of miR-25 expression induced a decrease in ROBO2 expression. In neurodevelopment, ROBO2 plays a crucial role in episodic learning and memory, so its down-regulation, caused by miR-25, could have a fundamental role in the intellectual disability that, until now, has been considered idiopathic.


Assuntos
Deficiência Intelectual , MicroRNAs , Humanos , Deficiência Intelectual/genética , MicroRNAs/genética , Encéfalo , Regulação para Baixo/genética , Aprendizagem , RNA Mensageiro , Proteínas Roundabout , Receptores Imunológicos/genética
2.
J Leukoc Biol ; 116(1): 95-102, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38717738

RESUMO

The immune response to SARS-CoV-2 has been extensively studied following the pandemic outbreak in 2020; however, the presence of specific T cells against SARS-CoV-2 before vaccination has not been evaluated in Mexico. In this study, we estimated the frequency of T CD4+ and T CD8+ cells that exhibit a specific response to S (spike) and N (nucleocapsid) proteins in a Mexican population. We collected 78 peripheral blood samples from unvaccinated subjects, and the presence of antibodies against spike (RBD) and N protein was determined. Peripheral blood mononuclear cells were isolated and stimulated with a pool of S or N protein peptides (Wuhan-Hu-1 strain). IL-1ß, IL-4, IL-6, IL-10, IL-2, IL-8, TNF-α, IFN-γ, and GM-CSF levels were quantified in the supernatant of the activated cells, and the cells were stained to assess the activation and memory phenotypes. Differential activation frequency dependent on serological status was observed in CD4+ cells but not in CD8+ cells. The predominantly activated population was the central memory T CD4+ cells. Only 10% of the population exhibited the same phenotype with respect to the response to nucleocapsid peptides. The cytokine profile differed between the S and N responses. S peptides induced a more proinflammatory response compared with the N peptides. In conclusion, in a Mexican cohort before vaccination, there was a significant response to the S and N SARS-CoV-2 proteins resulting from previous infections with seasonal coronaviruses or previous undetected exposure to SARS-CoV-2.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vacinação , Humanos , México/epidemiologia , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , Feminino , Masculino , Adulto , Linfócitos T CD8-Positivos/imunologia , Pessoa de Meia-Idade , Linfócitos T CD4-Positivos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Citocinas/metabolismo , Vacinas contra COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Adulto Jovem , Fosfoproteínas/imunologia , Idoso , Ativação Linfocitária/imunologia
3.
J Leukoc Biol ; 113(3): 315-325, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36808495

RESUMO

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is still fatal in many cases. T cell blasts are characterized by hyperactivation and strong proliferative and migratory capacities. The chemokine receptor CXCR4 is involved in mediating malignant T cell properties, and cortactin has been shown to control CXCR4 surface localization in T-ALL cells. We have previously shown that cortactin overexpression is correlated with organ infiltration and relapse in B-ALL. However, the role of cortactin in T cell biology and T-ALL remains elusive. Here, we analyzed the functional relevance of cortactin for T cell activation and migration and the implications for T-ALL development. We found that cortactin is upregulated in response to T cell receptor engagement and recruited to the immune synapse in normal T cells. Loss of cortactin caused reduced IL-2 production and proliferation. Cortactin-depleted T cells showed defects in immune synapse formation and migrated less due to impaired actin polymerization in response to T cell receptor and CXCR4 stimulation. Leukemic T cells expressed much higher levels of cortactin compared to normal T cells that correlated with greater migratory capacity. Xenotransplantation assays in NSG mice revealed that cortactin-depleted human leukemic T cells colonized the bone marrow significantly less and failed to infiltrate the central nervous system, suggesting that cortactin overexpression drives organ infiltration, which is a major complication of T-ALL relapse. Thus, cortactin could serve as a potential therapeutic target for T-ALL and other pathologies involving aberrant T cell responses.


Assuntos
Cortactina , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Animais , Camundongos , Linfócitos T/metabolismo , Leucócitos , Recidiva , Movimento Celular/fisiologia
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