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Mol Neurobiol ; 58(11): 5421-5436, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33983546

RESUMEN

Maintaining an intact pool of neural progenitor cells (NPCs) is crucial for generating new and functionally active neurons. Methamphetamine (METH) can exacerbate the HIV-induced deficit of adult neurogenesis; however, potential mechanisms of this influence are still poorly understood. In the present study, we present evidence that chronic exposure to METH combined with brain infection by EcoHIV results in enhanced proliferation of NPCs in the subventricular zone (SVZ) in mice. This effect was long-lasting as it was preserved ex vivo in NPCs isolated from the exposed mice over several passages in the absence of additional treatments. Increased proliferation in response to METH plus HIV was associated with dysregulation of cyclin B1 and cyclin D. Transcriptomic studies indicated that 27 out of the top 30 differentially expressed genes in response to METH plus EcoHIV were targets of the forkhead box O transcriptional factor (FOXO) and primarily FOXO3. Additional ex vivo studies and in vitro experiments using human NPCs exposed to METH and infected with HIV revealed upregulation of the CXCL12-CXCR4 axis, leading to activation of downstream pAkt and pErk, the pathways that can phosphorylate FOXO3 and force its exports from the nuclei into the cytoplasm. Indeed, nuclear expulsion of FOXO3 was demonstrated both in mice exposed to METH and infected with EcoHIV and in cell cultures of human NPCs. These results provide novel information that exposure to METH combined with HIV infection can induce aberrant proliferation of SVZ-derived NPCs and identifies CXCL12-CXCR4-Akt-1-mediated phosphorylation of FOXO3 as the mechanism responsible for this effect.


Asunto(s)
Proteína Forkhead Box O3/fisiología , VIH-1/fisiología , Metanfetamina/toxicidad , Células-Madre Neurales/efectos de los fármacos , Complejo SIDA Demencia/complicaciones , Complejo SIDA Demencia/virología , Animales , Encéfalo/patología , Encéfalo/virología , Ciclo Celular , División Celular , Células Cultivadas , Quimiocina CXCL12/biosíntesis , Quimiocina CXCL12/genética , Cromonas/farmacología , Modelos Animales de Enfermedad , Regulación Viral de la Expresión Génica , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Humanos , Ventrículos Laterales/patología , Masculino , Metanfetamina/farmacología , Ratones , Ratones Endogámicos C57BL , Morfolinas/farmacología , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Células-Madre Neurales/virología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/fisiología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores CXCR4/biosíntesis , Receptores CXCR4/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Trastornos Relacionados con Sustancias/complicaciones
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