RESUMEN
Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived mediator, induces cell survival in uncompensated oxidative stress (OS), neurodegenerations or ischemic stroke. The molecular principles underlying this protection remain unresolved. We report here that, in retinal pigment epithelial cells, NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways. RelB expression follows a similar pattern as BIRC3, indicating that NPD1 also is required to activate cREL-mediated RelB expression. These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation. BIRC3 silencing prevents NPD1 induction of survival against OS. Moreover, brain NPD1 biosynthesis and selective neuronal BIRC3 abundance are increased by DHA after experimental ischemic stroke followed by remarkable neurological recovery. Thus, NPD1 bioactivity governs key counter-regulatory gene transcription decisive for retinal and brain neural cell integrity when confronted with potential disruptions of homeostasis.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Proto-Oncogénicas c-rel/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIB/genética , Factor de Transcripción ReIB/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
In a recent study (Tafet, Toister-Achituv, & Shinitzky, 2001), we demonstrated that cortisol induces an increase in the expression of the gene coding for the serotonin transporter, associated with a subsequent elevation in the uptake of serotonin. This stimulatory effect, produced upon incubation with cortisol in vitro, was observed in peripheral blood lymphocytes from normal subjects. In the present work we investigated the cortisol-induced increase in serotonin uptake in lymphocytes from hypercortisolemic patients, including subjects with major depressive disorder (n = 8), and subjects with generalized anxiety disorder (n = 12), in comparison with a control group of normal healthy subjects (n = 8). A significant increase in serotonin uptake (+37% + 14, M + SD) was observed in the control group, whereas neither the generalized anxiety disorder nor the major depression group exhibited changes in serotonin uptake upon incubation with cortisol. It is likely that under chronic stress or depression, the capacity for increase in serotonin transporter has reached its limit due to the chronically elevated blood cortisol level. The physiological and diagnostic implications of this observation are discussed.
Asunto(s)
Proteínas Portadoras/fisiología , Trastorno Depresivo Mayor/fisiopatología , Hidrocortisona/fisiología , Glicoproteínas de Membrana/fisiología , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Serotonina/sangre , Estrés Psicológico/fisiopatología , Adulto , Nivel de Alerta/fisiología , Proteínas Portadoras/genética , Enfermedad Crónica , Ritmo Circadiano/fisiología , Femenino , Expresión Génica/fisiología , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Linfocitos/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/fisiopatología , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Our research objective was to characterize the biochemical effect of streptomycin during postnatal rat cerebral cortex development using a sensitive method that preserves the in situ topological relationship. We found a decrease in the mannosylation of asparagine-linked oligosaccharides without affecting polypeptide synthesis, DNA synthesis or glucose and mannose disappearance from the medium in mini-tissue units derived from P5. In addition, the rate of Dolp-GlcNAc2 Man9 Glc3 synthesis and the oligosaccharide protein transferase activity did not change in the presence of the aminoglycoside. These findings strongly suggested that the alteration of protein mannosylation occurred downstream of G3 transfer to nascent polypeptides. Further, the mini-tissue units may be useful for the assessment of neurological toxicity of antibacterial agents.