RESUMEN
Impairment of learning and memory has been documented in the later life of offspring to maternal consumption with high energy diet. Environmental stimulation enhances the ability of learning and memory. However, potential effects of environmental stimulation on the programming-associated deficit of learning and memory have not been addressed. Here, we examined the effects of enriched-housing on hippocampal learning and memory in adult female offspring rats from mother fed with 60% high fructose diet (HFD) during pregnancy and lactation. Impairment of spatial learning and memory performance in HFD group was observed in offspring at 3-month-old. Hippocampal brain-derived neurotrophic factor (BDNF) was decreased in the offspring. Moreover, the HFD group showed an up-regulation of histone deacetylase 4 (HDAC4) in the nuclear fractions of hippocampal neurons. Stimulation to the offspring for 4weeks after winning with an enriched-housing environment effectively rescued the decrease in cognitive function and hippocampal BDNF level; alongside a reversal of the increased distribution of nuclear HDAC4. Together these results suggest that later life environmental stimulation effectively rescues the impairment of hippocampal learning and memory in female offspring to maternal HFD intake through redistributing nuclear HDAC4 to increase BDNF expression.
Asunto(s)
Ambiente , Fructosa/administración & dosificación , Histona Desacetilasas/metabolismo , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cognición/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Aprendizaje Espacial/efectos de los fármacosRESUMEN
Hydroxychloroquine (HCQ) is an antimalarial drug also used in treating autoimmune diseases. Its antiviral activity was demonstrated in restricting HIV infection in vitro; however, the clinical implications remain controversial. Infection with dengue virus (DENV) is a global public health problem, and we lack an antiviral drug for DENV. Here, we evaluated the anti-DENV potential of treatment with HCQ. Immunofluorescence assays demonstrated that HCQ could inhibit DENV serotype 1-4 infection in vitro. RT-qPCR analysis of HCQ-treated cells showed induced expression of interferon (IFN)-related antiviral proteins and certain inflammatory cytokines. Mechanistic study suggested that HCQ activated the innate immune signaling pathways of IFN-ß, AP-1, and NFκB. Knocking down mitochondrial antiviral signaling protein (MAVS), inhibiting TANK binding kinase 1 (TBK1)/inhibitor-κB kinase É (IKKÉ), and blocking type I IFN receptor reduced the efficiency of HCQ against DENV-2 infection. Furthermore, HCQ significantly induced cellular production of reactive oxygen species (ROS), which was involved in the host defense system. Suppression of ROS production attenuated the innate immune activation and anti-DENV-2 effect of HCQ. In summary, HCQ triggers the host defense machinery by inducing ROS- and MAVS-mediated innate immune activation against DENV infection and may be a candidate drug for DENV infection.
Asunto(s)
Virus del Dengue/inmunología , Dengue/tratamiento farmacológico , Células Epiteliales/efectos de los fármacos , Hidroxicloroquina/farmacología , Interferones/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Línea Celular , Células Epiteliales/inmunología , Células Epiteliales/virología , Regulación Viral de la Expresión Génica/efectos de los fármacos , Humanos , Inmunidad Innata/efectos de los fármacos , Interferones/genética , Ratones , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Dengue virus (DENV) infection is the most common mosquito-borne viral disease threatening human health around the world. Type I interferon (IFN) and cytokine production are crucial in the innate immune system. We previously reported that DENV serotype 2 (DENV-2) induced low levels of interferon regulatory factor 3 and NF-κB activation, thus leading to reduced production of IFN-ß in the early phase of infection. Here, we determined whether DENV infection not only hampers type I IFN activation but also cytokine production triggered by Toll-like receptor (TLR) signaling. METHODOLOGY/PRINCIPAL FINDINGS: We used quantitative RT-PCR and found that only low levels of IFN-ß and inflammatory cytokines such as interleukin 10 (IL-10), IL-12 and tumor necrosis factor α (TNFα) mRNA were detected in DENV-2-infected bone-marrow-derived dendritic cells. Furthermore, DENV-2 infection repressed cytokine production triggered by TLR signaling. To elucidate the molecular mechanisms underlying this suppression event, we measured NF-κB activation by p65 nuclear translocation and luciferase reporter assay and found that NF-κB activation triggered by TLR ligands was blocked by DENV-2 infection. As well, extracellular signal-regulated kinase (ERK) activity was suppressed by DENV-2 infection. CONCLUSIONS/SIGNIFICANCE: To downregulate the host innate immunity, DENV-2 by itself is a weak inducer of type I IFN and cytokines, furthermore DENV-2 can also block the TLR-triggered ERK-NF-κB activation and cytokine production.
Asunto(s)
Citocinas/biosíntesis , Virus del Dengue/fisiología , Regulación hacia Abajo , Proteína Quinasa 1 Activada por Mitógenos/biosíntesis , Proteína Quinasa 3 Activada por Mitógenos/biosíntesis , FN-kappa B/metabolismo , Animales , Células de la Médula Ósea/citología , Línea Celular Tumoral , Chlorocebus aethiops , Células Dendríticas/citología , Células Dendríticas/metabolismo , Células Dendríticas/virología , Activación Enzimática , Femenino , Humanos , Interferón beta/biosíntesis , Interleucina-10/biosíntesis , Ligandos , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Transducción de Señal , Receptores Toll-Like/metabolismoRESUMEN
It is known that enrichment of glutamatergic transmission in the nucleus tractus solitarii (NTS) plays an important role in central cardiovascular regulation. Our previous study demonstrated that nicotine decreased blood pressure and heart rate in the NTS probably acting via the nicotinic acetylcholine receptors (nAChRs)-Ca²âº-calmodulin-eNOS-NO signaling pathway. The possible relationship between glutamate and nicotine in the NTS for cardiovascular regulation is poorly understood. This study investigated the involvement of glutamate receptors in the cardiovascular effects of nicotine in the NTS. Nicotine (a non-selective nAChRs agonist), MK801 (a non-competitive NMDA receptor antagonist), APV (a competitive NMDA receptor antagonist), or NBQX (a selective AMPA receptor antagonist) was microinjected into the NTS of anesthetized Wistar-Kyoto rats. Microinjection of nicotine (1.5 pmol) into the NTS produced decreases in blood pressure and heart rate. The hypotensive and bradycardic effects of nicotine were abolished by prior administration of MK801 (1 nmol) and APV (10 nmol), but was completely restored after 60 min of recovery. In contrast, prior administration of NBQX (10 pmol) into the NTS did not alter the cardiovascular effects of nicotine. The nitrate (served as total NO) production in response to nicotine microinjection into the NTS was suppressed by prior administration of APV. These results suggest that the hypotensive and bradycardic effects of nicotine in the NTS might be mediated through NMDA receptors, and that the nAChRs-NMDA receptor-NO pathway could be involved.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bradicardia/inducido químicamente , Frecuencia Cardíaca/efectos de los fármacos , Hipotensión/inducido químicamente , Nicotina/farmacología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Presión Sanguínea/fisiología , Bradicardia/fisiopatología , Maleato de Dizocilpina/farmacología , Interacciones Farmacológicas , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/fisiología , Frecuencia Cardíaca/fisiología , Hipotensión/fisiopatología , Masculino , Agonistas Nicotínicos/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Endogámicas WKY , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/fisiología , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Recent evidence has suggested that nicotine decreases blood pressure (BP) and heart rate (HR) in the nucleus tractus solitarii (NTS), indicating that nicotinic acetylcholine receptors (nAChRs) play an important role in BP control in the NTS. However, the signalling mechanisms involved in nAChR-mediated depressor effects in the NTS are unclear. Hence, the aim of this study was to investigate these signalling mechanisms. EXPERIMENTAL APPROACH: Depressor responses to nicotine microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of an antagonist of α7 nAChR, the calcium chelator ethylene glycol tetraacetic acid, a calmodulin-specific inhibitor, nitric oxide (NO) synthase (NOS) inhibitor, endothelial NOS (eNOS)-selective inhibitor or neuronal NOS (nNOS)-specific inhibitor. KEY RESULTS: Microinjection of nicotine into the NTS produced a dose-dependent decrease in BP and HR, and increased nitrate levels. This depressor effect of nicotine was attenuated after pretreatment with a nAChR antagonist or blockers of the calmodulin-eNOS pathway. In contrast, N5-(1-Imino-3-butenyl)-L-ornithine (vinyl-L-NIO), nNOS-specific inhibitor, did not diminish these nicotine-mediated effects. Calmodulin was found to bind eNOS after nicotine injection into NTS. However, nicotine did not affect the eNOS phosphorylation level or eNOS upstream extracellular signal-regulated kinases (ERK)1/2 and Akt phosphorylation levels. Furthermore, pretreatment with an ERK1/2 or Akt inhibitor did not attenuate nicotine-induced depressor effects in the NTS. CONCLUSIONS AND IMPLICATIONS: These results suggest that the nAChR-Ca(2+) -calmodulin-eNOS-NO signalling pathway, but not nNOS, plays a significant role in central BP regulation, and neither the ERK1/2 nor Akt signalling pathway are significantly involved in the activation of eNOS by nAChRs in the NTS.