RESUMEN
Sepsis is life-threatening organ dysfunction due to dysregulated systemic inflammatory and immune response to infection, often leading to cognitive impairments. Growing evidence shows that artemisinin, an antimalarial drug, possesses potent anti-inflammatory and immunoregulatory activities. In this study we investigated whether artemisinin exerted protective effect against neurocognitive deficits associated with sepsis and explored the underlying mechanisms. Mice were injected with LPS (750 µg · kg-1 · d-1, ip, for 7 days) to establish an animal model of sepsis. Artemisinin (30 mg · kg-1 · d-1, ip) was administered starting 4 days prior LPS injection and lasting to the end of LPS injection. We showed that artemisinin administration significantly improved LPS-induced cognitive impairments assessed in Morris water maze and Y maze tests, attenuated neuronal damage and microglial activation in the hippocampus. In BV2 microglial cells treated with LPS (100 ng/mL), pre-application of artemisinin (40 µΜ) significantly reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-6) and suppressed microglial migration. Furthermore, we revealed that artemisinin significantly suppressed the nuclear translocation of NF-κB and the expression of proinflammatory cytokines by activating the AMPKα1 pathway; knockdown of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin in BV2 microglial cells. In conclusion, atemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect is probably mediated by activation of the AMPKα1 signaling pathway in microglia.
Asunto(s)
Artemisininas/uso terapéutico , Microglía/efectos de los fármacos , Trastornos Neurocognitivos/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Sepsis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/patología , Muerte Celular/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/metabolismo , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Microglía/metabolismo , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/metabolismo , Neuronas/efectos de los fármacos , Sepsis/inducido químicamente , Sepsis/complicaciones , Sepsis/metabolismoRESUMEN
Gastric cancer is the fourth most common cancer type and the second leading cause of cancerassociated mortality worldwide. Metastasis is a crucial feature of its progression. DNA methylation provides a key epigenetic signature in the epigenetic regulation pathway, and is implicated in transcriptional regulation. CpG sites, which are associated with gene transcriptional activity, are underrepresented in the mammalian genome and tend to be clustered within CpG islands (CGIs) located in the vicinity of the transcription start sites of the majority of the proteincoding genes in humans. The DNA methylation inhibitor, decitabine (DAC), has been demonstrated to be active in hematological disorders. The majority of previous studies in cancer cells demonstrated that DAC inhibits cell proliferation and the motility of the cells. However, since demethylation across the entire genome alters the expression of a large number of genes, the effects of DAC in different tumor cell types are difficult to accurately predict. Neural precursor cellexpressed, developmentally downregulated (NEDD)41, a member of the NEDD4 family, which belongs to the E3ubiquitin ligase family, was reported to be highly expressed in a wide range of tumor types, and it activates the phosphoinositide 3kinase/Akt pathway by degrading phosphatase and tensin homolog. NEDD41 promotes the migration and invasion of glioma cells via the ubiquitination and subsequent degradation of cyclic nucleotideRas guanine nucleotide exchange factors (CNrasGEFs). In gastric cardia adenocarcinoma, NEDD41 acts as an exceptional prognostic biomarker. In the present study, DAC was revealed to promote the invasive properties of MGC803 gastric cancer cells. NEDD41 targeted the CNrasGEFmediated DAC invasionpromoting activity in MGC803 cells, and CGI methylation in neither the NEDD4 promoter nor the first intron was demonstrated to be associated with this effect. The results of the present study revealed that DAC exerts variable effects in different gastric cancer cell lines and may provide a reference for DAC administration in the clinic.
Asunto(s)
Azacitidina/análogos & derivados , Movimiento Celular/efectos de los fármacos , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Neoplasias Gástricas/genética , Ubiquitina-Proteína Ligasas/genética , Regulación hacia Arriba , Azacitidina/farmacología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Metilación de ADN/efectos de los fármacos , Decitabina , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/fisiología , Humanos , Ubiquitina-Proteína Ligasas Nedd4 , Invasividad Neoplásica/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/fisiologíaRESUMEN
OCT4 is an essential transcription factor for maintaining the self-renewal and the pluripotency of embryonic stem cells (ESCs). The human OCT4 gene can generate three mRNA isoforms (OCT4A, OCT4B and OCT4B1) by alternative splicing. OCT4A protein is a transcription factor for the stemness of ESCs, while the function of OCT4B isoforms remains unclear. Most types of cancer express a relatively low level of OCT4 protein, particularly the OCT4B isoforms. In the present study, we found that OCT4A and OCT4B mRNA were co-expressed in several types of tumor cell lines and tumor samples, and we demonstrated that OCT4B functioned as a non-coding RNA, modulating OCT4A expression in an miRNA-dependent manner [competing endogenous RNA (ceRNA) regulation] at the post-transcription level in the tumor cell lines. This is the first time that ceRNA regulation was observed among spliced isoforms of one gene, and may pave the way for identification of new targets for cancer treatment.
Asunto(s)
Factor 3 de Transcripción de Unión a Octámeros/genética , ARN Mensajero/genética , ARN no Traducido/genética , Empalme Alternativo/genética , Línea Celular Tumoral , Células HCT116 , Humanos , Isoformas de Proteínas/genética , Procesamiento Postranscripcional del ARN/genética , Factores de Transcripción/genéticaRESUMEN
Synchronized activities among retinal ganglion cells (RGCs) via gap junctions can be increased by exogenous dopamine (DA). During DA application, single neurons' firing activities become more synchronized with its adjacent neighbors. One intriguing question is how the enhanced spatial synchronization alters the temporal firing structure of single neurons. In the present study, firing activities of bullfrog's dimming detectors in response to binary pseudo-random checker-board flickering were recorded via a multi-channel recording system. DA was applied in the retina to modulate synchronized activities between RGCs, and the effect of DA on firing activities of single neurons was examined. It was found that, during application of DA, synchronized activities between single neuron and its neighboring neurons was enhanced. At the meantime, the temporal structures of single neuron spike train changed significantly, and the temporal correlation in single neuron's response decreased. The pharmacological study results indicated that the activation of D1 receptor might have effects on gap junction permeability between RGCs. Our results suggested that the dopaminergic pathway participated in the modulation of spatial and temporal correlation of RGCs' firing activities, and may exert critical effects on visual information processing in the retina.