RESUMEN

Forkhead box A1 (FOXA1) plays an important role in the central nervous system, and its loss can lead to the downregulation of tyrosine hydroxylase, which directly affects the synthesis of dopamine, thus leading to Parkinson's disease (PD). The present study aimed to explore the specific role of FOXA1 in PD. Blood samples from patients with PD were collected to determine the expression levels of FOXA1 using reverse transcription-quantitative PCR (RT-qPCR). In addition, mouse dopaminergic neuron MES23.5 cells were induced with 6-hydroxydopamine (6-OHDA) to construct an in vitro PD model in order to study the effect of FOXA1 overexpression on cell inflammation, oxidative stress and apoptosis with RT-qPCR, assay kits and TUNEL assays, respectively. Subsequently, the expression of FOXA1 was silenced to assess the effect on the downstream mechanism. The results revealed that the expression level of FOXA1 was downregulated in patients with PD, and FOXA1 overexpression attenuated 6-OHDA-induced inflammation, oxidative stress and apoptosis in MES23.5 cells. Furthermore, FOXA1 could bind to the trefoil factor 1 (TFF1) promoter, and the effects of FOXA1 overexpression on cells were reversed by TFF1 silencing, indicating that TFF1 mediated the mechanism of FOXA1 overexpression in MES23.5 cells. In conclusion, following FOXA1 transcription, TFF1 expression was activated, thereby relieving 6-OHDA-induced cell inflammation, oxidative stress and apoptosis. The present findings suggested that FOXA1 may serve as a target for the treatment of PD.

RESUMEN

PURPOSE: As the population ages, the incidence of clinical dementia has been rising around the world. It has been reported that microRNAs act as key diagnostic biomarkers and targets for various neurological conditions, including dementia. MiR-322-5p has been revealed to play an important role in multiple diseases. In this study, we aimed to investigate the role and regulatory mechanism of miR-322-5p in vascular dementia. MATERIALS AND METHODS: In this study, neonatal rat neurons (NRNs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce cell injury. The animals were subjected to permanent bilateral occlusion of the carotid arteries (2-vessel occlusion, 2VO) to induce the model of chronic brain hypoperfusion. RESULTS: MiR-322-5p expression was significantly downregulated in the neurons exposed to OGD/R and the hippocampi of 2VO rats. Overexpression of miR-322-5p ameliorated cell apoptosis and the inflammatory response in vitro. In a mechanistic study, miR-322-5p was confirmed to directly target and negatively regulate tetraspanin 5 (TSPAN5) in cultured NRNs. Moreover, overexpression of TSPAN5 could counteract the effects of miR-322-5p overexpression on cell apoptosis and the inflammatory response in OGD/R-treated neurons. More importantly, miR-322-5p improved cognitive ability and inhibited inflammatory production in 2VO rats. CONCLUSION: Overall, the results suggest that miR-322-5p alleviates vascular dementia development by targeting TSPAN5. This discovery may provide a potential therapeutic target for dementia.

Asunto(s)

RESUMEN

BACKGROUND AND PURPOSE: Neurotoxicity of anesthetics has been widely observed by clinicians. It is reported that inflammation and oxidative stress are involved in the pathological process. In the present study, we aimed to assess the therapeutic effects of agomelatine against isoflurane-induced inflammation and damage to brain endothelial cells. MATERIALS AND METHODS: MTT assay was used to detect cell viability in order to determine the optimized concentration of agomelatine. The bEnd.3 brain endothelial cells were treated with 2% isoflurane in the presence or absence of agomelatine (5, 10 µM) for 24 h. LDH release was evaluated and the ROS levels were checked using DHE staining assay. The expressions of IL-6, IL-8, TNF-α, VEGF, TF, VCAM-1, and ICAM-1 were evaluated using real-time PCR and ELISA. Real-time PCR and Western blot analysis were used to determine the expression level of Egr-1. RESULTS: The decreased cell viability promoted LDH release and elevated ROS levels induced by isoflurane were significantly reversed by the introduction of agomelatine in a dose-dependent manner. The expression levels of IL-6, IL-8, TNF-α, VEGF, TF, VCAM-1, and ICAM-1 were elevated by stimulation with isoflurane, which were significantly suppressed by the administration of agomelatine. The up-regulation of transcriptional factor Egr-1 induced by isoflurane was down-regulated by agomelatine. CONCLUSION: Agomelatine might attenuate isoflurane-induced inflammation and damage via down-regulating Egr-1 in brain endothelial cells.

Asunto(s)

RESUMEN

Congenital generalized lipodystrophy 2 (CGL2) is characterized by loss of adipose tissue, insulin resistance and cognitive deficits and caused by mutation of BSCL2/seipin gene. Seipin deletion in mice and rats causes severe lipodystrophy, insulin resistance, and cognitive impairment. Hippocampal neurons express seipin protein. This study aimed to investigate the influence of systemic seipin knockout (seipin-sKO), neuronal seipin knockout (seipin-nKO) or adipose seipin knockout (seipin-aKO) in hippocampal tau phosphorylation and aggregation. Levels of tau phosphorylation at Thr212/Ser214 and Ser202/Thr205 and oligomer tau protein were increased in seipin-sKO mice and seipin-nKO mice with a decrease in axonal density and expression of PPARγ. Neuronal seipin deletion increased activities of GSK3ß and Akt/mTOR signaling, which were corrected by the administration of PPARγ agonist rosiglitazone for 7 days. The autophagosome formation was reduced in seipin-sKO mice and seipin-nKO mice, which was rescued by the Akt and mTOR inhibitors. The administration of rosiglitazone or Akt, mTOR and GSK3ß inhibitors for 7 days could correct the hyperphosphorylation and aggregation of tau. On the other hand, seipin-sKO mice appeared insulin resistance and an increase in phosphorylation of tau at Ser396 and JNK, which were corrected by treatment with rosiglitazone for 30 days rather than 7 days. Inhibition of JNK in seipin-sKO mice corrected the hyperphosphorylated tau at Ser396. The results indicate that neuronal seipin deletion causes hyperphosphorylation and aggregation of tau protein leading to axonal atrophy through reduced PPARγ to enhance GSK3ß and Akt/mTOR signaling; systemic seipin deletion-induced insulin resistance causes tau hyperphosphorylation via cascading JNK pathway.

Asunto(s)