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Hypoxic–ischemic brain injury is an important cause of neonatal neurological deficits. Our previous study demonstrated that dexmedetomidine (Dex) provided neuroprotection against neonatal hypoxic brain injury; however, the underlying mechanisms remain incompletely elucidated. Overactivation of NADPH oxidase 2 (NOX2) can cause neuronal apoptosis and neurological deficits. Hence, we aimed to investigate the role of neuronal NOX2 in Dex-mediated neuroprotection and to explore its potential mechanisms. Hypoxic injury was modeled in neonatal rodents in vivo and in cultured hippocampal neurons in vitro. Our results showed that pre- or post-treatment with Dex improved the neurological deficits and alleviated the hippocampal neuronal damage and apoptosis caused by neonatal hypoxia. In addition, Dex treatment significantly suppressed hypoxia-induced neuronal NOX2 activation; it also reduced oxidative stress, as evidenced by decreases in intracellular reactive oxygen species (ROS) production, malondialdehyde, and 8-hydroxy-2-deoxyguanosine, as well as increases in the antioxidant enzymatic activity of superoxide dismutase and glutathione peroxidase in neonatal rat hippocampi and in hippocampal neurons. Lastly, the posthypoxicneuroprotective action of Dex was almost completely abolished in NOX2-deficient neonatal mice and NOX2-knockdown neurons. In conclusion, our data demonstrated that neuronal NOX2-mediated oxidative stress is involved in the neuroprotection that Dex provides against apoptosis and neurological deficits in neonates following hypoxia.
Bone cancer pain (BCP)–depression comorbidity has become a complex clinical problem during cancer treatment; however, its underlying molecular mechanisms have not been clarified. Several long noncoding RNAs (lncRNAs) have been demonstrated to be promising therapeutic targets in depression, but research on the role of lncRNAs in BCP–depression comorbidity has been limited. Therefore, high-throughput RNA sequencing was performed to detect differentially expressed profiles in the amygdala of a BCP–depression rat model in this study. We detected 330 differentially expressed mRNAs (DEmRNAs) and 78 differentially expressed lncRNAs (DElncRNAs) in the BCP–depression comorbidity model and then verified the expression of six DEmRNAs and six DElncRNAs with the greatest degrees of difference by RT-qPCR. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that differentially expressed genes were strongly enriched in inflammatory and immunologic systemic responses. Then the nuclear factor kappa B (NF-κB) signaling pathway and the Th17 differentiation pathway showed significant differences, as determined by Western blot analysis. Finally, we constructed a protein–protein interaction (PPI) network to explore the potential regulatory mechanism of DEmRNAs. In conclusion, our study reveals a new resource for the understanding of dysregulated lncRNAs and mRNAs in BCP–depression comorbidity and provides novel potential therapeutic targets for further approaches.
Neurodegenerative diseases and postoperative cognitive dysfunction (POCD) involve the accumulation of β-amyloid peptide (Aβ). High glucose can inhibit autophagy, which facilitates intracellular Aβ clearance.The α2-adrenoreceptor agonist dexmedetomidine (DEX) can provide neuroprotection against several neurological diseases; however, the mechanism remains unclear. This study investigated whether DEX regulated autophagy via the AMPK/mTOR pathway to improve high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells. SH-SY5Y/APP695 cells were cultured with high glucose with/without DEX. To examine the role of autophagy, the autophagy activator rapamycin (RAPA) and the autophagy inhibitor 3methyladenine (3-MA) were used. The selective AMPK inhibitor compound C was used to investigate the involvement of the AMPK pathway. Cell viability and apoptosis were examined by CCK-8 and annexin V-FITC/PI ow cytometric assays, respectively. Autophagy was analyzed by monodansylcadaverine (MDC) staining of autophagic vacuoles. Autophagy-and apoptosis-related protein expression and the phosphorylation levels of AMPK/mTOR pathway molecules were quanti ed by western blotting. DEX pretreatment signi cantly suppressed high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells, as evidenced by the enhanced viability, restoration of cellular morphology, and reduction in apoptotic cells.Furthermore, RAPA had a protective effect similar to that of DEX, but 3-MA eliminated the protective effect of DEX by promoting mTOR activation. Moreover, the AMPK/mTOR pathway involved DEX-mediated autophagy. Compound C signi cantly suppressed autophagy and reversed the protective effect of DEX against high glucose in SH-SY5Y/APP695 cells. Our ndings demonstrated that DEX protected SH-SY5Y/APP695 cells against high glucose-induced neurotoxicity by upregulating autophagy through the AMPK/mTOR pathway, suggesting a role of DEX in treating POCD in diabetic patients.
Flat heat pipe has many excellent characteristics such as high thermal conductivity, reversibility of heat flow direction and so on. In this paper, a flat heat pipe model with multiple microchannels is established, and the effects of different microchannel shapes and different materials on the heat transfer efficiency of flat heat pipe are studied. Then, based on the general rectangular and inverted trapezoidal microchannel shape, the enhancement is carried out. That is to fill a number of materials in the bottom of the microchannel to change the bottom shape of the microchannel. In the steady-state thermal simulation of flat heat pipe, the axial temperature of the flat heat pipe with enhanced microchannel shape is lower than that of the flat heat pipe with general microchannel, which shows that the enhanced microchannel shape is helpful to the heat dissipation of flat heat pipe. The fluid simulation results show that the enhanced rectangular microchannel shape can accelerate the current velocity of working fluid. Therefore, the flat heat pipe with enhanced microchannel shape has better heat transfer performance. In order to obtain the local temperature of flat heat pipe quickly, the transient analytical solution is provided. In this paper, the temperature field calculated by using transient analytical solution is compared with that simulated by COMSOL. The results show that the maximum error between the results of discrete heat source model and continuous heat source model calculated by transient solution and COMSOL simulation results is less than 2%.INDEX TERMS Flat heat pipe, microchannel shape, heat dissipation, analytical solution.
Cancer-induced bone pain (CIBP) occurs frequently among advanced cancer patients. Voltage-gated sodium channels (VGSCs) have been associated with chronic pain, but how VGSCs function in CIBP is poorly understood. Here, we aimed to investigate the specific role of VGSCs in the dorsal root ganglia (DRGs) in CIBP. A CIBP rat model was generated by the intratibial inoculation of MRMT-1 breast carcinoma cells. Transcriptome sequencing was conducted to assess the gene expression profiles. The expression levels of key genes and differentiated genes related to activated pathways were measured by Western blotting and qPCR. We implanted a catheter intrathecally for the administration of lentivirus and drugs. Then, the changes in the mechanical withdrawal threshold (MWT) were measured. We identified 149 differentially expressed mRNAs (DEmRNAs) in the DRGs of CIBP model rats. The expression of Nav1.6, which was among these DEmRNAs, was significantly upregulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the DEmRNAs showed that they were mainly enriched in the mitogen-activated protein kinase (MAPK) pathway. The decrease in MWT induced by bone cancer was attenuated by Nav1.6 knockdown. Western blot analysis revealed that a p38 inhibitor decreased the expression of Nav1.6 and attenuated pain behavior. Our study shows that the upregulation of Nav1.6 expression by p38 MAPK in the DRGs of rats contributes to CIBP.
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