It is well established that developmental exposure of sevoflurane (an inhalational anesthetic) is capable of inducing neuronal apoptosis and subsequent learning and memory disorders. Synaptic NMDA receptors activity plays an essential role in cell survival, while the extra-synaptic NMDA receptors activation is usually associated with cell death. However, whether synaptic or extra-synaptic NMDA receptors mediate developmental sevoflurane neurotoxicity is largely unknown. Here, we show that developmental sevoflurane treatment decreased NR2A, but increased NR2B subunit expression both in vitro and in vivo. Sevoflurane-induced neuronal apoptosis was attenuated by synaptic NMDA receptors activation or low dose of exogenous NMDA in vitro. Interestingly, these effects could be abolished by NR2A inhibitor PEAQX, but not NR2B inhibitor Ifenprodil in vitro. In contrast, activation of extra-synaptic NMDA receptors alone had no effects on sevoflurane neurotoxicity. In the scenario of extra-synaptic NMDA receptors stimulation, however, sevoflurane-induced neuronal apoptosis could be prevented by addition of Ifenprodil, but not by PEAQX in vitro. In addition, sevoflurane neurotoxicity could also be rescued by memantine, an uncompetitive antagonist for preferential blockade of extra-synaptic NMDA receptors both in vitro and in vivo. Furthermore, we found that developmental sevoflurane-induced phospho-ERK1/2 inhibition was restored by synaptic NMDA receptor activation (in vitro), low dose of NMDA (in vitro) or memantine (in vivo). And the neuroprotective role of synaptic NMDA activity was able to be reversed by MEK1/2 inhibitor U0126 in vitro. Finally, administration of memantine or NMDA significantly improved spatial learning and memory dysfunctions induced by developmental sevoflurane exposure without influence on locomotor activity. These results indicated that activation of synaptic NR2A-containing NMDA receptors, or inhibition of extra-synaptic NR2B-containing NMDA receptors contributed to the relief of sevoflurane neurotoxicity, and the ERK1/2 MAPK signaling may be involved in this process.

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Study objectives To assess the effect of dexmedetomidine (DEX) on postoperative sleep quality using polysomnography (PSG) to identify possible interventions for postoperative sleep disturbances. Methods An electronic search of PubMed/MEDLINE, EMBASE, Cochrane Library and Web of Science was conducted from database inception to November 20, 2022. Randomized controlled trials (RCTs) on the effect of DEX administration on postoperative sleep quality using PSG or its derivatives were included. No language restrictions were applied. The sleep efficiency index (SEI), arousal index (AI), percentages of stage N1, N2 and N3 of non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were measured in our meta-analysis. Results Five studies, involving 381 participants were included. Administration of DEX significantly improved SEI, lowered AI, decreased the duration of stage N1 sleep and increased the duration of stage N2 sleep compared to placebo groups. There were no significant differences in the duration of stage N3 sleep and REM sleep. DEX administration lowered the postoperative Visual Analogue Scale (VAS) score and improved the Ramsay sedation score with no adverse effect on postoperative delirium (POD). However, high heterogeneity was observed in most of the primary and secondary outcomes. Conclusions Our study provides support for the perioperative administration of DEX to improve postoperative sleep quality. The optimal dosage and overall effect of DEX on postoperative sleep quality require further investigation using large-scale randomized controlled trials.

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Background Ropivacaine is commonly applied for local anesthesia and may cause neurotoxicity. Dexmedetomidine (DEX) exhibits neuroprotective effects on multiple neurological disorders. This study investigated the mechanism of DEX pretreatment in ropivacaine-induced neurotoxicity. Methods Mouse hippocampal neuronal cells (HT22) and human neuroblastoma cells (SH-SY5Y) were treated with 0.5 mM, 1 mM, 2.5 mM, and 5 mM ropivacaine. Then the cells were pretreated with different concentrations of DEX (0.01 μM, 0.1 μM, 1 μM, 10 μM, and 100 μM) before ropivacaine treatment. Proliferative activity of cells, lactate dehydrogenase (LDH) release, and apoptosis rate were measured using CCK-8 assay, LDH detection kit, and flow cytometry, respectively. miR-10b-5p and BDNF expressions were determined using RT-qPCR or Western blot. The binding of miR-10b-5p and BDNF was validated using dual-luciferase assay. Functional rescue experiments were conducted to verify the role of miR-10b-5p and BDNF in the protective mechanism of DEX on ropivacaine-induced neurotoxicity. Results Treatment of HT22 or SH-SY5Y cells with ropivacaine led to the increased miR-10b-5p expression (about 1.7 times), decreased BDNF expression (about 2.2 times), reduced cell viability (about 2.5 times), elevated intracellular LDH level (about 2.0–2.5 times), and enhanced apoptosis rate (about 3.0–4.0 times). DEX pretreatment relieved ropivacaine-induced neurotoxicity, as evidenced by enhanced cell viability (about 1.7–2.0 times), reduced LDH release (about 1.7–1.8 times), and suppressed apoptosis rate (about 1.8–1.9 times). DEX pretreatment repressed miR-10b-5p expression (about 2.5 times). miR-10b-5p targeted BDNF. miR-10b-5p overexpression or BDNF silencing reversed the protective effect of DEX pretreatment on ropivacaine-induced neurotoxicity, manifested as reduced cell viability (about 1.3–1.6 times), increased intracellular LDH level (about 1.4–1.7 times), and elevated apoptosis rate (about 1.4–1.6 times). Conclusions DEX pretreatment elevated BDNF expression by reducing miR-10b-5p expression, thereby alleviating ropivacaine-induced neurotoxicity.

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Background: The nucleoplasmin/nucleophosmin (NPM) family was previously regarded as a critical regulator during disease development, and its mediation in carcinogenesis has achieved intensive attention recently. However, the clinical importance and functional mechanism of NPM3 in lung adenocarcinoma (LUAD) have not been reported yet. Objective: This study aimed to investigate the role and clinical significance of NPM3 in the development and progression of LUAD, including the underlying mechanisms. Method: The expression of NPM3 in pan-cancer was analyzed via GEPIA. The effect of NPM3 on prognosis was analyzed by the Kaplan-Meier plotter and the PrognoScan database. In vitro, cell transfection, RT-qPCR, CCK-8 assay, and wound healing assay were employed to examine the role of NPM3 in A549 and H1299 cells. Gene set enrichment analysis (GSEA) was performed using the R software package to analyze the tumor hallmark pathway and KEGG pathway of NPM3. The transcription factors of NPM3 were predicted based on the ChIP-Atlas database. Dual-luciferase reporter assay was applied to verify the transcriptional regulatory factor of the NPM3 promoter region. Results: The NPM3 expression was found to be markedly higher in the LUAD tumor group than the normal group and to be positively correlated with poor prognosis, tumor stages, and radiation therapy. In vitro, the knockdown of NPM3 greatly inhibited the proliferation and migration of A549 and H1299 cells. Mechanistically, GSEA predicted that NPM3 activated the oncogenic pathways. Further, the NPM3 expression was found to be positively correlated with cell cycle, DNA replication, G2M checkpoint, HYPOXIA, MTORC1 signaling, glycolysis, and MYC targets. Besides, MYC targeted the promoter region of NPM3 and contributed to the enhanced expression of NPM3 in LUAD. Conclusion: The overexpression of NPM3 is an unfavorable prognostic biomarker participating in oncogenic pathways of LUAD via MYC translational activation and it contributes to tumor progression. Thus, NPM3 could be a novel target for LUAD therapy.