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Investigating the sevoflurane-induced perturbation in the differentiation of mouse embryonic stem cells (mESCs) into neural stem cells (mNSCs), our study delineates a novel SIRT1/PRRX1/DRD2/PKM2/NRF2 axis as a key player in this intricate process. Sevoflurane treatment hindered mESC differentiation, evidenced by altered expression patterns of pluripotency and neural lineage markers. Mechanistically, sevoflurane downregulated Sirt1, setting in motion a signaling cascade. Sevoflurane may inhibit PKM2 dimerization and NRF2 signaling pathway activation by inhibiting the expression of SIRT1 and its downstream genes Prrx1 and DRD2, ultimately inhibiting mESCs differentiation into mNSCs. These findings contribute to our understanding of the molecular basis of sevoflurane-induced neural toxicity, presenting a potential avenue for therapeutic intervention in sevoflurane-induced perturbation in the differentiation of mESCs into mNSCs by modulating the SIRT1/PRRX1/DRD2/PKM2/NRF2 axis.
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Sevoflurane, as a commonly used inhaled anesthetic for pediatric patients, has been reported that multiple sevoflurane exposures are associated with a greater risk of developing neurocognitive disorder. N6-Methyladenosine (m6A), as the most common mRNA modification in eukaryotes, has emerged as a crucial regulator of brain function in processes involving synaptic plasticity, learning and memory, and neurodevelopment. Nevertheless, the relevance of m6A RNA methylation in the multiple sevoflurane exposure-induced developmental neurotoxicity remains mostly elusive. Herein, we evaluated the genome-wide m6A RNA modification and gene expression in hippocampus of mice that received with multiple sevoflurane exposures using m6A-sequencing (m6A-seq) and RNA-sequencing (RNA-seq). We discovered 19 genes with differences in the m6A methylated modification and differential expression in the hippocampus. Among these genes, we determined that a total of nine differential expressed genes may be closely associated with the occurrence of developmental neurotoxicity induced by multiple sevoflurane exposures. We further found that the alkB homolog 5 (ALKBH5), but not methyltransferase-like 3 (METTL3) and Wilms tumor 1-associated protein (WTAP), were increased in the hippocampus of mice that received with multiple sevoflurane exposures. And the IOX1, as an inhibitor of ALKBH5, significantly improved the learning and memory defects and reduced neuronal damage in the hippocampus of mice induced by multiple sevoflurane exposures. The current study revealed the role of m6A methylated modification and m6A-related regulators in sevoflurane-induced cognitive impairment, which might provide a novel insight into identifying biomarkers and therapeutic strategies for inhaled anesthetic-induced developmental neurotoxicity.
Assuntos
Adenosina , Homólogo AlkB 5 da RNA Desmetilase , Hipocampo , Síndromes Neurotóxicas , Sevoflurano , Sevoflurano/toxicidade , Animais , Camundongos , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Adenosina/análogos & derivados , Adenosina/metabolismo , Anestésicos Inalatórios/toxicidade , Camundongos Endogâmicos C57BL , Metilação/efeitos dos fármacos , Metiltransferases/metabolismo , Metiltransferases/genéticaRESUMO
Acute respiratory distress syndrome (ARDS) is a serious lung condition that often leads to hospitalization in intensive care units and a high mortality rate. Sevoflurane is a volatile anesthetic with growing interest for sedation in ventilated patients with ARDS. It has been shown to have potential lung-protective effects, such as reduced inflammation and lung edema, or improved arterial oxygenation. In this study, we investigated the effects of sevoflurane on lung injury in cultured human carcinoma-derived lung alveolar epithelial (A549) cells. We found that sevoflurane was associated with improved wound healing after exposure to inflammatory cytokines, with preserved cell proliferation but no effect on cell migration properties. Sevoflurane exposure was also associated with enhanced cell viability and active autophagy in A549 cells exposed to cytokines. These findings suggest that sevoflurane may have beneficial effects on lung epithelial injury by promoting alveolar epithelial wound healing and by influencing the survival and proliferation of A549 epithelial cells in vitro. Further research is needed to confirm these findings and to investigate the key cellular mechanisms explaining sevoflurane's potential effects on lung epithelial injury.
Assuntos
Proliferação de Células , Sobrevivência Celular , Síndrome do Desconforto Respiratório , Sevoflurano , Cicatrização , Sevoflurano/farmacologia , Humanos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/patologia , Cicatrização/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células A549 , Proliferação de Células/efeitos dos fármacos , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Movimento Celular/efeitos dos fármacos , Anestésicos Inalatórios/farmacologia , Citocinas/metabolismo , Autofagia/efeitos dos fármacos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologiaRESUMO
Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.
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Anestésicos Inalatórios , Córtex Pré-Frontal , Sevoflurano , Animais , Sevoflurano/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Camundongos , Anestésicos Inalatórios/toxicidade , Masculino , Animais Recém-Nascidos , Feminino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estudo de Associação Genômica AmplaRESUMO
Postoperative cognitive dysfunction (POCD) is a prevalent central nervous system complication predominantly observed in elderly patients. Sevoflurane, a general anaesthetic agent, has been implicated in the development of POCD, yet the underlying regulatory mechanisms potentially involving Sestrin1 (SESN1), a stress-responsive protein that plays a critical role in cellular homeostasis and protection against stress-induced damage, including oxidative stress and DNA damage, remain elusive. This study endeavoured to elucidate the impact of SESN1 on sevoflurane-induced cognitive impairment in rats. Employing a model in which SESN1 was transfected into SD male rats and cognitive dysfunction was induced by sevoflurane. The Morris Water Maze test was used for behavioural evaluation, Enzyme-Linked Immunosorbent Assay, Western blotting and immunofluorescence were applied to assess the influence of SESN1 on the inflammatory response and mitophagy in the rat hippocampus. The study further aimed to uncover the putative mechanism by which SESN1, through SIRT1, might modulate cognitive function. Concurrently, levels of malondialdehyde, superoxide dismutase and mitochondrially produced ATP within the rat hippocampus were quantified. Experimental outcomes suggested that SESN1 overexpression significantly mitigated the deleterious effects of sevoflurane anaesthesia, ameliorated neuroinflammation and inflammasome activation, modified mitochondrial function and facilitated mitophagy. Additionally, SESN1, via the activation of SIRT1, may suppress inflammasome activation and mitochondrial dysfunction. Collectively, these findings underscore SESN1's integral role in counteracting sevoflurane-induced cognitive impairment, impeding inflammasome activation, enhancing mitochondrial function and fostering mitophagy, which appear to be intricately linked to SESN1-mediated SIRT1 activation. SESN1 is a novel therapeutic target for POCD, potentially advancing neuroprotective strategies in clinical settings.
Assuntos
Anestesia , Disfunção Cognitiva , Humanos , Masculino , Ratos , Animais , Idoso , Sevoflurano/farmacologia , Sirtuína 1/metabolismo , Mitofagia , Inflamassomos/efeitos adversos , Inflamassomos/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Anestesia/efeitos adversos , Hipocampo/metabolismo , Sestrinas/metabolismoRESUMO
OBJECTIVE: Anesthetics have been linked to cognitive alterations, particularly in the elderly. The current research delineates how Fibroblast Growth Factor 2 (Fgf2) modulates tau protein phosphorylation, contributing to cognitive impairments in aged rats upon sevoflurane administration. METHODS: Rats aged 3, 12, and 18 months were subjected to a 2.5% sevoflurane exposure to form a neurotoxicity model. Cognitive performance was gauged, and the GEO database was employed to identify differentially expressed genes (DEGs) in the 18-month-old cohort post sevoflurane exposure. Bioinformatics tools, inclusive of STRING and GeneCards, facilitated detailed analysis. Experimental validations, both in vivo and in vitro, examined Fgf2's effect on tau phosphorylation. RESULTS: Sevoflurane notably altered cognitive behavior in older rats. Out of 128 DEGs discerned, Fgf2 stood out as instrumental in regulating tau protein phosphorylation. Sevoflurane exposure spiked Fgf2 expression in cortical neurons, intensifying tau phosphorylation via the PI3K/AKT/Gsk3b trajectory. Diminishing Fgf2 expression correspondingly curtailed tau phosphorylation, neurofibrillary tangles, and enhanced cognitive capacities in aged rats. CONCLUSION: Sevoflurane elicits a surge in Fgf2 expression in aging rats, directing tau protein phosphorylation through the PI3K/AKT/Gsk3b route, instigating cognitive aberrations.
Assuntos
Anestésicos Inalatórios , Disfunção Cognitiva , Éteres Metílicos , Idoso , Animais , Humanos , Lactente , Ratos , Anestésicos Inalatórios/efeitos adversos , Anestésicos Inalatórios/metabolismo , Cognição , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Éteres Metílicos/farmacologia , Éteres Metílicos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sevoflurano/metabolismo , Sevoflurano/farmacologia , Proteínas tau/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismoRESUMO
BACKGROUND: Sevoflurane (Sevo) preconditioning and postconditioning play a protective role against injury induced by hepatic ischemia/reperfusion (I/R). At the same time, the involvement of macrophage infiltration in this process and the precise mechanisms are unclear. Here, we designed this research to elucidate the protective effects of Sevo against hepatic I/R injury and the molecules involved. METHODS: The alleviating effect of Sevo on the liver injury was analyzed by liver function analysis, hematoxylin and eosin staining, Masson trichrome staining, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling, western blot analysis and an enzyme-linked immunosorbent assay. An in vitro cell model was developed using alpha mouse liver 12 (AML12) cells, and the cell model was treated with oxygen-glucose deprivation and reoxygenation and Sevo. Multiple bioinformatics databases were used to screen transcriptional regulators related to hepatic I/R injury and the targets of Krueppel-like factor 5 (KLF5). KLF5 expression was artificially upregulated alone or with integrin beta-2 (ITGB2) knockdown to substantiate their involvement in Sevo-mediated hepatoprotection. RESULTS: Sevo protected the liver against I/R injury by reducing cell apoptosis and inflammatory response. KLF5 was upregulated in liver tissues following I/R injury, whereas KLF5 overexpression aggravated macrophage infiltration and liver injury induced by I/R injury. KLF5 bound to the promoter of ITGB2 to enhance ITGB2 transcription. Knockdown of ITGB2 reversed the aggravation of injury caused by KLF5 overexpression in mice and AML12 cells. CONCLUSIONS: Sevo blocked KLF5-mediated transcriptional activation of ITGB2, thereby inhibiting macrophage infiltration in hepatic I/R injury.
Assuntos
Cadeias beta de Integrinas , Fatores de Transcrição Kruppel-Like , Fígado , Macrófagos , Traumatismo por Reperfusão , Sevoflurano , Animais , Camundongos , Apoptose , Antígenos CD18/metabolismo , Antígenos CD18/genética , Linhagem Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Fatores de Transcrição Kruppel-Like/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/genética , Sevoflurano/farmacologia , Ativação Transcricional , Cadeias beta de Integrinas/efeitos dos fármacos , Cadeias beta de Integrinas/genética , Cadeias beta de Integrinas/metabolismoRESUMO
Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy that, if not promptly treated, culminates in right heart failure. Therefore, pre-clinical studies are needed to support and optimize therapeutic approaches of PAH. Here, we explore a prospective function of sevoflurane in experimental PAH through regulating TRAF6. Monocrotaline (MCT)-induced PAH rats were subjected to sevoflurane inhalation and intratracheal instillation of lentivirus overexpressing TRAF6. Platelet-derived growth factor (PDGF)-treated pulmonary artery smooth muscle cells (PASMCs) were exposed to sevoflurane and genetically manipulated for TRAF6 overexpression. It was found that MCT and PDGF challenge upregulated the levels of TRAF6 in rat lung tissues and PASMCs, but sevoflurane treatment led to reduced TRAF6 expression. Sevoflurane inhalation in MCT-induced rats resulted in alleviative pulmonary vascular remodeling, mitigated right ventricular dysfunction and hypertrophy, improved mitochondrial function and dynamics, and inactivation of NF-κB pathway. In vitro studies confirmed that exposure to sevoflurane repressed PDGF-induced proliferation, migration, and phenotype switching of PASMCs, and suppressed mitochondrial dysfunction and NF-κB activation in PDGF-stimulated PASMCs. The beneficial impact of sevoflurane on pathological changes of lung and cell phenotype of PASMCs were reversed by overexpression of TRAF6. In summary, our study suggested the protective properties of sevoflurane in targeting PAH by downregulating TRAF6 expression, providing a novel avenue for the management of PAH.
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Postoperative cognitive decline (POCD) is a common and serious complication following anesthesia and surgery; however, the precise mechanisms of POCD remain unclear. Our previous research showed that sevoflurane impairs adult hippocampal neurogenesis (AHN) and thus cognitive function in the aged brain by affecting neurotrophin-3 (NT-3) expression; however, the signaling mechanism involved remains unexplored. In this study, we found a dramatic decrease in the proportion of differentiated neurons with increasing concentrations of sevoflurane, and the inhibition of neural stem cell differentiation was partially reversed after the administration of exogenous NT-3. Understanding the molecular underpinnings by which sevoflurane affects NT-3 is key to counteracting cognitive dysfunction. Here, we report that sevoflurane administration for 2 days resulted in upregulation of histone deacetylase 9 (HDAC9) expression, which led to transcriptional inactivation of cAMP-response element binding protein (CREB). Due to the colocalization of HDAC9 and CREB within cells, this may be related to the interaction between HDAC9 and CREB. Anyway, this ultimately led to reduced NT-3 expression and inhibition of neural stem cell differentiation. Furthermore, knockdown of HDAC9 rescued the transcriptional activation of CREB after sevoflurane exposure, while reversing the downregulation of NT-3 expression and inhibition of neural stem cell differentiation. In summary, this study identifies a unique mechanism by which sevoflurane can inhibit CREB transcription through HDAC9, and this process reduces NT-3 levels and ultimately inhibits neuronal differentiation. This finding may reveal a new strategy to prevent sevoflurane-induced neuronal dysfunction.
Assuntos
Fenômenos Fisiológicos do Sistema Nervoso , Neurônios , Adulto , Humanos , Idoso , Sevoflurano/farmacologia , Diferenciação Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Elementos de RespostaRESUMO
In this study, we aimed to validate the hypothesis that the interplay between sevoflurane, oxidative stress and ferroptosis is crucial for the pathogenesis of sevoflurane-induced cognitive impairment in aged individuals. The mice with sevoflurane-induced cognitive impairment were used to explore the effects of sevoflurane on oxidative stress, iron homeostasis, and cognitive function in aged mice. Iron content and oxidative stress markers were analyzed in hippocampal tissue homogenates using specific assays. Additionally, the levels of iron death-related markers (Fth1 and Gpx4) were assessed by real-time PCR and Western blotting. Morris Water Maze and novel object recognition (NOR) tests were conducted to evaluate cognitive function. Sevoflurane exposure in aged mice resulted in a significant increase in iron overloading in the hippocampus, followed by a subsequent stabilization. Oxidative stress levels were elevated in the hippocampal tissue of sevoflurane-exposed mice, and a significant correlation was observed between iron death and oxidative stress. Liproxstatin-1, a ferroptosis inhibitor, effectively ameliorated the decline in memory and learning abilities induced by sevoflurane anesthesia. Liproxstatin-1 treatment reduced iron overload and oxidative stress in the hippocampal tissue of aged mice. The expression of Fth1 and Gpx4, iron death-related markers, was downregulated following Liproxstatin-1 intervention. Our findings suggest that sevoflurane anesthesia disrupts iron homeostasis, leading to increased oxidative stress and cognitive impairment in aged mice. These results highlight the potential of targeting iron-mediated processes to mitigate sevoflurane-induced cognitive impairment in the aging population.
Assuntos
Anestesia , Disfunção Cognitiva , Ferroptose , Quinoxalinas , Compostos de Espiro , Animais , Camundongos , Sevoflurano/efeitos adversos , Sevoflurano/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Estresse Oxidativo , Anestesia/efeitos adversos , Cognição , Ferro/efeitos adversos , Ferro/metabolismo , Hipocampo/metabolismoRESUMO
Acute lung injury (ALI) frequently occurs after video-assisted thoracoscopic surgery (VATS). Ferroptosis is implicated in several lung diseases. Therefore, the disparate effects and underlying mechanisms of the two commonly used anesthetics (sevoflurane (Sev) and propofol) on VATS-induced ALI need to be clarified. In the present study, enrolled patients were randomly allocated to receive Sev (group S) or propofol anesthesia (group P). Intraoperative oxygenation, morphology of the lung tissue, expression of ZO-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), glutathione (GSH), Fe2+, glutathione peroxidase 4 (GPX4), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in the lung tissue as well as the expression of TNF-α and IL-6 in plasma were measured. Postoperative complications were recorded. Of the 85 initially screened patients scheduled for VATS, 62 were enrolled in either group S (n = 32) or P (n = 30). Compared with propofol, Sev substantially (1) improved intraoperative oxygenation; (2) relieved histopathological lung injury; (3) increased ZO-1 protein expression; (4) decreased the levels of TNF-α and IL-6 in both the lung tissue and plasma; (5) increased the contents of GSH and SOD but decreased Fe2+ concentration; (6) upregulated the protein expression of p-AKT, Nrf2, HO-1, and GPX4. No significant differences in the occurrence of postoperative outcomes were observed between both groups. In summary, Sev treatment, in comparison to propofol anesthesia, may suppress local lung and systemic inflammatory responses by activating the PI3K/Akt/Nrf2/HO-1 pathway and inhibiting ferroptosis. This cascade of effects contributes to the maintenance of pulmonary epithelial barrier permeability, alleviation of pulmonary injury, and enhancement of intraoperative oxygenation in patients undergoing VATS.
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Endothelial dysfunction often accompanies sepsis. Sevoflurane (Sev) is a widely used inhaled anesthetic that has a protective effect on sepsis-associated damage. We aimed to elucidate the role of Sev in endothelial dysfunction by using a model of LPS induced HUVECs. Sev increased the viability and decreased the apoptosis of HUVECs exposed to LPS. Inflammation and endothelial cell adhesion were improved after Sev addition. Besides, Sev alleviated LPS-induced endothelial cell permeability damage in HUVECs. RORα served as a potential protein that bound to Sev. Importantly, Sev upregulated RORα expression and inhibited endoplasmic reticulum (ER) stress in LPS-treated HUVECs. RORα silencing reversed the impacts of Sev on ER stress. Moreover, RORα deficiency or tunicamycin (ER stress inducer) treatment restored the effects of Sev on the viability, apoptosis, inflammation and endothelial permeability damage of HUVECs exposed to LPS. Taken together, Sev ameliorated LPS-induced endothelial cell damage by targeting RORα to inhibit ER stress.
Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Células Endoteliais da Veia Umbilical Humana , Inflamação , Lipopolissacarídeos , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares , Sevoflurano , Regulação para Cima , Humanos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Sevoflurano/farmacologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Inflamação/patologia , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Permeabilidade/efeitos dos fármacosRESUMO
It is well established that sevoflurane exposure leads to widespread neuronal cell death in the developing brain. Adenosine deaminase acting on RNA-1 (ADAR1) dependent adenosine-to-inosine (A-to-I) RNA editing is dynamically regulated throughout brain development. The current investigation is designed to interrogate the contributed role of ADAR1 in developmental sevoflurane neurotoxicity. Herein, we provide evidence to show that developmental sevoflurane priming triggers neuronal pyroptosis, apoptosis and necroptosis (PANoptosis), and elicits the release of inflammatory factors including IL-1ß, IL-18, TNF-α and IFN-γ. Additionally, ADAR1-P150, but not ADAR1-P110, depresses cellular PANoptosis and inflammatory response by competing with Z-DNA/RNA binding protein 1 (ZBP1) for binding to Z-RNA in the presence of sevoflurane. Further investigation demonstrates that ADAR1-dependent A-to-I RNA editing mitigates developmental sevoflurane-induced neuronal PANoptosis. To restore RNA editing, we utilize adeno-associated virus (AAV) to deliver engineered circular ADAR-recruiting guide RNAs (cadRNAs) into cells, which is capable of recruiting endogenous adenosine deaminases to promote cellular A-to-I RNA editing. As anticipated, AAV-cadRNAs diminishes sevoflurane-induced cellular Z-RNA production and PANoptosis, which could be abolished by ADAR1-P150 shRNA transfection. Moreover, AAV-cadRNAs delivery ameliorates developmental sevoflurane-induced spatial and emotional cognitive deficits without influence on locomotor activity. Taken together, these results illustrate that ADAR1-P150 exhibits a prominent role in preventing ZBP1-dependent PANoptosis through A-to-I RNA editing in developmental sevoflurane neurotoxicity. Application of engineered cadRNAs to rectify the compromised ADAR1-dependent A-to-I RNA editing provides an inspiring direction for possible clinical preventions and therapeutics.
Assuntos
Adenosina Desaminase , Adenosina , Edição de RNA , Proteínas de Ligação a RNA , Sevoflurano , Animais , Adenosina/metabolismo , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Apoptose/efeitos dos fármacos , Inosina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Piroptose/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
Long-term use of sevoflurane, an inhalation anesthetic, could negatively impact cognitive function. Current studies have suggested that cognitive impairment induced by sevoflurane may be associated with neuroinflammation. Sestrin2 (SESN2), which belongs to a family of stress-inducible genes, has been reported to exert neuroprotective effects against brain injury. However, its role and underlying mechanisms in sevoflurane-induced cognitive dysfunction in aged rats remain unknown. A sevoflurane-induced aging rat injury model with or without SESN2 overexpression was constructed. The learning and memory abilities of rats were evaluated by the MWM test. ELISA assay and qRT-PCR were conducted to analyze the level of pro-inflammatory factors in the hippocampus. Levels of oxidative stress markers were measured by DHE staining or kit methods. Neuronal apoptosis in the hippocampus was detected using TUNEL assay. Expression of proteins were analyzed by western blot. Sevoflurane exposure caused elevated protein level of SESN2 in hippocampus and cognitive impairment of aged rats. Importantly, overexpression of SESN2 alleviated sevoflurane-induced cognitive dysfunction and inhibited the production of pro-inflammatory factors, oxidative stress, and neuronal apoptosis in the hippocampus. Furthermore, SESN2 overexpression suppressed NLRP3 inflammasome activation induced by sevoflurane. These findings suggested that SESN2 could exert neuroprotective against sevoflurane-induced nerve injury of aged rats through anti-oxidant and anti-inflammatory effects.
Assuntos
Disfunção Cognitiva , Doenças Neuroinflamatórias , Ratos , Animais , Sevoflurano/farmacologia , Ratos Sprague-Dawley , Disfunção Cognitiva/etiologia , Cognição , HipocampoRESUMO
Sevoflurane is one of the most widely used inhaled anesthetics. MicroRNAs (miRNAs) have been demonstrated to affect sevoflurane anesthesia-induced neuron damage. The purpose of this study was to investigate the role and mechanism of miR-181a-5p in sevoflurane-induced hippocampal neuronal injury. Primary hippocampal neurons were identified using microscopy and immunofluorescence. The viability and apoptosis of sevoflurane anesthesia-induced neurons were detected by cell counting kit-8 (CCK-8) assay and terminal-deoxynucleoitidyl transferase-mediated nick end-labeling (TUNEL) staining assay, respectively. The levels of apoptosis- and oxidative stress-related proteins as well as the markers in the Wnt/ß-catenin signaling pathway were examined by immunoblotting. Enzyme-linked immuno-sorbent assays were performed to examine the levels of inflammatory cytokines. Luciferase reporter assay was conducted to validate the combination between miR-181a-5p and DEAD-box helicase 3, X-linked (DDX3X). Sevoflurane exposure led to significantly inhibited hippocampal neuron viability and elevated miR-181a-5p expression. Knockdown of miR-181a-5p alleviated sevoflurane-induced neuron injury by reducing cell apoptosis, inflammatory response, and oxidative stress. Additionally, DDX3X was targeted and negatively regulated by miR-181a-5p. Moreover, miR-181a-5p inhibitor activated the Wnt/ß-catenin pathway via DDX3X in sevoflurane-treated cells. Rescue experiments revealed that DDX3X knockdown or overexpression of Wnt antagonist Dickkopf-1 (DKK1) reversed the suppressive effects of miR-181a-5p inhibitor on cell apoptosis, inflammatory response, and oxidative stress in sevoflurane-treated neuronal cells. MiR-181a-5p ameliorated sevoflurane-triggered neuron injury by regulating the DDX3X/Wnt/ß-catenin axis, suggesting the potential of miR-181a-5p as a novel and promising therapeutic target for the treatment of sevoflurane-evoked neurotoxicity.
Assuntos
Anestesia , MicroRNAs , Humanos , Apoptose , beta Catenina/metabolismo , Proliferação de Células , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neurônios/metabolismo , Sevoflurano/farmacologia , Via de Sinalização WntRESUMO
BACKGROUND: Propofol and sevoflurane are two of the most commonly used anaesthetics for paediatric surgery. Data from some clinical trials suggest that postoperative pain incidence is lower when propofol is used for maintenance of anaesthesia compared with sevoflurane, although this is not clear. METHODS: This meta-analysis compared postoperative pain following maintenance of anaesthesia with propofol or sevoflurane in paediatric surgeries. PubMed Medline, Embase, Scopus, Web of Science and Cochrane Library were searched for randomised controlled trials (RCTs) that compared postoperative pain between sevoflurane and propofol anaesthesia in children. After quality assessment, a meta-analysis was carried out using bias-adjusted inverse heterogeneity methods, heterogeneity using I2 and publication bias using Doi plots. RESULTS: In total, 13 RCTs with 1174 children were included. The overall synthesis suggested nearly two-fold higher odds of overall postoperative pain in the sevoflurane group compared with the propofol group (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.12-3.15, I2=58.2%). Further, children in the sevoflurane group had higher odds of having higher pain scores (OR 3.18, 95% CI 1.83-5.53, I2=20.9%), and a 60% increase in the odds of requiring postoperative rescue analgesia compared with propofol (OR 1.60, 95% CI 0.89-2.88, I2=58.2%). CONCLUSIONS: Children maintained on inhalational sevoflurane had higher odds of postoperative pain compared with those maintained on propofol. The results also suggest that sevoflurane is associated with higher odds of needing postoperative rescue analgesia compared with propofol. REGISTRATION: The protocol for this systematic review and meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO) with registration ID CRD42023445913.
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Anestésicos Inalatórios , Anestésicos Intravenosos , Dor Pós-Operatória , Propofol , Sevoflurano , Humanos , Sevoflurano/efeitos adversos , Propofol/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Criança , Anestésicos Inalatórios/efeitos adversos , Anestésicos Intravenosos/efeitos adversos , Pré-Escolar , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Repeated exposure to sevoflurane during early developmental stages is a risk factor for social behavioural disorders, but the underlying neuropathological mechanisms remain unclear. As the hippocampal cornu ammonis area 2 subregion (CA2) is a critical centre for social cognitive functions, we hypothesised that sevoflurane exposure can lead to social behavioural disorders by disrupting neuronal activity in the CA2. METHODS: Neonatal mice were anaesthetised with sevoflurane 3 vol% for 2 h on postnatal day (PND) 6, 8, and 10. Bulk RNA sequencing of CA2 tissue was conducted on PND 12. Social cognitive function was assessed by behavioural experiments, and in vivo CA2 neuronal activity was recorded by multi-channel electrodes on PND 60-65. RESULTS: Repeated postnatal exposure to sevoflurane impaired social novelty recognition in adulthood. It also caused a decrease in the synchronisation of neuronal spiking, gamma oscillation power, and spike phase-locking between GABAergic spiking and gamma oscillations in the CA2 during social interaction. After sevoflurane exposure, we observed a reduction in the density and dendritic complexity of CA2 GABAergic neurones, and decreased expression of transcription factors critical for GABAergic neuronal development after. CONCLUSIONS: Repeated postnatal exposure to sevoflurane disturbed the development of CA2 GABAergic neurones through downregulation of essential transcription factors. This resulted in impaired electrophysiological function in adult GABAergic neurones, leading to social recognition deficits. These findings reveal a potential electrophysiological mechanism underlying the long-term social recognition deficits induced by sevoflurane and highlight the crucial role of CA2 GABAergic neurones in social interactions.
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BACKGROUND: The neural mechanisms underlying sevoflurane-induced loss of consciousness and recovery of consciousness after anaesthesia remain unknown. We investigated whether glutamatergic pedunculopontine tegmental nucleus (PPT) neurones are involved in the regulation of states of consciousness under sevoflurane anaesthesia. METHODS: In vivo fibre photometry combined with electroencephalography (EEG)/electromyography recording was used to record changes in the activity of glutamatergic PPT neurones under sevoflurane anaesthesia. Chemogenetic and cortical EEG recordings were used to explore their roles in the induction of and emergence from sevoflurane anaesthesia. Optogenetic methods combined with EEG recordings were used to explore the roles of glutamatergic PPT neurones and of the PPT-ventral tegmental area pathway in maintenance of anaesthesia. RESULTS: The population activity of glutamatergic PPT neurones was reduced before sevoflurane-induced loss of righting reflex and gradually recovered after return of righting reflex. Chemogenetic inhibition of glutamatergic PPT neurones accelerated induction of anaesthesia (hM4Di-CNO vs mCherry-CNO, 76 [17] vs 121 [27] s, P<0.0001) and delayed emergence from sevoflurane anaesthesia (278 [98] vs 145 [53] s, P<0.0001) but increased sevoflurane sensitivity. Optogenetic stimulation of glutamatergic PPT neurons or of the PPT-ventral tegmental area pathway promoted cortical activation and behavioural emergence during steady-state sevoflurane anaesthesia, reduced the depth of anaesthesia, and caused cortical arousal during sevoflurane-induced EEG burst suppression. CONCLUSIONS: Glutamatergic PPT neurones regulate induction and emergence of sevoflurane anaesthesia.
Assuntos
Núcleo Tegmental Pedunculopontino , Sevoflurano , Inconsciência , Animais , Camundongos , Eletroencefalografia , Neurônios , Sevoflurano/farmacologia , Inconsciência/induzido quimicamenteRESUMO
BACKGROUND: Anaesthesia contributes substantially to the environmental impact of healthcare. To reduce the ecological footprint of anaesthesia, a set of sustainability interventions was implemented in the University Hospital Zurich, Switzerland. This study evaluates the environmental and economic implications of these interventions. METHODS: This was a single-centre retrospective observational study. We analysed the environmental impact and financial implications of changes in sevoflurane, desflurane, propofol, and plastic consumption over 2 yr (April 2021 to March 2023). The study included pre-implementation, implementation, and post-implementation phases. RESULTS: After implementation of sustainability measures, desflurane use was eliminated, there was a decrease in the consumption of sevoflurane from a median (inter-quartile range) of 25 (14-39) ml per case to 11 (6-22) ml per case (P<0.0001). Propofol consumption increased from 250 (150-721) mg per case to 743 (370-1284) mg per case (P<0.0001). Use of plastics changed: in the first quarter analysed, two or more infusion syringes were used in 62% of cases, compared with 74% of cases in the last quarter (P<0.0001). Two or more infusion lines were used in 58% of cases in the first quarter analysed, compared with 68% of cases in the last quarter (P<0.0001). This resulted in an 81% reduction in overall environmental impact from 3 (0-7) to 1 (0-3) CO2 equivalents in kg per case (P<0.0001). The costs during the final study phase were 11% lower compared with those in the initial phase: from 25 (13-41) to 21 (14-31) CHF (Swiss francs) per case (P<0.0001). CONCLUSIONS: Implementing sustainable anaesthesia interventions can significantly reduce the environmental impact and cost of anaesthesia.
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BACKGROUND: Interest in passive flow filter systems to remove sevoflurane from anaesthetic machine exhaust have increased recently to mitigate the environmental impact of volatile anaesthetics. These filter systems consist of chemically activated carbon, with limited evidence on their performance characteristics. We hypothesised that their efficiency depends on filter material. METHODS: Binding capacity was tested for three carbon filter materials (CONTRAfluran®, FlurAbsorb®, and Anaesthetic Agent Filter AAF633). Adsorption efficiency and resistive pressure were determined during simulated ventilation at different stages of filter saturation and fresh gas flow. In addition, sevoflurane concentration in filtered gas was measured at randomly selected anaesthesia workstations. RESULTS: Sevoflurane concentration in filtered gas exceeded 10 ppm when saturated with 184 ml sevoflurane each for CONTRAfluran and FlurAbsorb and 276 ml for AAF633. During simulated ventilation, sevoflurane concentration >10 ppm passed through CONTRAfluran and AAF633 at fresh gas flow 10 L min-1 only at maximum saturation, but through FlurAbsorb at all stages of saturation. The resistance pressure of all filters was negligible during simulated ventilation, but increased up to 5.2 (0.2) cm H2O during simulated coughing. At two of seven anaesthesia workstations, sevoflurane concentration in filtered exhaust gas was >10 ppm. CONCLUSIONS: Depending on the filter material and saturation, the likelihood of sevoflurane passing through passive flow carbon filters depends on the filter material and fresh gas flow. Combining the filter systems with anaesthetic gas scavenging systems could protect from pollution of ambient air with sevoflurane.