The effect of sevoflurane exposure on cell-type-specific changes in the prefrontal cortex in young mice.

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.

Single-nucleus Atlas of Sevoflurane-induced Hippocampal Cell Type- and Sex-specific Effects during Development in Mice.

BACKGROUND: Multiple neonatal exposures to sevoflurane induce neurocognitive dysfunctions in rodents. The lack of cell type-specific information after sevoflurane exposure limits the mechanistic understanding of these effects. In this study, the authors tested the hypothesis that sevoflurane exposures alter the atlas of hippocampal cell clusters and have neuronal and nonneuronal cell type-specific effects in mice of both sexes. METHODS: Neonatal mice were exposed to 3% sevoflurane for 2 h at postnatal days 6, 8, and 10 and analyzed for the exposure effects at postnatal day 37. Single-nucleus RNA sequencing was performed in the hippocampus followed by in situ hybridization to validate the results of RNA sequencing. The Morris Water Maze test was performed to test neurocognitive function. RESULTS: The authors found sex-specific distribution of hippocampal cell types in control mice alongside cell type- and sex-specific effects of sevoflurane exposure on distinct hippocampal cell populations. There were important changes in male but not in female mice after sevoflurane exposure regarding the proportions of cornu ammonis 1 neurons (control vs. sevoflurane, males: 79.9% vs. 32.3%; females: 27.3% vs. 24.3%), dentate gyrus (males: 4.2% vs. 23.4%; females: 36.2% vs. 35.8%), and oligodendrocytes (males: 0.6% vs. 6.9%; females: 5.9% vs. 7.8%). In male but not in female mice, sevoflurane altered the number of significantly enriched ligand-receptor pairs in the cornu ammonis 1, cornu ammonis 3, and dente gyrus trisynaptic circuit (control vs. sevoflurane, cornu ammonis 1-cornu ammonis 3: 18 vs. 42 in males and 15 vs. 21 in females; cornu ammonis 1-dentate gyrus: 21 vs. 35 in males and 12 vs. 20 in females; cornu ammonis 3-dentate gyrus: 25 vs. 45 in males and 17 vs. 20 in females), interfered with dentate gyrus granule cell neurogenesis, hampered microglia differentiation, and decreased cornu ammonis 1 pyramidal cell diversity. Oligodendrocyte differentiation was specifically altered in females with increased expressions of Mbp and Mag. In situ hybridization validated the increased expression of common differentially expressed genes. CONCLUSIONS: This single-nucleus RNA sequencing study reveals the hippocampal atlas of mice, providing a comprehensive resource for the neuronal and nonneuronal cell type- and sex-specific effects of sevoflurane during development.

Remote Ischemic Preconditioning Reduces Acute Kidney Injury After Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Results from previous studies evaluating the effects of remote ischemic preconditioning (RIPC) on morbidity and mortality after cardiac surgery are inconsistent. This meta-analysis of randomized controlled trials (RCTs) aims to determine whether RIPC improves cardiac and renal outcomes in adults undergoing cardiac surgery. METHODS: PubMed, EMBASE, and Cochrane Library were comprehensively searched to identify RCTs comparing RIPC with control in cardiac surgery. The coprimary outcomes were the incidence of postoperative myocardial infarction (MI) and the incidence of postoperative acute kidney injury (AKI). Meta-analyses were performed using a random-effect model. Subgroup analyses were conducted according to volatile only anesthesia versus propofol anesthesia with or without volatiles, high-risk patients versus non-high-risk patients, and Acute Kidney Injury Network (AKIN) or Kidney Disease Improving Global Outcomes (KDIGO) criteria versus other criteria for AKI diagnosis. RESULTS: A total of 79 RCTs with 10,814 patients were included. While the incidence of postoperative MI did not differ between the RIPC and control groups (8.2% vs 9.7%; risk ratio [RR] = 0.87, 95% confidence interval [CI], 0.76-1.01, P = .07, I2 = 0%), RIPC significantly reduced the incidence of postoperative AKI (22% vs 24.4%; RR = 0.86, 95% CI, 0.77-0.97, P = .01, I2 = 34%). The subgroup analyses showed that RIPC was associated with a reduced incidence of MI in non-high-risk patients, and that RIPC was associated with a reduced incidence of AKI in volatile only anesthesia, in non-high-risk patients, and in the studies using AKIN or KDIGO criteria for AKI diagnosis. CONCLUSIONS: This meta-analysis demonstrates that RIPC reduces the incidence of AKI after cardiac surgery. This renoprotective effect of RIPC is mainly evident during volatile only anesthesia, in non-high-risk patients, and when AKIN or KDIGO criteria used for AKI diagnosis.

[Characteristics of Organic Matter Composition and Oxidation Potential in Road Dust in Winter in Xi'an].

Roads are the main places where urban people are exposed to atmospheric particulate matter from outdoor activities, and certain oxidatively active substances contained in road particulate matter are important components that induce the generation of reactive oxygen species (ROS), which in turn endanger human health. Here, we explored the characteristics of organic matter composition in water-soluble (WSM) and methanol-soluble fractions (MSM) of road dust in Xi'an and its oxidation potential (OP). Additionally, we investigated the organic fractions and their distribution based on parallel factor analysis (PARAFAC) and analyzed the correlation between organic matter types and OP. The results showed that the water-insoluble fraction of road dust in Xi'an contained more chromophoric organic matter with an average total concentration of (4.71±1.27)×104 R.U., which was 12 times higher than that of WSM[(3.96±1.10)×103 R.U.], of which low-oxidizing humic-like substances (HULIS) were the main organic matter (34.8%-43.7% of the total organic matter). The results of cluster analysis showed that the important sources of organic matter in road dust in Xi'an were fuel combustion and industrial production. The mean value of dust oxidative toxicity was (0.34±0.08) pmol·(min·µg)-1, with the water-insoluble fraction providing 70% of the total oxidative toxicity of dust particles, which was 2.4 times higher than the water-soluble fraction. The main precursors of oxidative toxicity of dust particles were metal elements, and special types of organic substances were also one of the important oxidative toxicity precursors, among which chromophore organic matter was the main cause of OP production in the WSM fraction (r=0.35, P<0.01), and protein-like organic matter and highly oxidized HULIS in WSM may have been the main two types of organic substances for OP production. However, there was no significant correlation between organic matter concentration in MSM and water-insoluble OP (OPTotal-OPWSM) (r=-0.04, P>0.1), so the oxidative toxicity of the water-insoluble particulate matter fraction was mainly generated from non-organic matter.

[Pollution Characteristics and Chromophore Types of Brown Carbon in Xi'an].

To explore the optical characteristics and chemical composition of atmospheric brown carbon (BrC) in Xi'an, particulate phase and gas phase atmospheric samples were collected using an atmospheric particulate sampler and adsorbent, and the samples were analyzed using an ultraviolet-visible spectrophotometer and a three-dimensional (3D) fluorescence photometer. The absorption and fluorescence properties of BrC were analyzed using the parallel factor analysis (PARAFAC) method to obtain type and compositional information. The results show that at a wavelength of 365 nm, the absorbances of the BrC particulate and the gas phases were (13.8±7.9) Mm-1 and (8.0±3.1) Mm-1, with proportions of 63% and 37%, respectively. No significant correlation was found between the absorbance of the gas and particulate phases. PARAFAC results show that in winter, atmospheric BrC in Xi'an is composed of humic-like and protein-like chromophores, with different proportions in the gas and particulate phases. Humic-like and protein-like chromophores are dominant in the particulate phase (41% and 36%, respectively), while the gas phase mainly contains phenolic chromophores (accounting for 78%). These results reveal that gas phase BrC may be an important factor contributing to positive radiative forcing in the atmosphere as well as an important atmospheric component that participates in atmospheric photochemical reactions.

[Seasonal Variation of Water-soluble Ions in PM2.5 in Xi'an].

To explore the seasonal variations and sources of water-soluble ions, PM2.5 samples were collected from 2017 to 2018. Water-soluble ions including SO42-, NO3-, Cl-, F-, Na+, Mg2+, NH4+, K+, and Ca2+ were determined via ion chromatography. Furthermore, the existing form of NH4+, nitrogen oxidation rate (NOR), sulfur oxidation rate (SOR), and [NO3-]/[SO42-] ratio were explored. The results showed that dust, coal combustion, biomass burning, and secondary aerosols were the dominant contributors to water-soluble ions. Ca2+, SO42-, NH4+, and NO3- were the main water-soluble ions in PM2.5 in Xi'an. Correlation analysis results showed that NH4+ could not completely neutralize SO42- in spring; unneutralized SO42- could be mainly combined with K+ and Ca2+. NH4+ mainly existed in the form of ① NH4HSO4 and (NH4)2SO4 in summer; ② NH4HSO4 and NH4NO3 in autumn; and ③ (NH4)2SO4 and NH4NO3 in winter. The yearly mean values of SOR and NOR were 0.35 and 0.16, respectively, indicating a high secondary aerosol transformation rate during the study period. The [NO3-]/[SO42-] ratio showed Xi'an was mainly affected by stationary sources in spring and summer, while the contribution of mobile sources in autumn and winter was greater than stationary sources.

Heat Shock Protein 70 Protects the Heart from Ischemia/Reperfusion Injury through Inhibition of p38 MAPK Signaling.

BACKGROUND: Heat shock protein 70 (Hsp70) has been shown to exert cardioprotection. Intracellular calcium ([Ca2+]i) overload induced by p38 mitogen-activated protein kinase (p38 MAPK) activation contributes to cardiac ischemia/reperfusion (I/R) injury. However, whether Hsp70 interacts with p38 MAPK signaling is unclear. Therefore, this study investigated the regulation of p38 MAPK by Hsp70 in I/R-induced cardiac injury. METHODS: Neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation for 6 h followed by 2 h reoxygenation (OGD/R), and rats underwent left anterior artery ligation for 30 min followed by 30 min of reperfusion. The p38 MAPK inhibitor (SB203580), Hsp70 inhibitor (Quercetin), and Hsp70 short hairpin RNA (shRNA) were used prior to OGD/R or I/R. Cell viability, lactate dehydrogenase (LDH) release, serum cardiac troponin I (cTnI), [Ca2+]i levels, cell apoptosis, myocardial infarct size, mRNA level of IL-1ß and IL-6, and protein expression of Hsp70, phosphorylated p38 MAPK (p-p38 MAPK), sarcoplasmic/endoplasmic reticulum Ca2+-ATPase2 (SERCA2), phosphorylated signal transducer and activator of transcription3 (p-STAT3), and cleaved caspase3 were assessed. RESULTS: Pretreatment with a p38 MAPK inhibitor, SB203580, significantly attenuated OGD/R-induced cell injury or I/R-induced myocardial injury, as evidenced by improved cell viability and lower LDH release, resulted in lower serum cTnI and myocardial infarct size, alleviation of [Ca2+]i overload and cell apoptosis, inhibition of IL-1ß and IL-6, and modulation of protein expressions of p-p38 MAPK, SERCA2, p-STAT3, and cleaved-caspase3. Knockdown of Hsp70 by shRNA exacerbated OGD/R-induced cell injury, which was effectively abolished by SB203580. Moreover, inhibition of Hsp70 by quercetin enhanced I/R-induced myocardial injury, while SB203580 pretreatment reversed the harmful effects caused by quercetin. CONCLUSIONS: Inhibition of Hsp70 aggravates [Ca2+]i overload, inflammation, and apoptosis through regulating p38 MAPK signaling during cardiac I/R injury, which may help provide novel insight into cardioprotective strategies.

Effects of Perioperative Dexmedetomidine on Postoperative Mortality and Morbidity: A Systematic Review and Meta-analysis.

PURPOSE: Major postoperative complications translate into increased health care resource utilization, prolonged hospital stays, and increased mortality. We aimed to assess the effects of perioperative dexmedetomidine use on postoperative mortality and the prevalence of major complications after cardiac and noncardiac surgery. METHODS: We searched the PubMed, EMBASE, and Cochrane databases to analyze all published evidence from randomized controlled trials (RCTs) and cohort studies comparing perioperative dexmedetomidine use versus no dexmedetomidine use in adult patients undergoing cardiac and noncardiac surgery. The primary outcome was postoperative mortality. Secondary outcomes were the durations of mechanical ventilation, intensive care unit (ICU) stay, and hospital stay, and the prevalence of major complications. FINDINGS: Twenty-three studies in cardiac surgery (n = 7635) and 8 studies in noncardiac surgery (n = 1805) were included. In cardiac surgery, dexmedetomidine use reduced postoperative 30-day mortality (risk ratio [RR], 0.35 [95% CI, 0.24 to 0.51]); durations of mechanical ventilation (mean difference [MD], -1.56 h [-2.52 to -0.60]), ICU stay (MD, -0.22 day [-0.35 to -0.08]), and hospital stay (MD, -0.65 day [-1.12 to -0.18]); and the prevalences of delirium (RR, 0.50 [0.36 to 0.69]), atrial fibrillation (RR, 0.74 [0.57 to 0.97]), and cardiac arrest (RR, 0.34 [0.13 to 0.87]). In noncardiac surgery, dexmedetomidine use was associated with decreases in the durations of mechanical ventilation and hospital stay, with a trend toward a lower prevalence of delirium (RR, 0.57 [0.32 to 1.01]). The prevalence of bradycardia was increased in dexmedetomidine-treated patients undergoing cardiac surgery (RR, 1.70 [1.19 to 2.44]) and noncardiac surgery (RR, 1.64 [1.05 to 2.58]). IMPLICATIONS: Dexmedetomidine use may help to reduce postoperative 30-day mortality, durations of mechanical ventilation, ICU stay, and hospital stay, and the prevalences of delirium, atrial fibrillation, and cardiac arrest in patients who undergo cardiac surgery. The majority of the benefits of dexmedetomidine were not significant in patients undergoing noncardiac surgery. An increased risk for bradycardia should be taken into consideration when prescribing dexmedetomidine. International Prospective Register of Systematic Reviews identifier: CRD42017070791.

[Characteristics of Carbonaceous Aerosol Pollution in PM2.5 in Xi'an].

Mass concentration, seasonal variation and sources of organic carbon (OC), element carbon (EC), methanol-soluble organic carbon (MSOC), and seven carbon components (OC1-4, EC1-3) were detected by thermal-optical analysis of 353 PM2.5 samples in Xi'an in 2017. The results show that the average mass concentrations of OC, EC, and MSOC were (17.56±11.83), (4.08±2.95) and (11.10±6.77) µg·m-3, respectively. The seasonal trend of the OC concentration follows the order winter > spring > summer > autumn. The seasonal trend in EC concentration follows the order winter > spring≈autumn > summer. The average MSOC/OC value is 0.64±0.20. The highest value is observed in winter and the lowest in summer. The correlation between OC and EC is good in spring (r2=0.76), but the correlation is poor in winter (r2=0.43). These results indicate that the source of the carbon aerosols was different. The content of secondary organic aerosols was estimated by the EC tracing method. The average mass concentration of SOC accounted for 51.9%, 38.4%, 37.3% and 44.0% of OC in spring, summer, autumn, and winter, respectively. The main sources of carbonaceous aerosols were analyzed by principal component analysis. The results show that carbonaceous aerosols originate mainly from coal and vehicle emissions in Xi'an.

Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling.

PURPOSE: Intracellular calcium ([Ca2+]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca2+ signaling. METHODS: H9c2 cardiomyocytes were subjected to OGD for 12 h, followed by 3 h of reoxygenation. DEX was administered 1 h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca2+]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed. RESULTS: Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca2+]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX. CONCLUSION: This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca2+]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.

Cognitive impairment and transcriptomic profile in hippocampus of young mice after multiple neonatal exposures to sevoflurane.

Children with repeated inhalational anesthesia may develop cognitive disorders. This study aimed to investigate the transcriptome-wide response of hippocampus in young mice that had been exposed to multiple sevoflurane in the neonatal period. Mice received 3% sevoflurane for 2 h on postnatal day (PND) 6, 8, and 10, followed by arterial blood gas test on PND 10, behavioral experiments on PND 31-36, and RNA sequencing (RNA-seq) of hippocampus on PND 37. Functional annotation and protein-protein interaction analyses of differentially expressed genes (DEGs) and quantitative reverse transcription polymerase chain reaction (qPCR) were performed. Neonatal sevoflurane exposures induced cognitive and social behavior disorders in young mice. RNA-seq identified a total of 314 DEGs. Several enriched biological processes (ion channels, brain development, learning, and memory) and signaling pathways (oxytocin signaling pathway and glutamatergic, cholinergic, and GABAergic synapses) were highlighted. As hub-proteins, Pten was involved in nervous system development, synapse assembly, learning, memory, and behaviors, Nos3 and Pik3cd in oxytocin signaling pathway, and Cdk16 in exocytosis and phosphorylation. Some top DEGs were validated by qPCR. This study revealed a transcriptome-wide profile in mice hippocampus after multiple neonatal exposures to sevoflurane, promoting better understanding of underlying mechanisms and investigation of preventive strategies.

[Analysis of estrogens, nonylphenol, 4-tert-octylphenol and bisphenol A in the sediments].

Estrogens and alkylphenols have received much attention because of its endocrine disrupting effects to aquatic ecosystem in recent years. The fate of these compounds in sediments which is a repository of many organic pollutants has an important significance on the study of behaviors of target compounds in the environment. It is difficult to separate trace estrogens from sediments with complex matrices. Alkali extraction, liquid-liquid extraction and LC-MS/MS were used to analyze estrogens, nonylphenol, 4-tert-octylphenol and bisphenol A in sediments based on their physicochemical properties. The results showed that recoveries of the seven target compounds were 61.3%-93.7%. The established pretreatment method can effectively remove pollutants that cannot dissolve in alkali solution or that cannot dissolve in both acid and alkali solution. It can widely be used to analyze sediments and soil samples because of its low cost and simple operation but with high recoveries and low detection limit.