Protective role of TRPV2 in synaptic plasticity through the ERK1/2-CREB-BDNF pathway in chronic unpredictable mild stress rats.

PURPOSE: Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms. METHODS: In vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins. RESULTS: Decreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2. CONCLUSION: These findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.

Silencing EIF3A ameliorates pulmonary arterial hypertension through HDAC1 and PTEN/PI3K/AKT pathway in vitro and in vivo.

Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation, and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro. EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo. In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.

Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder.

Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unknown. TWIK-related K+ channel 1 (TREK-1) has been demonstrated to regulate the action of antidepressants. Nevertheless, its mechanisms and effects on A1-like astrocyte stimulation in MDD are not clear. Therefore, we conducted in vivo and in vitro experiments using TREK-1 specific inhibitor spadin. In vivo, rats were subjected to a 6-week chronic unpredictable mild stress (CUMS) followed by spadin treatment. Behavioral tests were employed to surveil depressive-like behaviors. Hippocampal proteomic analysis was carried out with the purpose of identifying differentially expressed proteins after CUMS and spadin treatments. In vitro, astrocyte-conditioned medium and spadin were used to treat rat astrocyte cell line. The activated microglia, inflammatory factors, A1 astrocyte markers, and activated nuclear factor kappa B (NF-κB) pathway were later analyzed using immunofluorescence, western blot, and RT-qPCR. Our findings indicated that blockage of TREK-1 reduced CUMS-induced depressive-like behavior in rats, inhibited the microglial stimulation, reduced inflammatory factor levels, and suppressed the activation of A1-like reactive astrocytes in the hippocampus. We also verified that the suppression of A1-like astrocytes by spadin necessitated the NF-κB pathway. According to the findings, blocking TREK-1 inhibited the activation of A1-like reactive astrocytes via the NF-κB signaling pathway in MDD. Our study preliminarily identifies a novel antidepressant mechanism of TREK-1 action and provides a therapeutic path for MDD.

Baclofen attenuates cognitive deficits in post-cardiac arrest brain injury.

Between 30% and 50% of survivors of cardiac arrest (CA) suffer from cognitive deficits. However, no effective medical intervention is available to alleviate cognitive deficits. Baclofen is known to protect damaged neurons, but researchers have still not clearly whether baclofen alleviates CA-induced cognitive deficits. The present study aimed to investigate whether baclofen protects against post-CA cognitive deficits and to reveal the protective mechanism of baclofen. Rats underwent 10 min of asphyxia to establish CA models. Intriguingly, our results indicated that baclofen improved spatial memory 72 h after CA. Baclofen increased plasticity-related protein (PSD95, and GAP43) expression in the brain after CA. Baclofen reduced microglial number and the release of inflammatory factors (IL-1ß and IL-18). Furthermore, baclofen significantly reduced the expression of pyroptosis-related molecules after CA. Notably, activation of NLRP3 abolished the anti-pyroptosis effect of baclofen and reduced the expression of synaptic plasticity-related proteins after CA. Taken together, this study first shows that baclofen attenuates cognitive deficits induced by brain injury after CA. The mechanism is at least partially attributed to baclofen regulating pyroptosis by inhibition of NLRP3 activation.

Bicuspidization reconstruction for regurgitant quadricuspid pulmonary valve concomitant pulmonary artery aneurysm graft replacement.

Large pulmonary artery aneurysm with severe pulmonary valve regurgitation due to the quadricuspid pulmonary valve (Type F) was found in a 54-year-old woman with fatigue and dyspnea on exertion, and in New York Heart Association (NYHA) functional class III. The annulus plication and bicuspidization technique were successfully used for the pulmonary valvular reconstruction. Then, the main pulmonary artery was replaced with Dacron graft and the left pulmonary arterioplasty was performed. Postoperative echocardiography confirmed a satisfactory motion of the reconstructed pulmonary valve with trivial regurgitation and no stenosis.

Age progression from vicenarians (20-29 year) to nonagenarians (90-99 year) among a population pharmacokinetic/pharmacodynamic (PopPk-PD) covariate analysis of propofol-bispectral index (BIS) electroencephalography.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) modeling has made an enormous contribution to intravenous anesthesia. Because of their altered physiological, pharmacological and pathological aspects, titrating general anesthesia in the elderly is a challenging task. METHODS: Eighty patients were consecutively enrolled divided by decades from vicenarians (20-29 year) to nonagenarians (90-99 year) into eight groups. Using target controlled infusion (TCI) and electroencephalographic (EEG)-derived bispectral index (BIS) we set propofol plasma concentration (Cp) to gradually reach 3.5 µg mL-1 over 3.5-min. In each patient, we constructed a PK/PD model and conducted a population PK/PD (PopPK-PD) covariate analysis. RESULTS: Age was significant covariate for baseline BIS effect (E0), inhibitory propofol concentration at 50% BIS decline (IC50) and maximum BIS decline (Emax). First-order rate constant Ke0 of 0.47 min-1 in vicenarians (20-29 year) gradually increased with age-progression to 1.85 min-1 in nonagenarians (90-99 year). Simulation modelling showed that clinically recommended Cp of 3.5 µg mL-1 for 20-29 year BIS 50 should be reduced to 3.0 for 30-49 year, 2.5 for 50-69 year and 2.0 for 80-89 year. CONCLUSION: We quantified and graded EEG-BIS age-progression among different age groups divided by decades. We demonstrated deeper BIS values with decades' age progression. Our data has important implications for propofol dosing. The practical information for physicians in their daily clinical practice is using propofol Cp of 3.5 µg mL-1 might not yield BIS value of 50 in elderly patients. Our simulations showed that the recommended regimen of Cp 3.5 µg mL-1 for 20-29 year should be gradually decreased to 2.0 µg mL-1 for 80-89 year. CLINICAL TRIAL REGISTRY NUMBERS: European Community Clinical Trials Database EudraCT (http://eudract.emea.eu) initial trial registration number: 2011-002847-81, and subsequently registered at www.clinicaltrials.gov; trial registration number: NCT02585284. Xijing Hospital of Fourth Military Medical University ethics committee approval number 20110707-4.

Dexmedetomidine modulates neuroinflammation and improves outcome via alpha2-adrenergic receptor signaling after rat spinal cord injury.

BACKGROUND: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury. METHODS: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model. RESULTS: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1ß, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist. CONCLUSIONS: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling.

TnI and IL-18 levels are associated with prognosis of sepsis.

AIM: To evaluate the diagnostic value of interleukin-18 (IL-18) and troponin (TnI) in sepsis. METHODS: This retrospective analysis included 117 patients with sepsis (patient group) and 92 subjects who attended regular physical examinations (control group). We compared IL-18 and TnI expressions before treatment (T1) and on day 5 (T2), day 10 (T3) and day 15 (T4) of treatment. Acute Physiology and Chronic Health Evaluation II (APACHE II) guidelines were used to analyse the correlation between IL-18, TnI and APACHE II scores. RESULTS: At T1, T2, T3 and T4, the IL-18 and TnI levels were all higher in the patient group than in the control group (p<0.001). In the patient group, peak IL-18 and TnI levels were noted at T1, followed by T2, T3 and T4 (p<0.001). The linear correlation analysis revealed positive correlations between IL-18 and TnI levels and APACHE II score (r =0.759, 0.866, p <0.001). The 3-year survival rates of subjects with high IL-18 or TnI expression levels were all lower than of those with low expression levels (p=0.047, 0.048). In patients with sepsis, the expression of TnI and IL-18 is high and is positively correlated with APACHE II scores. CONCLUSIONS: Monitoring TnI and IL-18 levels can effectively evaluate the severity and recovery of patients with sepsis.

MicroRNA-15a inhibits the growth and invasiveness of malignant melanoma and directly targets on CDCA4 gene.

MicroRNAs can affect behaviors of tumor cells by modulating the expression of the target genes that involve tumor growth, invasiveness, and death. The goal of this research is to examine the effects of miR-15a on the proliferation and invasiveness of malignant melanoma cells in vitro, as well as the therapeutic effect of miR-15a in a mouse melanoma model. miR-15a displayed inhibitory effects on proliferation and invasiveness of several malignant melanoma cell lines. miR-15a also caused cell cycle arrest at G1/G0 phase. miRNA 15a downregulated the expressions of CDCA4 and AKT-3 in melanoma cell lines. In vivo, experiment showed that miRNA 15a significantly retarded the growth of melanoma tumors in the mouse model. The luciferase reporter assay demonstrated that miR15a can suppress gene expression through the binding site in the 3 'UTR of CACD4, which is a bona fide target of miRNA 15a. In conclusion, miRNA 15a suppressed the growth and invasiveness of melanoma cells, suggesting that miRNA 15a may represent a viable microRNA-based therapy against melanoma.

Activation of neurotensin receptor 1 facilitates neuronal excitability and spatial learning and memory in the entorhinal cortex: beneficial actions in an Alzheimer's disease model.

Neurotensin (NT) is a tridecapeptide distributed in the CNS, including the entorhinal cortex (EC), a structure that is crucial for learning and memory and undergoes the earliest pathological alterations in Alzheimer's disease (AD). Whereas NT has been implicated in modulating cognition, the cellular and molecular mechanisms by which NT modifies cognitive processes and the potential therapeutic roles of NT in AD have not been determined. Here we examined the effects of NT on neuronal excitability and spatial learning in the EC, which expresses high density of NT receptors. Brief application of NT induced persistent increases in action potential firing frequency, which could last for at least 1 h. NT-induced facilitation of neuronal excitability was mediated by downregulation of TREK-2 K(+) channels and required the functions of NTS1, phospholipase C, and protein kinase C. Microinjection of NT or NTS1 agonist, PD149163, into the EC increased spatial learning as assessed by the Barnes Maze Test. Activation of NTS1 receptors also induced persistent increases in action potential firing frequency and significantly improved the memory status in APP/PS1 mice, an animal model of AD. Our study identifies a cellular substrate underlying learning and memory and suggests that NTS1 agonists may exert beneficial actions in an animal model of AD.

Bombesin facilitates GABAergic transmission and depresses epileptiform activity in the entorhinal cortex.

Bombesin and the bombesin-like peptides including neuromedin B (NMB) and gastrin-releasing peptide (GRP) are important neuromodulators in the brain. We studied their effects on GABAergic transmission and epileptiform activity in the entorhinal cortex (EC). Bath application of bombesin concentration-dependently increased both the frequency and amplitude of sIPSCs recorded from the principal neurons in the EC. Application of NMB and GRP exerted the same effects as bombesin. Bombesin had no effects on mIPSCs recorded in the presence of TTX but slightly depressed the evoked IPSCs. Omission of extracellular Ca(2+) or inclusion of voltage-gated Ca(2+) channel blockers, Cd(2+) and Ni(2+), blocked bombesin-induced increases in sIPSCs suggesting that bombesin increases GABA release via facilitating extracellular Ca(2+) influx. Bombesin induced membrane depolarization and slightly increased the input resistance of GABAergic interneurons recorded from layer III of the EC. The action potential firing frequency of the interneurons was also increased by bombesin. Bombesin-mediated depolarization of interneurons was unlikely to be mediated by the opening of a cationic conductance but due to the inhibition of inward rectifier K(+) channels. Bath application of bombesin, NMB and GRP depressed the frequency of the epileptiform activity elicited by deprivation of Mg(2+) from the extracellular solution suggesting that bombesin and the bombesin-like peptides have antiepileptic effects in the brain.

Changes in plasma orexin-A levels in sevoflurane-remifentanil anesthesia in young and elderly patients undergoing elective lumbar surgery.

BACKGROUND: Delayed emergence from general anesthesia frequently occurs in elderly patients, but the reason is not clear. Orexin has been shown to be involved in arousal from general anesthesia. In this study, we examined plasma orexin-A levels in both elderly and young patients during the anesthesia arousal cycle. METHODS: We recruited 41 patients scheduled for elective lumbar surgery and eventually evaluated 34 patients. Patients were divided into a young group (age 30-55, N = 16) and an elderly group (age 65-77, N = 18). Anesthesia with sevoflurane-remifentanil was titrated to maintain the Bispectral Index between 45 and 65. The times from stopping anesthesia to eyes opening and extubation were recorded. Arterial blood was collected, and plasma orexin-A was determined by radioimmunoassay at the following 4 time points: preanesthesia (T0), 1 hour after anesthesia induction (T1), emergence (5 minutes after tracheal extubation) (T2), and 30 minutes after tracheal extubation (T3). RESULTS: The times from stopping anesthesia to eyes opening and tracheal extubation were both significantly longer in the elderly group than in the young group (P = 0.004, P = 0.01, respectively). Basal (T0) orexin-A levels were higher in the elderly group than in the young group (T0, 26.13 ± 1.25 vs 17.9 ± 1.30 pg/mL, P < 0.0001). Plasma orexin-A levels did not change during induction of anesthesia in either group but significantly increased at T2 (vs T0, P <0.0001) in both elderly (35.0 ± 1.7 pg/mL) and young (29.2 ± 1.9 pg/mL) groups. Orexin-A levels were significantly higher in the elderly than in the young group at T1, T2, and T3. CONCLUSION: Plasma orexin-A levels are not responsible for the delayed emergence from general anesthesia in elderly patients.

Gut microbiota-derived metabolite trimethylamine N-oxide aggravates cognitive dysfunction induced by femoral fracture operation in mice.

An increasing number of elderly individuals are experiencing postoperative cognitive dysfunction (POCD) problems after undergoing hip replacement surgery, with gut microbiota metabolites playing a role in its pathogenesis. Among these, the specific effects of trimethylamine N-oxide (TMAO) on POCD are still unclear. This study aimed to explore the role of TMAO on cognitive dysfunction and underlying mechanisms in mice. The POCD model was created through femoral fracture surgery in elderly mice, followed by cognitive function assessments using the Morris Water Maze and Novel Object Recognition tests. The gut microbiota depletion and fecal microbiota transplantation were performed to examine the relationship between TMAO levels and cognitive outcomes. The effects of TMAO treatment on cognitive dysfunction, microglial activation, and inflammatory cytokine levels in the brain were also evaluated, with additional assessment of the role of microglial ablation in reducing TMAO-induced cognitive impairment. Elevated TMAO levels were found to be associated with cognitive decline in mice following femoral fracture surgery, with gut microbiota depletion mitigating both TMAO elevation and cognitive dysfunction. In contrast, fecal microbiota transplantation from postoperative mice resulted in accelerated cognitive dysfunction and TMAO accumulation in germ-free mice. Furthermore, TMAO treatment worsened cognitive deficits, neuroinflammation, and promoted microglial activation, which were reversed through the ablation of microglia. TMAO exacerbates cognitive dysfunction and neuroinflammation in POCD mice, with microglial activation playing a crucial role in this process. Our findings may provide new therapeutic strategies for managing TMAO-related POCD and improving the quality of life for elderly patients.

NMT2 alleviates depression-like behavior in a rat model of chronic unpredictable stress: An integrated proteomic and phosphoproteomic analysis.

Proteomics has been widely used to investigate multiple diseases. Combining the analyses of proteomics with phosphoproteomics can be used to further explain the pathological mechanisms of depression. In this study, depression-like behavior was induced in a rat model of chronic unpredictable mild stress (CUMS). We subsequently conducted the sucrose preference test, open field experiment, and forced swimming test to assess depressive-like behavior. Proteomic and phosphoproteomic sequencing of the hippocampal tissues from depressive-like behavior and normal rats were analyzed to identify differentially expressed proteins (DEPs) and differentially phosphorylated proteins (DPPs). Differentially expressed phosphorylated proteins (DEPPs) were obtained by intersecting the DEPs and DPPs, and functional enrichment analysis, as well as ingenuity pathway analysis (IPA), were subsequently performed. The study also investigated correlations among the DEPPs and used qRT-PCR to quantify the expression levels of key genes. Five DEPPs were identified, Gys1, Nmt2, Lrp1, Bin1, and Atp1a1, which were found to activate the synaptogenesis signaling pathway, induce mitochondrial dysfunction, and activate the phosphoinositide biosynthesis and degradation pathways. The qRT-PCR results confirmed the proteomic findings for Gys1, Nmt2, Lrp1, and Atp1a1. Importantly, inhibiting Nmt2 was found to alleviate depression-like behavior and alleviate neuronal apoptosis in the hippocampus of CUMS rats. In conclusion, we identified five DEPPs associated with the synaptogenesis signaling pathway, mitochondrial dysfunction, and phosphoinositide biosynthesis and degradation in depression. Furthermore, NMT2 may be a potential target for the treatment or diagnosis of depression. Our findings provide novel insights into the molecular mechanisms of depression.

ATF3 is a neuron-specific biomarker for spinal cord injury and ischaemic stroke.

BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.

Different propofol-remifentanil or sevoflurane-remifentanil bispectral index levels for electrocorticographic spike identification during epilepsy surgery.

BACKGROUND: Medical therapy, the cornerstone of managing epilepsy, still fails a substantial portion of patients. Little information is available regarding the potential impact of different bispectral index (BIS) levels on electrocorticographic spike identification for surgical epileptic foci resection. METHODS: Twenty-two intractable epilepsy subjects were randomly allocated to the propofol-remifentanil or sevoflurane-remifentanil groups, and were further randomized to four BIS85 (BIS 71-85), BIS70 (BIS 56-70), BIS55 (BIS 41-55), and BIS40 (BIS ≤40) sequence order. RESULTS: Two-way ANOVA revealed no differences between groups in spike frequency (P = 0.720), spike amplitude (P = 0.647), or number of spiking leads (P = 0.653). In the propofol and sevoflurane groups, decreasing BIS levels increased mean ± SD spike/min frequency (P < 0.001 and P < 0.001) at BIS85 (10 ± 12 and 10 ± 8), BIS70 (19 ± 17 and 17 ± 15), BIS55 (22 ± 17 and 18 ± 8), and BIS40 (25 ± 15 and 23 ± 17). Furthermore, in the propofol and sevoflurane groups, decreasing BIS levels increased spike microvolt amplitude (P = 0.006 and P = 0.009) at BIS85 (1,100 ± 400 and 750 ± 400), BIS70 (1,200 ± 460 and 850 ± 490), BIS55 (1,300 ± 560 and 940 ± 700), and BIS40 (1,400 ± 570 and 1,300 ± 700). Whereas, in the propofol and sevoflurane groups, there was no difference in the location or number of spiking leads (P = 0.057 and P = 0.109) at the four BIS levels. Compared with BIS85, spike frequency in the propofol and sevoflurane groups increased 100 and 170% at BIS70, 116 and 180% at BIS55, and 132 and 230% at BIS40. Compared with BIS85, spike amplitude increased 108 and 113% at BIS70, 121 and 125% at BIS55, and 128 and 170% at BIS40. CONCLUSION: Decreasing BIS levels in the propofol and sevoflurane groups enhanced epileptogenic spike frequency and amplitude with the same location and number of spiking leads.

The Emerging Roles of Ferroptosis in Pathophysiology and Treatment of Acute Lung Injury.

Ferroptosis, a programmed cell death discovered in recent years, is an iron-dependent lipid peroxidation accumulation. Unlike other modes of cell death (autophagy, necroptosis, pyroptosis, cuproptosis, etc.), ferroptosis has unique morphological characteristics and plays an important role in a variety of diseases. In recent years, there has been great progress in the study of ferroptosis. Studies have found that ferroptosis is associated with acute lung injury (ALI), a condition with a high mortality rate and limited treatment options. This paper summarizes the mechanism of ferroptosis from the perspectives of iron metabolism, lipid metabolism, amino acid metabolism, and glutathione metabolism. It also discusses the research progress of ferroptosis in ALI in order to find new directions for the prevention and treatment of this condition.

Bibliometric Analysis of Anesthetic Drugs' Effects on Immune Function- Current Knowledge, Hotspots and Future Perspectives.

Objective: The objective of this study is to conduct a bibliometric analysis of the present status, areas of focus, and upcoming developments in the research of anesthetic drugs and their impact on immune function, along with other related research domains. Methods: From January 1, 2008 to June 9, 2023, A thorough exploration of anesthetic drug-related literature pertaining to immune function was carried out through the utilization of the Web of Science. The bibliometric analysis was predominantly executed by means of CiteSpace, GraphPad Prism 8.0, and the acquisition of data regarding the country, institution, author, journal, and keywords associated with each publication. Results: This study analyzed a comprehensive total of 318 publications, consisting of 228 articles and 90 reviews, to determine the publication output of anesthetic drugs on immune function. Notably, China exhibited the highest publication output with (109, 34.28%) articles. Among the institutions analyzed, Harvard University was found to be the most productive with (12, 3.77%) publications. The study findings indicate that Buggy, Donal J (5, 1.57%) and Yuki, Koichi (5, 1.57%) had the highest publication records. Anesthesiology was the most frequently cited journal with a total of (206) citations. The results also revealed that "surgery" was the most frequently used keyword, appearing (48 times), followed by "general anesthesia" (41 times) and "breast cancer" (37 times). The study has identified several current areas of interest, with a particular emphasis on "metastasis", "inflammation", "recurrence", "anesthesia technique", and "induction". It is anticipated that forthcoming research endeavors will concentrate on exploring the impacts of isoflurane, sevoflurane, and ketamine on immune function. Conclusion: This study provided a thorough analysis of the research trends and developments in investigating the impact of anesthetic drugs on immune function, incorporating pertinent research and collaborative entities such as authors, institutions, and countries.

GABAB Receptor Activation Attenuates Neuronal Pyroptosis in Post-cardiac Arrest Brain Injury.

Brain injury is a major cause of death and disability after cardiac arrest (CA). Previous studies have shown that activating GABAB receptors significantly improves neurological function after CA, but the mechanism of this neuronal protection of damaged neurons remains unclear. Thus, the present study aimed to investigate whether GABAB receptor activation protects against neuronal injury and to reveal the underlying protective mechanisms. In this study, rats underwent 10 min of asphyxia to induce CA, and SH-SY5Y cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish in vivo and in vitro models of hypoxic neuronal injury. Differential gene expression between CA rats and sham-operated rats was identified using RNA-seq. TUNEL and Nissl staining were used to evaluate cortical neuron damage, while Western blotting, qRT-PCR, and immunofluorescence assays were conducted to measure pyroptosis-related indicators. Furthermore, cellular models with high expression of caspase-11 were established to reveal the novel molecular mechanisms by which GABAB receptor activation exerts neuroprotective effects. Intriguingly, our results showed that caspase-11 and GSDMD were highly expressed in rats experiencing cardiac arrest. Specifically, GSDMD was expressed in neurons in the M1 area of the cerebral cortex. Moreover, activation of the GABAB receptor exerted a protective effect on neurons both in vivo and in vitro. Baclofen attenuated caspase-11 activation and neuronal pyroptosis after CA, and the anti-neuronal pyroptosis effect of baclofen was abolished by overexpression of caspase-11 in neuronal cells. In conclusion, GABAB receptor activation may play a neuroprotective role by alleviating neuronal pyroptosis through a mechanism involving caspase-11.

PirB negatively regulates the inflammatory activation of astrocytes in a mouse model of sleep deprivation.

Reactive astrocytes play a potential regulatory role in sleep deprivation (SD). Paired immunoglobulin-like receptor B (PirB) is expressed in reactive astrocytes, suggesting that PirB may participate in regulating the inflammatory response of astrocytes. We used lentiviral and adeno-associated viral approaches to interfere with the expression of PirB in vivo and in vitro. C57BL/6 mice were sleep deprived for 7 days and neurological function was measured via behavioral tests. We found that overexpressed PirB in SD mice could decrease the number of neurotoxic reactive astrocytes, alleviate cognitive deficits, and promote reactive astrocytes tended to be neuroprotective state. IL-1α, TNFα, and C1q were used to induce neurotoxic reactive astrocytes in vitro. Overexpression of PirB relieved the toxicity of neurotoxic astrocytes. Silencing PirB expression had the opposite effect and exacerbated the transition of reactive astrocytes to a neurotoxic state in vitro. Moreover, PirB-impaired astrocytes demonstrated STAT3 hyperphosphorylation which could be reversed by stattic (p-STAT3 inhibitor). Furthermore, Golgi-Cox staining confirmed that dendrite morphology defects and synapse-related protein were significantly increased in PirB-overexpressed SD mice. Our data demonstrated that SD induced neurotoxic reactive astrocytes and contributed to neuroinflammation and cognitive deficits. PirB performs a negative regulatory role in neurotoxic reactive astrocytes via the STAT3 signaling pathway in SD.