Copper-catalyzed thiocyanation of cyclobutanone oxime esters using ammonium thiocyanate.

A copper-catalyzed thiocyanation of cycloketone oxime esters with ammonium thiocyanate has been developed for the first time. This innovative approach allows access to cyano and thiocyano bifunctionally substituted alkanes, which can be further transformed into their respective trifluoromethylthiol-substituted or difluoromethylthiol-substituted alkylnitriles, alkynyl sulfides, and phosphorothioate esters. The readily available nature of ammonium thiocyanate and the cost-effectiveness of the copper catalyst make this method a promising strategy for the synthesis of sulfur-containing alkylnitriles.

Regulation of the PD-1/PD-L1 Axis and NK Cell Dysfunction by Exosomal miR-552-5p in Gastric Cancer.

OBJECTIVE: NK cells play a vital role in tumor immune resistance. Various factors affect NK cell activity. While NK cell dysfunction has been observed in numerous malignancies, the underlying mechanisms in gastric cancer remain unclear. METHOD: Flow cytometry was used to identify the phenotypic distribution and expression of activated receptors on NK cells. ELISA was used to determine the expression of cytokines. We examined the expression of NK cell-related genes and explored their association with survival and prognosis. Additionally, we conducted PCR detection of miR-552-5p expression levels in plasma exosomes of patients and investigated its correlation with phenotypic distribution and activated receptors. We used flow cytometry and ELISA to verify the role of miR-552-5p in NK cell dysfunction. Furthermore, we investigated the potential role of PD-1/PD-L1 in regulating NK cell dysfunction in patients' cells. RESULTS: We observed a significant decrease in the percentage of NKG2D and NKp30 and IFN-γ and TNF-α in patients than in healthy volunteers. Patients with low levels of CD56, CD16, NKG2D, and NKP46 exhibited poorer survival prognoses. Moreover, increased expression levels of plasma exosomal miR-552-5p in patients were negatively associated with NK cell phenotypic distribution and activated receptor expression. MiR-552-5p downregulated the secretion of perforin, granzyme, and IFN-γ as well as the expression of NKp30, NKp46, and NKG2D. Additionally, it suppressed the cytotoxicity of NK cells. The inhibitory effect of miR-552-5p, on NK cell function was reversed when anti-PD-L1 antibodies were used. CONCLUSION: Exosomal miR-552-5p targets the PD-1/PD-L1 axis, leading to impaired NK cell function.

Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human.

Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural development, including cilia organization, neuron migration and axon navigation. Here, we address its role in axon regeneration. We show that Celsr2 is highly expressed in both mouse and human spinal motor neurons. Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants. Similarly, cultured Celsr2 mutant motor neurons extend longer neurites and larger growth cones, with increased expression of end-binding protein 3 and higher potassium-induced calcium influx. Mice with Celsr2 conditional knockout in spinal motor neurons do not exhibit any behavioural deficits; however, after branchial plexus injury, axon regeneration and functional forelimb locomotor recovery are significantly improved. Similarly, knockdown of CELSR2 using shRNA interference in cultured human spinal motor explants and motor neurons increases axonal fasciculation and growth. In mouse adult spinal cord after root avulsion, in mouse embryonic spinal cords, and in cultured human motor neurons, Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun. In conclusion, Celsr2 negatively regulates motor axon regeneration and is a potential target to improve neural repair.

Association between fear of progression and sleep quality in patients with chronic heart failure: A cross-sectional study.

AIMS: This study aimed to measure sleep quality and its possible association with fear of progression (FOP) in patients with chronic heart failure (HF). DESIGN: A cross-sectional study. METHODS: A total of 254 patients with chronic HF were recruited from two tertiary hospitals in China. The sociodemographic and clinical data of participants were collected using a general information questionnaire. The Pittsburgh Sleep Quality Index and Fear of Progression Questionnaire-Short Form were used to evaluate sleep quality over 1 month and FOP. Pearson correlation and hierarchical regression were conducted to analyse the relationship between sleep quality and FOP. RESULTS: Of all participants, 85.8% had poor sleep quality, with a mean score of 12.3 ± 4.2 (possible score could be 0 to 21). The severity of FOP was positively correlated with poor sleep quality. HF hospitalization in the past year, numbers of HF drugs, monthly income and total score of FOP were strong predictors of decreased sleep quality, accounting for 24.2% of the variance in the sleep quality of these patients. CONCLUSIONS: Patients with chronic HF generally reported poor sleep quality, which should be highly concerned for medical workers. Alleviating FOP as a therapeutic strategy may improve sleep quality. IMPACT: It is urgent to raise clinical attention that Chinese patients with chronic HF have poor sleep quality, which is not just due to the symptoms of HF itself. FOP is an important psychological factor influencing sleep quality in patients with chronic HF, which has not been explored in China. This study provides a new perspective on targeted interventions for poor sleep quality in chronic HF. PATIENT AND PUBLIC INVOLVEMENT: No patient or public involvement.

Path-Dependent Anisotropic Colloidal Assembly of Magnetic Nanocomposite-Protein Complexes.

Anisotropic self-assembly of nanoparticles (NPs) stems from the fine-tuning of their surface functionality and NP interaction. Strategies involving ligand interaction, protein interaction, and external stimulus have been developed. However, robust construction of monodispersed magnetic NPs to tens of microns of anisotropically aligned colloidal assembly triggered by adsorbed protein intermolecular interaction is yet to be elucidated. Here, we present the NP-protein interaction, magnetic force, and protein corona intermolecular interaction serially but independently induced path-dependent self-assembly of 100 nm Fe3O4@SiO2 nanocomposites. Dynamic formation of the micron-sized anisotropic magnetic assembly was reproducibly realized in a continuous medium in a controllable manner. Formation of the primary globular clusters upon the unique NP-protein complexes with the help of ions acts as the prerequisite for the anisotropic colloidal assembly, followed by the magnetic force-driven pre-organization and protein intermolecular electrostatic interaction-mediated elongation. The protein concentration rather than the protein original structure plays a more pivotal role in the NP-protein interaction and subsequent colloidal assembly process. Two typical serum proteins fibrinogen and bovine serum albumin enable formation of the anisotropic colloidal assembly but with a different subtle morphology. Furthermore, the obtained micron-sized magnetic colloidal assembly can be dissociated rapidly by adding a negative electrolyte in the medium due to the interference in the NP-protein interaction. However, the self-assembly process can be recycled based on the dissociated colloidal assembly.

Early Forebrain Neurons and Scaffold Fibers in Human Embryos.

Neural progenitor proliferation, neuronal migration, areal organization, and pioneer axon wiring are critical events during early forebrain development, yet remain incompletely understood, especially in human. Here, we studied forebrain development in human embryos aged 5 to 8 postconceptional weeks (WPC5-8), stages that correspond to the neuroepithelium/early marginal zone (WPC5), telencephalic preplate (WPC6 & 7), and incipient cortical plate (WPC8). We show that early telencephalic neurons are formed at the neuroepithelial stage; the most precocious ones originate from local telencephalic neuroepithelium and possibly from the olfactory placode. At the preplate stage, forebrain organization is quite similar in human and mouse in terms of areal organization and of differentiation of Cajal-Retzius cells, pioneer neurons, and axons. Like in mice, axons from pioneer neurons in prethalamus, ventral telencephalon, and cortical preplate cross the diencephalon-telencephalon junction and the pallial-subpallial boundary, forming scaffolds that could guide thalamic and cortical axons at later stages. In accord with this model, at the early cortical plate stage, corticofugal axons run in ventral telencephalon in close contact with scaffold neurons, which express CELSR3 and FZD3, two molecules that regulates formation of similar scaffolds in mice.

Prenatal sevoflurane exposure causes neuronal excitatory/inhibitory imbalance in the prefrontal cortex and neurofunctional abnormality in rats.

The balance of excitatory and inhibitory neurons in the central nervous system is critical for maintaining brain function and sevoflurane, a general anesthetic and an GABA receptor modulator, may change the balance of excitatory and inhibitory neurons in the cortex during early brain development. Herein, we investigated whether prenatal sevoflurane exposure (PSE) disturbs cortical neuronal development and brain function. Pregnant rats at the gestational day 14.5 were subjected to sevoflurane exposure at 3.0% for 3 h and their offspring were studied thereafter. We found a significant increase of parvalbumin-positive neurons, vesicular GABA transporter (VGAT) and GAD67 expression, and GABA neurotransmitter, and a significant decrease of vesicular glutamate transporter 1 (VGLUT1) expression and glutamate in the medial prefrontal cortex (mPFC) of offspring. Pyramidal neurons showed atrophy with shorter dendrites, less branches and lower spine density visualized by Golgi stain and a decrease of excitability with the increased miniature inhibitory postsynaptic current (mIPSC) frequency and amplitude, the decreased miniature excitatory postsynaptic current (mEPSC) frequency and excitation/inhibition (E/I) ratio using whole-cell recording in offspring. There was a significant increase of inhibitory synapse in the mPFC detected by electron microscopy. Furthermore, PSE animals showed hypo-excitatory phenotype including depression-like behaviors and learning deficits. Thus, our studies provide novel evidence that PSE causes the persisted imbalance of excitatory and inhibitory neurons in the mPFC, and this is very likely the mechanisms of the sevoflurane-induced brain functional abnormalities.

The relationship between symptom perception and fear of progression in patients with chronic heart failure: a multiple mediation analysis.

AIMS: Studies have shown that symptom perception is associated with fear of progression (FOP) in many diseases and regulated by psychological factors. Whether the association also occurs in patients with chronic heart failure (HF) remains unclear, as do the specific mechanisms involved. This study aimed to explore the multiple mediation effects of self-care confidence and mental resilience on the relationship between symptom perception and FOP in Chinese patients with chronic HF. METHODS AND RESULTS: A cross-sectional study was conducted on 247 patients with chronic HF recruited from two hospitals in Yangzhou, China. The sociodemographic and clinical data and self-reported questionnaires including heart failure somatic perception, fear of progression, self-care confidence, and mental resilience were collected. Data analysis relating to correlations and mediating effects was carried out by SPSS 26.0 and PROCESS v3.3 macro. Fear of progression was positively correlated with symptom perception (r = 0.599, P < 0.01), but negatively correlated with self-care confidence (r = -0.663, P < 0.01), mental resilience-strength (r = -0.521, P < 0.01), and mental resilience-toughness (r = -0.596, P < 0.01). The relationship between symptom perception and FOP was mediated by self-care confidence [effect = 0.095, 95% confidence interval (CI) (0.054-0.142)] and mental resilience-toughness [effect = 0.033, 95% CI (0.006-0.074)], respectively, and together in serial [effect = 0.028, 95% CI (0.011-0.050)]. The proportion of the mediating effect accounting for the total effect was 31.0%. CONCLUSION: Self-care confidence and mental resilience-toughness were multiple mediators of the association between symptom perception and FOP in patients with chronic HF. Interventions targeted at strengthening self-care confidence and mental resilience may be beneficial for the reduction of FOP, especially with regard to toughness.

Lactate Efflux Inhibition by Syrosingopine/LOD Co-Loaded Nanozyme for Synergetic Self-Replenishing Catalytic Cancer Therapy and Immune Microenvironment Remodeling.

An effective systemic mechanism regulates tumor development and progression; thus, a rational design in a one-stone-two-birds strategy is meant for cancer treatment. Herein, a hollow Fe3 O4 catalytic nanozyme carrier co-loading lactate oxidase (LOD) and a clinically-used hypotensor syrosingopine (Syr) are developed and delivered for synergetic cancer treatment by augmented self-replenishing nanocatalytic reaction, integrated starvation therapy, and reactivating anti-tumor immune microenvironment. The synergetic bio-effects of this nanoplatform stemmed from the effective inhibition of lactate efflux through blocking the monocarboxylate transporters MCT1/MCT4 functions by the loaded Syr as a trigger. Sustainable production of hydrogen peroxide by catalyzation of the increasingly residual intracellular lactic acid by the co-delivered LOD and intracellular acidification enabled the augmented self-replenishing nanocatalytic reaction. Large amounts of produced reactive oxygen species (ROS) damaged mitochondria to inhibit oxidative phosphorylation as the substituted energy supply upon the hampered glycolysis pathway of tumor cells. Meanwhile, remodeling anti-tumor immune microenvironment is implemented by pH gradient reversal, promoting the release of proinflammatory cytokines, restored effector T and NK cells, increased M1-polarize tumor-associated macrophages, and restriction of regulatory T cells. Thus, the biocompatible nanozyme platform achieved the synergy of chemodynamic/immuno/starvation therapies. This proof-of-concept study represents a promising candidate nanoplatform for synergetic cancer treatment.

Influencing factors of kinesiophobia in older patients with chronic heart failure: A structural equation model.

BACKGROUND: Our recent study has demonstrated that kinesiophobia is common in Chinese inpatients with chronic heart failure (CHF). Symptoms of heart failure (HF), coping mode, self-efficacy for exercise (SEE), and social support have been reported to be associated with kinesiophobia. However, little is known about the relationships between these four variables and kinesiophobia in older patients with CHF. OBJECTIVE: To test a model of influencing factors of kinesiophobia in older CHF patients. METHODS: A cross-sectional design was conducted from January 2021 to October 2021. The general information questionnaire, the Chinese version of the Tampa Scale for Kinesiophobia Heart (TSK-SV Heart-C), Symptom Status Questionnaire-Heart Failure, SEE, the Medical Coping Modes Questionnaire, and Social Support Rating Scale were used. Spearman correlation analysis and structural equation model (SEM) were performed for data analysis. RESULTS: A total of 270 older patients with CHF were recruited. Symptom status of HF (r = 0.455, p < .01), avoidance coping mode (r = 0.393, p <.01), and yielding coping mode (r = 0.439, p < .01) were positively correlated with kinesiophobia, while SEE (r = -0.530, p < .01), facing coping mode (r = -0.479, p < .01), and social support (r = -0.464, p < .01) were negatively correlated with kinesiophobia. SEM analysis showed that social support could affect kinesiophobia through the mediating variables of symptom status of HF, avoidance coping mode, and exercise self-efficacy. CONCLUSIONS: Symptoms of HF, coping mode, SEE, and social support may play role in kinesiophobia in older CHF patients. We should pay more attention to the synergies among these four variables in the improvement of kinesiophobia.

Fabrication and evaluation of 3D printed poly(l-lactide) copolymer scaffolds for bone tissue engineering.

The application of poly(L-lactic acid) (PLLA) in tissue engineering is limited due to its brittleness and uncontrollable degradation rate. In this study, the flexible p-dioxanone (PDO) and highly reactive glycolide (GA) units were introduced into PLLA segments by chemical modification to prepare poly(l-lactide-ran-p-dioxanone-ran-glycolide) (PLPG) copolymers. The copolymers were then processed into the PLPG scaffold by a 3D printing technology. The physicochemical properties of the PLPG copolymers were studied by NMR, DSC, XRD, GPC, and SEM. Furthermore, the mechanical properties, degradation properties, and biocompatibility of the PLPG scaffolds were also studied. The results showed that introducing PDO and GA units disrupted the regularity of PLLA, decreasing the crystallinity of the PLPG copolymers. However, introducing PDO and GA units could effectively improve the mechanical and degradation properties of the PLLA scaffolds. In vitro cell culture experiments indicated that the PLPG scaffolds supported proliferation, growth, and differentiation of MC3T3-E1 cells. The PLPG scaffolds reported herein, with controllable degradation rates and mechanical performance, may find applications in bone tissue engineering.

Multimodal MRI for Estimating Her-2 Gene Expression in Endometrial Cancer.

PURPOSE: To assess the value of multimodal MRI, including amide proton transfer-weighted imaging (APT), diffusion kurtosis imaging (DKI), and T2 mapping sequences for estimating human epidermal growth factor receptor-2 (Her-2) expression in patients with endometrial cancer (EC). METHODS: A total of 54 patients with EC who underwent multimodal pelvic MRI followed by biopsy were retrospectively selected and divided into the Her-2 positive (n = 24) and Her-2 negative (n = 30) groups. Her-2 expression was confirmed by immunohistochemistry (IHC). Two observers measured APT, mean kurtosis (MK), mean diffusivity (MD), and T2 values for EC lesions. RESULTS: The Her-2 (+) group showed higher APT values and lower MD and T2 values than the Her-2 (-) group (all p < 0.05); there was no significant difference in MK values (p > 0.05). The area under the receiver operating characteristic curve (AUC) of APT, MD, T2, APT + T2, APT + MD, T2 + MD, and APT + MD + T2 models to identify the two groups of cases were 0.824, 0.695, 0.721, 0.824, 0.858, 0.782, and 0.860, respectively, and the diagnostic efficacy after combined APT + MD + T2 value was significantly higher than those of MD and T2 values individually (p = 0.018, 0.028); the diagnostic efficacy of the combination of APT + T2 values was significantly higher than that of T2 values separately (p = 0.028). Weak negative correlations were observed between APT and T2 values (r = -0.365, p = 0.007), moderate negative correlations between APT and MD values (r = -0.560, p < 0.001), and weak positive correlations between MD and T2 values (r = 0.336, p = 0.013). The APT values were independent predictors for assessing Her-2 expression in EC patients. CONCLUSION: The APT, DKI, and T2 mapping sequences can be used to preoperatively assess the Her-2 expression in EC, which can contribute to more precise treatment for clinical preoperative.

Altered intestinal barrier contributes to cognitive impairment in old mice with constipation after sevoflurane anesthesia.

Background: Elderly patients have a high risk of developing postoperative cognitive dysfunction (POCD). Gastrointestinal disorders, such as constipation, in the elderly population may be involved in the pathogenesis of neurological disorders by promoting inflammatory responses due to a 'leaky gut'. General anesthetic sevoflurane may impair gastrointestinal function in elderly patients to trigger neurological complications following surgery. Therefore, we hypothesized that elderly individuals with gastrointestinal dysfunction may be more vulnerable to sevoflurane and consequently develop POCD. Methods: Aged mice were randomly divided into four groups: control (CTRL), CTRL+sevoflurane (Sev), slow transit constipation (STC), and STC + Sev. Mice in the STC and STC + Sev groups were intra-gastrically administrated loperamide (3 mg/kg, twice a day for 7 days) to induce a slow transit constipation (STC) model determined with fecal water content and the time of first white fecal pellet, whereas mice in the other groups received the similar volume of saline. One week later, mice in the CTRL+Sev group and STC + Sev group received 2% sevoflurane for 2 h. The gut permeability evaluated with 4-kDa fluorescein isothiocyanate (FITC)-dextran, serum cytokines, microglia density, TLR4/NF-κB signaling expression, and POCD-like behavioral changes were determined accordingly. Results: The loperamide-induced STC mice had decreased fecal water content and prolonged time of first white fecal pellet. Sevoflurane exposure caused significantly increased gut permeability and serum cytokines, as well as the activation of microglia and the TLR4/NF-κB signaling pathway in the prefrontal cortex of the aged STC mice. Sevoflurane also caused cognitive impairment and emotional phenotype abnormality in aged STC mice. Conclusion: Aged STC mice were more vulnerable to sevoflurane anesthesia and consequently developed POCD-like behavioral changes. Our data suggest that gastrointestinal disorders including constipation may contribute to the development of POCD.

Kinesiophobia and Its Association With Fatigue in CHF Patients.

Kinesiophobia is related with adverse outcomes in various diseases, but it has not been studied in chronic heart failure (CHF). Fatigue often causes movement avoidance in CHF patients, and thereby, leads to a worsening of condition and increasing severity of symptom burden. The purpose of this study was to explore kinesiophobia and its related factors and the relationship between the kinesiophobia and fatigue in CHF patients. We recruited (n = 236) inpatients with CHF from October 2020 to March 2021 and administered a self-designed demographic questionnaire, the Chinese version of the Tampa Scale for Kinesiophobia Heart (TSK-Heart-C), and the Multidimensional Fatigue Inventory (MFI-20), and collected related electronic medical record data. Findings revealed that 63% of participants had kinesiophobia. was a moderate correlation between fatigue and kinesiophobia (r = .49, p < .01). Educational background, monthly family income, disease course, and fatigue explained 41% of the variance in kinesiophobia, of which fatigue independently accounted for 9%.

Effects on the crystallization behavior and biocompatibility of poly(LLA-ran-PDO-ran-GA) with poly(d-lactide) as nucleating agents.

The blends of poly(l-lactide acid-p-dioxanone-glycolide) (PLPG) with poly(d-lactide) (PDLA) (PLPG/PDLA) were prepared by a solution-casting method. The effects of PDLA on the properties of the PLPG were studied. DSC and WAXD results confirmed that PLA stereocomplex (sc-PLA) crystals were formed by blending PLLA segments in PLPG with PDLA, and the melting endotherm for both PLLA and sc-PLA relied on PDLA content. The non-isothermal crystallization results indicated that the crystallization process was remarkably accelerated by the addition of PDLA. Meanwhile, the results of isothermal crystallization indicated that the half-time of crystallization decreased with the increase of PDLA content. Besides, the enzymatic degradation behavior of the samples showed that with the increase of PDLA content, the mass loss gradually decreased. Furthermore, TGA and DTG results indicated that the thermal degradation of the samples was a complex process. Moreover, the biocompatibility of the samples was tested by cell culture and using CCK-8 and live/dead staining. Results showed that the samples possessed lower cytotoxicity. Therefore, the PLPG/PDLA blends are promising candidate materials in biomedical applications.

Biodegradable membrane of poly(l-lactide acid-dioxanone-glycolide) and stereocomplex poly(lactide) with enhanced crystallization and biocompatibility.

The membranes of poly(l-lactide acid-p-dioxanone-glycolide) (PLPG) with stereocomplex poly(lactic acid) (sc-PLA) were prepared by the solution blending way. It was observed that sc-PLA significantly heightened the crystallizing behavior of PLLA segments of the PLPG matrix. The crystallizing behavior displayed that the temperature of crystallization shifted to a higher range than that of PLPG. Moreover, the half-time of crystallization sharply decreased in value as the sc-PLA content increased in value on account of the pre-eminent nucleation ability of sc-PLA. TGA results revealed the thermal stability of the samples with the increase of sc-PLA compared to PLPG. Meanwhile, enzymatic degradation results indicated that the mass loss rate of the membrane decreased with the introduction of sc-PLA, but the overall degradation ability was still greater than that of PLLA. In the meantime, the biological experiment indicated that the membrane possessed low cytotoxicity.

Long non-coding RNA rhabdomyosarcoma 2-associated transcript contributes to neuropathic pain by recruiting HuR to stabilize DNA methyltransferase 3 alpha mRNA expression in dorsal root ganglion neuron.

Introduction: Long non-coding RNAs (lncRNAs) act as key regulators in multiple human diseases. In particular, the dysfunction of lncRNAs in dorsal root ganglion (DRG) contributes to the pathogenesis of neuropathic pain (NP). Nevertheless, the role and mechanism of most lncRNAs in NP remain unclear. Methods: Two classic chronic NP models, including L4 spinal nerve ligation (SNL) model and chronic constriction injury (CCI) of the sciatic nerve, were performed. Mechanical allodynia and heat hyperalgesia were used to evaluate neuropathic pain. DRG microinjection was used to deliver agents into DRG. qRT-PCR, immunofluorescence, immunoprecipitation, western blotting, siRNA transfection, AAV transduction were performed to investigate the phenotypes and molecular basis. Results: Here, we discovered that Rmst as a lncRNA was specifically expressed in Atf3 + injured DRG neurons and significantly upregulated following peripheral nerve damage. Rmst overexpression by direct DRG injection of AAV5-Rmst causes neuropathic symptoms in the absence of nerve damage. Conversely, blocking Rmst expression in injured DRGs alleviated nerve injury-induced pain hypersensitivities and downregulated Dnmt3a expression. Furthermore, we found peripheral nerve damage induced Rmst increase could interact with RNA-binding protein HuR to stabilize the Dnmt3a mRNA. Conclusion: Our findings reveal a crucial role of Rmst in damaged DRG neurons under NP condition and provide a novel target for drug development against NP.

Prolonged sevoflurane exposure causes abnormal synapse development and dysregulates beta-neurexin and neuroligins in the hippocampus in neonatal rats.

BACKGROUND: The underlying molecular mechanisms of the excitatory/inhibitory (E/I) imbalance induced by sevoflurane exposure to neonates remain poorly understood. This study aimed to investigate the long-term effects of prolonged sevoflurane exposure to neonatal rats during the peak period of synaptogenesis on the changes of trans-synaptic neurexin-neuroligin interactions, synaptic ultrastructure in the hippocampus and cognition. METHODS: A total of 30 rat pups at postnatal day (P) 7 was randomly divided into two groups: the control group (exposed to 30 % oxygen balanced with nitrogen) and the sevoflurane group (exposed to 2.5 % sevoflurane plus 30 % oxygen balanced with nitrogen) for 6 h. Neurocognitive behaviors were assessed with the Open field test at P23-25 and the Morris water maze test at P26-30. The expression of ß-neurexin (ß-NRX), N-methyl-d-aspartate receptor 2 subunit (NR2A and NR2B), neuroligin-1 (NLG-1), neuroligin-2 (NLG-2), postsynaptic density protein-95 (PSD-95), α1-subunit of the γ-aminobutyric acid A receptor (GABAAα1) and gephyrin in the hippocampus at P30 were measured by Western blot. The ultrastructure of synapses was examined under electron microscope. RESULTS: Prolonged sevoflurane exposure at P7 resulted in cognitive deficiency in adolescence, as well as the downregulation of ß-NRX, NR2A, NR2B, NLG-1, and PSD-95, and the upregulation of GABAAα1, NLG-2, and gephyrin in the hippocampal CA3 region. Sevoflurane anesthesia also increased the number of symmetric synapses in the hippocampus. CONCLUSIONS: Prolonged sevoflurane exposure during the brain development leads to cognitive deficiency and disproportion of excitatory/inhibitory synapses which may be caused by dysregulated expression of synaptic adhesion molecules of ß-NRX and neuroligins.

Sevoflurane Ameliorates Schizophrenia in a Mouse Model and Patients: A Pre-Clinical and Clinical Feasibility Study.

BACKGROUND: GABAergic deficits have been considered to be associated with the pathophysiology of schizophrenia, and hence, GABA receptors subtype A (GABAARs) modulators, such as commonly used volatile anesthetic sevoflurane, may have therapeutic values for schizophrenia. The present study investigates the therapeutic effectiveness of low-concentration sevoflurane in MK801-induced schizophrenia-like mice and schizophrenia patients. METHODS: Three weeks after MK801 administration (0.5 mg kg-1, i.p. twice a day for 5 days), mice were exposed to 1% sevoflurane 1hr/day for 5 days. Behavioral tests, immunohistochemical analysis, western blot assay, and electrophysiology assessments were performed 1-week post-exposure. Ten schizophrenia patients received 1% sevoflurane 5 hrs per day for 6 days and were assessed with the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18) at week 1 and week 2. RESULTS: MK801 induced hypolocomotion and social deficits, downregulated expression of NMDARs subunits and postsynaptic density protein 95 (PSD95), reduced parvalbumin - and GAD67-positive neurons, altered amplitude and frequency of mEPSCs and mIPSCs, and increased the excitation/inhibition ratio. All these changes induced by MK-801 were attenuated by sevoflurane administration. Six and eight patients achieved a response defined as a reduction of at least 30% in the PANSS total score at 1st and 2nd week after treatments. The BPRS-18 total score was found to be significantly decreased by 38% at the 2nd week (p < 0.01). CONCLUSION: Low-concentration sevoflurane effectively reversed MK801-induced schizophrenialike disease in mice and alleviated schizophrenia patients' symptoms. Our work suggests sevoflurane to be a valuable therapeutic strategy for treating schizophrenia patients.