METTL14 regulates microglia/macrophage polarization and NLRP3 inflammasome activation after ischemic stroke by the KAT3B-STING axis.

N6-methyladenosine (m6A) plays a crucial role in ischemic stroke, whereas the role of methyltransferase-like 14 (METTL14) in ischemic stroke remains unknown. A model of middle cerebral artery occlusion (MCAO) in rats and oxygen-glucose deprivation/reperfusion (OGD/R) model in HAPI cells were used to simulate ischemic stroke in vivo and in vitro. We found that METTL14 level was upregulated in microglia/macrophage after MCAO and OGD/R. METTL14 enhanced the expression of KAT3B by promoting the m6A modification of KAT3B mRNA. STING has been identified as a target for KAT3B and KAT3B increased STING expression by enhancing H3K27ac in the STING promoter. METTL14 promoted M1 polarization and NLRP3 inflammasome/pyroptosis axis by the KAT3B-STING signaling after OGD/R. METTL14 depletion relieved brain injury by inhibiting M1-like microglia/macrophage polarization and NLRP3 inflammasome/pyroptosis axis in MCAO rats. These findings indicate that METTL14 depletion relieves MCAO-induced brain injury, probably via switching microglia/macrophage from M1 towards M2 and restraining NLRP3 inflammasome/pyroptosis axis in microglia/macrophage.

Influence of Minimum Alveolar Concentration and Inhalation Duration of Sevoflurane on Facial Nerve Electromyography in Hemifacial Spasm: A Randomized Controlled Trial.

BACKGROUND: The lateral spread response (LSR) is an electromyography feature of hemifacial spasm; intraoperative reduction in the LSR is associated with positive surgical outcomes. This study examined the effects of different minimum alveolar concentrations (MACs) and durations of sevoflurane inhalation on the LSR. METHODS: Eighty patients undergoing microvascular decompression surgery for hemifacial spasm were randomly allocated to receive propofol-remifentanil total intravenous anesthesia alone or in combination with sevoflurane at 0.5, 0.75, or 1 MAC. The LSR and orbicularis oculi muscle wave were recorded before and at 15 and 30 minutes after the start of sevoflurane administration. RESULTS: Sevoflurane reduced the LSR amplitude in a dose-dependent and duration-dependent manner. The curve representing the LSR amplitude preservation ratio change according to sevoflurane concentration is best fitted by regression analysis using a cubic model, as the cubic equations had the largest coefficient of determination; at 15 minutes ( R2 =0.76, F =78.36, P <0.05) and at 30 minutes ( R2 =0.882, F =189.94, P <0.05). The inhibitory effect of sevoflurane on the LSR amplitude was greater in the first 15 minutes than in the second 15 minutes of sevoflurane administration. Sevoflurane at 1 MAC for 30 minutes mildly decreased the amplitude of the orbicularis oculi muscle wave. The latencies of the LSR and the orbicularis oculi muscle wave were not affected by sevoflurane at all MACs studied. CONCLUSIONS: The combination of intravenous propofol-remifentanil anesthesia with 0.5 MAC sevoflurane allows reliable intraoperative LSR monitoring in hemifacial spasm patients. Our findings support the central rather than peripheral hypothesis of the LSR.

Analysis of m6A modulator-mediated methylation modification patterns and the tumor microenvironment in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. In the development and progression of LUAD, epigenetic aberration plays a crucial role. However, the function of RNA N6-methyladenosine (m6A) modifications in the LUAD progression is unknown. The m6A regulator modification patterns in 955 LUAD samples were analyzed comprehensively. Patterns were systematically correlated with the tumor microenvironment (TME) cell-infiltration characteristics. Using principal component analysis algorithms, the m6Ascore was generated to quantify m6A modification patterns in individual tumors. Then, their values for predicting prognoses and therapeutic response in LUAD patients were assessed. Three distinct m6A modification patterns in LUAD were identified. Among them, the prognosis of m6Acluster C was the best, while the prognosis of m6Acluster A was the worst. Interestingly, the characterization of TME cell infiltration and biological behavior differed among the three patterns. To evaluate m6A modification patterns within individual tumors, an m6Ascore signature was constructed. The results showed that the high m6Ascore group was associated with a better prognosis; tumor somatic mutations and tumor microenvironment differed significantly between the high- and low- m6Ascore groups. Furthermore, in the cohort with anti-CTLA-4 treatment alone, patients with a high m6Ascore had higher ICI scores, which indicated significant therapeutic advantage and clinical benefits.

Nomogram Prediction for Postoperative Mortality of Orthotopic Liver Transplantation.

OBJECTIVES: The purpose of this study was to assess and predict risk factors for death within 30 days after orthotopic liver transplant and to develop a nomogram to predict mortality after liver transplant. MATERIALS AND METHODS: We retrospectively studied 185 patients who underwent orthotopic livertransplant at Sichuan Provincial People's Hospital from January 1, 2010, to December 31, 2018. Multivariable logistic regression analyses were used to identify independent risk factors. A nomogram model was developed to predict mortality after liver transplant. The performance of the prediction model was assessed and validated by receiver operating characteristic curve and bootstrap methods (1000 replications). RESULTS: Multivariable logistic regression analyses revealed that tracheal extubation time, postoperative infection, and intraperitoneal hemorrhage posttransplant were independentrisk factors for mortality after liver transplant. The receiver operating characteristic curve of the nomogram prediction model was 0.896 (96% CI, 0.803-0.989), and the mean absolute error of internal validation by bootstrap (1000 replications) was 0.019 (n = 184). These results showed that the nomogram model had an excellent prediction accuracy. CONCLUSIONS: A nomogram model can provide clinicians with an individualized risk assessment of perioperative mortality in liver transplant recipients.

Effects of ultrasound-guided erector spinae plane block on the immune function and postoperative recovery of patients undergoing radical mastectomy.

BACKGROUND: To explore the effects of ultrasound-guided erector spinae plane (ESP) block on the immune function and postoperative recovery of patients undergoing radical mastectomy. METHODS: One hundred and four patients with breast cancer were randomly divided into the observation group and control group, with 52 cases in each group. The control group underwent induction of routine general anesthesia and thoracic paravertebral block, while the observation group underwent ultrasound-guided ESP block combined with general anesthesia. The recovery of autonomous respiration, eye opening, extubation time, postoperative eating, first anal exhaust, leaving bed and hospitalization time in both groups were statistically analyzed after surgery. The immune function indexes [CD4+, CD8+, interferon-γ (IFN-γ)] and the expression levels of serum neuropeptide Y (NPY), prostaglandin E2 (PGE2) and serotonin (5-HT) were compared between the two groups at 24 and 48 h before and after surgery. The visual analog scale (VAS) scores at rest and during exercise were recorded at 6, 12, 24, and 48 h after surgery. RESULTS: There was no significant difference in the recovery of autonomous respiration, eye opening, and extubation time between the two groups (P>0.05). However, postoperative eating, first anal exhaust, leaving bed, and hospitalization time in the observation group were shorter than those in the control group (P<0.05). At 24 and 48 h after surgery, compared with the control group, CD4+ and IFN-γ levels were increased significantly (P<0.05), CD8+ and levels of serum NPY, PGE2, 5-HT and the incidence of postoperative complications was decreased significantly in the observation group (P<0.05). VAS scores at rest and during exercise in the observation group were lower than those in the control group (P<0.05). At 5 and 10 min after intubation, the observation group had higher epinephrine (E) level and lower serum cortisol (Cor) level than the control group (P<0.05). CONCLUSIONS: The analgesic effect of ultrasound-guided ESP block is significant after radical mastectomy. There are few adverse reactions and few effects on immune function, and it can promote the postoperative recovery of patients.

FBXO10 prevents chronic unpredictable stress-induced behavioral despair and cognitive impairment through promoting RAGE degradation.

AIMS: Depression is one of the leading causes of disability worldwide. The receptor for advanced glycosylation end products (RAGE) is closely related to chronic stress and is a target of F-box protein O10 (FBXO10) which promotes the degradation of RAGE by ubiquitination. Here, we explored the role of FBXO10 and RAGE in chronic unpredictable stress (CUS)-induced behavioral despair, cognitive impairment, neuroinflammation, and the polarization microglia. METHODS: Male C57BL/6 mice with or without infusion of viral in the medial prefrontal cortex (PFC) were subjected to CUS. Then the mice were exposed to forced swim test, sucrose consumption test, novelty-suppressed feeding test, and temporal object recognition task to assess the behavioral despair and cognitive impairment. Inflammatory cytokines and the neurotrophic factor brain-derived neurotrophic factor (BDNF) levels in PFC were assessed by enzyme-linked immunosorbent assay. Immunofluorescence and immunohistochemistry staining were performed to observe the activation and phenotypic transformation of microglia in PFC. LPS-induced cell model was constructed to explore the effect of FBXO10/RAGE axis in the polarization of microglia in vitro. RESULTS: FBXO10 promoted RAGE degradation by ubiquitination in BV2 cells. FBXO10 protein levels were reduced whereas RAGE protein levels were enhanced in CUS mice. FBXO10 overexpression or RAGE knockdown inhibited proinflammatory cytokine release, promoted BDNF expression, mitigated the depressive-like and cognitive impairment behaviors, and affected the polarization of microglia induced by CUS exposure. FBXO10/RAGE axis promoted the polarization of microglia from the M1 to the M2 phenotype in vitro. Moreover, p38 MAPK and NF-κΒ were identified to be the downstream effect factors for FBXO10/RAGE axis. CONCLUSIONS: FBXO10 administration prevents CUS-induced behavioral despair, cognitive impairment, neuroinflammation, and the polarization of microglia through decreasing the accumulation of RAGE, p38 MAPK, and NF-κΒ, suggesting potential therapeutic strategies for the prevention and treatment of depression.

A randomised trial: effects of different anesthesia methods on early perioperative pain sensitivity and cellular immune function in patients undergoing radical mastectomy.

BACKGROUND: This study sought to investigate the effects of transversus thoracic muscle plane-pectoral nerves (TTP-PECS) block combined with propofol anesthesia on early perioperative pain sensitivity and cellular immune function in patients undergoing radical mastectomy. METHODS: A total of 115 patients who underwent radical mastectomy for breast cancer at our hospital from January 2019 to January 2021 were selected as the study subjects. The patients were allocated to the control group (n=57) or observation group (n=58) using a random number method. The control group was given simple general anesthesia, and the observation group was given TTP-PECS block combined with propofol anesthesia. The recovery time, pain [visual analogue scoring (VAS)] scores, and incidences of adverse reactions were compared between the 2 groups. Hemodynamic indicators [i.e., heart rate (HR), mean arterial pressure (MAP)], stress indicators [i.e., blood glucose (GLU), epinephrine (E), cortisol (Cor)], and the cellular immune function ofthe2 groups before anesthesia (T0), at the end of operation (T1), 1day after operation (T2) and 3days after operation (T3) were recorded. RESULTS: The spontaneous respiration recovery time, time to full wakefulness and the extubation time of the observation group were shorter than those of the control group (P<0.05). The observation group had lower VAS scores than the control group at 2, 8, 12, and 24 h after operation (P<0.05). The levels of MAP, HR, GLU, E and Cor in the observation group at T1, T2, and T3 were lower than those in the control group (P<0.05). Compared to the control group, the observation group had increased cluster of differentiation (CD)3+, CD4+, and CD4+/CD8+ cells (P<0.05), but there were no significant differences in CD8+ and natural killer (NK) cells between the 2 groups (P>0.05). The incidence of adverse reactions in the observation group was lower than that in the control group (8.62% vs. 24.56%) (P<0.05). CONCLUSIONS: TTP-PECS block combined with propofol anesthesia can relieve pain, shorten the recovery time, stabilize the hemodynamic level, and alleviate the stress responses of patients undergoing radical mastectomy with a slight suppression of cellular immune function and high safety. TRIAL REGISTRATION: Chinese Clinical Trial Registration Center ChiCTR2100048438.

Elevation of miR-146a Inhibits BTG2/BAX Expression to Ameliorate Postoperative Cognitive Dysfunction Following Probiotics (VSL#3) Treatment.

It has been reported that the gut microbiome modulates postoperative cognitive dysfunction (POCD), and that administration of probiotics (VSL#3) may effectively relieve POCD. In this study, we aimed to identify the underlying mechanism of VSL#3 in POCD. A mouse model of POCD was constructed in adult male C57BL/6 mice, which were then treated with VSL#3. VSL#3 exerted a protective role against POCD and resultant neuronal apoptosis. The expression of miR-146a was found to be downregulated in hippocampal tissues of POCD mice, while VSL#3 could restore its expression. Loss- and gain-function approaches were conducted to determine the roles of microRNA (miR)-146a, B-cell translocation gene 2 (BTG2), and Bcl-2-associated X protein (Bax) in post-operative effects on cognitive function and neuronal apoptosis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured to determine oxidative stress in brain tissue. The dual-luciferase reporter gene assay identified that miR-146a could target BTG2 and negatively regulate its expression. BTG2 knockdown suppressed neuronal apoptosis and contributed to shortened time of latency, prolonged time of mice spent in the target quadrant, and reduced oxidative stress through downregulating Bax expression. Finally, VSL#3 treatment upregulated the expression of miR-146a to block BTG2/Bax axis and consequently inhibited neuronal apoptosis and reduced oxidative stress in POCD mice. Taken together, the study suggested that miR-146a-mediated suppression of BTG2/Bax contributed to the protective role of probiotics treatment against POCD.

Integrated analysis of RNA-binding proteins in thyroid cancer.

Recently, the incidence of thyroid cancer (THCA) has been on the rise. RNA binding proteins (RBPs) and their abnormal expression are closely related to the emergence and pathogenesis of tumor diseases. In this study, we obtained gene expression data and corresponding clinical information from the TCGA database. A total of 162 aberrantly expressed RBPs were obtained, comprising 92 up-regulated and 70 down-regulated RBPs. Then, we performed a functional enrichment analysis and constructed a PPI network. Through univariate Cox regression analysis of key genes and found that NOLC1 (p = 0.036), RPS27L (p = 0.011), TDRD9 (p = 0.016), TDRD6 (p = 0.002), IFIT2 (p = 0.037), and IFIT3 (p = 0.02) were significantly related to the prognosis. Through the online website Kaplan-Meier plotter and multivariate Cox analysis, we identified 2 RBP-coding genes (RPS27L and IFIT3) to construct a predictive model in the entire TCGA dataset and then validate in two subsets. In-depth analysis revealed that the data gave by this model, the patient's high-risk score is very closely related to the overall survival rate difference (p = 0.038). Further, we investigated the correlation between the model and the clinic, and the results indicated that the high-risk was in the male group (p = 0.011) and the T3-4 group (p = 0.046) was associated with a poor prognosis. On the whole, the conclusions of our research this time can make it possible to find more insights into the research on the pathogenesis of THCA, this could be beneficial for individualized treatment and medical decision making.

Topiramate Reverses Physiological and Behavioral Alterations by Postoperative Cognitive Dysfunction in Rat Model Through Inhibiting TNF Signaling Pathway.

This study aimed to investigate the effects of topiramate (TPM) on rats with postoperative cognitive dysfunction (POCD) and elucidate the underlying mechanism. Differentially expressed genes in propofol-treated group and vehicle control group were filtered out and visualized in heatmap based on R program. POCD rat models were established for validation of TPM's anti-inflammatory action and Morris water maze (MWM) test was employed for assessment of spatial learning and memory ability of rats. Hematoxylin and eosin (HE) staining was applied to detect the neurodegeneration, and the apoptosis status was detected using TUNEL assay. In vitro, hippocampal microglia was treated with lipopolysaccharide or TPM to validate the TPM's anti-inflammatory action. Cell apoptosis was detected with flow cytometry. Inflammatory factors were detected by enzyme-linked immunosorbent assay, and factor-associated suicide (Fas), Fas-associated protein with death domain (FADD) expression were detected by western blot. As results, TPM administration improved the spatial learning and memory ability in POCD rat by decreasing the expression levels of Fas, FADD, and inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-1ß, IL-1ß; interleukin-6, IL-6) in POCD rats. In addition, TPM down-regulated cell apoptotic rate to suppress POCD by decreasing the expression of Caspase8, Bcl2-associated X (Bax), and poly ADP-ribose polymerase-1 (PARP1) yet enhancing B-cell lymphoma-2 (Bcl-2) expression. Besides, inhibition of Fas enhanced TPM-induced down-regulation of apoptosis of neuronal cell in hippocampus tissues of POCD rats. Our results revealed that treatment of POCD rats with TPM could suppress neuronal apoptosis in the hippocampus tissues, and the neuroprotective effects of TPM may relate with the regulation of tumor necrosis factor (TNF) signaling pathway.