The pathogenesis of acute lung injury (ALI), sepsis, and ulcerative colitis (UC) is closely interrelated. As inflammatory diseases, they are all characterized by the excessive production of inflammatory cytokines. Therefore, suppression of these cytokines represents a promising therapeutic strategy. Herein, we designed and synthesized a series of N-(4-(pyridin-4-yloxy)phenyl)-1,4-dihydropyridazine-3-carboxamide derivatives based on integrating three structural fragments relating to anti-inflammation. The anti-inflammatory activities of these compounds were evaluated in J774A.1 macrophages, and most compounds effectively inhibited interleukin-6 (IL-6) release in vitro. Compound z18 was identified as the most promising candidate and was further investigated for its dose-dependent effects. Preliminary mechanistic studies indicated that compound z18 suppresses c-Kit kinase activity and subsequently inhibits the NF-κB signaling pathway. z18 exhibited significant anti-inflammatory effects in vivo in LPS-induced ALI, sepsis, and UC mouse models. The preliminary drug-like properties of z18 were also evaluated. z18 demonstrated favorable stability in body fluid stability studies, and its favorable safety profile was further confirmed by subacute toxicity studies. In summary, this study offers novel insights into the design of anti-inflammatory agents and presents z18 as a promising candidate for the treatment of ALI, sepsis, and UC.

Myeloid differentiation factor 88 (MyD88) is a critical mediator of inflammatory signaling. However, the development of MyD88 inhibitors has been limited, and there are no reports on MyD88 degraders. Based on our previously identified MyD88 inhibitor c17 and employing a template-assisted modification strategy, we designed and synthesized 40 novel derivatives, and identified the optimal compound d21, which could inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway activation by facilitating the interaction between ring finger protein 126 (RNF126) (an E3 ubiquitin ligase) and MyD88, thereby promoting ubiquitination and subsequent degradation of MyD88. The subacute toxicity test indicated that d21 had good safety profile. Furthermore, it demonstrated significant anti-inflammatory effects in both cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) induced acute lung injury (ALI) models, effectively ameliorating ALI symptoms. These findings suggest that d21 holds considerable promise as a MyD88-targeting molecular glue degrader for the treatment of ALI.

BACKGROUND:Electroacupuncture (EA) is widely used for analgesia, but its central mechanisms remain unclear. We investigated whether EA alleviates neuropathic pain by suppressing metabotropic glutamate receptor 5 (mGluR5) signaling in the anterior cingulate cortex (ACC). METHODS:In naïve mice, we manipulated ACC pyramidal neurons using adeno-associated viral (AAV) vectors encoding calcium/calmodulin-dependent protein kinase II (CaMKII)-driven opsins-channelrhodopsin-2 (ChR2) or halorhodopsin (NpHR3.0)-followed by blue- or yellow-light stimulation to assess behavioral responses. In a chronic constriction injury (CCI) model, mice received EA and were evaluated for mechanical and thermal withdrawal thresholds. Western blotting (WB) and immunofluorescence (IF) quantified ACC mGluR5 expression. Then CaMKII-targeted adeno-associated viruses expressing chemogenetic receptors, such as hM3Dq or hM4Di, were injected into the ACC. Two weeks later, CCI was induced, and mice received either EA or intraperitoneal clozapine-N-oxide (CNO) while pain behaviors were monitored. Finally, proteomic profiling of ACC tissue compared CCI and EA groups. RESULTS:Optogenetic activation of ACC pyramidal neurons in naïve mice reduced both mechanical and thermal withdrawal thresholds, indicating a pronociceptive effect, whereas optogenetic inhibition increased thresholds. In CCI mice, EA significantly attenuated hypersensitivity and downregulated ACC mGluR5 protein levels by WB and IF. Chemogenetic inhibition of ACC pyramidal neurons similarly elevated thresholds in CCI mice, imitating EA. Notably, combining chemogenetic inhibition with EA produced no additional improvement, suggesting convergence on a common ACC mGluR5-dependent pathway. CONCLUSIONS:EA relieves neuropathic pain in mice, at least in part, by suppressing ACC pyramidal neuron activity via inhibition of mGluR5 signaling.

Background and Aims:Tubeless microlaryngoscopic surgery provides an unobstructed operative field, but carbon dioxide accumulation remains a concern during apnoea. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) maintains oxygenation but has limited capacity for carbon dioxide clearance. This study compared THRIVE combined with jet ventilation with THRIVE alone during tubeless vocal fold polyp surgery. Methods:In this single-blind randomised controlled trial, 100 adults undergoing microlaryngoscopic vocal fold polyp surgery were allocated to THRIVE alone (Group T) or THRIVE combined with jet ventilation (Group M). The primary endpoint was the change in transcutaneous carbon dioxide partial pressure (ΔPtcCO2) from the onset of apnoea to the end of surgery. Oxygenation, adverse events, conversion to tracheal intubation, and recovery characteristics were also assessed. Results:Compared with Group T, patients in Group M showed a markedly smaller ΔPtcCO2 (-0.56 ± 2.74 vs 10.98 ± 5.41 ± 5.41 mmHg; P < 0.001) and a lower end-of-surgery PtcCO2 (36.42 ± 2.13 vs 47.02 ± 6.16 mmHg; P < 0.001). Mild oxygen desaturation occurred more frequently in Group T than in Group M [7/50 (14%) vs 0/50 (0%); P = 0.019], whereas no patient in either group developed hypoxaemia or required tracheal intubation. Conclusion:Adding jet ventilation to THRIVE reduced intraoperative carbon dioxide accumulation during tubeless microlaryngoscopic vocal fold polyp surgery without increasing perioperative adverse events.

IntroductionPropofol-based sedation for gastroscopy is effective but may cause dose-dependent cardiorespiratory depression; therefore, optimizing adjunct strategies to reduce propofol exposure is clinically important.MethodsWe conducted a prospective, single-center, randomized, double-blind, dose-response trial to evaluate the propofol-sparing effect of remimazolam during procedural sedation for gastroscopy. A total of 150 ASA I-II adults aged 18–59 years were randomly assigned to receive remimazolam 0, 0.05, 0.1, 0.15, or 0.2 mg·kg−1, and propofol was titrated to achieve adequate sedation. The primary outcomes were the propofol effect-site EC50 and propofol requirement (mg·kg−1·min−1). Secondary outcomes included recovery profiles, post-anesthesia care unit (PACU) duration, and sedation-related adverse events.ResultsRemimazolam reduced the propofol EC50 in a dose-dependent manner, from 3.05 (95% CI, 2.88–3.21) μg·mL−1 at 0.05 mg·kg−1 to 1.47 (95% CI, 1.30–1.64) μg·mL−1 at 0.2 mg·kg−1, and decreased propofol requirement from 0.587 ± 0.193 mg·kg−1·min−1 in the control group to 0.414 ± 0.121 mg·kg−1·min−1 at 0.1 mg·kg−1 and 0.298 ± 0.088 mg·kg−1·min−1 at 0.2 mg·kg−1. Procedure duration and PACU duration did not differ significantly among groups, and the incidence of sedation-related adverse events was comparable.DiscussionAdjunctive remimazolam provided a dose-dependent propofol-sparing effect during gastroscopy sedation. Among the tested doses, 0.1 mg·kg−1 appeared to offer a favorable balance between reduced propofol requirement and recovery profile, supporting its clinical feasibility under the conditions studied.Clinical Trial RegistrationChinese Clinical Trial Registry, identifier ChiCTR2400094449.

Sepsis-associated encephalopathy (SAE) is a serious condition in which the immune system uncontrollably responds to infection, causing organ dysfunction. Neuroinflammation is one of the primary mechanisms underlying SAE. N6-methyladenosine (m6A) methylation is a common and reversible chemical modification of RNA molecules. Increasing evidence suggests that this modification plays a vital role in the inflammatory immune response. AlkB homolog 5 (ALKBH5) is an enzyme responsible for removing m6A modifications from RNA molecules and is known as a demethylase. However, the specific role of ALKBH5 in neuroinflammation remains unclear. To explore the role of ALKBH5 in neuroinflammation, researchers have used lipopolysaccharide (LPS) to induce inflammation in BV2 cells and mice. This study found that treatment of BV2 cells with LPS (1 μg/mL) significantly increased the total RNA m6A level and the ALKBH5 protein decreased significantly. Meanwhile, the NF-κB inflammatory signaling pathway was activated, leading to an obvious increase in IL-1β, IL-6, and TNF-α mRNA. The LPS-induced inflammatory response was alleviated when ALKBH5 was overexpressed in BV2 cells. This is due to a slower degradation rate of NFKBIA mRNA, an increase in NFKBIA protein levels, and inhibition of the NF-κB inflammatory signal pathway. When ALKBH5 was overexpressed in mice, as expected, there was an improvement in behavioral abnormalities induced by LPS. Compared to healthy volunteers, ALKBH5 mRNA levels were significantly decreased in peripheral blood mononuclear cells (PBMCs) from patients with sepsis and correlated with GCS and IL-6 levels. In summary, this study suggested that ALKBH5 is a potential therapeutic target for enhancing NFKBIA mRNA stability and alleviating neuroinflammation. Thus, ALKBH5 may provide new insights into the diagnosis and treatment of SAE.

Background: Ischemic stroke is a serious clinical condition that is challenging to cure; therefore, slowing down the depletion of ATP is crucial to enhancing the tolerance of ischemic tissue through preconditioning. Electroacupuncture (EA) preconditioning induces tolerance to cerebral ischemia; however, the underlying mechanism remains unclear. Objective: The P2×7 receptor (P2×7R) mediates the stimulation of microglial cells and is involved in the development of cerebral ischemia-reperfusion (I/R) damage. We hypothesized that the protective effect of EA preconditioning is associated with the downregulation of P2×7R expression. Methods: We performed EA at the ''Baihui'' and ''Fengfu'' for 30 min before establishing a rat model of cerebral I/R induced based on the middle cerebral artery occlusion model (MCAO). MCAO rats were administered a ventricular injection of 2 '(3′)-O-(4-benzoyl) adenosine triphosphate (BzATP), a P2×7R agonist, 30 min before EA. Neurologic scoring, infarction volume, and expression of cytokines, Bcl-2 and Bax, Iba1, P2×7R, p38, and phosphorylated p38 (p-p38) in ischemia penumbra were detected 24 h after cerebral I/R. Results: EA preconditioning ameliorated neurologic scoring, decreased infarction volume, and neuronal injury, and decreased cytokine release, while BzATP exacerbated cerebral I/R damage and inflammation events, unlike the favorable efficacy of EA. EA inhibited the expression of Iba-1, P2×7R, and p-p38/p38 in the ischemic penumbra, whereas BzATP reversed this effect. Conclusions: EA could induce cerebral tolerance to I/R damage by suppressing P2×7R expression and release of inflammatory factors.

Cerebral ischemia-reperfusion injury (CIRI) involves innate immunity activation in astrocytes and the inflammatory response. The interferon-induced transmembrane protein 3 (IFITM3) is an immune protein whose role in CIRI remains largely unexplored. This study investigated the role of IFITM3 in CIRI in mice. Adeno-associated virus (AAV)-mediated delivery of siRNA was used to inhibit IFITM3 expression, assessing effects on astrocyte activation, inflammatory cytokine expression. Primary cultured astrocytes were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to study IFITM3's role in vitro. Western blotting (WB) was employed to measure C-reactive protein (CRP) and IFITM3 levels, and enzyme-linked immunosorbent assay (ELISA) was used to quantify inflammatory cytokines. γ-Secretase activity, as well as Aβ40 and Aβ42 peptide levels, were measured to evaluate its activity. IFITM3 expression in astrocytes was significantly elevated following CIRI (p < 0.001), leading to increased γ-secretase activity and higher production of Aβ40 and Aβ42 peptides (p < 0.001). CRP levels were also upregulated in the context of IFITM3 expression (p < 0.01). Inhibiting IFITM3 expression via AAV-mediated delivery of siRNA significantly reduced astrocyte activation, inflammatory cytokine expression (p < 0.001 for IL-1β, IL-6, TNF-α, and IFN-γ), and improved neurobehavioral scores (p < 0.001). In vitro, IFITM3 inhibition significantly reduced the protein and mRNA levels of IFITM3, suppressed astrocyte activation, and decreased the expressions of inflammatory factors (p < 0.01). IFITM3 inhibition reduced the apoptosis of co-cultured neuronal cells (p < 0.01) and suppressed TLR4/NF-κB expression (p < 0.01), thereby attenuating the production of inflammatory factors. Inhibiting IFITM3 expression in astrocytes not only regulates γ-secretase activity but also mitigates neuroinflammation, thereby alleviating CIRI.

Objective:The aim of this study is to evaluate the effect of transcutaneous electrical acupoint stimulation (TEAS) during the perioperative period on the quality of postoperative recovery among patients undergoing pterygium excision. Methods:A total of 110 patients scheduled for unilateral pterygium excision were enrolled and randomly assigned in equal numbers to the TEAS group or the control group. In the TEAS group, patients received TEAS at the LI4 and PC6 acupoints, initiated 30 min before anesthesia induction and continued until the conclusion of surgery. In the control group, patients had electrode pads applied without active stimulation. Numerical Rating Scale (NRS) scores, State-Trait Anxiety Inventory (S-TAI) scores, and Quality of Recovery-40 Questionnaire (QoR-40) scores were collected from both groups. Results:No statistically significant differences were observed in baseline demographic and clinical characteristics between the two groups. At 24 h postoperatively, patients in the TEAS group demonstrated significantly higher QoR-40 scores and significantly lower NRS pain scores and postoperative SAI scores compared to the control group. Conclusion:TEAS was effective in reducing postoperative pain and anxiety levels while enhancing the quality of postoperative recovery in patients undergoing pterygium surgery. Clinical trial registration:https://www.chictr.org.cn, identifier ChiCTR2200056062.

This study aimed to investigate the relationship between the unique weather change and acute ischemic stroke (AIS) in the southern Zhejiang Province of China and to provide evidence for better predicting and preventing stroke. We retrospectively collected 14,996 ischemic stroke patients data and weather data from January 2019 to December 2021 in the southern Zhejiang Province of China. The correlation and risk between meteorological factors and the number of AIS daily cases were calculated. Wilcoxon rank sum test was used to calculate the difference in the number of cases between typhoon-affected and non-affected periods. A prediction model obeying Poisson regression was established, and the accuracy of the correlation factors in predicting the number of cases was verified. In southern Zhejiang Province, the number of AIS was the highest in summer and the lowest in spring. Stroke onset is associated with temperature, water vapor pressure and typhoons (P < 0.05). The presence of typhoon (RR 0.882; 95

Background: Postoperative high-activity delirium (PDHA) manifests as a high alertness, restlessness, hallucinations, and delusions. Occurrence of PDHA represents an increased risk of poor prognosis for patients. Objective: To establish and validate a nomogram prediction model for high-activity delirium after non-cardiac surgery in a post- anesthesia care unit (PACU). Methods: This study retrospectively enrolled adult patients who underwent non-cardiac surgery and were observed in the PACU as training data. Patients were divided into PDHA (199 patients) and non-PDHA (396 patients) groups. Patients' general data, preoperative indicators, intraoperative conditions, and postoperative PACU conditions were collected. The risk factors for PDHA were identified using univariate and multivariate logistic regression analyses. A predictive column chart was created using R language. Adult patients who underwent non-cardiac surgery and entered the PACU for observation were randomly selected as the validation set data (198 cases) for model performance validation. Results: The incidence rate of adult PDHA in the PACU was 0.275%. Sex, age, smoking history, low preoperative albumin level, Society of Anesthesiologists (ASA) classification, anesthesia duration, and postoperative PACU pain score were independent risk factors for hyperactive delirium in PACU adults. In this study, an adult PACU PDHA nomogram prediction model was developed. The training dataset verified that the ROC curve (area under the curve) and 95% confidence interval (95% CI) were 0.936 (0.917-0.955). The ROC curve of the validation data row showed that the area under the curve and 95% CI were 0.926 (0.885-0.967). Conclusion: The nomogram predictive model for PACU adult high-activity delirium constructed in this study showed good predictive performance. This model could enable the visualization and graphical prediction of adult high-activity delirium occurrence after PACU, which has clinical value.

Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, is often used to treat lactic acidosis and malignant tumors. Increasing studies have shown that DCA has neuroprotective effects. Here, we explored the role and mechanism of DCA in Sepsis associated encephalopathy (SAE). Single-cell analysis was used to determine the important role of PDK4 in SAE and identify the cell type. GO and GSEA analysis were used to determine the correlation between DCA and pyroptosis. Through LPS + ATP stimulation, a microglia pyroptosis model was established to observe the expression level of intracellular pyroptosis-related proteins under DCA intervention, and further detect the changes in intracellular ROS and JC-1. Additionally, a co-culture environment of microglia and neuron was simply constructed to evaluate the effect of DCA on activated microglia-mediated neuronal apoptosis. Finally, Novel object recognition test and the Morris water maze were used to explore the effect of DCA on cognitive function in mice from different groups after intervention. Based on the above experiments, this study concludes that DCA can improve the ratio of peripheral and central M1 macrophages, inhibit NLRP3-mediated pyroptosis through ROS and mitochondrial membrane potential (MMP). DCA can reduce neuron death caused by SAE and improve cognitive function in LPS mice. In SAE, DCA may be a potential candidate drug for the treatment of microglia-mediated neuroinflammation.

Background The aim of this study was to identify the risk factors for postoperative delirium (POD) in elderly patients undergoing heart valve surgery with cardiopulmonary bypass (CPB). Methods Elderly patients undergoing elective heart valve surgery with CPB in The First Affiliated Hospital of Wenzhou Medical University between March 2022 and March 2023 were selected for this investigation. They were divided into a POD group and a non-POD group. Their baseline information was collected and recorded, and the patients were subjected to neurocognitive function assessment using the Mini-Mental State Examination and the Montreal Cognitive Assessment scales before surgery. We also recorded their intraoperative indicators such as duration of surgery, duration of CPB, duration of aortic cross-clamp, blood transfusion, and postoperative indicators such as duration of mechanical ventilation, postoperative 24-hour drainage volume, and pain score. Regional cerebral oxygen saturation was monitored intraoperatively by near-infrared spectroscopy based INVOS5100C Regional Oximeter. Patients were assessed for the occurrence of POD using Confusion Assessment Method for the Intensive Care Unit, and logistic regression analysis of risk factors for POD was performed. Results The study finally included 132 patients, with 47 patients in the POD group and 85 ones in the non-POD group. There were no significant differences in baseline information and preoperative indicators between the two groups. However, marked differences were identified in duration of surgery, duration of CPB, duration of aortic cross-clamp, duration of postoperative mechanical ventilation, postoperative length of stay in cardiac intensive care unit, postoperative length of hospital stay, intraoperative blood transfusion, postoperative pain score, and postoperative 24-hour drainage volume between the two groups ( p < 0.05). Additionally, the two groups had significant differences in rScO 2 at each intraoperative time point and in the difference of rScO 2 from baseline at each intraoperative time point ( p < 0.05). Multivariate logistic regression analysis showed that duration of surgery > 285 min (OR, 1.021 [95% CI, 1.008–1.035]; p = 0.002), duration of postoperative mechanical ventilation > 23.5 h (OR, 6.210 [95% CI, 1.619–23.815]; p = 0.008), and postoperative CCU stay > 3.5 d (OR, 3.927 [95% CI, 1.046–14.735]; p = 0.043) were independent risk factors of the occurrence of POD while change of rScO 2 at T 1 >50.5 (OR, 0.832 [95% CI 0.736–0.941]; p = 0.003) was a protective factor for POD. Conclusion Duration of surgery duration of postoperative mechanical ventilation and postoperative CCU stay are risk factors for POD while change of rScO 2 at T 1 is a protective factor for POD in elderly patients undergoing heart valve surgery with CPB.

BACKGROUND Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery. The effects of transcutaneous electrical acupoint stimulation (TEAS) remain unclear. AIM To explore the potential effects of TEAS on the recovery of gastrointestinal function after gastrectomy and colorectal resection. METHODS Patients scheduled for gastrectomy or colorectal resection were randomized at a 2:3:3:2 ratio to receive: (1) TEAS at maximum tolerable current for 30 min immediately prior to anesthesia induction and for the entire duration of surgery, plus two 30-min daily sessions for 3 consecutive days after surgery (perioperative TEAS group); (2) Preoperative and intraoperative TEAS only; (3) Preoperative and postoperative TEAS only; or (4) Sham stimulation. The primary outcome was the time from the end of surgery to the first bowel sound. RESULTS In total, 441 patients were randomized; 405 patients (58.4 +/- 10.2 years of age; 247 males) received the planned surgery. The time to the first bowel sounds did not differ among the four groups (P = 0.90; log-rank test). On postoperative day 1, the rest pain scores differed significantly among the four groups (P = 0.04; Kruskal-Wallis test). Post hoc comparison using the Bonferroni test showed lower pain scores in the perioperative TEAS group (1.4 +/- 1.2) than in the sham sti-mulation group (1.7 +/- 1.1; P = 0.04). Surgical complications did not differ among the four groups. CONCLUSION TEAS provided analgesic effects in adult patients undergoing major abdominal surgery, and it can be added to clinical practice as a means of accelerating postoperative rehabilitation of these patients.

ABSTRACT Sepsis-induced cardiomyopathy (SIC) is one of the most common complications of infection-induced sepsis. An imbalance in inflammatory mediators is the main factor leading to SIC . N 6 -methyladenosine (m 6 A) is closely related to the occurrence and development of sepsis. N 6 -methyladenosine reader YTH domain containing 1 (YTHDC1) is an m 6 A N 6 -methyladenosine recognition protein. However, the role of YTHDC1 in SIC remains unclear. Herein, we demonstrated that YTHDC1-shRNA inhibits inflammation, reduces inflammatory mediators, and improves cardiac function in a LPS-induced SIC mouse model. Based on the Gene Expression Omnibus database analysis, serine protease inhibitor A3N is a differential gene of SIC. Furthermore, RNA immunoprecipitation indicated that serine protease inhibitor A3N (SERPINA3N) mRNA can bind to YTHDC1, which regulates the expression of SERPINA3N. Serine protease inhibitor A3N–siRNA reduced LPS-induced inflammation of cardiac myocytes. In conclusion, the m 6 A reader YTHDC1 regulates SERPINA3N mRNA expression to mediate the levels of inflammation in SIC. Such findings add to the relationship between m 6 A reader YTHDC1 and SIC, providing a new research avenue for the therapeutic mechanism of SIC.

Background: We studied AKI incidence and prognosis in cardiac surgery patients under and over 60 years old.Methods: We studied AKI in patients who underwent cardiac surgery at the First Affiliated Hospital of Wenzhou Medical University between Jan 2020 and Dec 2021, using improved global prognostic criteria for diagnosis.Results: After analyzing 781 patients (402 males, 379 females), AKI incidence after surgery was 30.22 %. Adjusting for propensity scores revealed no significant difference in AKI incidence between young males (24.1 %) and females (19.3 %). However, young females had higher AKI stages. Among older patients, AKI incidence was comparable between males (43.4 %) and females (42.2 %), but females had longer intubation times. Independent risk factors for AKI included age, male gender, and BMI, while intraoperative hemoglobin level was protective.Conclusions: No gender gap in AKI frequency for <60 years old and >= 60 years old post-cardiac surgery, yet women display increased AKI severity and extended intubation duration.

Background: Postoperative nausea and vomiting (PONV) is one of the most common complications after general anesthesia. The traditional comprehensive management of PONV usually uses one or two drugs, but this regimen fails to meet the requirements of the latest version of PONV guidelines. The purpose of this study was to evaluate the effect of transcutaneous electrical acupoint stimulation (TEAS) on high-risk PONV patients who are undergoing laparoscopic gynecological surgery. Methods: In total, 162 high-risk PONV patients were randomly divided into an experimental group (n = 81) and a control group (n = 81). Both groups were injected with 4 mg of dexamethasone and 0.25 mg of palonosetron. In the experimental group, Nei-guan (PC6) and He-gu (LI4) were stimulated by a transcutaneous acupoint electrical stimulation instrument (HANS200E) 30 min before the surgery. The control group also received electrodes but no stimulation. Variance analysis and rank sum test were used to compare the differences between the two groups. Results: The results of the incidence of postoperative nausea, vomiting, NRS score, degree of abdominal distension, and time to first flatus in the experimental group were lower than those in the control group. Nursing satisfaction of the experimental group was higher than that of the control group. Conclusions: The study demonstrates that TEAS combined with dexamethasone and palonosetron can effectively prevent PONV, reduce postoperative abdominal distension and postoperative pain, and shorten the first postoperative flatus time in high-risk patients with PONV. At the same time, it can improve nursing satisfaction.

Neuroinflammation mediated by microglial pyroptosis is an important pathogenic mechanism of septic encephalopathy (SAE). It has been reported that TRIM45 is associated with tumours and inflammatory diseases. However, the role of TRIM45 in SAE and the relationship between TRIM45 and microglial pyroptosis are unknown. In this study, we found that TRIM45 played an important role in regulating microglial pyroptosis and the molecular mechanism. SAE was induced by intraperitoneal injection of LPS in WT and AAV-shTRIM45 mice. BV2 cells were treated with LPS/ATP in vitro. Cognitive function was assessed by the Morris water maze. Nissl staining was used to evaluate histological and structural lesions. ELISA was used to dectect neuroinflammation. qPCR was used to detect the mRNA levels of inflammatory cytokines, NLRP3, and autophagy genes. Western blotting and immunofluorescence analysis were used to analyse the expression of the proteins. Changes in reactive oxygen species (ROS) in cells were observed by flow cytometry. Changes in mitochondrial membrane potential in BV2 cells were detected by JC-1 staining. Peripheral blood mononuclear cells were extracted from blood by density gradient centrifugation and then used for qPCR, western blotting and flow detection. To further explore the mechanism, we used the overexpression plasmids TRIM45 and Atg5 as well as siRNA-TRIM45 and siRNA-Atg5 to analyse the downstream pathway of NLRP3. The protein and mRNA levels of TRIM45 in peripheral blood mononuclear cells from sepsis patients were examined. Knocking down TRIM45 protected against neuronal damage and cognitive impairment in septic mice. TRIM45 knockdown inhibited microglial pyroptosis and the secretion of inflammatory cytokines in vivo and in vitro, which was mediated by NLRP3/Gsdmd-N activation. Overexpression of TRIM45 could activate NLRP3 and downstream proteins. Further examination showed that TRIM45 regulated the activation of NLRP3 by altering Atg5 and regulating autophagic flux. It was also found that overexpression and knockdown of TRIM45 affected the changes in ROS and mitochondrial membrane potential. Thus, knocking down TRIM45 could reduce microglial pyroptosis, the secretion of proinflammatory cytokines, and neuronal damage and improve cognitive function. In addition, the level of TRIM45 protein in septic patients was increased. There was a positive linear correlation between APACHE II score and TRIM45, between SOFA score and TRIM45. Compared to group GCS > 9, level of TRIM45 were increased in group GCS ≤ 8. TRIM45 plays a key role in neuroinflammation caused by LPS, and the mechanism may involve TRIM45-mediated exacerbation of microglial pyroptosis via the Atg5/NLRP3 axis.

BACKGROUND: Glycogen synthase kinase-3β (GSK3β), fat mass and obesity-associated protein (FTO), and toll-like receptors 4 (TLR4) take on critical significance in different biological processes, whereas their interactions remain unclear. The objective was the investigation of the interaction effect in cerebral ischemia-reperfusion (I/R) injury. METHODS: The function of the cerebral cortex in the mouse middle cerebral artery occlusion (MCAO) model (each group n = 6) and P12 cells oxygen-glucose deprivation/reoxygenation (OGD/R) model was analyzed using short hairpin GSK3β lentivirus and overexpression of FTO lentivirus (in vitro), TLR4 inhibitor (TAK242), and LiCl to regulate GSK3β, FTO, TLR4 expression, and GSK3β activity, respectively. RESULTS: After GSK3β knockdown in the OGD/R model of PC12 cells, the levels of TLR4 and p-p65 were lower than in the control, and the level of FTO was higher than in the control. Knockdown GSK3β reversed the OGD/R-induced nuclear factor kappa-B transfer to the intranuclear nuclei. As indicated by the result, TLR4 expression was down-regulated by overexpressed FTO, and TLR4 expression was up-regulated notably after inhibition of FTO with the use of R-2HG. After the inhibition of the activity of GSK3β in vivo, the reduction of FTO in mice suffering from MCAO was reversed. CONCLUSIONS: Our research shows that GSK3β/FTO/TLR4 pathway contributes to cerebral I/R injury.

The sleep disturbance in cancer patients is more prevalent, and it significantly affects these patients’ recovery after the operation. However, the clinical characteristics regarding sleep quality are scarce. This study aimed to evaluate the quality of preoperative sleep quality and its risk factors in different cancer patients requiring elective surgery. Cancer patients who were scheduled for elective surgery were selected. The demographic data, basic preoperative diseases, and factors related to the preoperative hospital environment were also recorded. Self-made questionnaires (such as gender, age, and personal history), and the Anxiety Self-Assessment Scale were used to assess the patient's underlying condition. The modified Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the preoperative sleep status. A total of 297 patients completed the investigation. The incidence of preoperative sleep disturbance in cancer patients was 47.8