ObjectiveThis paper aims to investigate the effects of Xixintang on aquaporin-4 （AQP4） polarity distribution， blood-brain barrier （BBB） function， and neuroinflammationin rats with Alzheimer's disease （AD）， thereby revealing the potential mechanism through which this formula protects the BBB by regulating AQP4 polarization. The aim is to provide a scientific basis for clinical treatment. MethodsSixty Sprague-Dawley （SD） rats were randomly divided into a normal group， a model group， a probiotic group， a donepezil group， and an Xixintang group. The model was established by intraperitoneal injection of D-galactose （D-Gal） combined with bilateral intracerebroventricular injection of amyloid-β_25-35 （Aβ_25-35）. The probiotic group （30.85 mg·kg^-1）， donepezil group （0.88 mg·kg^-1）， and Xixintang group （1.174 g·kg^-1） received daily gavage administration， while the normal and model groups received intragastric administration with an equal volume of normal saline for one month. Cognitive ability was assessed by using the Morris water maze. BBB permeability was detected via Evans blue extravasation. The contents of interleukin-6 （IL-6）， amyloid-β_1-42 （Aβ_1-42）， and tumor necrosis factor-α （TNF-α） in the hippocampal tissues were measured by enzyme-linked immunosorbent assay （ELISA）. The protein expressions of zonula occludens-1 （ZO-1）， occludin， tissue inhibitor of metalloproteinase-1 （TIMP-1）， matrix metalloproteinase-9 （MMP-9）， and AQP4 in the hippocampal tissues were detected by western blot. The expression and co-localization levels of Aβ_1-42， ionized calcium-binding adapter molecule 1 （IBA1）， and AQP4/platelet endothelial cell adhesion molecule 31 （CD31） in the hippocampal region were examined by immunofluorescence. ResultsCompared with the normal group， the model group exhibited a significant decline in cognitive ability （P<0.01） and a marked increase in Evans blue extravasation in the brain （P<0.01）. The expressions of ZO-1， occludin， and TIMP-1 were significantly decreased （P<0.01）， while the expressions of AQP4 and MMP-9 were significantly increased （P<0.01）. The co-localization level of AQP4/CD31 was significantly reduced （P<0.01）， and the expressions of Aβ_1-42， IL-6， TNF-α， and IBA1 were significantly elevated （P<0.01）. Compared with the model group， the Xixintang group showed significant improvement in cognitive ability （P<0.01） and a significant reduction in Evans blue extravasation in the brain （P<0.01）. The expressions of occludin， TIMP-1， and ZO-1 were significantly increased （P<0.05， P<0.01）， while the expressions of AQP4 and MMP-9 were significantly decreased （P<0.05）. The co-localization level of AQP4/CD31 was significantly enhanced （P<0.01）， and the expressions of Aβ_1-42， IL-6， TNF-α， and IBA1 were significantly reduced （P<0.05， P<0.01）. ConclusionXixintang may improve cognitive function and alleviate AD pathology in AD model rats by regulating AQP4 polarity distribution， thereby breaking the vicious cycle of "Aβ deposition-neuroinflammation-BBB damage" and restoring the homeostasis of the microenvironment in the brain.

ObjectiveThis study aims to investigate whether Xixintang could ameliorate cognitive dysfunction in an Alzheimer's disease （AD） rat model induced by D-galactose and β-amyloid （Aβ_25-35）， by means of repairing the colonic mucosal barrier， regulating the Toll-like receptor 4 （TLR4）/nuclear factor-κB p65 （NF-κB p65） signaling pathway， and intervening in the pathological process mediated by the gut-brain axis. MethodsSixty specific pathogen-free （SPF） male Sprague-Dawley （SD） rats were randomly divided to five groups （n=12）： A control group， a model group， a donepezil group， an Xixintang group， and a probiotic group. Except for those in the control group， rats in all other groups received daily intraperitoneal injections of D-galactose for six consecutive weeks. Subsequently， aggregated Aβ_25-35 was injected stereotactically into the bilateral ventricles to establish the AD model. During the intervention periods， the rats in all groups were administered their respective drugs and normal saline by gavage. The Morris water maze test was used to assess the capacity for spatial learning and memory. Hematoxylin-eosin （HE） staining was employed to observe the histopathological changes in the colon tissues. Immunofluorescence was used to detect Aβ_1-41 deposition in the hippocampal region and Mucin 2 （MUC2） expression in the colonic mucosa. Western blot was performed to measure the protein expression levels of FFAR2，TLR4， NF-κB p65， occludin （OCLN）， zonula occludens-1 （ZO-1）， and MUC2 in the colonic tissues. Enzyme-linked immunosorbent assay （ELISA） was used to determine the contents of interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， serum amyloid A （SAA）， and Aβ_1-42 in the hippocampal region from the colonic tissues. The lipopolysaccharide （LPS） concentrations in colon tissues of rats were measured by using a dynamic chromogenic limulus assay. ResultsCompared with those in the control group， the rats in the model group exhibited a significantly prolonged escape latency and a markedly shorter duration in the target quadrant （P<0.01）. The integrity of the colonic mucosal structure was compromised， with disordered gland arrangement and a reduced number of goblet cells. The Aβ_1-42 deposition in the hippocampal region was significantly increased （P<0.01）. The protein expression levels of TLR4 and NF-κB p65 in colonic tissues were significantly upregulated （P<0.01）， while those of occludin and ZO-1 were downregulated （P<0.01）. The contents of inflammatory factors such as IL-6， TNF-α， and SAA were significantly elevated （P<0.01）， and the LPS level in the serum was markedly increased （P<0.01）. In comparison to those in the model group， the rats in the Xixintang group showed a significantly shortened escape latency and a prolonged duration in the target quadrant （P<0.01）. The colonic mucosal structure was ameliorated， with neat gland arrangement and an increased number of goblet cells. The Aβ_1-42 deposition in the hippocampal region was reduced （P<0.01）. The protein expressions of TLR4 and NF-κB p65 in the colon tissues were decreased （P<0.05，P<0.01）， while the protein levels of occludin and ZO-1 were increased （P<0.01）. The contents of IL-6， TNF-α， and serum amyloid A （SAA） were decreased （P<0.01）， and the LPS level was reduced （P<0.01）. ConclusionXixintang can significantly ameliorate cognitive dysfunction of AD model rats， by means of restoring the colonic mucosal barrier structure， reducing cerebral Aβ deposition， and suppressing peripheral and central inflammatory response. Its mechanism of action may be closely associated with the suppression of the TLR4/NF-κB signaling pathway activation， reduction of endotoxin levels， and regulation of the gut-brain axis.

ObjectiveThis study aims to investigate whether Xixintang could ameliorate cognitive dysfunction in an Alzheimer's disease （AD） rat model induced by D-galactose and β-amyloid （Aβ_25-35）， by means of repairing the colonic mucosal barrier， regulating the Toll-like receptor 4 （TLR4）/nuclear factor-κB p65 （NF-κB p65） signaling pathway， and intervening in the pathological process mediated by the gut-brain axis. MethodsSixty specific pathogen-free （SPF） male Sprague-Dawley （SD） rats were randomly divided to five groups （n=12）： A control group， a model group， a donepezil group， an Xixintang group， and a probiotic group. Except for those in the control group， rats in all other groups received daily intraperitoneal injections of D-galactose for six consecutive weeks. Subsequently， aggregated Aβ_25-35 was injected stereotactically into the bilateral ventricles to establish the AD model. During the intervention periods， the rats in all groups were administered their respective drugs and normal saline by gavage. The Morris water maze test was used to assess the capacity for spatial learning and memory. Hematoxylin-eosin （HE） staining was employed to observe the histopathological changes in the colon tissues. Immunofluorescence was used to detect Aβ_1-41 deposition in the hippocampal region and Mucin 2 （MUC2） expression in the colonic mucosa. Western blot was performed to measure the protein expression levels of FFAR2，TLR4， NF-κB p65， occludin （OCLN）， zonula occludens-1 （ZO-1）， and MUC2 in the colonic tissues. Enzyme-linked immunosorbent assay （ELISA） was used to determine the contents of interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， serum amyloid A （SAA）， and Aβ_1-42 in the hippocampal region from the colonic tissues. The lipopolysaccharide （LPS） concentrations in colon tissues of rats were measured by using a dynamic chromogenic limulus assay. ResultsCompared with those in the control group， the rats in the model group exhibited a significantly prolonged escape latency and a markedly shorter duration in the target quadrant （P<0.01）. The integrity of the colonic mucosal structure was compromised， with disordered gland arrangement and a reduced number of goblet cells. The Aβ_1-42 deposition in the hippocampal region was significantly increased （P<0.01）. The protein expression levels of TLR4 and NF-κB p65 in colonic tissues were significantly upregulated （P<0.01）， while those of occludin and ZO-1 were downregulated （P<0.01）. The contents of inflammatory factors such as IL-6， TNF-α， and SAA were significantly elevated （P<0.01）， and the LPS level in the serum was markedly increased （P<0.01）. In comparison to those in the model group， the rats in the Xixintang group showed a significantly shortened escape latency and a prolonged duration in the target quadrant （P<0.01）. The colonic mucosal structure was ameliorated， with neat gland arrangement and an increased number of goblet cells. The Aβ_1-42 deposition in the hippocampal region was reduced （P<0.01）. The protein expressions of TLR4 and NF-κB p65 in the colon tissues were decreased （P<0.05，P<0.01）， while the protein levels of occludin and ZO-1 were increased （P<0.01）. The contents of IL-6， TNF-α， and serum amyloid A （SAA） were decreased （P<0.01）， and the LPS level was reduced （P<0.01）. ConclusionXixintang can significantly ameliorate cognitive dysfunction of AD model rats， by means of restoring the colonic mucosal barrier structure， reducing cerebral Aβ deposition， and suppressing peripheral and central inflammatory response. Its mechanism of action may be closely associated with the suppression of the TLR4/NF-κB signaling pathway activation， reduction of endotoxin levels， and regulation of the gut-brain axis.

Objective To explore the potential causal relationship between occupational pneumoconiosis (hereinafter referred to as "pneumoconiosis") and five mental disorders (depression, bipolar disorder, schizophrenia, insomnia and anxiety) using the two-sample Mendelian randomization (MR) method. Methods Single nucleotide polymorphisms (SNPs) loci associated with pneumoconiosis and five mental disorders were screened from Genome-Wide Association Studies. Inverse variance weighting (IVW), weighted median (WM) and MR-Egger regression methods were used to evaluate the significance of the causal relationship between pneumoconiosis and five mental disorders. Sensitivity analysis was used to evaluate the accuracy and reliability of the research results. Results After matching data of pneumoconiosis and the five mental disorders, 16 SNPs were ultimately included as instrumental variables in this study. The result of MR analysis revealed a positive causal relationship between pneumoconiosis and both depression [IVW: odds ratio (OR) and 95% confidence interval (CI) was 1.017 (1.000-1.035), P<0.05] and bipolar disorder [IVW: OR(95%CI)was 1.046(1.009-1.083), P<0.05; WM: OR (95%CI) was 1.055(1.007-1.105), P<0.05]. Result of sensitivity analysis indicated there was no heterogeneity and horizontal pleiotropy in the above results. There was no causal association observed between pneumoconiosis and schizophrenia, insomnia, or anxiety disorders (all P>0.05). Conclusion This study provides genetic evidence supporting a positive causal relationship between pneumoconiosis and both depression and bipolar disorder.

BACKGROUND: This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate. RESULTS: A total of 409 patients, 65.0% ( n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% ( n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 10 9 /L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 10 9 /L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs. CONCLUSIONS A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Lung Neoplasms/metabolism* ; Aged ; B7-H1 Antigen/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; Adult ; Aged, 80 and over ; Immune Checkpoint Inhibitors/therapeutic use*

Acute lung injury (ALI) is a severe disease caused by viral infection that triggers an uncontrolled inflammatory response. This study investigated the capacity of jasurolignoside (JO), a natural compound, to bind to Toll-like receptor 4 (TLR4) and treat ALI. The anti-inflammatory properties of JO were evaluated in vitro through Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and co-immunoprecipitation. The investigation utilized a lipopolysaccharide (LPS)-induced ALI animal model to examine the therapeutic efficacy and mechanism of JO in vivo. JO attenuated inflammatory symptoms in infected cells and tissues by modulating the NOD-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome and the nuclear factor κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathway. Molecular docking simulations revealed JO binding to TLR4 active sites, confirmed by cellular thermal shift assay. Surface plasmon resonance (SPR) demonstrated direct interaction between JO and TLR4 with a Kd value of 35.1 μmol·L^-1. Moreover, JO inhibited tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 secretion and reduced leukocyte, neutrophil, lymphocyte, and macrophage infiltration in ALI-affected mice. JO also enhanced lung function and reduced ALI-related mortality. Immunohistochemical staining demonstrated JO's ability to suppress TLR4 expression in ALI-affected mouse lung tissue. This study establishes that JO can bind to TLR4 and effectively treat ALI, indicating its potential as a therapeutic agent for clinical applications.
Toll-Like Receptor 4/chemistry* ; Animals ; Acute Lung Injury/chemically induced* ; Mice ; Humans ; Ilex/chemistry* ; Molecular Docking Simulation ; Male ; NF-kappa B/immunology* ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology* ; Tumor Necrosis Factor-alpha/genetics* ; Interleukin-1beta/genetics* ; RAW 264.7 Cells ; Disease Models, Animal

Objective: To explore the relationship between related factors of non-suicidal self-injury behavior (NSSI) among middle school students in Guizhou Province, so as to provide the evidence for preventing high risk behaviors in adolescents. Methods: A stratified cluster random sampling method was used to select 1 034 junior and senior middle school students from Zunyi City, Qiannan Prefecture and Tongren City in Guizhou Province from April to October in 2023. Questionnaire survey was conducted to collect information including Adolescent Self injury Scale and Family Assessment Device. The R 4.4.1 software was employed for network analysis visualization, centrality indicators, and result stability assessment. Results: The detection rate of NSSI behavior among middle school students in Guizhou province was 29.6%, with a detection rate of 25.5% for boys and 33.1% for girls, showing a statistically significant difference ( χ 2=7.07, P <0.05). There were statistically significant differences in scores of emotional communication, egoism, family rules, positive communication, problem solving, expression of positive emotions and management of negative emotions self-efficacy, and bullying victimization in various dimensions between middle school students with and without NSSI ( Z =-13.66 to -7.05, P <0.01). NSSI among middle school students was positively correlated with social/relational bullying, depression and anxiety, and there were relatively close connections in the network ( r =0.35, 0.43, 0.42, P <0.01). Centrality indicators showed that the highest in strength and closeness centrality were stress ( Z =1.29, 1.58), the highest in betweenness centrality was for emotional communication ( Z =1.91), and the highest in expected influence index was for physical bullying ( Z =1.44)( P < 0.05). Conclusions Stress, emotional communication and physical bullying have significant impacts in the network of factors related to NSSI. Social/relational bullying, depression and anxiety have strong direct correlations with NSSI behavior among middle school students.

Objective To analyze the influencing factors and action paths of frailty in elderly patients with col-orectal cancer,so as to provide a theoretical clinical intervention.Methods A convenience sampling method was adopted.A total of 254 elderly patients with colorectal cancer who were scheduled for elective surgery in a tertiary A hospital in Shanxi Province from March 2023 to September 2024 were selected as the research subjects.General information questionnaires,Fried frailty phenotype,Perceived Ageism Scale,Multidimensional Assessment Scale of In-teroceptive Awareness Version 2-Chinese,Cancer Patient Self-Management Assessment Scale,and Anderson Symptom Inventory were used for the investigation,and a structural equation model was constructed.Results The incidence of frailty in elderly colorectal cancer patients before surgery is 38.98％.Anderson Symptom Assessment and Per-ceived Ageism were positively correlated with frailty(r=0.534,0.568,P＜0.01),while interoceptive sensitivity and the self-management level were negatively correlated with frailty(r=-0.444,-0.659,P＜0.01).Self-management behavior had only a direct effect on patients' frailty(β=-0.349,P＜0.001),while Anderson Symptom Assessment,perceived age discrimination and interoceptive sensitivity had both direct and indirect effects on patients' frailty(direct effects β=0.235,0.287,-0.220;indirect effects β=0.147,0.090,-0.113;all P＜0.001).Conclusion The incidence of frailty in elderly patients with colorectal cancer before surgery is high.Attention should be paid to patients who are elderly,female and have a low level of education.Medical staff can take targeted measures to enhance patients' interocep-tive concentration and stability,so that patients can better monitor and regulate their bodies and emotions,and im-prove their health-promoting decisions and behaviors.At the same time,attention should also be paid to the prob-lem of age discrimination to create a good medical environment for patients.

Objective:To evaluate the effect of trans-nasal humidified rapid insufflation ventilatory exchange (THRIVE) on the early postoperative atelectasis in patients undergoing prolonged non-intubated intravenous anesthesia for gastrointestinal endoscopic procedures.Methods:In this randomized double-blind controlled trial, 150 patients of either sex, aged 18-80 yr, with American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ and body mass index of 18-30 kg/m 2, scheduled for endoscopic mucosal resection of multiple colorectal polyps at Northern Jiangsu People′s Hospital Affiliated to Yangzhou University from February 18 to June 15, 2024, were divided into 2 groups ( n=75 each) using simple random allocation: THRIVE group (group T) and conventional oxygen therapy group (group C). In group T, the oxygen flow rate was 10 L/min before anesthesia induction and increased to 50 L/min after induction until the end of operation, and the inhaled oxygen concentration was 100%. Group C used conventional mask oxygen inhalation, with an oxygen flow rate of 10 L/min during anesthesia induction and maintenance. Lung ultrasonography was performed immediately before anesthesia induction and after the end of surgery, and the modified lung ultrasound score and diaphragm mobility during quiet breathing were recorded to assess the occurrence of atelectasis and diaphragmatic dysfunction. The lowest intraoperative SpO 2 value, adverse events during surgery and in the postanesthesia care unit (PACU), duration of PACU stay, adverse events within 7 days after operation, hospitalization duration, and satisfaction scores of both patients and endoscopists were recorded. Results:Compared with group C, the postoperative modified lung ultrasound score and incidence of atelectasis and diaphragmatic dysfunction were significantly decreased, the lowest intraoperative SpO 2 value was increased, the incidence of hypoxemia was decreased, the duration of PACU stay was shortened, and endoscopists′ satisfaction scores were increased ( P<0.05), and no statistically significant changes were observed in diaphragm mobility, incidence of other intraoperative adverse events, incidence of adverse events during PACU stay and within 7 days after operation, or patients′ satisfaction scores in group T ( P>0.05). Conclusions:THRIVE can reduce the risk of early postoperative atelectasis and intraoperative hypoxemia, thereby promoting postoperative recovery of patients undergoing gastrointestinal endoscopy under long-term non-intubated anesthesia.

Objective:To explore the differences in early clinical features between Kawasaki disease shock syndrome (KDSS) and septic shock (SS).Methods:A retrospective case-control study was conducted. Clinical data was collected from 64 children who were diagnosed with KDSS or SS and admitted to the Department of Critical Care Medicine of Capital Center for Children′s Health, Capital Medical University from January 2018 to February 2025. Mann-Whitney U test, χ2 test, or Fisher′s exact test were used to compare the differences in clinical features, treatment, and outcomes between children with KDSS and SS. Lasso regression was applied to screen predictive variables, and multivariable logistic regression analysis was performed to identify factors associated with KDSS. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of parameters for KDSS. Results:Among the 64 children (30 males and 34 females), the age was 3.6 (1.2, 6.5) years. There were 51 cases in the SS group and 13 cases in the KDSS group. Compared to children with SS, children with KDSS had a longer pre-shock fever duration, lower lactate levels and serum albumin levels, and higher soluble interleukin-2 receptor (sIL-2R) levels (all P<0.05). Additionally, they exhibited a higher incidence of coronary involvement, pericardial effusion, and ascites, a higher utilization rate of intravenous immunoglobulin, and a lower utilization rate of invasive mechanical ventilation (all P<0.05). There was no significant difference in in-hospital mortality between KDSS and SS ( P=0.574). Multivariate logistic regression analysis identified pre-shock fever duration and sIL-2R as independent factors associated with KDSS ( OR=1.52 and 1.54 per 1 000 U increase, 95% CI 1.12-2.05 and 1.06-2.24, respectively; both P<0.05). ROC curve analysis showed that the areas under the curve for pre-shock fever duration and sIL-2R in identifying KDSS were 0.83 (95% CI 0.73-0.94, P=0.001) and 0.70 (95% CI 0.53-0.87, P=0.042), respectively. The optimal cutoff values were 3.5 d and 3.8×10 6 U/L, with sensitivities of 0.91 and 0.82, and specificities of 0.71 and 0.62, respectively. Conclusions:Children with KDSS have higher incidences of coronary involvement, pericardial effusion, and ascites compared to those with SS. Pre-shock fever duration and sIL-2R may serve as potential early indicators for distinguishing KDSS from SS.