This paper aims to evaluate the pharmacodynamic effect and mechanism of Zhifuxin in the prevention and treatment of vascular dementia(VD), providing a theoretical basis for later development. Bilateral common carotid artery ligation in male Wistar rats was conducted to replicate the long-term hypoperfused VD model, and the drug was given to groups after one month. The rats were fed daily with nimodipine of 20 mg·kg~(-1), Zhifuxin of 50, 100, and 200 mg·kg~(-1), or the same volume of solvent for four weeks. 24 hours after the last dose, Morris water maze experiments were performed to detect the learning and memory abilities of rats. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the brain tissue of rats; the immunohistochemical method was used to detect the expression of muscarinic acetylcholine receptors M1 and M4 in rats and determine the content of acetyl choline(Ach), acetylcholin esterase(AchE), malondialdehyde(MDA), choline acetyl transferase(ChAT), and dimethyl arginine hydrolase 1(DDAH1) in the cerebral cortex of rats. Western blot was employed to detect protein expression of endothelial nitric oxide synthase(eNOS), caveolin-1, monoamine oxidase A(MAO-A), and monoamine oxidase B(MAO-B). RT-qPCR was utilized to detect mRNA expression of eNOS, caveolin-1, MAO-A, and MAO-B. The results showed that compared with the model group, the different doses of Zhifuxin were able to shorten the latency of VD rats in the water maze positioning navigation test, increase the number of crossing platforms in the space exploration test, and alleviate cone cell contracture in the hippocampus of VD rats. The expression of biochemical indicators related to the cholinergic system in the cerebral cortex: M1 and M4 receptors increased, as well as ChAT activity, and AchE activity significantly decreased. The protein and mRNA expression of indicators related to the eNOS/NO pathway: DDAH1 content, eNOS, and caveolin-1 increased, and that of indicators related to monoamine oxidase(MAO): MAO-A and MAO-B significantly decreased. The results show that Zhifuxin can improve cognition ability in long-term hypoperfused VD rats, and its mechanism of action may be related to its ability to modulate the cholinergic system and the eNOS/NO pathway and inhibit MAO expression.
Animals ; Dementia, Vascular/metabolism* ; Male ; Rats, Wistar ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Maze Learning/drug effects* ; Nitric Oxide Synthase Type III/genetics* ; Acetylcholinesterase/metabolism* ; Humans ; Choline O-Acetyltransferase/genetics* ; Disease Models, Animal

This study aims to investigate the molecular mechanism by which naringin alleviates cerebral ischemia/reperfusion(CI/R) injury through DRP1/LRRK2/MCU signaling axis. A total of 60 SD rats were randomly divided into the sham group, the model group, the sodium Danshensu group, and low-, medium-, and high-dose(50, 100, and 200 mg·kg~(-1)) naringin groups, with 10 rats in each group. Except for the sham group, a transient middle cerebral artery occlusion/reperfusion(tMCAO/R) model was established in SD rats using the suture method. Longa 5-point scale was used to assess neurological deficits. 2,3,5-Triphenyl tetrazolium chloride(TTC) staining was used to detect the volume percentage of cerebral infarction in rats. Hematoxylin-eosin(HE) staining and Nissl staining were employed to assess neuronal structural alterations and the number of Nissl bodies in cortex, respectively. Western blot was used to determine the protein expression levels of B-cell lymphoma-2 gene(Bcl-2), Bcl-2-associated X protein(Bax), cleaved cysteine-aspartate protease-3(cleaved caspase-3), mitochondrial calcium uniporter(MCU), microtubule-associated protein 1 light chain 3(LC3), and P62. Mitochondrial structure and autophagy in cortical neurons were observed by transmission electron microscopy. Immunofluorescence assay was used to quantify the fluorescence intensities of MCU and mitochondrial calcium ion, as well as the co-localization of dynamin-related protein 1(DRP1) with leucine-rich repeat kinase 2(LRRK2) and translocase of outer mitochondrial membrane 20(TOMM20) with LC3 in cortical mitochondria. The results showed that compared with the model group, naringin significantly decreased the volume percentage of cerebral infarction and neurological deficit score in tMCAO/R rats, alleviated the structural damage and Nissl body loss of cortical neurons in tMCAO/R rats, inhibited autophagosomes in cortical neurons, and increased the average diameter of cortical mitochondria. The Western blot results showed that compared to the sham group, the model group exhibited increased levels of cleaved caspase-3, Bax, MCU, and the LC3Ⅱ/LC3Ⅰ ratio in the cortex and reduced protein levels of Bcl-2 and P62. However, naringin down-regulated the protein expression of cleaved caspase-3, Bax, MCU and the ratio of LC3Ⅱ/LC3Ⅰ ratio and up-regulated the expression of Bcl-2 and P62 proteins in cortical area. In addition, immunofluorescence analysis showed that compared with the model group, naringin and positive drug treatments significantly decreased the fluorescence intensities of MCU and mitochondrial calcium ion. Meanwhile, the co-localization of DRP1 with LRRK2 and TOMM20 with LC3 in cortical mitochondria was also decreased significantly after the intervention. These findings suggest that naringin can alleviate cortical neuronal damage in tMCAO/R rats by inhibiting DRP1/LRRK2/MCU-mediated mitochondrial fragmentation and the resultant excessive mitophagy.
Animals ; Rats, Sprague-Dawley ; Reperfusion Injury/genetics* ; Flavanones/administration & dosage* ; Rats ; Dynamins/genetics* ; Male ; Brain Ischemia/genetics* ; Protein Serine-Threonine Kinases/genetics* ; Signal Transduction/drug effects* ; Humans ; Drugs, Chinese Herbal/administration & dosage*

OBJECTIVES: To investigate the chain mediating role of family care and emotional management in the relationship between social support and anxiety among rural primary school students. METHODS: A questionnaire survey was conducted among students in grades 4 to 6 from four counties in Hunan Province. Data were collected using the Social Support Rating Scale, Family Care Index Scale, Emotional Intelligence Scale, and Generalized Anxiety Disorder -7. Logistic regression analysis was used to explore the influencing factors of anxiety symptoms. Mediation analysis was conducted to assess the chain mediating effects of family care and emotional management between social support and anxiety. RESULTS: A total of 4 141 questionnaires were distributed, with 3 874 valid responses (effective response rate: 93.55%). The prevalence rate of anxiety symptoms among these students was 9.32% (95%CI: 8.40%-10.23%). Significant differences were observed in the prevalence rates of anxiety symptoms among groups with different levels of social support, family functioning, and emotional management ability (P<0.05). The total indirect effect of social support on anxiety symptoms via family care and emotional management was significant (β=-0.137, 95%CI: -0.167 to -0.109), and the direct effect of social support on anxiety symptoms remained significant (P<0.05). Family care and emotional management served as significant chain mediators in the relationship between social support and anxiety symptoms (β=-0.025,95%CI:-0.032 to -0.018), accounting for 14.5% of the total effect. CONCLUSIONS Social support can directly affect anxiety symptoms among rural primary school students and can also indirectly influence anxiety symptoms through the chain mediating effects of family care and emotional management. These findings provide scientific evidence for the prevention of anxiety in primary school students from multiple perspectives.
Humans ; Female ; Male ; Social Support ; Anxiety/etiology* ; Child ; Students/psychology* ; Emotions ; Logistic Models

Numerous c-mesenchymal-epithelial transition (c-MET) inhibitors have been reported as potential anticancer agents. However, most fail to enter clinical trials owing to poor efficacy or drug resistance. To date, the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed. In this study, we constructed the largest c-MET dataset, which included 2,278 molecules with different structures, by inhibiting the half maximal inhibitory concentration (IC₅₀) of kinase activity. No significant differences in drug-like properties were observed between active molecules (1,228) and inactive molecules (1,050), including chemical space coverage, physicochemical properties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding (t-SNE) high-dimensional data. Further clustering and chemical space networks (CSNs) analyses revealed commonly used scaffolds for c-MET inhibitors, such as M5, M7, and M8. Activity cliffs and structural alerts were used to reveal "dead ends" and "safe bets" for c-MET, as well as dominant structural fragments consisting of pyridazinones, triazoles, and pyrazines. Finally, the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules, including at least three aromatic heterocycles, five aromatic nitrogen atoms, and eight nitrogen-oxygen atoms. Overall, our analyses revealed potential structure-activity relationship (SAR) patterns for c-MET inhibitors, which can inform the screening of new compounds and guide future optimization efforts.

Objective:To investigate the clinical characteristics of patients with hepatitis B virus（HBV）-related primary hepatocellular carcinoma（HCC）who were treated in a multidisciplinary team（MDT）for liver cancer，so as to provide a basis for clinical optimization of the diagnosis and treatment of patients with chronic hepatitis B（CHB）.Methods:A retrospective analysis was performed for 482 HBV-related HCC patients who were treated with HCC-MDT every Thursday afternoon in The First Affiliated Hospital of the Army Medical University from January 2022 to May 2024，aged 18-87（55.54±10.84）years，86.93%（419/482）males and 13.07%（63/482）females. According to the different underlying liver diseases at the time of initial medical treatment and the different prognostic outcomes at the later follow-up，the differences in clinical characteristics between groups under different conditions were compared and analyzed，and the influencing factors of HCC prognosis were understood by Logistic regression analysis. Results:At the time of MDT presentation，the differences in HBeAg status（ χ2=6.311 ，P=0.043），γ-glutamyl traspeptidase（GGT）（ Z=6.277， P=0.043），alkaline phosphatase（ALP）（ Z=7.236 ，P=0.027），and model for end-stage liver disease（MELD）scores（ Z=6.111， P=0.047）among patients with different underlying liver diseases were statistically significant. At follow-up，6.75%（11/163）of HBV-related HCC patients who presented to MDT had a family history of HCC，and their cumulative mortality rate was as high as 60.8%（205/337）at least for 1 year. Mulitivariate Logistic regression analysis showed that different underlying liver disease at the time of initial medical treatment，HBV DNA replication level，MELD score and choice of anti-cancer treatment regimen were the influencing factors for the prognosis of HCC（all P<0.05）. The worse the degree of cirrhosis at the initial presentation，the higher the level of HBV DNA replication，and the higher the MELD score，the worse the prognosis for HCC. Conclusion:Advancing the diagnosis and treatment of CHB，maximizing the inhibition of HBV DNA replication，reducing the MELD score，and optimizing the anti-cancer treatment regimen can reduce the mortality rate of HBV-related HCC.

Objective:To investigate the efficacy of fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet count ratio (APRI), liver stiffness value (LSM), and Agile 3+ score and their combined model in predicting advanced-stage liver fibrosis in patients with chronic hepatitis B (CHB) combined with metabolic-associated fatty liver disease (MAFLD).Methods:A multicenter retrospective cohort study was conducted on the BMOVE population.Nine hundred twenty CHB cases combined with MAFLD who underwent liver biopsy at seven medical centers in China from April 2006 to December 2023 were included. The patients were divided into advanced-stage liver fibrosis (159 cases) and non-advanced-stage liver fibrosis (761 cases) according to the Scheuer's scoring system.The area under the receiver operating characteristic curve (AUROC), decision curve, and calibration curve analysis were used to evaluate the efficacy of the firbrosis-4 index (FIB-4) score, NFS score, APRI index, LSM, and Agile 3+ score and their combined model in predicting advanced-stage fibrosis. The liver fibrosis grade of all patients was diagnosed by liver biopsy. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each scoring model and combined model, as well as the proportion of correctly classified patients, were calculated based on different cutoff values.Results:AUROC analysis showed that Agile 3+ (0.814, 95% CI: 0.787-0.838) and LSM (0.805, 95% CI: 0.778-0.829) had similar accuracy and were superior to FIB-4 (0.721, 95% CI: 0.691-0.749), NFS (0.687, 95% CI: 0.656-0.716) and APRI ( 0.689, 95% CI: 0.658-0.718); however, HBV DNA level and HBV e antigen status had no effect on this outcome. Decision curve analysis showed that interventions based on LSM and Agile 3+ had provided higher net benefits compared with serological scores. Calibration curves showed that Agile 3+ had better predicitive accuracy than all other models. Agile 3+ had the highest PPV (0.54), minimal uncertainty interval (11.6%), and the highest proportion of correctly classified patients (76%); followed by LSM (PPV: 0.43, uncertainty interval: 15.5%, correct classification rate: 66%), and FIB-4 (PPV: 0.42, uncertainty interval: 26.1%, correct classification rate: 62.6%) in terms of identifying advanced-stage liver fibrosis. Combined model analysis demonstrated that FIB-4 combined with Agile 3+ had improved the correct classification rate and reduced the proportion of missed patients compared with FIB-4 combined with LSM. Conclusion:The Agile 3+ score is superior than LSM, FIB-4, NFS, and APRI index at identifying advanced-stage fibrosis in patients with CHB combined with MAFLD. This study supports the use of FIB-4 index combined with Agile 3+ for risk stratification in patients with CHB combined with MAFLD.

BACKGROUND:Treadmill training is one of the effective ways to promote the recovery of motor function after spinal cord injury.Treadmill training can promote neurogenesis,but the effect of different intensities of treadmill training on the activation of endogenous stem cells is still unclear. OBJECTIVE:To analyze the activation effect of different intensities of treadmill training on endogenous neural stem cells in the spinal cord of mice after spinal cord injury. METHODS:Fifty female C57BL/6J mice were divided into control group,spinal cord injury group,low-,moderate-,and high-intensity exercise groups with 10 mice in each group by random number table method.T10 segment spinal cord injury model was constructed by the clamp method in spinal cord injury group,low-,moderate-,and high-intensity exercise groups.On day 7 after spinal cord injury,mice in the low-,moderate-,and high-intensity exercise groups were respectively trained on the treadmill with corresponding intensity,3 times/d,10 min/times,6 times a week for 28 consecutive days.At 3,7,14,21,and 28 days after treadmill training,the hind limb motor function was evaluated by BMS score.At 28 days after treadmill training,the spinal cord tissue of the injured area was obtained,and the expression of epidermal growth factor receptor,glial fibrillary acidic protein,and 5-Ethynyl-2'-deoxyuridine(EdU),a proliferative marker,was detected.Hematoxylin-eosin staining was used to observe the morphology of spinal cord. RESULTS AND CONCLUSION:(1)The BMS score of mice in the spinal cord injury group was lower than that in the control group(P<0.05).With the extension of treadmill training time,the BMS scores of mice with spinal cord injury gradually increased,and the BMS scores of mice in moderate-intensity exercise group on days 14 and 21 after treadmill training were higher than those in spinal cord injury group and low-and high-intensity exercise groups(P<0.05).The BMS score of mice in moderate-and high-intensity exercise group was higher than that in spinal cord injury group and low-intensity exercise group at 28 days after treadmill training(P<0.05).(2)Compared with the control group,the proportion of epidermal growth factor receptor and EdU positive cells was increased in spinal cord injury group(P<0.05).Compared with spinal cord injury group,the proportion of epidermal growth factor receptor and EdU positive cells was increased in low-,moderate-,and high-intensity exercise groups(P<0.05),and the highest was found in moderate-intensity exercise group.Compared with control group,the proportion of glial fibrillary acidic protein positive cells was increased in spinal cord injury group(P<0.05).Compared with spinal cord injury group,the proportion of glial fibrillary acidic protein positive cells was lower in low-,moderate-,and high-intensity exercise groups(P<0.05),and the moderate-intensity exercise group was the lowest.(3)Hematoxylin-eosin staining showed that a large cavity was formed in the injured area of mice with spinal cord injury,and the cavity in the injured area of mice with spinal cord injury decreased after different intensities of treadmill training,and the decrease was most obvious in the moderate-intensity exercise group.(4)These results indicate that low-,moderate-,and high-intensity treadmill training can promote the recovery of motor function of mice with spinal cord injury by activating endogenous neural stem cells,and the effect of moderate-intensity exercise training is the most obvious.

Objective:To explore the application value of a novel bag respirator assisted ventilation device in postoperative transport under general anesthesia with laryngeal mask.Methods:A total of 133 patients in postoperative transport who underwent elective bron-choscopy or treatment under general anesthesia with laryngeal mask in the First Affiliated Hospital of Chongqing Medical University,from June to August 2023 were selected.The patients were randomly divided into control group(n=65)and experimental group(n=68),and received manual bag respirator assisted ventilation and the novel bag respirator assisted ventilation device during their postop-erative transport,respectively.The pulse oxygen saturation(SpO2),heart rate(HR),and ventilation frequency during transport,trans-port duration,and transport-related adverse events were compared between the two groups.Results:The difference in SpO2 was signifi-cant when comparing the two groups(Fbetween groups=18.588,P<0.001),and the SpO2 of patients in the experimental group was signifi-cantly higher than that of patients in the control group during and after transport(P<0.001).The difference in HR was not significant when comparing the two groups(Fbetween groups=0.089,P=0.766),but it was significant between the control and experimental groups before and after transport(Ftime point=12.430,P<0.001);the HR in the con-trol and experimental groups before and during transport was signifi-cantly lower than that after transport(all P<0.001).The ventilation frequency of the experimental group was significantly lower than that of the control group(P<0.001).The transport duration in the ex-perimental group was longer than that in the control group,but the difference was not significant(P=0.987).Both groups successfully completed the trial without transport-related adverse events and achieved safe transport.Conclusion:Compared with the manual bag respirator assisted ventilation technology,the novel bag respirator assisted ventilation device for respiratory support during postopera-tive transport in patients under general anesthesia with laryngeal mask is more able to reduce the impact on the patient's hemodynam-ics and conducive to the maintenance of the patient's stable vital signs,showing a good clinical application value.It is expected to be a safe and effective ventilation method during intrahospital transport in some patients under general anesthesia.

Objective To investigate the impacts of long non-coding RNA SNHG14(lncRNA SNHG14)on proliferation,apoptosis,and inflammatory response of alveolar epithelial cells infected with Streptococcus pneumoniae by targeting the miR-17-5p/forkhead box K2(FOXK2)axis.Methods Alveolar epithelial cells A549 were divided into control group,infection group,sh-NC group,sh-SNHG14 group,sh-SNHG14+inhibi-tor NC group,and sh-SNHG14+miR-17-5p inhibitor group.The mRNA expressions of lncRNA SNHG14,miR-17-5p and FOXK2 were detected by RT-qPCR,the proliferation of A549 cells was detected by CCK-8 kit,and the apoptosis of A549 cells was detected by flow cytometry.The levels of IL-1β,TNF-α and IL-6 were de-tected by ELISA.Dual luciferase reporter gene assay was used to detect the binding of lncRNA SNHG14 to miR-17-5p,miR-17-5p and FOXK2.Results Compared with control group,lncRNA SNHG14,FOXK2 mR-NA expression,cell apoptosis rate,IL-6,TNF-α and IL-1β levels were increased in infection group,while miR-17-5p level and absorbance(A)value were decreased,with statistical significance(P＜0.05).LncRNA SNHG14 and FOXK2 mRNA expression,cell apoptosis rate,IL-6,TNF-α and IL-1β levels in sh-SNHG14 group were lower than those in infection group and sh-NC group,while miR-17-5p expression level and A val-ue were higher than those in infection group and sh-NC group,and the differences were statistically significant(P＜0.05).FOXK2 mRNA expression,apoptosis rate,IL-6,TNF-α and IL-1β levels of sh-SNHG14+miR-17-5p inhibitor group were all increased compared with sh-SNHG14+miR-17-5p inhibitor group,and the miR-17-5p expression and A value were decreased compared with sh-SNHG14+inhibitor NC group,the differences were statistically significant(P＜0.05).Dual luciferase reporter gene test results showed that lncRNA SNHG14 and miR-17-5p,as well as miR-17-5p and FOXK2 had a targeting relationship.Conclusion Interfer-ing the expression of lncRNA SNHG14 can up-regulate the expression of miR-17-5p and down-regulate the expression of FOXK2,thus inhibiting the apoptosis and inflammatory response of alveolar epithelial cells in-fected with Streptococcus pneumoniae infected cells and promoting the cell proliferation.