ObjectiveTo examine the inhibitory effects of berberine compounds， including columbamine， on acetylcholinesterase from the perspectives of drug-target binding affinity and kinetics and explore the blood-brain barrier （BBB） permeability of these compounds in different multi-component backgrounds. MethodThe median inhibitory concentration （IC₅₀） of acetylcholinesterase by berberine compounds including columbamine was measured using the Ellman-modified spectrophotometric method. The binding kinetic parameters （K_off） of these compounds with acetylcholinesterase were determined using the enzyme activity recovery method. A qualitative analysis of the ability of these components to penetrate the BBB and arrive at the brain tissue in diverse multi-component backgrounds （including medicinal herbs and compound formulas） was conducted using ultra performance liquid chromatography-high resolution mass spectrometry （UPLC-HRMS）. ResultBerberine compounds， including columbamine， exhibited strong inhibition of acetylcholinesterase， with IC₅₀ values in the nanomolar range. Moreover， they displayed better drug-target binding kinetics characteristics （with smaller K_off values） than the positive control of donepezil hydrochloride （P<0.01）， indicating a longer inhibition duration of acetylcholinesterase. Berberine components such as columbamine could penetrate the BBB to arrive at brain tissue in the form of a monomer， as well as in the multi-component backgrounds of Coptis and Phellodendri Chinensis Cortex medicinal extracts and the compound formula Huanglian Jiedutang. ConclusionThese berberine compounds such as columbamine exhibit a strong inhibitory effect on acetylcholinesterase and can arrive at brain tissue in multi-component backgrounds. In the level of pharmacological substance， this supports the clinical efficacy of compound Huanglian Jiedutang in improving Alzheimer's disease， providing data support for elucidating the pharmacological basis of compound Huanglian Jiedutang.

ObjectiveTo identify the prototypical components and metabolites absorbed into blood and cerebrospinal fluid of Schisandrae Chinensis Fructus（SCF） based on sequential metabolism combined with liquid chromatography-mass spectrometry. MethodBlood and cerebrospinal fluid samples of integrated metabolism， intestinal metabolism and hepatic metabolism were collected from male SD rats after gavage and in situ intestinal perfusion administration， and ultra-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry（UPLC Q-Exactive Orbitrap MS） was used to analyze and compare the differences in the spectra of SCF extract， blank plasma， administered plasma， blank cerebrospinal fluid and administered cerebrospinal fluid with ACQUITY UPLC BEH Shield RP18 column（2.1 mm×100 mm， 1.7 µm）， the mobile phase was acetonitrile（A）-0.1% formic acid aqueous solution（B） for gradient elution（0-7 min， 95%B； 7-12 min， 95%-35%B； 12-17 min， 35%-15%B； 17-20 min， 15%-12%B； 20-22 min， 12%-5%B； 22-23 min， 5%B； 23-25 min， 5%-95%B； 25-28 min， 95%B）. And heated electrospray ionization（HESI） was used with positive and negative ion modes， the scanning range was m/z 100-1 500. The prototypical constituents and their metabolites absorbed into blood and cerebrospinal fluid of SCF were identified according to the retention time， characteristic fragments， molecular formulae and the information of reference substances. ResultA total of 42 chemical components were identified in the extract of SCF， including lignans， flavonoids， amino acids， tannins， and others， of which lignans were the main ones. A total of 27 prototypical components and 14 metabolites were identified in plasma samples from different sites. A total of 15 prototypical components and 9 metabolites were identified in cerebrospinal fluid. The main metabolic reactions involved in the formation of metabolites were mainly demethylation， methylation， demethoxylation and hydroxylation. ConclusionThrough the systematic identification of the prototypical components and metabolites of SCF in rats， it provides data support for further better exploring the material basis of SCF in the treatment of central nervous system diseases.

BACKGROUND:The specific mechanism of Gushukang,as a Chinese traditional patent medicine for the treatment of postmenopausal osteoporosis of kidney deficiency and blood stasis,needs further studies. OBJECTIVE:To investigate the effect of Gushukang on serum sex hormones,bone microstructure and estrogen receptor in postmenopausal osteoporosis. METHODS:Firstly,network pharmacological analysis was performed.The active ingredients and action targets of Gushukang and the targets of postmenopausal osteoporosis were obtained respectively.Cytoscape was used to construct the active ingredient-target network.STRING database and Cytoscape were used for protein-protein interaction analysis and screening of core targets.DAVID database was used for Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses of intersection targets.Then the ovariectomized Sprague-Dawley rats were used in the animal experiment.Gushukang was administered by gavage for 3 months.The serum estrogen level was detected by ELISA,the bone microstructure was detected by microCT,and the protein expression of estrogen receptor α and estrogen receptor β in bone tiusse was detected by western blot. RESULTS AND CONCLUSION:The network pharmacological research results identified 132 active ingredients and 150 targets of Gushukang and 1155 targets of postmenopausal osteoporosis.After intersections with 1155 postmenopausal osteoporosis targets,87 targets of active ingredients of Gushukang against postmenopausal osteoporosis were obtained.By constructing the active ingredient-target network,it was found that the active ingredients at the core were quercetin,kaempferol,luteolin,naringin and isorhamnetin,and the targets at the core were NCOA2,ESR2,AR,F2,ESR1 and PTGS1.The final targets obtained after the protein-protein interaction analysis and screening included MAPK8,ESR1,JUN,R3C1,RELA and FOS,of which ESR1 was the common core target obtained from the two analyses.KEGG enrichment analysis showed estrogen,tumor necrosis factor,apoptosis and other signaling pathways.Therefore,animal experiments focused on the effect of Gushukang on different subtypes of estrogen receptors in the estrogen signaling pathway.The results showed that in the Gushukang group,bone microstructure was significantly improved,serum estrogen level had no significant change,but the protein expression of estrogen receptor α and β in bone tissue was significantly increased.All the findings indicate that the mechanism of Gushukang in the treatment of postmenopausal osteoporosis may be related to its hormone-like effect and the enhancement of estrogen receptor expression.

Objective To evaluate the pharmacokinetic characteristics and safety of single and multiple oral azvudine tablets in healthy young and elderly Chinese subjects.Methods This was a open-label and parallel-group study.The trial consisted of two groups:healthy young subjects group and healthy elderly subjects group,with 12 subjects in each group.Enrolled subjects were first given a single dose,fasting oral azvudine tablet 5 mg,after a 3-day cleansing period entered the multiple dose phase,fasting oral azvudine tablet 5 mg·d-1 for 7 days.Results After a single dose of azvudine 5 mg,Cmax and AUC0-∞ were(4.76±2.12)ng·mL-1,(6.53±2.20)ng·mL-1·h,and Tmax,t1/2 were 0.75,1.87 h in young subjects;Cmax and AUC0-∞ were(6.40±3.25)ng·mL-1,(9.50±3.70)ng·mL-1·h,and Tmax,t1/2 were 0.63,2.66 h in elderly subjects.After a multiple dose of azvudine 5 mg·d-1 for 7 d,Cmax and AUC0-∞ were(3.26±1.61)ng·mL-1,(5.38±2.19)ng·mL-1·h,and Tmax,ss,t1/2,ss were 0.88,2.13 h in young subjects;Cmax,ss and AUC0-∞,ss were(3.97±2.09)ng·mL-1,(6.71±3.26)ng·mL-1·h,and Tmax,ss,t1/2,ss were 0.75,2.56 h in elderly subjects.Elderly/young geometric mean ratios and 90％CIs were 128.37％(88.23％-186.76％),139.93％(105.42％-185.72％),140.03％(106.33％-184.41％)for azvudine Cmax,AUC0-t,AUC0-∞ after a single dose,and were 118.66％(80.83％-174.20％),118.41％(83.60％-167.69％),118.95％(84.78％-166.89％)for azvudine Cmax,AUC0-t,AUC0_∞ after a multiple dose of azvudine 5 mg·d-1 for 7 d.Conclusion After single and multiple oral administration of azvudine tablets,systemic exposure to azvudine was higher in healthy elderly subjects compared with healthy young subjects.After taking azvudine tablets,the types,severity and incidence of adverse events and adverse drug reactions in healthy elderly people were not significantly different from those in healthy young subjects.Azvudine was found to be safe and well tolerated in healthy elderly subjects.

Background The mental health problems of employees in administrative organs and public institutions are highly valued.However,there is a lack of understanding regarding the mental health status of employees in provincial and municipal administrative organs and public institutions in Qinghai region.Objective To analyze the anxiety and depression of employees in provincial and municipal administrative organs and public institutions in Qinghai region,so as to provide references for promoting their mental health and intervening in psychological problems.Methods From October 23 to 28,2022,a total of 3 096 employees in provincial and municipal administrative organs and public institutions in Qinghai region were enrolled using stratified cluster sampling technique,and were assessed using Self-rating Anxiety Scale(SAS)and Self-rating Depression Scale(SDS).Results A total of 1797(58.04％)employees in municipal and above administrative organs and public institutions in Qinghai region completed a valid questionnaire survey.Depressive symptoms were noted in 579(32.22％).SDS scores yielded statistical difference among the selected employees of different ethnicities,types of job positions and educational levels(F=9.074,101.488,4.477,P<0.01),and the severity of depressive symptoms also demonstrated statistical difference among the selected employees with different ethnicities,educational levels and types of job positions(H=49.196,17.028,160.848,P<0.01).Anxiety symptoms were detected in 711(39.57％)employees.SAS scores exhibited statistical difference among the employees with different genders,ages,ethnicities,educational levels,marital status and types of job positions(t=-4.571,F=6.648,3.950,5.243,12.008,22.253,P<0.01).Statistical differences were also illustrated in the severity of anxiety symptoms among the selected employees with different ages,genders,ethnicities,educational levels,marital status and types of job positions(H=24.361,-3.788,28.365,24.268,25.976,56.204,P<0.01).Conclusion About one-third of employees in municipal and above administrative organs and public institutions in Qinghai region may have symptoms of depression and anxiety.The depression symptoms are more severe among Tibetan people,those with low education levels and ordinary civil servants.The anxiety symptoms are more severe among employees aged 30 and below,those with low education levels,unmarried and those in technical positions.

Objective:To investigate the influencing factors for total number, total volume, and total iron burden of cerebral microbleeds (CMBs) and the relationship between CMBs with cognitive impairment in end-stage renal disease (ESRD) using semi-automatic quantitative susceptibility mapping (QSM).Methods:The study was a cross-sectional study. Clinical and imaging data of 46 ESRD patients with≥1 CMBs who attended Tianjin First Central Hospital from November 2018 to August 2022 were retrospectively analyzed. There were 26 males and 20 females, aged 42-75 years. All patients underwent susceptibility-weighted imaging (SWI) scanning, then SWI data was post-processed to obtain QSM. The semi-automatic dynamic programming algorithm was used to get the volume and mean susceptibility value of each CMB by sketching the boundary of CMBs. The CMBs iron load total volume were calculated. Stepwise linear regression analysis was used to explore independent influencing factors for the number, total volume, and total iron burden of CMBs in ESRD patients. Partial correlation analysis was used to explore the relationship between CMBs and cognitive impairment with the other signs of cerebral small vessel diseases as covariates.Results:In patients with ESRD, CMBs were located in the frontal lobe in 19 cases, parietal lobe in 9 cases, temporal lobe in 19 cases, occipital lobe in 14 cases, basal ganglia in 27 cases, dorsal thalamus in 15 cases, centrum semiovale in 14 cases, cerebellum in 14 cases, and brainstem in 13 cases. C-reactive protein levels (95% CI 101.81-157.85, r=0.96, P=0.001) and creatinine levels (95% CI 5.32-29.61, r=0.71, P=0.010) were influencing factors for the total iron burden of CMBs. C-reactive protein levels (95% CI 0.72-1.15, r=0.99, P=0.001) and creatinine levels (95% CI 0.03-0.22, r=0.89, P=0.014) were influencing factors for the total volume of CMBs. C-reactive protein levels (95% CI 0.10-0.12, r=0.96, P=0.001) and alkaline phosphatase levels (95% CI 0.16-0.38, r=0.59, P=0.001) were influencing factors for the number of CMBs. The total volume ( r=-0.61, P=0.009) and total iron burden ( r=-0.71, P=0.002) of CMBs in the frontal lobe were negatively correlated with cognitive function. However, although the number of CMBs in the frontal lobe was negatively correlated with cognitive function, the statistics analysis was insignificant ( r=-0.53, P=0.063). Conclusions:C-reactive protein and creatinine are influencing factors for CMBs′ total volume and total iron burden; C-reactive protein levels and alkaline phosphatase are influencing factors for the number of CMBs. The total iron burden and total volume of CMBs in the frontal lobe may be the biomarkers of cognitive impairment in patients with end-stage renal disease.

Aim To explore the mechanism of Guso-ngYigu decoction(GSYG)in the treatment of postm-enopausal osteoporosis(PMOP)based on the gut mi-crobiota.Methods Sixty SPF grade SD rats were ran-domly divided into Control group(Control),Model group(Model),GSYG low-dose group(GSYG-L,1.25 g·kg-1),medium-dose group(GSYG-M,2.5 g·kg-1)and high-dose group(GSYG-H,5 g·kg-1)and alendronate group(Al,0.89 mg·kg-1),with 10 rats in each group.The changes of bone histomorpholo-gy were detected by HE staining and the changes of fe-mur tissue structure were observed by micro-CT.The fecal samples from the colon of Control group,Model group,GSYG-H group were taken to extract the DNA of fecal samples.The Illumina Miseq platform was used to carry out high-throughput sequencing.Results Compared with the Control group,bone trabecula in the Model group was sparse,BV/TV,Tb.Th,Tb.N and BMD decreased(P＜0.01),while SMI and Tb.Sp increased(P＜0.01);compared with the Model group,the number of bone trabeculae in GSYG-L,GSYG-M,GSYG-H group and Al group increased,the bone microstructure was improved,BV/TV,Tb.Th,Tb.N and BMD increased significantly(P＜0.05),and SMI and Tb.Sp increased(P＜0.05).Sequencing results of gut microbiota showed that,compared with the Control group,the gut microbiota diversity of Mod-el group decreased,the flora abundance of Firmicutes decreased,while the Bacteroidetes abundance in-creased.Compared with the Model group,the Firmi-cutes abundance increased and Bacteroidetes abundance decreased in GSYG-H group.Conclusions GSYG can improve bone microstructure and increase bone mineral density,and its mechanism may be related to increasing the diversity of gut microbiota and regulating the structure of gut microbiota.

Objective To establish a cost-benefit evaluation (CBE) index system which is suitable for health enterprise construction, and provide an effective tool for conducting economic evaluation of health enterprise development. Methods The index pool of CBE index system for health enterprise construction was initially established by comprehensive use of field surveys, key informant interviews and literature review. The improved Delphi method was used to conduct two rounds of expert correspondences with 21 experts, through which the evaluation indicator system was adjusted and refined based on the experts' opinions, ultimately the CBE indicator system suitable for health enterprise construction was determined. Results The effective questionnaire recovery rates of the two rounds of expert consultations were 100.0%. The expert authority coefficients was 0.88, and the Kendall's W coordination coefficients of the cost input indicator and benefit indicator in the second round of expert consultation were 0.14 and 0.15 (all P<0.001), with Cronbach's α coefficient of reliability evaluation of index system were all >0.80. The final CBE index system for health enterprise construction includes cost input indicators focusing on four dimensions: “improving management systems”, “building a healthy environment”, “enhancing health management and services”, and “cultivating a healthy culture”. It covered four primary indicators, ten secondary indicators, and 22 tertiary indicators. The benefit indicators mainly focused on the four primary indicators, including “health productivity”, “clinical output”, “economic output”, and “cultural output”, ten secondary indicators, and 23 tertiary indicators. Conclusion The CBE indicator system for health enterprise construction developed in this study is highly reliable, scientific, and practical. It can serve as a tool for the preliminary evaluation and general application of the cost-benefit evaluation of health enterprise construction and provide strong support for future research.

Aim To investigate the effect of XNST and its monomeric components on the barrier structure and tight junction protein expression of brain microvascular endothelial cells damaged by oxygen glucose deprivation/reoxygenation (OGD/R) and the possible mechanism. Methods The mouse brain microvascular endothelial cell line bEnd. 3 was inoculated in the upper layer of the Transwell chamber to establish an OGD/R damage model, and the effect of the drug on the integrity of the endothelial cell barrier was investigated by the transmembrane resistance value and fluorescein-so-dium transmittance. Claudin-5 immunofluorescence staining was used to observe the changes of tight junction structure between endothelial cells. RT-PCR and Western blot were employed to detect mRNA and protein expression levels of tightly linked proteins Claudin-5 , Occludin, ZO-1. Western blot was applied to detect the expression levels of MAPKs (JNK, p38, ERK) , I kappa B a, I kappa B kinase phosphorylated protein expression, and Western blot and immunofluorescence were utilized to detect NF-K.B/p65 nucleation expression. Results XNST and its three monomers could significantly increase endothelial cell resistance and de- crease fluorescein-sodium transmittance. Claudin-5 fluorescence staining showed that the tight junction between cells in the model group was significantly damaged , while XNST and its monomer components could significantly improve its tight structure. RT-PCR and Western blot results showed that it could significantly upregulate the expression of mRNA and protein of Claudin-5, Occludin and ZO-1, and further study on the mechanism showed that XNST and its monomer components could significantly inhibit the phosphoryla-tion of JNK, p38 and ERK, inhibit the phosphorylation of I kappa B a and I kappa B kinases, and significantly inhibit the nuclear translocation of NF-KB/p65. Conclusion Both XNST and its monomeric components can exert cerebroprotective effects by increasing the tight junction structure between cells to promote barrier integrity, and the mechanism may be related to inhibition of NF-kB and MAPKs signaling pathway activation.

Objective:To investigate the value of the ultrasonography in the diagnosis of the white matter injury of premature infants based on gray-scale ultrasonography radiomics.Methods:A total of 256 premature infants in Huazhong University of Science and Technology Union Shenzhen Hospital and Shenzhen Hospital of Southern Medical University from August 2018 to April 2022 were analyzed retrospectively. The computer-generated random numbers were assigned to the training set and the verification set according to 6∶4 ratio. On the basis of standardized collection of craniocerebral ultrasound images, the radiomics features were extracted from imaging by Pyradiomics 3.0.1 software package, the Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) and stepwise regression were used to select the optimal features. Then the Logistic regression was used to build radiomics model. According to MRI, ROC curve was utilized to evaluate the performance of the model. The craniocerebral ultrasound images in the validation set were independently diagnosed by a senior physician and a junior physician, and then the above two physicians diagnosed again with the help of the radiomics, and the diagnostic abilities of this model were compared with those of the junior and senior physicians with and without radiomics assist. Results:A total of 5 optimal features were selected to develop radiomics model. The sensitivity, specificity, accuracy and the area under the ROC curve (AUC) in the training and validation sets were 0.861, 0.775, 0.799, 0.818; 0.929, 0.824, 0.853, 0.876, respectively. The sensitivity, specificity, accuracy and AUC in the senior sonographer, the junior sonographer, and both of them with radiomics assist for the dagnosis in the validation set were 0.929, 0.892, 0.902, 0.910; 0.714, 0.743, 0.735, 0.729; 0.929, 0.919, 0.922, 0.924; 0.857, 0.824, 0.833, 0.841, respectively. Performance of radiomics model reached the level of the senior sonographer (AUC: 0.876 vs 0.910, P=0.284), which was significantly better than the performance of the junior sonographer(AUC: 0.876 vs 0.729, P=0.001). Performance of the junior sonographer with radiomics assist was significantly better than the performance of the junior sonographer(AUC: 0.841 vs 0.729, P=0.003). Performance of the senior sonographer with radiomics assist was comparable to that of the senior sonographer(AUC: 0.924 vs 0.910, P=0.156). Conclusions:The ultrasound diagnosis method based on radiomics technology shows good diagnostic performance for the white matter injury of premature infants. It is helpful to improve the diagnostic ability of junior sonographer. It is expected to assist the sonographers in diagnosis and provide objective, consistent and accurate results for clinical practice.