Acute pancreatitis (AP) is a life-threatening gastrointestinal disorder for which no effective pharmacological treatments are currently available. One of the pharmacological targets that merits further research is the neurokinin 1 receptor (NK1R), which is found on pancreatic acinar cells and responds to the neuropeptide substance P (SP) that participates in AP. Although a few studies have stated the involvement of SP/NK1R in neurogenic inflammation in AP development, the regulatory mechanism remains unclear. In this study, we found that following activation of NK1R by SP, β-arrestin1, a scaffold protein of NK1R, down-regulated transcription of Adss, Adsl, and Ampd in the purine nucleotide cycle, thereby inhibiting mitochondrial function through fumarate depletion. Interestingly, we identified magnolol as a new and natural NK1R inhibitor with a non-nitrogenous biphenyl core structure. It exhibited a beneficial effect on AP by restoring purine nucleotide cycle metabolic enzymes and fumarate levels. Our study not only provides new therapeutic strategies, leading compounds, and drug translation possibilities for AP, but also provides important clues for the study of downstream mechanisms driven by SP in other diseases.

ObjectiveTo explore the role and mechanism of Hei Xiaoyaosan in regulating the protein kinase B （Akt）/glycogen synthase kinase-3β （GSK-3β）/nuclear factor E₂-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1） signaling pathway in cascade modulation of oxidative stress and apoptosis for preventing and treating Alzheimer's disease （AD）. MethodsNinety male SD rats of 4 months old were randomly assigned into a control group （n=10）， a sham group （with injection of 1 μL normal saline into bilateral hippocampi， n=10）， and a modeling group （with injection of 1 μL beta-amyloid 1-42 solution into bilateral hippocampi to induce AD， n=70）. One week after modeling， 50 successfully modeled rats were selected and randomly allocated into model， donepezil hydrochloride （0.45 mg·kg^-1）， and high-， medium-， and low-dose （15.30， 7.65， 3.82 g·kg^-1， respectively） Hei Xiaoyaosan groups. The rats were administrated with corresponding drugs once daily for six consecutive weeks. The Morris water maze was used to assess the learning and memory abilities of rats. Hematoxylin-eosin （HE） staining was performed to reveal hippocampal morphological changes in AD rats. Apoptosis in the hippocampal CA3 region was detected by terminal-deoxynucleotidyl transferase-mediated Nick end labeling. Immunofluorescence was used to visualize the expression of neuronal nuclear antigen （NeuN） in the CA1 region. Additionally， enzyme-linked immunosorbent assay was performed to assess the activities of glutathione peroxidase （GSH-Px）， glutathione-S-transferase （GST）， and catalase （CAT） in the hippocampus. Real-time PCR was conducted to measure the mRNA levels of Akt， GSK-3β， Nrf2， and HO-1， while Western blot was employed to determine the protein levels of phosphorylated Akt （p-Akt）/Akt， phosphorylated GSK-3β （p-GSK-3β）/GSK-3β， Nrf2， and HO-1. ResultsCompared with the control group， the model group on day 5 showed an increase in total swimming distance （P<0.01）， a reduction in the percentage of time spent in the target quadrant （P<0.01）， reduced and disarranged neurons， nuclear condensation， varying degrees of cellular damage， increased apoptosis of hippocampal neurons （P<0.01）， decreased NeuN content （P<0.01）， weakend activities of GSH-Px， GST， and CAT （P<0.01）， and down-regulated mRNA levels of Nrf2 and HO-1 （P<0.01） and protein levels of p-Akt/Akt， p-GSK-3β/GSK-3β， Nrf2， and HO-1 （P<0.01） in the hippocampus. Compared with the model group， donepezil hydrochloride and high， medium， and low doses of Hei Xiaoyaosan shortened the total swimming distance on day 5 （P<0.05， P<0.01）， increased the percentage of time spent in the target quadrant （P<0.05， P<0.01）， improved the arrangement and morphology of neurons， reduced nuclear condensation and the apoptosis rate of hippocampal neurons （P<0.01）， increased the NeuN content （P<0.01）， enhanced the activities of GSH-Px， GST， and CAT （P<0.05， P<0.01）， and up-regulated the mRNA levels of Nrf2 and HO-1 （P<0.05， P<0.01） and the protein levels of p-Akt/Akt， p-GSK-3β/GSK-3β， Nrf2， and HO-1 （P<0.05， P<0.01） in the hippocampus. ConclusionHei Xiaoyaosan can regulate the Akt/GSK-3β/Nrf2/HO-1 pathway to enhance the antioxidant stress capacity and inhibit neuron apoptosis to exert the neuroprotective effect， thereby ameliorating the cognitive dysfunction and pathological damage in AD rats.

ObjectiveTo explore the mechanism of Hei Xiaoyaosan in improving the cognitive function in Alzheimer's disease （AD） from cell apoptosis mediated by the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/nuclear factor kappa B （NF-κB） signaling pathway. MethodsFour-month-old SD male rats were randomly assigned into a blank group， a sham group， a model group， a donepezil hydrochloride （0.45 mg·kg^-1） group， and high-， medium-， and low-dose （15.30， 7.65， and 3.82 g·kg^-1， respectively） Hei Xiaoyaosan groups， with 10 rats in each group. The sham group received bilateral hippocampal injection of 1 μL normal saline， while the other groups received bilateral hippocampal injection of 1 μL beta-amyloid 1-42 （Aβ_1-42） solution for the modeling of AD. Rats were administrated with corresponding agents once a day for 42 consecutive days. The Morris water maze test was carried out to assess the learning and memory abilities of rats. Hematoxylin-eosin staining was employed to observe pathological changes in the hippocampus of rats. Enzyme-linked immunosorbent assay was employed to measure the levels of cysteinyl aspartate-specific proteinase-3 （Caspase-3）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. Western blot was employed to determine the protein levels of PI3K， Akt， and NF-κB. A cell model of AD was established by co-culturing Aβ_1-42 and PC12 cells in vitro. Cell viability and apoptosis were detected by the cell-counting kit 8 （CCK-8） assay and flow cytometry （FC）， respectively. ResultsAnimal experiments showed that compared with the blank group， the model group had a prolonged escape latency （P<0.01）， a reduced number of crossing platforms （P<0.01）， disarrangement and a reduced number of hippocampal neurons， up-regulated expression of Bax and Caspase-3， down-regulated expression of Bcl-2 （P<0.01）， decreased p-PI3K/PI3K and p-Akt/Akt levels， and an increased p-NF-κB/NF-κB level （P<0.01）. Compared with the model group， donepezil hydrochloride and high- and medium-dose Hei Xiaoyaosan shortened the escape latency and increased the number of crossing platforms （P<0.05， P<0.01）， improved the arrangement and increased the number of hippocampal neurons， down-regulated the expression levels of Bax and Caspase-3， up-reguated the expression level of Bcl-2 （P<0.05， P<0.01）， increased the p-PI3K/PI3K and p-Akt/Akt levels （P<0.05， P<0.01）， and reduced the p-NF-κB/NF-κB level （P<0.05， P<0.01）. Cell experiments showed that compared with the blank group， the model group exhibited an increased apoptosis rate （P<0.01）. Compared with the model group， the serum containing Hei Xiaoyaosan at various doses improved the cell viability （P<0.01）， and the serum containing Hei Xiaoyaosan at the high dose decreased the cell apoptosis （P<0.01）. ConclusionHei Xiaoyaosan may improve the learning and memory abilities of AD model rats by regulating cell apoptosis， while increasing the vitality and reducing the apoptosis rate of AD model cells via the PI3K/Akt/NF-κB signaling pathway.

ObjectiveTo investigate the effects of Hei Xiaoyaosan on cognitive impairment and the histone deacetylase sirtuin-1 （SIRT1）/tumor suppressor p53/solute carrier family 7 member 11 （SLC7A11） signaling pathway in the rat model of Alzheimer's disease （AD）. MethodsA total of 90 16-week-old SPF-grade SD male rats were randomly assigned in a blank group （n=10）， a sham group （n=10， with injection of 1 μL normal saline into the bilateral hippocampi）， and an AD modeling group （n=70， with injection of 1 μL β amyloid 1-42 solution into the bilateral hippocampi）. According to the random number table method， fifty successfully modeled rats were assigned into model， donepezil hydrochloride （0.45 mg·kg^-1）， and high-， medium-， and low-dose （15.30， 7.65， and 3.82 g·kg^-1， respectively） Hei Xiaoyaosan groups， and they were administrated with corresponding agents via gavage once a day for 42 consecutive days. Morris water maze test was carried out to examine the cognitive function of rats. Nissl staining was employed to observe the morphology of hippocampal neurons in each group， and Prussian blue staining was used to detect iron deposition in the hippocampal tissue. Biochemical kits were used to measure the levels of superoxide dismutase （SOD）， malondialdehyde （MDA）， and iron ion （Fe²⁺） in the hippocampal tissue. Western blot and real-time quantitative polymerase chain reaction （Real-time PCR） were employed to determine the protein and mRNA levels， respectively， of SIRT1， p53， SLC7A11， glutathione peroxidase 4 （GPX4）， and acyl-CoA synthetase long-chain family member 4 （ACSL4） in the hippocampus. ResultsCompared with the blank group， the model group showed reductions in target quadrant movement distance （P<0.01） and target quadrant residence time （P<0.05）， disarrangement of hippocampal neurons， increased ferroptosis deposition in the hippocampus， a lowered level of SOD， risen levels of MDA and Fe²⁺ （P<0.05， P<0.01）， down-regulated protein and mRNA levels of SIRT1， SLC7A11， and GPX4 （P<0.05， P<0.01）， up-regulated protein and mRNA levels of p53 and ACSL4 （P<0.01）， and aggravated pathological process of AD. Compared with the model group， donepezil hydrochloride extended the target quadrant residence time and the target quadrant movement distance （P<0.05， P<0.01）. High- and medium- doses of Hei Xiaoyaosan extended the target quadrant residence time and the target quadrant movement distance （P<0.05， P<0.01）， improved the neuron arrangement and reduced the ferroptosis deposition in the hippocampus， elevated the SOD level， lowered the MDA and Fe²⁺ levels （P<0.05， P<0.01）， up-regulated the protein and mRNA levels of SIRT1， SLC7A11， and GPX4 （P<0.01， P<0.05）， and down-regulated the protein and mRNA levels of p53 and ACSL4 （P<0.05， P<0.01）. ConclusionHei Xiaoyaosan can regulate the SIRT1/p53/SLC7A11 signaling pathway to mitigate oxidative stress and inhibit ferroptosis， thereby ameliorating the cognitive dysfunction in AD rats.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in healthcare facilities in major regions of China in 2023.Methods Clinical isolates collected from 73 hospitals across China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2023 Clinical & Laboratory Standards Institute (CLSI) breakpoints.Results A total of 445199 clinical isolates were collected in 2023,of which 29.0％ were gram-positive and 71.0％ were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species (excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi) (MRSA,MRSE and MRCNS) was 29.6％,81.9％ and 78.5％,respectively.Methicillin-resistant strains showed significantly higher resistance rates to most antimicrobial agents than methicillin-susceptible strains (MSSA,MSSE and MSCNS).Overall,92.9％ of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 91.4％ of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis had significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 93.1％ in the isolates from children and and 95.9％ in the isolates from adults.The resistance rate to carbapenems was lower than 15.0％ for most Enterobacterales species except for Klebsiella,22.5％ and 23.6％ of which were resistant to imipenem and meropenem,respectively .Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.6％ to 10.0％.The resistance rate to imipenem and meropenem was 21.9％ and 17.4％ for Pseudomonas aeruginosa,respectively,and 67.5％ and 68.1％ for Acinetobacter baumannii,respectively.Conclusions Increasing resistance to the commonly used antimicrobial agents is still observed in clinical bacterial isolates.However,the prevalence of important crabapenem-resistant organisms such as crabapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a slightly decreasing trend.This finding suggests that strengthening bacterial resistance surveillance and multidisciplinary linkage are important for preventing the occurrence and development of bacterial resistance.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in healthcare facilities in major regions of China in 2023.Methods Clinical isolates collected from 73 hospitals across China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2023 Clinical & Laboratory Standards Institute (CLSI) breakpoints.Results A total of 445199 clinical isolates were collected in 2023,of which 29.0％ were gram-positive and 71.0％ were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species (excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi) (MRSA,MRSE and MRCNS) was 29.6％,81.9％ and 78.5％,respectively.Methicillin-resistant strains showed significantly higher resistance rates to most antimicrobial agents than methicillin-susceptible strains (MSSA,MSSE and MSCNS).Overall,92.9％ of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 91.4％ of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis had significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 93.1％ in the isolates from children and and 95.9％ in the isolates from adults.The resistance rate to carbapenems was lower than 15.0％ for most Enterobacterales species except for Klebsiella,22.5％ and 23.6％ of which were resistant to imipenem and meropenem,respectively .Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.6％ to 10.0％.The resistance rate to imipenem and meropenem was 21.9％ and 17.4％ for Pseudomonas aeruginosa,respectively,and 67.5％ and 68.1％ for Acinetobacter baumannii,respectively.Conclusions Increasing resistance to the commonly used antimicrobial agents is still observed in clinical bacterial isolates.However,the prevalence of important crabapenem-resistant organisms such as crabapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a slightly decreasing trend.This finding suggests that strengthening bacterial resistance surveillance and multidisciplinary linkage are important for preventing the occurrence and development of bacterial resistance.

Objective To determine the effect of high dose albumin on permeability of blood brain barrier (BBB) in brain of rats after ischemic-reperfusion (IR) in order to explore its possible mechanism.Methods Establishment of brain ischemic reperfusion rat model by using middle cerebral artery occlusion (MCAO).Medicine treatment was given by caudal vein injection after 2 hours of MCAO.Thirty-six healthy male SD rats were then randomly (random number) divided into 6 groups (n =6 in each):6 h and 24 h sham-operation groups (Group Sham:operation without ischemia),6 h and 24 h normal saline groups (Group NS:NS injection 5 ml/kg) and 6 h and 24 h albumin group (Group Alb:25 ％ Alb injection 1.25 g/kg).Six hours and 24 hours after the end of reperfusion,rats were measured by Zea-Longa score (neural function deficit) separately.Serum concentration of S100B was examined by the ELISA kit and Evans blue in brain tissue was detected by spectrophotometer.The level of AQP4 was examined by Western blot and immunohistochemistry.All data were analyzed by one-way analysis of variance (ANOVA),The intergroup comparisons were analyzed by the least-significant-difference (LSD) test by using SPSS version 17.0 software.Differences were considered statistically significant if P ＜ 0.05.Results Zea-Longa score significantly increased in both group NS and group Alb at 6 h and 24 h (P =0.000).However,there was no significant difference in ZEA-LONGA score of 6 h and 24 h between group Alb and group NS (P =1.000).The serum concentration of S100B in group NS 6 h was significantly lower than that in group Alb at 6h (196.67±20.11 vs 160.04±14.00,P=0.000),and at24h (2.45±0.07 vs.2.23±0.07,P=0.000).Furthermore,concentration of Evans blue in brain tissue in group Alb was significantly higher than that in group NS at both 6 h (0.97 ± 0.08 vs.0.74 ± 0.06,P =0.000) and 24 h (2.45 ± 0.07 vs.2.23 ± 0.07,P =0.000).The expression of AQP4 in brain tissue was higher in group Alb than that in group NS at both 6 h (0.72 ±.0.11 vs.0.57 ± 0.06,P ＜ 0.01) and 24 h (0.80 ± 0.03 vs 0.61 ± 0.02,P ＜0.01).Conclusions High dose albumin contribute slightly in improvement of neural deficit in rats after IR.On the contrary,it can also aggravate the IR injury,which increases brain edema then increase the permeability of BBB.The mechanism may be associated with over-expression of AQP4 in brain tissue.

Objective To investigated the application value in the efficacy evaluation of transcranial Doppler (TCD) in encephalo-duro-arterio-synangiosis (EDAS) for moyamoya disease. Methods The patients with moyamoya disease treated with EDAS conducted digital subtraction angiography (DSA) and TCD examinations before procedure and at 6 months after procedure respectively. The pulsatility index (PI), resistance index (RI) and mean flow velocity (MFV) before and after the superficial temporal artery surgery were measured respectively. The correlation between the TCD parameter variation rate and DSA efficacy grading was evaluated. Using the receiver operator characteristic (ROC) curve to calculate the optimal cut-off value of the TCD parameters for predicting the operation efficacy. Results A total of 46 patients with moyamoya disease were enroled, 40 patients were bilateral hemisphere involvement and 6 were unilateral involvement. A total of 86 hemispheres were treated with EDAS. According to the results of DSA reexaminations, the grades of efficacy were as folows: grade 0, 18 sides, grade 1, 37 sides, grade 2, 18 sides, and grade 3, 13 sides. When the DSA grade was 0, there were no significant differences in PI, RI and MFV before and after procedure, and there were significant differences in the postoperative change of other TCD parameters at al levels (al P < 0. 001). At 6 months after procedure, the change rates of PI, RI and MFV were - 30. 83% ± 21. 71% , - 19. 64% ± 14. 45% and 96. 08% ± 100. 76% , respectively, and they had good correlation with the results of DSA efficacy grading. Their Spearman correlation coefficients were- 0. 879, - 0. 891 and 0. 715, respectively (al P < 0. 001). ROC curve analysis showed that the best cutoff values of the TCD parameter change rates for predicting good operative effect were as folows: PI decrease rate, 36% (area under the curve, 0. 966; sensitivity, 0. 968, specificity, 0. 891; P < 0. 001), RI decrease rate, 27% (area under the curve, 0. 973; sensitivity, 0. 903, specificity, 0. 946; P < 0. 001), and MFV increase rate, 111% (area under the curve, 0. 879; sensitivity, 0. 742, specificity, 0. 927; P < 0. 001). Conclusions TCD can detect hemodynamic parameter changes of superficial temporal arteries after EDAS. It has higher application value in the long-term postoperative efficacy evaluation.

Objective To investigate the relationship between carotid artery plaque formation and blood pressure(BP),pulse pressure(PP),mean blood pressure(MBP) in elderly men.Methods A total of 1461elderly men were divided into carotid artery plaque group(n =1012)and non-carotid artery plaque group(n =449) according to vascular ultrasound examination.Systolic blood pressure(SBP) and diastolic blood pressure(DBP) were recorded by 24-hour ambulatory blood pressure monitoring(ABPM),at the same time pulse pressure (PP)and mean arterial blood pressure(MBP)were calculated.The relationship between carotid artery plaque formation and SBP,DBP,PP,MBP were analyzed.Results The age in carotid artery plaque group was significantly higher than that in non-carotid artery plaque group[(80.5±5.4) years old vs(77.3±5.9) years old,t =-4.233,P ＜ 0.01];The levels of SBP,PP and M BP in artery plaque group were significantly higher than those in non-carotid artery plaque group[SBP:(132.2±17.0) mm Hg vs(127.5±16.0) mm Hg,t =-4.893,P ＜ 0.001; PP:(60.8±13.4) mm Hg vs(55.9±12.5) mm Hg,t =-5.021,P ＜0.001) ;MBP:(92.6±10.3)mm Hg vs(91.0±9.9)mm Hg,t =-3.897,P ＜ 0.01].The incidence of carotid artery plaque was closely related to age(OR =1.061,P =0.0001),myocardial infarction(OR =1.896,P =0.0135),hypertension grades(OR =1.177,P =0.0019),high cholesterol(OR =1.353,P =0.0335),reduced systolic function(OR =2.466,P =0.0001),lower extremity arterial plaque(OR =5.453,P =0.0001).Conclusion In elderly men,formation of the carotid artery plaque is closely related to increased SBP,PP and MBP,but independent to DBP.