Xanthine oxidase (XO) is an important therapeutic target for the treatment of hyperuricemia and gout. Based on the previously identified potent XO inhibitor 1, seventeen oxadiazoles and their ring-opening analogues were designed and synthesized via the bioisostere replacement strategy. Among them, compounds 2l, 2n, and 3b showed obvious XO inhibitory activity at the concentration of 10 μmol·L^-1, and compound 3b exhibited an IC₅₀ value of 1.45 μmol·L^-1.

Objective To analyze the relationship between frailty and acute kidney injury(AKI)after hip fracture surgery in the elderly.Methods A total of 405 elderly patients who underwent hip fracture surgery in Jieyang People's Hospital from August 2021 to January 2023 were retrospectively analysed.According to the modified frailty index(mFI),they were divided into frail group(mFI≥0.27,n=112)and non-frail group(mFI<0.27,n=293).Postoperative AKI was defined according to the Kidney Disease:Improving Global Outcomes(KDIGO)criteria.After 1:1 propensity score matching(PSM),100 cases in each group were successfully matched.Univariable and multivariable logistic regression models,propensity score adjustment,PSM,inverse probability of treatment weighting(IPTW),standardized mortality ratio weighting(SMRW),pairwise algorithm(PA)weighting,and overlap weighting(OW)methods were used to analyze the relationship between frailty and postoperative AKI.Stratified analyses were performed according to age(≥80 or<80 years),gender,whether angiotensin-converting enzyme inhibitors(ACEI)/angiotensin Ⅱreceptor antagonists(ARB)were used,and whether intraoperative hypotension occurred.Results After PSM,there were no significant differences between the two groups in age,sex,surgical type,ACEI/ARB,blood urea nitrogen,serum creatinine,intraoperative blood loss,and intraoperative hypotension[standardized mean difference(SMD)<0.1].In both the original cohort and the matched cohort,the incidence of AKI was higher in frail group than in non-frail group(25.9%vs.8.9%,P<0.001;28.0%vs.11.0%,P=0.002).Analysis of the risk of postoperative AKI in elderly hip fracture patients in frail group found that compared with the non-frail group,in the univariate logistic regression model the odds ratio(OR)and a 95%confidence interval(CI)for the frail group was 3.59(2.00-6.43),P<0.001,and in the multivariable logistic regression model,the OR(95%CI)for frail group was 3.04(1.55-5.95),P=0.001.After adjustment for propensity score,the OR(95%CI)for frail group was 2.85(1.52-5.34),P=0.001,and the OR(95%CI)for frail group after PSM was 3.15(1.47-6.75),P=0.003.After IPTW,SMRW,PA weighting,and OW,the OR(95%CI)for frail group were 2.48(1.37-4.50),2.43(1.41-4.19),2.63(1.25-5.54),and 2.69(1.07-6.78),respectively,with P<0.05.The interaction tests were not statistically significant for age,sex,use of ACEI/ARB,and intraoperative hypotension(P>0.05).Conclusion In elderly patients with hip fractures,preoperative frailty may be a risk factor for postoperative AKI.

Objective To establish a stable,reliable,and clinically relevant porcine model of endotoxin-induced acute respiratory distress syndrome(ARDS).Methods Ten 8-month-old male Bama minipigs were deeply sedated,followed by invasive mechanical ventilation and electrocardiographic monitoring.Lipopolysaccharide(LPS)was intravenously pumped at 600 μg/(kg·h)for 3 hours,then maintained at 15 μg/(kg·h)thereafter.Dynamic monitoring was performed at five time points after LPS injection(LPS 0,1,3,5,and 8 h),including arterial blood gas analysis and chest computed tomography(CT)scans.Pathological examination of lung tissues obtained via bronchoscopic biopsy(HE staining and transmission electron microscopy)was conducted.These indicators were comprehensively used to evaluate the success of the animal model.Results At 5 hours after LPS administration,8 minipigs developed symptoms such as skin cyanosis,elevated body temperature,and respiratory distress.The oxygenation index decreased to<300 mmHg.Chest CT scans showed diffuse pulmonary infiltrates.Histopathology revealed alveolar edema and hyaline membrane formation.Transmission electron microscopy demonstrated disruption of pulmonary blood-air barrier,depletion of lamellar bodies in type Ⅱ pneumocytes,inflammatory cell infiltration,and exudation of plasma proteins and fibrin.Compared with LPS 0 h,at LPS 8 h,the oxygenation index and arterial blood pH were significantly decreased(P<0.001),while blood lactic acid and serum potassium were significantly increased(P<0.05);serum calcium and base excess were significantly decreased(P<0.05),and the lung injury score based on HE-stained lung sections was significantly increased(P<0.01).Conclusion The porcine ARDS model established by continuous LPS injection can dynamically simulate the pathophysiological characteristics and typical pathological manifestations of clinical septic ARDS,making it an effective tool to study the pathogenesis,prevention,and treatment strategies of septic ARDS.

Anti-tumor traditional Chinese medicine has a long history of clinic application, in which the star molecules have always been the hotspot of modern drug research, but they are limited by the solubility, stability, targeting, bioactivity or toxicity of the monomer components of traditional Chinese medicine anti-tumor star molecules and other pharmacokinetic problems, which hinders the traditional Chinese medicine anti-tumor star molecules for further clinical translation and application. Currently, the nanosystems prepared by supramolecular technologies such as molecular self-assembly and nanomaterial encapsulation have broader application prospects in improving the anti-tumor effect of active components of traditional Chinese medicine, which has attracted extensive attention from scholars at home and abroad. In this paper, we systematically review the research progress in preparation of supramolecular nano-systems from anti-tumor star molecule of traditional Chinese medicine, and summarize the two major categories and ten small classes of carrier-free and carrier-based supramolecular nanosystems and their research cases, and the future development direction is put forward. The purpose of this paper is to provide reference for the research and clinical transformation of using supramolecular technology to improve the clinical application of anti-tumor star molecule of traditional Chinese medicine.

The anti-inflammatory effect of simplified Zhiqin Decoction was observed by using lipopolysaccharide (LPS)-induced inflammation mouse model. The main chemical constituents and the main mechanism of action of simplified Zhiqin Decoction were predicted by network pharmacology. Animal experiments verified the anti-inflammatory mechanism of simplified Zhiqin Decoction (this experiment was approved by the Animal Experiment Ethics Committee of Southwest University, approval number: IACUC-20210825-02). Simplifying Zhiqin Decoction has a significant anti-inflammatory effect on inflammatory mice, can significantly improve the overall macro shape of mice, reduce body temperature, water intake, increase the number of autonomous activities; alleviate liver, lung, spleen, thymus inflammation and pathological damage; decrease tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, nitric oxide (NO), prostaglandin E₂ (PGE₂) content in serum and urine. The contents of serum immune factors IgG, IgA and IgM were increased. Network pharmacology predicted 66 potential anti-inflammatory active components of simplified Zhiqin Decoction involving 132 inflammatory targets, and the key anti-inflammatory signaling pathway involved PI3K/AKT, TNF, JAK-STAT, etc. Animal experiments show that simplified Zhiqin Decoction can significantly reduce the expression of JAK2/STAT-PI3K/AKT-NF-κB-TNF signaling pathway related proteins in lung tissue of inflammatory mice. The results of this study showed that simplified Zhiqin Decoction had significant anti-inflammatory effects, and its main anti-inflammatory components were quercetin, β-sitosterol, kaempferol, wogonin, stigmasterol, luteolin, neobaicalein, etc. The main mechanism of its anti-inflammatory action is that it significantly inhibits the expression of JAK2/STAT-PI3K/AKT-NF-κB-TNF signaling pathway protein.

Objective To investigate the in vitro anti-inflammatory effects of Sophora davidii Hance leaves total alkaloids(SDLTAs)and possible molecular mechanisms.Methods The lipopolysaccharide(LPS)-induced inflammation model of RAW264.7 cells was used,and different concentrations of SDLTAs(50,100 and 200 μg/mL)were administered,and the effect of SDLTAs on cellular NO expression was detected by the Griess method;ELISA method was used to detect the effect of SDLTAs on the expression of IL-6,TNF-α and IL-1β;The expression of iNOS,NF-κB p65 and IκBα mRNA was detected by RT-qPCR;Western blotting was used to detecte the expres-sion of p-p38,p-p65 and p-JNK in the cells and NF-κB p65 in the nucleus.Results SDLTAs could significantly inhibit the LPS-induced inflammatory response in RAW264.7 cells.SDLTAs significantly decreased the secretion of NO,IL-6,TNF-α and IL-1β in cells(P<0.01),and significantly decreased the mRNA expressions of iNOS,NF-κB p65 and IκBα in cells(P<0.01).Significantly decreased the protein expression of p-p38,p-p65 and p-JNK in cells and NF-κB p65 in nucleus(P<0.01).Conclusion SDLTAs can exert anti-inflammatory effects by regulating the MAPK/NF-κB signalling pathway.

Objective To study the clinical characteristics and bacterial antimicrobial susceptibility testing results of patients with clinically isolated Ralstonia pickettii(R.pickettii),and provide basis for the rational use of antimi-crobial agents.Methods Inpatients with R.pickettii infection who were treated at the Tianjin First Central Hospi-tal from January 2014 to December 2023 were analyzed retrospectively.Clinical characteristics and antimicrobial sus-ceptibility testing results were analyzed.Results A total of 80 strains of Ralstonia spp.were isolated over 10-year period,including 42(52.5％)non-repetitive strains of R.pickettii.Among 42 R.pickettii strains,64.3％were isolated from male patients.The strains isolated from sputum,catheter,blood,throat swabs,and drainage fluid specimens accounted for 38.1％,28.6％,19.0％,4.8％,and 2.4％,respectively.The clinical distribution of R.pickettii was highest in the intensive care unit(ICU),with a proportion of 52.4％.The number of infected patients first increased and then decreased with the years,followed by a slight fluctuation.There was no statistically signifi-cant difference in the number of infected patients in each department over the years(P＞0.05).R.pickettii had higher susceptibility rates to doxycycline,levofloxacin,ciprofloxacin,and minocycline,susceptibility rates were 78.3％-90.9％,but was completely resistant to compound sulfamethoxazole and cefazolin(100％),it also had higher resistance rates to aztreonam,colistin,cefotetan,tobramycin,amikacin,ceftazidime,and gentamicin(80.0％-97.4％).There was no statistically significant difference in the resistance rates to 21 antimicrobial agents among different years(all P＞0.05).Conclusion R.pickettii is mainly from ICU,and the majority of the infected population are adult males.Most strains are isolated from sputum and catheter.R.pickettii presents multidrug re-sistance.Attention should be paid to the changes in the resistance rates of antimicrobial agents,strengthen the dy-namic monitoring of bacterial resistance and guide the rational selection of antimicrobial agents in clinic,implement early and effective treatment to improve the prognosis of the patients.

Objective To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/-mice.Methods The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/-mice.Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers.Results Proteomic analysis showed that there were 43 significantly up-regulated and 58 sig-nificantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group.Among them,GBP2,TAOK3,TFR1 and UCP1 were biomarkers with great diagnostic potential.KEGG pathway enrichment analysis indicated that fer-roptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model.The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model.Conclusion Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferrop-tosis.Four potential biomarkers are selected for myocardial injury diagnosis,providing a new direction for sudden cardiac death(SCD)caused by hyperlipidemia combined with the restraint stress.

Objective:This study was aimed to provide ideas for identifying the antibodies to high-frequency antigens by analyzing a female case of high-frequency antigen antibody(anti-Ku)using serological and sequencing method.Methods:The methods for identification of blood group,erythrocyte antigen,screening and identification of antibody were used to detect the blood type and antibody in the proband.The proband's serum and reagent screening cells treated with Sulfhydryl reagent were applied to judge the type and characteristics of this antibodies when reacted with the regaent screening cells or proband's serum respectively.Gene sequencing was used to determine the genotype of the proband's blood group.Results:The proband's red blood cells were determined as O type RhD positive,whose serum showed strong positive reaction to antibody-screening cells and antibody identification cells with the same intensity in saline and IAT medium,however,the self-cells showed negative effect.The Direct Antihuman Globulin of proband's red blood cells also showed weak positive reaction,and the other blood types were CcEe,Jk(a+b-),P1-,Le(a-b-),Lu(a-b+),K-,k-,Kp(a-b-).Serum of the proband treated with 2-ME still react with three groups of screening cells in IAT medium.The reaction intensity of proband's serum was also unchanged with the cells modified with papain and bromelain,but showed negative effect when the cells were treated with sulfhydryl agents including DTT and 2-ME.Gene sequencing revealed that the KEL genotype of the patient was KEL*02N.24.This patient had a rare K0 phenotype.Conclusion:The rare Kell-null blood group(also known as K0)were identified by serological and molecular tests in the proband who produced both IgG and IgM type of antibody to high-frequency antigen(anti-Ku).These two methods are of great significance in the identification of this rare blood group as well as the antibody to high frequency antigen.

Objective:To explore the overall survival and prognostic factors of patients over 50 years old with acute myeloid leukemia(AML).Methods:The clinical data of 222 AML patients aged over 50 years in our hospital from January 2016 and June 2021 were retrospectively analyzed.Kaplan-Meier method was used to evaluate the overall survival(OS)rate,and Cox regression model to evaluate the prognostic factors.Results:The 1-year and 3-year OS rates of all patients were 46.8％and 28.8％,respectively.The recurrence rate of patients who achieved remission during follow-up time was 57％.Both univariate and multivariate analysis showed that advanced age,MLL family fusion gene,PHF6 gene mutation,TP53 gene mutation,intolerance to standard chemotherapy,incomplete remission,complex karyotype,+mar karyotype and inv(3)karyotype were significantly correlated with prognosis(all P＜0.05).Negative fusion gene and positive AML-ETO fusion gene had no obvious survival advantage in this population.In patients with complete remission,there was no significant survival advantage in those who achieved minimal residual disease negative.Conclusion:AML patients aged over 50 years have a poor outcome and high recurrence rate.The prognosis is affected by multiple factors and has its own characteristics.