OBJECTIVE: To explore the protective effects and underlying mechanisms of H ₂S against lipid peroxidation-mediated carbonyl stress in the uranium-treated NRK-52E cells. METHODS: Cell viability was evaluated using CCK-8 assay. Apoptosis was measured using flow cytometry. Reagent kits were used to detect carbonyl stress markers malondialdehyde, 4-hydroxynonenal, thiobarbituric acid reactive substances, and protein carbonylation. Aldehyde-protein adduct formation and alcohol dehydrogenase, aldehyde dehydrogenase 2, aldo-keto reductase, nuclear factor E2-related factor 2 (Nrf2), and cystathionine β-synthase (CBS) expression were determined using western blotting or real-time PCR. Sulforaphane (SFP) was used to activate Nrf2. RNA interference was used to inhibit CBS expression. RESULTS: GYY4137 (an H ₂S donor) pretreatment significantly reversed the uranium-induced increase in carbonyl stress markers and aldehyde-protein adducts. GYY4137 effectively restored the uranium-decreased Nrf2 expression, nuclear translocation, and ratio of nuclear to cytoplasmic Nrf2, accompanied by a reversal of the uranium-decreased expression of CBS and aldehyde-metabolizing enzymes. The application of CBS siRNA efficiently abrogated the SFP-enhanced effects on the expression of CBS, Nrf2 activation, nuclear translocation, and ratio of nuclear to cytoplasmic Nrf2 and concomitantly reversed the SFP-enhanced effects of the uranium-induced mRNA expression of aldehyde-metabolizing enzymes. Simultaneously, CBS siRNA reversed the SFP-mediated alleviation of the uranium-induced increase in reactive aldehyde levels, apoptosis rates, and uranium-induced cell viability. CONCLUSION H ₂S induces Nrf2 activation and nuclear translocation, which modulates the expression of aldehyde-metabolizing enzymes and the CBS/H ₂S axis. Simultaneously, the Nrf2-controlled CBS/H ₂S axis may at least partially promote Nrf2 activation and nuclear translocation. These events form a cycle-regulating mode through which H ₂S attenuates the carbonyl stress-mediated NRK-52E cytotoxicity triggered by uranium.
NF-E2-Related Factor 2/genetics* ; Animals ; Hydrogen Sulfide/pharmacology* ; Rats ; Signal Transduction/drug effects* ; Lipid Peroxidation/drug effects* ; Cell Line ; Uranium/toxicity* ; Antioxidant Response Elements ; Kidney/metabolism* ; Oxidative Stress/drug effects* ; Cell Survival/drug effects* ; Apoptosis/drug effects*

Metabolic dysfunction-associated fatty liver disease （MAFLD） has become one of the critical chronic liver diseases requiring global attention， and the degree of hepatic fibrosis in these patients is closely associated with their prognosis. Therefore， control or even reversal of hepatic fibrosis is an indispensable part of the long-term management of MAFLD patients. A large number of studies have shown that the Wnt signaling pathway is involved in the development and progression of MAFLD. This article systematically describes the Wnt signaling pathway and elaborates on its mechanism of action in MAFLD-associated hepatic fibrosis， in order to provide a reference for the treatment of hepatic fibrosis in patients with MAFLD.

Objectives:To explore the predictive value of angiography-derived index of microcirculatory resistance(Angio-IMR)for early prognosis in patients with acute ST-segment elevation myocardial infarction(STEMI)after percutaneous coronary intervention(PCI).Methods:This multicenter study enrolled 1 629 consecutive STEMI patients who underwent successful PCI at three grade A tertiary hospitals(The Second Affiliated Hospital,Zhejiang University School of Medicine;Shengjing Hospital of China Medical University;Renji Hospital,Shanghai Jiao Tong University School of Medicine)from June 1,2017,to May 31,2020.According to postoperative Angio-IMR,patients was stratified into two groups:the Angio-IMR>40 group(n=508)and the Angio-IMR≤40 group(n=1 121).The incidence of major adverse cardiovascular events(MACE;defined as a composite endpoint including cardiac death,heart failure rehospitalization,cardiogenic shock,malignant arrhythmia,cardiopulmonary resuscitation and stent thrombosis)within 1-month post-PCI was compared between the two groups.Results:The median Angio-IMR after PCI was 32.4(22.3,42.6).The cumulative incidence of early-term MACE was significantly higher in patients with Angio-IMR>40,compared to those with Angio-IMR≤40(5.5%vs.2.3%,log-rank P<0.001).Multivariate Cox regression analysis showed that Angio-IMR>40 was an independent predictor of early-term MACE(HR=2.07,95%CI:1.20-3.58,P=0.009).The addition of Angio-IMR enhanced the predicting performance of the clinical risk model to predict early adverse outcomes(AUC:0.820 vs.0.794,P=0.043).Conclusions:In patients with STEMI after PCI,Angio-IMR can predict the occurrence of early-term MACE.The incorporation of Angio-IMR to clinical models significantly improves the model ability to predict early adverse outcomes in these patients.

In this experiment, self-assembled nanoparticles(SANs) were prepared by the pH-driven method, and Her-HCP SAN was constructed by using herpetrione(Her) and Herpetospermum caudigerum polysaccharides(HCPs). The average particle size and polydispersity index(PDI) were used as evaluation indexes for process optimization, and the quality of the final formulation was evaluated in terms of particle size, PDI, Zeta potential, and microstructure. The proposed Her-HCP SAN showed a spheroid structure and uniform morphology, with an average particle size of(244.58±16.84) nm, a PDI of 0.147 1±0.014 8, and a Zeta potential of(-38.52±2.11) mV. Her-HCP SAN significantly increased the saturation solubility of Her by 2.69 times, with a cumulative release of 90.18% within eight hours. The results of in vivo unidirectional intestinal perfusion reveal that Her active pharmaceutical ingredient(API) is most effectively absorbed in the jejunum, where both K_a and P_(app) are significantly higher compared to the ileum(P<0.001). However, the addition of HCP leads to a significant reduction in the P_(app) of Her in the jejunum(P<0.05). Furthermore, the formation of the Her-HCP SAN results in a notably lower P_(app) in the jejunum compared to Her API alone(P<0.001), while both K_a and P_(app) in the ileum are significantly increased(P<0.001, P<0.05). The absorption of Her-HCP SAN at different concentrations in the ileum shows no significant differences, and the pH has no significant effect on the absorption of Her-HCP SAN in the ileum. The addition of the transporter protein inhibitors(indomethacin and rifampicin) significantly increases the absorption parameters K_a and P_(app) of Her-HCP SAN in the ileum(P<0.05,P<0.01), whereas the addition of verapamil has no significant effect on the intestinal absorption parameters of Her-HCP SAN, suggesting that Her may be a substrate for multidrug resistance-associated protein 2 and breast cancer resistance proteins but not a substrate of P-glycoprotein.
Nanoparticles/metabolism* ; Polysaccharides/pharmacokinetics* ; Intestinal Absorption/drug effects* ; Animals ; Rats ; Particle Size ; Drugs, Chinese Herbal/pharmacokinetics* ; Male ; Rats, Sprague-Dawley ; Drug Carriers/chemistry* ; Drug Compounding ; Cucurbitaceae/chemistry*

Objectives:To explore the predictive value of angiography-derived index of microcirculatory resistance(Angio-IMR)for early prognosis in patients with acute ST-segment elevation myocardial infarction(STEMI)after percutaneous coronary intervention(PCI).Methods:This multicenter study enrolled 1 629 consecutive STEMI patients who underwent successful PCI at three grade A tertiary hospitals(The Second Affiliated Hospital,Zhejiang University School of Medicine;Shengjing Hospital of China Medical University;Renji Hospital,Shanghai Jiao Tong University School of Medicine)from June 1,2017,to May 31,2020.According to postoperative Angio-IMR,patients was stratified into two groups:the Angio-IMR>40 group(n=508)and the Angio-IMR≤40 group(n=1 121).The incidence of major adverse cardiovascular events(MACE;defined as a composite endpoint including cardiac death,heart failure rehospitalization,cardiogenic shock,malignant arrhythmia,cardiopulmonary resuscitation and stent thrombosis)within 1-month post-PCI was compared between the two groups.Results:The median Angio-IMR after PCI was 32.4(22.3,42.6).The cumulative incidence of early-term MACE was significantly higher in patients with Angio-IMR>40,compared to those with Angio-IMR≤40(5.5%vs.2.3%,log-rank P<0.001).Multivariate Cox regression analysis showed that Angio-IMR>40 was an independent predictor of early-term MACE(HR=2.07,95%CI:1.20-3.58,P=0.009).The addition of Angio-IMR enhanced the predicting performance of the clinical risk model to predict early adverse outcomes(AUC:0.820 vs.0.794,P=0.043).Conclusions:In patients with STEMI after PCI,Angio-IMR can predict the occurrence of early-term MACE.The incorporation of Angio-IMR to clinical models significantly improves the model ability to predict early adverse outcomes in these patients.

Objective:To investigate the current status of vocational training for pediatric clinical research coordinators (CRC), and discuss the construction of base-based pediatric CRC training, and to promote the ability of pediatric CRCs.Methods:From July 25 to October 16, 2023, an anonymous self-designed questionnaire survey was conducted through the Wenjuanxing platform to investigate the current situation of pediatric CRC vocational training and base training needs. The data were collated using Excel. Categorical data were described as numbers and percentages.Results:A total of 328 usable questionnaires were returned. Only 7.62% (25 people) believed that existing CRC training was sufficient and could meet actual work needs; 4.88% (16 people) responded that there was no training; 46.34% (152 people) believed that the training was insufficient to support actual work needs; 87.50% (287 people) believed that continuous CRC training was needed; 46.95% (154 people) preferred experienced CRCs for teaching, who should have at least 3 years of CRC work experience; and 46.95% (154 people) preferred a duration of 3 months for CRC training. The preferred training methods were: practice under the direction of experienced CRCs (90.85%, 298 people), step-by-step teaching of practical skills (88.41%, 290 people), case analysis and discussion (87.20%, 286 people), process simulation (83.23%, 273 people), and lecture-based teaching (76.52%, 251 people). The preferred post-training assessment methods were: case analysis (76.52%, 251 people), operation simulation (74.09%, 243 people), process simulation (73.17%, 240 people), written examination (66.16%, 217 people), and interview (63.72%, 209 people).Conclusions:The current pediatric CRC training is not enough to meet actual work needs. It is urgent to develop and promote a CRC training system that can meet work needs, laying the foundation for the construction of pediatric clinical research ecology in China.

Helicobacter pylori (Hp) is a unipolar, microaerobic, multiflagellar, spiral-shaped Gram-negative bacterium that survives and colonizes human gastric mucosa. As a classⅠcarcinogen associated with gastric cancer, long-term stimulation of gastric mucosa by Hp can cause atrophic gastritis, peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. It has been reported that Hp can cause epithelial-mesenchymal transition (EMT) in gastric epithelial cells, thereby inducing gastric cancer. We review the mechanism of Hp-induced EMT in gastric epithelial cells, in order to provide new insights for early diagnosis and targeted therapy of gastric cancer.

Objective To examine the changing antimicrobial resistance profile of Enterobacter spp.isolates in 53 hospitals across China from 2015 t0 2021.Methods The clinical isolates of Enterobacter spp.were collected from 53 hospitals across China during 2015-2021 and tested for antimicrobial susceptibility using Kirby-Bauer method or automated testing systems according to the CHINET unified protocol.The results were interpreted according to the breakpoints issued by the Clinical & Laboratory Standards Institute(CLSI)in 2021(M100 31st edition)and analyzed with WHONET 5.6 software.Results A total of 37 966 Enterobacter strains were isolated from 2015 to 2021.The proportion of Enterobacter isolates among all clinical isolates showed a fluctuating trend over the 7-year period,overall 2.5％in all clinical isolates amd 5.7％in Enterobacterale strains.The most frequently isolated Enterobacter species was Enterobacter cloacae,accounting for 93.7％(35 571/37 966).The strains were mainly isolated from respiratory specimens(44.4±4.6)％,followed by secretions/pus(16.4±2.3)％and urine(16.0±0.9)％.The strains from respiratory samples decreased slightly,while those from sterile body fluids increased over the 7-year period.The Enterobacter strains were mainly isolated from inpatients(92.9％),and only(7.1±0.8)％of the strains were isolated from outpatients and emergency patients.The patients in surgical wards contributed the highest number of isolates(24.4±2.9)％compared to the inpatients in any other departement.Overall,≤ 7.9％of the E.cloacae strains were resistant to amikacin,tigecycline,polymyxin B,imipenem or meropenem,while ≤5.6％of the Enterobacter asburiae strains were resistant to these antimicrobial agents.E.asburiae showed higher resistance rate to polymyxin B than E.cloacae(19.7％vs 3.9％).Overall,≤8.1％of the Enterobacter gergoviae strains were resistant to tigecycline,amikacin,meropenem,or imipenem,while 10.5％of these strains were resistant to polycolistin B.The overall prevalence of carbapenem-resistant Enterobacter was 10.0％over the 7-year period,but showing an upward trend.The resistance profiles of Enterobacter isolates varied with the department from which they were isolated and whether the patient is an adult or a child.The prevalence of carbapenem-resistant E.cloacae was the highest in the E.cloacae isolates from ICU patients.Conclusions The results of the CHINET Antimicrobial Resistance Surveillance Program indicate that the proportion of Enterobacter strains in all clinical isolates fluctuates slightly over the 7-year period from 2015 to 2021.The Enterobacter strains showed increasing resistance to multiple antimicrobial drugs,especially carbapenems over the 7-year period.

Objective:To investigate the influence of novel CRM1 inhibitor KPT-330 on the autophagy of mantle cell lymphoma(MCL)cells,and effect of KPT-330 on the prolifiration of MCL cells in the presence or absence of autophagy inhibitor.Methods:CCK-8 assay was used to detect the effect of KPT-330 on MCL cell lines Z-138,Jeko-1,Granta-519,Rec-1.The effect of KPT-330 on autophagy features were determined by detecting acidic vesicular organelles(AVO)by MDC staining under fluorescence microscope and detecting protein expression of LC3B-Ⅱ assessed by Western blot.Further combined application of lysosomal inhibitor Chloroquine(CQ)was used to observe its effect on the increase of LC3B-Ⅱ caused by KPT-330.CalcuSyn 2.0 software was used to detected the Combination index(CI)of KPT-330 combined with CQ.Results:The proliferation of MCL cell lines(Z-138,Jeko-1,Grant-519,Rec-1)could be inhibited by KPT-330 in a dose-dependent manner(r=0.930,0.946,0.691,0.968 respectively).The number of acidic vesicular organelles(AVO)and the expression of LC3B-Ⅱ were increased in KPT-330 treated Jeko-1 and Granta-519 cells in a dose-dependent manner(rJeko-1=0.993,rGranta-519=0.971).LC3B-Ⅱ protein amounts still increased upon KPT-330 treatment with the existence of lysosomal inhibitor CQ in Jeko-1 and Granta-519 cells,which was higher than CQ or KPT-330 single drug group.The combination of KPT-330 and CQ produced the synergistic effects on cells proliferation inhibition with CalcuSyn 2.0 analysis.Conclusion:KPT-330 can inhibit MCL cell proliferation and induce autophagy.KPT-330 combined with autophagy inhibitor CQ could produce synergistic anti MCL effects,providing experimental basis for clinical combination therapy.