OBJECTIVE: To investigate the anti-tumor effects of cinobufacini (CINO) on hepatocellular carcinoma (HCC) induced by des-gamma-carboxy-prothrombin (DCP) and to uncover the underlying mechanisms. METHODS: The inhibitory effect of CINO on HCC cell proliferation was evaluated using the cell counting kit-8 method, and the apoptosis rate was quantified using flow cytometry. Immunofluorescence and Western blot analyses were used to investigate the differential expression of proteins associated with cell growth, apoptosis, migration, and invasion pathways after CINO treatment. The therapeutic potential of CINO for HCC was confirmed, and the possibility of combining cinobufacini with c-Met inhibitor for the treatment of primary HCC was further validated by in vivo experiments. RESULTS: Under the induction of DCP, CINO inhibited the activity of HCC cells, induced apoptosis, and inhibited migration and invasion. Upon the induction of DCP, CINO regulated c-Met activation and the activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways. In a mouse model of HCC, CINO exhibited significant antitumor effects by inhibiting the phosphorylation of c-Met and the downstream PI3K/AKT and MEK/ERK pathways in tumor tissues. CONCLUSIONS CINO inhibited HCC cell growth, promoted apoptosis, and suppressed HCC cell invasion and migration by targeting c-Met and PI3K/AKT and MEK/ERK signaling pathways under DCP induction.
Carcinoma, Hepatocellular/drug therapy* ; Proto-Oncogene Proteins c-met/metabolism* ; Liver Neoplasms/drug therapy* ; Signal Transduction/drug effects* ; Animals ; Humans ; Cell Movement/drug effects* ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Amphibian Venoms/therapeutic use* ; Cell Line, Tumor ; Neoplasm Metastasis ; Cell Survival/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Neoplasm Invasiveness ; Mice, Inbred BALB C ; Mice, Nude ; Mice ; Male ; Bufanolides/therapeutic use* ; Protein Precursors ; Prothrombin ; Biomarkers

The development of anticancer drugs to treat triple-negative breast cancer (TNBC) is an ongoing challenge. Immunogenic cell death (ICD) has garnered considerable interest worldwide as a promising synergistic modality for cancer chemoimmunotherapy. However, only few drugs or treatment modalities can trigger an ICD response and none of them exert a considerable clinical effect against TNBC. Therefore, new agents with potentially effective chemoimmunotherapeutic response are required. In this study, five new cyclometalated Ir(III) complexes containing isoquinoline alkaloid CˆN ligands were designed and synthesized. Among them, Ir-1 exhibited the highest in vitro cytotoxicity. Mechanistically, Ir-1 could trigger autophagy-dependent ferroptosis and a subsequent ferroptosis-dependent ICD response as well as indoleamine 2,3-dioxygenase (IDO) inhibition via reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress in MDA-MB-231 cells. When immunocompetent BALB/c mice were vaccinated with Ir-1-treated dying TNBC cells, antitumor CD8⁺ T-cell response and Foxp3⁺ T-cell depletion were induced, resulting in long-lasting antitumor immunity in TNBC cells. Moreover, combination therapy with Ir-1 and anti-PD1 could substantially augment in vivo therapeutic effects. Based on these results, Ir-1 is a promising candidate for chemoimmunotherapy against TNBC and its effects are mediated synergistically via ICD induction and IDO blockage.

Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.
Animals ; Female ; Mice ; CA1 Region, Hippocampal/metabolism* ; Cell Adhesion Molecules/metabolism* ; CRF Receptor, Type 1/metabolism* ; Memory Disorders/etiology* ; Mice, Inbred C57BL ; Nectins/genetics* ; Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors* ; Recognition, Psychology/physiology* ; Stress, Psychological/complications*

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Objective:To investigate the relationship between the virulence and the carbapenem resistance phenotype of Klebsiella pneumoniae from blood infection,and to identify carbapenem-resistant and hypervirulent Klebsiella pneumoniae(CR-HVKP)strains.Methods:A total of 192 Klebsiella pneumoniae strains were isolated from blood culture of patients with bloodstream infections from 2016 to 2019,of which 96 isolates were carbapenem-resistant Klebsiella pneumoniae(CRKP)and 96 were carbapenem-sensitive Klebsiella pneumoniae(CSKP).The drug susceptibility was detected by VITEK-2 automatic microbial analyzer;carbapenemase genes,virulence genes and capsule typing were detected by polymerase chain reaction;the high viscosity phenotype of strains was detected by string test,and the genome characteristics of CR-HVKP were detected by whole genome sequencing.Serum killing and biofilm formation test were used to further verify the virulence of CR-HVKP.Results:There were significant differences in drug resistance to common antibiotics,except for minocycline between CSKP and CRKP isolates(all P<0.05).92 out of 96 CRKP isolates carried carbapenemase genes,mainly blaKPC-2.The string tests were positive in 4 isolates of CRKP and 36 isolates of CSKP(P<0.05).The detection rates of virulence genes Kfu,aerobictin,iutA,ybtS,rmpA,magA,allS,and capsule antigen K1 and K2 in CSKP group were significantly higher than those in CRKP group(all P<0.05).One HVKP strain was detected in the CRKP group(CR-HVKP)and 36 HVKP was detected in the CSKP group(P<0.05).The CR-HVKP strain belonged to the MLST412,serotype K57,expressed iutA,entB,mrkD,fimH,and rmpA virulence genes,and showed strong biofilm formation and significantly increased serum resistance.Whole genome sequencing results showed that this CR-HVKP isolate carried blaSHV-145,blaTEM-1,blaCTX-M-3,fosA6,oqxA5,oqxB26,and aac(3)-Ⅱd resistance genes,accompanied by abnormalities in outer membrane protein K(OmpK)35 and OmpK36.Conclusions:The drug resistance of CRKP is significantly higher than that of CSKP,while CRKP carrying fewer virulence genes in both number and types compared to CSKP.A new MLST type of carbapenem-resistant and hypervirulent Klebsiella pneumoniae strain has been detected,which requires clinical awareness and epidemiological monitoring.

Objective To investigate the main active components and pharmacological mechanism of Bushen Huoxue Decoction in the treatment of osteoporotic fractures by network pharmacology.Methods The chemical constituents of Bushen Huoxue Decoction were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).The disease targets of osteoporosis were collected through the DisGeNET database.The predictive targets of Bushen Huoxue Decoction in the treatment of osteoporosis were screened by Venn diagram.Through gene ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,the biological processes and signaling pathways of Bushen Huoxue Decoction in the treatment of osteoporotic fractures were preliminarily obtained.Cytoscape 3.9.1 software was used to construct the network diagram of Chinese medicinal components-disease targets-pathways.Through the analysis of topological parameters and the degree value as the investigation,the main active components of Bushen Huoxue Decoction in the treatment of osteoporotic fractures were obtained.The protein-protein interaction(PPI)network was constructed by online String 11.5 software,and the pharmacological mechanism of Bushen Huoxue Decoction in the treatment of osteoporotic fractures at the protein molecular level was obtained by topological parameter analysis.Results A total of 1 236 chemical components were screened out,including 72 predicted targets.It involves biological processes such as DNA transcription,translation,and even binding between enzymes,and intersects with KEGG signaling pathways such as diabetes,atherosclerosis and cancer.Conclusion Bushen Huoxue Decoction mainly through dehydrodiethylene glycol 4,Yangambin,Atropine,arachidonic acid,ellagic acid,stigmasterol,isorhamnetin and other major components acting on nuclear transcription factor p65,mitogen-activated protein kinase,estrogen receptor,tumor necrosis factor,cell tumor antigen and other protein molecules play a role in the promotion of osteoporotic fractures healing.

Chronic kidney disease(CKD)commonly used dietary assessments including 24-hour dietary recall(24 h DR)/3-day dietary recall(3DDR),food frequency questionnaire(FFQ),dietary records,and estimation of dietary protein intake based on nitrogen balance.Given the high prevalence of CKD patients in Asian population and the scarcity of research using FFQ method,it is crucial to develop an FFQ suitable for Chinese CKD patients.This review summarizes the advantages and disadvantages of dietary assessment methods for CKD,the current research status,and the content and steps involved in establishing an FFQ,with the aim of providing reference for the modification of FFQ for Chinese CKD patients.

Objective To investigate the implementation of surveillance,prevention and control measures for healthcare-associated infection(HAI)in maternal and child healthcare(MCH)institutions,and provide policy evi-dence for optimizing HAI prevention and control in MCH institutions.Methods Stratified sampling was conducted among the MCH institutions at provincial,municipal and county levels in 8 provinces/autonomous regions.A uni-fied questionnaire was designed and the online survey was conducted through"Questionnaire Star".Results The data from 123 MCH institutions were included in the analysis.90.24％of the MCH institutions carried out compre-hensive surveillance on HAI.The ratios of MCH institutions which implemented targeted surveillance on HAI in neonatal intensive care unit(NICU),surgical site infection,multidrug-resistant organisms(MDROs)and HAI in intensive care units(non-NICU excluded)were 89.66％,85.96％,80.77％,and 74.19％,respectively.51.22％MCH institutions adopted information surveillance system on HAI cases.94.31％MCH institutions carried out surveillance on hand hygiene compliance.Over 90％MCH institutions carried out surveillance on environment hy-giene in high-risk departments.71.54％MCH institutions conducted centralized cleaning,disinfection,sterilization and supply for reusable medical instruments in the central sterile supply department(CSSD).Over 90％MCH insti-tutions established three-level pre-examination triage systems.86.18％set up transitional wards.MCH institutions generally adopted a management model with established effective communication,full appointment visits,and sepa-rate visits for special medical groups,such as registered pregnant women,high-risk newborns,healthcare groups,and long-term rehabilitation patients.However,the ratio of institutions conducting on-line follow-up visits was less than 50％.Conclusion MCH institutions have generally carried out comprehensive and targeted surveillance on HAI.Information surveillance need to be facilitated.Hand hygiene and environmental hygiene surveillance has been popularized to a certain extent at all levels of MCH institutions.The cleaning,disinfection,sterilization,and supply processes of reusable medical devices in a few MCH institutions are not standardized.Special medical populations get effective management.On-line healthcare is to be further promoted.

Ovarian cancer has become the most lethal gynecological tumor due to the difficulty in early diagnosis,the late stage when diagnosed and the high recurrence rate.Resistance to platinum-based anti-tumor chemotherapy drugs is an important reason for the poor prognosis of ovarian cancer.circular RNA(circRNA)is more stable than mRNA in cells due to its special structure,and it is involved in the regulation of the occurrence,development and chemotherapy resistance of a variety of tumors.circRNA can be used as a competing endogenous RNA(ceRNA)of miRNA to bind to proteins,and regulates the phenotypic polarization of macrophages,it can also be used as an exosomal circRNA to regulate the sensitivity of platinum resistance in ovarian cancer.circRNA is expected to be a new marker of platinum resistance and a new target for the treatment of platinum resistance.In order to further explore the relationship between circRNA and platinum resistance in ovarian cancer,this article summarizes the recent literature related to circRNA and platinum resistance in ovarian cancer.

Objective To observe the clinical efficacy of thumb-tack needling for subcutaeous embedding combined with joint mobilization in the treatment of post-stroke shoulder-hand syndrome.Methods A total of 80 patients with post-stroke shoulder-hand syndrome were randomly divided into a treatment group and a control group,with 40 patients in each group.Both groups were given arthrocentesis,the control group was given ordinary acupuncture on the basis of arthrocentesis,and the treatment group was combined with thumb-tack needling for subcutaeous embedding.One course of treatment was 4 weeks and a total of 4 weeks of treatment was given.After 1 month of treatment,the clinical efficacy of the two groups was evaluated.The changes of Visual Analogue Scale(VAS)of pain scores and simplified Fugl-Meyer Assessment(FMA)scores,as well as the pain-free passive forward flexion and abduction of the shoulder joint of the affected limb were observed before and after treatment.The Simple Quality of Life Scale(SF-36)scores of the patients in the two groups were compared after treatment.The safety and the occurrence of adverse reactions in the two groups were also evaluated.Results(1)The total effective rate was 95.00%(38/40)in the treatment group and 80.00%(32/40)in the control group.The efficacy of the treatment group was superior to that of the control group,and the difference was statistically significant(P＜0.05).(2)After treatment,the VAS scores and upper extremity FMA scores of the patients in the two groups were significantly improved(P＜0.05),and the treatment group was significantly superior to the control group in improving the VAS scores and upper extremity FMA scores,and the differences were statistically significant(P＜0.05).(3)After treatment,the joint mobility of patients in the two groups were significantly improved(P＜0.05),and the improvement of shoulder joint movement in the treatment group was superior to that in the control group,and the difference was statistically significant(P＜0.05).(4)After treatment,the SF-36 Quality of Life Scale scores of the treatment group were significantly superior to those of the control group in terms of physical function,psychological function,emotional health,and social function levels,and the difference was statistically significant(P＜0.05).(5)There was no significant difference in the incidence of adverse reactions between the treatment group and the control group(P＞0.05).Conclusion Thumb-tack needling for subcutaeous embedding combined with joint mobilization exert certain effect in the treatment of post-stroke shoulder-hand syndrome.It can significantly improve the pain symptoms of patients,thus improving their quality of life,and the clinical effect is remarkable.