Background Lead smelting workers are exposed to mixed heavy metals such as lead (Pb) and cadmium (Cd). However, the specific associations and molecular mechanisms by which their combined exposure induces genetic damage remain unclear. Objective To clarify the association between combined Pb-Cd exposure and genetic damage and to explore the possible biological mechanisms through occupational epidemiological investigations and animal experiments. Methods (1) Population study: A cross-sectional study was conducted on 374 lead smelting workers in northern China. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect urinary levels of 8 metals including Pb and Cd, and graphite furnace atomic absorption spectroscopy (GFAAS) was used to quantify blood levels of Pb and Cd. The cytokinesis-block micronucleus assay (CBMN) was used to assess genetic damage. Poisson regression was used to analyze the association between metal exposure and micronucleus rates. (2) In vivo experiment: Thirty SD rats were randomly assigned to five groups: control (pure water), Pb (300 mg·L⁻¹ lead acetate), Cd (50 mg·L⁻¹ cadmium chloride), combined exposure (Pb + Cd), and resveratrol intervention (Pb + Cd + 50 mg·L⁻¹ resveratrol). After 8 weeks of ad libitum drinking water exposure, liver pathology, oxidative stress indicators [reactive oxygen species (ROS), reduced glutathione (GSH), oxidized glutathione (GSSG), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)], genetic damage (Comet assay and γ-H2AX) were evaluated. Furthermore, cell cycle distribution, apoptosis rates, and mRNA expression of DNA damage response (DDR), DNA repair, and apoptosis-related genes were measured. Results (1) The geometric mean (GM, 95%CI) of urinary Pb and Cd were 14.69 (13.14, 16.51) µg·L⁻¹ and 2.11 (1.90, 2.33) µg·L⁻¹, respectively; the blood Pb and Cd levels were 117.10 (105.59, 129.87) µg·L⁻¹ and 4.55 (4.23, 4.89) µg·L⁻¹, respectively among the 374 workers. The mean micronucleus rate was (1.64±0.081) ‰, with significantly higher rates in males (1.65±0.083) ‰ than females (1.53±0.334) ‰ (U=4.166, P=0.041). All Pb and Cd biomarkers were positively correlated with micronucleus rate (FR>1, P<0.05), with a significant interaction effect observed between Pb and Cd (FR>1, P<0.05). (2) In rats, co-exposure to Pb and Cd caused liver tissue damage and inflammatory infiltration. Significant increases were observed in lymphocyte ROS; GSSG and MDA in lung tissue increased, while GSH and CAT activity decreased. Comet assay indicators and γ-H2AX levels were significantly elevated. Co-exposure induced S-phase arrest and increased apoptosis. mRNA levels of DDR (ATM, ATR, Chk2, and P53) and pro-apoptotic genes (Bax and Caspase-3) were upregulated, while the anti-apoptotic gene Bcl-2 and DNA repair genes (BRCA1, BRCA2, RAD51, RAD52, and CtIP) were downregulated. Two-way ANOVA confirmed synergistic effects on GSSG, Comet assay indicators, and ATR/Chk2 mRNA expression. Conclusion Occupational co-exposure to Pb and Cd synergistically induces genetic damage. This damage is mediated by oxidative stress and DNA damage, which activates the DDR pathway and inhibits the expression of DNA repair genes, ultimately leading to cell cycle arrest and apoptosis.

Background Lead smelting workers are exposed to mixed heavy metals such as lead (Pb) and cadmium (Cd). However, the specific associations and molecular mechanisms by which their combined exposure induces genetic damage remain unclear. Objective To clarify the association between combined Pb-Cd exposure and genetic damage and to explore the possible biological mechanisms through occupational epidemiological investigations and animal experiments. Methods (1) Population study: A cross-sectional study was conducted on 374 lead smelting workers in northern China. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect urinary levels of 8 metals including Pb and Cd, and graphite furnace atomic absorption spectroscopy (GFAAS) was used to quantify blood levels of Pb and Cd. The cytokinesis-block micronucleus assay (CBMN) was used to assess genetic damage. Poisson regression was used to analyze the association between metal exposure and micronucleus rates. (2) In vivo experiment: Thirty SD rats were randomly assigned to five groups: control (pure water), Pb (300 mg·L⁻¹ lead acetate), Cd (50 mg·L⁻¹ cadmium chloride), combined exposure (Pb + Cd), and resveratrol intervention (Pb + Cd + 50 mg·L⁻¹ resveratrol). After 8 weeks of ad libitum drinking water exposure, liver pathology, oxidative stress indicators [reactive oxygen species (ROS), reduced glutathione (GSH), oxidized glutathione (GSSG), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)], genetic damage (Comet assay and γ-H2AX) were evaluated. Furthermore, cell cycle distribution, apoptosis rates, and mRNA expression of DNA damage response (DDR), DNA repair, and apoptosis-related genes were measured. Results (1) The geometric mean (GM, 95%CI) of urinary Pb and Cd were 14.69 (13.14, 16.51) µg·L⁻¹ and 2.11 (1.90, 2.33) µg·L⁻¹, respectively; the blood Pb and Cd levels were 117.10 (105.59, 129.87) µg·L⁻¹ and 4.55 (4.23, 4.89) µg·L⁻¹, respectively among the 374 workers. The mean micronucleus rate was (1.64±0.081) ‰, with significantly higher rates in males (1.65±0.083) ‰ than females (1.53±0.334) ‰ (U=4.166, P=0.041). All Pb and Cd biomarkers were positively correlated with micronucleus rate (FR>1, P<0.05), with a significant interaction effect observed between Pb and Cd (FR>1, P<0.05). (2) In rats, co-exposure to Pb and Cd caused liver tissue damage and inflammatory infiltration. Significant increases were observed in lymphocyte ROS; GSSG and MDA in lung tissue increased, while GSH and CAT activity decreased. Comet assay indicators and γ-H2AX levels were significantly elevated. Co-exposure induced S-phase arrest and increased apoptosis. mRNA levels of DDR (ATM, ATR, Chk2, and P53) and pro-apoptotic genes (Bax and Caspase-3) were upregulated, while the anti-apoptotic gene Bcl-2 and DNA repair genes (BRCA1, BRCA2, RAD51, RAD52, and CtIP) were downregulated. Two-way ANOVA confirmed synergistic effects on GSSG, Comet assay indicators, and ATR/Chk2 mRNA expression. Conclusion Occupational co-exposure to Pb and Cd synergistically induces genetic damage. This damage is mediated by oxidative stress and DNA damage, which activates the DDR pathway and inhibits the expression of DNA repair genes, ultimately leading to cell cycle arrest and apoptosis.

Objective: To characterize perioperative dynamic changes in immune-cell phenotypes and inflammatory cytokines in patients undergoing CPB (cardiopulmonary bypass) cardiac surgery, and to explore their associations with postoperative outcomes. Methods: In this prospective cohort study, 120 adult patients who underwent elective cardiac surgery under CPB at West China Hospital from May 2022 to March 2023 were enrolled. Perioperative immune-cell phenotypes and concentrations of 40 inflammation-related cytokines were measured. The primary outcomes were the sequential organ failure assessment (SOFA) score at 24 h after surgery and ΔSOFA (the peak SOFA score within 48 h after surgery minus the preoperative SOFA score). Secondary outcomes included major adverse cardiovascular events (MACE), acute kidney injury (AKI), respiratory failure, severe liver injury, and infection. Results: The mean age of enrolled patients was 57±10 years. Of these, 52% (62/120) were male and 90% (108/120) underwent valve surgery. During the rewarming to the end of CPB, neutrophil counts rapidly increased (7.39×10 /L vs preoperative 3.07×10 /L, P<0.001), with significant upregulation of CD11b (7.30×10 /L vs preoperative 3.05×10 /L, P<0.001) and CD54 (7.15×10 /L vs preoperative 2.99×10 /L, P<0.001). Lymphocyte counts increased at the end of CPB (1.75×10 /L vs preoperative 1.12×10 /L, P<0.001) but decreased significantly at 24 h after surgery (0.59×10 /L vs preoperative 1.12×10 /L, P<0.001). Plasma analysis showed that multiple pro-inflammatory cytokines increased during CPB and remained elevated up to 24 h after surgery; five chemokines and the anti-inflammatory cytokine IL-10 peaked at the end of CPB. The SOFA score increased from 1 (1, 2) preoperatively to 7 (5, 10) at 24 h after surgery, with a ΔSOFA of 6 (4, 8). Within 30 days after surgery, 48 patients (40.0%) developed AKI, 17 (14.2%) developed infection, 4 (3.3%) developed severe liver injury, 3 (2.5%) developed respiratory failure, and 3 (2.5%) experienced MACE. During the 2-year follow-up, 8 patients (6.7%) experienced MACE and 5 (4.2%) died. Conclusion: Multi-organ dysfunction is common after cardiac surgery under CPB (median ΔSOFA, 6), accompanied by perioperative activation of multiple immune-cell subsets and upregulation of pro-inflammatory, anti-inflammatory, and chemotactic mediators. This study provides data-driven evidence and research clues for further investigation of the associations between CPB-related immune perturbations and postoperative organ dysfunction and clinical outcomes.

Alcoholic liver fibrosis is a critical step in the progression of alcoholic liver disease toward liver cirrhosis， yet there is currently still a lack of effective and specific anti-fibrotic therapeutic strategies. Recent studies have shown that as an iron-dependent， lipid peroxidation-driven form of regulated cell death， ferroptosis plays an important role in alcohol-related hepatocellular injury and fibrogenesis. Reactive oxygen species generated during alcohol metabolism can damage hepatocytes， impair their antioxidant defense ability， and lead to disruption of iron homeostasis and accumulation of lipid peroxides， ultimately triggering ferroptosis. Hepatocyte ferroptosis can promote fibrosis by amplifying inflammatory responses and activating hepatic stellate cells， whereas selective induction of ferroptosis in activated hepatic stellate cells may attenuate fibrosis， highlighting the “double-edged sword” effect of ferroptosis. Current interventions against ferroptosis mainly focus on applying antioxidant approaches， reducing iron burden， or blocking the amplification of lipid peroxidation， which have shown preliminary efficacy and a potential clinical value， but there are still limitations such as single-target actions and insufficient cell selectivity. In the future， nanotechnology-based delivery and other targeting strategies may help to realize multi-pathway coordination and cell-specific modulation， thereby improving the anti-fibrotic efficacy of ferroptosis-oriented therapies.

AIM:This study investigated the role of solute carrier family 7 member 11(SLC7A11)in sul-fasalazine(SAS)-induced ferroptosis in acute myeloid leukemia(AML)cells,focusing on the inhibitory effect of nuclear factor E2-related factor 2(NRF2)nuclear translocation-mediated activation of SLC7A11 on ferroptosis and its underlying mechanisms.METHODS:SAS-induced proliferation in AML cell lines,Kasumi-1 and THP-1,was assessed using the MTS assay.Cell death inhibitors were employed to determine the mode of cell death.Lipid reactive oxygen species(ROS)levels were measured by flow cytometry;Fe2+,malonodialdehyde(MDA),glutathione(GSH)levels,and glutathione per-oxidase 4(GPX4)activity were assessed using micromethods.Quantitative PCR(qPCR)was performed to evaluate changes in SLC7A11 mRNA during SAS-induced ferroptosis,while Western blot measured SLC7A11 and GPX4 protein levels.Moreover,Western blot assessed NRF2 nuclear translocation post-SAS treatment.The NRF2 inhibitor ML385 was used to validate these effects.SLC7A11 mRNA and protein levels were then measured following combined SAS and ML385 treatment via qPCR and Western blot.Cell viability and ferroptosis-related indices were evaluated under the same treatment conditions.Furthermore,a shRNA vector targeting SLC7A11 was constructed to assess changes in cell viability and ferroptosis markers after SLC7A11 knockdown with SAS.GPX4 protein levels were examined following SLC7A11 knockdown.RESULTS:SAS significantly inhibited the proliferation of Kasumi-1 and THP-1 cells at 200 μmol/L and 300 μmol/L,respectively(P<0.05).Only ferroptosis inhibitors(Fer-1 and DFO)significantly reversed SAS-induced cy-totoxicity(P<0.01).SAS increased lipid ROS,Fe2+,and MDA levels(P<0.01),while reducing GSH and GPX4 activity(P<0.01).The mRNA and protein expressions of SLC7A11 increased during SAS-induced ferroptosis(P<0.01),where-as GPX4 protein decreased significantly(P<0.01).SAS significantly increased the nuclear-to-cytoplasmic NRF2 ratio(P<0.01),which decreased upon co-treatment with ML385(P<0.05).Following SAS and ML385 co-treatment,both SLC7A11 mRNA and protein levels were downregulated(P<0.01).This combination treatment further reduced AML cell viability(P<0.01),an effect reversed by Fer-1 and DFO(P<0.01).Compared with SAS alone,the combination of SAS and ML385 significantly increased lipid ROS,Fe2+,and MDA while reducing GSH levels and GPX4 activity(P<0.01).SLC7A11 knockdown was successfully achieved.Compared with the NC shRNA group,SLC7A11 knockdown cells showed significantly decreased viability after SAS treatment,which was reversed by Fer-1 and DFO(P<0.01).Lipid ROS,Fe2+,and MDA content were significantly increased(P<0.01),and GSH and GPX4 were substantially decreased(P<0.05).Moreover,GPX4 protein expression was considerably reduced after SLC7A11 knockdown(P<0.01).CONCLUSION:SAS induces ferroptosis in AML cells.It promotes the nuclear translocation of NRF2 protein,which activates SLC7A11 ex-pression.Inhibition of NRF2 or downregulation of SLC7A11 sensitizes AML cells to SAS-induced ferroptosis.

OBJECTIVE To investigate the protective effects of hydroxytyrosol hydroxybutyrate(HTHB)against cognitive impairment induced by acute sleep deprivation in mice and to explore the underlying mechanisms.METHODS Male C57BL/6J mice were assigned to the following groups:normal control,normal groups administered with HTHB 30,60 and 120 mg·kg-1 or hydroxytyrosol(HT 19.25,38.5 and 77 mg·kg-1),a sleep deprivation(SD)model group,and SD groups co-administered with the same doses of HTHB or HT.Acute sleep deprivation was induced for 72-96 h using a rotarod apparatus in all groups except the normal control and normal drug-treated groups.Based on dose-response assess-ments in the Y-maze and novel object recognition tests,the effective doses(HTHB 60 mg·kg-1 and HT 38.5 mg·kg-1)were selected for subsequent evaluation in the two-choice visual discrimination task that was performed in a subset of groups:normal control,normal+HTHB 60 mg·kg-1,normal+HT 38.5 mg·kg1,SD model,SD+HTHB 60 mg·kg-1,and SD+HT 38.5 mg·kg-1.Cognitive functions that were assessed included spatial working memory(Y-maze spontaneous alternation),object recognition memory(novel object recognition)and visual discrimination ability(two-choice visual discrimination task).Biochemically,levels of hippocampal reactive oxygen species(ROS)were quantified by ELISA while the ATP content was determined using a firefly luciferase-based assay.RESULTS In non-sleep-deprived mice,neither HTHB nor HT administration significantly altered locomotor activity,spatial working memory,object recognition memory,or visual discrimination performance.Following sleep deprivation,the model group displayed significant cognitive deficits,including reduced spontaneous alternation rate,lower novel object recognition indexes,and decreased accuracy in the visual discrimination task at 48 and 96 h.These impairments were accompanied by elevated hippocampal ROS levels and reduced ATP contents com-pared to the control group.Treatment with HT 38.5 and 77 mg·kg-1 significantly attenuated the deficit in spontaneous alternation,but did not affect other parameters.In contrast,HTHB at 60 and 120 mg·kg-1 produced broader restorative effects and significantly reversed impairment in both spontaneous alterna-tion and novel object recognition.Furthermore,HTHB at 60 mg·kg-1 significantly improved visual discrimination accuracy at 48 and 96 h,while lowering hippocampal ROS levels and increasing ATP contents.CONCLUSION HTHB effectively mitigates acute sleep deprivation-induced impairment in spatial working memory,object recognition memory,and visual discrimination in mice.This protection is likely mediated by the enhancement of mitochondrial antioxidant capacity and the restoration of energy metabolism.

Objective:To establish the predictive model for major adverse cardiovascular events(MACE) following endovascular repair in elderly patients with abdominal aortic aneurysm(AAA).Methods:The clinical data and postoperative MACE were retrospectively collected from elderly patients with AAA who underwent their first endovascular aneurysm repair(EVAR)in Beijing Hospital and Tibet Autonomous Region People's Hospital between January 2016 and December 2023.Patients were randomly divided into training and validation cohorts at a ratio of 7∶3.Predictive models were using logistic regression, LASSO regression, random forest, linear discriminant analysis, na?ve Bayes, k-nearest neighbor algorithm, support vector machine, decision tree, and AdaBoost.Models were evaluated using receiver operating characteristic(ROC)curves.Results:A total of 171 elderly AAA patients were enrolled, aged 60 to 94 years(mean 73.0 ± 7.5 years), of whom 145 were male.MACE occurred after EVAR in 30 patients(17.5%). LASSO regression identified monocyte count, history of coronary artery disease, the ratio of maximum AAA diameter to body mass index(DBR), neutrophil-lymphocyte count ratio(NLR), and age as significant predictors, yielding an area under the ROC curve(AUC)of 0.816.Logistic regression achieved an AUC of 0.813 in the training cohort and 0.772 in the validation cohort.Among all models, AdaBoost demonstrated the best performance, with an AUC of 0.92 in the validation cohort.Conclusions:Age, monocyte count, DBR, NLR and creatinine could predict the occurrence of MACE after EVAR in AAA patients.The AdaBoost model provides the most accurate prediction of postoperative MACE.

In the context of comprehensively advancing the Healthy China initiative,the high-quality development of public hospitals must be guided by the core principle of"people's health".It provides a systematic analysis of the historical evolution of developmental paradigms in Chinese public hospitals.By integrating the current policy requirements for their high-quality development,it proposes key pathways including the innovation of development concepts,the reconstruction of hospital connotations,the extension of service management,the optimization of the system structure,and the empowerment of digital and intelligent technologies.Through empirical case studies that demonstrate the viability of these pathways,it aims to provide theoretical support and practical reference for the high-quality development of public hospitals centered on people's health.

Objective:To compare the sustained virological response (SVR) and viral recurrence in patients with chronic hepatitis C (CHC) after antiviral treatment, and to further analyze the influencing factors of liver-related events (LRE).Methods:This was a retrospective cohort study. A total of 1 844 CHC patients who visited the Department of Infectious Diseases of Hainan General Hospital from January 1st, 2013 to December 31st, 2022 were included. After screening, 891 patients were selected and divided into direct-acting antiviral agent (DAA) treatment group, interferon treatment group and non-antiviral treatment group based on different intervention measures. Propensity score matching was performed, and SVR and viral recurrence were compared among the three groups. Statistical analysis was performed using the chi-square test, and multivariate Cox regression analysis was used to evaluate the risk factors for LRE.Results:The confirmed CHC patients showed an increasing trend year by year (average annual change percentage=19.97%, 95% confidence interval ( CI) 10.46% to 30.30%, t=4.32, P<0.001). After propensity score matching, the total sample size of 891 CHC patients was 451, including 100 in the interferon treatment group, 311 in the DAA treatment group, and 40 in the non-antiviral treatment group. In the interferon treatment group, 89 cases (89.00%) achieved SVR and nine cases (9.00%) had recurrence. In the DAA treatment group, 306 cases (98.39%) achieved SVR and 10 cases (3.22%) had recurrence. The differences were statistically significant ( χ2=17.84 and 6.22, respectively, both P<0.05). Cox multivariate regression analysis showed that age (hazard ratio ( HR)=1.065, 95% CI 1.028 to 1.104, P<0.001), alcohol consumption ( HR=3.034, 95% CI 1.302 to 7.071, P=0.010) were independent risk factors for LRE in CHC patients, while albumin ( HR=0.858, 95% CI 0.802 to 0.917, P<0.001), DAA treatment ( HR=0.267, 95% CI 0.103 to 0.692, P=0.007) were protective factors. In CHC patients receiving antiviral treatment, diabetes ( HR=6.719, 95% CI 2.242 to 20.137, P<0.001), total bilirubin ( HR=1.111, 95% CI 1.054 to 1.171, P<0.001) and viral recurrence ( HR=4.646, 95% CI 1.322 to 16.321, P=0.017) were independent risk factors for LRE. Conclusions:Compared with interferon treatment, DAA treatment has a significantly higher SVR rate and a lower recurrence rate. Age and alcohol consumption are independent risk factors for LRE, while higher albumin levels and DAA treatment are protective factors. In CHC patients receiving antiviral treatment, diabetes, viral recurrence, and total bilirubin are independent risk factors for LRE.

Classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) comprise a group of clonal disorders originating from hematopoietic stem cells, commonly characterized by thrombotic events, extramedullary hematopoiesis, and a propensity for malignant progression to myelofibrosis or acute leukemia. With the inclusion in the core diagnostic criteria, molecular biomarkers has exhibited applicational valus in multiple levels in the aspects of personalized therapy to subtype MPN, interpret phenotypic heterogeneity, and predict clinical outcomes. Molecular biomarkers are currently being applied in disease diagnosis, progression prediction, therapeutic strategy refinement, precision monitoring, familial MPN screening, and the development of emerging detection technologies, advancing the shift from fundamental MPN research to individualized clinical management.