Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is usually diagnosed at a late stage and has a modest clinical response and poor prognosis. Therefore, identifying targets for the effective treatment of PDAC is particularly important. STAM-binding protein (STAMBP) is a JAMM metalloprotease of the deubiquitinase (DUB) family that typically regulates the stabilization and trafficking of substrates in a range of cell types by specifically removing ubiquitin chains. However, its roles in the initiation and progression of PDAC remain unclear. Here, we found that STAMBP is highly expressed in PDAC and is associated with a poor prognosis. STAMBP facilitates the proliferation and migration of PDAC cells and the growth of pancreatic cancer xenograft tumours in mice. We then identified the cochaperone BAG3, which plays a pivotal role in tumourigenesis, as a potential substrate of STAMBP using mass spectrometry (MS). Mechanistically, STAMBP interacts with BAG3 and promotes its stabilization by removing its K63-linked polyubiquitin chains. The Lys29 and Lys60 residues of BAG3 are essential for the K63-linked ubiquitination of BAG3. Moreover, a phosphorylation-dependent mechanism of STAMBP was identified as follows: STAMBP is phosphorylated by IKKα at Ser2 without affecting STAMBP protein abundance, and this phosphorylation enables it to deubiquitinate BAG3. In addition, we found that STAMBP deficiency effectively increases cisplatin/oxaliplatin sensitivity in PDAC. Overall, IKKα phosphorylates STAMBP at Ser 2, which activates STAMBP to deubiquitinase BAG3, thus resulting in an IKKα/STAMBP/BAG3 signaling axis that promotes PDAC progression. STAMBP might serve as a potential therapeutic target for PDAC therapy.

Exposure to excessive selenium (Se) is hazardous to human health, while Se is also an essential trace element. Therefore, exploring the appropriate exposure dose of Se has received widespread attention. Currently, the impact of Se exposure on blood lipids remains uncertain, and the potential mechanism is still unclear. Evidence from our earlier study pointed to PLCH2 as a potentially pivotal element in the association between Se exposure and total cholesterol (TC). This study aims to explore the appropriate exposure dose of Se on blood lipids, and effects of PLCH2 gene on the relationship between Se exposure and blood lipids through a longitudinal epidemiological study. Repeated measurements of urinary Se (Se-U) for 6260 participants with 9347 observations from the Wuhan-Zhuhai cohort were performed, and a U-shaped relationship between Se-U and TC was observed, the turning point of Se-U was 2.229 μg/mmol Cr. When lower than the turning point, Se-U was negatively associated with TC, while higher than the turning point, Se-U was positively associated with TC. Then, 2985 participants (6026 observations) were genotyped, and all 109 single-nucleotide polymorphisms (SNPs) within PLCH2 gene were included. Significant interaction (Pint<0.05) was observed between a haplotype of the PLCH2 and Se-U on TC: the U-shaped relationship was still observed in the PLCH2-ATCTCA haplotype carriers but not in the haplotype non-carriers. The results suggested PLCH2 gene can modify the U-shaped relationship between Se exposure and TC, which showed a new gene-environment interaction and will provide a new perspective on the relationship between Se exposure and TC.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants of global concern, yet their associations with predicted cardiovascular risk remain unclear. In this prospective Wuhan-Zhuhai cohort study, concentrations of seven serum PCBs (PCB-28, 52, 101, 118, 138, 153, and 180) were measured using GC-MS/MS. The validated China-PAR equation was used to calculate predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risk, and urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) served as a marker of oxidative stress. Multivariable linear and logistic regression models were fitted to evaluate PCB-related differences in continuous predicted risk and predicted high-risk status. Cross-sectionally, each one-unit increase in ln-transformed PCB-118, PCB-138, PCB-153, and ΣPCB was associated with 1.249-, 1.253-, 1.457-, and 1.829-percentage-point higher predicted 10-year ASCVD risk, respectively (all P < 0.05). The associations for PCB-118, PCB-138, and PCB-153 remained significant after FDR correction. Longitudinally, persistent high PCB-118 exposure was associated with a 0.510 percentage-point greater increase in predicted 10-year ASCVD risk (95 % confidence interval [CI]: 0.023-0.996, P < 0.05) and a higher risk of transitioning to predicted high-risk status (RR = 1.432, 95 % CI: 1.012-2.027, P < 0.05) compared with persistent low exposure, although neither association remained significant after FDR correction. Exploratory mediation analysis suggested that urinary 8-iso-PGF2α was statistically consistent with partial indirect pathways for the associations, with estimated indirect proportions ranging from 3.29 % to 11.62 %. Database-derived bioinformatics analyses highlighted TNF/NF-κB/IL-17 pathways and identified IL-6, TNF, IL-1β, and ICAM1 as candidate hub genes. Overall, several PCB measures were cross-sectionally associated with higher predicted ASCVD risk, whereas longitudinal evidence was limited and was strongest for persistent high PCB-118 exposure. Exploratory mediation and bioinformatics findings highlighted possible oxidative-stress and inflammation-related pathways that require further validation.

Systemic inflammation has been implicated as an important hallmark of cardiovascular disease, asthma, and aging. However, its adverse effect on lung function in the general population, along with its combined impact with polycyclic aromatic hydrocarbons (PAHs) exposure remains largely unknown. We developed a systemic inflammation score incorporating white blood cell (WBC) count, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-22 (IL-22), and club cell secretory protein-16 (CC16), based on biomarker-lung function associations identified in a panel study of 221 observations (n = 120). Using data from the Wuhan-Zhuhai (WHZH) cohort (5662 observations), we examined the cross-sectional and longitudinal associations of the systemic inflammation score and urinary mono-hydroxylated PAH metabolites (OH-PAHs) with lung function. Each unit increase in the inflammation score was associated with reductions in forced expiratory volume in 1 s (FEV1) (-6.94 mL), forced vital capacity (FVC) (-8.03 mL), and peak expiratory flow (PEF) (-14.50 mL/s). Longitudinal analysis revealed that participants with consistently high inflammation scores experienced accelerated annual declines in FEV1 (-13.41 mL/year), FVC (-19.04 mL/year), and PEF (-93.51 mL/s·year) compared to those with consistently low scores. Although OH-PAHs were not significantly associated with inflammation scores, participants with high levels of both OH-PAHs and inflammation scores exhibited significantly lower lung function (FEV1: -132.20 mL; FVC: -155.80 mL) than those with low levels of both. Our findings suggest that systemic inflammation is independently associated with lung function decline, and its combination with PAH exposure accelerates this process. These results highlighted the importance of monitoring systemic inflammation in environmental exposures related respiratory impairment in the general population.

Abnormal sleep duration represents a significant contributor to dementia; however, this association has not been explored among the elderly Chinese population. Therefore, this study investigated the relationship between sleep duration and dementia among the Chinese elderly population. Data were obtained from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). This study included 7,680 participants aged 65 years and older at baseline in 2011. Cox proportional hazards models were performed to determine the relationship between sleep duration and dementia risk in this patient population. Over a total follow-up period of 28,147 person-years, 398 dementia cases were identified. The mean age of participants was 85.55 ± 11.09 years, with female predominance (54.71

Background:Locally advanced pancreatic cancer (LAPC) is mostly unresectable at initial diagnosis. Conversion therapy has become core treatment to downstage tumors for radical resection, yet consensus on optimal first-line regimen remains lacking. This real-world study compared three mainstream conversion regimens and identified independent survival predictors to guide individualized treatment. Methods:A single-center retrospective cohort of 172 unresectable LAPC patients receiving gemcitabine plus nab-paclitaxel (AG), modified FOLFIRINOX (mFOLFIRINOX), or AG sequential chemoradiotherapy (CRT) from 2019 to 2023 was enrolled. Tumor conversion, surgical, survival and safety outcomes were analyzed. Cox regression was adopted to screen independent prognostic factors, with P<0.05 defined as statistical significance. Results:The overall conversion rate reached 38.4%. mFOLFIRINOX yielded the highest conversion rate (52.8%) versus AG (32.6%) and AG + CRT (33.3%). Among 66 converted patients, 87.9% achieved R0 resection, with 34.8% major pathological response (MPR). Median overall survival (OS) of converted patients reached 32.5 months, far superior to non-converted cases (12.3 months). Multivariate analysis confirmed preoperative carbohydrate antigen 19-9 (CA19-9) normalization and prognostic nutritional index (PNI) ≥41.7 as two independent favorable prognostic markers. Grade 3-4 adverse events were most frequent in the mFOLFIRINOX group (56.6%). Conclusions:For physically fit unresectable LAPC patients, mFOLFIRINOX provides superior conversion efficacy despite higher toxicity. Normalized CA19-9 and well-maintained nutritional status are reliable prognostic biomarkers. This real-world evidence supports mFOLFIRINOX as preferred first-line conversion regimen and routine monitoring of CA19-9 and nutrition during therapy.

The exposure load of polycyclic aromatic hydrocarbons (PAHs) is elevating especially in the elderly population, but their impacts on biological aging remains unclear. Herein, we assessed the cross-sectional and longitudinal associations between PAHs exposure and aging acceleration via a repeated-measures study involving 7407 observations from the Wuhan-Zhuhai cohort, and explored the underlying mechanisms through network toxicology and a gene-environment interaction analysis. Urinary mono-hydroxylated PAHs (OH-PAHs) levels were measured, and the acceleration of clinical age calculated by Klemera-Doubal method (KDM_AA) and Phenotypic Age algorithm (PHE_AA) as well as methylated age proposed by Zhang et al. (Zhang_AA) and Levine et al. (Levine_AA) were constructed. Linear mixed models were used in the statistical analyses. Positive associations between several OH-PAHs and aging acceleration were observed. Each 1-unit increase in ln-transformed 3-OHPh and 1-OHPh was associated with an increase in KDM_AA of 0.456 (95% confidence interval 0.285, 0.627) and 0.198 (0.018, 0.377) years, and an annual rate of change in KDM_AA of 0.506 (0.136, 0.876) and 0.778 (0.416, 1.141) years/year, respectively. Similarly, each 1-unit increase in ln-transformed 9-OHPh and 1-OHP was associated with an increase in Zhang_AA of (0.026, 0.385) and 0.171 (0.054, 0.288) years, and an annual rate of change of 0.020 (0.003, 0.036) and 0.015 (0.002, 0.029) years/year, respectively. The reactive intermediate of phenanthrene showed binding affinity to AKT1 protein. AKT1 genetic variants exhibited interactions with OH-PAHs on aging acceleration, and individuals with high-risk genotypes and high OH-PAHs were susceptible to accelerated aging. Our study indicated that PAHs exposure was associated with aging acceleration, and AKT1 as a possible target molecule was involved.

Colorectal cancer (CRC) cells reprogram multiple metabolic pathways, including anaerobic glycolysis, lipogenesis and amino acid metabolism, to support their rapid cell division. However, the key regulators driving these metabolic alterations in CRC remain unknown. In the present study, immunohistochemistry staining of a tissue microarray demonstrated that yes‑associated protein 1 (YAP1) was markedly upregulated in CRC tissues and strongly associated with worse patient survival. Knocking down YAP1 inhibited the proliferation and cholesterol accumulation of CRC cells both in vitro cell growth assays and in vivo xenograft model. Mechanistically, western blotting, co‑immunoprecipitation and immunofluorescence assays showed that YAP1 not only transcriptionally upregulated sterol regulatory element binding protein 2 (SREBP2) expression but also physically interacted with it to facilitate its nuclear translocation. This coordinated regulation drove the expression of genes governing de novo cholesterol synthesis and exogenous cholesterol influx. Functional experiments revealed that the SREBP2‑dependent cholesterol metabolic pathway was essential for YAP1‑driven tumorigenesis and proliferation in CRC. These findings uncovered a YAP1‑SREBP2 axis involved in CRC metabolic reprogramming and suggested that targeting this interaction may represent a promising metabolic intervention strategy for CRC management.

Background: Amide herbicides were extensively utilized, and their health effects warranted attention. Objectives: To assess the effects of amide herbicides on lung function. Methods: A total of 4470 participants from the Wuhan-Zhuhai cohort were included, 2052 of whom engaged in the 3-year follow-up. Serum and dietary amide herbicides including metolachlor, acetochlor, and butachlor were measured; PM2.5 exposure levels were estimated; lung function was tested; and lung function-related polygenic risk score (PRS) was calculated. Linear mixed models were used to estimate the associations of serum amide herbicides and the interaction between PRS with lung function. Machine learning models were used to evaluate the contributions of dietary amide herbicide intake amounts and PM2.5 exposure levels to serum amide herbicide levels. Results: Cross-sectionally, negative associations between amide herbicides with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were observed (P < 0.05). Longitudinally, a 34.61 mL and 7.48 mL decrease in FVC was associated with a 2-fold increase in metolachlor and butachlor, and a 26.06 mL decrease in FEV1 was associated with a 2-fold increase in metolachlor over 3 years. Participants with high amide herbicide levels and high PRS showed the greatest lung function reduction. Contribution analyses showed that PM2.5 exposure and dietary intake were the potential prominent contributors to serum amide herbicides. Conclusions: Amide herbicide exposure was associated with lung function decline, and participants with high PRS showed greater lung function reduction; PM2.5 exposure and dietary intake were the potential primary sources of amide herbicide exposure.

BACKGROUND:Cadmium (Cd), a toxic heavy metal, is classified as a human carcinogen by the International Agency for Research on Cancer (IARC). Epidemiological studies suggested a potential link between cadmium exposure and lung cancer risk, but evidence has remained inconsistent, particularly regarding differences between occupational and general populations. This protocol will outline a systematic review and meta-analysis to quantify the association between cadmium exposure (via blood, urine, hair, or environmental samples) and lung cancer risk. METHODS:This study protocol will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines. A comprehensive search of PubMed, Embase, Web of Science, Medline, and Cochrane databases will identify observational studies published from inception to December 2024. Two reviewers will independently screen studies, extract data, and assess the quality of included using the Newcastle-Ottawa Scale (NOS). We will harmonize data to calculate pooled relative risks (RRs) with 95% confidence intervals (CIs). Random-effects model is anticipated for high-heterogeneous results, while fixed-effects model will be adopted for low- heterogeneous results. Sub-group analyses (e.g., population type (general/occupational), geographic region, year of publication), sensitivity analyses, and assessments of publication bias (Egger's test, funnel plots) will be conducted to ensure the robustness and reliability of the findings. The analyses will be conducted via RevMan 5.3 and STATA 15 software. DISCUSSION:This protocol will guide the standard process of the systematic review, providing synthesized evidence on the short-, and long-term effect of cadmium on lung risk in general and occupational populations. CONCLUSION:This systematic review and meta-analysis will provide synthesized evidence regarding cadmium exposure with lung cancer risk in both occupational and general populations. The evidence obtained in this study can inform the public and the policy-making bodies. REGISTER ON PROSPERO:CRD42024527248.

Chromium (Cr) exposure has been reported to be associated with heart rate variability (HRV) decline, whereas the underlying mechanism remains unknown. In present study, a cross-sectional study was conducted in Chinese urban adults to explore the potential role of microRNAs (miRNAs) in the relationship between urinary chromium and HRV decline. In the discovery stage, 20 Cr-related miRNAs were screened out by high-throughput sequencing. Both generalized linear model and differential expression analysis were conducted and miR-450a-1-3p was chosen for further analyses. Then, the quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to measure the concentration of plasma miR-450a-1-3p and generalized linear model was used to estimate the association between urinary chromium, plasma miR-450a-1-3p and HRV indices and further to explore the potential role of miR-450a-1-3p in chromium-induced HRV reduction. Precisely, a positive association of chromium exposure with plasma miR-450a-1-3p was observed and HRV indices were negatively related to urinary chromium or plasma miR-450a-1-3p concentrations elevating (all P < 0.05). Furthermore, plasma miR-450a-1-3p significantly mediated and affected the relationship between chromium exposure and HRV reduction. Finally, we used KEGG analysis to study the potential pathway of miR-450a-1-3p and inferred the arrhythmogenic right ventricular cardiomyopathy and calcium signaling pathway were involved in the chromium-induced HRV reduction.

Polycyclic aromatic hydrocarbons （PAHs） and their derivatives, nitrated polycyclic aromatic hydrocarbons （NPAHs） and oxygenated polycyclic aromatic hydrocarbons （OPAHs）, have been under constant scrutiny for their prominent carcinogenicity and mutagenicity. In this study, fine particulate matter （PM2.5） was collected in the urban area of Shanghai from 2022 to 2023. Their diurnal and nocturnal mass concentration variations, sources, and health risk assessment were analyzed. Two-dimensional gas chromatography-time-of-flight mass spectrometry （GC×GC-ToF-MS） was used to quantify PAHs, NPAHs, and OPAHs. The results showed that the daily average concentrations of PAHs, NPAHs, and OPAHs were 4.44, 0.89, and 2.38 ng·m-3, respectively, in winter. The concentration levels were much lower in summer than those in winter, which were 0.20, 0.04, and 0.40 ng·m-3, respectively. The ratio of the concentrations of NPAHs to those of PAHs and OPAHs concentrations by 1-2 orders of magnitude. The substance concentrations of PAHs and NPAHs in summer were higher in the daytime than those at nighttime and vice versa for OPAHs. Concentrations of the few target substances in winter samples were higher at night. The substances with the highest concentrations of PAHs during the sampling period were fluoranthene and benzo（b）fluoranthene, whereas the substances with the highest concentrations of NPAHs and OPAHs were 9-nitroanthracene and 9,10-anthraquinone, respectively. Based on the results of correlation analysis and source analysis by the diagnostic ratios, PAHs and their derivatives in PM2.5 in the urban area of Shanghai were affected by mixed emission sources, with primary emissions accounting for a significant portion. In addition to vehicle emissions and some coal and biomass combustion, the generation of PAHs was also affected by aerosol aging. Vehicle emissions were the major source of NPAHs, whereas OPAHs might be from the same primary emission sources as those of PAHs. Primary emissions contributed more to PAHs in winter than in summer. Comparison of the toxic equivalents of PAHs, NPAHs, and OPAHs in PM2.5 in winter and summer during the sampling period revealed that the average daily TEQ value was higher in winter （441.4 pg·m-3） than that in summer （39.8 pg·m-3）, which was consistent with the seasonal variation of mass concentrations. The toxicity of PAHs and their derivatives in PM2.5 in the Shanghai urban area was higher during nighttime than that in the daytime. Most of the potential carcinogenic risk originated from PAHs, and the ILCR values caused by NPAHs and OPAHs were 1-2 orders of magnitude lower than those caused by PAHs. The results of health risk assessment based on incremental lifetime cancer risk modeling showed that the total cancer risk was higher in adults than that in adolescents and children and that females had a higher cancer risk than males through different exposure pathways. Adults had a higher risk of cancer from respiratory inhalation and dermal exposure than that of adolescents and children, whereas adolescents had a higher risk of cancer from oral ingestion. The results showed that the carcinogenic risk of PAHs and their derivatives in the atmosphere in the urban area of Shanghai in winter and summer was within controllable range.

BACKGROUND:Zinc pollution is alarming, demanding urgent attention to its adverse effects. METHODS:The prospective study was conducted among 10057 general Chinese observations from the Wuhan-Zhuhai cohort. Genetic susceptibility was assessed by calculating the lung function-related polygenic risk score (PRS). Aging acceleration of Klemera-Doubal age (KDM_AA) and phenotypic age (PHE_AA) were constructed from clinical parameters. The associations between urinary zinc and lung function were assessed using group-based trajectory models and linear mixed models (LMMs). The relationships of urinary zinc with KDM_AA and PHE_AA were evaluated using LMMs, and the mediating role of aging acceleration was assessed via longitudinal mediation analyses. RESULTS:Urinary zinc was negatively associated with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), especially in the third PRS quantile group. Each 1-unit increase in ln-transformed value of urinary zinc was associated with the annual change rate in FVC and FEV1 of -10.624 (95 % confidence interval -17.617, -3.550) mL/year and -6.826 (-12.113, -1.469) mL/year, respectively. Positive longitudinal associations were observed between urinary zinc and aging acceleration, with the annual change rate of 0.128 (0.038, 0.219) years/year for KDM_AA and 0.077 (0.036, 0.118) years/year for PHE_AA. Moreover, aging acceleration partially mediated the associations of urinary zinc with FVC and FEV1, and the mediated proportion ranged from 11.38 % to 18.60 %. CONCLUSIONS:Zinc exposure was associated with lung function decline especially among individuals genetically vulnerable. Biological aging acceleration caused by zinc exposure may be the potential mechanism.

Background:Studies examining associations between meteorological factors and outpatient visits for chronic rhinosinusitis (CRS) are limited. This study aimed to investigate the effects of daily mean temperature, relative humidity (RH) and precipitation on outpatient visits for CRS. Methods:Electronic records of CRS outpatient visits were collected from Tongji hospital in Wuhan, China from January 1, 2018 to December 31, 2019. Daily meteorological data were obtained from the Wuhan Meteorological Bureau during the same period. A generalized additive negative binomial regression model combined with a distributed lag non-linear model (DLNM) was employed to analyze the lag-exposure-response relationship between meteorological factors and the number of CRS outpatient visits. Stratified analyses were conducted to identify potential effect modifications by age and season. Results:A total of 14,259 CRS outpatient visits were recorded. Relative humidity and precipitation showed no significant association with daily CRS visits, whereas low temperatures significantly elevated CRS outpatient visits. Specifically, extreme temperature (-1.8°C, 1st percentile) was found to be associated with 1.946 (95% CI 1.273-2.973) times the risk of outpatient visits due to CRS, compared to the reference value of 32.9°C. Furthermore, the number of outpatient visits for childhood and younger individuals with CRS showed a negative correlation with temperatures, whereas middle-aged individuals and older adult individuals showed no such correlation. Conclusion:This study suggests that meteorological phenomena may have detrimental effects on health, thereby contributing to a better understanding of the environmental risk factors associated with this disease.

Metal exposure could induce oxidative stress, yet the underlying epigenetic mechanisms remain unclear. Herein, we aimed to investigate the DNA methylation signatures associated with oxidative stress biomarkers, including 8-hydroxyguanine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α), and evaluate their mediating role in metal-induced oxidative stress. A genome-wide DNA methylation association study was conducted in discovery panel (Shiyan, N = 155) with validation in an independent replication panel (Wuhan-Zhuhai, N = 50). We identified 24 differentially methylated positions (DMPs) associated with 8-OHdG (P < 1 × 10-5), 17 of which were replicated (P < 0.05), along with one validated DMP associated with 8-iso-PGF2α. Two-sample Mendelian randomization analyses supported the causal role of cg15457217 (WDFY1) for 8-OHdG and cg16689883 (LOC284930) for 8-iso-PGF2α. Among the 18 replicated DMPs, five were significantly associated with the expression levels of their annotated genes (KIDINS220, SBF2, DENND1A, PIWIL4, KAT6B). Urinary levels of individual metals (e.g., arsenic, cadmium, molybdenum, strontium) and metal mixtures (assessed by weighted quantile sum regression) were positively associated with both oxidative stress biomarkers. Mediation analyses revealed that 14 replicated DMPs mediated 12.54-33.44 % of the associations for 8-OHdG and 12.60-13.83 % for 8-iso-PGF2α. Notably, cg06197624 (SMIM20) and cg09953898 (KIDINS220) exhibited a significant inverse association with 8-OHdG (FDR < 0.05) and mediated up to 33.44 % of the effect of metal exposure on oxidative DNA damage. These findings demonstrated the mediating role of DNA methylation in metal-induced oxidative stress, highlighting the epigenetic loci involved in redox-related biological responses. Further studies with larger sample sizes and longitudinal assessments are warranted to validate our findings.

In recent years, the release of substantial amounts of synthetic endocrine-disrupting chemicals (EDCs) into the environment has posed significant threats to human health. Among these EDCs, bisphenol A (BPA) and its substitutes, such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), are widely used and have been implicated in disrupting various biological processes. This research aimed to evaluate the potential link between bisphenol-related gene expression and lung cancer prognosis. Using the Comparative Toxicogenomics Database (CTD), we identified genes involved in bisphenol metabolism and their significant associations with key oncogenes and hormone-disrupting pathways, including INS, ESR1, ESR2, AR, MAPK1, MAPK3, PPARG, and CYP19A1. Our Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicate that bisphenol-related genes may be associated with a variety of cancers, particularly lung cancer. To develop a risk model, we employed Cox regression and LASSO regression analyses, constructing a prognostic prediction model for lung cancer based on bisphenol-related gene expression (BBPPM). This model demonstrated prognostic significance, with lung cancer patients categorized into high-risk and low-risk groups, revealing significant differences in survival rates and highlighting the model's accuracy in predicting lung cancer outcomes. In addition to bioinformatics analyses, experimental studies were conducted to evaluate the effect of BPA on lung cancer cell behavior. BPA exposure significantly promoted the proliferation of A549 lung cancer cells, as assessed by the CCK-8 assay, and increased the clonogenic potential of the cells in a colony formation assay.

Disrupted brain iron metabolism and activated ferroptosis during ageing constitute significant precursors to neurodegenerative diseases. However, whether exercise intervention can modulate ferroptosis-related genes in the central nervous system remains unsystematically elucidated. This study integrated an aged cohort transcriptome dataset (GSE110298) from the GEO database (comprising 11 low-exercise and 23 high-exercise samples). Differential expression genes were screened using the limma package (|log2FC| > 1, FDR<0.05) using the limma package, intersecting these with the FerrDb V2.0 ferroptosis gene set to identify 42 exercise-responsive ferroptosis-associated genes (DFEGs). Multilevel bioinformatics analyses (KEGG/GO enrichment, STRING protein interaction networks, CytoHubba hub gene screening, GSEA pathway activity assessment, and miRNA-transcription factor regulatory network construction) revealed key molecular mechanisms. Hub gene identification: ACSL3, PPARD and TXN were identified as core targets regulating ferroptosis during exercise. Their altered expression was significantly correlated with lipid peroxidation inhibition (ACSL3), enhanced mitochondrial biogenesis (PPARD), and redox homeostasis restoration (TXN). Pathway Mechanisms: DFEGs exhibited significant enrichment in peroxisome metabolism (p=3.2×10 −5 , including 7 genes such as PEX3 and ACOX1) and the PPAR signalling pathway (p=1.8×10−□, including 5 genes such as PPARD and FABP3). GSEA analysis revealed a 31% reduction in Alzheimer’s disease-associated pathway activity in the high-exercise group (NES = -1.68, FDR = 0.032). Regulatory network: A multi-level regulatory network was constructed encompassing three hub genes, five transcription factors (FOXA2, HNF4A, etc.) and three exercise-responsive miRNAs (miR-124-3p, miR-182-5p, miR-93-5p). Among these, miR-124-3p’s targeted inhibition of ACSL3/TXN (TargetScan score >90) may mediate exercise-induced resistance to ferroptosis. This study first reveals a novel mechanism whereby exercise synergistically regulates brain ferroptosis through multiple targets. It proposes that the ACSL3/PPARD/TXN expression combination could serve as a potential biomarker for assessing exercise-induced neuroprotective efficacy, and provides a theoretical basis for developing intervention strategies for neurodegenerative diseases based on exercise-epigenetic interactions.

Background High-level exposure to crystalline silica dust is the key factor in silicosis. Long-term exposure to low-level silica dust, for example, lower than that in occupational exposure limits, still needs to be studied for their risk of silicosis. Methods A total of 30 697 workers were included from a cohort in China. Low-level silica dust exposure was defined as those having a lifetime mean silica dust concentration equal to or under permissible exposure limits, including 0.05 mg/m 3 , 0.10 mg/m 3 and 0.35 mg/m 3 . Cumulative respirable silica dust exposure (CDE) for individual workers was assessed by linking a job-exposure matrix to personal work history. Results Among those with average exposure level equal to or lower than 0.05 mg/m 3 , compared with the lowest quartile CDE (Q1), the HRs of silicosis were 1.32 (95% CI 0.82 to 2.10) for Q2, 1.87 (95% CI 1.22 to 2.88) for Q3 and 2.00 (95% CI 1.30 to 3.09) for Q4. Among those exposed to 0.10 mg/m 3 or less exposure level, compared with Q1, the HRs were 2.52 (95% CI 1.88 to 3.38) for Q2, 4.08 (95% CI 3.09 to 5.39) for Q3 and 4.02 (95% CI 3.04 to 5.32) for Q4. Among those exposed to 0.35 mg/m 3 or less exposure level, compared with Q1, the HRs were 2.80 (95% CI 2.38 to 3.28) for Q2, 5.76 (95% CI 4.93 to 6.73) for Q3 and 7.14 (95% CI 6.07 to 8.40) for Q4, respectively. Stratified analysis showed that the results and trends did not change with facilities and smoking status. Conclusion Long-term exposure to low-level silica dust is still associated with a higher risk of silicosis. Control measurements and personal protective equipment should be emphasised to protect the health of workers.

Cervical cancer (CC) is a major health threat to women, with immunotherapies targeting the programmed death receptor 1/programmed death ligand 1(PD-1/PD-L1) axis showing promise but encountering resistance in a significant patient population. This resistance has driven a critical quest to uncover the underlying mechanisms. This study uncovers a novel metabolic axis involving the nicotinamide adenine dinucleotide (NAD+) salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the deacetylase Sirtuin 1 (SIRT1), which regulates PD-L1 expression and nuclear localization in CC. This axis may be a key factor contributing to the resistance observed in immunotherapy. This study reveals that PD-L1 overexpression in cancers is regulated by both transcriptional and post-transcriptional processes. Acetyl-proteomic analysis pinpoints SIRT1 as a central regulator in the deacetylation of histone H3 at lysines 27, which may influence PD-L1 subcellular distribution. This finding reveals the epigenetic control of immune checkpoint proteins by metabolic pathways, offering a new perspective on the regulation of PD-L1. The identification of the NAMPT/SIRT1 metabolic axis as a critical factor suggests that targeting this axis may enhance therapeutic responses.

Fish oil supplements and plasma fatty acid levels were reported to be associated with lung function. We aimed to investigate the association of fish oil supplements and plasma fatty acids with lung function. We included 248,133 participants with complete data on relative index of plasma fatty acids from the UK Biobank. Linear regression models were used to investigate associations of fish oil supplements and plasma fatty acids with pulmonary function. Mediation analysis was performed to identify the potential mediating role of plasma fatty acid. All analyses were multivariable-adjusted. Higher lung function was observed in fish oil users (14.59 ml for FEV1 and 17.92 ml for FVC). We found that each 1-unit increment of plasma PUFA, omega-3, omega-6, DHA, LA, and PUFA/MUFA were positively associated with lung function (6.74 ml, 6.15 ml, 5.81 ml, 22.23 ml, 7.44 ml, and 66.67 ml for FEV1, respectively; 9.04 ml, 3.39 ml 8.63 ml, 25.51 ml, 9.53 ml, and 93.02 ml for FVC, respectively), while SFA and MUFA were inversely associated with lung function (−8.74 ml and −8.19 ml for FEV1, respectively; −10.44 ml and −11.83 ml for FVC, respectively). Omega-6/omega-3 only showed a negative association with FEV1 (−1.17 ml). Mediation analysis suggested that plasma fatty acids partly mediated the associations between fish oil supplements intake and lung function, mainly DHA (34.70