Polycyclic aromatic hydrocarbons (PAHs) are neurotoxicants that may induce cognitive deficits via thyroid dysfunction. Older adults, due to physiological decline, are more susceptible to such toxicants. This crosssectional study involving 433 elderly adults examined the relationships between PAH exposure, cognitive decline and thyroid-mediated pathways. Urinary PAH metabolites were measured and cognitive performance was assessed using the Mini-Mental State Examination (MMSE). Participants were categorized into low-risk (n = 367) and high-risk mild cognitive impairment (MCI) groups (n = 66) based on MMSE scores. Logistic regression results indicated that the odds of MCI risk increased with each one-unit increase in log-transformed levels of 2-OHNap, 2-OHFlu, and 3-OHFlu. Linear modeling further revealed that these metabolites (OH-Nap and OH-Flu) were dose-dependently negatively associated with orientation, attention and memory. In addition, there was a nonlinear dose-response relationship between 1-OHNap and verbal ability, and Sigma OH-PAHs and attention/ memory. Critically, mediating effect analysis showed that the FT3/FT4 ratio mediated the association between PAH metabolites and MMSE scores with a contribution of 22.5 %-26.3 %. This study reveals the mechanism by which PAHs exposure may mediate cognitive decline in the elderly by interfering with thyroid function, providing an important scientific basis for the prevention of environmental factor-induced neurodegenerative diseases.

Atherosclerosis (AS) is a disease characterized by chronic vascular wall inflammation and lipid deposition. Although lipid-lowering drugs such as statins have significantly reduced cardiovascular event rates, "residual inflammatory risk" remains a key factor driving disease progression and plaque rupture. As a central regulator of the inflammatory response, the nuclear factor-κappaB (NF-κB) signaling network comprises both canonical pro-inflammatory pathways and functionally more complex non-canonical pathways. Increasing evidence in recent years indicates that abnormal and sustained activation of the non-canonical NF-κB signaling pathway plays a pivotal role in driving plaque rupture. This review first elaborates on the shift in AS strategies from "lipid-lowering" to "anti-inflammatory" approaches, followed by an in-depth analysis of the molecular activation mechanisms of the NF-κB signaling pathway and its distinctiveness in the AS pathological process, along with its epigenetic regulation. It emphasizes how this pathway drives pathological angiogenesis and regulates vascular smooth muscle cell (VSMC) phenotypic switching and macrophage function, thereby forming a vicious cycle that amplifies inflammation and structural damage, ultimately leading to acute cardiovascular events. Finally, we systematically summarize current progress and challenges in drug development targeting the NF-κB pathway (e.g., targeting key kinases like NIK and IKKα), aiming to provide theoretical foundations and future directions for novel therapeutic strategies to stabilize coronary plaques and prevent acute coronary syndromes.

Aromatic amine antioxidants (AAs) and p-phenylenediamine quinones (PPD-Qs) are novel environmental contaminants derived from tire wear, with emerging neurotoxic concerns, but epidemiological evidence linking them to cognitive health is lacking. This study investigated associations between exposure to these chemicalsand cognitive performance in older adults, and explored the potential mediating role of thyroid hormones. We measured urinary concentrations of nineteen AAs and six PPD-Qs in 439 older adults from Shenzhen, China, and assessed cognitive function using the Mini-Mental State Examination (MMSE). Higher urinary levels of specific compounds, such as N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q), 4-(cyclohexylamino) diphenylamine-quinone (CPPD-Q), and 4-phenylaminodiphenylamine-quinone (DPPD-Q), were significantly associated with lower MMSE scores and increased risks of cognitive impairment. Mixture analyses further indicated that combined exposure to these chemicals was linked to poorer cognitive performance, with 6PPD-Q and CPPD-Q as the most significant contributors. Additionally, specific thyroid hormones were associated with both chemical exposures and cognitive outcomes. Exploratory mediation analysis suggested that thyrotropin (TSH) and total triiodothyronine (TT3) may mediate the association between DPPD-Q exposure and poorer performance in specific cognitive domains. These findings provide the first epidemiological evidence that AAs and PPD-Qs exposure may be associated with cognitive decline in the elderly, potentially via disruption of thyroid hormone homeostasis. These observations warrant confirmation in longitudinal studies.

DNA damage is considered one of the major contributors to aging. DHCR24, a multifunctional enzyme located within the endoplasmic reticulum (ER), is closely related to DNA damage. Our previous study showed that DHCR24 could delay vascular endothelial cells (ECs) senescence. The relationship between DHCR24 and DNA damage during ECs senescence requires further investigation. Here, we demonstrate that aging activates ATM-mediated DNA damage response (DDR) in human umbilical vein endothelial cells (HUVECs) and mouse pulmonary microvascular endothelial cells (PMVECs), and DHCR24 expression is downregulated. Knocking down DHCR24 in young HUVECs induces the activation of ATM-mediated DDR, which has been confirmed in PMVECs of DHCR24 endothelial-specific knockout mice. Consistently, RNAseq indicated that DHCR24 was essential for cell cycle regulation. Further investigations revealed that both replicatively senescent HUVECs and young HUVECs with DHCR24 knockout exhibited ER stress and mitochondrial dysfunction, which might be attributable to calcium overload resulting from DHCR24 deficiency. In this pathological process, the DHCR24-deficiency-induced upregulation of ENKUR markedly exacerbates calcium overload. Conversely, ENKUR knockdown not only alleviates the ER stress and mitochondrial dysfunction caused by DHCR24 inhibition, but also suppresses the ATM-mediated DDR. Moreover, DHCR24 overexpression reduces the elevated ENKUR levels and simultaneously mitigates DOX-induced calcium overload in HUVECs. Collectively, these findings identify DHCR24-ENKUR-dependent Ca2+ signaling as a mechanism linking ER-mitochondrial homeostasis to endothelial DNA damage and senescence. Accordingly, restoring DHCR24 function or regulating calcium signal transduction through this pathway may hold therapeutic potential for delaying vascular ECs senescence and preventing age-related diseases.

Thyroid function in both pregnant women and newborns is vital for ensuring healthy child growth and development. Existing evidence suggests that exposure to air pollutants during pregnancy may disrupt maternal and neonatal thyroid function; however, findings across studies remain inconsistent. This systematic review and meta-analysis included 24 studies (55,814 pregnant women and 84,645 neonates) published until April 30, 2025. Results indicated that each 10 μg/m3 increase in PM2.5 was associated with a significant decrease in maternal FT4 levels (-0.42%; 95% CI: -0.83%, -0.01%) and neonatal FT4 levels (-0.90%; 95% CI: -1.52%, -0.29%). PM2.5 exposure also increased the risk of maternal hypothyroxinemia (OR = 1.49; 95% CI: 1.16, 1.91). Subgroup analyses revealed stronger effects in the first and third trimesters. Additionally, the study found a nonlinear relationship between PM2.5 exposure and thyroid hormone levels in pregnant women while potential breakpoints vary across thyroid parameters, which range from 20.60 to 71.02 μg/m3, the collective patterns indicate that the most dynamic PM2.5-related effects on maternal thyroid function occur within the 20-60 μg/m3 exposure window. Above approximately 60 μg/m3, response slopes generally diminish, reflecting a sublinear curvature in the exposure-response relationships. These breakpoints notably exceed the World Health Organization air quality guideline (10 μg/m3). These findings underscore the need for stricter air quality regulations to protect maternal and neonatal thyroid health. Further research is warranted to explore the underlying mechanisms and identify critical exposure windows.

To investigate essential metals’ association with anxiety/depression symptoms in the elderly, and explore serum thyroid hormones’ potential mediating role in this association. Study included 416 Shenzhen elderly. The Hamilton Anxiety Scale (HAMA) and the Geriatric Depression Scale (GDS) were utilized to evaluate symptoms of anxiety and depression. Essential metals in urine were measured using inductively coupled plasma mass spectrometry (ICP-MS), while thyroid hormone information was sourced from medical records. Mediation analysis assessed serum thyroid hormones’ mediating effect in the link between essential metals and anxiety/depression. Urinary zinc (Zn) level was negatively linked to the risk of anxiety symptoms [odds ratio (OR) = 0.308, 95

Vascular endothelial senescence is a pivotal driver of age-related pathologies. Metabolism plays a critical regulatory role in endothelial cell senescence. Our previous studies have shown that deficiency of DHCR24, a gene involved in lipid metabolism, promotes endothelial cell senescence. However, how DHCR24 participates in endothelial cell senescence through lipid metabolism remains unclear. Using endothelial-specific DHCR24 knockout mice and replicative senescent human umbilical vein endothelial cells, we demonstrate that DHCR24 depletion significantly reduced intracellular sphingosine-1-phosphate (S1P) levels. Mechanistically, DHCR24 loss downregulated sphingosine kinase 2 (SPHK2), impairing S1P synthesis, while concurrently upregulating the S1P transporter (SPNS2), enhancing S1P export. Critically, SPHK2 overexpression rescued senescence phenotypes in DHCR24-deficient cells. SPHK2 knockdown recapitulated SPNS2 upregulation and endothelial senescence, whereas pharmacological inhibition of SPNS2 with 16d attenuated SPHK2 knockdown-induced increases in p16, p21 and SA-β-gal activity, and restored eNOS expression and nitric oxide (NO) production. In vivo, endothelial-specific DHCR24 knockout increased circulating S1P levels, and plasma S1P was positively correlated with pulse wave velocity in humans. Collectively, these findings suggest the DHCR24-SPHK2/SPNS2-S1P axis as an important pathway involved in endothelial senescence.

BACKGROUND:Gestational diabetes mellitus (GDM) is common complication in pregnancy. Most studies on the relationship between metal and GDM have centered on a single metal or a few metals mixed, and it remains unclear whether bile acids are associated with this relationship. OBJECTIVE:To investigate the association between exposure to multiple metals in early pregnancy and GDM risk, and the mediating role of serum bile acids. METHODS:Based on a Guangxi Zhuang Birth Cohort, 650 pregnant women recruited were included in the study. Multiple machine models were used to explore the key metal variables and estimate the effects of mixed metal exposure. Then, a nested case-control study was designed with 1:1 individual matching by maternal age and gestational age (n = 304). Mediation analysis was used to assess the mediating role of serum bile acids between metal exposure and GDM. RESULTS:Mo and Sb were found to be negatively associated with GDM risk, while Cd was positively associated with GDM risk. The BKMR model showed that mixed exposure to Mo, Cd and Sb were negatively correlated with GDM risk. Besides, multiple bile acids (such as glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA)) and nine bile acid ratios were correlated with GDM risk. Mo, Cd and Sb were significantly correlated with bile acid levels. The TCA/CA and TCDCA/CDCA played a mediating role in Sb exposure and GDM risk. CONCLUSIONS:Our findings indicate that exposure to Mo, Cd and Sb is significantly associated with the risk of GDM, and bile acids may play a mediating role in this.

Lipid metabolism has been identified as a potential target for the treatment of doxorubicin-induced cardiomyopathy (DIC). Mitochondria, as a central regulator of energy production and utilization, plays a crucial role in this process, and enhancing mitophagy holds promise in mitigating myocardial damage in DIC. However, the relationship between mitophagy and lipid metabolism remains unclear, and the key molecules mediating this connection remain to be elucidated. Among these candidates, heterogeneous nuclear ribonucleoprotein K (hnRNPK) emerges as a potential regulator of mitophagy and metabolism. However, its specific role in DIC remains unclear. In this study, we established chronic DIC models both in vivo and in vitro to assess the relationship between hnRNPK levels, mitophagy, and lipid metabolism, as well as to evaluate the impact of hnRNPK on cardiac function. Our findings revealed that hnRNPK expression is significantly reduced in the hearts of doxorubicin (DOX)-treated mice. Notably, hnRNPK overexpression improves cardiac function and effectively reduces lipid accumulation by enhancing mitophagy. Mechanistically, hnRNPK expression was found to be downregulated in DIC, accompanied by its translocation from the nucleus to the cytoplasm, thereby reducing the transcriptional regulation of PINK1. Overexpression of hnRNPK and inhibition of its cytoplasmic translocation alleviates DOX-induced lipid accumulation by regulating the PINK1/Parkin pathway. These findings underscore a previously unrecognized role of hnRNPK in inhibiting lipid accumulation to prevent DIC.

Dysregulation of RNA modifiers is common across cancer types and has essential roles in tumor therapy resistance. Chen and colleagues reported that YTHDF2 played dual roles in B cell malignancies by enhancing cell proliferation and promoting immune evasion. Targeting YTHDF2 with inhibitors offers an approach to tumor treatment by regulating the epitranscriptome.

Background:Metastatic breast cancer (MBC) presents a significant challenge in the field of oncology, with limited treatment options and generally poor survival outcomes. Therefore, the discovery of new biomarkers and therapeutic targets is crucial for improving the management of MBC. Our previous studies have shown that JAM2, as a tumor suppressor, can reduce the invasiveness and migration of breast cancer cells by inhibiting the epithelial-mesenchymal transition (EMT) pathway, thus playing a key role in tumor biology. These findings suggest the importance of further investigating the specific mechanisms of JAM2. Methods:This study employed various techniques to comprehensively evaluate the expression and function of JAM2. First, we analyzed clinical samples from breast cancer patients using immunohistochemistry and quantitative PCR to determine JAM2 expression levels and its correlation with disease prognosis and metastasis. Additionally, we established a nude mouse model of breast cancer metastasis by injecting MDA-MB-231 cells with altered JAM2 expression to observe its effects on tumor growth and metastasis. We also used HA-tagged immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to screen for proteins interacting with JAM2 and further analyzed these interactions using Western blot, quantitative PCR, and Transwell invasion assays. Results:The results showed that JAM2 expression was generally low in breast cancer tissues, and its low expression was closely associated with poor prognosis and high metastasis rates. In the nude mouse model, JAM2 overexpression significantly inhibited tumor growth and metastasis. In vitro studies further revealed a direct interaction between JAM2 and IGF2BP2, where JAM2 overexpression significantly reduced IGF2BP2 levels, decreasing cell invasiveness and migration. Conversely, JAM2 knockdown increased IGF2BP2 expression, enhancing the invasiveness of breast cancer cells. Moreover, JAM2 inhibits the expression of the key EMT transcription factor Snail2 by affecting IGF2BP2, further emphasizing its role in inhibiting EMT and metastasis. Conclusion:The findings of this study highlight the important biological function of JAM2 as a metastasis suppressor in breast cancer, providing new insights into the key proteins and pathways it regulates during tumor progression. JAM2 may inhibit the EMT and the invasiveness and migration of breast cancer cells by downregulating the m6A reader protein IGF2BP2, thus reducing the stability of SNAI2 mRNA. This suggests that enhancing JAM2 expression could be a viable therapeutic strategy to combat breast cancer metastasis. Future studies are needed to fully elucidate the mechanisms by which JAM2 exerts its effects and to explore its potential clinical applications. Citation Format: Yang Peng, Han Li, Ailin Lan, Yang Liu, Zehao Cai, Shengchun Liu. Exploring JAM2's Potential in Reducing Breast Cancer Invasiveness through IGF2BP2 Regulation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-10-25.

Background: Hormone Receptor Positive (HR+) breast cancer is predominantly managed with endocrine therapies that target the Estrogen Receptor Alpha (ERα), a key mediator of estrogen's role in promoting tumor growth. However, the emergence of endocrine resistance poses a significant clinical challenge, limiting the efficacy of these treatments and impeding optimal patient outcomes. Understanding the mechanisms behind ERα's importance and the development of resistance is crucial for advancing therapeutic strategies against HR+ breast cancer. Methods: In our study, we utilized the GEO database to identify ADP-Ribosylation Factor-Like GTPase 3 (ARL3) as a gene associated with tamoxifen resistance in HR+ breast cancer. We constructed cell lines with ARL3 knockout and overexpression to assess the impact of ARL3 on cell proliferation, migration, and tamoxifen sensitivity. RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC/MS) were employed to demonstrate the influence of ARL3 knockout on downstream ERα pathways. Furthermore, co-immunoprecipitation (CO-IP), immunofluorescence and Western blot (WB) assays confirmed the role of ARL3 in the ubiquitination and degradation pathway of ERα. Results: In our analysis of TCGA breast cancer subtypes, we also observed that ARL3 is highly expressed in luminal breast cancer. Additionally, our collection of breast cancer tissue mRNA and immunohistochemistry data revealed that ARL3 expression is elevated in HR+ breast cancer, indicating a correlation with estrogen receptors. We found that ARL3 promotes the proliferation and migration of HR+ breast cancer. Furthermore, overexpression of ARL3 was associated with reduced sensitivity to tamoxifen, and in vivo tumorigenesis in nude mice showed that tumor volume and weight were significantly decreased compared to the control group. To investigate the underlying mechanisms, RNA-seq analysis of ARL3 knockout and control groups revealed a pronounced inhibition of the MYC pathway. Western blot (WB) validation confirmed that ARL3 knockout suppresses the expression of downstream pathways of ERα. Our data suggest that the association between ARL3 and ERα primarily occurs in the cytoplasm, mainly binding to the ligand-binding domain (LBD) of ERα, which is consistent with ARL3 not being recruited to the promoters occupied by ERα. We also discovered that the ARL3/ERα cascade promotes mitochondrial autophagy to enhance mitochondrial oxidative phosphorylation. In summary, our study establishes a non-genomic mechanism whereby ARL3 controls the transcription of estrogen-dependent genes associated with breast cancer cell proliferation by stabilizing ERα levels. Conclusion: In our study, we posit that ADP-ribosylation factor-like GTPase 3 (ARL3) exerts a pivotal influence on the proliferative capacity, metastatic potential, and responsiveness to endocrine therapies in hormone receptor-positive (HR+) breast cancer. ARL3 modulates the stability of estrogen receptor alpha (ERα), thereby regulating the activation of downstream signaling cascades and the mitochondrial functionality within neoplastic cells. Our findings suggest that ARL3 represents a promising therapeutic target for HR+ breast cancer. We envision that in-depth investigation into the molecular underpinnings of ARL3's role could pave the way for the development of innovative pharmacological agents capable of overcoming endocrine resistance in patients, ultimately enhancing their clinical outcomes and survival rates. Citation Format: Han Li, Yang Liu, Zehao Cai, Dan Shu, Yang Peng, Kang Li, Shengchun Liu. ARL3 Promotes Hormone Receptor Positive Breast Cancer Progression and Tamoxifen Resistance through ERα Stablization [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-04-10.

BACKGROUND:The long-term effects of early famine exposure on cognitive function remain understudied. This study examined the association between famine exposure and 10-year trajectories of cognitive function, and also assessed the mediating role of depressive symptoms. METHODS:We included 2434 participants from waves 1-5 of the China Health and Retirement Longitudinal Study (CHARLS), with complete baseline data and at least three cognitive assessments. Famine exposure data were obtained from the 2000 China Census, and its severity was determined using the pre-famine Cohort Size Shrinkage Index. Group-based trajectory modeling was used to identify distinct 10-year cognitive function trajectories, and logistic regression was used to estimate the association between famine exposure and trajectory membership. The mediating effect of depressive symptoms was assessed using the Karlson-Holm-Breen method. RESULTS:Among the 2434 participants, two global cognitive function trajectories were identified: persistently low (n = 743, 30.5 %) and persistently high (n = 1691, 69.5 %). Similar patterns were found across cognitive dimensions, including orientation, memory, computation, and drawing. In the fully adjusted model, moderate famine exposure was associated with an increased risk of a persistently low global cognition trajectory [odds ratio (OR) = 1.37, 95 % confidence interval (CI): 1.04-1.82], and severe famine exposure showed a similar trend (OR = 1.57, 95 % CI: 0.97-2.56). Moreover, both moderate (OR = 1.67, 95 % CI: 1.28-2.15) and severe (OR = 1.61, 95 % CI: 1.01-2.54) famine exposures were linked to a heightened risk of a persistently low trajectory for computation, while severe famine exposure was additionally associated with a persistently low trajectory for orientation (OR = 1.90, 95 % CI: 1.15-3.14). Moderate famine exposure, however, was not associated with a persistently low trajectory for orientation (OR = 0.98, 95 % CI: 0.71-1.36). Additionally, while depressive symptoms did not mediate the associations between moderate famine and any cognitive trajectories, they partially mediated the associations between severe famine and global, computation, and orientation trajectories by 20.07 %, 11.76 %, and 10.38 %, respectively. CONCLUSION:Our study identified two distinct cognitive function trajectories, with both moderate and severe famine exposure being linked to persistently low trajectories. Furthermore, depressive symptoms partially mediated the association between severe famine exposure and cognitive function in middle-aged and older adults.

Parabens are among the most prevalent preservatives utilized in daily life. According to studies, parabens are endocrine disruptors that may be harmful to human health. This study used urine (N = 370,460) and blood (N = 19,521) data from 203 publications from 29 countries to calculate the global estimated daily intakes (EDIs) and grouped EDIs (EDIGs) of parabens in different countries and populations, assess the global exposure trends of parabens from 2000 to 2024, and determine the potential health risks of parabens exposure. Global EDIs for methyl -, ethyl -, propyl -, and butyl parabens were 8.00, 1.06, 2.50, and 0.27 μg/kg bw/day in urine, and 0.25, 0.01, 0.19, and 0.01 μg/kg bw/day in blood, respectively. The EDIGs of parabens exhibited significant variations across countries. Compared with the adults, children and pregnant women exhibited higher parabens exposure levels. The hazard quotients of all countries were less than 1; however, potential health risks could not be ignored. Globally, parabens exposure demonstrated a consistent decline from 2000 to 2024, as evidenced by the decrease in methylparaben (MeP) exposure from 12.48 μg/kg bw/day (pre-2005) to 4.97 μg/kg bw/day (post-2020). To our knowledge, this study is the first to evaluate overall parabens exposure levels using published global biomonitoring data, addressing a gap in parabens risk assessment and providing significant insights into the potential health effects of parabens exposure on humans.

The existing studies on the association between multi-metal mixture exposure and cognitive function in the older adults are limited and controversial, with no studies considering the mediating effect of thyroid hormones on the connection between them. This study of 441 urban older adults assessed 21 urinary metal levels and cognitive function using the Mini-Mental State Examination (MMSE). Urinary metal levels were measured via inductively coupled plasma mass spectrometry (ICP-MS), and thyroid hormones levels were obtained from medical records. Mediation analysis evaluated the role of thyroid hormones in the link between metals exposure and cognitive function. The General Linear Model (GLM) showed negative correlations between MMSE scores and titanium (Ti), copper (Cu), rubidium (Rb), and molybdenum (Mo), and positive correlations with selenium (Se) and barium (Ba). Nonlinear inverse U-shaped associations between Mo, Rb, and MMSE scores were identified using Restricted Cubic Splines (RCS) and Bayesian Kernel Machine Regression (BKMR). Mediation analysis revealed that Free Thyroxine (FT4) mediated the relationship between Rb and MMSE scores by 29.10 % and between Zinc (Zn) and language performance by 35.00 %. Total thyroxine (TT4) mediated the link between Cu and orientation score by 24.69 %, and Thyroid Stimulating Hormone (TSH) mediated the association between Cu and attention score by 38.96 %. Ti, Se, Rb, Mo, Ba and Cu were significantly associated with cognitive impairment risk. Mixed exposure to Mo and Rb was linked to an increased risk of cognitive impairment. Additionally, levels of TSH, FT4 and TT4 were associated with cognitive function, mediating the effects of Rb, Zn and Cu on cognitive function.

Polycyclic aromatic hydrocarbons (PAHs) are well-known for their adverse health effects and have garnered significant global attention. This study assessed the levels of ten monohydroxy metabolites of PAHs (OH-PAHs), derived from naphthalene, fluorene, phenanthrene, and pyrene, in urine samples collected from 495 elderly individuals in southern China. OH-PAH concentrations ranged from 0.134 to 183 ng/mL, with OH-Nap (the monohydroxy metabolite of naphthalene) being the most prevalent, accounting for 76.8 % of total metabolites. Significant correlations were observed between urinary OH-PAH levels and demographic factors including gender, smoking, and alcohol consumption, with smoking emerging as the strongest determinant. Regression analyses indicated that steaming significantly reduced PAH exposure (e.g., for 1-OHNap: β = -0.103, 95 % CI: -0.67, -0.04, p < 0.05), while dietary factors, such as fish, mycorrhizal algae, soy products, and coarse grains, influenced OH-PAH concentrations (p < 0.05). Monte Carlo simulations revealed a hazard index below the safety threshold of 1 and an overall carcinogenic risk ranging from 6.40 × 10⁻⁸ to 1.05 × 10⁻⁴, with approximately 85 % of individuals exceeding the acceptable carcinogenic risk threshold (lg(CR) > -6), primarily due to pyrene and naphthalene, which together accounted for 87.2 % of the total. This study delineates the link between PAH metabolites and dietary habits, uncovering health risks for the elderly population in the region. It provides a scientific basis for environmental health and pollution prevention policies aimed at mitigating the adverse effects of PAHs on environmental and public health.

Maternal oxidative stress during pregnancy plays a role as a hazardous factor of offspring neurodevelopment in animal models. However, epidemiological evidence remains limited. In this prospective cohort, we aimed to investigate the associations between maternal oxidative stress biomarkers (OSBs) across pregnancy and neurodevelopmental outcomes in different stages across early childhood. This was a prospective cohort study conducted in 1791 mother–child pairs from Wuhan, China. Three OSBs, including DNA oxidative damage marker (8-hydroxy-2′-deoxyguanosine, 8-OHdG), RNA oxidative damage marker (8-hydroxyguanosine, 8-OHG) and lipid oxidative damage marker (4-hydroxy nonenal mercapturic acid, HNE-MA), were measured in repeatedly collected urine samples in three trimesters across pregnancy. We followed children at age 2, age 3, and age 6 years. At age 2 years, the Bayley Scales of Infant Development of China Revision (BSID-CR) was employed to assess children’s mental and psychomotor development. Brain-derived neurotrophic factor (BDNF) levels were measured in children’s plasma at age 3 years. The Wechsler Preschool and Primary Scale—Fourth Edition (WPPSI-IV) was used to assess children’s intelligence quotients at ages 6 years. Generalized estimating equation models were applied to estimate the associations between OSBs and neurodevelopmental outcomes. Higher maternal HNE-MA levels in late pregnancy were associated with lower mental development index at age 2 years (β = − 0.95, 95

Metabolic disorders often arise in senescent endothelial cells, which impair endothelial function, lead to diminished vasodilation, increase vascular stiffness, and ultimately contribute to CVD pathogenesis. Despite notable advancements, the molecular mechanisms driving endothelial senescence and its contribution to vascular aging remain incompletely understood, thereby limiting the development of effective therapeutic strategies. Here, we investigated the protective role of terazosin (TZ) against vascular endothelial senescence using both in vivo (aged mice) and in vitro (human umbilical vein endothelial cells) models, combined with senescence-associated β-galactosidase staining, lipidomics, and molecular docking simulations. TZ treatment significantly improved endothelium-dependent vasodilation, reduced vascular stiffness, and attenuated the expression of senescence markers in aged mice. Mechanistically, lipidomics revealed that TZ reduced intracellular palmitic acid (PA) accumulation in senescent endothelial cells. Furthermore, clinical observations confirmed decreased plasma PA levels and improved endothelial function in patients receiving TZ. Monoglyceride lipase (MGLL), which hydrolyzes monoglycerides into PA and glycerol, was markedly upregulated in senescent endothelial cells and aged vascular tissues. TZ directly bound to MGLL and inhibited its enzymatic activity, thereby mitigating PA-driven endothelial senescence. Collectively, these findings identify MGLL as a novel metabolic driver of endothelial senescence and establish TZ as a potential therapeutic agent for age-related vascular diseases.

Vascular smooth muscle cell (VSMC) senescence is a pivotal driver of atherosclerosis (AS), but molecular links to ageing-related dysfunction are unclear. It is aimed to identify regulators of VSMC senescence and develop clinical interventions for ageing-related AS. Using single-cell RNA sequencing of human atherosclerotic carotid arteries and immunofluorescence validation, activating transcription factor 3 (ATF3) is identified as central to VSMC senescence. Mechanistic studies employ SMC-specific ATF3 knockout mice, CUT&Tag-seq, RNA/protein interaction assays, and m6A epitranscriptomic analyses. To bridge discovery to therapy, high-throughput virtual screening is performed for ATF3-targeting compounds and functionally validated hits. ATF3 deficiency in VSMCs accelerates ageing-induced AS by promoting senescence. Multi-omics showed ATF3 activates ATG7, triggering autophagy, while cytoplasmic ATG7 enhances ATF3 nuclear translocation, establishing a positive feedback loop. Ageing increases m6A methylation and decreases the stability of Atf3 mRNA. Terazosin (TZ) diminishes the interaction between YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) and Atf3 mRNA, helping to preserve Atf3 mRNA stability. TZ is a promising therapeutic strategy for delaying VSMC senescence and preventing AS. ATF3 protects against VSMC senescence and AS by orchestrating autophagy via a novel ATF3-ATG7 amplification loop. Repurposing TZ to stabilize ATF3 offers a translatable approach to combat ageing-driven cardiovascular disease.