Prenatal exposure to bisphenol analogs is becoming increasingly common and may affect the development of myopia in children. However, human evidence and mechanistic studies remain limited. In this study, 370 mother-child pairs from the Shanghai-Minhang Birth Cohort Study (S-MBCS) were analyzed. We measured the concentrations of five bisphenol analogs in maternal urine, quantified genome-wide DNA methylation (DNAm) in placental samples, and assessed the myopia status and spherical equivalent (SE) of school-aged children. Multiple CpG sites with methylation levels significantly associated with SE were identified, and Kyoto Encyclopedia of Genes and Genomes analysis identified cellular senescence as a pathway significantly associated with SE in the left eye. Dozens of differentially methylated regions are associated with the risk of myopia or SE. Prenatal exposure to bisphenol A and bisphenol AF increased the risk of myopia and decreased SE. Guided by a meet-in-the-middle approach, mediation analysis showed that the effects of bisphenol AF exposure on SE might be partially mediated by changes in methylation at the cg23146659 locus (mapping to TDRD3 in the left eye) and a differentially methylated region annotated as MROH1 (in the right eye). Our findings suggest that placental DNAm is associated with myopia development, and that specific DNAm changes may partially explain the association between prenatal chemical exposure and myopia. This study delineates how long-term prenatal exposure to environmental factors influences ocular development in children and informs early identification of myopia risk.

It remains unknown whether noise and nonoptimum temperature exposures are linked to myocardial ischemia, either separately or jointly. We conducted a multicenter panel study with 24 h real-time personal measurements among generally healthy middle-aged and elderly individuals to investigate potential effects of short-term personal exposures to noise and temperature on ST-segment depression event (STDE) and whether the effects of noise are modified by temperature and vice versa. Generalized linear mixed-effect model and stratified analyses were used. A total of 117 eligible participants completed 256 person-visits. We found increased risks of STDE associated with personal noise exposure and U-shaped exposure-effect relationships between personal temperature exposure and risks of STDE, both occurring over minutes to hours. The nonoptimum temperatures, including low and high temperatures, significantly enhanced the adverse effects of noise on STDE. Significant effect modifications on temperature-related STDE risk by noise were found in both the low and high temperature ranges. Exploratory analyses suggested that decreases in heart rate variability variables, reflecting autonomic imbalance, may explain exposure-related STDE occurrence. Our study identified the independent effects and two-way effect modifications of personal noise and temperature exposures on STDE risk, providing novel insights into the pathways linking these environmental factors to adverse cardiovascular outcomes.

Introduction Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is the hepatic manifestation of the metabolic syndrome. When it co-occurs with type 2 diabetes (T2DM), it presents a significant therapeutic challenge due to a higher risk of fibrosis progression and adverse outcomes. While new treatments for MASH are emerging, their efficacy in the T2DM subpopulation remains an unmet need. Chiglitazar is a novel peroxisome proliferator-activated receptor pan-agonist that regulates key pathways in lipid metabolism, glucose homeostasis and inflammation. This trial aims to evaluate the efficacy and safety of chiglitazar as a combination therapy for patients with MASH and T2DM.Methods and analysis This is a prospective, multicentre, randomised, double-blind, placebo-controlled study. This trial will enrol 300 adult patients aged 18–75 years with biopsy-confirmed MASH and fibrosis stage F1 or higher. Participants will be randomised (1:1) to receive either chiglitazar 48 mg daily or a matching placebo. All participants will also receive background therapy consisting of vitamin E (100 mg three times a day) and polyene phosphatidyl choline (456 mg three times a day). The treatment duration is 78 weeks. The primary efficacy endpoint is resolution of steatohepatitis with no worsening of liver fibrosis. Key secondary endpoints include improvement in liver fibrosis by at least one stage and changes in metabolic and liver safety biomarkers.Ethics and dissemination Ethical approval has been obtained from the Shanghai Punan Hospital of Pudong New District Ethics Committee (Punan Branch of Renji Hospital Ethics Committee, Shanghai Jiaotong University School of Medicine). KY2025-066. The findings will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences.Trial registration number NCT07303803.

Evidence regarding maternal per- and polyfluoroalkyl substances (PFAS) exposure on offspring physical development is inconsistent. This study included 937 mother-infant pairs from the Jiashan Birth Cohort. Thirteen PFAS congeners were quantified in maternal peripheral blood at the first prenatal visit (< 16 weeks of gestation). Data on offspring weight and length from birth to 24 months of age were extracted, and Z-scores for weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) were calculated. Group-based trajectory modeling (GBTM) was applied to fit growth trajectories. Maternal PFTrDA exposure was associated with higher likelihood of offspring in WAZ "rising" groups, specifically the "Low-start rapid-rise" (OR: 1.37, 95% CI: 1.09, 1.71), "High-start slow-rise" (OR: 1.29, 95% CI: 1.07, 1.56), and "High-start rapid-rise" (OR: 1.46, 95% CI: 1.10, 1.96) groups. PFHxS and PFNA were linked to the LAZ-"Low-start rapid-rise" group (OR: 1.48, 95% CI: 1.07, 2.05; OR: 1.24, 95% CI: 1.02, 1.51, respectively), while PFTrDA was associated with the LAZ-"High-start rapid-rise" group (OR: 1.23, 95% CI: 1.01, 1.51). Most PFAS were associated with elevated likelihood of offspring in the WLZ-"Medium-start rapid-rise" group (ORs: 1.26-1.43). Bayesian kernel machine regression further confirmed the joint effects of the PFAS mixture on rising WAZ/WLZ trajectories and PFTrDA as the key chemical driving the association with the WAZ-"High-start rapid-rise" group. These findings provide evidence for associations between maternal PFAS exposure and offspring growth trajectories during early life.

Chimeric antigen receptor (CAR)-based cell therapy holds great promise for the treatment of both hematological malignancies and solid tumors. However, primary and acquired resistance to CAR-based cell therapy remains a key obstacle to achieving effective and durable immunotherapy responses. Unlike small molecules or antibodies, CAR-engineered immune cells offer unique opportunities to design therapeutic agents, thereby enabling the improved products with potential to overcome multiple therapy resistance mechanisms. Therefore, elucidating the mechanisms of resistance to CAR-based cell therapy is crucial for the development of the next-generation CAR-based cell therapy. In this review, we outline the biological rationale of CAR-T, CAR-natural killer (NK), and CAR-macrophages, as well as other emerging CAR-based cell therapies. We focus on the mechanisms of resistance to CAR-based cell therapy, involving structural and functional defects of CAR products, tumor-intrinsic factors, and susceptibility of CAR-engineered cells to the hostile tumor microenvironment. We discuss key strategies to overcome multiple resistance mechanisms, such as targeting multiple antigens, optimizing CAR design and function, modifying the immunosuppressive tumor microenvironment, and developing combination treatment strategies. By systematically dissecting these multifaceted challenges, this review will provide insights for optimizing CAR-based cell therapy to overcome resistance and improve treatment efficacy.

Cardiovascular toxicity is a leading cause of drug attrition. Conventional animal models are constrained by cost, duration, and interspecies discrepancies. Organoids provide physiologically relevant alternatives for toxicity assessment. Here, we developed cardiovascular organoids (CVOs) by co-differentiating cardiomyocytes and vascular progenitor cells from human embryonic stem cells. CVOs demonstrated enhanced vascular and myocardial maturation relative to standalone cardiomyocyte or vascular organoids. In pharmacological assays, CVOs accurately recapitulated amiodarone bleomycin and cisplatin induced endothelial stress and captured dexamethasone and Vitamin C anti-inflammatory and antioxidant properties. CVOs generated results consistent with established toxicity profiles, exhibiting superior discriminatory capacity between positive and negative compounds. The prediction accuracy of the selected specific markers for all model compounds was about 90%. These findings confirm that CVOs reliably mirror in vitro cardiovascular toxicity profiles and represent a human-relevant platform for first-line screening of compounds.

The non-protein calorie-to-nitrogen ratio (NPC/N, kcal/g) is recognized as a valuable metric for assessing the balance between non-protein energy intake and nitrogen derived from protein. This study aimed to investigate the association between NPC/N and mortality among overweight and obese adults. Data were obtained from the National Health and Nutrition Examination Survey (1999-2018), with mortality follow-up through December 31, 2019. Among 22,892 participants, 3,332 all-cause deaths occurred over up to 20 years of follow-up. Kaplan-Meier curves showed that the intermediate NPC/N group (90-160 kcal/g) had lower mortality than both the low (< 90 kcal/g) and high (≥ 160 kcal/g) groups (log-rank test P = 0.012). Restricted cubic spline analysis demonstrated a U-shaped association between NPC/N and all-cause mortality, with the risk nadir at approximately 120 kcal/g (P for non-linearity = 0.027, P for overall = 0.022). In fully adjusted models, NPC/N was inversely associated with all-cause mortality below the nadir (HR = 0.61, 95% CI: 0.39-0.94, P = 0.030) and positively associated above it (HR = 1.12, 95% CI: 1.01-1.25, P = 0.040); log-likelihood ratio test P = 0.006. These suggest that both lower and higher NPC/N are associated with increased mortality.

The progression of chronic liver disease results in severe complications. However, current treatment options remain limited. Research indicates that environmental pollutants, such as microplastics (MPs), pose a threat to the progression of chronic liver disease and represent a substantial challenge to human health. Current studies widely suggest that MPs tend to accumulate in the liver upon entering the body, potentially leading to the onset or acceleration of chronic liver disease. This article seeks to provide a comprehensive overview of the effects of MPs on chronic liver disease through various interconnected mechanisms, including cell death and autophagy, oxidative stress, inflammatory response, fibrosis, metabolic regulation, and microbial regulation. Additionally, we will briefly examine the correlation between the occurrence of chronic liver disease and microplastic exposure, as well as review the exacerbating effect of MPs on liver damage caused by other hepatotoxic substances. This study aims to serve as a reference for future research on the mechanisms of MPs in liver diseases and the development of treatment strategies for chronic liver conditions.

Evidence regarding the mortality risk associated with cardiometabolic risk factors (CMRFs) in patients with metabolic dysfunction- associated steatotic liver disease (MASLD) remains limited. We aimed to explore the association between CMRFs and mortality and to develop a practical risk stratification method for patients with MASLD. MASLD patients from the National Health and Nutrition Examination Survey (NHANES III) database were included as the evaluation cohort, while NHANES 2003–2018 served as the validation cohort. The observational endpoints of the current study were all-cause and cardiac-specific mortality. Univariate and multivariate Cox proportional hazards regression models were employed to investigate the association of CMRFs with long-term mortality. A total of 3,545 MASLD patients were included in the evaluation cohort. During a median follow-up period of 26 years, 1,344 subjects died, of whom 347 deaths were attributable to cardiac-specific causes. Multivariate Cox regression models revealed elevated glucose and hypertension as significant predictors for both all-cause and cardiac-specific mortality. Based on the type and number of CMRFs, we stratified the MASLD patients into three risk groups. After risk stratification, the cumulative incidence of all-cause and cardiac-specific mortality at 20 years was 11.5

Microplastics (MPs, <5 mm) are pervasive in foods, the environment, and humans, posing emerging health risks. Traditional two-dimensional (2D) cell models inadequately replicate micron-scale MP uptake, whereas three-dimensional (3D) organoids better mimic tissue complexity. Here, we developed a hepatic organoids (HOs)-in-cage system using human pluripotent stem cell-derived HOs and a 3D-printed porous poly(ε-caprolactone) carrier for efficient organoid retrieval. We established a label-free Nile Red (NR)-based spatiotemporal imaging and flow cytometric quantification pipeline to investigate the uptake dynamics and hepatotoxicity of UV-aged, size-mixed polypropylene (PP, 1 to 20 μm), as well as to colocalize the MP and potential biomarkers within HOs. Contrary to 2D models where >5 μm particles show negligible internalization, 3D HOs exhibited significant accumulation of intact micron-scale MPs via tissue-layer penetration and paracellular retention, with PP uptake peaking at ∼40% within 48 h and ∼18% retained long-term. This triggered dose- and time-dependent hepatotoxicity (40-4000 ng/mL), marked by CD36 upregulation from 8 h, mitochondrial impairment, and elevated LDH and AST levels. Notably, NR fluorescence intensity was governed by polymer chemistry rather than surface roughness, enabling material-specific detection. This work provides novel label-free techniques within 3D in vitro models to explore the depot and effective concentration of micron-scale MPs, advancing understanding of MP-induced cellular damage upon uptake and deposition.

Micro- and nanoplastics (MNPs) are pervasive environmental contaminants and efficient carriers of coexisting pollutants, including heavy metals, organic chemicals, and antibiotics. Their capacity to adsorb, transport, and release contaminants has raised growing concern over mixture toxicity under realistic exposure scenarios. This review systematically examines the mechanistic basis of MNPs-mediated combined toxicity and evaluates the emerging role of network toxicology as a systems-based tool for hazard assessment. MNPs alter the bioavailability, environmental fate, tissue distribution, and intracellular delivery of associated pollutants through hydrophobic, electrostatic, and other intermolecular interactions. Carrier-mediated uptake, particularly the “Trojan horse” effect, appears to be a major driver of non-additive toxicity in co-exposure systems. We then outline the core workflow of network toxicology, encompassing target identification, network construction, pathway enrichment, and experimental validation, and discuss its application in decoding mixture toxicity. Oxidative stress, inflammatory signaling, metabolic disturbance, barrier dysfunction, and programmed cell death emerge as conserved and interconnected pathways underlying synergistic multi-organ injury. These findings indicate that toxicity in complex exposure systems is governed not only by the intrinsic properties of particles or chemicals, but also by their dynamic physicochemical and biological interactions. We further assess current advances and limitations in network toxicology and propose a next-generation risk assessment (NGRA)-oriented framework to support mechanism-based risk assessment and regulatory decision-making. Although current evidence is dominated by binary, high-dose laboratory studies, network toxicology offers strong potential as a new approach methodology (NAM) for predictive evaluation of environmentally relevant mixtures. Future priorities include standardized multi-omics integration, dose–time–response modeling, human-relevant validation, and regulatory translation.

Psychosocial stress and ambient fine particulate matter (PM2.5, particulate matter with aerodynamic equivalent diameters ≤ 2.5 μm) independently impair cardiac health, yet their interactive effects remain unclear. This study investigated whether psychosocial stress modifies the acute cardiac response to personal PM2.5 exposure. A multi-center panel study was conducted among 129 middle-aged and elderly adults in China during 2018-2023, with 24 h monitoring of personal PM2.5 exposure and ambulatory electrocardiogram. Associations between personal PM2.5 exposure and cardiac health indicators were analyzed using generalized or linear mixed-effects models, and the effect modification by psychosocial stress was evaluated by incorporating multiplicative interaction terms between personal PM2.5 exposure and psychosocial stress scores. The final analysis included 116 participants (260 person-visits), with a mean age of 52.1 years and female proportion of 67.2%. Personal PM2.5 exposure was associated with increased risks of ST-segment depression event (STDE), accelerated heart rate, and decreased heart rate variability (HRV). For instance, per interquartile range increase in PM2.5 (31.5 μg/m3) at the 3 h exposure window, the risk ratio of STDE in the lateral leads was 1.11 (95% confidence interval: 1.05, 1.17), and the percent changes in heart rate and standard deviation of normal-to-normal intervals (SDNN) were 0.23% (0.09%, 0.37%) and -1.96% (-2.42%, -1.51%), respectively. The marginal effects of personal PM2.5 exposure on STDE and HRV were generally more pronounced under higher psychosocial stress. The study findings highlight the possible synergistic roles of psychosocial stress and personal PM2.5 exposure in eliciting adverse cardiac effects, and provide a scientific basis for identifying vulnerable populations and formulating targeted measures to mitigate air pollution-related cardiac health risks.

Plant-derived extracellular vesicles (PEVs) have emerged as a promising area of research in biotechnology with enormous potential in drug delivery, skincare, and functional foods. Currently, PEVs are obtained primarily from fresh and dried materials through soaking and extraction; however, little is known about the differences in their contents. Using Portulaca oleracea L. as the research object, this study firstly employed a method that combined differential and ultracentrifugation with membrane filtration to separate and purify exosome-like nanoparticles from dried material (D-PELNs) and fresh material (F-PELNs). Then, multi-omics analysis compared the small-molecule metabolites, lipid profiles, and protein expression patterns. Both D-PELNs and F-PELNs showed typical cup-shaped morphology, with mean particle sizes of 139 nm and 186 nm, and mean zeta potentials of −16.015 ± 0.335 mV and −6.29 ± 0.19 mV, respectively. Both types contained diverse small-molecule metabolites. Among them, terpenoids (e.g., caesaldekarin e) were more abundant in F-PELNs, whereas carboxylic acids and their derivatives (e.g., citric acid) were predominantly found in D-PELNs. Both types had abundant lipids. D-PELNs exhibited greater lipid diversity than F-PELNs, with notable enrichment in phosphatidylcholine (18.48%) and ceramide (17.02%). F-PELNs mainly consisted of functional neutral lipids, such as monoglycerides and triglycerides. Proteins involved in plant morphogenesis and secondary-metabolite biosynthesis were also identified. Proteins from both Portulaca oleracea L.-derived exosome-like nanoparticles (PELNs) were localized to intracellular structures, including the cytoplasm and mitochondria of the cells. D-PELNs had a higher protein content related to carbon metabolism, whereas F-PELNs were more enriched in proteins related to secondary metabolite synthesis. In summary, D-PELNs and F-PELNs were successfully isolated and characterized, and their compositions were analyzed and compared using multi-omics approaches. These findings identify the specific chemical components of PELNs and offer new insights for comparing the compositional differences between exosome-like nanoparticles derived from dried and fresh plant states.

The protective effect of isorhamnetin on myocardial injury induced by isoproterenol (ISO) was investigated to identify the key targets and pathways involved, offering potential therapeutic insights for cardiovascular diseases. A myocardial injury model was established through intraperitoneal ISO injection, and the effects of isorhamnetin on apoptosis and oxidative stress in ISO-induced myocardial injury rats were assessed. Additionally, an ISO-induced H9c2 cell injury model was established to evaluate the impact of isorhamnetin on cellular damage. The transcriptomic sequencing of H9c2 cells was conducted to identify differentially expressed genes, followed by gene enrichment analysis. Intracellular glucose, lactate, and ATP levels were quantified, and the protein expression of key pathway targets ENO1, PPARα, and PGC-1α was analyzed via immunoblotting. Isorhamnetin improved cardiac function and morphological damage, reduced serum markers of cardiac injury, and exerted cardioprotective effects by regulating oxidative stress and inhibiting apoptosis. Compared to the ISO group, the glycolytic process—with ENO1 as a key target and the PPAR signaling pathway as the core regulator—was significantly suppressed in the isorhamnetin-pretreated group. Furthermore, isorhamnetin pretreatment reduced intracellular glucose and lactate levels while increasing ATP content in a concentration-dependent manner. These findings suggest that isorhamnetin protects the heart by inhibiting ENO1, activating the PPARα/PGC-1α signaling axis, reversing isoprenaline-induced metabolic shifts in H9c2 cells, suppressing glycolysis, and enhancing ATP release, thereby mitigating apoptosis and oxidative stress.

Microplastics (MP), as pervasive environmental pollutants, inevitably undergo ageing processes, resulting in the formation of aged MP (aMP). Humans are chronically exposed to aMP, posing potential health risks. As the primary circulatory conduits, blood vessels play a critical role in systemic MP distribution following exposure through multiple routes. However, the vascular toxicity of MP remains poorly understood. The vascular toxicity of aged polypropylene MP (aPP) was evaluated using human embryonic stem cell-derived vascular organoids (VOs) and Balb/c mice, with doses reflecting human internal exposure levels. It was observed that aPP induced cytotoxicity, dysregulated lysyl oxidase (LOX) and Elastin expression, and caused vascular structural abnormalities. Additionally, aPP disrupted copper (Cu) homeostasis, manifested through significantly upregulated SLC31A1, ATOX1, COX17, FDX1, and DLAT expression, along with downregulated ATP7B and LOX levels. Reductive stress was also induced, featuring elevated SOD, NADH, GSH-Px, and reduced MDA contents. Collectively, these results indicate that aPP disrupted Cu homeostasis and induced reductive stress both in vitro and in vivo, suggesting a potential threat to vascular health.

Microplastics (MP) have distributed ubiquitously and emerged as a significant health risk to human beings. The adverse effect induced by aged MP at concentrations being equivalent to human internal exposure level, has raised special concern, however, is still unclear. In this study, human embryonic stem cells-derived liver organoids (LOs), a novel three-dimensional in vitro model, were exposed to 75 ng/mL self-made polypropylene (PP) and aged PP (aPP), following UV-photoaging for 0- and 500-h respectively, were subject to transcriptomic and metabolomic analysis individually and jointly, to explore the potential adverse effect of PP and aPP on human liver. The mean size of PP and aPP were 7.60 and 6.91 μm, with rough and irregular surface, and varied carbonyl index (CI) (0.08 and 0.25 respectively), indicating there were distinguished physicochemical properties. Transcriptomic analysis suggested the NADH dehydrogenase at mitochondrial complex and ATP synthesis maybe more sensitive to aPP, rather than PP. Metabolomic analysis enriched KEGG pathways including cysteine (Cys) and methionine metabolism significantly. Collectively, the homocysteine (Hcy) metabolism, were anchored upon integrated analysis. To validate, the changes in NADH dehydrogenase-encoding genes, activities of complexs, mitochondrial membrane potential, Hcy and Cys contents, as well, the cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), were detected both in vitro and in vivo. Finally, increased serum Cys and decreased hepatic Cys were confirmed, without inflammation in the liver. The peripheral Hcy may serve as a potential biomarker for indicating the MP-induced systematic adverse health outcomes, due to the disturbance in the Hcy metabolism in the liver.

BackgroundIn the past few decades, selective serotonin reuptake inhibitors (SSRIs) became widely used antidepressants worldwide. Therefore, the adverse reactions of patients after SSRI administration became a public and clinical concern. In this study, we conducted a pharmacovigilance study using the Adverse Event Reporting System (FAERS) database of the US Food and Drug Administration. Our main goal was to evaluate adverse events related to SSRIs, with a particular focus on abnormal weight gain and glucose/lipid metabolism disorders.MethodThe adverse event data for representative SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) was extracted from the FAERS database from 2004Q1 to 2023Q4. The reporting odds ratio and proportional reporting ratio were employed to explore relevant adverse event reports (ADEs) signals. Univariate logistic regression analysis was utilized to explore factors associated with glucose/lipid metabolism abnormality following SSRIs treatment.ResultsWe identified 143,744 ADE reports associated with SSRIs and revealed significant abnormal signals related to weight gain and glucose/lipid metabolism in depressed patients. Variations were observed among different SSRIs medications. Specifically, citalopram was associated with abnormal weight gain (ROR: 4, 95% CI: 3.1-5.2) and hepatic steatosis (ROR: 2.8, 95% CI: 2.1-3.6); escitalopram was correlated with gestational diabetes (ROR: 9.1, 95% CI: 6.6-12.4) and cholestasis (ROR: 2.4, 95% CI: 1.75-3.38); fluoxetine was associated with obesity (ROR: 2.8, 95% CI: 2.08-3.78); fluvoxamine was linked to arteriospasm coronary (ROR: 13.87, 95% CI: 4.47-43.1); and sertraline was implicated in neonatal jaundice (ROR: 16.1, 95% CI: 12.6-20.6). Females and younger age are important risk factors for the development of associated adverse effects.ConclusionOur study screened for adverse effects associated with abnormal glucose/lipid metabolism, such as abnormal body weight and fatty liver, in depressed patients taking selective serotonin reuptake inhibitors by utilizing FAERS database. This provides valuable insights for healthcare professionals in accepting and managing patients treated with SSRIs.