N6-methyladenosine (m6A) methylation, a dynamic and reversible modification of eukaryotic mRNAs, plays critical roles in diverse cellular processes. Although METTL3-mediated m6A deposition has been implicated in cellular senescence, the mechanisms controlling METTL3 stability and activity during senescence remain poorly defined. Here, we demonstrate that both m6A levels and METTL3 protein abundance are significantly reduced in replication-induced and stress-induced senescence models. METTL3 depletion promotes senescence by inducing telomere dysfunction via diminished expression of shelterin components TRF2 and POT1. Mechanistically, we identify PRKN (Parkin) as a senescence-associated E3 ubiquitin ligase that promotes METTL3 proteasomal degradation through K48-linked polyubiquitination at lysine 164. Genetic PRKN inhibition in pre-senescent cells rescues METTL3 expression, restores TRF2/POT1 levels, reduces telomere dysfunction-induced foci (TIFs), and attenuates senescence-associated β-galactosidase (SA-β-gal) activity. Crucially, PRKN overexpression accelerates telomere dysfunction and senescence in wild-type METTL3-expressing cells but not in cells expressing the ubiquitination-resistant K164R METTL3 mutant. Our findings establish METTL3 ubiquitination as a pivotal regulator of telomere integrity and senescence progression, unveiling a therapeutic target for age-related pathologies.

Benzene, toluene, and xylene (BTX) are pervasive in industrial settings. However, how their shared lipophilicity and lipid dysregulation synergistically contribute to genotoxicity at low dose exposures remain unclear, limiting the development of targeted preventive measures. In a longitudinal cohort of 736 petrochemical workers (523 followed for 5 years), with cumulative exposure doses derived from workplace monitoring. Blood lipids [total cholesterol (TC), triglycerides (TG), low-/high-density lipoprotein cholesterol (LDL-C/HDL-C)] and genotoxicity markers [olive tail moment (OTM), Tail DNA%, Tail moment, 8-hydroxy-2 '- deoxyguanosine (8-OHdG)] were measured. Generalized linear and log-binomial regression models evaluated baseline and longitudinal associations, while generalized weighted quantile sum (gWQS) regression captured mixture effects. Mediation models assessed lipid-driven genotoxicity. BTX co-exposure was associated with increased TC, LDL-C, and HDL-C at baseline, and elevated risks of hypercholesterolemia (RR = 1.64, 95 % CI: 1.05, 2.58) and high LDL-C (RR = 1.32, 95 % CI: 1.01, 1.71) during follow-up. Workers with baseline hyperlipidemia showed stronger lipid responses and greater DNA damage under exposure (P-(interaction) < 0.05). Longitudinal analyses showed that benzene and toluene exposure elevated higher follow-up 8-OHdG levels among hypercholesterolemic workers (P-interaction < 0.05) supporting oxidative damage as a downstream mechanism.Total cholesterol mediated 8.22 % of BTX-related genotoxicity (P < 0.05). Consistently, network toxicology highlighted lipid metabolism as key pathway linking BTX exposure to DNA damage. These findings demonstrate that BTX co-exposure disrupts lipid homeostasis and that toluene and xylene contribute significantly to this dysregulation, which in turn exacerbates benzene-initiated genotoxicity. The study highlights lipid metabolism as a critical mediator and amplifier of BTX mixture toxicity, underscoring the necessity of incorporating metabolic pathways and mixture effects into occupational risk assessments.

Although inhalation of nanoplastics (NPs) is widely recognized as a trigger of pulmonary injury, the mechanisms underlying lung damage induced by orally ingested NPs remain largely uncharacterized. Computational toxicology profiling predicted the involvement of efferocytosis in nanoplastic toxicity. Protein phosphatase 2A (PP2A) is an important regulator of macrophage function, and PP2A Aα deficiency impaired efferocytosis. To delineate the contribution of efferocytosis to nanoplastics-induced pulmonary toxicity, myeloid-specific PP2A Aα-deficient (HO) mice model (Ppp2r1a gene deletion) and matched wild-type (WT) littermates were administrated with polystyrene nanoplastics (PS-NPs) by gavage at dose of 10 mg/kg·bw for 4 successive weeks. PS-NPs treatment led to sex-dependent lung inflammation, oxidative damage, and apoptosis in WT mice, which were further aggravated in HO mice. Proteomics analysis revealed impaired efferocytosis in HO mice was associated with perturbations in protein kinase A, ERK/MAPK, Hedgehog signaling pathway etc. In vitro studies confirmed that PP2A Aα deficiency dysregulated Hedgehog signaling, thereby suppressing macrophage efferocytosis and exacerbating pulmonary injury following PS-NPs exposure. Notably, we identified biochanin A as a compound capable of attenuating PS-NPs-induced pulmonary inflammation by enhancing efferocytosis. Together, these findings uncover a novel PP2A-Hedgehog-efferocytosis axis in NPs-induced pulmonary injury and highlight biochanin A as a potential intervention candidate for particulate pollutants-associated respiratory diseases. • Myeloid-specific deletion of the PP2A Aα gene impairs macrophage efferocytosis. • Efferocytosis plays a role in PS-NPs-induced pulmonary injury and is mediated by the PP2A/Hedgehog signaling pathway. • Biochanin A alleviates PS-NPs-induced pulmonary inflammatory injury by activating macrophage efferocytosis.

BackgroundAir pollution has been associated with the development and exacerbation of atopic dermatitis (AD), but the molecular signatures connecting pollutant-related targets with AD-associated immune dysregulation remain incompletely characterized.MethodsWe applied an integrated systems toxicology and transcriptomic framework to prioritize candidate pollutant-related immune signatures in AD. Pollutant-associated targets were intersected with high-confidence AD-related genes, followed by protein–protein interaction analysis, GO/KEGG enrichment, machine learning, immune infiltration analysis, single-cell transcriptomics, in silico CCL22 perturbation, 1-fluoro-2, 4-dinitrobenzene (DNFB)-induced AD-like mouse validation, and exploratory molecular docking.ResultsShared pollutant–AD targets were mainly enriched in cytokine activity, chemokine signaling, pattern-recognition receptor activity, IL-17 signaling, cytokine–cytokine receptor interaction, and Toll-like receptor-related inflammatory pathways. A machine learning framework based on 15 algorithms and 175 predictive combinations identified plsRglm + AdaBoost as the optimal model, with an AUC of 0.963 in the training cohort and AUCs of 1.000, 0.909, and 0.966 in three validation cohorts. The model identified a pollutant-prioritized AD signature including CCL22, CCL5, CSF2, F2RL1, HRH4, ICAM1, IFNG, IL10, IL17A, and IL18. CCL22 was upregulated in AD samples and mainly localized to dendritic cells and macrophages. In silico CCL22 perturbation was associated with extracellular matrix and stromal remodeling programs, while DNFB-induced AD-like dermatitis confirmed increased CCL22 expression in lesional skin.ConclusionThese findings identify CCL22-associated immune and stromal remodeling signatures as candidate molecular features of air pollution-related AD and generate testable hypotheses for future controlled exposure studies.

The increasing frequency of heat waves, combined with elevating ozone levels, constitutes an increasingly significant threat to public health. In this study, 8-week-old male C57BL/6J mice were subjected to individual or combined exposure of ozone (1 ppm) and heat (34°C) for 4 weeks. Both ozone and heat exposure disrupted intestinal barrier integrity and intestinal stem cell (ISC) function, with the most severe effects observed under combined exposure. Notably, co-exposure to ozone and heat resulted in the largest increase in Alistipes finegoldii (A. finegoldii) abundance, accompanied by enhanced tryptophan metabolism activity. Gut microbiota depletion and vertical microbiota transfer, together with intestinal content gavage, demonstrated the critical role of gut microbiota and their metabolites in mediating intestinal disruption. Colonization by A. finegoldii impaired ISC proliferation and differentiation, with elevated levels of indole and its derivatives, including indole-3-acetic acid (IAA) and tryptamine. Moreover, inhibition of aryl hydrocarbon receptor (AhR) signaling alleviated co-exposure-induced of intestinal injury. Mechanistically, AhR activation contributed to mitochondrial dysfunction. Interaction analysis indicated that ozone and heat primarily acted in an additive manner on gut integrity and microbiota dysbiosis. This study reveals that the A. finegoldii-tryptophan catabolite-AhR axis mediates the disruption of intestinal homeostasis induced by combined ozone and heat exposure.

BACKGROUND:Microplastics (MPs) or nanoplastics (NPs) are emerging environmental pollutants, but current studies predominantly focus on the hepatotoxicity of high-dose MPs, whereas the health effects of low-dose MPs under high-fat diet (HFD) conditions remain unclear. We aimed to investigate the hepatotoxicity induced by combined exposure to high-fat diet and low-dose microplastics. METHODS:Male Wistar rats were administered a high-fat diet (HFD) without (HFD) or with polystyrene nanoparticles (PS-NPs) (HFD-NP) for consecutive 90 days. In vitro experiments were conducted using primary hepatocytes treated with PS-NPs and palmitic acid (PA) in the presence or absence of AMPK or an autophagy inhibitor for 24 h. RESULTS:H&E staining revealed significant lipid accumulation, inflammation, and hepatic fibrosis in livers from HFD group, whereas no obvious pathological changes were observed in NP group. Notably, these effects were greatly diminished in HFD-NP group, compared with HFD group. In vitro experiments also showed that PS-NPs displayed no apparent effect on the viability of primary hepatocytes, while significantly alleviated palmitic acid (PA)-induced hepatocyte apoptosis and lipid droplet accumulation. These observations indicate that low-dose PS-NPs mitigate hepatotoxicity induced by HFD. Furthermore, hepatic lipid oxidation and utilization were enhanced in HFD-NP rats, suggesting that PS-NPs may modulate lipid metabolism upon HFD. Transcriptomic analysis revealed the mechanism might involve the activated AMPK signalling pathway and inhibited mTOR signalling pathway, important regulators for autophagy, implying the involvement of lipophagy in this process. Furthermore, in vitro experiments showed the inhibition of lipid droplet autophagy exacerbated HFD-induced hepatotoxicity. CONCLUSION:Our results indicate low-dose PS-NPs can activate the AMPK pathway and lipophagy, thereby alleviating liver injury through a stress adaptation response under high-fat diet conditions. Our findings elucidate the context-dependent interaction between microplastics and dietary patterns in liver diseases development and provide novel insights into the health effects of microplastics.

Microplastics (MPs) are ubiquitous environmental pollutants that accumulate in human liver tissue, yet their hepatotoxicity in humans remains incompletely defined. To investigate the association between occupational MPs exposure and hepatic dysfunction in humans, we recruited 141 participants from the Health Examination Centre of Guangxi Workers' Hospital, China, including 43 plastic-factory workers with ≥6 months of occupational exposure and 98 occupationally unexposed controls. An eight-item questionnaire-derived exposure risk score (0-8) was used to quantify MPs exposure levels. Linear and logistic regression models, adjusted for smoking, alcohol consumption, dust exposure, body mass index (BMI), and physical activity, were employed to analyze relationships between exposure (occupational status/risk score) and liver-function markers. Exposed workers exhibited higher risk scores (1.9 ± 1.1 vs 1.4 ± 0.9, P = 0.013) and twice the prevalence of abnormal liver function (48.8% vs 26.5%, P = 0.013). Each one-point increase in the risk score was associated with a significant elevation in aspartate aminotransferase (AST) by 2.82 U/L (β = 2.82, 95% CI: 0.27-5.38,P = 0.031) and total bilirubin (T-Bil) by 1.05 μmol/L (β = 1.05, 95% CI: 0.34-1.76,P = 0.004). Occupational exposure independently predicted abnormal liver function (OR = 3.97, 95% CI: 1.64-10.3, P = 0.041), with longer exposure duration linked to higher AST elevation rates. These results demonstrate that occupational MPs exposure impairs liver function, providing evidence for health-risk assessment of microplastics.

Ozone pollution is a growing global health threat, yet current evidence lacks cellular-level resolution to pinpoint its systemic damage. This randomized controlled crossover trial introduces plasma cell-free DNA (cfDNA) as a novel, sensitive biosensor for ozone-induced injury. In 29 healthy adults, acute ozone exposure (282.2 +/- 44 ppb) significantly altered cfDNA characteristics: it reduced the proportion of 150-165 bp fragments and increased cfDNA derived from megakaryocytes (21.35%), vascular endothelia (135.10%), and B/NK/T cells (174.69%), revealing these as key cellular targets. Epigenetic analysis revealed increased perplexity at transcription start sites, indicating enhanced entropy and potential transcriptional dysregulation. These cfDNA signatures correlated with systemic physiological changes, including elevated inflammatory markers (interleukin-6, tumor necrosis factor-alpha), oxidative stress (8-hydroxy-2 '-deoxyguanosine), endothelial dysfunction (endothelin-1), and lung epithelial injury (Clara cell secretory protein 16). Our findings demonstrate that cfDNA profiling can dynamically reflect ozone-induced cellular damage in the vascular, hematopoietic, and immune systems, moving beyond organ-level assessments. This approach provides a powerful and noninvasive tool for monitoring early systemic effects of air pollution, with implications for understanding mechanistic pathways and developing targeted interventions.

IntroductionThe pathology of diabetic foot ulcer (DFU) is characterized by keratinocyte dysfunction, non-resolving inflammation, and oxidative stress. We aim to investigate the effects and mechanisms of piroxicam on DFU healing through regulating mitochondrial function and suppressing inflammation.MethodsDFU was established in male C57BL/6 J mice and ovariectomized female mice. Piroxicam (1% or 0.33%) solution or saline was then applied for 9 days. HaCaT cells were induced with high glucose (HG) and subsequently incubated with piroxicam (0, 1.2, 3.7, 11, 33, 100 nM).Results and DiscussionPiroxicam significantly promoted DFU healing and inhibited the fibrosis in male diabetic mice at a low dose. Consistently, piroxicam enhanced proliferation and migration, and inhibited inflammation, fibrosis, and cellular senescence in HG-induced HaCaT cells. Mechanistically, piroxicam alleviated HG-induced mitochondrial dysfunction by stabilizing the mitochondrial respiratory chain, increasing biogenesis, and enhancing mitophagy. These effects further attenuated oxidative stress and inhibited the cGAS-STING-NF-κB inflammatory pathway, thereby reducing the release of pro-inflammatory factors. Furthermore, molecular docking revealed that piroxicam bound to ERα, a finding further confirmed by a cellular thermal shift assay. HG induced a significant decrease in nuclear ERα protein levels, which was reversed by piroxicam, especially at 11 and 33 nM. Additionally, piroxicam’s pro-healing and anti-inflammation effects were attenuated in ovariectomized female DFU mice. Piroxicam’s protection of mitochondrial function and suppression of oxidative stress was also abolished upon blocking ERα by tamoxifen. In conclusion, piroxicam alleviates mitochondrial dysfunction and suppresses inflammatory responses by binding to ERα, which ultimately promotes DFU healing at low doses.

Cadmium (Cd), a widespread environmental pollutant, has linked with various adverse health effects. However, the paternally inherited transgenerational effects of cadmium exposure on hepatotoxicity inoffspring and the underlying mechanism remained undefined. To address this issue, male mice (F0) were administrated with 100 mg/L cadmium chloride (CdCl2) in drinking water for 3 months. Then, F0 males were mated with healthy female mice to produce F1 and F2 offspring.Liver function was assessed at age of 6 weeks and 6 months, respectively. Herein, we showed ancestral cadmium exposure led to liver injury in F1 male and F2 mice, characterized by hepatic steatosis and impaired glucose homeostasis. These results suggest that ancestral exposure to cadmium could induce the transgenerational inheritance of cadmium-induced liver injury, which was more profound in male offspring. Furthermore, methylated RNA immunoprecipitation (MeRIP) sequencing analysis identified 285 and 734 differentially methylation expressed genes in mice liver tissue treated with CdCl2 for 3 months and 9 months, respectively. Among them, suppression of Irs1 and Il6st led to enhanced cytotoxicity induced by CdCl2, indicating that Irs1 and Il6st might be involved in CdCl2-induced liver injury. More importantly, the alteration of Irs1 and Il6st RNA methylation was also observed in F1 males and F2 mice, consistent with the phenotypes. Further analysis suggested the involvement of Irs1 methylation in the transgenerational inheritance of cadmium-induced hepatotoxicity, possibly mediated by METTL3. Collectively, these findings uncover the novel role of RNA methylation in the transgenerational inheritance of adverse effects and deepen the understanding of the etiology of disease.

Arsenic (As) is classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC). Exposure to As has been associated with an increased risk of various cancers, particularly lung cancer. However, the precise molecular mechanisms contributing to this carcinogenesis are not well understood. In our study, we analyzed transcriptomic data from the GEO database (GSE36684), identifying 764 differentially expressed genes (DEGs) in BEAS-2B cells treated with environmentally relevant doses of As for 8 weeks. A KEGG pathway enrichment analysis suggested that the FoxO pathway activation might be a novel key signaling event in As-induced carcinogenesis. We further analyzed the expression of 11 DEGs involved in the FoxO pathway using the TCGA-LUSC dataset. The findings revealed that four genes displayed expression patterns in tumor tissues consistent with those observed after As treatment in GEO dataset. Among them, USP7 was upregulated, while ATM, S1PR1, and PLK2 were downregulated in cancer tissues. High USP7 expression was specifically linked to a poor prognosis in lung squamous cell carcinoma (LUSC). To explore the role of USP7 in As-induced malignant transformation, BEAS-2B cells were exposed to NaAsO2 concentrations of 0.2 μM and 2 μM for up to 20 weeks. Experimental results confirmed that NaAsO2 treatment suppressed the FoxO transcriptional activity by upregulating USP7 expression, subsequently downregulating ATM and PLK2 expression, which led to abnormalities in cell cycle regulation and apoptosis. Notably, knocking down USP7 in As-transformed cells resulted in significant reductions in cell proliferation, colony formation, and tumor formation ability in nude mice, indicating the USP7-regulated FOXO3A pathway could be central to As-induced lung carcinogenesis. Moreover, our research demonstrated that USP7 inhibited FOXO3A's ability to translocate from the cytoplasm to the nucleus by affecting its monoubiquitination status. Additionally, we speculated that As-induced the elevation of USP7 expression due to the excessive inflammatory cytokines secretion and the activation of mTORC1/WTAP pathway. These findings offer novel insights into the molecular mechanisms underlying As-mediated lung cancer.

Background GI cancers pose an increasing global health burden, with their impact on the working-age population (WAP) aged 15-64 years remaining largely unexplored despite the crucial role of this group in societal and economic well-being.Objective To assess trends and cross-country inequality in the global burden of six GI cancers from 1990 to 2021 among individuals in the WAP.Design The 2021 Global Burden of Disease study dataset was used to obtain estimates of GI cancer incidence and 95% uncertainty intervals, including the number of cases, crude incidence rate and age-standardised incidence rate (ASIR). WAP GI cancer epidemiology was assessed at the national, regional and global levels, evaluating trends from 1990 to 2021 from overall, local and Sociodemographic Index (SDI) perspectives and using standard health equity methods to quantify cross-country inequality.Results Colorectal cancer exhibited the greatest burden of GI cancer among the WAP in 2021. From 1990 to 2021, the number of GI cancer cases rose by 51.9%, although the ASIR declined by 23.4%. These rates exhibit geographic variation, with the most cases and the highest ASIR in China and Mongolia, respectively. Incidence was disproportionately concentrated in higher SDI countries, and worsening inequality was evident over time.Conclusions While the ASIR of GI cancer is trending downwards among the WAP, high incidence rates, regional variability and an unequal burden of disease emphasise the need for flexible, targeted medical interventions to support policymaking and medical resource allocation.

Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) implicated in the onset and advancement of various human cancers. Among these, circFOXK2 has been linked to non-small cell lung cancer (NSCLC); however, its precise functions and underlying molecular mechanisms are not fully understood. This study shows the first experimental findings that circFOXK2 promotes NSCLC tumor progression by modulating the miR-328-5p/PKP3 signaling pathway. Levels of circFOXK2, miR-328-5p, and PKP3 were evaluated by qRT-PCR. Cellular (NSCLSC) proliferation was examined via CCK-8 assays, migratory capacity via wound healing, and invasive potential via Transwell assays. Potential binding interactions between miR-328-5p and circFOXK2 were first assessed using bioinformatic analysis and verified using a dual-luciferase reporter assay (DLRGAs). Regulatory relationships among circFOXK2, miR-328-5p, and PKP3 were further investigated through qRT-PCR analysis. Elevated expression of circFOXK2 and reduced levels of miR-328-5p were observed in NSCLC cell lines and tissues. Functionally, circFOXK2 enhanced cellular propagation, dissemination, and invasion in vitro. Mechanistic evaluation revealed that circFOXK2 upregulates PKP3 by acting as an miR-328-5p sponge. The findings demonstrate that circFOXK2 contributes to NSCLC tumorigenesis via modulation of the miR-328-5p/PKP3 pathway, identifying this signaling axis as a potential therapeutic target in NSCLC.

Global warming has increased the frequency of simultaneous ozone and heat exposure, raising significant public health concerns. This study investigates the impacts of gestational exposure to ozone (1 ppm) and heat (34°C) under real-world conditions on fetal and placental development in C57BL/6 J mice, with a particular focus on the role of maternal hepatic lipid metabolism. Pregnant mice were exposed from gestational day (GD) 0 to GD17. Co-exposure to ozone and heat significantly reduced fetal birth weight and crown-rump length, and exacerbated adverse pregnancy outcomes, while exposure to ozone or heat alone did not significantly reduce fetal birth weight or crown-rump length. Placental development was impaired in the co-exposure group, particularly in the trophoblast zone. Ex vivo cell experiments revealed that plasma from co-exposed pregnant mice induced functional impairment in HTR-8/SVneo trophoblast cells. Maternal plasma analysis revealed a strong association between impaired placental and fetal development and abnormal lipid levels, which play a key role in causing developmental toxicity. Transcriptomic analysis of maternal liver tissue revealed that ozone exposure suppressed LDL and VLDL absorption, while heat promoted triglyceride synthesis. Co-exposure further exacerbated disruptions in hepatic lipid homeostasis. These findings highlight the detrimental effects of ozone and heat co-exposure on maternal and fetal health, suggesting that fetal impairments may be mediated by maternal hepatic lipid metabolism dysregulation.

Di(2-ethylhexyl) phthalate (DEHP) is a widespread ubiquitous phthalate environmental contaminant. The male reproductive toxicity (MRT) from exposure to DEHP and its main metabolite, mono(2-ethylhexyl) phthalate (MEHP), has been well documented. Fully elucidating its toxic mechanism and discovering effective antagonists are desirable means to reduce the health risks of DEHP. In this study, 552 genes related to MRT induced by DEHP/MEHP were screened out from the Comparative Toxicogenomics Database (CTD) and DisGeNET database. Next, we developed a global adverse outcome pathway (AOP) network based on the existed AOP-wiki. After functional enrichment analyses and mapping to the global AOP network, we found that the increased ROS level, cell cycle arrest, and increased apoptosis are key events (KEs) involved in DEHP-mediated MRT, which was validated in TM3 Leydig cell model. Among them, cellular apoptosis is the core KE in DEHP-induced MRT via network topological analysis. Eventually, we developed a novel in silico antagonist screening platform (http://43.136.69.224:3838/wlab/) based on drug-target gene set enrichment analysis (dtGSEA version 2.0). Several potential candidates that mitigate DEHP-mediated cellular apoptosis have been screened out, including quercetin, taurine, methionine, and phloridzin. Further experimental results demonstrated that phloridzin provided the most effective protection against MEHP-induced apoptosis in TM3 cells probably through the p53 and MAPK signaling pathways. Molecular docking and molecular dynamics simulations suggest that STAT3 and RUNX1 may be important targets for phloridzin to antagonize MEHP-induced MRT. Our study provides a new approach to discover the antagonists for the toxicity of environmental contaminants based on AOP network and dtGSEA methods.

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase in the brain. Mutations in PPP2R1A, encoding the scaffolding subunit, are linked to intellectual disability, although the underlying mechanisms remain unclear. This study examined mice with heterozygous deletion of Ppp2r1a in forebrain excitatory neurons (NEX-het-conditional knockout [NEX-het-cKO]). These mice exhibited impaired spatial learning and memory, resembling Ppp2r1a-associated intellectual disability. Ppp2r1a haploinsufficiency also led to increased excitatory synaptic strength and reduced inhibitory synapse numbers on pyramidal neurons. The increased excitatory synaptic transmission was attributed to increased presynaptic release probability, likely due to reduced levels of 2-arachidonoyl glycerol (2-AG). This reduction in 2-AG was associated with increased transcription of monoacylglycerol lipase (MAGL), driven by destabilization of enhancer of zeste homolog 2 (EZH2) in NEX-het-cKO mice. Importantly, the MAGL inhibitor JZL184 effectively restored both synaptic and learning deficits. Our findings uncover an unexpected role of PPP2R1A in regulating endocannabinoid signaling, providing fresh molecular and synaptic insights into the mechanisms underlying intellectual disability.

Environmental ozone pollution may adversely impact human health, while dysbiosis is implicated in various health outcomes. However, the effects of ozone exposure on the human microbiome remain unclear. This study conducted a controlled, randomized, crossover ozone exposure trial with 29 participants exposed to filtered air and ozone. Oral microbiome samples were collected for 16S rRNA sequencing. A mixed-effects model was used to analyze the impact of ozone exposure on the diversity and composition of the oral microbiome, as well as their association with lung functions. The results showed that the ozone concentration remained stable at 5 ± 5.1 parts per billion (ppb) under filtered air and 282.2 ± 44 ppb during ozone exposure. Acute ozone exposure significantly impaired lung function and reduced oral microbiome diversity, with forced vital capacity (FVC) decreasing by 0.41 L, expiratory volume in one second (FEV1) by 0.36 L, and peak expiratory flow (PEF) by 0.81 L, while observed species richness (Sobs), abundance-based coverage estimator (Ace), and chao indices (Chao) decreased by 21.83, 22.24, and 21.87%, respectively. Males exhibited greater sensitivity to ozone exposure than females, reflected in both reduced lung function and alterations in the oral microbiome. The altered microbiome was mainly enriched in metabolic pathways. Among the microbiome, Treponema medium exhibited a significant correlation and mediating effect on ozone-induced lung function impairment, which may serve as a sensitive indicator of changes in lung function. These findings provide new insights into the health effects caused by ozone exposure.

Although the effects of ozone and heat on health have been studied independently, the impact of combined exposure remains poorly understood. In this study, C57BL/6 J male mice were individually exposed to ozone (1 ppm), heat (34 degrees C), or both in combination for 4 weeks (5 days/week, 3 h/day). In the Co-exposure group, stress hormones were increased, intensifying the activation of both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis. Co-exposure to ozone and heat disrupted lipid homeostasis, as evidenced by elevated low-density lipoprotein cholesterol (LDL-C) and free fatty acids (FFA). Additionally, the combined exposure promoted hepatic lipid accumulation and oxidative stress. Co-exposure also induced the whitening of brown adipose tissue, reducing its capacity for thermogenesis and potentially worsening lipid dysregulation in the liver and systemic circulation. Transcriptomic analysis of the liver identified perturbations in key pathways related to cellular stress response and lipid metabolism. Notably, key enzymes responsible for cholesterol clearance, such as cholesterol 7 alpha-hydroxylase (Cyp7a1), and ATP-binding cassette transporters G5 (Abcg5) and G8 (Abcg8) were suppressed in the Co-exposure group. These findings underscore the additive effects of simultaneous ozone and heat exposure in lipid metabolism, highlighting the increased risk of metabolic disorders under environmental stress.

Aristolochic Acid I (AAI) is widely present in traditional Chinese medicines derived from the Aristolochia genus and is known to cause significant damage to renal tubular epithelial cells. Genome-wide screening has proven to be a powerful tool in identifying critical genes associated with the toxicity of exogenous substances. To identify undiscovered key genes involved in AAI-induced renal toxicity, a genome-wide CRISPR library screen was conducted in the human kidney-2 (HK-2) cell line. Among the altered sgRNAs, a significant enrichment of those targeting the E2F transcription factor 1 (E2F1) gene was observed in surviving HK-2 cells in the AAI-treated group. Interestingly, the role of E2F1 had not been previously explored in studies of AAI nephrotoxicity. Further investigations revealed that E2F1 promotes apoptosis by activating the p53 signaling pathway and upregulating pro-apoptotic genes, such as BAK and BAX. Additionally, using the high-throughput experiment- and reference-guided database of traditional Chinese medicine (HERB), cannabidiol (CBD) was identified as an inhibitor of E2F1 by suppressing the activity of NF-κB pathway. In vitro and in vivo models confirmed that CBD inhibits AAI-induced upregulation of E2F1, thereby suppressing p53-mediated apoptosis. In conclusion, this study highlights the crucial role of E2F1 in AAI-induced renal cell apoptosis and identifies CBD as a novel therapeutic candidate for mitigating AAI nephrotoxicity.