BackgroundPhysical frailty is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying metabolic mechanisms remain unclear. This study aimed to identify a frailty-related metabolic signature and examine its association with incident MASLD and its mediating role in the frailty-MASLD relationship.MethodsWe analysed data from 244,187 UK Biobank participants. Frailty was assessed using the Fried Frailty Phenotype. Incident MASLD was ascertained via hospital records and death registries. An elastic net regression model identified frailty-associated metabolites to construct a weighted metabolic signature. Cox proportional hazards models estimated associations with MASLD risk, and mediation analysis quantified the signature’s contribution.ResultsOver a median follow-up of 13.7 years, 3,408 incident MASLD cases occurred. A 96-metabolite signature was identified. Each 1-standard deviation increase in the signature was associated with a 21% higher MASLD risk (HR = 1.21, 95% CI: 1.16-1.25). Compared with robust participants, pre-frail and frail individuals had HRs of 1.51 (95% CI: 1.40-1.63) and 2.22 (95% CI: 1.97-2.50), respectively. The metabolic signature mediated 4.25% of the frailty-MASLD association.ConclusionFrailty and its associated metabolic signature are independently associated with increased incident MASLD risk. The signature partially mediates this relationship, suggesting metabolic dysregulation links physical frailty to hepatic steatosis. Identifying this signature may enable earlier MASLD detection in frail individuals.

Background: Globally, the increasing frequency of extreme heat events and ozone pollution incidents has significantly intensified public health risks. However, empirical evidence regarding their synergistic impacts remains limited in central China. Methods: A two-stage analysis was conducted using data from 121 counties in Henan (2013-2019). Quasi-Poisson generalized additive models were used to assess county-specific associations, adjusting for PM2.5, RH, and temporal trends. The combined effect of air temperature (non-linear) and ozone (linear) was captured through multiplicative interaction terms. Random-effects meta-analyses were applied to pool the results. Subgroup analyses examined differences by age, sex, marital status, and cause of death. Results: During the study period, 1,280,429 deaths were recorded. Both high temperatures and elevated ozone levels were associated with increased mortality. Their joint effects were stronger than individual exposures. At high ozone levels, mortality risk increased by 2 percentage points (from 9.3 % to 11.3 %) between temperature distribution percentiles 75th and 99th. Under high-temperature conditions (31.4 degrees C, 90th percentile), a 10 mu g/m3 elevation in ozone was associated with a 0.94 % (95 % CI: 0.49 %-1.38 %) increase in mortality. Older adults, females, other marital statuses (including unmarried, divorced, or widowed), and those with cardiovascular or respiratory diseases were more susceptible to its effects. Conclusion: High temperature and ozone synergistically increase mortality risk. Targeted interventions are needed to protect vulnerable groups under climate change.

Dioxins, a group of environmental pollutants, can cause developmental toxicity through interaction with the aromatic hydrocarbon receptor (AHR). Retinoic acid (RA) functions via binding to retinoic acid receptor (RAR)/retinoid X receptor (RXR). Both AHR and RA pathways can be activated by dioxins. TCDD or atRA exposure similarly alters the expression of the long non-coding RNA (lncRNA) Meg3 in mouse palatal tissue. This study further examined the mechanism of TCDD-induced cleft palate (CP) via the RA pathway in mouse embryonic palatal mesenchymal (MEPM) cells. Results showed that in MEPM cells TCDD treatment increased Meg3 and RARA expression, inhibited cell proliferation, and had a synergistic effect with atRA. RNA pull-down-MS and RIP assays revealed that Meg3 binds to NONO, which belongs to the drosophila behavior human splicing family (DBHS) and have been reported to be associated with cell cycle regulation. NONO interacts with RAR and inhibits RARA expression. TCDD and atRA treatment reduced NONO expression. Silencing Meg3 raised NONO levels and mitigated the impact of TCDD or atRA on RA pathway activation, cell proliferation and survival. These findings suggest that TCDD affects Meg3 and NONO expression and the RA pathway activation, Meg3 interacts with NONO which may regulate RARA in palatal tissue. Thus, we propose that the RA pathway activation in TCDD-induced cleft palate may be mediated by the Meg3-NONO-RAR axis.

Table S1 shows the application of PRMT inhibitors in gastrointestinal tumors.

Chronic kidney disease (CKD) is a significant global health issue associated with cardiovascular complications. While coffee, tea, and caffeine consumption have been linked to various health benefits, their relationship with CKD remains unclear. We conducted a cross-sectional analysis of NHANES 1999–2018 data, including 49,827 participants, assessing dietary intake through two 24-hour recalls and determining CKD status via the CKD-EPI equation. Our results showed that after adjusting for covariates, higher coffee consumption (> 352.5 g/day) was associated with lower odds of CKD (OR 0.760, 95% CI 0.701–0.823), as was tea consumption (OR 0.913, 95% CI 0.843–0.89). The highest tertile of caffeine consumption also showed a significantly reduced odds of CKD (OR 0.734, 95% CI 0.674–0.799). These findings suggest that coffee, tea, and caffeine consumption may be associated with better renal function, highlighting potential dietary strategies for CKD prevention.

2, 3, 7, 8-tetrachlorodiphenyl-p-dioxin (TCDD) and all-trans retinoic acid (atRA) have been shown to be inducers of cleft palate (CP). Relevant studies have shown that Oct transcription factor 4 (Oct4) can regulate the expression of the aromatic hydrocarbon receptor (AhR), a target gene of TCDD, as well as influence the retinoic acid signaling pathway. However, the mechanism of Oct4 regulating the interaction between TCDD and atRA in CP pathogenesis remains unclear. In order to solve the above problems, mouse embryonic palatal mesenchymal (MEPM) cells were used for further study. The results show that, TCDD and atRA induce a similar pattern of CP in vivo and significantly inhibit the proliferation of MEPM cells. In vitro, TCDD exposure led to up-regulation of AhR and cytochrome P450 1A1 (CYP1A1) expression and down-regulation of cellular retinoic acid binding protein 2 (CRABP2) and retinoic acid receptor-alpha (RARA) expression in MEPM cells. In addition, atRA exposure resulted in decreased expression of AhR and CYP1A1, and increased protein levels of RARA and CRABP2. When Oct4 was overexpressed, the down-regulation of CRABP2 and RARA by TCDD and the down-regulation of AhR by RA were reversed. The cross results of mass spectrometry and Biogrid database show that HSP90AB1 can bind to Oct4 and AhR. Co-immunoprecipitation (Co-IP) results showed that Oct4 and CRABP2 were combined, which further suggested the mediating effects of Oct4 in CP development. In summary, we hypothesize that AhR-HSP90AB1-Oct4-CRABP2 axis may play the key role mediating the interaction between TCDD and atRA in CP pathogenesis.

The amount of data that is currently accessible on ambient air pollution and children's health has significantly increased. Although numerous systematic reviews and meta-analyses have evaluated the effect of air pollution on children's health, the results are mixed, including positive, negative, or null associations. The objective of this umbrella review is to thoroughly evaluate the validity of existing research on the connection between air pollution and children's health. We identified 33 systematic reviews of observational studies in which a diversity of health outcomes for children were reviewed, including mortality, respiratory diseases, hypertension, etc. According to our review's findings, being exposed to air pollution increases the chance of developing leukemia among children, as well as autism spectrum disorders, hypertension, otitis media, obesity, pneumonia, asthma, respiratory diseases, eczema, and allergic rhinitis. Additionally, there was a sizable positive association between air pollution and child mortality. The findings of this extensive umbrella review provide convincing proof that exposing children to air pollution increases the risk of developing multiple diseases. Our results have implications for strengthening childhood health care, reducing air pollution, and improving intergenerational equity.

Background: Systemic lupus erythematosus (SLE) is associated with adverse pregnancy outcome (APO). However, the genetic causality of this association remains unclear. In this study, Mendelian randomization (MR) was used to explore the potential causal relationship between SLE and APO risk. Methods: We selected 45 single nucleotide polymorphisms (SNPs) associated with SLE from published genome-wide association studies (GWAS). APO's statistics are obtained from the GWAS database. MR estimates were performed using the inverse variance-weighted (IVW) method, the MR-Egger method, and the weighted median (WM) method. Sensitivity analysis was performed using Cochran's Q test, MR-Egger intercept, MR-pleiotropic residual and outlier method, stay-one analysis and funnel plot. Results: The results showed a causal relationship between SLE and pre-eclampsia (OR = 1.036, 95 % confidence interval 1.006 to 1.068, P = 0.019), and no significant causal relationship was found between SLE and other adverse pregnancy outcomes, including postpartum hemorrhage, placental abruption, spontaneous abortion, premature rupture of membranes, fetal distress, gestational diabetes mellitus. These findings were robust in several sensitivity analyses. Conclusion: This MR study demonstrated the causal effect of SLE on preeclampsia. It provides important clues for identifying and early predicting risk factors for preeclampsia.

Retinol-binding protein 4 (RBP4) was controversially associated with type 2 diabetes mellitus (T2DM). This meta-analysis aimed at evaluating the association between RBP4 level and T2DM risk. MEDLINE and EMBASE were searched to identify relevant studies up to 3 December 2022. Random effects model was used to pool multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Publication bias was estimated by Funnel plot and Egger's test, it was considered to be significant when P < 0.05. Eight studies including 8087 participants were finally included. Compared to those with the lowest level, subjects with the highest level of RBP4 have a higher risk of T2DM (OR = 1.47, 95% CI: 1.16-1.78, P < 0.001, I2 = 86.9%). No publication bias among the included studies was found (t = 0.94, P = 0.377). This meta-analysis indicated that high RBP4 level was associated with increasing risk of T2DM.

Exposure to organophosphate esters (OPEs) is associated with several chronic diseases, but the relationship with mortality risk is unclear. Therefore, we used the National Health and Nutrition Examination Survey 2011-2018 data to evaluate these relationships. 6,869 participants aged 18 years or older were included. Survival status information was obtained through the National Death Index through 31 December 2019. Multivariable COX regression model was adopted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships of urinary OPEs metabolites with mortality risk. During an average of 5.0 years of follow-up, 406 deaths were documented. After adjusting for confounders, bis(2-chloroethyl) phosphate was associated with an increased risk of all-cause mortality [HR (95%CI) = 1.12(1.05-1.20)] and cardiovascular mortality [HR (95%CI) = 1.15(1.04-1.26)]. Our study found that exposure to OPEs was significantly associated with increased risks of all-cause and cardiovascular mortality. Consequently, controlling OPEs exposure is needed to alleviate the health-related burden.

The available evidence on the effects of ambient fine particulate matter (PM2.5) and pregnancy outcomes (birth outcomes and pregnancy complications) has increased substantially. The purpose of this umbrella review is to refine the evidence of the association between birth outcome (birth defects) and PM2.5; and summarize the credibility of existing research on the association between pregnancy complications and PM2.5. We searched PubMed, Web of Science, Embase, and Cochrane databases for relevant systematic reviews and meta-analyses up to March 16, 2022 in accordance with PRISMA guidelines. Two independent investigators conducted data extraction. AMSTAR 2 and GRADE assessment criteria were used to evaluate the methodological and evidence quality. We performed subgroup analyses by trimesters of pregnancy. The review protocol for this study has been registered in PROSPERO (CRD42022325550). This umbrella review identified a total of 41 systematic reviews, including 28 articles evaluating the influence of PM2.5 on birth outcomes and 13 on pregnancy complications. Positive associations between perinatal PM2.5 exposure and adverse birth outcomes were found, including low birth weight, preterm birth, stillbirth, small for gestational age, and birth defects. Pregnant women exposed to PM2.5 had a significantly higher risk of developing hypertensive disorder of pregnancy, gestational diabetes mellitus, gestational hypertension, and preeclampsia. The findings of subgroup analysis demonstrated that the effects of ambient PM2.5 exposure on pregnancy outcomes varied by trimesters. The findings of this extensive umbrella review provide convincing proof that exposure to ambient PM2.5 raises the risks of unfavorable birth outcomes and pregnancy complications. Some associations show considerable disparity between trimesters. These findings have implications for strengthen perinatal health care on air pollution and improving intergenerational equity.

Abstract Posttranslational modification of proteins increases their diversity and maintains the stability of the intracellular environment. Protein arginine methyltransferases (PRMT) are an important family of epigenetic modification enzymes, which play a critical role in posttranslational modification. In recent years, with the in-depth study of the role of epigenetics, the structure and function of PRMTs have been gradually understood. PRMT enzymatic activity is related to a variety of cellular processes in digestive system malignancies, such as inflammation and immune response, activation of cell cycle and proliferation, inhibition of apoptosis, DNA damage repair, and epithelial–mesenchymal transition. A variety of chemical tools are developed to inhibit PRMT activity, which have been verified by tumor models and clinical trials. This review summarizes the structure and functions of PRMTs as a prelude to our further studies on their role in tumors. The involvement of different PRMTs in the pathogenesis of gastrointestinal tumors is then reviewed. In addition, the application of PRMT inhibitors as therapeutic agents for digestive system cancers is highlighted. In conclusion, PRMTs play an important role in the pathogenesis of gastrointestinal tumors, and their prognostic and therapeutic potential warrants further investigation.

Nocturnal temperature is observed increasing with global warming. However, evidence on night-time non-optimal temperature on the risk of preterm birth (PTB) is limited, and the potential interactions with air pollution on PTB has not been well clarified. We therefore conducted a population-based retrospective cohort study to evaluate the effect of night-time temperature extremes on the risk of PTB and its interaction with air pollution. Records of 196,780 singleton births from 4 counties in Huai River Basin (2013-2018) were obtained. Gridded data on night-time temperature were collected from a high-quality Chinese Air Quality Reanalysis dataset. We used a multivariate logistic regression to evaluate the effects of night-time heat and cold exposure on the risk of PTB as well as its subtypes. Potential interactions between night-time temperature extremes and fine particulate matter < 2.5 µm (PM2.5) were examined using the relative excess risk due to interaction (RERI). We found that the risk of PTB was positively associated with third trimester night-time extremely heat and cold exposure, with adjusted OR of 1.898 (95 %CI: 1.655-2.177) and 2.044 (95 %CI: 1.786-2.339). Similar effects were observed for PTB subtypes, moderately PTB (mPTB) and very PTB (vPTB). Synergistic effects (RERI greater than 0) of each trimester night-time temperature extremes exposure and PM2.5 on PTB were observed. We identified consistent positive interactions between night-time temperature extremes and PM2.5 on mPTB. No significant interaction of night-time temperature extremes and PM2.5 on vPTB was found. In conclusion, this large retrospective cohort study found that third trimester night-time heat and cold exposure significantly increased the risk of PTB and its subtypes. There is a synergistic effect between night-time temperature extremes and high PM2.5 levels on PTB and mPTB. In the context of climate warming, our results add new evidence to the current understanding of night-time non-optimal temperature exposure on PTB.

Previous studies on particulate matter (PM) exposure and neurodegenerative disorders showed inconsistent results, and few studies systematically examined the long-term effect of PM on neurodegenerative diseases, including all-cause dementia, Alzheimer’s disease, Parkinson’s disease, vascular dementia, amyotrophic lateral sclerosis, and cognitive function decline. We systematically searched for published studies in PubMed, Embase, Cochrane Library, and Web of Science up to October 31, 2022. To facilitate a comparison of effect sizes from different studies, we standardized units across studies to a 10 μg/m3 increase for PM. Heterogeneity was assessed by Cochran’s Q test and I2 statistic. Publication bias was evaluated using funnel plots and Egger’s tests. Subgroup analysis, meta-regression, and sensitivity analysis were performed. The protocol for this review was registered with PROSPERO (CRD42021277112). Of the 3403 originally identified studies, a meta-analysis was finally performed in 49 studies. The results showed that there was a significant positive association between long-term PM2.5 exposure and all-cause dementia, Alzheimer’s disease as well as Parkinson’s disease, with pooled OR of 1.30 (95

A systematic review and meta-analysis was conducted to evaluate recent epidemiological evidence on the association of air pollution with congenital anomalies (CAs). Of 11,014 records, 49 were finally included in this meta-analysis. Per 10 mu g/m(3) increase in air pollutant, PM10 exposure during the 1st month of pregnancy and at the first trimester (T1) was associated with increased overall CAs. Further, exposure to PM10 was associated with congenital heart disease (OR = 1.055, 95% CI: 1.035, 1.074) and patent ductus arteriosus (OR = 1.094, 95% CI: 1.020, 1.168) at T1, with chromosomal anomalies during the entire pregnancy and with nervous system anomalies when exposure occurred 3 months prior to pregnancy, during the 1st, 2nd months of pregnancy and at T1. Besides, a significant association with overall CAs was observed for a combined exposure of PM10 and SO2 during the 1st month of gestation (OR: 1.101, 95% CI: 1.023, 1.180). A combined exposure of PM10 and CO was also associated with tetralogy of Fallot during 3-8 weeks of gestation (OR: 1.016, 95% CI: 1.005, 1.027). No significant associations were observed between PM2.5, NO2, and O-3 exposure and CAs.

Antibiotic resistance is currently one of the greatest threats to human health. Widespread use and residues of antibiotics in humans, animals, and the environment can exert selective pressure on antibiotic resistance bacteria (ARB) and antibiotic resistance gene (ARG), accelerating the flow of antibiotic resistance. As ARG spreads to the population, the burden of antibiotic resistance in humans increases, which may have potential health effects on people. Therefore, it is critical to mitigate the spread of antibiotic resistance to humans and reduce the load of antibiotic resistance in humans. This review briefly described the information of global antibiotic consumption information and national action plans (NAPs) to combat antibiotic resistance and provided a set of feasible control strategies for the transmission of ARB and ARG to humans in three areas including (a) Reducing the colonization capacity of exogenous ARB, (b) Enhancing human colonization resistance and mitigating the hor-izontal gene transfer (HGT) of ARG, (c) Reversing ARB antibiotic resistance. With the hope of achieving inter-disciplinary one-health prevention and control of bacterial resistance.

Emerging evidence suggests residential surrounding green space is beneficial for human health. The association between green space and GDM showed inconsistent results, and potential effect modification of green space with air pollution is still unclear. This study aims to evaluate the association between green space and GDM, and further explore potential interaction and medication effects. Participants were recruited from a retrospective cohort study between 2015 and 2020 in Henan, China. Residential green space based on normalized difference vegetation index (NDVI) and air pollution exposure were estimated using spatial-statistical models. Multivariate logistic regression was applied to evaluate the association between per 0.1 unit increase in NDVI with 4 buffer sizes (250 m, 500 m, 1000 m, 2000 m) and GDM. We examined potential interaction of green space and air pollutants on GDM. Mediating effects of air pollution associated with green space exposure on GDM were also investigated by causal mediation analyses. A total of 46,665 eligible pregnant women were identified. There were 4092 (8.8 %) women diagnosed with GDM according to the IADPSG criteria. We found that per 0.1-unit increment in NDVI250 m, NDVI500 m, NDVI1000 m and NDVI2000 m in second trimester were associated with the decreased risk of GDM, with adjusted OR of 0.921(95 %CI: 0.890-0.953), 0.922 (95 %CI: 0.891-0.953), 0.921 (95 %CI: 0.892-0.952) and 0.921 (95 %CI: 0.892-0.951), respectively. We identified significant interactions between second trimester PM2.5 and O3 exposure and NDVI for GDM (Pinteraction < 0.001). The causal mediation analysis showed that PM2.5 mediated approximately 2.5-5.5 % of the association between green space and GDM, while the estimated mediating effect of O3 was approximately 30.1-38.5 %. In conclusion, our study indicates that residential green space was associated with a reduced risk of GDM, particularly second trimester. Green space may benefit to GDM partly mediated by a reduction in PM2.5 and O3.

目的:探讨转化生长因子β(TGF-β)2、TGF-β3启动子甲基化模式在2,3,7,8-四氯二苯并对二噁英(TC-DD)诱导腭裂发生中的作用.方法:将42只C57BL/6N孕鼠分为对照组和TCDD组,每组各21只.在妊娠第10天(GD10)暴露于64μg/kg TCDD建立腭裂小鼠模型,对照组采用等体积的玉米油灌胃.3～5 d后分别收集胎鼠头部用于后续检测.HE染色观察GD13～GD15胎鼠的腭部发育,取GD14胎鼠腭组织检测TGF-β2和TGF-β3启动子甲基化水平,利用qRT-PCR检测GD13～GD15胎鼠腭组织中TGF-β2、TGF-β3 mRNA的表达水平.结果:HE染色显示TCDD组胎鼠出现腭裂,而对照组未见腭发育异常.与对照组相比,TCDD组TGF-β2片段1的CpG10位点甲基化水平降低;TGF-β2片段2中以下CpG位点甲基化水平升高:CpG14、CpG18.19、CpG25和CpG29;而CpG32.33.34甲基化水平降低;TGF-β3片段1中,CpG2.3、CpG16.17.18位点均出现甲基化水平升高;TGF-β3片段2的CpG6甲基化水平升高,而CpG18甲基化水平降低(P<0.05).与对照组相比,TCDD组GD13～GD15胎鼠腭组织中TGF-β2和TGF-β3 mRNA表达均降低(P<0.05).结论:TCDD可能使TGF-β2和TGF-β3启动子部分位点发生甲基化而影响TGF-β2和TGF-β3在胎鼠腭部的表达,从而导致腭裂.

Background and aims The evidence regarding folate intake and mortality risk among patients with type 2 diabetes (T2D) remains unclear. This study aimed to investigate the association of folate intake with the risk of mortality among individuals with T2D. Methods A total of 9,196 participants with T2D from the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES 1999–2014 were included. The data of survival were obtained by the cohort database linked with the national death index up to 31 December 2015. The Cox proportional hazard model was used to evaluate the relationship between dietary folate with all-cause and cause-specific mortality. Results Among patients with T2D, dietary folate intake was negatively correlated with all-cause mortality, cardiovascular mortality, and cancer mortality in men, and for women with all-cause mortality and cardiovascular mortality. The multivariate adjustment hazard ratio (HR) (95% CIs) for men of highest vs. lowest quartile was 0.77 (0.66–0.90), 0.61 (0.45–0.83), and 0.70 (0.49–0.99) for all-cause, cardiovascular, and cancer mortality, respectively. Among women, the multivariate adjustment HR (95% CIs) of highest vs. lowest quartile was 0.77 (0.64–0.92), 0.52 (0.33–0.83), and 0.78 (0.50–1.22) for all-cause, cardiovascular, and cancer mortality, respectively. Conclusion Higher dietary intake of folate was significantly associated with lower all-cause and cardiovascular mortality. This cohort study suggested that increasing the dietary folate intake may reduce mortality risk among U.S. adults with T2D.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent organic pollutant that is strongly associated with a number of human diseases and birth defects, including cleft palate. Transforming growth factor (TGF) plays a significant role during mammalian palatogenesis. However, the epigenetic mechanism of transforming growth factors in the process of TCDD-induced cleft palate is unclear. The purpose of this research was to investigate the relationship and potential mechanism between TGF-β2/3 promoter DNA methylation and Smad signaling during TCDD-induced cleft palate. Pregnant C57BL/6N mice were exposed to 64 µg/kg TCDD on gestational day 10 (GD10) to establish the cleft palate model and palatal tissues of embryos were collected on GD13, GD14, and GD15 for subsequent experiments. TGF-β2/3 mRNA expression, TGF-β2/3 promoter methylation, and Smad signaling molecules expression were assessed in the palate of the two groups. The results showed that the incidence of cleft palate was 94.7% in the TCDD-treated group whereas no cleft palate was found in the control group. TCDD-treated group altered specific CpG sites of TGF-β2/3 promoter methylation. Compared to the control group, the proliferation of mouse embryonic palate mesenchymal stromal cells (MEPM), the expressions of TGF-β2/3, p-Smad2, and Smad4 were all reduced, while the expression of Smad7 was significantly increased in the atAR group. Smad signaling was downregulated by TCDD. Therefore, we suggest that TGF-β2/3 promoter methylation and Smad signaling may be involved in TCDD-induced cleft palate formation in fetal mice.