Associations of short-term ambient temperature exposure with lung function in middle-aged and elderly people: A longitudinal study in China.

The short-term associations of ambient temperature exposure with lung function in middle-aged and elderly Chinese remain obscure. The study included 19,128 participants from the Dongfeng-Tongji cohort's first (2013) and second (2018) follow-ups. The lung function for each subject was determined between April and December 2013 and re-assessed in 2018, with three parameters (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and peak expiratory flow [PEF]) selected. The China Meteorological Data Sharing Service Center provided temperature data during the study period. In the two follow-ups, a total of 25,511 records (average age: first, 64.57; second, 65.80) were evaluated, including 10,604 males (41.57%). The inversely J-shaped associations between moving average temperatures (lag01-lag07) and FVC, FEV1, and PEF were observed, and the optimum temperatures at lag04 were 16.5 °C, 18.7 °C, and 16.2 °C, respectively. At lag04, every 1 °C increase in temperature was associated with 14.07 mL, 9.78 mL, and 62.72 mL/s increase in FVC, FEV1, and PEF in the low-temperature zone (

Associations of polychlorinated biphenyls exposure, lifestyle, and genetic susceptibility with dyslipidemias: Evidence from a general Chinese population.

Polychlorinated biphenyls (PCBs) are endocrine-disrupting chemicals that have been associated with various adverse health conditions. Herein we explored the associations of PCBs with dyslipidemia and further assessed the modification effect of genetic susceptibility and lifestyle factors. Six serum PCBs (PCB-28, 101, 118, 138, 153, 180) were determined in 3845 participants from the Wuhan-Zhuhai cohort. Dyslipidemia, including hyper-total cholesterol (HyperTC), hyper-triglyceride (HyperTG), hyper-low density lipoprotein cholesterol (HyperLDL-C), and hypo-high density lipoprotein cholesterol (HypoHDL-C) were determined, and lipid-specific polygenic risk scores (PRS) and healthy lifestyle score were constructed. We found that all six PCB congeners were positively associated with the prevalence of dyslipidemias, and ΣPCB level was associated with HyperTC, HyperTG, and HyperLDL-C in dose-response manners. Compared with the lowest tertiles of ΣPCB, the odds ratios (95% confidence intervals) in the highest tertiles were 1.490 (1.258, 1.765) for HyperTC, 1.957 (1.623, 2.365) for HyperTG, and 1.569 (1.316, 1.873) for HyperLDL-C, respectively. Compared with those with low ΣPCB, healthy lifestyle, and low genetic risk, participants with high ΣPCB, unfavorable lifestyle, and high genetic risk had the highest odds of HyperTC, HyperTG, and HyperLDL-C. Our study provided evidence that high PCB exposure exacerbated the association of genetic risk and unhealthy lifestyle with dyslipidemia.

Role and mechanism of WNT5A in benzo(a)pyrene-induced acute lung injury and lung function decline.

Benzo(a)pyrene was sparsely studied for its early respiratory impairment. The non-canonical ligand WNT5A play a role in pneumonopathy, while its function during benzo(a)pyrene-induced adverse effects were largely unexplored. Individual benzo(a)pyrene, plasma WNT5A, and spirometry 24-hour change for 87 residents from Wuhan-Zhuhai cohort were determined to analyze potential role of WNT5A in benzo(a)pyrene-induced lung function alternation. Normal bronchial epithelial cell lines were employed to verify the role of WNT5A after benzo(a)pyrene treatment. RNA sequencing was adopted to screen for benzo(a)pyrene-related circulating microRNAs and differentially expressed microRNAs between benzo(a)pyrene-induced cells and controls. The most potent microRNA was selected for functional experiments and target gene validation, and their mechanistic link with WNT5A-mediated non-canonical Wnt signaling was characterized through rescue assays. We found significant associations between increased benzo(a)pyrene and reduced 24-hour changes of FEF50% and FEF75%, as well as increased WNT5A. The benzo(a)pyrene-induced inflammation and epithelial-mesenchymal transition in BEAS-2B and 16HBE cells were attenuated by WNT5A silencing. hsa-miR-122-5p was significantly and positively associated with benzo(a)pyrene and elevated after benzo(a)pyrene induction, and exerted its effect by downregulating target gene TP53. Functionally, WNT5A participates in benzo(a)pyrene-induced lung epithelial injury via non-canonical Wnt signaling modulated by hsa-miR-122-5p/TP53 axis, showing great potential as a preventive and therapeutic target.

Ambient temperature exposure causes lung function impairment: The evidence from Controlled Temperature Study in Healthy Subjects (CTSHS).

BACKGROUND: The effect of non-optimal ambient temperatures (low and high temperatures) on lung function and the underlying mechanisms remains unclear. METHODS: Forty-three (20 males, 23 females) healthy non-obese volunteers with an average of 23.9 years participated in the controlled temperature study. All volunteers underwent three temperature exposures in a sequence (moderate [18 °C], low [6 °C], and high [30 °C] temperatures) lasting 12 h with air pollutants controlled. lung function parameters (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and peak expiratory flow [PEF]) were determined in each exposure. Blood and urine samples were collected after each exposure and assayed for inflammatory markers [C-reactive protein (CRP), procalcitonin (PCT), platelet-lymphocyte ratio (PLR), and neutrophil-lymphocyte ratio (NLR)] and oxidative damage markers [protein carbonylation (PCO), 4-hydroxy-2-nominal-mercapturic acid (HNE-MA), 8-iso-prostaglandin-F2α (8-isoPGF2α), and 8-hydroxy-2-deoxyguanosine (8-OHdG)]. Mixed-effects models were constructed to assess the changes of the above indexes under low or high temperatures relative to moderate temperature, and then the repeated measures correlation analyses were performed. RESULTS: Compared with moderate temperature, a 2.20% and 2.59% net decrease in FVC, FEV1, and a 5.68% net increase for PEF were observed under low-temperature exposure, while a 1.59% net decrease in FVC and a 7.29% net increase in PEF under high-temperature exposure were found (all P < 0.05). In addition, low temperature elevated inflammatory markers (PCT, PLR, and NLR) and oxidative damage markers (8-isoPGF2α, 8-OHdG), and high temperature elevated HNE-MA. Repeated measures correlation analyses revealed that PCT (r = -0.33) and NLR (r = -0.31) were negatively correlated with FVC and HNE-MA (r = -0.35) and 8-OHdG (r = -0.31) were negatively correlated with the FEV1 under low-temperature exposure (all P < 0.05). CONCLUSION: Non-optimal ambient temperatures exposure alters lung function, inflammation, and oxidative damage. Inflammation and oxidative damage might be involved in low temperature-related lung function reduction.

Long-term effect of styrene and ethylbenzene exposure on fasting plasma glucose: A gene-environment interaction study.

Styrene and ethylbenzene (S/EB) are hazardous pollutants that have attracted worldwide concern. In this prospective cohort study, S/EB exposure biomarker (the sum of mandelic acid and phenylglyoxylic acid [MA+PGA]) and fasting plasma glucose (FPG) were repeatedly measured three times. The polygenic risk score (PRS) based on 137 single nucleotide polymorphisms for type 2 diabetes mellitus (T2DM) was calculated to evaluate cumulative genetic effect. In repeated-measures cross-sectional analyses, MA+PGA (ß [95% confidence interval]: 0.106 [0.022, 0.189]) and PRS (0.111 [0.047, 0.176]) were significantly related to FPG. For long-term effect assessment, participants with sustained high MA+PGA or with high PRS had 0.021 (95% CI: -0.398, 0.441) or 0.465 (0.064, 0.866) mmol/L increase in FPG, respectively, over 3 years follow-up, and had 0.256 (0.017, 0.494) or 0.265 (0.004, 0.527) mmol/L increase in FPG, respectively, over 6 years follow-up. We further detected a significant interaction effect between MA+PGA and PRS on FPG change, compared with participants with sustained low MA+PGA and low PRS, those with sustained high MA+PGA and high PRS had 0.778 (0.319, 1.258) mmol/L increase in FPG (P for interaction=0.028) over 6 years follow-up. Our study provides the first evidence that long-term exposure to S/EB potentially increases FPG, which might be aggravated by genetic susceptibility.

The potential role of plasma miR-4301 in PM2.5 exposure-associated lung function reduction.

The effect of PM2.5 exposure on lung function reduction has been well-documented, but the underlying mechanism remains unclear. MiR-4301 may be involved in regulating pathways related to lung injury/repairment, and this study aimed to explore the potential role of miR-4301 in PM2.5 exposure-associated lung function reduction. A total of 167 Wuhan community nonsmokers were included in this study. Lung function was measured and personal PM2.5 exposure moving averages were evaluated for each participant. Plasma miRNA was determined by real-time polymerase chain reaction. A generalized linear model was conducted to assess the relationships among personal PM2.5 moving average concentrations, lung function, and plasma miRNA. The mediation effect of miRNA on the association of personal PM2.5 exposure with lung function reduction was estimated. Finally, we performed pathway enrichment analysis to predict the underlying pathways of miRNA in lung function reduction from PM2.5 exposure. We found that each 10 µg/m3 increase in the 7-day personal PM2.5 moving average concentration (Lag0-7) was related to a 46.71 mL, 1.15%, 157.06 mL/s, and 188.13 mL/s reductions in FEV1, FEV1/FVC, PEF, and MMF, respectively. PM2.5 exposure was negatively associated with plasma miR-4301 expression levels in a dose‒response manner. Additionally, each 1% increase in miR-4301 expression level was significantly associated with a 0.36 mL, 0.01%, 1.14 mL/s, and 1.28 mL/s increases in FEV1, FEV1/FVC, MMF, and PEF, respectively. Mediation analysis further revealed that decreased miR-4301 mediated 15.6% and 16.8% of PM2.5 exposure-associated reductions in FEV1/FVC and MMF, respectively. Pathway enrichment analyses suggested that the wingless related-integration site (Wnt) signaling pathway might be one of the pathways regulated by miR-4301 in the reduction of lung function from PM2.5 exposure. In brief, personal PM2.5 exposure was negatively associated with plasma miR-4301 or lung function in a dose‒response manner. Moreover, miR-4301 partially mediated the lung function reduction associated with PM2.5 exposure.

Plasma microRNA expression profiles associated with zinc exposure and type 2 diabetes mellitus: Exploring potential role of miR-144-3p in zinc-induced insulin resistance.

Zinc exposure has been linked with disordered glucose metabolism and type 2 diabetes mellitus (T2DM) development. However, the underlying mechanism remains unclear. We conducted population-based studies and in vitro experiments to explore potential role of microRNAs (miRNAs) in zinc-related hyperglycemia and T2DM. In the discovery stage, we identified plasma miRNAs expression profile for zinc exposure based on 87 community residents from the Wuhan-Zhuhai cohort through next-generation sequencing. MiRNAs profiling for T2DM was also performed among 9 pairs newly diagnosed T2DM-healthy controls. In the validating stage, plasma miRNA related to both of zinc exposure and T2DM among the discovery population was measured by qRT-PCR in 161 general individuals derived from the same cohort. Furthermore, zinc treated HepG2 cells with mimic or inhibitor were used to verify the regulating role of miR-144-3p. Based on the discovery and validating populations, we observed that miR-144-3p was positively associated with urinary zinc, hyperglycemia, and risk of T2DM. In vitro experiments confirmed that zinc-induced increase in miR-144-3p expression suppressed the target gene Nrf2 and downstream antioxidant enzymes, and aggravated insulin resistance. Our findings provided a novel clue for mechanism underlying zinc-induced glucose dysmetabolism and T2DM development, emphasizing the important role of miR-144-3p dysregulation.

Neutralization of interleukin-11 attenuates silica particles-induced pulmonary inflammation and fibrosis in vivo.

Environmental exposure to crystalline silica particles can lead to silicosis, which is one of the most serious pulmonary interstitial fibrosis around the world. Unfortunately, the exact mechanism on silicosis is unclear, and the effective treatments are lacking to date. In this study, we aim to explore the molecular mechanism by which interleukin-11 (IL-11) affects silica particles-induced lung inflammation and fibrosis. We observed that IL-11 expressions in mouse lungs were significantly increased after silica exposure, and maintained at high levels across both inflammation and fibrosis phase. Immunofluorescent dual staining further revealed that the overexpression of IL-11 mainly located in mouse lung epithelial cells and fibroblasts. Using neutralizing anti-IL-11 antibody could effectively alleviate the overexpression of pro-inflammatory cytokines (i.e., interleukin-6 and tumor necrosis factor-α) and fibrotic proteins (i.e., collagen type I and matrix metalloproteinase-2) induced by silica particles. Most importantly, the expressions of IL-11 receptor subunit α (IL-11Rα), Glycoprotein 130 (GP130), and phosphorylated extracellular signal-regulated kinase (p-ERK) were significantly increased in response to silica, whereas blocking of IL-11 markedly reduced their levels. All findings suggested that the overexpression of IL-11 was involved in the pathological of silicosis, while neutralizing IL-11 antibody could effectively alleviate the silica-induced lung inflammation and fibrosis by inhibiting the IL-11Rα/GP130/ERK signaling pathway. IL-11 might be a promising therapeutic target for lung inflammation and fibrosis caused by silica particles exposure.

PM2.5-related DNA methylation and the association with lung function in non-smokers.

PM2.5 exposure leads to lung function alteration. The potential pathway underlying above association, especially the role of DNA methylation is unclear. The objectives of this study are to evaluate the associations of personal PM2.5 concentrations with DNA methylation at the epigenome-wide level, and investigate how PM2.5-related DNA methylation affects lung function. A total of 402 observations of non-smokers were selected from the Wuhan-Zhuhai cohort. PM2.5 exposure was estimated through a model established in the same population. Blood DNA methylation levels were determined through Illumina Infinium MethylationEPIC BeadChips. Lung function was tested through spirometry on the day of blood sampling. The associations of PM2.5 exposure with DNA methylation and DNA methylation with lung function were determined through linear mixed models. Ten PM2.5-related CpG sites (mapped to 7 different genes) were observed with false discovery rate <0.05. Methylation levels of cg24821877, cg24862131, cg23530876, cg11149743 and cg10781276 were positively associated with PM2.5 concentrations. While methylation levels of cg10314909, cg08968107, cg18362281, cg24663971 and cg17834632 were negatively associated with PM2.5 concentrations. The top CpG was cg24663971 (P = 1.51✕10-9). Among the above 10 sites, significantly positive associations of methylation levels of cg24663971 with FVC%pred and FEV1%pred, and cg10314909 with FVC, FVC%pred, and FEV1%pred were observed. Age had modification effect on the associations between cg24663971 methylation and FVC%pred, and the associations were more obvious among participants with age ≥58 years. In conclusion, PM2.5 exposure was associated with DNA methylation, and PM2.5-related DNA methylation was associated with lung function among Wuhan urban non-smokers.

Insights into the mechanism underlying crystalline silica-induced pulmonary fibrosis via transcriptome-wide m6A methylation profile.

Silicosis is one of the most severe interstitial lung fibrosis diseases worldwide, caused by crystalline silica exposure. While the mechanisms and pathogenesis underlying silicosis remained unknown. N6-methyladenosine (m6A) methylation has received significant attention in a variety of human diseases. However, whether m6A methylation is involved in silicosis has not been clarified. In this study, we conducted methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and transcriptome sequencing (RNA-Seq) to profile the m6A modification in normal and silicosis mouse models (n = 3 pairs). The global levels of m6A methylation were further assessed by m6A RNA methylation quantification kits, and the major regulators of m6A RNA methylation were verified by qRT-PCR. Our results showed that long-term exposure to crystalline silica led to silicosis, accompanied by increasing levels of m6A methylation. Upregulation of METTL3 and downregulation of ALKBH5, FTO, YTHDF1, and YTHDF3 might contribute to aberrant m6A modification. Compared with controls, 359 genes showed differential m6A methylation peaks in silicosis (P < 0.05 and FC ≥ 2). Among them, 307 genes were hypermethylated, and 52 genes were hypomethylated. RNA-Seq analysis revealed 1091 differentially expressed genes between the two groups, 789 genes were upregulated and 302 genes were downregulated in the lungs of silicosis mice (P < 0.05 and FC ≥ 2). In the conjoint analysis of MeRIP-Seq and RNA-Seq, we identified that 18 genes showed significant changes in both m6A modification and mRNA expression. The functional analysis further noted that these 18 m6A-mediated mRNAs regulated pathways that were closely related to "phagosome", "antigen processing and presentation", and "apoptosis". All findings suggested that m6A methylation played an essential role in the formation of silicosis. Our discovery with multi-omics approaches not only gives clues for the epigenetic mechanisms underlying the pathogenesis of silicosis but also provides novel and viable strategies for the prevention and treatment of silicosis.

Cross-sectional and longitudinal relationships between urinary 1-bromopropane metabolite and pulmonary function and underlying role of oxidative damage among urban adults in the Wuhan-Zhuhai cohort in China.

1-bromopropane is a US Environmental Protection Agency-identified significant hazardous air pollutant with concerned adverse respiratory effect. We aimed to investigate the relationship between 1-bromopropane exposure and pulmonary function and the underlying role of oxidative damage, which all remain unknown. Pulmonary function and urinary biomarkers of 1-bromopropane exposure (N-Acetyl-S-(n-propyl)-L-cysteine, BPMA) and oxidative damage to DNA (8-hydroxy-deoxyguanosine, 8-OHdG) and lipid (8-iso-prostaglandin-F2α, 8-iso-PGF2α) were measured for 3259 Chinese urban adults from the Wuhan-Zhuhai cohort. The cross-sectional relationship of BPMA with pulmonary function and the joint relationship of BPMA and 8-OHdG or 8-iso-PGF2α with pulmonary function were investigated by linear mixed models. The mediating roles of 8-OHdG and 8-iso-PGF2α were evaluated by mediation analysis. Additionally, a panel of 138 subjects was randomly convened from the same cohort to evaluate the stability of BPMA repeatedly measured in urine samples collected over consecutive three days and intervals of one, two, and three years, and to estimate the longitudinal relationship of BPMA with pulmonary function change in three years. We found each 3-fold increase in BPMA was cross-sectionally related to FVC and FEV1 reductions by 29.88-mL and 25.67-mL, respectively (all P < 0.05). Joint relationship of BPMA and 8-OHdG rather than 8-iso-PGF2α with reduced pulmonary function was observed. Moreover, 8-OHdG significantly mediated 9.44% of the BPMA-related FVC reduction. Findings from the panel revealed a fair to excellent stability (intraclass correlation coefficient: 0.43-0.79) of BPMA in repeated urines collected over a period of three years. Besides, BPMA was longitudinally related to pulmonary function reduction in three years: compared with subjects with persistently low BPMA level, those with persistently high BPMA level had 79.08-mL/year and 49.80-mL/year declines in FVC and FEV1, respectively (all P < 0.05). Conclusively, 1-bromopropane exposure might impair pulmonary function of urban adult population, and oxidative DNA damage might be a potential mechanism underlying 1-bromopropane impairing pulmonary function especially FVC.

The global burden of disease attributable to high fasting plasma glucose in 204 countries and territories, 1990-2019: An updated analysis for the Global Burden of Disease Study 2019.

AIMS: High fasting plasma glucose (HFPG) is an independent risk factor for several adverse health outcomes and has become a serious public health problem. We aimed to evaluate the spatial pattern and temporal trend of disease burden attributed to HFPG from 1990 to 2019 using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. MATERIALS AND METHODS: Using data from GBD 2019, we estimated the numbers and age-standardized rates of deaths and disability-adjusted life years (DALYs) attributed to HFPG by calendar year, age, gender, country, region, Socio-demographic Index (SDI), and specific causes. The joinpoint regression analysis was used to assess the temporal trends of deaths and DALYs from 1990 to 2019. RESULTS: In 2019, globally, the numbers of deaths and DALYs attributable to HFPG were approximately 6.50 million and 172.07 million, respectively, with age-standardized rates of 83.00 per 100,000 people and 2104.26 per 100,000 people, respectively. From 1990 to 2019, the global numbers of deaths and DALYs attributed to HFPG have over doubled. The age-standardized rate of DALYs showed an increasing trend, particularly in males and in regions with middle SDI or below. The leading causes of the global disease burden attributable to HFPG in 2019 were diabetes mellitus, ischaemic heart disease, stroke, and chronic kidney disease. CONCLUSIONS: HFPG is an important contributor to increasing the global and regional disease burden. Necessary measures should be taken to curb the growing burden attributed to HFPG, particularly in males and in regions with middle SDI or below.

Cross-sectional and longitudinal associations of styrene and ethylbenzene exposure with heart rate variability alternation among urban adult population in China.

Styrene and ethylbenzene (S/EB) are the monomers of polystyrene (PS) and polyethylene (PE), respectively, and have been identified as significant hazardous air pollutants by the U.S. Environmental Protection Agency. However, the adverse effects of S/EB on human health, especially cardiovascular health, have not been well established. Urinary biomarker of S/EB exposure and heart rate variability (HRV) were measured in urban adults from the Wuhan-Zhuhai cohort and were repeated after 3-year and 6-year follow-ups. Linear mixed models were used to estimate associations of S/EB exposure biomarker with HRV and longitudinal additional annual change of HRV. The mediating role of transforming growth factor (TGF)-ß1 was tested by using mediation analysis. A total of 2842 general adults were included at baseline analysis, and 4748 observations were included in the repeated measurement study. In the cross-sectional analysis, each 1% increment in urinary S/EB exposure biomarker was significantly associated with a 0.106 % (95 % CI: -0.160, -0.052), 0.109 % (-0.169, -0.049), 0.099 % (-0.145, -0.053), 0.040 % (-0.060, -0.020), and 0.031 % (-0.054, -0.007) decrement in low frequency (LF), high frequency (HF), total power (TP), standard deviation of all normal-to-normal intervals (SDNN), and square root of the mean squared difference between adjacent normal-to-normal interval, respectively. Smoking status modified the relationships of urinary S/EB exposure biomarker with TP and SDNN. TGF-ß1 mediated 3.09-5.16 % of the association between urinary S/EB biomarker and lower HRV. The follow-up analyses detected a negative association between urinary S/EB exposure biomarker and the additional annual change of LF (ß: -0.016; 95 % CI: -0.028, -0.004), HF (-0.014; -0.026, -0.001), and TP (-0.011; -0.021, -0.001). Our findings demonstrated that S/EB exposure was associated with HRV reduction among the general urban adults and the TGF-ß pathway may play a part of the mediating role in this association.

Cross-sectional and longitudinal associations of acrolein exposure with pulmonary function alteration: Assessing the potential roles of oxidative DNA damage, inflammation, and pulmonary epithelium injury in a general adult population.

BACKGROUND: Acrolein is a significant high priority hazardous air pollutant with pulmonary toxicity and the leading cause of most noncancer adverse respiratory effects among air toxics that draws great attention. Whether and how acrolein exposure impacts pulmonary function remain inconclusive. OBJECTIVES: To assess the association of acrolein exposure with pulmonary function and the underlying roles of oxidative DNA damage, inflammation, and pulmonary epithelium integrity. METHODS: Among 3,279 Chinese adults from the Wuhan-Zhuhai cohort, associations of urinary acrolein metabolites (N-Acetyl-S-(2-carboxyethyl)-L-cysteine, CEMA; N-Acetyl-S-(3-hydroxypropyl)-L-cysteine, 3HPMA) as credible biomarkers of acrolein exposure with pulmonary function were analyzed by linear mixed models. Joint effects of biomarkers of oxidative DNA damage (8-hydroxy-deoxyguanosine), inflammation (C-reactive protein, CRP), and pulmonary epithelium integrity (Club cell secretory protein, CC16) with acrolein metabolites on pulmonary function and the mediating roles of these biomarkers were assessed. Besides, a subgroup (N = 138) was randomly recruited from the cohort to assess the stabilities of acrolein metabolites and their longitudinal associations with pulmonary function change in three years. RESULTS: Significant inverse dose-response relationships between acrolein metabolites and pulmonary function were found. Each 10-fold increment in CEMA, 3HPMA, or ΣUACLM (CEMA + 3HPMA) was cross-sectionally related to a 68.56-, 40.98-, or 46.02-ml reduction in FVC and a 61.54-, 43.10-, or 50.14-ml reduction in FEV1, respectively (P < 0.05). Furthermore, acrolein metabolites with fair to excellent stabilities were found to be longitudinally associated with pulmonary function decline in three years. Joint effects of acrolein metabolites with 8-hydroxy-deoxyguanosine, CRP, and CC16 on pulmonary function were identified. CRP significantly mediated 5.97% and 5.51% of CEMA-associated FVC and FEV1 reductions, respectively. 8-hydroxy-deoxyguanosine significantly mediated 6.78%, 6.88%, and 7.61% of CEMA-, 3HPMA-, and ΣUACLM-associated FVC reductions, respectively. CONCLUSIONS: Acrolein exposure of general adults was cross-sectionally and longitudinally related to pulmonary function decline, which was aggravated and/or partly mediated by oxidative DNA damage, inflammation, and pulmonary epithelium injury.

Inhibition of Gas6 promotes crystalline silica-induced inflammatory response of macrophages via blocking autophagy flux.

Inhalation of crystalline silica (CS) can cause silicosis, which is one of the most serious interstitial lung diseases worldwide. Autophagy dysfunction is an essential step in silicosis progression. In this study, we aim to identify the effect of growth arrest-specific protein 6 (Gas6) during autophagy induction and macrophage inflammatory response caused by CS. After RAW 264.7 macrophages exposed to CS, the levels of Gas6 and autophagy markers (p62, Beclin1, and LC3-II/LC3-I) were increased, accompanied with enhanced inflammatory cytokines secretion. Using autophagy activator (rapamycin) repressed, whereas autophagy inhibitor (3-methyladenine) promoted inflammatory cytokines release. Besides, inhibition of Gas6 aggravated CS-induced inflammatory response, and autophagy inhibition facilitated the promoted effect of Gas6 silencing, resulting in elevated expression of inflammatory cytokines. These findings reveal the protective effects of Gas6 and autophagy in macrophages in response to CS exposure, and highlight the autophagy regulated by Gas6 may be a potential prevention target for CS-induced lung inflammatory response.

Acrylamide exposure increases cardiovascular risk of general adult population probably by inducing oxidative stress, inflammation, and TGF-ß1: A prospective cohort study.

Acrylamide (ACR) exposure and consequent health hazards are alarming public health issues that attract worldwide concern. The World Health Organization urges more researches into health hazards from ACR exposure. However, whether and how ACR exposure increases cardiovascular risk remain unclear, and we sought to address these issues in this prospective cohort study conducted on 3024 general adults with 3-year follow-up (N = 871 at follow-up). Individual urinary ACR metabolites (N-Acetyl-S-(2-carbamoylethyl)-L-cysteine [AAMA] and N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine [GAMA]) as credible biomarkers of ACR exposure were detected to assess their cross-sectional and longitudinal relationships with 10-year cardiovascular disease (CVD) risk, a well measure of overall cardiovascular risk. Besides, biomarkers of oxidative stress (urinary 8-hydroxy-deoxyguanosine [8-OHdG] and 8-iso-prostaglandin-F2α [8-iso-PGF2α]) and inflammation (circulating mean platelet volume [MPV] and plasma C-reactive protein [CRP]) as well as plasma transforming growth factor-ß1 (TGF-ß1) were measured to assess their mediating/mechanistic roles in the relationships of ACR metabolites with 10-year CVD risk. We found AAMA, GAMA, and ΣUAAM (AAMA + GAMA) were cross-sectionally and longitudinally related to increased 10-year CVD risk with odds ratios (95% confidence intervals [CIs]) of 1.32 (1.04, 1.70), 1.81 (1.36, 2.40), and 1.40 (1.07, 1.82), respectively, and risk ratios (95% CIs) of 1.99 (1.10, 3.60), 2.48 (1.27, 4.86), and 2.13 (1.15, 3.94), respectively. Furthermore, 8-OHdG, 8-iso-PGF2α, MPV, CRP, and TGF-ß1 were found to significantly mediate 8.06-48.92% of the ACR metabolites-associated 10-year CVD risk increment. In summary, daily ACR exposure of general adults was cross-sectionally and longitudinally associated with increased cardiovascular risk, which was partly mediated by oxidative stress, inflammation, and TGF-ß1, suggesting for the first time that ACR exposure may well increase cardiovascular risk of general adult population partly by mechanisms of inducing oxidative stress, inflammation, and TGF-ß1. Our findings have important public health implications that provide potent epidemiological evidence and vital mechanistic insight into cardiovascular risk increment from ACR exposure.

Association of caffeine and caffeine metabolites with obesity among children and adolescents: National Health and Nutrition Examination Survey (NHANES) 2009-2014.

The effect of caffeine exposure on children's health remains poorly understood. We aimed to characterize the associations of caffeine and caffeine metabolites with adiposity outcomes among children and adolescents. We performed cross-sectional analyses of 1,447 children and adolescents aged 6-19 years from the 2009-2014 National Health and Nutrition Examination Survey. The linear regression and weighted quantile sum (WQS) regression were used to explore the associations of urinary caffeine and 14 caffeine metabolites with adiposity outcomes, including body mass index (BMI) z-score, waist circumference (WC), obesity, and overweight. In linear regression models, compared with the participants who consumed low caffeine, higher BMI z-score, WC, and risks of obesity and overweight were more likely among those who consumed high caffeine (P < 0.05). In WQS regression models, an interquartile range increase in the weighted caffeine index was significantly associated with increased BMI z-score (ß = 0.10, 95% CI = 0.01, 0.17) and WC (ß = 1.20, 95% CI = 0.31, 2.09), and risks of obesity (OR = 1.09, 95% CI = 1.02, 1.17). Totally, no modification effect of age or gender was observed in the linear regression model. Nonetheless, in WQS models, the positive associations of caffeine exposure with WC and risks of obesity and overweight were significant in children aged 6-11 years rather than 12-19 years. When stratified by gender, caffeine exposure was significantly associated with BMI z-score and WC in both boys and girls. These results add novel evidence that caffeine exposure might be associated with adverse adiposity outcomes among children and adolescents.

Benzo(a)pyrene induces airway epithelial injury through Wnt5a-mediated non-canonical Wnt-YAP/TAZ signaling.

Wnt5a is a key mediator of non-canonical Wnt signaling, and an early indicator of epithelial injury and lung dysfunction. Polycyclic aromatic hydrocarbons (PAHs) could induce acute pulmonary pathogenesis, of which the underlying mechanism remains unclear. To elucidate the potential role of Wnt5a-mediated non-canonical Wnt-YAP/TAZ signaling in the lung injury induced by short-term exposure of benzo(a)pyrene (BaP, a representative PAHs), intratracheally instilled mouse model was used and further interfered with its Wnt5a level by small molecule antagonists and agonists. Our data revealed that BaP exposure induced the lung inflammatory response and reduced the expression of Clara cell secretory protein (CC16) in a dose-dependent manner. More importantly, the activation of Wnt5a and downstream YAP/TAZ were accompanied with the enhanced release of epithelial-derived thymic stromal lymphopoietin and interleukin-33, which acted as pro-inflammatory cytokines. Functionally, inhibition of Wnt5a attenuated the BaP-induced inflammation and recuperated CC16 expression, as well as suppressed the epithelial cytokines release. Whereas promoting Wnt5a expression affected the toxic effects of BaP oppositely. Our findings together suggest that Wnt5a is a potential endogenous regulator in lung inflammation and airway epithelial injury, and Wnt5a-YAP/TAZ signaling contributes to lung dysfunction in acute exposure to BaP.

Extracellular signal-regulated kinase signaling pathway and silicosis.

Silicosis is a scarring lung disease caused by inhaling fine particles of crystalline silica in the workplace of many industries. Due to the lack of effective treatment and management, the continued high incidence of silicosis remains a major public health concern worldwide, especially in the developing countries. Till now, related molecular mechanisms underlying silicosis are still not completely understood. Multiple pathways have been reported to be participated in the pathological process of silicosis, and more complex signaling pathways are receiving attention. The activated extracellular signal-regulated kinase (ERK) signaling pathway has been recognized to control some functions in the cell. Recent studies have identified that the ERK signaling pathway contributes to the formation and development of silicosis through regulating the processes of oxidative stress, inflammatory response, proliferation and activation of fibroblasts, epithelial-mesenchymal transformation, autophagy, and apoptosis of cells. In this review article, we summarize the latest findings on the role of ERK signaling pathway in silica-induced experimental models of silicosis, as well as clinical perspectives.

Triiodothyronine ameliorates silica-induced pulmonary inflammation and fibrosis in mice.

Environmental exposure to silica or particles is very common in natural, agricultural and industrial activities. Chronic silica exposure can lead to silicosis, which remains one of the most serious interstitial lung diseases all through the world, while viable therapeutic choices are restricted. Triiodothyronine (T3) has been shown to exert a defensive role in many pulmonary diseases, however, rare data are available regarding the role of T3 on silica-induced injury. We constructed an experimental silicosis mouse model and T3 was intraperitoneally administrated after instillation of silica to observe the effect of T3 on silica-induced lung inflammation and fibrosis. Our results showed that the silicosis mouse model was accompanied by changes in thyroid morphology and function, and T3 supplement reduced silica-induced lung damage, inflammation and collagen deposition. The protective properties of T3 on silica-induced lung injury could be partially mediated through thyroid hormone receptors. And the mechanism by which T3 treatment ameliorated silica-induced fibrosis appeared to be via the reduction of glycolysis. Also, T3 could sufficiently postpone the progression of pulmonary fibrosis in established silicosis. Our findings reveal that administration of T3 could down-regulate the inflammatory response, pulmonary fibrosis and other lung damage caused by silica. The reduction of glycolysis may be one of the mechanisms.