Jingyi Zhang’s research while affiliated with Capital Medical University and other places

Background: Exposure to fine particulate matter (PM2.5) is associated with the risk of developing metabolic-associated fatty liver disease (MAFLD). Melatonin is the main secreted product of the pineal gland and has been reported to prevent hepatic lipid metabolism disorders. However, it remains uncertain whether melatonin could protect against PM2.5-induced MAFLD. Methods and results: The purpose of our study was to investigate the mitigating effects of melatonin on hepatic fatty degeneration accelerated by PM2.5 in vivo and in vitro. Histopathological analysis and ultrastructural images showed that PM2.5 induced hepatic steatosis and lipid vacuolation in ApoE-/- mice, which could be effectively alleviated by melatonin administration. Increased ROS production and decreased expression of antioxidant enzymes were detected in the PM2.5-treated group, whereas melatonin showed recovery effects after PM2.5-induced oxidative damage in both the liver and L02 cells. Further investigation revealed that PM2.5 induced oxidative stress to activate PTP1B, which in turn had a positive feedback regulation effect on ROS release. When a PTP1B inhibitor or melatonin was administered, SP1/SREBP-1 signalling was effectively suppressed, while Nrf2/Keap1 signalling was activated in the PM2.5-treated groups. Conclusion: Our study is the first to show that melatonin alleviates the disturbance of PM2.5-triggered hepatic steatosis and liver damage by regulating the ROS-mediated PTP1B and Nrf2 signalling pathways in ApoE-/- mice. These results suggest that melatonin administration might be a prospective therapy for the prevention and treatment of MAFLD associated with air pollution.

Air pollution, especially PM2.5 (particulate matter with an aerodynamic diameter ≤2.5 μm) in China, is severe and related to a variety of diseases while the potential mechanisms have not been clearly clarified yet. This study was conducted using a randomized crossover trial protocol among young and healthy college students. Plasma samples were collected before, during, and post two typical air pollution waves with a washout interval of at least 2 weeks under true and sham air purification treatments, respectively. A total of 144 blood samples from 24 participants were included in the final analysis. Metabolomics analysis for the plasma samples was achieved by Ultrahigh Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). Orthogonal Partial Least Squares Discrimination Analysis (OPLS-DA) and linear mixed-effect models were used to identify the differentially expressed metabolites and their associations with PM2.5 exposure. Further use MetaboAnalyst 5.0 to conduct pathway enrichment analysis and correlation analysis of differential metabolites. A total of 40 metabolites were identified to be differentially expressed between the true and sham air purification treatments, and eleven metabolites showed consistent significant changes upon outdoor, indoor, and time-weighted personal PM2.5 exposures. Short-term exposure to PM2.5 might cause disturbances in metabolic pathways such as linoleic acid metabolism, arachidonic acid metabolism, and tryptophan metabolism.

Ambient air pollution is a leading cause of non-communicable disease in the world. PM2.5 has the potential to change the miRNAs profiles, which in turn causes cardiovascular effects. Hypoxia-inducible factor (HIF)-1 plays a critical role in the development of atherosclerosis. Yet, the possible role of miR-939-5p/HIF-1α in PM2.5-induced endothelial injury remains elusive. Therefore, the study aims to investigate the effects of miR-939-5p and HIF-1α on PM2.5-triggered endothelial injury. The results from immunofluorescence, qRT-PCR, LSCM, and western blot assays demonstrated that PM2.5 increased the levels of HIF-1α, inflammation and apoptosis in human aortic endothelial cells (HAECs). Yet, the inflammatory response and mitochondrial-mediated apoptosis pathway were effectively inhibited in HIF-1α knockdown HAECs lines. The expression of miR-939-5p was significantly down-regulated in HAECs after exposed to PM2.5. The luciferase reporter, qRT-PCR and western blot results demonstrated that miR-939-5p could directly targeted HIF-1α. And the miR-939-5p overexpression restricted PM2.5-triggered decreases in cell viability and increases in lactic dehydrogenase (LDH) activity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and inflammation. In addition, miR-939-5p overexpression remarkably suppressed PM2.5-triggered BcL-2/Bax ratio reduction and Cytochrome C, Cleaved Caspase-9 and Cleaved Caspase-3 expression increase, revealed that miR-939-5p hampered PM2.5-induced endothelial apoptosis through mitochondrial-mediated apoptosis pathway. Our results demonstrated that PM2.5 increased the expression of HIF-1α followed by a pro-inflammatory and apoptotic response in HAECs. The protective effect of miR-939-5p on PM2.5-triggered endothelial cell injury by negatively regulating HIF-1α. miR-939-5p might present a new therapeutic target for PM2.5 induced endothelial injury.

The in-utero environmental exposure to fine particulate matter (PM2.5) might lead to adverse birth outcomes, such as low birth weight (LBW) and preterm birth (PTB), thereby increasing susceptibility to diseases in later life. However, no studies have examined the underlying mechanism through cross-omics of lipidome and adipokines profiling, as well as the possible effect modification by maternal hyperlipidemia. In total, 203 mother-newborn pairs were recruited in the birth cohort study ongoing since February 2017 in Beijing, China. Individual-level of PM2.5 exposure was estimated using a satellite data based random forest model. Cord blood lipidome and adipokines were assessed through the lipidomic approaches and antibody-based array. Multivariable logistic/linear regression models and moderation analysis were employed in this study. We observed a significantly increased risk of PTB associated with PM2.5 exposure during the second trimester, especially in pregnant women with pre-existing hyperlipidemia. 9 lipid classes and 21 adipokines were associated with PM2.5 exposure independently or significantly influenced by the interaction of maternal PM2.5 exposure and hyperlipidemia. In addition, 4 adipokines (ANGPTL4, IGFBP-2, IL-12p40, and TNF-RII) and 3 lipid classes [phosphatidylcholines (PCs), phosphatidylinositols (PIs), and triglycerides (TGs)] were related to the increased risk of PTB, indicating that inflammation, IGF/IGFBP axis, and lipolysis induced lipid homeostasis disorder of PCs, TGs, and PIs might be the possible mediators for the PM2.5-induced adverse birth outcomes. Our results substantiated the need for reducing exposure in susceptible populations.

Ambient and indoor air pollution contributes annually to approximately seven million premature deaths. Air pollution is a complex mixture of gaseous and particulate materials. In particular, fine particulate matter (PM2.5) plays a major mortality risk factor particularly on cardiovascular diseases through mechanisms of atherosclerosis, thrombosis and inflammation. A review on the PM2.5-induced atherosclerosis is needed to better understand the involved mechanisms. In this review, we summarized epidemiology and animal studies of PM2.5-induced atherosclerosis. Vascular endothelial injury is a critical early predictor of atherosclerosis. The evidence of mechanisms of PM2.5-induced atherosclerosis supports effects on vascular function. Thus, we summarized the main mechanisms of PM2.5-triggered vascular endothelial injury, which mainly involved three aspects, including vascular endothelial permeability, vasomotor function and vascular reparative capacity. Then we reviewed the relationship between PM2.5-induced endothelial injury and atherosclerosis. PM2.5-induced endothelial injury associated with inflammation, pro-coagulation and lipid deposition. Although the evidence of PM2.5-induced atherosclerosis is undergoing continual refinement, the mechanisms of PM2.5-triggered atherosclerosis are still limited, especially indoor PM2.5. Subsequent efforts of researchers are needed to improve the understanding of PM2.5 and atherosclerosis. Preventing or avoiding PM2.5-induced endothelial damage may greatly reduce the occurrence and development of atherosclerosis.

Silica nanoparticles (SiNPs) have become one of the most widely studied nanoparticles in nanotechnology for environmental health and safety. Although many studies have devoted to evaluating the hepatotoxicity of SiNPs, it is currently impossible to predict the extent of liver lipid metabolism disorder by identifying changes in metabolites. In the present study, 40 male Sprague-Dawley (SD) rats were randomly divided into control group and 3 groups with different doses (1.8 mg/kg body weight (bw), 5.4 mg/kg bw, 16.2 mg/kg bw), receiving intratracheal instillation of SiNPs. Liver tissue was taken for lipid level analysis, and serum was used for blood biochemical analysis. Then, the metabolites changes of liver tissue in rats were systematically analyzed using 1H nuclear magnetic resonance (1H NMR) techniques in combination with multivariate statistical analysis. SiNPs induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG) elevation in treated groups; TG and low-density lipoprotein cholesterol (LDL-C) were significantly higher in SiNPs-treated groups of high-dose, however high-density lipoprotein cholesterol (HDL-C) showed a declining trend in liver tissue. The orthogonal partial least squares discriminant analysis (OPLS-DA) scores plots revealed different metabolic profiles between control and high-dose group (Q2 =0.495, R2Y=0.802, p = 0.037), and a total of 11 differential metabolites. Pathway analysis indicated that SiNPs treatment mainly affected 10 metabolic pathways including purine metabolism, glucose-alanine cycle and metabolism of various amino acids such as glutamate, cysteine and aspartate (impact value>0.1, false discovery rate (FDR)

Fine particulate matter (PM2.5) exposure is correlated with the risk of developing cardiac fibrosis. Melatonin is a major secretory product of the pineal gland that has been reported to prevent fibrosis. However, whether melatonin affects the adverse health effects of PM2.5 exposure has not been investigated. Thus, this study was aimed to investigate the protective effect of melatonin against PM2.5‐accelerated cardiac fibrosis. The echocardiography revealed that PM2.5 had impaired both systolic and diastolic cardiac function in ApoE‐/‐ mice. Histopathological analysis demonstrated that PM2.5 induced cardiomyocyte hypertrophy and fibrosis, particularly perivascular fibrosis. While the melatonin administration was effective in alleviating PM2.5‐induced cardiac dysfunction and fibrosis in mice. Results of electron microscopy and confocal scanning laser microscope confirmed that melatonin had restorative effects against impaired mitochondrial ultrastructure and augmented mitochondrial ROS generation in PM2.5‐treated group. Further investigation revealed melatonin administration could significantly reverse the PM2.5‐induced phenotypic modulation of cardiac fibroblasts into myofibroblasts. For the first time, our study found that melatonin effectively alleviates PM2.5‐induced cardiac dysfunction and fibrosis via inhibiting mitochondrial oxidative injury and regulating SIRT3‐mediated SOD2 deacetylation. Our findings indicate that melatonin could be a therapy medicine for prevention and treatment of air pollution associated cardiac diseases.

Background Large-scale production and application of amorphous silica nanoparticles (SiNPs) have enhanced the risk of human exposure to SiNPs. However, the toxic effects and the underlying biological mechanisms of SiNPs on Caenorhabditis elegans remain largely unclear. Purpose This study was to investigate the genome-wide transcriptional alteration of SiNPs on C. elegans. Methods and Results In this study, a total number of 3105 differentially expressed genes were identified in C. elegans. Among them, 1398 genes were significantly upregulated and 1707 genes were notably downregulated in C. elegans. Gene ontology analysis revealed that the significant change of gene functional categories triggered by SiNPs was focused on locomotion, determination of adult lifespan, reproduction, body morphogenesis, multicellular organism development, endoplasmic reticulum unfolded protein response, oocyte development, and nematode larval development. Meanwhile, we explored the regulated effects between microRNA and genes or signaling pathways. Pathway enrichment analysis and miRNA-gene-pathway-network displayed that 23 differential expression microRNA including cel-miR-85-3p, cel-miR-793, cel-miR-241-5p, and cel-miR-5549-5p could regulate the longevity-related pathways and inflammation signaling pathways, etc. Additionally, our data confirmed that SiNPs could disrupt the locomotion behavior and reduce the longevity by activating ins-7, daf-16, ftt-2, fat-5, and rho-1 genes in C. elegans. Conclusion Our study showed that SiNPs induced the change of the whole transcriptome in C. elegans, and triggered negative effects on longevity, development, reproduction, and body morphogenesis. These data provide abundant clues to understand the molecular mechanisms of SiNPs in C. elegans.

Epidemiological studies have confirmed that PM2.5 could contribute to the development of atherosclerosis accompanied with lipids dysregulation. However, the lipids biomarkers involved in this progress remain largely unknown. In this study, a targeted lipidomic approach was used to find out the possible lipid biomarkers involved in the development of atherosclerosis after PM2.5 exposure or during a recovery period. Also, we assessed the pro-atherosclerosis effects of PM2.5 and follow-up influence using pulse wave (PW) Doppler ultrasound, oil red O staining and H&E staining. The vascular stiffness was elevated after 2-month PM2.5 exposure and might persist after 1-month recovery. While the lesions mostly concentrated in the aortic arch was significantly increased in 2-month PM2.5 exposure group and remained an increasing trend after 1-month recovery. The expressions of pro-inflammatory cytokines detected by Mouse Inflammation Array were elevated after ApoE-/- mice treated with PM2.5 for 2-month and restored following 1-month recovery. Yet, IL-10 was significantly decreased during 1-month recovery. Additionally, the targeted lipidomic analysis demonstrated that cholesterol ester (CE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM) were significantly increased while lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), diacylglycerol (DG), triacylglycerol (TG) were reduced after 2-month PM2.5 exposure, indicating that PM2.5 could disrupt glycerophospholipids, glycerolipids and sphingolipids metabolism. And a persistent impact of PM2.5 on glycerophospholipids and glycerolipids metabolism was found after 1-month recovery. Our study demonstrated that PM2.5-induced inflammation response might promote atherosclerotic lesions probably through lipid dysregulation, and the influence probably persisted after 1-month recovery.

Background: Ambient particulate matter (PM) is closely associated with morbidity and mortality from cardiovascular disease. Urine metabolites can be used as a non-invasive means to explore biological mechanisms for such associations, yet has not been performed in relation to different sizes of PM. In this randomized crossover study, we used metabolomics approach to explore the urine biomarkers linked with cardiovascular effects after PM exposure in a subway environment. Methods and results: Thirty-nine subjects were exposed to PM for 4 h in subway system, with either a respirator intervention phase (RIP) with facemask and no intervention phase (NIP) in random order with a 2-week washout period. Electrocardiogram (ECG) parameters and ambulatory blood pressure (BP) were monitored during the whole riding period and urine samples were collected for metabolomics analysis. After exposure to PM for 4 h in subway system, 4 urine metabolites in male and 7 urine metabolites in female were screened out by UPLC/Q-TOF MS/MS-based metabolomics approach. Cardiovascular parameters (HRV and HR) predominantly decreased in response to all size-fractions of PM and were more sensitive in response to different size-fractioned PM in males than females. Besides LF/HF, most of the HRV indices decrease induced by the increase of all size-fractioned PM while PM1.0 was found as the most influential one on indicators of cardiovascular effects and urine metabolites both genders. Prolyl-arginine and 8-OHdG were found to have opposing role regards to HRV and HR in male. Conclusion: Our data indicated that short-term exposure to PM in a subway environment may increase the risk of cardiovascular disease as well as affect urine metabolites in a size dependent manner (besides PM0.5), and male were more prone to trigger the cardiovascular events than female after exposure to PM; whereas wearing facemask could effectively reduce the adverse effects caused by PM.