Single ethanol binge causes severe liver injury in mice fed Western diet.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) and NAFLD often coexist in Western societies that consume energy-rich and cholesterol-containing Western diets. Increased rates of ALD mortality in young people in these societies are likely attributable to binge drinking. It is largely unknown how alcohol binge causes liver damage in the setting of Western diets. APPROACH AND RESULTS: In this study, we showed that a single ethanol binge (5 g/kg body weight) induced severe liver injury as shown by marked increases in serum activities of the 2 aminotransferases AST and ALT in C57BL/6J mice that have been fed a Western diet for 3 weeks. The Western diet plus binge ethanol-fed mice also displayed severe lipid droplet deposition and high contents of triglycerides and cholesterol in the liver, which were associated with increased lipogenic and reduced fatty acid oxidative gene expression. These animals had the highest Cxcl1 mRNA expression and myeloperoxidase (MPO)-positive neutrophils in the liver. Their hepatic ROS and lipid peroxidation were the highest, but their hepatic levels of mitochondrial oxidative phosphorylation proteins remained largely unaltered. Hepatic levels of several ER stress markers, including mRNAs for CHOP, ERO1A, ERO1B, BIM, and BIP, as well as Xbp1 splicing and proteins for BIP/GRP78 and IRE-α were also the highest in these animals. Interestingly, Western diet feeding for 3 weeks or ethanol binge dramatically increased hepatic caspase 3 cleavage, and the combination of the 2 did not further increase it. Thus, we successfully established a murine model of acute liver injury by mimicking human diets and binge drinking. CONCLUSIONS: This simple Western diet plus single ethanol binge model recapitulates major hepatic phenotypes of ALD, including steatosis and steatohepatitis characterized by neutrophil infiltration, oxidative stress, and ER stress.

Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) pathologies include steatosis, inflammation, and injury, which may progress to fibrosis, cirrhosis, and cancer. The liver receives ~60% of fatty acids from adipose tissue triglyceride hydrolysis, but the role of this lipolytic pathway in ALD development has not been directly examined in any genetic animal models with selective inactivation of adipose lipolysis. APPROACH AND RESULTS: Using adipose-specific comparative gene identification-58 (CGI-58) knockout (FAT-KO) mice, a model of impaired adipose lipolysis, we show that mice deficient in adipose lipolysis are almost completely protected against ethanol-induced hepatic steatosis and lipid peroxidation when subjected to the National Institute on Alcohol Abuse and Alcoholism chronic and binge ethanol feeding model. This is unlikely due to reduced lipid synthesis because this regimen of ethanol feeding down-regulated hepatic expression of lipogenic genes similarly in both genotypes. In the pair-fed group, FAT-KO relative to control mice displayed increased hepatocyte injury, neutrophil infiltration, and activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the liver; and none of these were exacerbated by ethanol feeding. Activation of STAT3 is associated with a marked increase in hepatic leptin receptor mRNA expression and adipose inflammatory cell infiltration. CONCLUSIONS: Our findings establish a critical role of adipose lipolysis in driving hepatic steatosis and oxidative stress during ALD development.

Deficiency of interleukin-6 receptor ameliorates PM2.5 exposure-induced pulmonary dysfunction and inflammation but not abnormalities in glucose homeostasis.

BACKGROUND: Ambient fine particulate matter (PM2.5) exposure increases local and systemic interleukin-6 (IL-6). However, the pathogenic role of IL-6 signalling following PM2.5 exposure, particularly in the development of pulmonary dysfunction and abnormal glucose homeostasis, has hardly been investigated. RESULTS: In the study, IL-6 receptor (IL-6R)-deficient (IL-6R-/-) and wildtype littermate (IL-6R+/+) mice were exposed to concentrated ambient PM2.5 (CAP) or filtered air (FA), and their pulmonary and metabolic responses to these exposures were analyzed. Our results demonstrated that IL-6R deficiency markedly alleviated PM2.5 exposure-induced increases in lung inflammatory markers including the inflammation score of histological analysis, the number of macrophages in bronchoalveolar lavage fluid (BALF), and mRNA expressions of TNFα, IL-1ß and IL-6 and abnormalities in lung function test. However, IL-6R deficiency did not reduce the hepatic insulin resistance nor systemic glucose intolerance and insulin resistance induced by PM2.5 exposure. CONCLUSION: Our findings support the crucial role of IL-6 signalling in the development of pulmonary inflammation and dysfunction due to PM2.5 exposure but question the putative central role of pulmonary inflammation for the extra-pulmonary dysfunctions following PM2.5 exposure, providing a deep mechanistic insight into the pathogenesis caused by PM2.5 exposure.

The Social and Natural Environment's Impact on SARS-CoV-2 Infections in the UK Biobank.

COVID-19 has caused a global pandemic with considerable impact. Studies have examined the influence of socioeconomic status and air pollution on COVID-19 risk but in low detail. This study seeks to further elucidate the nuances of socioeconomic status, as defined by the Index of Multiple Deprivation (IMD), air pollution, and their relationship. We examined the effect of IMD and air pollution on the likelihood of testing positive for SARS-CoV-2 among 66,732 UKB participants tested for SARS-CoV-2 from 16 March 2020 through 16 March 2021. Logistic regression was performed controlling for age, sex, ancestry and IMD or air pollution in the respective models. IMD and its sub-scores were significantly associated with increased risk of testing positive for SARS-CoV-2. All particulate matter less than 2.5 µm (PM2.5), nitrogen oxide (NOx), and nitrogen dioxide (NO2) levels were associated with increased likelihood of testing positive for SARS-CoV-2. Measures of green space and natural environment around participants' homes were associated with reduced likelihood of SARS-CoV-2. Socioeconomic status and air pollution have independent effects on the risk of testing positive for SARS-CoV-2. Green space and natural environment space in the proximity of people's homes may mediate the effect of air pollution on the risk of testing positive for SARS-CoV-2.

Differential Roles of Water-Insoluble and Water-Soluble Fractions of Diesel Exhaust Particles in the Development of Adverse Health Effects Due to Chronic Instillation of Diesel Exhaust Particles.

Ambient fine particulate matter (PM2.5) has a marked temporospatial variation in chemical composition, but how the composition of PM2.5 influences its toxicity remains elusive. To explore the roles of individual PM2.5 components in the pathogenesis following PM2.5 exposure, we prepared water-soluble (WS-DEP) and water-insoluble (WIS-DEP) fractions of diesel exhaust particles (DEP) and performed 15-week intratracheal instillation on C57Bl/6J mice using these fractions. Their effects on pulmonary and systemic inflammation, hepatic steatosis and insulin resistance, systemic glucose homeostasis, and gut microbiota were then assessed. Compared to control, instillation of DEP or WIS-DEP, but not WS-DEP, significantly increased pulmonary inflammatory scores and expression of inflammatory markers, bronchoalveolar lavage fluid cell number, and circulating pro-inflammatory cytokines. Consistently, DEP- or WIS-DEP-instilled but not WS-DEP-instilled mice versus control had significant hepatic steatosis and insulin resistance and systemic glucose intolerance. In contrast, instillation of WS-DEP versus instillation of WIS-DEP had effects on the gut microbiota more comparable to that of instillations of DEP. The pulmonary and systemic inflammation, hepatic steatosis and insulin resistance, and systemic glucose intolerance following chronic DEP instillation are all attributable to the WIS-DEP, suggesting that PM2.5 may have a solubility-dependent basal toxicity.

PM2.5 Exposure of Mice during Spermatogenesis: A Role of Inhibitor κB Kinase 2 in Pro-Opiomelanocortin Neurons.

BACKGROUND: Epidemiological studies have shown that exposure to ambient fine particulate matter with aerodynamic diameter less than or equal to 2.5 µm (PM2.5) correlates with a decrease in sperm count, but the biological mechanism remains elusive. OBJECTIVES: This study tested whether hypothalamic inflammation, an emerging pathophysiological mediator, mediates the development of lower epididymal sperm count due to PM2.5 exposure. METHODS: Inhibitor κB kinase 2 (IKK2) was conditionally knocked out either in all neurons or subtypes of hypothalamic neurons of mice. Effects of concentrated ambient PM2.5 (CAP) exposure on hypothalamic inflammation, the hypothalamic-pituitary-gonadal (HPG) axis, and epididymal sperm count of these mouse models were then assessed. Furthermore, to test whether hypothalamic inflammation is sufficient to decrease sperm production, we overexpressed constitutively active IKK2 (IKK2ca) either in all neurons or subtypes of hypothalamic neurons and assessed hypothalamic inflammation, the HPG axis, and sperm production of these overexpression mouse models. RESULTS: CAP-exposed wild-type control mice vs. filtered air (FA)-exposed wild-type control mice had a higher expression of hypothalamic inflammatory markers, lower functional indexes of the HPG axis, and a lower epididymal sperm count. In contrast, all these measurements for CAP- vs. FA-exposed mice deficient of IKK2 in all neurons were comparable. We also found that overexpression of IKK2ca in either all neurons or pro-opiomelanocortin (POMC) neurons only, but not in Agouti-related protein (AgRP) neurons only, resulted in lower functional indexes of the HPG axis and a lower epididymal sperm count. Moreover, we showed that CAP- vs. FA-exposed mice deficient of IKK2 in POMC neurons had a comparable expression of hypothalamic inflammatory markers, comparable functional indexes of the HPG axis, and a comparable epididymal sperm count. DISCUSSION: This mouse model study shows a causal role of IKK2 of POMC neurons in the development of lower epididymal sperm count due to PM2.5 exposure, providing a mechanistic insight into this emerging pathogenesis. https://doi.org/10.1289/EHP8868.

RRY Inhibits Amyloid-ß1-42 Peptide Aggregation and Neurotoxicity.

BACKGROUND: Current understanding of amyloid-ß protein (Aß) aggregation and toxicity provides an extensive list of drugs for treating Alzheimer's disease (AD); however, one of the most promising strategies for its treatment has been tri-peptides. OBJECTIVE: The aim of this study is to examine those tri-peptides, such as Arg-Arg-Try (RRY), which have the potential of Aß1-42 aggregating inhibition and Aß clearance. METHODS: In the present study, in silico, in vitro, and in vivo studies were integrated for screening tri-peptides binding to Aß, then evaluating its inhibition of aggregation of Aß, and finally its rescuing cognitive deficit. RESULTS: In the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aß1-42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aß1-42 in vitro. In the in vivo studies, Morris water maze, ELISA, and Diolistic staining were used, and data showed that RRY was capable of rescuing the Aß1-42-induced cognitive deficit, reducing the Aß1-42 load and increasing the dendritic spines in the transgenic mouse model. CONCLUSION: Such converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aß1-42 aggregation and treatment for Aß-induced cognitive deficit.

Personal exposure to fine particulate matter and blood pressure: Variations by particulate sources.

Fine particulate matter (PM2.5) is a complex mixture of components which has been associated with various cardiovascular effects, such as elevated blood pressure (BP). However, evidences on specific sources behind these effects remain uncertain. Based on 140 72-h personal measurements among a panel of 36 health college students in Shanghai, China, we assessed associations between source-apportioned PM2.5 exposure and BP changes. Based on personal filter samples, PM2.5 source apportionment was conducted using Positive Matrix Factorization (PMF) model. Linear mixed-effects models were applied to evaluate associations of source-specific PM2.5 exposure with BP changes. Seven sources were identified in PMF analysis. Among them, secondary sulfate (41%) and nitrate (24%) sources contributed most to personal PM2.5, followed by industrial emissions (15%), traffic-related source (10%), coal combustion (6.2%), dust (2.4%) and aged sea salt (1.1%). We found nitrate, traffic-related source and coal combustion were significantly associated with increased BP. For example, an interquartile range increase in PM2.5 from traffic-related source was significantly associated with increase in systolic BP [1.5 (95% CI: 0.26, 2.7) mmHg], diastolic BP [1.2 (95% CI: 0.10, 2.2) mmHg] and mean arterial pressure [1.2 (95% CI: 0.15, 2.2) mmHg]. This is the first investigation linking personal PM2.5 source profile and BP changes. This study provides evidence that several anthropogenic emissions (especially traffic-related emission) may be particularly responsible for BP increases, and highlights that the importance of development of health-oriented PM2.5 source control strategies.

Paternal Exposure to PM2.5 Programs Offspring's Energy Homeostasis.

Considerable studies show that maternal exposure to ambient fine particulate matter (PM2.5) programs offspring's susceptibility to obesity. However, few studies have investigated the effect of paternal PM2.5 exposure on offspring's energy homeostasis. This study thus tested whether paternal PM2.5 exposure programs offspring's energy homeostasis. Male C57Bl/6J mice were exposed to filtered air or concentrated ambient PM2.5 (CAP) for 12 weeks and then mated with normal female C57Bl/6J mice. The offspring were assessed for growth trajectories, food intakes, and body compositions, and the sperm miRNAs of those sires were profiled by microarray. Zygotic injection was used to test whether the miRNA identified by the microarray mediates the impact of paternal PM2.5 exposure on offspring's energy homeostasis. Paternal CAP exposure resulted in significant hypophagia and weight loss in male, but not female, offspring. The weight loss of male offspring was accompanied by decreases in the liver and kidney masses and paradoxically an increase in the adipose mass. Without further exposure to CAP, this programming was three-generationally transmitted along the paternal line. The sperm miRNA profiling revealed that mmu-mir6909-5p was the sole differentially expressed sperm miRNA due to PM2.5 exposure, and zygotic injection of mmu-mir6909-5p mimicked all the effects of paternal PM2.5 exposure on offspring's energy homeostasis. Paternal PM2.5 exposure programs offspring's energy homeostasis through increasing paternal sperm mmu-mir6909-5p.

Exposure to different fractions of diesel exhaust PM2.5 induces different levels of pulmonary inflammation and acute phase response.

AIM: Ambient fine particulate matter (PM2.5) consists of various components, and their respective contributions to the toxicity of PM2.5 remains to be determined. To provide specific recommendations for preventing adverse effects due to PM2.5 pollution, we determined whether the induction of pulmonary inflammation, the putative pathogenesis for the morbidity and mortality due to PM2.5 exposure, was fractioned through solubility-dependent fractioning. METHODS: In the present study, the water and heptane solubilities-dependent serial fractioning of diesel exhaust particulate matter (DEP), a prominent source of urban PM2.5 pollution, was performed. The pro-inflammatory actions of these resultant fractions were then determined using both an intratracheal instillation mouse model and cultured BEAS-2B cells, a human bronchial epithelial cell line. RESULTS: Instillation of the water-insoluble, but not -soluble fraction elicited significant pulmonary inflammatory and acute phase responses, comparable to those induced by instillation of DEP. The water-insoluble fraction was further fractioned using heptane, a polar organic solvent, and instillation of heptane-insoluble, but not -soluble fraction elicited significant pulmonary inflammation and acute phase responses. Furthermore, we showed that DEP and water-insoluble DEP, but not water-soluble DEP, activated pro-inflammatory signaling in cultured BEAS-2B cells, ruling out the possibility that the solubility impacts the in vivo distribution and thus the pulmonary inflammatory response.

Hypothalamic-pituitary-adrenal axis mediates ambient PM2.5 exposure-induced pulmonary inflammation.

Ambient fine particulate matter (PM2.5) exposure correlates with adverse cardiometabolic effects. The underlying mechanisms have not yet been fully understood. Hypothalamic-pituitary-adrenal (HPA) axis, as the central stress response system, regulates cardiometabolic homeostasis and is implicated in the progression of various adverse health effects caused by inhalational airborne pollutant exposure. In this study, we investigated whether ambient PM2.5 exposure activates HPA axis and its effect mediating PM2.5-induced pulmonary inflammation. C57Bl/6 J mice were intratracheally instilled with different concentrations of diesel exhaust PM2.5 (DEP), and plasma was harvested at different times. Assessments of plasma stress hormones revealed that DEP instillation dose- and time-dependently increased mouse circulating corticosterone and adrenocorticotropic hormone (ACTH) levels, strongly supporting that DEP instillation activates HPA axis. To determine which components of DEP activate HPA axis, C57Bl/6J mice were intratracheally instilled with water-soluble and -insoluble fractions of DEP. Plasma analyses showed that water-insoluble but not -soluble fraction of DEP increased circulating corticosterone and ACTH levels. Consistently, concentrated ambient PM2.5 (CAP) exposure significantly increased mouse urine and hair corticosterone levels, corroborating the activation of HPA axis by ambient PM2.5. Furthermore, deletion of stress hormones by total bilateral adrenalectomy alleviated PM2.5-induced pulmonary inflammation, providing insights into the contribution of central neurohormonal mechanisms in modulating adverse health effects caused by exposure to PM2.5.

Intermittent fasting ameliorates PM2.5 exposure-induced abnormalities in glycaemic control.

Exposure to ambient fine particulate matter (PM2.5) elicits various abnormalities in glycaemic control and thus correlates with type 2 diabetes. Intermittent fasting is an emerging treatment for type 2 diabetes. This study, therefore, tested whether intermittent fasting ameliorates PM2.5 exposure-induced abnormalities in glycaemic control. To this end, C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) for 16 weeks and concurrently subject to ad libitum feeding or intermittent fasting. The food intake assessment showed that CAP exposure transiently reduced food intake in ad libitum fed mice, but persistently reduced food intake in intermittently fasted mice. In contrast, CAP exposure persistently promoted mouse weight gain in ad libitum fed mice, while intermittent fasting blocked this CAP exposure-induced weight gain. The glucose homeostasis assessments revealed that CAP exposure elicited insulin resistance and glucose intolerance and meanwhile increased glucose-induced insulin secretion (GIIS). The insulin resistance and glucose intolerance, but not the increase in GIIS, induced by CAP exposure were blocked by intermittent fasting. Analysis of Akt phosphorylation, the indicator of local insulin signaling, showed that CAP exposure reduced insulin signaling in the liver and adipose tissues but not in the skeletal muscle. Intermittent fasting blocked CAP exposure-induced insulin resistance in the liver but not in the adipose tissues. The present study demonstrates that intermittent fasting ameliorates PM2.5 exposure-induced insulin resistance and glucose intolerance, strongly supporting that it may be used to prevent type 2 diabetes due to exposure to PM2.5.

cis-4-[18F]fluoro-L-proline Molecular Imaging Experimental Liver Fibrosis.

Introduction: Early-stage liver fibrosis is potentially reversible, but difficult to diagnose. Clinical management would be enhanced by the development of a non-invasive imaging technique able to identify hepatic injury early, before end-stage fibrosis ensues. The analog of the amino acid proline, cis-4-[18F]fluoro-L-proline ([18F]fluoro-proline), which targets collagenogenesis in hepatic stellate cells (HSC), was used to detect fibrosis. Methods: Acute steatohepatitis was induced in experimental animals by liquid ethanol diet for 8 weeks, intra-gastric binge feedings every 10th day along with lipopolysaccharide (LPS) injection. The control animals received control diet for 8 weeks and an equivalent volume of saline on the same schedule as the acute steatohepatitis model. First, in vitro cellular experiments were carried out to assess [3H]proline uptake by HSC, hepatocytes and Kupffer cells derived from rats with acute steatohepatitis (n = 14) and controls (n = 14). Next, ex vivo liver experiments were done to investigate unlabeled proline-mediated collagen synthesis and its associated proline transporter expression in acute steatohepatitis (n = 5) and controls (n = 5). Last, in vivo dynamic and static [18F]fluoro-proline micro-PET/CT imaging was performed in animal models of acute steatohepatitis (n = 7) and control (n = 7) mice. Results: [3H]proline uptake was 5-fold higher in the HSCs of steatohepatitis rats than controls after incubation of up to 60 min. There was an excellent correlation between [3H]proline uptake and liver collagen expression (r-value > 0.90, p < 0.05). Subsequent liver tissue studies demonstrated 2-3-fold higher proline transporter expression in acute steatohepatitis animals than in controls, and proline-related collagen synthesis was blocked by this transporter inhibitor. In vivo micro-PET/CT studies with [18F]fluoro-proline showed 2-3-fold higher uptake in the livers of acute steatohepatitis mice than in controls. There was an excellent correlation between [18F]fluoro-proline uptake and liver collagen expression in the livers of acute steatohepatitis mice (r-value = 0.97, p < 0.001). Conclusion: [18F]fluoro-proline localizes in the liver and correlates with collagenogenesis in acute steatohepatitis with a signal intensity that is sufficiently high to allow imaging with micro-PET/CT. Thus, [18F]fluoro-proline could serve as a PET imaging biomarker for detecting early-stage liver fibrosis.

Chronic exposure to diesel exhaust particulate matter impairs meiotic progression during spermatogenesis in a mouse model.

Exposure to ambient PM2.5 may correlate with the decline of semen quality, and the underlying biological mechanism has not been fully understood. In the present study, mice were intratracheally instilled with diesel exhaust PM2.5 (DEP), and its effects on the spermatogenic process as well as the alterations of testicular gene expression profile were assessed. Our results showed that chronic exposure to DEP impaired the fertility of male mice without influencing their libido. Compared with Vehicle-exposed group, the sperm count and motility from DEP-exposed mice were significantly decreased. In addition, immunohistological staining of γH2AX and DMC1, biomarkers for meiotic double strand breaks (DSBs), demonstrated that chronic exposure to DEP comprised the repair of meiotic DSBs, thus disrupting the spermatogenesis. Deep RNA sequencing test showed altered expressions of testicular genes including the GnRH signaling pathway. In summary, our research demonstrated that chronic exposure to DEP may disrupt spermatogenesis through targeting the meiotic recombination, providing a new perspective for the research on the male reproductive system damage caused by air pollution.

Associations between fine particulate matter constituents and daily cardiovascular mortality in Shanghai, China.

Limited evidence is available for the associations between fine particulate matter (PM2.5) constituents and daily cardiovascular disease (CVD) mortality in China. In present study, a time-series analysis was conducted to evaluate the associations of PM2.5 constituents (two carbonaceous fractions, eight water-soluble inorganic ions and fifteen elements) with daily CVD mortality in Pudong New Area of Shanghai, China, from 2014 to 2016. Results showed that the effect estimates for the associations of PM2.5 and its constituents with CVD mortality were generally strongest when using the exposures of the previous two day concentrations. The associations of organic carbon, sulfate, ammonia, potassium, copper, arsenic, and lead with daily CVD mortality were robust to the adjustment of PM2.5 total mass, their collinearity with PM2.5 total mass, and criteria gaseous air pollutants. An interquartile range increase in the previous two day concentrations of PM2.5, organic carbon, sulfate, ammonia, potassium, copper, arsenic, and lead were associated with significant increments of 2.21% (95% confidence interval [95%CI]: 0.54%, 3.88%), 2.83% (95% CIs: 1.16%, 4.50%), 1.90% (95% CIs: 0.35%, 3.45%), 2.29% (95% CIs: 0.80%, 3.77%), 0.94% (95% CIs: 0.13%, 1.75%), 1.53% (95% CIs: 0.37%, 2.69%), 2.08% (95% CIs: 0.49%, 3.68%) and 1.98% (95% CIs: 0.49%, 3.47%) in daily CVD mortality, respectively, in single-pollutant models. In conclusion, this study suggested that organic carbon, sulfate, ammonia, potassium, copper, arsenic, and lead might be mainly responsible for the associations between short-term PM2.5 exposures and increased CVD mortality in Shanghai, China.

The acute effects of fine particulate matter constituents on circulating inflammatory biomarkers in healthy adults.

BACKGROUND: Systemic inflammation is considered one of the key mechanisms in the development of cardiovascular diseases induced by fine particulate matter (PM2.5) air pollution. However, evidence concerning the effects of various PM2.5 constituents on circulating inflammatory biomarkers were limited and inconsistent. OBJECTIVES: To evaluate the associations of short-term exposure to a variety of PM2.5 constituents with circulating inflammatory biomarkers. METHODS: We conducted a panel study from May to October 2016 among 40 healthy adults in Shanghai, China. We monitored the concentrations of 27 constituents of PM2.5. We applied linear mixed-effect models to analyze the associations of PM2.5 and its constituents with 7 inflammatory biomarkers, and further assessed the robustness of the associations by fitting models adjusting for PM2.5 mass and/or their collinearity. Benjamini-Hochberg false discovery rate was used to correct for multiple comparisons. RESULTS: The associations of PM2.5 were strongest at lag 0 d with tumor necrosis factor-α (TNF-α), at lag 1 d with interleukin-6, interleukin-8, and interleukin-17A, at lag 02 d with monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1). After correcting for multiple comparisons in all models, Cl-, K+, Si, K, As, and Pb were significantly associated with interleukin-8; SO42- and Se were marginally significantly associated with interleukin-8; SO42-, As, and Se were marginally significantly associated with TNF-α; and Si, K, Zn, As, Se, and Pb were marginally significantly associated with MCP-1. CONCLUSIONS: Our results suggested that some constituents (SO42-, Cl-, K+, and some elements) might be mainly responsible for systemic inflammation triggered by short-term PM2.5 exposure.

Particulate air pollution and ischemic stroke hospitalization: How the associations vary by constituents in Shanghai, China.

BACKGROUND: The identification of constituents of fine particulate matter (PM2.5) air pollution that had key impacts of ischemic stroke (the predominant subtype of stroke) is important to understand the underlying biological mechanisms and develop air pollution control policies. OBJECTIVES: To explore the associations between PM2.5 constituents and hospitalization for ischemic stroke in Shanghai, China. METHODS: We conducted a time-series study to explore the associations between 27 constituents of PM2.5 and hospitalization for ischemic stroke in Shanghai, China from 2014 to 2016. The over-dispersed generalized additive models with adjustment for time, day of week, holidays, and weather conditions were used to estimate the associations. We also evaluated the robustness of the effect estimates for each constituent after adjusting for the confounding effects of PM2.5 total mass and gaseous pollutants and the collinearity (the residual) between this constituent and PM2.5 total mass. We also compared the associations between seasons. RESULTS: In total, we identified 4186 ischemic stroke hospitalizations during the study period. The associations of ischemic stroke were consistently significant with elemental carbon and several elemental constituents (Chromium, Iron, Copper, Zinc, Arsenic, Selenium, and Lead) at lag 1 day in single-constituent models, models adjusting for PM2.5 total mass or gaseous pollutants and models adjusting for collinearity. The associations were much stronger in cool season than in warm season. CONCLUSIONS: The current study provides suggestive evidence that elemental carbon and some metallic elements may be mainly responsible for the risks of ischemic stroke hospitalization induced by short-term PM2.5 exposure.

Liver Fibrosis Conventional and Molecular Imaging Diagnosis Update.

Liver fibrosis is a serious, life-threatening disease with high morbidity and mortality that result from diverse causes. Liver biopsy, considered the "gold standard" to diagnose, grade, and stage liver fibrosis, has limitations in terms of invasiveness, cost, sampling variability, inter-observer variability, and the dynamic process of fibrosis. Compelling evidence has demonstrated that all stages of fibrosis are reversible if the injury is removed. There is a clear need for safe, effective, and reliable non-invasive assessment modalities to determine liver fibrosis in order to manage it precisely in personalized medicine. However, conventional imaging methods used to assess morphological and structural changes related to liver fibrosis, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), are only useful in assessing advanced liver disease, including cirrhosis. Functional imaging techniques, including MR elastography (MRE), US elastography, and CT perfusion are useful for assessing moderate to advanced liver fibrosis. MRE is considered the most accurate noninvasive imaging technique, and US elastography is currently the most widely used noninvasive means. However, these modalities are less accurate in early-stage liver fibrosis and some factors affect the accuracy of these techniques. Molecular imaging is a target-specific imaging mechanism that has the potential to accurately diagnose early-stage liver fibrosis. We provide an overview of recent advances in molecular imaging for the diagnosis and staging of liver fibrosis which will enable clinicians to monitor the progression of disease and potentially reverse liver fibrosis. We compare the promising technologies with conventional and functional imaging and assess the utility of molecular imaging in precision and personalized clinical medicine in the early stages of liver fibrosis.

The effects of fine particulate matter constituents on exhaled nitric oxide and DNA methylation in the arginase-nitric oxide synthase pathway.

BACKGROUND: Fine particulate matter (PM2.5) has been widely associated with airway inflammation represented by increased fractional concentration of exhaled nitric oxide (FeNO). However, it remains unclear whether various PM2.5 constituents have different impacts on FeNO and its production process from the arginase (ARG)-nitric oxide synthase (NOS) pathway. OBJECTIVES: To investigate the acute effects of PM2.5 constituents on FeNO and DNA methylation of genes involved. METHODS: We conducted a longitudinal panel study among 43 young adults in Shanghai, China from May to October in 2016. We monitored the concentrations of 25 constituents of PM2.5. We applied the linear mixed-effect model to evaluate the associations of PM2.5 constituents with FeNO and DNA methylation of the ARG2 and NOS2A genes. RESULTS: Following PM2.5 exposure, NOS2A methylation decreased and ARG2 methylation increased only on the concurrent day, whereas FeNO increased most prominently on the second day. Nine constituents (OC, EC, K, Fe, Zn, Ba, Cr, Se, and Pb) showed consistent associations with elevated FeNO and decreased NOS2A methylation or increased ARG2 methylation in single-constituent models and models adjusting for PM2.5 total mass and collinearity. An interquartile range increase of these constituents was associated with respective decrements of 0.27-1.20 in NOS2A methylation (%5mC); increments of 0.48-1.56 in ARG2 methylation (%5mC); and increments of 7.12%-17.54% in FeNO. CONCLUSIONS: Our results suggested that OC, EC, and some metallic elements may be mainly responsible for the development and epigenetic regulation of airway inflammatory response induced by short-term PM2.5 exposure.

Developmental programming of obesity by maternal exposure to concentrated ambient PM2.5 is maternally transmitted into the third generation in a mouse model.

BACKGROUND: Obesity is an uncontrolled global epidemic and one of the leading global public health challenges. Maternal exposure to ambient fine particulate matter (PM2.5) may adversely program offspring's adiposity, suggesting a specialized role of PM2.5 pollution in the global obesity epidemic. However, the vulnerable window for this adverse programming and how it is cross-generationally transmitted have not been determined. Therefore, in the present study, female C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during different periods, and the development and adulthood adiposity of their four-generational offspring were assessed. RESULTS: Our data show that the pre-conceptional but not gestational exposure to CAP was sufficient to cause male but not female offspring's low birth weight, accelerated postnatal weight gain, and increased adulthood adiposity. These adverse developmental traits were transmitted into the F2 offspring born by the female but not male F1 offspring of CAP-exposed dams. In contrast, no adverse development was noted in the F3 offspring. CONCLUSIONS: The present study identified a pre-conceptional window for the adverse programming of adiposity by maternal exposure to PM2.5, and showed that it was maternally transmitted into the third generation. These data not only call special attention to the protection of women from exposure to PM2.5, but also may facilitate the development of intervention to prevent this adverse programming.