Abstract 285: Bisphenol A Increases Atherosclerosis Mediated by the Human Pregnane X Receptor

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Yipeng Sui ◽  
Se-Hyung Park ◽  
Robert N Helsley ◽  
Changcheng Zhou
Keyword(s):  
Bisphenol A ◽  
Large Scale ◽  
Plasma Lipid ◽  
Pregnane X Receptor ◽  
Consumer Products ◽  
Environmental Chemicals ◽  
Cvd Risk ◽  
Humanized Mouse Model ◽  
Increased Risk ◽  
Underlying Mechanisms

Objective: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA has recently been associated with increased risk of cardiovascular disease (CVD) in multiple large-scale human population studies but the underlying mechanisms remain elusive. We previously reported that BPA activates the pregnane X receptor (PXR) which acts as a xenobiotic sensor to regulate xenobiotic metabolism and has pro-atherogenic effects in animal models upon activation. BPA is a potent agonist of human PXR but has no effects on mouse or rat PXR activity, which confounds the use of rodent models to evaluate mechanisms of BPA-mediated CVD risk. This study aims to investigate the atherogenic mechanism of BPA using a novel PXR-humanized mouse model. Approach and Results: We generated PXR-humanized ApoE deficient (huPXR•ApoE -/- ) mice that respond to human PXR ligands and therefore constitute a model to study the atherogenic effects of BPA. Feeding studies were performed to determine the effects of BPA exposure on atherosclerosis development. We found that exposure to BPA increased atherosclerosis in huPXR•ApoE -/- mice but not their control littermates. BPA exposure did not affect plasma lipid levels but increased CD36 expression and lipid accumulation in macrophages of huPXR•ApoE -/- mice. Conclusions: Our findings provide a molecular mechanism linking BPA exposure to increased risk of CVD in exposed individuals. PXR is therefore a relevant target for future risk assessment of BPA and related environmental chemicals in humans.

scholarly journals Markers of cardiovascular risk are not changed by increased whole-grain intake: the WHOLEheart study, a randomised, controlled dietary intervention

2010 ◽  
Vol 104 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Iain A. Brownlee ◽  
Carmel Moore ◽  
Mark Chatfield ◽  
David P. Richardson ◽  
Peter Ashby ◽  
...  
Keyword(s):  
Observational Studies ◽  
Large Scale ◽  
Dietary Intervention ◽  
Plasma Lipid ◽  
Study Groups ◽  
Risk Markers ◽  
Whole Grain ◽  
Cvd Risk ◽  
Percentage Body Fat ◽  
Randomised Controlled

Recommendations for whole-grain (WG) intake are based on observational studies showing that higher WG consumption is associated with reduced CVD risk. No large-scale, randomised, controlled dietary intervention studies have investigated the effects on CVD risk markers of substituting WG in place of refined grains in the diets of non-WG consumers. A total of 316 participants (aged 18–65 years; BMI>25 kg/m2) consuming < 30 g WG/d were randomly assigned to three groups: control (no dietary change), intervention 1 (60 g WG/d for 16 weeks) and intervention 2 (60 g WG/d for 8 weeks followed by 120 g WG/d for 8 weeks). Markers of CVD risk, measured at 0 (baseline), 8 and 16 weeks, were: BMI, percentage body fat, waist circumference; fasting plasma lipid profile, glucose and insulin; and indicators of inflammatory, coagulation, and endothelial function. Differences between study groups were compared using a random intercepts model with time and WG intake as factors. Although reported WG intake was significantly increased among intervention groups, and demonstrated good participant compliance, there were no significant differences in any markers of CVD risk between groups. A period of 4 months may be insufficient to change the lifelong disease trajectory associated with CVD. The lack of impact of increasing WG consumption on CVD risk markers implies that public health messages may need to be clarified to consider the source of WG and/or other diet and lifestyle factors linked to the benefits of whole-grain consumption seen in observational studies.

scholarly journals Targeting thrombogenicity and inflammation in chronic HIV infection

2019 ◽  
Vol 5 (6) ◽  
pp. eaav5463 ◽  
Author(s):  
Meagan P. O’Brien ◽  
M. Urooj Zafar ◽  
Jose C. Rodriguez ◽  
Ibeawuchi Okoroafor ◽  
Alex Heyison ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Immune Activation ◽  
Platelet Reactivity ◽  
Coronary Thrombosis ◽  
Myocardial Infarctions ◽  
Cvd Risk ◽  
Activation Markers ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
Chronic Hiv Infection

Persons with HIV infection (PWH) have increased risk for cardiovascular disease (CVD), but the underlying mechanisms remain unclear. Coronary thrombosis is known to provoke myocardial infarctions, but whether PWH have elevated thrombotic propensity is unknown. We compared thrombogenicity of PWH on antiretroviral therapy versus matched controls using the Badimon chamber. Measures of inflammation, platelet reactivity, and innate immune activation were simultaneously performed. Enrolled PWH were then randomized to placebo, aspirin (81 mg), or clopidogrel (75 mg) for 24 weeks to assess treatment effects on study parameters. Thrombogenicity was significantly higher in PWH and correlated strongly with plasma levels of D-dimer, soluble TNF receptors 1 and 2, and circulating classical and nonclassical monocytes in PWH. Clopidogrel significantly reduced thrombogenicity and sCD14. Our data suggest that higher thrombogenicity, interacting with inflammatory and immune activation markers, contributes to the increased CVD risk observed in PWH. Clopidogrel exhibits an anti-inflammatory activity in addition to its antithrombotic effect in PWH.

Associations between Maternal Exposure to Bisphenol A or Triclosan and Gestational Hypertension and Preeclampsia: The MIREC Study

2018 ◽  
Vol 36 (11) ◽  
pp. 1127-1135
Author(s):  
Louopou Rosalie Camara ◽  
Tye Elaine Arbuckle ◽  
Helen Trottier ◽  
William Donald Fraser
Keyword(s):  
Bisphenol A ◽  
Gestational Hypertension ◽  
First Trimester ◽  
Environmental Chemicals ◽  
Multinomial Regression ◽  
Hypertension In Pregnancy ◽  
Nulliparous Women ◽  
Increased Risk ◽  
Multiparous Women ◽  
Liquid Chromatography Tandem Mass

Background Little is known about the association between bisphenol A (BPA) or triclosan (TCS) exposure and hypertension in pregnancy. Objective To investigate potential associations between maternal urinary concentrations of BPA or TCS and gestational hypertension (GH) and preeclampsia. Study Design Among 1,909 pregnant women participating in the maternal-infant research on environmental chemicals (MIREC) study, urinary concentrations of BPA and TCS were measured in the first trimester by liquid chromatography-tandem mass spectrometry using isotope dilution. Blood pressure was measured during each trimester. Multinomial regression was performed to estimate the adjusted odds ratio (aOR) and 95% confidence intervals (CI) for the associations between these phenols and GH and preeclampsia. Results BPA and TCS were not associated with GH or preeclampsia. However, in multiparous women, BPA (0.50–1.30 µg/L) was associated with decreased risk of GH (aOR =0.45; 95%CI: 0.21–0.98) while among nulliparous women, TCS was associated with an increased risk of GH (3.60–32.60 µg/L; aOR = 2.58; 95% CI: 1.09–6.13 and > 32.60 µg/L: aOR = 2.74; 95% CI: 1.15–6.51). Conclusion BPA and TCS urinary concentrations were not associated with GH or preeclampsia; however, our results suggest an association between TCS and GH in nulliparous women. Additional studies are required to confirm our results.

scholarly journals Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Amand F. Schmidt ◽  
◽  
Michael V. Holmes ◽  
David Preiss ◽  
Daniel I. Swerdlow ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Large Scale ◽  
Plasma Lipid ◽  
Blood Lipid ◽  
Chronic Obstructive ◽  
Genetic Associations ◽  
Obstructive Pulmonary Disease ◽  
Pcsk9 Inhibitor ◽  
Increased Risk ◽  
Individual Participant

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

scholarly journals Distribution of LDL Particle Size in a Population-Based Sample of Children and Adolescents and Relationship with Other Cardiovascular Risk Factors

2005 ◽  
Vol 51 (7) ◽  
pp. 1192-1200 ◽  
Author(s):  
Simona Stan ◽  
Emile Levy ◽  
Edgard E Delvin ◽  
James A Hanley ◽  
Benoît Lamarche ◽  
...  
Keyword(s):  
Risk Factors ◽  
Particle Size ◽  
Plasma Lipid ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Ldl Particle Size ◽  
Small Dense Ldl ◽  
Ldl Particles ◽  
Ldl Size ◽  
Increased Risk

Abstract Background: Smaller, denser LDL particles are associated with an increased risk for cardiovascular diseases (CVD). In youths, data on the distribution of LDL particle size and on its association with other CVD risk factors are limited. Methods: We determined LDL peak particle size by nondenaturing 2%–16% gradient gel electrophoresis in a representative sample of 2249 youths 9, 13, and 16 years of age who participated in a school-based survey conducted in 1999 in the province of Quebec, Canada. Standardized clinical measurements and fasting plasma lipid, glucose, and insulin concentrations were available. Results: The LDL peak particle size distribution was gaussian. The 5th, 50th (median), and 95th percentiles by age and sex were 255.5–258.6, 262.1–263.2, and 268.1–269.5 Å, respectively. The prevalence of the small, dense LDL phenotype (LDL peak particle size ≤255 Å) was 10% in participants with insulin resistance syndrome (IRS), in contrast to 1% in those without IRS. In a multiple regression analysis, the association of LDL size with other CVD risk factors [apolipoprotein B, HDL-cholesterol (HDL-C), triglyceride (TG), and insulin concentrations, and body mass index] was strongest with TG and HDL-C concentrations: a 1 SD increase in loge-transformed TG concentration was associated with a 1.2 Å reduction in LDL size, and a 1 SD increase in HDL-C was associated with a 1.1 Å increase in LDL size. Conclusions: Although the small, dense LDL phenotype is less prevalent in youths than adults, its prevalence is clearly increased in childhood IRS. Metabolic correlates of LDL size are similar in youths and adults.

Abstract P373: Cardiac Depolarization and Repolarization Changes with Mental Stress are Associated with Mental Stress- Induced Ischemia

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Pratik M Pimple ◽  
Amit Shah ◽  
Ronnie Ramadan ◽  
Elsayed Z Soliman ◽  
Doug Bremner ◽  
...  
Keyword(s):  
Mental Stress ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Cvd Risk ◽  
Increased Risk ◽  
Qrs Duration ◽  
Artery Disease ◽  
Underlying Mechanisms ◽  
Structural Disease

Introduction: QRS duration and frontal QRS/T angle are simple and easily available electrocardiographic measures of cardiac depolarization and repolarization that predict cardiovascular disease (CVD) events and mortality. Such measures may be indicative of cardiac structural disease, ischemia, or primary conduction abnormalities. Mental stress-induced myocardial ischemia (MSI) is also associated with increased CVD risk, but the underlying mechanisms are unknown. We hypothesized that MSI is associated with stress-induced abnormalities in cardiac depolarization and repolarization, QRS duration and frontal QRS/T angle. Methods: We compared QRS duration & frontal QRS/T angle during mental stress between coronary artery disease (CAD) patients who were MSI positive (MSI+) and CAD patients who were MSI negative (MSI-). For each MSI+ case (n=22), one or two MSI- controls were matched for age, gender and race- ethnicity (n=41). QRS duration and frontal QRS/T angle were automatically computed by a 12-lead ECG (GE MAC 5000). QRS/T angle was calculated as absolute minimal difference between the frontal R and T axes in patients with QRS duration < 120 ms (n= 50). Mental stress was induced via speech stressor, and nuclear 99m-Tc-sestamibi gated Single-Photon Emission Computed Tomography (SPECT) was used to assess MSI. Results: Mean age was 65 years, 20 patients were black, and 55 were males. The two groups were similar in terms of demographics and past medical history. Both MSI+ and MSI- groups had similar QRS duration at baseline, but MSI+ patients had an adjusted 3.1 ms higher increase in QRS duration with mental stress than MSI- patients (95% CI: 0.5 to 5.7), after adjusting for CVD risk factors, hemodynamic changes during mental stress (blood pressure, heart rate), and baseline QRS duration. MSI+ patients had an adjusted 28.2 degrees larger QRS/T angle at baseline (95% CI: 2.5 to 53.9) compared to MSI- patients, but did not differ with regards to change in QRS/T angle with mental stress. However, among those with normal baseline conduction (QRS<100 ms, n=36), MSI+ patients had an adjusted 17.8 degrees larger change in QRS/T angle with mental stress compared to MSI- patients (95% CI: 3.1 to 32.4). In patients with mildly abnormal conduction (QRS duration between 100 and 119 ms, n=14), no differences were found, p=0.059 for QRS duration x MSI interaction. Conclusion: CAD patients exhibit changes in cardiac depolarization and repolarization during acute mental stress. Those with MSI have greater baseline QRS/T angle and larger changes in QRS/T angle and QRS duration with mental stress. These findings may help to explain the pathophysiology linking mental stress and CVD, as well as the increased risk in patients with MSI.

Contrasting underlying mechanisms of different barrier coating types

TAPPI Journal ◽  
2018 ◽  
Vol 17 (01) ◽  
pp. 31-37
Author(s):  
Bryan McCulloch ◽  
John Roper ◽  
Kaitlin Rosen
Keyword(s):  
Food Packaging ◽  
Underlying Mechanism ◽  
Consumer Products ◽  
Mechanical Degradation ◽  
Design Rules ◽  
Barrier Coatings ◽  
Barrier Materials ◽  
Barrier Coating ◽  
Coating Type ◽  
Underlying Mechanisms

Barrier coatings are used in applications including food packaging, dry goods, and consumer products to prevent transport of different compounds either through or into paper and paperboard substrates. These coatings are useful in packaging to contain active ingredients, such as fragrances, or to protect contents from detrimental substances, such as oxygen, water, grease, or other chemicals of concern. They also are used to prevent visual changes or mechanical degradation that might occur if the paper becomes saturated. The performance and underlying mechanism depends on the barrier coating type and, in particular, on whether the barrier coating is designed to prevent diffusive or capillary transport. Estimates on the basis of fundamental transport phenomena and data from a broad screening of different barrier materials can be used to understand the limits of various approaches to construct barrier coatings. These estimates also can be used to create basic design rules for general classes of barrier coatings.

Evolution of Metastable Structures in Bimetallic Catalysts from Microscopy and Machine-Learning Molecular Dynamics

2020 ◽  
Author(s):  
Jin Soo Lim ◽  
Jonathan Vandermause ◽  
Matthijs A. van Spronsen ◽  
Albert Musaelian ◽  
Christopher R. O’Connor ◽  
...  
Keyword(s):  
Machine Learning ◽  
Molecular Dynamics ◽  
Large Scale ◽  
Materials Science ◽  
Complete Characterization ◽  
Layer By Layer ◽  
Surface Restructuring ◽  
Metastable Structures ◽  
Mechanistic Investigation ◽  
Underlying Mechanisms

Restructuring of interface plays a crucial role in materials science and heterogeneous catalysis. Bimetallic systems, in particular, often adopt very different composition and morphology at surfaces compared to the bulk. For the first time, we reveal a detailed atomistic picture of the long-timescale restructuring of Pd deposited on Ag, using microscopy, spectroscopy, and novel simulation methods. Encapsulation of Pd by Ag always precedes layer-by-layer dissolution of Pd, resulting in significant Ag migration out of the surface and extensive vacancy pits. These metastable structures are of vital catalytic importance, as Ag-encapsulated Pd remains much more accessible to reactants than bulk-dissolved Pd. The underlying mechanisms are uncovered by performing fast and large-scale machine-learning molecular dynamics, followed by our newly developed method for complete characterization of atomic surface restructuring events. Our approach is broadly applicable to other multimetallic systems of interest and enables the previously impractical mechanistic investigation of restructuring dynamics.

Mechanisms underlying heart failure in type 2 diabetes mellitus

2019 ◽  
pp. 37-39
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Experimental Studies ◽  
Vascular Complications ◽  
Molecular Alterations ◽  
Increased Risk ◽  
Cardioprotective Effects ◽  
Underlying Mechanisms ◽  
Cardio Vascular

The prevalence of heart failure is markedly increased in individuals with diabetes mellitus. Numerous observational studies suggest that this increased risk for heart failure can be attributed to exacerbated vascular complications and the presence of increased risk factors in diabetic subjects. In addition, experimental studies revealed the presence of a number of distinct molecular alterations in the myocardium that occur independently of vascular disease and hypertension. Many of these molecular alterations are similarly observed in failing hearts of nondiabetic patients and have thus been proposed to contribute to the increased risk for heart failure in diabetes. The interest in understanding the underlying mechanisms of impaired cardio- vascular outcomes in diabetic individuals has much increased since the demonstration of cardioprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists in recent clinical trials. The current review therefore summarizes the distinct mechanisms that have been proposed to increase the risk for heart failure in diabetes mellitus.

Study of Biochemical and Clinical Markers in Steatohepatitis Related to Obesity

2018 ◽  
Vol 69 (6) ◽  
pp. 1501-1505
Author(s):  
Roxana Maria Livadariu ◽  
Radu Danila ◽  
Lidia Ionescu ◽  
Delia Ciobanu ◽  
Daniel Timofte
Keyword(s):  
Liver Disease ◽  
Liver Biopsy ◽  
Large Scale ◽  
Biological Data ◽  
Obese Patients ◽  
Clinical Markers ◽  
Mean Values ◽  
Nonalcoholic Fatty Liver ◽  
Obstructive Sleep ◽  
Increased Risk

Nonalcoholic fatty liver disease (NAFLD) is highly associated to obesity and comprises several liver diseases, from simple steatosis to steatohepatitis (NASH) with increased risk of developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma. Liver biopsy is the gold standard in diagnosing the disease, but it cannot be used in a large scale. The aim of the study was the assessment of some non-invasive clinical and biological markers in relation to the progressive forms of NAFLD. We performed a prospective study on 64 obese patients successively hospitalised for bariatric surgery in our Surgical Unit. Patients with history of alcohol consumption, chronic hepatitis B or C, other chronic liver disease or patients undergoing hepatotoxic drug use were excluded. All patients underwent liver biopsy during sleeve gastrectomy. NAFLD was present in 100% of the patients: hepatic steatosis (38%), NASH with the two forms: with fibrosis (31%) and without fibrosis (20%), cumulating 51%; 7 patients had NASH with vanished steatosis. NASH with fibrosis statistically correlated with metabolic syndrome (p = 0.036), DM II (p = 0.01) and obstructive sleep apnea (p = 0.02). Waist circumference was significantly higher in the steatohepatitis groups (both with and without fibrosis), each 10 cm increase increasing the risk of steatohepatitis (p = 0.007). The mean values of serum fibrinogen and CRP were significantly higher in patients having the progressive forms of NAFLD. Simple clinical and biological data available to the practitioner in medicine can be used to identify obese patients at high risk of NASH, aiming to direct them to specialized medical centers.

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