Androgen therapy and atherosclerotic cardiovascular disease

Cardiovascular disease (CVD) remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen use and abuse is increasing in our society, the alternate view that androgens may promote CVD in men is assuming increasing importance. Whether androgens adversely affect CVD in either men or women remains a contentious issue within both the cardiovascular and endocrinological fraternities. This review draws from basic science, animal and clinical studies to outline our current understanding regarding androgen effects on atherosclerosis, the major CVD, and asks where future directions of atherosclerosis-related androgen research may lie

The androgen receptor drives the sex-specific expression of vascular cell adhesion molecule-1 in endothelial cells but not lipid metabolism genes in monocyte-derived macrophages

Background: Anecdotal evidence suggests that male sex hormones are proatherogenic. We hypothesized that the male sex hormone receptor, the androgen receptor (AR), acts as a molecular switch in sex-specific inflammatory signaling in vascular cells. Materials and methods: AR expression in human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages (MDMs) or HeLa cells was modulated by transfection with AR siRNA or human AR cDNA expression vector. Activity and expression levels were measured by luciferase reporter assays, Western blotting or real-time PCR analysis. Results: AR knockdown reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in genetically male HUVECs. Conversely, AR upregulation in genetically female HUVECs induced VCAM-1 expression and increased dihydrotestos-terone-stimulated monocyte adhesion. Co-transfection of an AR expression vector with VCAM-1 or NF-kB-reporter vectors into phenotypically female, AR-negative HeLa cells confirmed AR regulation of VCAM-1 expression as well as AR activation of NF-kB. AR upregulation was not sufficient to increase ICAM-1 levels in female HUVECs or lipoprotein metabolism gene expression in female MDMs, despite AR knockdown limiting expression in their male counterparts. Conclusions: AR acts as a molecular switch to induce VCAM-1 expression. Low AR levels in female HUVECs limit NF-kB/VCAM-1 induction and monocyte adhesion and could contribute to the gender bias in cardiovascular disease. Unidentified factors in female cells limit induction of other proatherogenic genes not primarily regulated by NF-kB. © 2010, by Walter de Gruyter Berlin New York. All rights reserved

Inhibitory Effect of a French Maritime Pine Bark Extract-Based Nutritional Supplement on TNF-α-Induced Inflammation and Oxidative Stress in Human Coronary Artery Endothelial Cells

© 2015 Kristine C. Y. McGrath et al. Oxidative stress and inflammation, leading to endothelial dysfunction, contribute to the pathogenesis of atherosclerosis. The popularity of natural product supplements has increased in recent years, especially those with purported anti-inflammatory and/or antioxidant effects. The efficacy and mechanism of many of these products are not yet well understood. In this study, we tested the antioxidant and anti-inflammatory effects of a supplement, HIPER Health Supplement (HIPER), on cytokine-induced inflammation and oxidative stress in human coronary artery endothelial cells (HCAECs). HIPER is a mixture of French maritime pine bark extract (PBE), honey, aloe vera, and papaya extract. Treatment for 24 hours with HIPER reduced TNF-α-induced reactive oxygen species (ROS) generation that was associated with decreased NADPH oxidase 4 and increased superoxide dismutase-1 expression. HIPER inhibited TNF-α induced monocyte adhesion to HCAECs that was in keeping with decreased expression of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1 and decreased nuclear factor-kappa B (NF-B) activation. Further investigation of mechanism showed HIPER reduced TNF-α induced IBα and p38 and MEK1/2 MAP kinases phosphorylation. Our findings show that HIPER has potent inhibitory effects on HCAECs inflammatory and oxidative stress responses that may protect against endothelial dysfunction that underlies early atherosclerotic lesion formation

Apolipoprotein-AI mimetic peptides D-4F and L-5F decrease hepatic inflammation and increase insulin sensitivity in C57BL/6 mice.

BACKGROUND:Apolipoprotein-AI (apo-AI) is the major apolipoprotein found in high density lipoprotein particles (HDLs). We previously demonstrated that apo-AI injected directly into high-fat diet fed mice improved insulin sensitivity associated with decreased hepatic inflammation. While our data provides compelling proof of concept, apoA-I mimetic peptides are more clinically feasible. The aim of this study was to test whether apo-AI mimetic peptide (D-4F and L-5F) treatment will emulate the effects of full-length apo-AI to improve insulin sensitivity. METHODS:Male C57BL/6 mice were fed a high-fat diet for 16 weeks before receiving D4F mimetic peptide administered via drinking water or L5F mimetic peptide administered by intraperitoneal injection bi-weekly for a total of five weeks. Glucose tolerance and insulin tolerance tests were conducted to assess the effects of the peptides on insulin resistance. Effects of the peptides on inflammation, gluconeogenic enzymes and lipid synthesis were assessed by real-time PCR of key markers involved in the respective pathways. RESULTS:Treatment with apo-AI mimetic peptides D-4F and L-5F showed: (i) improved blood glucose clearance (D-4F 1.40-fold AUC decrease compared to HFD, P<0.05; L-4F 1.17-fold AUC decrease compared to HFD, ns) in the glucose tolerance test; (ii) improved insulin tolerance (D-4F 1.63-fold AUC decrease compared to HFD, P<0.05; L-5F 1.39-fold AUC compared to HFD, P<0.05) in the insulin tolerance test. The metabolic test results were associated with (i) decreased hepatic inflammation of SAA1, IL-1β IFN-γ and TNFα (2.61-5.97-fold decrease compared to HFD, P<0.05) for both mimetics; (ii) suppression of hepatic mRNA expression of gluconeogenesis-associated genes (PEPCK and G6Pase; 1.66-3.01-fold decrease compared to HFD, P<0.001) for both mimetics; (iii) lipogenic-associated genes, (SREBP1c and ChREBP; 2.15-3.31-fold decrease compared to HFD, P<0.001) for both mimetics and; (iv) reduced hepatic macrophage infiltration (F4/80 and CD68; 1.77-2.15-fold compared to HFD, P<0.001) for both mimetics. CONCLUSION:Apo-AI mimetic peptides treatment led to improved glucose homeostasis. This effect is associated with reduced expression of inflammatory markers in the liver and reduced infiltration of macrophages, suggesting an overall suppression of hepatic inflammation. We also showed altered expression of genes associated with gluconeogenesis and lipid synthesis, suggesting that glucose and lipid synthesis is suppressed. These findings suggest that apoA-I mimetic peptides could be a new therapeutic option to reduce hepatic inflammation that contributes to the development of overnutrition-induced insulin resistance

Preferences and Perceived Barriers to Treatment for Depression during the Perinatal Period

Abstract Background and methods: Little is understood about why few women during the perinatal period will use depression treatment. In particular, beliefs and barriers related to depression treatment use have not been studied. In this study, African American and white pregnant women (n = 108) who screened ≥10 on the Edinburgh Postnatal Depression Scale (EPDS) were asked about recent formal and informal treatment use in prenatal care settings. Confidence in the helpfulness of treatment, providers, and settings and perceived barriers to treatment were assessed and compared between African American and white women. Results: Pregnant women overall reported low rates of formal treatment use but frequently sought help from informal sources, such as friends, family, and printed materials. All women expressed greatest confidence in psychosocial treatments and lowest confidence in antidepressants. African American women reported less confidence in advice from family and friends and in antidepressants than did white women. Women expressed greatest confidence in treatments delivered by mental health professionals and religious leaders. African American women sought help more frequently and had significantly more confidence in religious leaders as treatment deliverers than white women. Women had greatest confidence in treatments delivered in professional and home settings, with African American women expressing greater confidence in religious settings than white women. All women reported greatest concern with structural barriers, compared with attitudinal and knowledge barriers. Conclusions: Understanding patterns of treatment use, beliefs, and barriers to depression treatment provides important information for tailoring and improving appropriate use of mental health treatment in women during the perinatal period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63189/1/jwh.2007.0631.pd

Attenuation of proinflammatory responses by S -[6]-Gingerol via inhibition of ROS/NF-Kappa B/COX2 activation in HuH7 cells

Introduction. Hepatic inflammation underlies the pathogenesis of chronic diseases such as insulin resistance and type 2 diabetes mellitus. S-[6]-Gingerol has been shown to have anti-inflammatory properties. Important inflammatory mediators of interleukins include nuclear factor B (NFB) and cyclooxygenase 2 (COX2). We now explore the mechanism of anti-inflammatory effects of S-[6]-gingerol in liver cells. Methods. HuH7 cells were stimulated with IL1β to establish an in vitro hepatic inflammatory model. Results. S-[6]-Gingerol attenuated IL1β-induced inflammation and oxidative stress in HuH7 cells, as evidenced by decreasing mRNA levels of inflammatory factor IL6, IL8, and SAA1, suppression of ROS generation, and increasing mRNA levels of DHCR24. In addition, S-[6]-gingerol reduced IL1β-induced COX2 upregulation as well as NFB activity. Similar to the protective effects of S-[6]-gingerol, both NS-398 (a selective COX2 inhibitor) and PDTC (a selective NFB inhibitor) suppressed mRNA levels of IL6, IL8, and SAA1. Importantly, PDTC attenuated IL1β-induced overexpression of COX2. Of particular note, the protective effect of S-[6]-gingerol against the IL1β-induced inflammatory response was similar to that of BHT, an ROS scavenger. Conclusions. The findings of this study demonstrate that S-[6]-gingerol protects HuH7 cells against IL1β-induced inflammatory insults through inhibition of the ROS/NFB/COX2 pathway. © 2013 Xiao-Hong Li et al

Acoustic emission sensing of pipe-soil interaction: Development of an early warning system for buried pipe deformation

This paper describes a programme of research that aims to develop a continuous, real-time acoustic emission (AE) monitoring system that can be distributed at discrete locations along buried pipelines to sense pipe/soil interaction and provide early warning of adverse behaviour to enable targeted and timely interventions. Pipe/soil interaction-generated AE propagates as guided waves along pipelines. Novel AE interpretation is allowing the evolution of the pipe/soil interaction behaviour to be characterised, and the rate and magnitude of deformation to be quantified. New understanding of AE propagation and attenuation in buried pipes is enabling source localisation methodologies to be developed. Results from normal faulting experiments performed on buried full-scale steel pipes at the buried infrastructure research facility at Queen’s University, Canada, are presented to demonstrate the potential of the AE technique for early detection of buried pipe deformation

Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Comment: Accepted by PLoS Comput Bio

Roosting Habitat Use by Sandhill Cranes and Waterfowl on the North and South Platte Rivers in Nebraska

Migration ecology and habitat use of spring migrating birds using the Central Platte River is a well-explored topic, yet less is known about use of the North and South Platte rivers (NSPR) in western Nebraska. The efficiency and effectiveness of conservation efforts in the NSPR could be greatly improved with access to information about where and when birds roost and landscape prioritization tools. We used aerial surveys to determine population distribution and migration phenology of sandhill cranes Antigone canadensis, Canada geese Branta canadensis, and ducks using the NSPR for roosting during the mid-February to mid-April spring migration. We used these data and geospatial information to identify important river reaches for these species and habitat covariates that discriminate between those used at lower and higher densities. We found that sandhill cranes and waterfowl generally roosted in different segments of the NSPR and, subsequently, different factors were associated with high densities. Sandhill crane density was positively correlated with distance from obstructions greater than 1 m high and negatively correlated with area of unvegetated sandbar within 1 km. Density of Canada geese and ducks was high in segments positively associated with wetland and sand pit habitats. Human disturbance variables such as roads and bridges in this rural region had little effect on identification of roosting areas used by high densities of all groups. On the basis of our results, habitat conservation efforts that specifically target sandhill cranes will not have similar positive effects on waterfowl use and distribution in the NSPR. Our identification of the most important river segments should allow managers to better target land acquisition or management resources to areas that will have the greatest effect on either waterfowl or sandhill cranes during spring migration

High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation

Obesity-induced liver inflammation can drive insulin resistance. HDL has anti-inflammatory properties, so we hypothesized that low levels of HDL would perpetuate inflammatory responses in the liver and that HDL treatment would suppress liver inflammation and insulin resistance. The aim of this study was to investigate the effects of lipid-free apoAI on hepatic inflammation and insulin resistance in mice. We also investigated apoAI as a component of reconstituted HDLs (rHDLs) in hepatocytes to confirm results we observed in vivo. To test our hypothesis, C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks and administered either saline or lipid-free apoAI. Injections of lipid-free apoAI twice a week for 2 or 4 weeks with lipid-free apoAI resulted in: i) improved insulin sensitivity associated with decreased systemic and hepatic inflammation; ii) suppression of hepatic mRNA expression for key transcriptional regulators of lipogenic gene expression; and iii) suppression of nuclear factor κB (NF-κB) activation. Human hepatoma HuH-7 cells exposed to rHDLs showed suppressed TNFα-induced NF-κB activation, correlating with decreased NF-κB target gene expression. We conclude that apoAI suppresses liver inflammation in HFD mice and improves insulin resistance via a mechanism that involves a downregulation of NF-κB activation. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc