High‐density lipoprotein‐associated paraoxonase 1: a possible prognostic biomarker for heart failure?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137330/1/ejhf817_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137330/2/ejhf817.pd

Extracellular matrix contributes to macrophage foam cell formation and atherosclerosis

During early atherogenesis, low density lipoprotein (LDL) induces the accumulation of cholesterol and oxysterols in arterial macrophages, and in the subendothelial accumulation of atherogenic lipoproteins in extracellular matrix (ECM), takes place. Retention of LDL and oxidized LDL (Ox-LDL) to ECM is mediated by the ECM proteoglycans (PGs), which in the presence of Lipoprotein Lipase (LPL, acting as a bridging element), bind the lipoproteins. The structures of the ECM proteoglycans, as well as the lipoproteins binding sites for PGs determine the extent of the interaction between ECM PGs and lipoproteins. Following its retention to the ECM, Ox-LDL is taken up by activated macrophages at enhanced rate, leading to cellular accumulation of cholesterol and oxysterols in arterial wall macrophages. Moreover, LDL oxidation in the arterial wall can also take place after lipoprotein retention to ECM PGs. In this case, retained Ox-LDL can be taken up by macrophage after its release from ECM PGs; but also as a complex of Ox-LDL with ECM PGs. The amount and composition of ECM, produced by all major cells of the arterial wall (monocyte-derived macrophages, endothelial cells and smooth muscle cells), determine the extent of lipoproteins cellular uptake. We have demonstrated that under oxidative stress, ECM PGs secretion from macrophages, binding of Ox-LDL to the ECM and uptake of the retained lipoproteins by macrophages are all significantly increased. Altogether, these processes contribute to macrophage foam cell formation and accelerated atherosclerosis.During early atherogenesis, low density lipoprotein (LDL) induces the accumulation of cholesterol and oxysterols in arterial macrophages, and in the subendothelial accumulation of atherogenic lipoproteins in extracellular matrix (ECM), takes place. Retention of LDL and oxidized LDL (Ox-LDL) to ECM is mediated by the ECM proteoglycans (PGs), which in the presence of Lipoprotein Lipase (LPL, acting as a bridging element), bind the lipoproteins. The structures of the ECM proteoglycans, as well as the lipoproteins binding sites for PGs determine the extent of the interaction between ECM PGs and lipoproteins. Following its retention to the ECM, Ox-LDL is taken up by activated macrophages at enhanced rate, leading to cellular accumulation of cholesterol and oxysterols in arterial wall macrophages. Moreover, LDL oxidation in the arterial wall can also take place after lipoprotein retention to ECM PGs. In this case, retained Ox-LDL can be taken up by macrophage after its release from ECM PGs; but also as a complex of Ox-LDL with ECM PGs. The amount and composition of ECM, produced by all major cells of the arterial wall (monocyte-derived macrophages, endothelial cells and smooth muscle cells), determine the extent of lipoproteins cellular uptake. We have demonstrated that under oxidative stress, ECM PGs secretion from macrophages, binding of Ox-LDL to the ECM and uptake of the retained lipoproteins by macrophages are all significantly increased. Altogether, these processes contribute to macrophage foam cell formation and accelerated atherosclerosis

Pomegranate Protection against Cardiovascular Diseases

The current paper summarizes the antioxidative and antiatherogenic effects of pomegranate polyphenols on serum lipoproteins and on arterial macrophages (two major components of the atherosclerotic lesion), using both in vitro and in vivo humans and mice models. Pomegranate juice and its by-products substantially reduced macrophage cholesterol and oxidized lipids accumulation, and foam cell formation (the hallmark of early atherogenesis), leading to attenuation of atherosclerosis development, and its consequent cardiovascular events

An assessment of financial sector rescue programmes

We analyse the wide array of rescue programmes adopted in several countries, following Lehman Brothers’ default in September 2008, in order to support banks and other financial institutions. We first provide an overview of the programmes, comparing their characteristics, magnitudes and participation rates across countries. We then consider the effects of the programmes on banks’ risk and valuation, looking at the behaviour of CDS premia and stock prices. We then proceed to analyse the issuance of government guaranteed bonds by banks, examining their impact on banks’ funding and highlighting undesired effects and distortions. Finally, we briefly review the recent evolution of bank lending to the private sector. We draw policy implications, in particular as regards the way of mitigating the distortions implied by such programmes and the need for an exit strategy.bank asset guarantees, capital injection, banks, financial sector, financial crisis, bank consolidation, bank mergers and acquisitions, event studies, government guaranteed bonds, credit crunch, exit strategy

Increased Levels of Human Carotid Lesion Linoleic Acid Hydroperoxide in Symptomatic and Asymptomatic Patients Is Inversely Correlated with Serum HDL and Paraoxonase 1 Activity

Human carotid plaque components interact directly with circulating blood elements and thus they might affect each other. We determined plaque paraoxonase1 (PON1) hydrolytic-catalytic activity and compared plaque and blood levels of lipids, HDL, PON1, and HbA1c, as well as plaque-oxidized lipids in symptomatic and asymptomatic patients. Human carotid plaques were obtained from symptomatic and asymptomatic patients undergoing routine endarterectomy, and the lesions were ground and extracted for PON activity and lipid content determinations. Plaque PONs preserved paraoxonase, arylesterase, and lactonase activities. The PON1-specific inhibitor 2-hydroxyquinoline almost completely inhibited paraoxonase and lactonase activities, while only moderately inhibiting arylesterase activity. Oxysterol and triglyceride levels in plaques from symptomatic and asymptomatic patients did not differ significantly, but plaques from symptomatic patients had significantly higher (135%) linoleic acid hydroperoxide (LA-13OOH) levels. Their serum PON1 activity, cholesterol and triglyceride levels did not differ significantly, but symptomatic patients had significantly lower (28%) serum HDL levels and higher (18%) HbA1c levels. Thus LA-13OOH, a major atherogenic plaque element, showed significant negative correlations with serum PON1 activity and HDL levels, and a positive correlation with the prodiabetic atherogenic HbA1c. Plaque PON1 retains its activity and may decrease plaque atherogenicity by reducing specific oxidized lipids (e.g., LA-13OOH). The inverse correlation between plaque LA-13OOH level and serum HDL level and PON1 activity suggests a role for serum HDL and PON1 in LA-13OOH accumulation

A pilot study for a non-invasive system for detection of malignancy in canine subcutaneous and cutaneous masses using machine learning

IntroductionEarly diagnosis of cancer enhances treatment planning and improves prognosis. Many masses presenting to veterinary clinics are difficult to diagnose without using invasive, time-consuming, and costly tests. Our objective was to perform a preliminary proof-of-concept for the HT Vista device, a novel artificial intelligence-based thermal imaging system, developed and designed to differentiate benign from malignant, cutaneous and subcutaneous masses in dogs.MethodsForty-five dogs with a total of 69 masses were recruited. Each mass was clipped and heated by the HT Vista device. The heat emitted by the mass and its adjacent healthy tissue was automatically recorded using a built-in thermal camera. The thermal data from both areas were subsequently analyzed using an Artificial Intelligence algorithm. Cytology and/or biopsy results were later compared to the results obtained from the HT Vista system and used to train the algorithm. Validation was done using a “Leave One Out” cross-validation to determine the algorithm's performance.ResultsThe accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the system were 90%, 93%, 88%, 83%, and 95%, respectively for all masses.ConclusionWe propose that this novel system, with further development, could be used to provide a decision-support tool enabling clinicians to differentiate between benign lesions and those requiring additional diagnostics. Our study also provides a proof-of-concept for ongoing prospective trials for cancer diagnosis using advanced thermodynamics and machine learning procedures in companion dogs

Synergistic Cytotoxicity of Methyl 4-Hydroxycinnamate and Carnosic Acid to Acute Myeloid Leukemia Cells via Calcium-Dependent Apoptosis Induction

Acute myeloid leukemia (AML) is a malignant hematopoietic disease with poor prognosis for most patients. Conventional chemotherapy has been the standard treatment approach for AML in the past 40 years with limited success. Although, several targeted drugs were recently approved, their long-term impact on survival of patients with AML is yet to be determined. Thus, it is still necessary to develop alternative therapeutic approaches for this disease. We have previously shown a marked synergistic anti-leukemic effect of two polyphenols, curcumin (CUR) and carnosic acid (CA), on AML cells in-vitro and in-vivo. In this study, we identified another phenolic compound, methyl 4-hydroxycinnamate (MHC), which among several tested phytochemicals could uniquely cooperate with CA in killing AML cells, but not normal peripheral blood mononuclear cells. Notably, our data revealed striking phenotypical and mechanistic similarities in the apoptotic effects of MHC+CA and CUR+CA on AML cells. Yet, we show that MHC is a non-fluorescent molecule, which is an important technical advantage over CUR that can interfere in various fluorescence-based assays. Collectively, we demonstrated for the first time the antileukemic activity of MHC in combination with another phenolic compound. This type of synergistically acting combinations may represent prototypes for novel antileukemic therapy

HDL Apolipoprotein A-I Attenuates Oxidative Modification of Low Density Lipoprotein: Studies in Transgenic Mice

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