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Chronic kidney disease (CKD) is a complex disease that affects the global population's health, with dyslipidemia being one of its major complications. High density lipoprotein (HDL) is regarded as the "hero" in the bloodstream due to its role in reverse cholesterol transport, which lowers cholesterol levels in the blood and prevents atherosclerosis. However, in the complex internal environment of CKD, even this "hero" may struggle to perform its beneficial functions and could potentially become harmful. This article reviews HDL heterogeneity, HDL subclasses, functional changes in HDL during the progression of CKD, and the application of HDL in CKD treatment. This review aims to deepen understanding of lipid metabolism abnormalities in CKD patients and provide a basis for new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease with inflammation as a critical feature. Recently, high‐density lipoprotein cholesterol (HDLc) have been evidenced to have anti‐inflammatory effects, suggesting a potential link between HDL and SLE that needs to be thoroughly studied. The aim was to explore the association between SLE and HDLc through a systematic review with meta‐analysis. Methods: A systematic review with meta‐analysis was conducted to assess mean differences in HDL levels between patients with SLE and healthy controls. Both qualitative and quantitative syntheses were performed, including an assessment of heterogeneity using I2, a publication bias evaluation, a methodologic quality assessment, and a forest plot under a random effects model. Subgroup analyses were conducted based on disease activity and the report of corticosteroid dosage. Results: A total of 53 studies were included in the qualitative synthesis, and 35 studies were included in the quantitative synthesis, comprising 3,002 patients with SLE and 2,123 healthy controls. Mean HDL levels were found to be lower in patients with SLE as follows: in the meta‐analysis including all articles −6.55 (95% confidence interval [CI] −8.77 to −4.33); in patients with mild disease activity −5.46 (95% CI −8.26 to −2.65); in patients with moderate or severe disease activity −9.42 (95% CI −15.49 to −3.34); in patients using corticosteroids −5.32 (95% CI −10.35 to −0.29); and in studies with excellent methodologic quality −8.71 (95% CI −12.38 to −5.03). Conclusion: HDL levels appear to be quantitatively altered in patients with SLE, suggesting a potential contribution to immune dysregulation, highlighting the importance of HDL in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Low levels of high‐density lipoprotein‐cholesterol (HDL‐C) is considered a major cardiovascular risk factor. However, recent studies have suggested a more U‐shaped association between HDL‐C and cardiovascular disease. It has been shown that the cardioprotective effect of HDL is related to the functions of HDL particles rather than their cholesterol content. HDL particles are highly heterogeneous and have multiple functions relevant to cardiometabolic conditions including cholesterol efflux capacity, anti‐oxidative, anti‐inflammatory, and vasoactive properties. There are quantitative and qualitative changes in HDL as well as functional abnormalities in both type 1 and type 2 diabetes. Non‐enzymatic glycation, carbamylation, oxidative stress, and systemic inflammation can modify the HDL composition and therefore the functions, especially in situations of poor glycemic control. Studies of HDL proteomics and lipidomics have provided further insights into the structure–function relationship of HDL in diabetes. Interestingly, HDL also has a pleiotropic anti‐diabetic effect, improving glycemic control through improvement in insulin sensitivity and β‐cell function. Given the important role of HDL in cardiometabolic health, HDL‐based therapeutics are being developed to enhance HDL functions rather than to increase HDL‐C levels. Among these, recombinant HDL and small synthetic apolipoprotein A‐I mimetic peptides may hold promise for preventing and treating diabetes and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes is a metabolic disease associated with a partial or absolute deficiency of insulin, hyperlipidemia, and impaired metabolism of carbohydrates, fats, and proteins. The present study aimed to compare the effects of different types of exercises on lipid profiles in menopausal women with type 2 diabetes. Methods: Fifty-six sedentary obese menopausal women with type 2 diabetes were randomly divided into 4 groups: aerobic exercise, resistance exercise, combined exercise, and a control group. Each group, except the control group, participated in their respective exercises for 8 weeks. Blood samples were collected from the subjects before and 48 hours after the training period. Data were analyzed using the analysis of variance (ANOVA) and paired sample t tests, with a significance level set at P<0.05. All calculations were performed using SPSS v. 20. Results: Triglyceride levels significantly decreased in the aerobic exercise (P = 0.017) and combined exercise (P = 0.0001) groups. Low-density lipoprotein levels significantly decreased in aerobic exercise (P = 0.034), resistance exercise (P = 0.003), and combined exercise groups (P = 0.009). Cholesterol levels significantly decreased in the aerobic exercise (P = 0.0001), resistance exercise (P = 0.030), and combined exercise (P = 0.01) groups. Additionally, high - density lipoprotein levels significantly increased in the aerobic exercise (P = 0.041) and combined exercise (P = 0.002) groups. Conclusion: It appears that combined exercises, rather than resistance or endurance exercises alone, are a more appropriate intervention for improving lipid profiles in menopausal women with type 2 diabetes. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme which is known to hydrolyse most pesticides including organophosphates (OPs) and prevent atherosclerosis by inhibiting oxidative modification of low-density lipoprotein (LDL). Glyphosate is one of the common organophosphate pesticides used in agriculture in many developing countries including Malaysia. The aim of this study to is to assess the PON1 ability to hydrolyse oxidized LDL in glyphosate exposed farm workers. MATERIALS AND METHODS: In this cross-sectional comparative study, a total of 103 subjects (53 Glyphosate-exposed and 50 non-exposed) were recruited. Fasting serum samples were analysed for PON1 activities towards substrates paraoxon, phenylacetate, and diazoxon, as well as for lipid profiles and oxidized-LDL (ox-LDL). RESULTS: The results showed lower basal paraoxonase activity [156.96 (58.87) vs 177.06 (66.78)], arylesterase activity [90.06 (17.14) vs 96.92 (23.87)] and diazoxonase activity [850.93 (206.75) vs 990.48 (248.73)] in glyphosate-exposed compared to non-exposed, however, only diazoxonase activity was statistically significant (p<0.05). PON1 activity is not significantly different with different length of period of exposure except for arylesterase. There was also significantly higher (p<0.05) ox-LDL in the exposed group but no significant differences in lipid profiles (p>0.05) between the two groups. The PON1 to ox-LDL ratio which probably reflects the ability of PON1 to hydrolyse ox-LDL were also significantly lower (p<0.05) among the glyphosate-exposed group. CONCLUSION: The results suggested that the decreased PON1 activity in glyphosate-exposed individuals could predispose them to the development of atherosclerosis and coronary artery disease through decreased PON1 ability to hydrolyse ox-LDL. [ABSTRACT FROM AUTHOR]

Previous interest in high-density lipoproteins (HDLs) focused on their possible protective role in atherosclerotic cardiovascular disease (ASCVD). Evidence from genetic studies and randomized trials, however, questioned that the inverse association of HDL-cholesterol (HDL-C) is causal. This review aims to provide an update on the role of HDL in health and disease, also beyond ASCVD. Through evolution from invertebrates, HDLs are the principal lipoproteins, while apolipoprotein B-containing lipoproteins first developed in vertebrates. HDLs transport cholesterol and other lipids between different cells like a reusable ferry, but serve many other functions including communication with cells and the inactivation of biohazards like bacterial lipopolysaccharides. These functions are exerted by entire HDL particles or distinct proteins or lipids carried by HDL rather than by its cholesterol cargo measured as HDL-C. Neither does HDL-C measurement reflect the efficiency of reverse cholesterol transport. Recent studies indicate that functional measures of HDL, notably cholesterol efflux capacity, numbers of HDL particles, or distinct HDL proteins are better predictors of ASCVD events than HDL-C. Low HDL-C levels are related observationally, but also genetically, to increased risks of infectious diseases, death during sepsis, diabetes mellitus, and chronic kidney disease. Additional, but only observational, data indicate associations of low HDL-C with various autoimmune diseases, and cancers, as well as all-cause mortality. Conversely, extremely high HDL-C levels are associated with an increased risk of age-related macular degeneration (also genetically), infectious disease, and all-cause mortality. HDL encompasses dynamic multimolecular and multifunctional lipoproteins that likely emerged during evolution to serve several physiological roles and prevent or heal pathologies beyond ASCVD. For any clinical exploitation of HDL, the indirect marker HDL-C must be replaced by direct biomarkers reflecting the causal role of HDL in the respective disease. [ABSTRACT FROM AUTHOR]

Cardiovascular disease-related deaths (one-third of global deaths) can be reduced with a simple screening test for better biomarkers than the current lipid and lipoprotein profiles. We propose using a highly atheroprotective subset of HDL with colocalized PON1 (PON1-HDL) for superior cardiovascular risk assessment. However, direct quantification of HDL proteomic subclasses are complicated by the peroxides/antioxidants associated with HDL interfering with redox reactions in enzymatic calorimetric and electrochemical immunoassays. Hence, we developed an enzyme-free Nanoparticle-Gated Electrokinetic Membrane Sensor (NGEMS) platform for quantification of PON1-HDL in plasma within 60 min, with a sub-picomolar limit of detection, 3–4 log dynamic range and without needing sample pretreatment or individual-sample calibration. Using NGEMS, we report our study on human plasma PON1-HDL as a cardiovascular risk marker with AUC~0.99 significantly outperforming others (AUC~0.6–0.8), including cholesterol/triglycerides tests. Validation for a larger cohort can establish PON1-HDL as a biomarker that can potentially reshape cardiovascular landscape. Measuring proteomic subfractions of HDL can help during cardiovascular risk assessment. Here, the authors show, using a Nanoparticle-Gated Electrokinetic Membrane Sensor, the efficacy of Paroxonase 1 on HDL in its ability to diagnose cardiovascular disease compared to other commonly used methods. [ABSTRACT FROM AUTHOR]

Aims: In heart failure with preserved ejection fraction (HFpEF), the reduction of nitric oxide (NO)‐bioavailability and consequently endothelial dysfunction leads to LV stiffness and diastolic dysfunction of the heart. Besides shear stress, high‐density lipoprotein (HDL) stimulates endothelial cells to increased production of NO via phosphorylation of endothelial nitric oxide synthase (eNOS). For patients with heart failure with reduced ejection fraction, earlier studies demonstrated a positive impact of exercise training (ET) on HDL‐mediated eNOS activation. The study aims to investigate the influence of ET on HDL‐mediated phosphorylation of eNOS in HFpEF patients. Methods and results: The present study is a substudy of the OptimEx‐Clin trial. The patients were randomized to three groups: (i) HIIT (high‐intensity interval training; (ii) MCT (moderate‐intensity continuous training); and (iii) CG (control group). Supervised training at study centres was offered for the first 3 months. From months 4–12, training sessions were continued at home with the same exercise protocol as performed during the in‐hospital phase. Blood was collected at baseline, after 3, and 12 months, and HDL was isolated by ultracentrifugation. Human aortic endothelial cells were incubated with isolated HDL, and HDL‐induced eNOS phosphorylation at Ser1177 and Thr495 was assessed. Subsequently, the antioxidative function of HDL was evaluated by measuring the activity of HDL‐associated paraoxonase‐1 (Pon1) and the concentration of thiobarbituric acid‐reactive substances (TBARS). After 3 months of supervised ET, HIIT resulted in increased HDL‐mediated eNOS‐Ser1177 phosphorylation. This effect diminished after 12 months of ET. No effect of HIIT was observed on HDL‐mediated eNOS‐Thr495 phosphorylation. MCT had no effect on HDL‐mediated eNOS phosphorylation at Ser1177 and Thr495. HIIT also increased Pon1 activity after 12 months of ET and reduced the concentration of TBARS in the serum after 3 and 12 months of ET. A negative correlation was observed between TBARS concentration and HDL‐associated Pon1 activity in the HIIT group (r = −0.61, P < 0.05), and a trend was evident for the correlation between the change in HDL‐mediated eNOS‐Ser1177 phosphorylation and the change in peak V̇O2 after 3 months in the HIIT group (r = 0.635, P = 0.07). Conclusions: The present study documented that HIIT but not MCT exerts beneficial effects on HDL‐mediated eNOS phosphorylation and HDL‐associated Pon1 activity in HFpEF patients. These beneficial effects of HIIT were reduced as soon as the patients switched to home‐based ET. [ABSTRACT FROM AUTHOR]

A scarcity of research assesses the effects of exposure to a combination of chemicals on lipid profiles as well as molecular mechanisms related to dyslipidemia. A cross-sectional study of 3692 adults aims to identify the association between chemical mixtures, including blood and urine 26 chemicals, and lipid profiles among Korean adults (aged ≥ 18) using linear regression models, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). In silico toxicogenomic data-mining, we assessed molecular mechanisms linked with dyslipidemia, including genes, miRNAs, pathways, biological processes, and diseases. In the linear regression models, heavy metals, volatile organic compound metabolites, and phthalate metabolites were found to be related to HDL-C, triglycerides, LDL-C, total lipids, and total cholesterol, and significant trends were observed for these chemical quartiles (p < 0.01). The WQS index was significantly linked with HDL-C, triglycerides, LDL-C, total cholesterol, and total lipids. The qgcomp index also found a significant association between chemicals and HDL-C, triglycerides, and total lipids. In BKMR analysis, the overall effect of the chemical mixture was significantly associated with HDL-C, triglycerides, total cholesterol, and total lipids. We found that mixed chemicals interacted with the PPARA gene and were linked with dyslipidemia. Several pathways ("SREBF and miR33 in cholesterol," "estrogen receptor pathway and lipid homeostasis," and "regulation of PGC-1α"), "negative regulation of hepatocyte apoptotic process," "negative regulation of sequestering of triglycerides," "regulation of hepatocyte apoptotic process," and "negative regulation of cholesterol storage," and "abdominal obesity metabolic syndrome" were identified as key molecular mechanisms that may be affected by mixed chemicals and implicated in the development of dyslipidemia. The highest interaction and expression of miRNAs involved in the process of dyslipidemia were also described. Especially, the cutoff levels for chemical exposure levels related to lipid profiles were also provided. [ABSTRACT FROM AUTHOR]

Background: Paraoxonase-1 (PON1), a glycoprotein associated with serum high-density lipoprotein (HDL), has a central role in metabolizing lipid peroxides, exhibiting antiatherogenic properties. The polymorphism p.Q192R has been previously associated with coronary artery disease (CAD) susceptibility and clopidogrel response. Purpose: We aimed at investigating the association of PON1 p.Q192R with CAD and clopidogrel response in Colombian population. Patients and Methods: The study was conducted among 163 patients diagnosed with CAD and treated with clopidogrel. The allele frequencies for the PON1 192Q and 192R alleles were determined in cases and Latin-American controls obtained from the public database gnomAD (n = 17,711). Response to clopidogrel was determined by assessing the platelet function using the INNOVANCE PFA-200 System. We determined the association between PON1 p.Q192R polymorphism, increased susceptibility to CAD and high on-treatment platelet reactivity (HPR) by using odds ratio (OR) and 95% confidence interval (CI) on four genetic models. Results: The allele frequencies for the PON1 192Q and 192R alleles were 0.60 and 0.40, respectively. The allele distribution was found to be statistically different from the control group and other ethnic groups. The allele 192R was positively associated with decreased susceptibility to CAD under a dominant model (OR, 0.58; 95% CI, 0.42– 0.8; P < 0.01). We found no association between the polymorphism and HPR. Conclusion: We propose that PON1 p.Q192R is a potentially useful marker for CAD susceptibility in the Colombian population and lacks association with HPR under clopidogrel treatment. [ABSTRACT FROM AUTHOR]

Purpose of Review: The term high density lipoproteins (HDL) refers to an eclectic collection of subparticles that play diverse roles in physiology. Here, we define the term "HDL subspecies" and review recent work on their molecular characterization and relation to disease, focusing on cardiovascular disease and diabetes. Recent Findings: The HDL family contains over 200 proteins and nearly 200 lipids that partition into different particles in plasma. Simple subfractionation of HDL based on a particular physicochemical property has not risen to the challenge of revealing the roles of specific particles in disease. However, by targeting minor protein or lipid components, a handful of compositionally defined HDL subspecies have been described and characterized. Summary: By combining targeted particle isolation techniques with the power of large human studies, progress is being made in understanding HDL subspecies functions and implications for disease. However, much work remains before these advancements can be translated into disease mitigation strategies. [ABSTRACT FROM AUTHOR]

Naturally occurring point mutations in apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL), may affect plasma HDL-cholesterol levels and cardiovascular risk. Here, we evaluated the effect of human apoA-I mutations L144R (associated with low HDL-cholesterol), L178P (associated with low HDL-cholesterol and increased cardiovascular risk) and A164S (associated with increased cardiovascular risk and mortality without low HDL-cholesterol) on the structural integrity and functions of lipid-free and lipoprotein-associated apoA-I in an effort to explain the phenotypes of subjects carrying these mutations. All three mutants, in lipid-free form, presented structural and thermodynamic aberrations, with apoA-I[L178P] presenting the greatest thermodynamic destabilization. Additionally, apoA-I[L178P] displayed reduced ABCA1-mediated cholesterol efflux capacity. When in reconstituted HDL (rHDL), apoA-I[L144R] and apoA-I[L178P] were more thermodynamically destabilized compared to wild-type apoA-I, both displayed reduced SR-BI-mediated cholesterol efflux capacity and apoA-I[L144R] showed severe LCAT activation defect. ApoA-I[A164S] was thermodynamically unaffected when in rHDL, but exhibited a series of functional defects. Specifically, it had reduced ABCG1-mediated cholesterol and 7-ketocholesterol efflux capacity, failed to reduce ROS formation in endothelial cells and had reduced capacity to induce endothelial cell migration. Mechanistically, the latter was due to decreased capacity of rHDL-apoA-I[A164S] to activate Akt kinase possibly by interacting with endothelial LOX-1 receptor. The impaired capacity of rHDL-apoA-I[A164S] to preserve endothelial function may be related to the increased cardiovascular risk for this mutation. Overall, our structure–function analysis of L144R, A164S and L178P apoA-I mutants provides insights on how HDL-cholesterol levels and/or atheroprotective properties of apoA-I/HDL are impaired in carriers of these mutations. [ABSTRACT FROM AUTHOR]

High-density lipoproteins (HDLs) represent a family of particle characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver conferring them a cardioprotective function. HDLs also display pleiotropic properties including antioxidant, anti-apoptotic, anti-thrombotic, anti-inflammatory, or anti-infectious functions. Clinical data demonstrate that HDL cholesterol levels decrease rapidly during sepsis and that these low levels are correlated with morbi-mortality. Experimental studies emphasized notable structural and functional modifications of HDL particles in inflammatory states, including sepsis. Finally, HDL infusion in animal models of sepsis improved survival and provided a global endothelial protective effect. These clinical and experimental studies reinforce the potential of HDL therapy in human sepsis. In this review, we will detail the different effects of HDLs that may be relevant under inflammatory conditions and the lipoprotein changes during sepsis and we will discuss the potentiality of HDL therapy in sepsis. [ABSTRACT FROM AUTHOR]

The changes in host lipid metabolism during leprosy have been correlated to fatty acid alterations in serum and with high-density lipoprotein (HDL) dysfunctionality. This is most evident in multibacillary leprosy patients (Mb), who present an accumulation of host lipids in Schwann cells and macrophages. This accumulation in host peripheral tissues should be withdrawn by HDL, but it is unclear why this lipoprotein from Mb patients loses this function. To investigate HDL metabolism changes during the course of leprosy, HDL composition and functionality of Mb, Pb patients (paucibacillary) pre- or post-multidrug therapy (MDT) and HC (healthy controls) were analyzed. Mb pre-MDT patients presented lower levels of HDL-cholesterol compared to HC. Moreover, Ultra Performance Liquid Chromatography-Mass Spectrometry lipidomics of HDL showed an altered lipid profile of Mb pre-MDT compared to HC and Pb patients. In functional tests, HDL from Mb pre-MDT patients showed impaired anti-inflammatory and anti-oxidative stress activities and a lower cholesterol acceptor capacity compared to other groups. Mb pre-MDT showed lower concentrations of ApoA-I (apolipoprotein A-I), the major HDL protein, when compared to HC, with a post-MDT recovery. Changes in ApoA-I expression could also be observed in M. leprae-infected hepatic cells. The presence of bacilli in the liver of a Mb patient, along with cell damage, indicated hepatic involvement during leprosy, which may reflect on ApoA-I expression. Together, altered compositional and functional profiles observed on HDL of Mb patients can explain metabolic and physiological changes observed in Mb leprosy, contributing to a better understanding of its pathogenesis. Author summary: Leprosy is a chronic disease caused by Mycobacterium leprae, which causes lesions on the skin and peripheral nerves. Some patients do not present an efficient immune response and have a disseminated infection (multibacillary, Mb). Mb patients have lipid accumulation in infected tissues that is important for microorganism survival. High-density lipoprotein (HDL) is composed of proteins and lipids and is produced in the liver. It removes excess of lipids from peripheral tissues and presents anti-inflammatory activity; however, these activities are not being properly performed in leprosy. To understand more about HDL metabolism on leprosy, the chemical composition and functionality of HDL from leprosy patients were analyzed before and after treatment with antibiotics (multidrug therapy, MDT). It was observed that HDL has an altered lipid composition in Mb patients before MDT, which may lead to an impairment of its functions. Apolipoprotein A-I (ApoA-I), the main HDL protein, seems to be highly affected during infection. These functions can be slightly recovered after MDT, but not in the levels of healthy individuals. Our data open new perspectives to elucidate the modulation of lipid metabolism in leprosy and consequently to prevent disease complications. [ABSTRACT FROM AUTHOR]

While increased levels of high‐density lipoprotein (HDL)‐cholesterol correlate with protection against cardiovascular disease, recent findings demonstrate that HDL function, rather than HDL‐cholesterol levels, may be a better indicator of cardiovascular risk. One mechanism by which HDL function can be compromised is through modification by reactive aldehydes such as acrolein (Acro), 4‐hydroxynonenal, and malondialdehyde (MDA). In this study, we tested the hypothesis that modification of HDL with reactive aldehydes would impair HDL's athero‐protective functions in macrophages. Compared to native HDL, Acro‐ and MDA‐modified HDL have impaired abilities to promote migration of primary peritoneal macrophages isolated from C57BL6/J mice. Incubation of macrophages with MDA‐HDL also led to an increased ability to generate reactive oxygen species. Our studies revealed that the changes in HDL function following aldehyde modification are likely not through activation of canonical nuclear factor‐kappa B signaling pathways. Consistent with this finding, treatment of either noncholesterol‐loaded macrophages or foam cells with modified forms of HDL does not lead to significant changes in expression levels of inflammatory markers. Importantly, our data also demonstrate that changes in HDL function are dependent on the type of modification present on the HDL particle. Our findings suggest that modification of HDL with reactive aldehydes can impair some, but not all, of HDL's athero‐protective functions in macrophages. [ABSTRACT FROM AUTHOR]

Many population studies have shown that blood concentrations of high‐density lipoprotein (HDL) cholesterol are inversely correlated with risk of cardiovascular disease (CVD). However, in recent studies, increasing blood HDL cholesterol concentrations failed to reduce CVD events. On the other hand, studies suggest that improving HDL quality can be a more efficient tool for assessing atherosclerotic risk than simply measuring blood HDL cholesterol concentration. Thus, improving HDL activity using natural substances might be a useful therapeutic approach to reducing CVD risk. We previously isolated a novel active compound from Nannochloropsis microalgae termed lyso‐diacylglyceryltrimethylhomoserine (lyso‐DGTS), which increased activity of paraoxonase 1, the main antioxidant enzyme associated with HDL. Here we examined the effect of lyso‐DGTS on HDL quality and function. Tryptophan‐fluorescence‐quenching assay showed that lyso‐DGTS interacts spontaneously with the entire HDL lipoprotein and with apolipoprotein A1 (ApoA1), the major structural and functional HDL protein, with high affinity (Ka = 2.17 × 104 M−1 at 37°C). Lyso‐DGTS added to HDL and to ApoA1 increased cholesterol efflux from macrophage cells, the main antiatherogenic function of HDL, dose‐dependently, and significantly increased HDL's ability to induce nitric oxide production from endothelial cells. In‐vivo supplementation of lyso‐DGTS to the circulation of mice fed a high‐fat diet via osmotic mini‐pumps implanted subcutaneously enhanced HDL anti‐inflammatory effect significantly as compared to controls. Our findings suggest that lyso‐DGTS may have a beneficial effect in decreasing atherosclerosis risk by interacting with HDL particles and improving their quality and antiatherogenic functions. [ABSTRACT FROM AUTHOR]

The combination of a lipid-lowering diet and scientifically proven nutritional supplements have the ability to reduce total cholesterol and low-density lipoprotein (LDL) cholesterol significantly; decrease LDL particle number; increase LDL particle size; lower triglycerides, remnant particles, and very low-density lipoprotein; increase total high-density lipoprotein (HDL) cholesterol and HDL particle number; provide beneficial effects on HDL subfractions; and improve HDL functionality. In addition, inflammation, oxidative stress, and abnormal vascular immune responses are decreased as a result of these interventions. In several prospective clinical trials, coronary heart disease and cardiovascular disease have been reduced with optimal nutrition and/or administration of several nutritional supplements, including omega-3 fatty acids, red yeast rice, alpha-linolenic acid, and niacin. A combined program of nutrition and nutritional supplements represents a scientifically valid alternative for patients who are statin intolerant or cannot take other drugs for the treatment of dyslipidemia, or for those who prefer alternative therapies for various other reasons. This new approach to decrease dyslipidemia-induced vascular disease goes beyond the present traditional use of evaluating only serum lipid levels, or even advanced lipid testing with particle number and particle size, to the recognition and treatment of the multiple steps/mechanisms that are involved in the development of atherosclerosis and coronary heart disease. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate (a) the properties of high-density lipoproteins (HDL)/cholesterol, which include apolipoprotein A-1 (ApoA1) and paraoxonase1 (PON1), both are negative predictors of cardiovascular risk and (b) HDL function, among women with preeclampsia (PE). PE is a multi-system disorder, characterized by onset of hypertension and proteinuria or other end-organ dysfunction in the second half of pregnancy. Preeclampsia is associated with increased risk for later cardiovascular disease. The inverse association between HDL, cholesterol levels and the risk of developing atherosclerotic cardiovascular disease is well-established.Methods: Twenty-five pregnant women [19 with PE and 6 with normal pregnancy (NP)] were recruited during admission for delivery. HDL was isolated from blood samples. PON1 activity and HDL were analyzed. An in vitro model of endothelial cells was used to evaluate the effect of HDL on the transcription response of vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase (eNOS) mRNA expression.Results: PON1 activity (units/ml serum) was lower in the PE group compared to normal pregnancy (NP) (6.51 ± 0.73 vs. 9.98 ± 0.54; P = 0.015). Increased ApoA1 was released from PE-HDL as compared to NP-HDL (3.54 ± 0.72 vs. 0.89 ± 0.35; P = 0.01). PE-HDL exhibited increased VCAM-1 mRNA expression and decreased eNOS mRNA expression on TNF-α stimulated endothelial cells as compared to NP-HDL.Conclusions: HDL from women with PE reduced PON1 activity and increased ApoA1 release from HDL particles. This process was associated with increased HDL diameter, suggesting impaired HDL anti-oxidant activity. These changes might contribute to higher long-term cardiovascular risks among women with PE. [ABSTRACT FROM AUTHOR]

Objective: To compare the activity of high‐density lipoprotein (HDL)–associated paraoxonase 1 (PON1) in patients with psoriasis (PsO) and patients with psoriatic arthritis (PsA), and to evaluate the association of PON1 activity with the extent of disease activity and severity of the cardiovascular disease (CVD) burden in these patients. Methods: Serum levels of paraoxonase and arylesterase activity (both measures of PON1 function in humans) were measured in patients with PsA (n = 198, 51.0% male) and patients with PsO (n = 145, 50.3% male) who were enrolled in a longitudinal psoriatic disease biorepository. Data on PsA disease activity (using the Disease Activity Score in 28 joints [DAS28], Clinical Disease Activity Index, and painful/swollen joint counts), preexistent CVD and CVD risk factors (including diabetes, dyslipidemia, hypertension, and smoking), Framingham Risk Scores for CVD, quality of life measures, and laboratory test findings (erythrocyte sedimentation rate, C‐reactive protein level, and lipid profiles) were recorded. Results: Serum arylesterase activities were significantly lower in patients with PsO and patients with PsA (mean ± SD 111.1 ± 25.5 μmoles/minute/ml and 124.4 ± 33.4 μmoles/minute/ml, respectively) compared to healthy controls (144.3 ± 33.4 μmoles/minute/ml) (each P < 0.001 versus healthy controls). Serum arylesterase activity decreased in parallel with increasing levels of disease activity (DAS28 scores, P = 0.012), older age (P = 0.013), higher body mass index (P = 0.042), greater incidence of metabolic syndrome (P = 0.004) and hypertension (P = 0.014), and worsening Framingham Risk Scores (P = 0.001). However, no correlation was seen between serum arylesterase activity and the extent of disease activity or CVD burden in patients with PsO. Serum paraoxonase activity trended lower both in patients with PsO and in patients with PsA (each P = 0.073 versus healthy controls). However, no association was seen between serum paraoxonase activity and the extent of disease activity or CVD burden in either of the patient cohorts. Conclusion: PON1 activity is decreased in psoriatic diseases. In the PsA cohort, decreases in arylesterase activity correlated with increasing severity of joint disease and CVD burden. Arylesterase activity, as compared to paraoxonase activity, appeared to serve as a more sensitive predictor of preexisting CV risk factors in the PsA cohort. However, this correlation was not observed in the PsO population. [ABSTRACT FROM AUTHOR]

This study was aimed to investigate the effect of human PON1 overexpression in mice on cholesterol efflux and reverse cholesterol transport. PON1 overexpression in PON1-Tg mice induced a significant 3-fold (p<0.0001) increase in plasma paraoxonase activity and a significant ~30% (p<0.0001) increase in the capacity of HDL to mediate cholesterol efflux from J774 macrophages compared to wild-type mice. It also caused a significant 4-fold increase (p<0.0001) in the capacity of macrophages to transfer cholesterol to apoA-1, a significant 2-fold (p<0.0003) increase in ABCA1 mRNA and protein expression, and a significant increase in the expression of PPARγ (p<0.0003 and p<0.04, respectively) and LXRα (p<0.0001 and p<0.01, respectively) mRNA and protein compared to macrophages from wild-type mice. Moreover, transfection of J774 macrophages with human PON1 also increased ABCA1, PPARγ and LXRα protein expression and stimulates macrophages cholesterol efflux to apo A1. In vivo measurements showed that the overexpression of PON1 significantly increases the fecal elimination of macrophage-derived cholesterol in PON1-Tg mice. Overall, our results suggested that the overexpression of PON1 in mice may contribute to the regulation of the cholesterol homeostasis by improving the capacity of HDL to mediate cholesterol efflux and by stimulating reverse cholesterol transport. [ABSTRACT FROM AUTHOR]

ABSTRACT Paraoxonase 1 (PON1) is a calcium-dependent esterase synthesized primarily in the liver and secreted into the plasma where it is associated with high-density lipoproteins (HDL). PON1 hydrolyzes and detoxifies some toxic metabolites of organophosphorus compounds (OPs) such as methyl parathion and chlorpyrifos. Thus, PON1 activity and expression levels are important for determining susceptibility against OPs poisoning. Some studies have demonstrated that OPs can modulate gene expression through interactions with nuclear receptors. In this study, we evaluated the effects of methyl parathion and chlorpyrifos on the modulation of PON1 in Human Hepatocellular Carcinoma (HepG2) cells by real-time PCR, PON1 activity assay, and western blot. The results showed that the treatments with methyl parathion and chlorpyrifos decreased PON1 mRNA and immunoreactive protein and increased inflammatory cytokines in HepG2 cells. The effects of methyl parathion and chlorpyrifos on the downregulation of PON1 gene expression in HepG2 cells may provide evidence of OPs cytotoxicity related to oxidative stress and an inflammatory response. A decrease in the expression of the PON1 gene may increase the susceptibility to OPs intoxication and the risk of diseases related to inflammation and oxidative stress. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 490-500, 2017. [ABSTRACT FROM AUTHOR]

The article aims to find clinical relevance of estimating serum paraoxonase1 (PON1) arylesterase and PON1 lactonase activity and its association with cardiovascular complications in patients with type 2 diabetes mellitus. It discusses the association of PON gene with high density lipoprotein (HDL) cholesterol and indicates the development of vascular complications in type 2 DM patients.

Objective Paraoxonase 1 (PON-1) is a high-density lipoprotein (HDL)-associated antioxidant enzyme that plays an important role in HDL-mediated cardioprotection. Although genetic polymorphisms are known to modulate PON-1 activity, its involvement in cardiovascular disease (CVD) in rheumatoid arthritis (RA) is controversial, suggesting that other factors may modulate its function. Since anti-HDL antibodies have been found to be related to an impaired lipid profile and occurrence of CVD in RA, this study was undertaken to examine the associations between PON-1 activity, anti-HDL antibodies, and CVD according to PON1 genetic variants in patients with RA. Methods Serum PON-1 activity, using paraoxon as substrate, and IgG anti-HDL antibodies were quantified in 212 RA patients and 110 healthy controls. The PON1 rs662 genotype (Q>R) was determined with TaqMan probes. An additional group of 13 biologics-naive patients with RA was prospectively followed up for 3 months. Results PON-1 activity was decreased in RA patients compared to healthy controls ( P = 0.005), and an effect of the rs662 genotype was noted in both groups, with Q/Q homozygotes exhibiting the lowest PON-1 activity. The distribution of rs662 genotypes did not differ between RA patients and healthy controls ( P = 0.215). In patients carrying the Q/Q genotype, anti-HDL antibodies were associated with impaired PON-1 activity ( P = 0.010), and levels of anti-HDL antibodies were associated with decreased HDL levels (r = −0.680, P < 0.001) and higher prevalence of cardiovascular events, as determined in univariate and multivariate models. Furthermore, change in anti-HDL antibody levels upon tumor necrosis factor blockade was an independent predictor of improved PON-1 activity (β = −0.369, 95% confidence interval −0.669, −0.069; P = 0.024). Conclusion PON-1 activity is impaired in RA in association with the rs662 genotype and anti-HDL antibodies, the latter being recognized as a pivotal player in the link between rs662 and CVD in patients with RA. [ABSTRACT FROM AUTHOR]

Background: Exposures to ambient particulate matter (PM) are associated with increased morbidity and mortality. PM2.5 (<2.5 µm) and ozone exposures have been shown to associate with carotid intima media thickness in humans. Animal studies support a causal relationship between air pollution and atherosclerosis and identified adverse PM effects on HDL functionality. We aimed to determine whether brief exposures to PM2.5 and/or ozone could induce effects on HDL anti-oxidant and anti-inflammatory capacity in humans. Methods: Subjects were exposed to fine concentrated ambient fine particles (CAP) with PM2.5 targeted at 150 µg/m³, ozone targeted at 240 µg/m³ (120 ppb), PM2.5 plus ozone targeted at similar concentrations, and filtered air (FA) for 2 h, on 4 different occasions, at least two weeks apart, in a randomized, crossover study. Blood was obtained before exposures (baseline), 1 h after and 20 h after exposures. Plasma HDL anti-oxidant/anti-inflammatory capacity and paraoxonase activity were determined. HDL anti-oxidant/anti-inflammatory capacity was assessed by a cell-free fluorescent assay and expressed in units of a HDL oxidant index (HOI). Changes in HOI (ΔHOI) were calculated as the difference in HOI from baseline to 1 h after or 20 h after exposures. Results: There was a trend towards bigger ΔHOI between PM2.5 and FA 1 h after exposures (p = 0.18) but not 20 h after. This trend became significant (p <0.05) when baseline HOI was lower (<1.5 or <2.0), indicating decreased HDL anti-oxidant/anti-inflammatory capacity shortly after the exposures. There were no significant effects of ozone alone or in combination with PM2.5 on the change in HOI at both time points. The change in HOI due to PM2.5 showed a positive trend with particle mass concentration (p = 0.078) and significantly associated with the slope of systolic blood pressure during exposures (p = 0.005). Conclusions: Brief exposures to concentrated PM2.5 elicited swift effects on HDL anti-oxidant/anti-inflammatory functionality, which could indicate a potential mechanism for how particulate air pollution induces harmful cardiovascular effects. [ABSTRACT FROM AUTHOR]

Paraoxonase 1 (PON1) is an enzyme responsible for the antioxidant properties of high density lipoprotein (HDL). The activity of PON1 is decreased in patients with coronary artery disease, myocardial infarction or chronic kidney disease. rs662 and rs854560 are single nucleotide polymorphisms (SNPs) associated with PON1 activity and 10-year cardiovascular mortality of patients with stable coronary artery disease. We investigated the association of rs662 and rs854560 SNPs of the PON1 gene with 5-year mortality in patients with ST-elevation myocardial infarction (STEMI) treated invasively. We analyzed the data of consecutive patients with STEMI treated with primary PCI. Genotyping was performed with the TaqMan method. The analyzed end-point was total 5-year mortality. Additional subgroup analysis was performed for survival of patients depending on their eGFR. The study group comprised 634 patients (mean age 62.3 ± 11.85 years; 25.2 % of women, n = 160; PCI successful in 92.3 %, n = 585). No clinically relevant differences in baseline characteristics were found between the genotypes. No association between either genotype and 5-year mortality was found: p = 0.4 for the rs662 SNP, p = 0.73 for the rs854560 one (log-rank test). However, in a subgroup of patients with eGFR below median value (78.6 ml/min/1.73m2) the rs854560 AA homozygotes had a significantly lower probability of survival ( p = 0.047, log-rank test). The AA genotype of the rs854560 SNPs of the PON1 gene is associated with increased mortality in patients after myocardial infarction in the subpopulation of patients with lowered eGFR. This phenomenon may be explained by potentially lower PON1 activity in kidney disease. [ABSTRACT FROM AUTHOR]

Small non-coding microRNAs (miRNAs) are implicated in gene regulation, including those involved in coronary artery disease (CAD). Our aim was to identify whether specific serum miRNAs present in the circulating lipoproteins (Lp) are associated with stable or vulnerable CAD patients. A cardiovascular disease-focused screening array was used to assess miRNAs distribution in sera collected from 95 CAD patients: 30 with stable angina (SA), 39 with unstable angina (UA), 26 at one month after myocardial infarction (MI) and 16 healthy control subjects. We found that miR-486, miR-92a and miR-122 presented the highest expression in CAD sera. These miRNA together with miR-125a, miR-146a and miR-33a were further individually analyzed by TaqMan assays. The results were consistent with PCR-array screening data that all of these miRNAs were significantly increased in CAD patients compared to controls. Using a binary logistic regression model, we established that miR-486 and miR-92a in association with some high-density lipoprotein (HDL) components can designate vulnerable CAD patients. Further, all classes of Lp were isolated from sera by density gradient ultracentrifugation. Analysis of the selected miRNAs in each Lp class showed that they were associated mainly with HDL, miR-486 and miR-92a having the highest levels. In UA and MI patients, miR-486 prevailed in HDL2, while miR-92a prevailed in HDL3, and their levels discriminate between stable and vulnerable CAD patients. We identified two circulating miRNAs that in association with some lipid metabolism biomarkers can be used as an additional tool to designate vulnerable CAD patients. [ABSTRACT FROM AUTHOR]

Background: The study aimed to evaluate the relationship of paraoxonase 2 ( PON2) gene Cys311Ser variants with blood pressure values, endothelial/hemostatic marker levels, and other laboratory parameters in asymptomatic dyslipidemic subjects. The same analyses were also performed with the common variants of PON2 Cys311Ser and -T1131C apolipoprotein A5 ( ApoA5) polymorphisms, and PON2 Cys311Ser and apolipoprotein E ( ApoE) polymorphisms. Methods: Two hundred and sixty-four individuals were included in the study. The laboratory parameters were assessed by routine kit methods, while methods based on polymerase chain reaction were used for PON2, ApoA5, and ApoE genotyping. Results: PON2 311 SS homozygous individuals had significantly lower systolic blood pressure values (SBP, p<0.01), C-reactive protein, and apolipoprotein A1 levels (p<0.05), as compared with C allele carriers. The analysis revealed no differences in the levels of endothelial/hemostatic markers, except for the increased adhesion molecule [soluble vascular cell adhesion molecule 1 (sVCAM-1)] concentrations in 311S/E2 carriers (p<0.05). PON2 311S subjects showed the lowest values of SBP in combination with 'neutral' ApoE3 allele (p<0.05). Conclusions: The presence of the PON2 311 C variant could represent an elevated risk of atherosclerotic complications in asymptomatic dyslipidemic individuals. Nevertheless, considering the study limitations, these relationships are necessary to be confirmed in further research. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is associated with oxidative damage of low density lipoproteins (ox-LDL). In order to investigate whether higher levels of ox-LDL are related to alterations of the activity of enzymes involved in lipid metabolism, we studied the activity of paraoxonase-1 (PON1) and platelet activating factor acetylhydrolase (PAF-AH) in AD patients and the relationship between biochemical markers and severity of the disease. Levels of ox-LDL, PON1 (paraoxonase, arylesterase, and lactonase activities), and PAF-AH activity were evaluated in plasma from 49 patients affected by AD and from 34 control subjects matched for gender and age. Our results demonstrated alterations in the activities of PON1 and PAF-AH in AD patients compared to controls and showed, for the first time, a relationship between the activities of these enzymes, ox-LDL levels, and severity of the disease. A significant negative correlation was observed between the ratio PON1/PAF-AH and ox-LDL. Whatever the causes that contribute to a systemic oxidative stress in AD, our results have shown that AD patients exhibit higher PAF-AH activity than control subjects and higher ox-LDL. This phenomenon, in combination with diminished PON1 in these patients and, consequently, the relatively lower ratio PON1/PAF-AH activity, could contribute to inflammation and oxidative stress of plasma lipoproteins. [ABSTRACT FROM AUTHOR]

Background Although cholesterol levels are known to be decreased in sickle cell disease (SCD), the level of pro-inflammatory high-density lipoprotein cholesterol (proHDL) and its association with clinical complications and laboratory variables has not been evaluated. Design and methods Plasma levels of total cholesterol, high-density lipoprotein cholesterol (HDL), proHDL, and selected clinical and laboratory variables were ascertained in a cohort of SCD patients and healthy African American control subjects in this single-center, cross-sectional study. Results Although total cholesterol was significantly lower in SCD patients compared with control subjects, HDL and proHDL levels were similar in both the SCD and control groups. In univariate analyses, proHDL was correlated with echocardiography-derived tricuspid regurgitant jet velocity. ProHDL was higher in SCD patients with suspected pulmonary hypertension (PHT) compared to patients without suspected PHT. ProHDL was positively correlated with lactate dehydrogenase, total bilirubin, direct bilirubin, indirect bilirubin, prothrombin fragment 1+2, D-dimer, and thrombin–antithrombin complexes. In multivariable analyses, only higher lactate dehydrogenase and direct bilirubin levels were associated with higher levels of proHDL. Conclusions SCD is characterized by hypocholesterolemia. Although proHDL is not increased in SCD patients compared with healthy controls, it is significantly associated with markers of liver disease. In addition, proHDL is associated with tricuspid regurgitant jet velocity and markers of coagulation, although these associations are not significant in multivariable analyses. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a state of augmented oxidative stress and diminished antioxidant capacity. High density lipoprotein (HDL) particles were shown to possess antioxidant and anti-inflammatory properties, as well as Paraoxonase 1 (PON1), which is an enzyme that is also protective against HDL oxidation. Previous studies suggested a possible role of decreased PON1 activity or HDL levels in sepsis patients. Aims: The present study was designed to test a hypothesis that higher PON1 activity and HDL-cholesterol levels could predict a better survival in sepsis patients. Study Design: Observational study. Methods: Venous blood samples were collected from sepsis patients for HDL-cholesterol levels, PON1 activity and cytokine assays (TNF-α and IL-6) and Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores were calculated in order to weight patients' disease severity on the day of sepsis diagnosis. Patients were followed-up until the 28th day for any cause intra-hospital mortality. Data were statistically analyzed for effects of study parameters on patients' survival. Results: In total, 85 patients with sepsis were included in the study. The mean age was 65.2±17.9 years and 48 were male; at the end of the 28-day follow-up period, 46 survived. TNF-α (86.9±10.5 vs 118.6Ü6.4) and IL-6 levels (906.7±82.7 vs 1323.Ü54.3) were significantly higher in non-survivors, while PON1 activity (140.7±42.3 vs 66.7±46.6) and HDL-cholesterol levels (43.6±8.1 vs 34.5±8.9) were significantly higher in survivors (p<0.001 for all). TNF-α (r=-0.763) and IL-6 levels (r=-0.947) showed strong negative correlations, PON1 activity (r=0.644) and HDL-cholesterol levels (r=0.477) showed positive correlations with patient survival (p<0.001 for all). Survival estimates significantly favored TNF-α (Log Rank 59.5, p<0.001) and IL-6 levels (Log Rank 53.2, p<0.001) according to PON1 activity (Log Rank 5.4, p<0.03) and HDL-cholesterol levels (Log Rank 8.3, p<0.005). Regression analyses for relative contributions of parameters to survival showed that higher IL-6 levels (t:-16.489, p<0.001) were the most significant negative factor for survival, and TNF-α levels (t:-4.417, p<0.001), whereas PON1 activity had a positive effect (t:3.210, p<0.003). Conclusion: The present study showed that although low PON1 activity and HDL-cholesterol levels were related to mortality, higher levels were not found to be as predictive as cytokine levels for survival. [ABSTRACT FROM AUTHOR]

In our in vitro study, we analyzed the effects of incubation of J774A.1 macrophages with reduced glutathione (GSH) and quercetin on the extent of cellular cholesterol efflux by high-density lipoprotein (HDL) or apolipoprotein A1 (apoA1). This combination was the most potent one among other exogenous and endogenous antioxidant combinations, since it significantly increased the extent of HDL-mediated cholesterol efflux from macrophages by 47% versus control cells, whereas quercetin (20 μM) or GSH (200 μM) alone increased it by only 37% or 17%, respectively. Similarly, apoA1-mediated cholesterol efflux was increased by 11% or 22% in quercetin or quercetin + GSH-treated cells, respectively, versus control cells. These stimulatory effects were noted only after 20 h of cell incubation. The combination of quercetin + GSH demonstrated high scavenging capacity of free radicals versus quercetin or GSH alone. In addition, quercetin + GSH significantly decreased macrophage oxidative stress as measured by the scavenging capacity of free radicals in the cells, the formation of reactive oxygen species, and the levels of cellular glutathione and lipid peroxides. There was no significant effect of quercetin + GSH on cellular HDL binding, on ATP-binding cassette A1 (ABCA1) activity, or on ABCG1 messenger RNA (mRNA) levels. In contrast, mRNA levels for ABCA1 and peroxisome proliferator-activated receptor alpha (PPARα) were both significantly increased by 89% and 93%, respectively, in quercetin + GSH-treated cells versus control cells. Quercetin alone increased the mRNA levels for ABCA1 or PPARα by 42% or 77%, respectively, whereas GSH alone increased it by 22% or 28%, respectively. Mass spectra analysis revealed that oxidized quercetin reacts with GSH to form a new adduct product. We thus conclude that the stimulatory effects of quercetin + GSH on apoA1- or HDL-mediated macrophage cholesterol efflux are related to the ability of GSH to preserve quercetin in its reduced form. [ABSTRACT FROM AUTHOR]

Restenosis is an integral pathological process central to the recurrent vessel narrowing after interventional procedures. Although the mechanisms for restenosis are diverse in different pathological conditions, endothelial dysfunction, inflammation, vascular smooth muscle cell (SMC) proliferation, and myofibroblasts transition have been thought to play crucial role in the development of restenosis. Indeed, there is an inverse relationship between high-density lipoprotein (HDL) levels and risk for coronary heart disease (CHD). However, relatively studies on the direct assessment of HDL effect on restenosis are limited. In addition to involvement in the cholesterol reverse transport, many vascular protective effects of HDL, including protection of endothelium, antiinflammation, antithrombus actions, inhibition of SMC proliferation, and regulation by adventitial effects may contribute to the inhibition of restenosis, though the exact relationships between HDL and restenosis remain to be elucidated. This review summarizes the vascular protective effects of HDL, emphasizing the potential role of HDL in intimal hyperplasia and vascular remodeling, which may provide novel prophylactic and therapeutic strategies for antirestenosis. [ABSTRACT FROM AUTHOR]

The article presents a study on the effects of dietary components on high-density lipoprotein cholesterol (HDL-C)-related measures using data from a carotid artery disease-case-control cohort. In the research, the subjects answered the Harvard Standardized Food Frequency Questionnaire to assess their daily micronutrient intake. Also mentioned are the use of the stepwise linear regression to analyze the effects of dietary covariates like dietary folates, alcohol, and myristic acid.

Introduction: Paraoxonase 1 (PON1) is an antioxidative enzyme manly associated with high density lipoproteins (HDL) in the peripheral blood. The aim of this study was to determine the PON1 paraoxonase and arylesterase activities in patients with chronic obstructive pulmonary disease (COPD). We also aimed to determine the concentration of reduced thiol groups as a marker of protein oxidation. Materials and methods: The study included 105 patients with stable COPD and 44 healthy controls. PON1 activities and thiols concentration were assayed in sera by spectrophotometry. Results: PON1 basal (POX) and salt-stimulated paraoxonase activity (POX1) as well as arylesterase activity (ARE) were significantly reduced in COPD patients. In addition, concentration of reduced thiol groups was significantly decreased in COPD group. PON1 activities were similar in patients with different disease severity (GOLD stages). However, a significant reduction in POX, POX1 and ARE was observed already in GOLD II stage when compared to controls. POX and POX1 showed modest while ARE yielded very good power for discrimination between healthy subjects and COPD patients. Univariate and multivariate logistic regression analysis indicated that ARE is a good COPD predictor. Conclusion: Reduction of PON1 activity observed in COPD patients could be partly caused by oxidative environment. Lower concentrations of reduced thiol groups in COPD patients suggest that a decrease in PON1 activity could reflect oxidative changes of enzyme free cysteine residues. Furthermore, decreased PON1 arylesterase activity might indicate a down-regulation of PON1 concentration. Our results suggest that ARE could be considered as potential biomarker for COPD diagnosis. [ABSTRACT FROM AUTHOR]

Alteration of endothelial cell functions, including reduced endothelial nitric oxide (NO) availability, increased endothelial cell apoptosis, adhesion molecule/chemokine expression and pro-thrombotic activation are thought to contribute to the pathophysiology of atherosclerosis and coronary-artery-disease (CAD) with its clinical complications, such as acute coronary syndromes. High-density lipoproteins (HDL) from healthy subjects or reconstituted HDL have been observed to exert potential direct anti-atherogenic effects by modulating these endothelial cell functions. Importantly, endothelial effects of HDL have now been reported to be highly heterogeneous, and are modulated as part of immune responses. More recently, this has also been observed for HDL of patients with CAD, where HDL becomes potentially pro-inflammatory and endothelial-protective properties are markedly altered. Several mechanisms may lead to these altered endothelial effects of HDL in patients with CAD, including oxidative modification of HDL-associated lipids and proteins, such as apoA-I and paraoxonase-1, and alterations of HDL-proteome. These findings have to be considered with respect to interpretation of recent clinical studies failing to demonstrate reduced cardiovascular events by HDL-cholesterol raising strategies in patients with CAD. Both clinical and genetic studies suggest that HDL-cholesterol levels alone are not a sufficient therapeutic target in patients with CAD. The focus of this review is to summarize the role of HDL onto endothelial homeostasis and to describe recently characterized molecular pathways involved. We highlight how structural and functional modifications of HDL particles in patients with CAD may perturb the physiological homeostasis and lead to a loss of endothelial-protective properties of HDL in patients with CAD. [ABSTRACT FROM AUTHOR]

Epidemiological, clinical, and experimental evidence has accumulated during the last decades suggesting that high-density lipoproteins (HDLs) may protect from atherosclerosis and its clinical consequences. However, more than 55 years after the first description of the link between HDL and heart attacks, many facets of the biochemistry, function, and clinical significance of HDL remain enigmatic. This applies particularly to the completely unexpected results that became available from some recent clinical trials of nicotinic acid and of inhibitors of cholesteryl ester transfer protein (CETP). The concept that raising HDL cholesterol by pharmacological means would decrease the risk of vascular disease has therefore been challenged. [ABSTRACT FROM AUTHOR]

Intermittent parathyroid hormone (PTH) administration has a potent ability to increase bone mass, regardless of underlying conditions or species. A recent study using LDLR mice showed that the anabolic effect of PTH was blunted by hyperlipidemia, whereas PTH anabolism was rescued by enhancement of high-density lipoprotein cholesterol (HDL-C) function. We conducted a retrospective longitudinal study to determine whether lipid profiles also affect the anabolic effect of intermittent PTH treatment in humans. Fifty-two patients (8 males and 44 females, ages 38-85 years) with severe osteoporosis who had been treated with teriparatide (TPTD, recombinant human PTH(1-34) for 12 months were studied at Severance Hospital, Yonsei University. C-telopeptide (CTX) and osteocalcin (OCN) were measured at 0, 3, and 12 months; and total cholesterol, triglycerides, and HDL-C were measured at baseline. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at 0 and 12 months. Lumbar spine BMD increased significantly after 12 months of treatment with TPTD (10.0 ± 9.3 %, p < 0.001). Initial 3-month changes in CTX and OCN levels revealed positive correlations with the increase in lumbar BMD ( r = 0.546, p = 0.001 and r = 0.500, p = 0.006, respectively). Moreover, percentage change in lumbar BMD at 12 months showed a negative correlation with baseline total cholesterol ( r = −0.438, p = 0.009) and a positive correlation with HDL-C ( r = 0.498, p = 0.016). A smaller 3-month increase in OCN and a lower HDL-C level at baseline were associated with a smaller lumbar BMD increase after TPTD treatment, even after adjustment for age, sex, and other confounding factors ( β = 0.462, p = 0.031 for ΔOCN and β = 0.670, p = 0.004 for HDL-C). Plasma levels of lipids, especially HDL-C, seem to be associated with the extent of osteoanabolic effects of TPTD in humans. [ABSTRACT FROM AUTHOR]

Background: Paraoxonase 1 (PON1) is a protein found associated with high density lipoprotein (HDL), thought to prevent oxidative modification of low-density lipoprotein (LDL). This enzyme has been implicated in lowering the risk of cardiovascular disease. Anoxia-reoxygenation and oxidative stress are important elements in cardiovascular and cerebrovascular disease. However, the role of PON1 in anoxia-reoxygenation or anoxic injury is unclear. We hypothesize that PON1 prevents anoxia-reoxygenation injury. We set out to determine whether PON1 expression in Drosophila melanogaster protects against anoxia-reoxygenation (A-R) induced injury. Methods: Wild type (WT) and transgenic PON1 flies were exposed to anoxia (100% Nitrogen) for different time intervals (from 1 to 24 hours). After the anoxic period, flies were placed in room air for reoxygenation. Activity and survival of flies was then recorded. Results: Within 5 minutes of anoxia, all flies fell into a stupor state. After reoxygenation, survivor flies resumed activity with some delay. Interestingly, transgenic flies recovered from stupor later than WT. PON1 transgenic flies had a significant survival advantage after A-R stress compared with WT. The protection conferred by PON1 expression was present regardless of the age or dietary restriction. Furthermore, PON1 expression exclusively in CNS conferred protection. Conclusion: Our results support the hypothesis that PON1 has a protective role in anoxia-reoxygenation injury, and its expression in the CNS is sufficient and necessary to provide a 100% survival protection. [ABSTRACT FROM AUTHOR]

Serum paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-bound mammalian enzyme exhibiting antiatherosclerotic activity. Despite years of research, an accurate model for the binding interaction between PON1 and HDL has not been established. However, it is reported that anchoring of PON1 to HDL is mainly governed by an N-terminal alpha helix H1 and another short helix H2. Here, we studied the molecular association of full-length human PON1 (huPON1) with a HDL-mimetic dipalmitoylphosphatidylcholine (DPPC) bilayer using homology modeling and molecular dynamics simulations. Our results indicate that H1 is the highly dynamic part of huPON1, showing clockwise rotation of up to 30° within the DPPC bilayer. However, without phospholipid molecules, H1 experiences helical distortions, illustrating an incompatible HDL-anchoring conformation. Snorkeling interactions of K3, R18, and R27 together with aromatic locks formed by Y187, Y190, W194, and W202 are highly essential for anchoring of huPON1 to HDL's surface. Molecular mechanics/Poisson-Boltzmann solvent-accessible surface area (MM/PBSA) binding free energy calculation revealed that H1 displays greater binding affinity towards lipid molecules compared with H2 and H3, suggesting that H1 is the most probable HDL-binding domain of PON1. Binding free energy decomposition showed that K3, R18, and R27 interact with polar headgroups of DPPC membrane through electrostatic interaction. Moreover, Y187, Y190, W194, and W202 interact with DPPC lipids mainly through van der Waals interaction. Taken together, these results show that the transmembrane helix H1 along with the interfacial positively charged and aromatic resides were crucial for PON1's association with HDL particle. The current study will be useful towards understanding the antiatherosclerotic and bioscavenging properties of this promiscuous enzyme. [ABSTRACT FROM AUTHOR]

Paraoxonase 1 (PON1) is associated with HDL and modulates the antioxidant and anti-inflammatory role of HDL. The goals of the present study were to investigate the effect of ageing and the role of PON1 on the anti-inflammatory activity of HDL, and to determine whether extra-virgin olive oil (EVOO) consumption could improve the atheroprotective activity of HDL. HDL and PON1 were isolated from the plasma of ten young (Y-HDL and Y-PON1) and ten elderly (E-HDL and E-PON1) healthy volunteers before and after 12 weeks of EVOO consumption. Inflammation was assessed by measuring intracellular adhesion molecule 1 (ICAM-1) expression. THP-1 (human acute monocytic leukaemia cell line) monocyte chemotaxis was measured using a Boyden chamber. Oxidative damage to HDL was assessed by measuring conjugated diene formation and changes in electrophoretic migration. Y-HDL had more anti-inflammatory activity than E-HDL. The conjugated diene content and the electrophoretic mobility of E-HDL were higher than those of Y-HDL. Y-PON1 had significant anti-inflammatory activity, reducing ICAM-1 expression by 32·64 (sd 2·63) %, while E-PON1 had no significant effect. THP-1 chemotaxis measurements confirmed the ICAM-1 expression results. The 12 weeks of EVOO consumption significantly increased the anti-inflammatory activities of both HDL and PON1. The anti-inflammatory activity of HDL was modulated by PON1 and was lower in the elderly volunteers. EVOO consumption increased the anti-inflammatory effect of HDL and reduced the age-related decrease in anti-atherogenic activity. [ABSTRACT FROM PUBLISHER]

Aims The aim of the present study was to evaluate the high-density lipoprotein (HDL) structure and endothelial NO synthase (eNOS) activation capacity in ST-elevation myocardial infarction (STEMI) patients with different acute-phase inflammatory response (APR). Methods and results Forty-five STEMI patients were stratified in quartiles according to the delta CRP level, calculated by subtracting the CRP value at admission from the CRP peak value (APR peak). The HDL structure and HDL capacity to stimulate NO production were evaluated at admission and at APR peak. STEMI patients with a low APR had a completely preserved HDL structure and HDL ability to activate eNOS and promote NO production, which did not change during STEMI. On the contrary, HDL from STEMI patients developing a significant APR had compromised ability to stimulate eNOS and promote NO production, and underwent a significant particle remodelling during STEMI. The defective capacity to stimulate NO production of HDL isolated from STEMI patients with high APR was explained, at least in part, by the reduced PON-1 and S1P content. The HDL ability to promote cell cholesterol efflux through different pathways was preserved in ACS patients independently of the inflammatory response. Conclusion The present results extend previous studies reporting an impaired eNOS-activating capacity of HDL from ACS patients, showing that only a subset of patients undergoing STEMI, and in particular those developing an important inflammatory response, have circulating HDL defective in stimulating endothelial eNOS and NO production. [ABSTRACT FROM AUTHOR]

High density lipoproteins (HDLs) have a number of properties that have the potential to inhibit the development of atherosclerosis and thus reduce the risk of having a cardiovascular event. These protective effects of HDLs may be reduced in patients with type 2 diabetes, a condition in which the concentration of HDL cholesterol is frequently low. In addition to their potential cardio-protective properties, HDLs also increase the uptake of glucose by skeletal muscle and stimulate the synthesis and secretion of insulin from pancreatic ß cells and may thus have a beneficial effect on glycemic control. This raises the possibility that a low HDL concentration in type 2 diabetes may contribute to a worsening of diabetic control. Thus, there is a double case for targeting HDLs in patients with type 2 diabetes: to reduce cardiovascular risk and also to improve glycemic control. Approaches to raising HDL levels include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. There is an ongoing search for HDL-raising drugs as agents to use in patients with type 2 diabetes in whom the HDL level remains low despite lifestyle interventions. [ABSTRACT FROM AUTHOR]

Background: Paraoxonase 1 activity shows a decline in patients with coronary artery disease. The C to T change in the -107 position of promoter is the most important genetic determinant of serum levels of paraoxonase 1. Study of this polymorphism and its relationship with the type of fatty acid composition of phospholipids in HDL particles can be found in the common pursuit of better medicines and considered in drug treatment Materials and Methods: In this descriptive study, 265 patients were selected and divided into two groups based on LDL level (131 in case and 134 in control groups). Lipid profile and paraoxanase 1 activity were measured by commercial kits and spectrophotometry method, respectively. Molecular studies were performed by PCR-RFLP after DNA extraction. Fatty acids of HDL phospholipids were measured by gas chromatography technic. Results: PON1aryl esterase activity had no significant changes after treatment with lovastatin but paraoxonase activity had more significant increases in the CC genitype of -C/T107 polymorphism. Oleic acid, linoleic acid, and icosapentanioc acid percents in HDL phospholipids were increased by lovastatin. Conclusion: Treatment with lovastatin in the CC genotype has probably a more protective effect against cardiovascular diseases. Following treatment, in patients with higher paraoxanase 1 activity, oleic acid and linoleic acid increased in HDL phospholipids. [ABSTRACT FROM AUTHOR]

Some enzymes are known to be drug target inhibitions of which can be critical for organisms. PON has a critical role to prevent atherogenesis by inhibiting lipid peroxidation. It is well known that paraoxonase 1 (PON1) plays an important function on high-density lipoprotein (HDL) structure to prevent lipid oxidation not only of low-density lipoprotein, but also of HDL itself. We investigated in vitro effects of some medical drugs on PON1 activity from human serum. Ki constants for oxytetracycline hydrochloride, netilmycin sulfate, lincomycin hydrochloride, clindamycin phosphate, and streptomycin sulfate were found as 0.2, 3.73, 18.30, 35.80, and 56.30 mM, respectively. Our results indicate that these commonly used drugs inhibit the activity of the enzyme at very low doses with different inhibition mechanisms. [ABSTRACT FROM AUTHOR]

High-density lipoproteins ( HDLs) represent a family of particles characterized by the presence of apolipoprotein A- I (apo A- I) and by their ability to transport cholesterol from peripheral tissues back to the liver. In addition to this function, HDLs display pleiotropic effects including antioxidant, anti-apoptotic, anti-inflammatory, anti-thrombotic or anti-proteolytic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide is also a hallmark of HDL action on endothelial cells. Endothelial cells express receptors for apo A- I and HDLs that mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects of HDLs on the endothelium in normal and pathological conditions with a particular focus on the potential use of HDL therapy to restore endothelial function and integrity. [ABSTRACT FROM AUTHOR]

Human serum paraoxonase 1 (PON1) is an enzyme with esterase activity, and is physically bound to high-density lipoproteins (HDL). It plays a key role in the action of HDL toward protection of lipoprotein and biological membrane against oxidative damage. It may have a protective role against atherosclerosis by virtue of its action on hydrolyzing lipid peroxides and preventing accumulation of phospholipids in oxidized low-density lipoprotein (LDL). PON1 is hypothesized to be an indicator of the risk of atherosclerosis and coronary artery disease development. Numerous studies have implicated PON1 activity in relation to various endocrine disorders. The current article reviews the clinical perspectives of PON1 activity with regards to obesity, diabetes mellitus with its complications, and dyslipidemia. [ABSTRACT FROM AUTHOR]

Background: Growth hormone deficiency (GHD) is associated with an increased cardiovascular mortality. Increased oxidative stress has been associated with development of cardiovascular and cerebrovascular diseases. In the present study, we aimed to evaluate oxidant and antioxidant status in patients with GHD by analyzing serum paraoxonase1 (PON1) activity, and malondialdehyde (MDA) and thiol levels. Materials and Methods: This study was a case-control study. Thirty patients with GHD were included in the study and compared with 20 healthy controls. Serum PON1 activity, and MDA and thiol levels were measured according to an enzymatic spectrophotometric method. Results: Serum MDA levels (2.8 ± 1.3 nmol/mL) were higher in GHD group than the controls (1.7 ± 0.5 nmol/mL) (P = 0.001). PON1 activity (149.9 ± 77.9 U/L) was lower in GHD group than the controls (286.3 ± 126.7 U/L) (P = 0.001). Thiol and high-density lipoprotein cholesterol (HDL-cholesterol) levels were lower in GHD group (218.6 ± 103.9 μmol/L and 32.6 ± 13.4 mg/dL, respectively) than the controls (289.6 ± 101.1 μmol/L and 54.3 ± 14.9 mg/dL, respectively) (P = 0.021 and P = 0.001, respectively). In GHD patients, serum MDA level was negatively correlated with serum HDL-cholesterol (r = -0.499, P = 0.001), and serum PON1 activity was positively correlated with serum thiol and HDL-cholesterol levels (r = 0.306, P = 0.032 and r = 0.303, P = 0.033, respectively). Conclusion: These data support that GHD is characterized by an imbalance between oxidant and antioxidant factors. This abnormality may contribute to the increased atherogenic risk in patients with GHD. [ABSTRACT FROM AUTHOR]

Paraoxonase 1 (PON1), a component of high-density lipoprotein (HDL), is a calcium-dependent multifunctional enzyme that connects metabolisms of lipoproteins and homocysteine (Hcy). Both PON1 and Hcy have been implicated in human diseases, including atherosclerosis and neurodegeneration. The involvement of Hcy in disease could be mediated through its interactions with PON1. Due to its ability to reduce oxidative stress, PON1 contributes to atheroprotective functions of HDL in mice and humans. Although PON1 has the ability to hydrolyze a variety of substrates, only one of them-Hcy-thiolactone-is known to occur naturally. In humans and mice, Hcy-thiolactonase activity of PON1 protects against N-homocysteinylation, which is detrimental to protein structure and function. PON1 also protects against neurotoxicity associated with hyperhomocysteinemia in mouse models. The links between PON1 and Hcy in relation to pathological states such as coronary artery disease, stroke, diabetic mellitus, kidney failure and Alzheimer's disease that emerge from recent studies are the topics of this review. [ABSTRACT FROM AUTHOR]

Objective: Synthetic class A amphipathic helical peptide analogs of polipoprotein-AI (apoAI; with varied phenylalanine residues) are emerging therapeutic approaches under investigation for atherosclerosis. Utilizing retroinverso sequencing, we designed reverse-D4F (Rev-D4F) peptide with 18 D-amino acids containing 4 phenylalanine residues and reverse order that allows the side chain residues to be of exact alignment and superimposable to those of the parent L-amino acid peptide. This study examined the effect of Rev-D4F on atherosclerosis in apolipoprotein E (apoE)-null mice and the underlying mechanisms. Materials/Methods: ApoE-null mice were fed a chow diet and administered water (control), Rev-D4F, or L4F mimetic peptides (0.4 mg/mL, equivalent to 1.6 mg/d) orally in drinking water for 6 weeks. Aortic root atherosclerotic lesion area, lesion macrophage content, and the ability of plasma high-density lipoprotein (HDL) to influence monocyte chemotaxis were measured. Results: Rev-D4F significantly decreased aortic sinus atherosclerotic lesion area and lesion macrophage content without affecting plasma total and HDL-cholesterol levels in apoE-null mice. The HDL from Rev-D4F-treated mice showed enhanced anti-inflammatory monocyte chemotactic activity, while low-density lipoprotein (LDL) exhibited reduced proinflammatory activity. In in vitro studies, Rev-D4F inhibited LDL oxidation, endothelial cell vascular cell adhesion molecule I (VCAM-I), and monocyte chemotactic factor I (MCP-I) expression, and monocyte adhesion to aortic endothelial cells. Conclusions: The Rev-D4F inhibits atherosclerosis by inhibiting endothelial inflammatory/oxidative events and improving HDL function. The data suggest that Rev-D4F may be an effective apoAI mimetic peptide for further development in preventing atherosclerosis. [ABSTRACT FROM PUBLISHER]