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Recently, atherosclerosis has been recognized as a chronic inflammatory disease, characterized by the activation of cells with phagocytotic and antigen-presenting capabilities, accumulation of oxidatively modified lipoproteins, increased in situ turnover of immune-competent cells and tissue damage, as well as hypertrophic degeneration of the arterial intima. Both cellular and humoral components of the immune system have been implicated in these atherosclerotic processes. The aim of the present review is to summarize the potential harmful immune-inflammatory steps in the development of atherosclerosis and to depict the therapeutic regimens presently in use, as well as to envision future drug developments that will hopefully be beneficial in the battle against this disease.

Human serum paraoxonase-1 (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (LDL); therefore, it may protect against atherosclerosis. Changes in the ratio of high-density lipoprotein (HDL) subfractions may alter the stability and the antioxidant capacity of PON1. The aim of the study was to examine the effect of atorvastatin treatment on the distribution of HDL subfractions, LDL size, cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and PON1 activity. In all, 33 patients with type IIa and IIb hypercholesterolemia were involved in the study. LDL sizes and HDL subfractions were determined by gradient gel electrophoresis. CETP, LCAT, and PON1 activities were measured spectrophotometrically. Three months of treatment with atorvastatin 20 mg daily significantly increased the HDL3 (+8.13%) and decreased the HDL2a and HDL2b subfractions (-1.57% and -6.55%, respectively). The mean LDL size was significantly increased (+3.29%). The level of oxidized LDL was significantly decreased (-46.0%). The PON1 activity was augmented by the atorvastatin treatment (+5.0%). The CETP activity positively correlated with the HDL2b level and negatively correlated with the HDL3 and HDL2a levels. Atorvastatin alters the HDL subfractions, which may improve its antiatherogenic effect via enhancement of the PON1 activity.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • It has been suggested that the human paraoxonase-1 (PON1) genotype is an important determinant of the therapeutic response given to statin treatment. • It is also known that the PON1 activity status is a better predictor of coronary heart disease risk than any of the known PON1 genotypes. • Our goal was to answer this previously uninvestigated, still clinically relevant question: does the PON1 phenotype have an impact on the paraoxonase-activating and lipid-lowering effect of different types of statins. WHAT THIS STUDY ADDS • All the statins (atorvastatin, simvastatin and fluvastatin) included in this study were able to increase serum paraoxonase activity and decrease triglyceride levels effectively; however, this response seemed to be more significant in patients with AB+BB PON1 phenotype than in those bearing AA PON1 phenotype. • Furthermore, the apolipoprotein B-lowering effect of atorvastatin was also found to be PON1 phenotype-dependent. • Our results indicate that the PON1 phenotype may be a novel predictive factor for the effectiveness of statin treatment on PON1 activity and serum lipid levels; however, different types of statins may exert different effects on these parameters. Aims Human serum paraoxonase-1 (PON1) protects lipoproteins against oxidation by hydrolysing lipid peroxides in oxidized low-density lipoprotein, therefore it may protect against atherosclerosis. One of the two common PON1 gene polymorphisms within the PON1 gene is the Q192R, whose prevalence can be estimated by phenotype distribution analysis. The goal of this study was to clarify the role of PON1 phenotypes on the effect of three different statins on paraoxonase activity and lipid parameters. Methods One hundred and sixty-four patients with type IIb hypercholesterolaemia were involved in the study. We examined the effect of 10 mg day−1 atorvastatin, 10/20 mg day−1 simvastatin and 80 mg day−1 extended-release fluvastatin treatment on lipid levels and paraoxonase activity in patients with different PON1 phenotypes. The phenotype distribution of PON1 was determined by the dual substrate method. Results Three months of statin treatment significantly increased paraoxonase activity in every statin-treated group. In patients with AB+BB phenotype, statin treatment was significantly more effective on paraoxonase activity than in the AA group. Statin treatment more effectively decreased triglyceride levels in the AB+BB group compared with the AA group in the whole study population and in the simvastatin-treated group. Atorvastatin treatment was significantly more effective on apolipoprotein B levels in patients with AB+BB phenotype than in the AA phenotype group. Conclusions The PON1 phenotype may be a novel predictive factor for the effectiveness of statin treatment on PON1 activity and serum lipid levels; however, different types of statins may exert different effects on these parameters.

A korábbi epidemiológiai tanulmányok eredményei azt igazolták, hogy a HDL-koleszterin a cardiovascularis megbetegedések önálló rizikófaktora, plazmaszintjének emelése a cardiovascularis prevenció egyik fontos eleme. A HDL-nek a reverz koleszterintranszportban betöltött központi szerepe mellett egyéb kedvező biológiai, az érelmeszesedés elleni védőhatása is van. Ezek közé tartozik az antioxidáns, az antiinflammatorikus, az antitrombotikus/profibrinolitikus és a vazoprotektív hatás. A jelenlegi ajánlások az agresszív életmódváltást, a niacin, a fibrátok, a statinok vagy ezek kombinációját javasolják a HDL-koleszterin-szint emelésére. Emellett számos új, a HDL-re épülő terápiás eljárás tesztelése történt meg az utóbbi években, illetve van folyamatban. Idetartoznak a nikotinsav-származékok új formái, illetve receptoragonistái, a CETP-inhibitorok, a kannabinoid-1-receptor-antagonisták, a PPAR-agonisták, az LXR/FXR receptoragonisták és az apoA1- és/vagy foszfolipidterápia. Jelen közleményünkben áttekintjük a korábbi klinikai tanulmányokat, epidemiológiai megfigyeléseket, alapkutatásokat, illetve a legfontosabb új terápiás eljárásokkal végzett klinikai vizsgálatok eredményeit.

Sulfhemoglobinemia (SHb) is an uncommon cause of cyanosis that is predominantly drug-induced in adults. We report an unusual case of sodium sulfate-induced sulfhemoglobinemia in a 61-year-old woman after surgical polypectomy. Fractional hemoglobin derivates were assayed by spectrophotometry and high-performance liquid chromatography. The SHb ratio was 8.6% in the first sample and 3.77% a month later measured by spectrophotometry. In the blood hemolysate, a new peak was identified as SHb with high-performance liquid chromatography (HPLC). HPLC showed the presence of 9.37% SHb in the first sample and 4.88% a month later. After removing the suspected toxic agent the cyanosis decreased significantly. The findings underline the importance of routine SHb detection in cyanosis of unknown origin especially in emergency cases.

Objectives High-density lipoprotein (HDL) inhibits low-density lipoprotein (LDL) oxidation therefore it is involved in the prevention of atherogenesis. HDL particles originating from different persons possess different antioxidant activities. Our aim was to establish a method for the measurement of HDL antioxidant capacity, which is suitable for testing the antioxidant activity of HDL samples in a wide range and produces data relevant to in vivo HDL–LDL interactions. Hemin was used as pro-oxidant since its role in the course of LDL oxidation and atherosclerosis is proven. Methods Hemin-induced and hydrogen peroxide catalyzed lipid peroxidation of LDL was performed in the presence and absence of HDL. The time interval required for reaching the maximum reaction velocity (ΔTVmax) was determined and HDL antioxidant capacity was expressed as the ratio of the ΔTVmax with and without HDL. HDL fractions (n = 8) isolated by ultracentrifugation from healthy donors were analyzed and their antioxidant capacities were compared. Results In parallel with their increasing density, HDL fractions expressed increasing antioxidant capacity (106.12–194.12%). Within-run and within-laboratory CVs of the method were 1.72–1.87% and 4.09–4.93%, respectively. Alterations of hydrogen peroxide concentration in the range of 50–125 μmol/L did not influence the assay results, while the elevation of hemin concentration (between 3 and 9 μmol/L) resulted in decreased antioxidant capacity. The values for hemin degradation correlated well with conjugated diene formation. Conclusions Hemin-induced LDL oxidation is a reliable assay system to test the antioxidant capacity of HDL and its subpopulations.

High-density lipoprotein (HDL)-associated antioxidant paraoxonase (PON) may reduce low-density lipoprotein (LDL) oxidation and prevent atherosclerosis. The aim of this present study was to investigate the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin on hydrogen-peroxide-induced DNA damage by comet assay and the correlation between oxidative DNA damage and antioxidant PON activity. Thirteen type-II/a hyperlipidemic patients were enrolled in the study. We examined the effect of 10 mg/day atorvastatin treatment on lipid levels and the degree of DNA damage in lymphocytes separated from hyperlipidemic patients, nitric oxide (NO), thiobarbituric acid-reactive substances (TBARS), PON levels and activity. After 6 months, atorvastatin treatment significantly decreased serum cholesterol and LDL-cholesterol levels. The triglyceride level did not change, and there was no significant change in the HDL cholesterol level. The visual score characteristic to the degree of DNA damage in comet assay was significantly decreased, as well as the TBARS level, while the level of NO was non-significantly increased. PON activity and the PON/HDL ratio were significantly increased after atorvastatin treatment. There was a negative correlation between DNA damage and PON activity, as well as between DNA damage and the PON/HDL ratio before and after atorvastatin treatment. These findings show that atorvastatin treatment favorably affected the lipid profile, increasing the activity of HDL-associated PON and decreasing the cytotoxic effect of oxidative stress.

Obesity and its co-morbidities as metabolic syndrome, type 2 diabetes mellitus and cardiovascular diseases are major health problems worldwide. Several reports indicated that nutrient excess and metabolic syndrome are linked with altered immune response. Indeed, metabolic syndrome is characterized by insulin resistance and chronic low-grade inflammation, which conditions are the consequences of the complex interaction between adipocytes and immune cells. Enlarged white adipose tissue is infiltrated by immune cells and secretes various bioactive substances, like adipokines, cytokines and other inflammatory mediators. Due to its special architecture in which metabolic and immune cells are in intimate proximity, metabolic and immunologic pathways are closely integrated in adipose tissue. With the contribution of altered gut microbiota, adipokines and cytokines modulate insulin signaling and immune response leading to adipose tissue inflammation and systemic insulin resistance. In this chapter, we focus on the cellular and molecular mechanisms that lead to impaired insulin sensitivity and chronic low-grade inflammation in obesity. We also detail the potential role of adipokines and immune cells in this deleterious process, and the concerns of vaccination in metabolic syndrome. Finally, we address the links between obesity and gut microbiota as an emerging new field of interest, and scratch the surface of potential therapeutic opportunities.

Obesity and its co-morbidities as metabolic syndrome, type 2 diabetes mellitus and cardiovascular diseases are major health problems worldwide. Several reports indicated that nutrient excess and metabolic syndrome are linked with altered immune response. Indeed, metabolic syndrome is characterized by insulin resistance and chronic low-grade inflammation, which conditions are the consequences of the complex interaction between adipocytes and immune cells. Enlarged white adipose tissue is infiltrated by immune cells and secretes various bioactive substances, like adipokines, cytokines and other inflammatory mediators. Due to its special architecture in which metabolic and immune cells are in intimate proximity, metabolic and immunologic pathways are closely integrated in adipose tissue. With the contribution of altered gut microbiota, adipokines and cytokines modulate insulin signaling and immune response leading to adipose tissue inflammation and systemic insulin resistance. In this chapter, we focus on the cellular and molecular mechanisms that lead to impaired insulin sensitivity and chronic low-grade inflammation in obesity. We also detail the potential role of adipokines and immune cells in this deleterious process, and the concerns of vaccination in metabolic syndrome. Finally, we address the links between obesity and gut microbiota as an emerging new field of interest, and scratch the surface of potential therapeutic opportunities.

The prevalence of obesity has been increasing worldwide. Chemerin is a recently discovered adipokine secreted by the enlarged adipose tissue with diverse biological effects that are not well detailed yet. This study aimed to elucidate the potential role of chemerin in oxidative stress and inflammation that are characteristics for excess weight and may eventually lead to insulin resistance and atherosclerotic complications. We also analysed the associations between chemerin and classical adipokines, namely leptin and adiponectin. Therefore, we investigated non-diabetic obese patients without manifest cardiovascular disease and compared their data to healthy lean individuals. Chemerin correlated positively with markers of oxidative stress and inflammation, while it showed a negative correlation with the measure of antioxidant status, characterized by the HDL-linked paraoxonase-1 enzyme. Chemerin also correlated positively with leptin and negatively with adiponectin respectively. In our study population, oxidized low-density lipoprotein and high-sensitivity C-reactive protein were found to be the strongest predictors of chemerin level. We conclude that chemerin may contribute to chronic inflammation and increased oxidative stress in obese individuals, even in the absence of manifest insulin resistance.

Paraoxonase lactonase activity protects against homocysteinylation; therefore, it can be a potential contributing factor to prevent atherosclerosis. We aimed to determine paraoxonase and HTLase activities and to clarify the relationship between HTLase activity and some cardiovascular risk factors, such as homocysteine, cystatin C asymmetric dimethylarginine (ADMA), and adipokines both in hemo dialyzed and transplanted patients. Among 114 hemodialyzed, 80 transplanted and 64 healthy control subjects, we investigated body mass index (BMI) as well as fasting serum contents of urea, uric acid, creatinine, cystatin C, homocysteine, glucose, lipids, total protein and albumin. Serum paraoxonase (PON 1) and HTLase activities were measured spectrophotometrically. ADMA, ADPN adiponectin, leptin (LEP) levels was determined with a sandwich enzyme-linked immunosorbent assay method. Dyslipidemic patients showed hypercholesterolemia, and high low-density lipoprotein (LDL); parallel with improved renal function, they displayed decreased cystatin C and homocysteine levels (P < .001). There was a significant negative correlation between PON 1 activity and cystatin C and homocysteine concentrations (P < .05). Obese patients revealed significantly higher LDL (P < .05) and leptin concentrations (P < .01). There was a significant positive correlation between PON 1 activity and adiponectin levels (P = .0276). Both dialyzed and transplanted patients displayed significantly lower HTLase activities compared to the control group (P < .001), particularly lower HTLase and PON 1 activities in dialyzed subjects compared with the transplanted group (P < .05). HTLase activity showed significant negative correlations with ADMA levels among the whole study population (P < .001), whereas positive associations were noted between PON 1 and HTLase activities (P < .001). HTLase activity may be a new predictor of cardiovascular risk in renal failure although it is modulated by other risk factors.

Serum paraoxonase (PON) is a high-density lipoprotein (HDL)-associated hydrolase, which inhibits low-density lipoprotein oxidation. Uremic and kidney-transplanted patients have an increased risk of atherosclerosis, to which an increased lipoprotein oxidation may contribute. The aim of our study was to determine whether the PON activity or phenotype is altered in uremic and kidney-transplanted patients, and to compare the values with those of healthy controls. 117 uremic patients on long-term hemodialysis treatment, 115 renal-transplanted patients, and 110 healthy controls were involved in the study. The PON activity was significantly reduced in the uremic patients compared to controls (PON 101.36±30.12 vs. control 188.05±58.96 U/ml; p < 0.001), while in kidney-transplanted patients the values were almost identical to those of controls (PON 161.5±35.39 U/ml). The different immunosuppressive drug combinations did not influence PON activity. To assess whether the altered PON activity was due to a decrease HDL level, we standardized the enzyme activity for the HDL concentration (PON/HDL ratio). We found that the standardized enzyme activity was lower in the uremic (102.7±54.8) and kidney-transplanted patients (144.5±32.7) when compared to controls (194.5±94.5; p < 0.001). The phenotypic distribution of PON in uremic, renal transplant and control patients are as follows: AA 66.67, 56.48 and 66.67%; AB 31.62, 33.3 and 26.67%; BB 1.71, 10.19 and 6.67%. We conclude that the decreased PON/HDL and PON/apoA-1 ratios may lead to a reduction in the antioxidant capacity of HDL, which might contribute to the accelerated development of atherosclerosis in uremic and kidney-transplanted patients.

OBJECTIVE: The aim of this study was to clarify the effect of Apolipoprotein E (ApoE) polymorphism on the efficacy of cholesterol absorption inhibitor ezetimibe monotherapy on lipid parameters. METHODS: 63 hyperlipidemic patients with statin induced adverse effects were involved in the study. We examined the effect of 10 mg/day ezetimibe treatment on lipid levels after 3, 6 and 12 months of treatment in patients on a diet of only different ApoE genotypes. RESULTS: Three months of ezetimibe treatment significantly decreased the total cholesterol (TC) (-10.1%), low-density lipoprotein (LDL-C) (-12.0%) (p < 0.001) and triglyceride (Tg) (-8%) levels (p < 0.05). After 6 and 12 months of treatment reduction in TC, LDL-C and Tg levels were even more pronounced. The genotype distribution of the patients were 2/2: 4.8%, 2/3: 7.9%, 3/3: 68.3%, 3/4: 19.0%. There were no patients with 2/4 and 4/4 genotypes. In patients with 2/3, 3/3 or 3/4 genotype, the ezetimibe treatment tended to be more effective on TC and LDL-C levels than in the 2/2 group, and the efficacy of ezetimibe on Tg levels were slightly better in 2/2 carriers compared to other patients. CONCLUSIONS: The ApoE genotype does not predict the efficacy of ezetimibe treatment on serum lipid parameters.

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Background/Methods: The association between nutritional status, antioxidant human paraoxonase-1 (PON1) activity and low grade inflammation in hemodialized (HD) patients with chronic kidney disease (CKD) is unclear. The aim of this study was to determine PON1 paraoxonase and lactonase activities, ADMA, adiponectin and leptin concentrations, and to clarify the relationship between paraoxonase activity and a set of cardiovascular risk factors in malnourished, normal weight and obese HD patients; 114 HD patients with end-stage renal failure were enrolled. Results: Leptin levels were significantly higher and PON1 paraoxonase activities were significantly lower in obese patients compared to the other groups. Plasma adiponectin concentration was significantly lower in obese subjects compared to malnourished patients. Paraoxonase activity was negatively correlated with CRP level in HD and malnourished patients. Furthermore, we found significant inverse correlation between paraoxonase activity and BMI in the whole patient group. In multiple regression analysis, PON1 lactonase activity, CRP level and leptin concentration proved to be independent predictors of paraoxonase activity. Conclusion: Despite the previous findings of reverse epidemiology for the mortality rate of HD patients, further studies are needed to clarify the effects of nutritional state on atherosclerosis in obese and malnourished patients with end-stage renal failure.

Niemann-Pick C1-like 1 is a sterol sensing domain-containing transmembrane protein that is highly expressed on the apical surface of absorptive enterocytes. Previous studies proved that this protein facilitates the movement of free cholesterol from the gut lumen into enterocytes. Biochemical studies showed that Niemann-Pick C1-like 1 is the target of ezetimibe, a potent cholesterol absorption inhibitor. Recent studies show that genetic variation in Niemann-Pick C1-like 1 may be responsible for the inter-individual variability observed in the rates of intestinal cholesterol absorption and the response to ezetimibe.

A case of a young man with fever of unknown origin is presented. This diagnosis can be frustrating for both patients and physicians because the diagnostic workup often involves numerous noninvasive and invasive procedures that sometimes fail to explain the fever. In the presented case some of the imaging diagnostic findings suggested malignant hematological disorder. However, histopathological and microbiological investigation proved vertebral osteomyelitis caused by Staphylococcus haemolyticus. Diagnosis was established by positron emission tomography, magnetic resonance imaging, and culture and histopathological analysis of a spinal biopsy. 3 months of antibiotic therapy was curative. Biopsy and microbiological investigation may be necessary in patients with fever, back pain and evidence of a spinal lesion on imaging, even if neoplastic disease is suspected.

Objectives. The aim of the study was to examine human serum paraoxonase 1 (PON1) activity, phenotype distribution and lipid parameters in patients with Sjogren's syndrome. The prevalence of cardio- and cerebrovascular diseases in SS patients was also evaluated after a 5-year follow-up. Methods. Fifty-seven SS patients and 17 age-matched healthy controls were enrolled into the study. PON1 and arylesterase activities were measured spectrophotometrically. The phenotype distribution of PON1 was determined by the dual-substrate method. Results. Significantly lower PON1 activity was found in patients with SS compared with the control group (98.00 6 69.21 versus 203.3 6 92.78 U ml 21 ; P < 0.001). There were significant differences in PON1 phenotype distribution of SS patients and controls (AA/AB/BB: 91.2/8.8/0 versus 58.8/29.4/11.8%; P < 0.01). No significant correlations were found between PON activity and disease-characteristic autoantibodies, including anti-Ro/SS-A and anti-La/SS-B concentrations. PON activity did not predict the cerebro/cardiovascular risk in SS patients during the 5-year follow-up. Conclusions: Despite the relatively small sample size that reduces the power of the study, decreased PON activity may be a possible cardiovascular risk factor in SS. Disadvantageous PON1 phenotype distribution may contribute to the decreased PON activity in these patients.

Obesity as a pathogenic disorder is a predisposing factor for cardiovascular diseases and shows an increasing incidence in the industrialized countries. Adipokines such as leptin, adiponectin and resistin have a great impact on the development of atherosclerosis in obesity. Elevated levels of leptin have been found to be atherogenic whereas decreased levels of adiponectin have been proved to be anti-atherogenic in recent studies. The exact role of resistin in the process of atherosclerosis has so far remained uncertain and controversial. In our recent work, we studied the alteration in human paraoxonase-1 (PON1) activity and adipokine levels; furthermore, we also aimed at identifying the potential correlation between these parameters in this metabolic disorder. We investigated the above-mentioned parameters both in adults and in children, with regard to the emerging role of childhood obesity and to get a clearer view of these factors during a whole lifetime. Investigating the adult population with a broad range of body mass index (BMI) we found significantly increased leptin and significantly decreased adiponectin and resistin levels and PON1 activity in the obese group compared to the lean controls. Adiponectin and resistin levels showed significantly positive correlation, while leptin and BMI showed significantly negative correlation with PON1 activity. Our findings were similar in childhood obesity: leptin showed significantly negative correlation, while adiponectin showed significantly positive correlation with PON1 activity. We found gender differences in the univariate correlations of leptin and adiponectin levels with PON1 activity in the adult population. In multiple regression analysis, adiponectin proved to be an independent factor of PON1 activity both in childhood and adult obesity, furthermore thiobarbituric acid-reactive substances (TBARS) also proved to be an independent predictor of the enzyme in adults, reflecting the important role of oxidative stress in obesity. Investigating PON 192 Q/R polymorphism by phenotypic distribution (A/B isoenzyme) in obese children, we found a significant correlation of PON1 arylesterase activity with leptin and adiponectin levels, and of body fat percentage with PON1 192 B isoenzyme. According to our studies, these metabolic changes in obesity predispose to the early development of atherosclerosis throughout our whole lifetime. Decreased activity of PON1 and alterations in adipokine levels in childhood obesity could contribute to an early commencement of this process, detected only later in adulthood by increased cardiovascular morbidity and mortality. Changed levels of leptin, adiponectin, resistin and PON1 activity at all ages, just like 192 Q/R polymorphism determined by phenotypic distribution, may be useful markers beside the general risk factors.

Extracorporeal photochemotherapy, or photopheresis is a low-risk therapeutical intervention, which has been introduced in a variety of hematological malignancies, autoimmune conditions and transplantation. The mode of action of photopheresis encompasses apoptosis-induction and modifications of immunoregulatory processes, leading to the elimination of malignant cells, as well as the down-modulation of harmful immune responses. Although the beneficial effects of the therapy have been depicted in numerous studies, little is known about the exact benefits and the molecular mechanisms behind. The aim of the present review was to portray some aspects of the molecular and clinical rationale of extracorporeal photochemotherapy in autoimmune diseases, malignancies and transplantation, and to provide an overview of the treatment in the modern clinical management of these diseases.

Obesity as a pathogenic disorder is a predisposing factor for cardiovascular diseases and shows an increasing incidence in the industrialized countries. Adipokines such as leptin, adiponectin and resistin have a great impact on the development of atherosclerosis in obesity. Elevated levels of leptin have been found to be atherogenic whereas decreased levels of adiponectin have been proved to be anti-atherogenic in recent studies. The exact role of resistin in the process of atherosclerosis has so far remained uncertain and controversial. In our recent work, we studied the alteration in human paraoxonase-1 (PON1) activity and adipokine levels; furthermore, we also aimed at identifying the potential correlation between these parameters in this metabolic disorder. We investigated the above-mentioned parameters both in adults and in children, with regard to the emerging role of childhood obesity and to get a clearer view of these factors during a whole lifetime. Investigating the adult population with a broad range of body mass index (BMI) we found significantly increased leptin and significantly decreased adiponectin and resistin levels and PON1 activity in the obese group compared to the lean controls. Adiponectin and resistin levels showed significantly positive correlation, while leptin and BMI showed significantly negative correlation with PON1 activity.

Dyslipidaemia including decreased high density lipoprotein cholesterol concentration is one of several factors that have been implicated in increased cardiovascular risk. Since their introduction in the 1980s, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have emerged as the one of the best-selling class of medications to date, with numerous trials demonstrating powerful efficacy in preventing cardiovascular diseases. Although statins have been shown to modestly raise or not alter HDL-cholesterol, their effect on HDL subfractions and on HDL-associated enzymes including human paraoxonase-1 (PON1) has not yet been fully explored. This review summarizes the currently available data on the effect of statins on HDL subfractions and on PON1 activity with a particular emphasis on the clinical relevance of these effects. Moreover, methodological problems of HDL subfraction and PON1 activity determinations are also discussed.

Background: Human paraoxonase-1 (PON1) inhibits LDL-oxidation and atherogenesis, and possesses lactonase activity. Decreased PON1 activity was found in hemodialyzed and renal transplanted patients. Cystatin C plays a protective role in atherosclerosis, and is a new, sensitive marker of renal function. The relationship between these two markers in renal failure has not been investigated.Aims: The goal of this study was to clarify the relationship between PON1 activity, cystatin C and homocysteine in chronic renal failure. We also determined the levels of oxidatively modified LDL (oxLDL) and thiobarbituric acid reactive substances (TBARS) to characterize lipid peroxidation.Patients and methods: 74 hemodialized (HD), 171 renal transplanted patients (TRX), and 110 healthy controls (C) were involved in the study. PON1 activity and TBARS levels were measured spectrophotometrically. OxLDL level was determined with sandwich ELISA.Results: There was a negative correlation between PON1 activity and cystatin C level. Homocysteine level correlated negatively with PON1 activity, and positively with cystatin C level. OxLDL and TBARS levels were significantly higher in the HD and TRX groups compared to C.Conclusions: Cystatin C may be a good predictive factor not only for homocysteine levels but for the antioxidant status in patients with renal failure and renal transplantation.

Background: Human serum paraoxonase-1 (PON1) is a high-density lipoprotein-associated ester hydrolase which can inhibit low-density lipoprotein oxidation and has an antiatherogenic effect. Two common polymorphisms are known in the PON1 gene in humans (at positions 55 and 192), from which the latter gene alteration has been mainly attributed to alter the activity of the protein. Moreover, significantly reduced PON1 activity was found in chronic kidney disease (CKD) and renal transplant patients. Methods: The aim of the present study was to investigate the genotype and phenotype distribution of the PON1 gene as well as its end product activity in patients with CKD (n = 117), in renal transplant recipients (n = 146) and in reference subjects (n = 1,180). Results: Unexpectedly high discordances between phenotype and genotype assessments were observed in all studied groups (28.2% in the CKD, 20.55% in the transplant and 30.9% in the reference group). Arylesterase activity was significantly lower in the CKD group compared to the reference sample. There were no significant differences between patients and the reference group in the frequencies of polymorphisms PON1–55 and PON1–192. PON1 activity did not differ in patients compared to the reference group. Conclusions: Both PON1 phenotype and genotype determinations are necessary to estimate PON1 status.

Lipid abnormalities are among the most important risk factors of the development of atherosclerosis. Inhibitors of 3-hydroxy-methyglutaryl-coenzyme A reductase (statins) and peroxisome proliferator-activated receptor (PPAR) alpha ligand (fibrates) are widely used as lipid lowering drugs in patients with disturbed lipid metabolism. Apart from reducing plasma lipid levels, these agents have additional beneficial effects on other processes involved in the atherosclerotic process. In the last few years the favourable effect of these drugs on human paraoxonase-1 activity was extensively investigated both in in vitro and in vivo studies. This chapter summarizes the results of in vivo and in vitro studies, and the putative mechanisms of altered PON1 activity caused by statin and fibrate administration. The possible causes of discrepancies in currently available data will be also discussed

Background: Human serum paraoxonase (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (oxLDL); therefore, it may protect against atherosclerosis. PON1 activity and polymorphisms have been inconsistently associated with carotid artery disease. The goal of this study was to clarify the role of PON1 activity and phenotype on carotid artery disease and its correlation with some inflammatory and immune markers in subjects under 55 years with early-onset carotid atherosclerosis. Methods: Sixty patients with occlusive carotid artery disease and 30 healthy controls were enrolled. Intima-media thickness (IMT) was measured by high-resolution ultrasound of both common carotid arteries. Anti-oxLDL antibody levels were determined by ELISA. Results: In the whole study population we found a negative correlation between PON1 activity and IMT (r = –0.27, p = 0.011), and between salt-stimulated PON1 activity and IMT (r = –0.24, p = 0.02). Both PON1 activity and salt-stimulated PON1 activity negatively correlated with anti-oxLDL levels (r = –0.28, p = 0.008; r = –0.26, p = 0.01). PON1 activity was lower in patients compared to controls; however, the difference was not significant.PON1 phenotype distribution of patients and controls did not differ significantly. Conclusion: The importance of PON1 activity as a predictive risk factor for early-onset occlusive carotid artery disease should be assessed in future studies.

Aims Diabetic dyslipidaemia with decreased high-density lipoprotein-cholesterol (HDL-C) concentration plays a key role in enhanced atherosclerosis. The antioxidant effect of HDL is due to the influence of human paraoxonase 1 (PON1) and several authors have described decreased activity of this enzyme in Type 2 diabetics and subjects with metabolic syndrome. The goal of this study was to examine the effect of daily ciprofibrate on serum PON1 and lipoprotein concentrations in patients with metabolic syndrome. Methods Fifty-one patients with metabolic syndrome were enrolled into the study. We examined the effect of 100 mg day−1 ciprofibrate treatment on lipid concentrations, oxidized low-density lipoprotein (LDL), PON1 concentrations and activity. We also investigated the calculated size of LDL-cholesterol (LDL-C). Results During the 3-month study, it was observed that following treatment with ciprofibrate, the serum triglyceride concentration decreased significantly (from 2.76 ± 0.9 mmol l−1 to 2.27 ± 1.6 mmol l−1; −18%; P

The role of transmembrane lipidtransporter molecules in the atherosclerotic process. The protective effect of high-density lipoprotein in the atherosclerotic process has been mainly attributed to its role in reverse cholesterol transport. Identification of mutations in the ATP-bindig casette transporter-A1 (ABCA1) as the genetic defect in genetic high-density lipoprotein-deficiency (Tangier disease) and selected patients with familiar hypoalphalipoproteinemia has generated interest in discovering the role of this lipid transporter molecule in the reverse cholesterol transport. It is well established, that the ABCA1 mediates cellular cholesterol efflux through transfer of phospholipids and cholesterol from the inner to the outer layer of the cell membrane, thus enabling the bindig to apolipoproteins. Previous studies showed that the ABCA1 is critically involved in cellular trafficking of cholesterol and phospholipids in total body of lipid homeostasis. In Tangier disease, the loss of the function of ABCA1, leads to an impaired formation of nascent high-density lipoprotein particles by preventing the release of cellular phospholipids and cholesterol to the acceptor apolipoprotein A1. This rare genetic disorder is characterized by a severe high-density lipoprotein deficiency, cholesterol deposition in macrophages and premature atherosclerosis. These findings implicate the ABCA1 as an important therapeutic target for preventing diseases that are associated with accelerated atherogenesis. The present review summarizes the current knowledge of the ABCA1, its pivotal role in the cholesterol homeostasis and preventing atherosclerosis.

Lipoproteins are known to exert direct and indirect effects on cardiovascular function, but their effects on ventricular repolarization have not yet been clearly elucidated.To assess the effect of hyperlipidemia on the longest QT interval (QTmax) of the 12-lead surface electrocardiogram (ECG) and on QT dispersion (QTd) in type IIb hyperlipidemic patients without myocardial ischemia, and to compare these patients with healthy control subjects.Ninety-six hyperlipidemic patients (44 men and 52 women; mean age 53+/-13 years) and 101 healthy control subjects (43 men and 58 women; mean age 46+/-16 years) were examined. Total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol (LDL-C), triglyceride, apolipoprotein (apo) A1, apo B, lipoprotein(a), QTmax and QTd were measured. According to heart rate, corrected QTmax and corrected QTd were also determined.A significant difference was observed between the two groups of subjects with respect to serum cholesterol, LDL-C, triglyceride, apo B, QTmax, corrected QTmax, QTd and corrected QTd. A positive significant correlation was found between cholesterol, triglyceride, LDL-C and all of the studied ECG parameters, between high density lipoprotein cholesterol and QTmax, apo B and QTd, and between body mass index and all of the studied ECG markers.Hyperlipidemia may have a direct effect on the studied ECG markers.

Background and aim Previous studies have demonstrated that oxidative stress is increased in obese patients. The high-density lipoprotein (HDL) associated human paraoxonase 1 (PON1) can inhibit low-density lipoprotein oxidation and has an antiatherogenic effect. Our objective was to assess the effects of orlistat therapy combined with diet on body mass index (BMI), waist circumference, lipid parameters, blood pressure, serum glucose level and PON1 activity. Methods and results A longitudinal, multicenter, randomized study with and without orlistat treatment was performed. One hundred thirty nine otherwise healthy, obese subjects were divided in to two groups: 78 persons received orlistat (120 mg three times a day) combined with diet while 61 persons were kept on diet only. Anthropometrical parameters, serum lipid levels and PON1 activity were measured at baseline and after 6 months of treatment. BMI and waist circumference were reduced more pronouncedly in the orlistat group than in the control group. Patients receiving orlistat also had significantly greater improvements in fasting blood glucose levels and blood pressure. The orlistat-treated group showed a greater reduction in total cholesterol and triglyceride levels. In addition, the serum PON1 activity in these patients was significantly increased compared to the diet-only group. Conclusions The 6-month treatment with orlistat had a beneficial effect on the lipid profile and improved the antioxidant status by increasing serum PON1 activity. However, because of the limited therapeutic effectiveness, obese patients with hypercholesterolemia should receive additional lipid lowering medications.

The genes for the human ATP-binding cassette (ABC) transporter ABCA7 and the minor histocompatibility antigen HA-1 are juxtaposed in close proximity on chromosome 19p13.3. The multispan transmembrane protein ABCA7 contains an extracellular domain that is recognized by antisera from patients with Sjogren's syndrome (“Sjogren-epitope”). Recent work from our laboratory demonstrating the involvement of ABCA7 in cellular ceramide and phosphatidylserine export suggests a role for this transporter in programmed cell death. In HA-1, a protein of unknown function, a His/Arg polymorphism (His168Arg), which constitutes the immunologic target for HA-1-specific cytotoxic T cells, has been causatively linked to graft-versus-host disease after allogeneic stem cell transplantation. Because these findings suggest a potential implication of ABCA7 and HA-1 in immune processes, we tested the hypothesis that allelic variants in both genes are associated with autoimmune disorders. We identified a total of 31 exonic single-nucleotide polymorphisms (SNP) in the ABCA7/HA-1 gene complex, nine of which represent non-synonymous nucleotide alterations. Genotypes of ABCA7 and HA-1 SNP were determined in three distinct Caucasian populations of patients with primary Sjogren's syndrome and ethnically matched controls. Comparison of allele frequencies between these groups revealed that the incidence of the HA-1 168His allele is significantly lower in Sjogren's syndrome patients than in controls (p

To evaluate the effect of micronised fenofibrate on serum paraoxonase (PON) and lipoprotein levels in coronary heart disease patients with type IIb hyperlipidemia.Fifty-two patients were investigated for the three-month effect of 200 mg per day micronised fenofibrate on the serum enzyme activity and concentration of PON and their relationship with serum lipids, high-density lipoprotein (HDL-C) parameters.Serum paraoxonase activity was lower in CHD patients with type IIb hyperlipoproteinemia. During the three-month study it was observed that following treatment with micronised fenofibrate, serum triglyceride and cholesterol levels decreased, while HDL-C increased significantly (p0.001). Low-density lipoprotein (p0.05) and apolipoprotein B-100 (p0.01) decreased, while HDL constituent apolipoprotein A-I (p0.05) increased after micronised fenofibrate treatment. The HDL-associated paraoxonase specific activity increased significantly (p0.05). To assess whether the increased PON activity was due to elevated HDL and apoA-I level, we standardized PON activity for HDL and apoA-I concentrations. The standardized values for HDL (PON/HDL) increased (p0.05) while the PON/apoA-I ratio did not change significantly.Three months of treatment with micronised fenofibrate is thought to normalize lipid profile and improve antioxidant status by increasing serum paraoxonase activity in these patients.

High-density lipoprotein (HDL)-associated paraoxonase (PON) activity may play an important role in the inhibition of low-density lipoprotein (LDL) oxidation. Previous studies have demonstrated that serum PON activity is decreased in patients with hyperlipoproteinaemia and coronary heart disease. The study presented here examined the effect of short-term treatment with simvastatin and atorvastatin on lipids and PON activity in patients with hyperlipoproteinaemia.A prospective, non-blinded, single-group, cross-over, comparative trial was performed. Following an 8-week dietary run-in period, 49 patients (23 men and 26 women, mean age: 59.8 +/- 7.9 years) with Fredrickson type IIa. and IIb. hyperlipoproteinaemias were randomized to receive either simvastatin 20 mg/day or atorvastatin 10 mg/day for 3 months. Following an 8-week washout period, patients were crossed-over to receive the other drug for a further 3 months. Serum lipids were measured and serum PON activity was determined spectrophotometrically using paraoxon as a substrate.Simvastatin treatment significantly reduced serum cholesterol, LDL-cholesterol (LDL-C) and apolipoprotein (apo) B levels (p0.001). Atorvastatin had a more pronounced cholesterol, LDL-C- and apo B-lowering effect (p0.001) compared with simvastatin. Both statins also significantly reduced serum triglyceride levels (p0.01). Simvastatin and atorvastatin caused no significant change in the levels of HDL-cholesterol (HDL-C) and apo A1. HDL-associated PON activity did not change significantly after simvastatin therapy, but significantly increased after atorvastatin treatment (p0.05).Short-term administration of simvastatin did not increase PON activity. Atorvastatin treatment had a favourable effect on lipid profile and increased the activity of HDL-associated PON.

Human paraoxonase (PON1) is a calcium-dependent esterase exclusively bound to apolipoprotein A-I and clusterin, containing high-density lipoprotein (HDL) particles that hydrolyzes organophosphates and aryl esters. Several studies have indicated that PON1 can prevent low-density lipoprotein (LDL) oxidation by hydrolyzing lipid peroxides in the lipoprotein, which is the crucial first step for atherogenesis. Therefore it may protect against the development of atherosclerosis. Serum PON1 activity has been shown to be decreased in familiar hypercholesterolemia and in diseases that are associated with accelerated atherogenesis. The PON1 gene has two common coding region polymorphisms, Leu 55 Met and Gln 192 →Arg. Both polymorphisms have been identified as independent risk factors for cardiovascular disease in diabetic and non-diabetic patients. We have established high-speed and easy-to-perform genotyping for the two most significant PON1 gene polymorphisms, employing the LightCycler technology and melting curves. This technique eliminates PCR contamination related to sample handling and does not require digestion of PCR products with restriction enzymes and/or fragment separation on gels.

In the present paper, we report data on the genotoxic properties of hydrogen peroxide in polymorphonuclear neutrophils (PMNLs) separated from normolipidemic and type II/a hyperlipidemic patients. In all, 15 hyperlipidemic patients (11 female, 4 male, mean age 54.6+/-10.25 years) were involved in the study, and 7 normolipidemic patients (5 female, 2 male, mean age 53.4+/-8.07 years) served as controls. Using the comet assay, there was a significant difference in the degree of DNA damage between the two groups. The visual score characteristic of the degree of DNA damage was 350.97+/-31.31 in the hyperlipidemic group, while it was 289.5+/-29.49 in the control group (P