Mariann Harangi

Serum paraoxonase activity changes in uremic and kidney-transplanted patients

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.

The effect of micronised fenofibrate on paraoxonase activity in patients with coronary heart disease

OBJECTIVE To evaluate the effect of micronised fenofibrate on serum paraoxonase (PON) and lipoprotein levels in coronary heart disease patients with type IIb hyperlipidemia. PATIENTS AND METHODS 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. RESULTS 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 (p<0.001). Low-density lipoprotein (p<0.05) and apolipoprotein B-100 (p<0.01) decreased, while HDL constituent apolipoprotein A-I (p<0.05) increased after micronised fenofibrate treatment. The HDL-associated paraoxonase specific activity increased significantly (p<0.05). 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 (p<0.05) while the PON/apoA-I ratio did not change significantly. CONCLUSION 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.

The human paraoxonase‐1 phenotype modifies the effect of statins on paraoxonase activity and lipid 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.

Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia

SUMMARY Objective: 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. Research design and methods: 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. Results: Simvastatin treatment significantly reduced serum cholesterol, LDL-cholesterol (LDL-C) and apolipoprotein (apo) B levels ( p < 0.001). Atorvastatin had a more pronounced cholesterol, LDL-C- and apo B-lowering effect ( p < 0.001) compared with simvastatin. Both statins also significantly reduced serum triglyceride levels ( p < 0.01). 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 ( p < 0.05). Conclusions: 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.

Determination of DNA damage induced by oxidative stress in hyperlipidemic patients

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<0.001). In the hyperlipidemic patients, a positive correlation was found between the degree of DNA damage and the basic oxidation of PMNLs (r=0.517), and the superoxide anion production of the cells stimulated with phorbolmiristate acetate (PMA) (r=0.326) and formyl-Met-Leu-Phe (FMLP) (r=0.525) as well. There was a negative correlation between DNA damage and HDL-associated antioxidant paraoxonase (PON) activity (r=-0.469), and the PON/HDL ratio (r=-0.631). No correlation was found between the degree of DNA damage and the plasma concentration of nitric oxide (NO) (r=0.098) and thiobarbituric acid-reactive substances (TBARS) (r=0.061) in hyperlipidemic patients. Our results show that in hyperlipidemic patients there is an increase in lymphocyte DNA damage caused by oxidative stress when compared to normolipidemic individuals as demonstrated by comet assay. Decreased antioxidant capacity in hyperlipidemic patients may play a significant role in this process.

Human paraoxonase-1 activity in childhood obesity and its relation to leptin and adiponectin levels.

Childhood obesity is a predisposing factor for adult cardiovascular diseases. Human serum paraoxonase (PON1) may protect against atherosclerosis by hydrolyzing lipid peroxides in oxidized LDL. Alterations and potential correlations of PON1 activities, leptin and adiponectin levels in childhood obesity were studied. We measured PON1 paraoxonase and arylesterase activities, anthropometric parameters, leptin and adiponectin levels in 59 white, obese (obese group-OB: BMI corrected for age: 95.1 ± 3.5 percentile, age: 11.9 ± 1.6 y) and 51 normal-weight children (control group-C: BMI corrected for age: 64.1 ± 8.4 percentile, age: 12.0 ± 3.9 y). Obese children had significantly lower PON1 paraoxonase (OB: 84.80 (64.33/144.74) U/L versus. C: 99.42 (83.33/152.05) U/L; p < 0.05) and arylesterase activities (OB: 94.40 (82.20/108.70) U/L versus. C: 115.20 (93.70/126.00) U/L; p < 0.01), higher leptin (OB: 37.05 (24.33/53.87) ng/mL versus. C: 4.62 (2.52/17.6) ng/mL; p < 0.0001) and lower adiponectin levels (OB: 7.56 (5.69/12.06) μg/mL versus. C: 11.51 (8.84/14.49) μg/mL; p < 0.001) compared with the normal-weight group. PON1 arylesterase activity showed inverse univariate correlation with leptin (r = −0.29; p < 0.05) and positive correlation with adiponectin levels (r = 0.39; p < 0.01). In multiple regression analysis adiponectin was strongly associated with PON1 arylesterase activity in obese children (β = 0.45, p < 0.02). Our results emphasize the importance of the investigated metabolic alterations which may have further effects on cardiovascular morbidity and mortality in later adulthood. Altered levels of leptin, adiponectin and PON1 activities may be useful markers beside the general risk factors in childhood obesity.

Effect of Gemfibrozil on HDL-Associated Serum Paraoxonase Activity and Lipoprotein Profile in Patients with Hyperlipidaemia

AbstractObjective: Earlier studies pointed out that the high density lipoprotein (HDL)-associated paraoxonase (PON) activity was decreased in patients with hyperlipidaemia compared with healthy age-matched controls. PON can inhibit low density lipoprotein (LDL) oxidation and has an antiatherogenic effect. The aim of the present study was to evaluate the effect of gemfibrozil on serum PON and lipoprotein levels in patients with hyperlipidaemia. Patients and Methods: 57 patients with hypertriglyceridaemia were enrolled in the study (26 males, 31 females). The mean (± SD) body mass index was 26.17 ±6.17 kg/m2. The effects of twice daily gemfibrozil 600mg on serum cholesterol, lipoproteins, triglyceride, apolipoproteins and fibrinogen levels as well as on liver and kidney function were measured. Serum PON activity was determined spectrophotometrically using paraoxon as substrate. Results: Following treatment with gemfibrozil for 3 months, serum triglyceride and cholesterol levels were significantly decreased (from 4.01 ± 1.95 to 2.69 ± 1.61 mmol/L; p < 0.003 and from 7.44 ± 2.45 to 6.22 ± 0.96 mmol/L; p < 0.05, respectively), while the protective HDL level was not significantly increased. Furthermore, the low density lipoprotein (LDL) level was not significantly decreased while the apolipoprotein B-100 level was significantly reduced (from 1.36 ± 0.29 to 1.28 ± 0.22 g/L; p < 0.05), and apolipoprotein A1 remained unchanged. The serum PON activity was significantly increased (from 220 ± 98 to 253 ± 100 U/L; p < 0.001). Standardised values for HDL (PON/HDL) were also significantly increased (from 190 ± 85 to 235 ± 104; p < 0.01). Conclusions: Gemfibrozil has a lipid-lowering effect in hypertriglyceridaemic patients and may improve the antioxidant status by increasing serum PON activity.

Association of chemerin with oxidative stress, inflammation and classical adipokines in non-diabetic obese patients

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.

The molecular and clinical rationale of extracorporeal photochemotherapy in autoimmune diseases, malignancies and transplantation

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.

Atorvastatin effect on the distribution of high-density lipoprotein subfractions and human paraoxonase activity

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.