Aleksandra Stefanović

Pulmonary function, oxidative stress and inflammatory markers in severe COPD exacerbation.

BACKGROUND Oxidative stress and inflammation play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). OBJECTIVE Pulmonary function, oxidative stress parameters and inflammatory markers were measured in 74 patients with severe COPD exacerbation and 41 healthy subjects. In patients all parameters were assessed at two time points: Firstly, one day after admission and secondly, after 7 10 days when they were clinically stable enough to be discharged. Patients were divided in two groups according the presence of ischemic heart disease (IHD): IHD positive (IHD+) patients and IHD negative (IHD-) patients. METHODS AND RESULTS During hospitalisation O2•-, malondialdehyde (MDA), advanced oxidation protein products (AOPP) and total oxidant status (TOS) increased and were higher at discharge compared with admission and the control group. Superoxide dismutase (SOD) activity was significantly lower in COPD patients at both time points compared with the control group. Total antioxidant status (TAS) was significantly lower and the prooxidant-antioxidant balance (PAB) was higher at both time points in COPD patients compared with the control group. High sensitive C-reactive protein (hsCRP) and also the neutrophil count were significantly higher at admission compared with discharge. Paraoxonase 1 (PON1) enzymatic activities in COPD patients did not differ compared with the control group. IHD+ COPD patients had significantly lower PON1 activity but higher PAB levels and hsCRP concentrations, compared with IHD COPD patients. CONCLUSION The oxidant/antioxidant imbalance was significantly pronounced in patients with COPD exacerbation for at least 24 hours following their admission and when they were clinically stable enough to be discharged. Increased oxidative stress, elevated systemic inflammation and decreased antioxidant defence were common in end-stage disease and particularly COPD patients with ischemic heart disease.

Glutathione S-transferase A1, M1, P1 and T1 null or low-activity genotypes are associated with enhanced oxidative damage among haemodialysis patients

BACKGROUND Increased oxidative stress is a hallmark of end-stage renal disease (ESRD). Glutathione S-transferases (GST) are involved in the detoxification of xenobiotics and protection of oxidative damage. We hypothesized that genetic polymorphism in antioxidant enzymes GSTA1, GSTM1, GSTP1 and GSTT1 is more frequent in ESRD and modulates the degree of oxidative stress in these patients. METHODS GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 ESRD patients and 199 age- and gender-matched controls. Markers of protein and lipid oxidative damage [thiol groups, carbonyl groups, advanced oxidative protein products, nitrotyrosine, malondialdehyde (MDA) and MDA adducts], together with total oxidant status and pro-oxidant-antioxidant balance were determined. RESULTS Individual GST polymorphisms influence vulnerability to both protein and lipid oxidation, with GSTM1-null gene variant having the most pronounced effect. Furthermore, a strong combined effect of null/low-activity GSTM1, GSTT1, GSTA1 and GSTP1 genotypes in terms of susceptibility towards oxidative and carbonyl stress was found in ESRD patients. When patients were stratified according to GSTM1 and GSTT1, the highest oxidant damage was noted in those with the GSTM1-null/GSTT1-null genotype. The observed effect was even stronger in patients with the third low-activity GSTP1 or GSTA1 genotype. Finally, the level of oxidative and carbonyl stress was most pronounced in the subgroup of patients with all four null or low-activity GSTM1, GSTT1, GSTP1 and GSTA1 genotypes. CONCLUSIONS According to the GST genotype, ESRD patients may be stratified in terms of the level of oxidative and carbonyl stress that might influence cardiovascular prognosis, but could also improve efforts towards individualization of antioxidant treatment.

Association of oxidative stress and PON1 with LDL and HDL particle size in middle‐aged subjects

Background  Alterations in plasma lipoprotein subclass distributions affect atherosclerosis risk. Smaller, denser low‐density lipoprotein (LDL) particles (sdLDL) are more susceptible to oxidation. In contrast, most of the protective effects of high‐density lipoproteins (HDL) are attributable to larger particles. This study investigates the connection between LDL and HDL particle heterogeneity and oxidative stress, antioxidative defence (AOD) and paraoxonase (PON1) status in a healthy middle‐aged Serbian population.

Paraoxonase-1 (PON1) activity, but not PON1Q192R phenotype, is a predictor of coronary artery disease in a middle-aged Serbian population

Abstract Background: Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated serum enzyme that protects lipoproteins from oxidative modifications. Polymorphisms in the gene, including PON1Q192R, have been studied. However, inconsistencies regarding the above-mentioned polymorphism obscure its association with vascular disease. Methods: Using a two-substrate (paraoxon/diazoxon) activity method, we investigated the frequencies of PON1Q192R phenotypes in 261 middle-aged subjects: 156 patients with angiographically assessed coronary heart disease (CHD) and 105 CHD-free subjects as the control group. The PON1192 phenotype was predicted from examination of the two-dimensional plot of hydrolysis rates of diazoxon vs. paraoxon and by using the antimode of the histogram of the ratio of diazoxonase/paraoxonase activity. Results: The PON1Q192R phenotype frequencies in 113 patients with occlusion >50% (coronary artery disease-positive, CAD+ group) vs. control population were as follows: QQ (0.552 vs. 0.510), QR (0.382 vs. 0.408) and RR (0.066 vs. 0.082); χ2=0.414, p=0.813. We found lower paraoxonase (POase) and diazoxonase (DZOase) activities in the CAD+ patients when compared to the control population. According to logistic regression analysis, POase activity was a better predictor of coronary disease onset compared with DZOase activity measurements and PON1Q192R phenotyping. Conclusions: We conclude that enzyme activity (within a particular phenotypic group) is more important than phenotype alone in predicting susceptibility to coronary artery disease. Clin Chem Lab Med 2006;44:1206–13.

Hyperlipidemia, oxidative stress, and intima media thickness in children with chronic kidney disease.

BackgroundThe roles of dyslipidemia and oxidative stress in the early phases of atherosclerosis were tested in children with chronic kidney disease (CKD). Intima media thickness of common carotid arteries (cIMT) is used as a measure of early atherosclerosis.MethodsFifty-two pediatric CKD patients were enrolled in the study (10 with chronic renal failure [CRF], 22 with a renal transplant [RT], 20 with chronic hemodialysis (cHD) patients, and 36 healthy children (control group, CG). Lipid status, oxidative stress, and paraoxonase 1 (PON1) status were assessed. cIMT was measured by ultrasound, adjusted for age and sex, and presented as standard deviation scores (SDS).ResultsChildren with CKD had disturbed lipid content, which was most pronounced in cHD children, with higher free cholesterol and triglycerides compared with healthy children. Oxidative stress was markedly increased (malodialdehyde [MDA, μmol/L]: CRF 1.50 ± 0.26, RT 1.55 ± 0.40, cHD 1.77 ± 0.34, CG 0.97 ± 0.33, p < 0.001) and antioxidative defense was compromised (superoxide dismutase [SOD, U/L]: CG 120 ± 21, CRF 84 ± 25, RT 93 ± 12, cHD 119 ± 37, p < 0.001). Multiple linear regression analysis showed that a model that included disease duration, blood pressure, urea, lipid, and oxidative status parameters accounted for more than 90% of the variability of cIMT-SDS.ConclusionsEarly atherosclerosis in CKD children is caused, at least in part, by dyslipidemia and oxidative stress. Monitoring of vessel wall changes, along with assessment of oxidative stress status and high density lipoprotein (HDL) functionality is necessary to ensure better therapeutic strategies for delaying atherosclerotic changes in their asymptomatic phase.

Relationship between bone resorption, oxidative stress and inflammation in severe COPD exacerbation.

BACKGROUND The natural course of chronic obstructive pulmonary disease (COPD) is complicated by the development of systemic consequences and co-morbidities. Increasing evidence indicates that COPD and osteoporosis are strongly linked. The common features in COPD pathology, history of smoking, age, inactivity, systemic inflammation, and use of systemic corticosteroids, are important risk factors for osteoporosis. METHODS Pulmonary function, matrix metalloproteinase, tissue inhibitor of metalloproteinases, oxidative stress parameters, inflammatory markers and bone resorption marker were measured in 85 COPD patients and 47 healthy subjects. In patients, all parameters were assessed at two time points: one day after admission during exacerbation and about 30 days after, in the stable state of disease. RESULTS In patients, bone resorption marker collagen type I β-isomerized C-terminal telopeptide (beta CL) was increased during exacerbation: geometric mean 0.521, compared with stable patients 0.408, p<0.01, and control subjects 0.362 ng/ml, p<0.001. During exacerbation high sensitivity C-reactive protein (hsCRP) and neutrophil count were significantly higher in COPD patients compared with the control group, p<0.001. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations were significantly higher in COPD patients, stable state or exacerbation, compared with control subjects, p<0.001. In patients during exacerbation, total oxidative status (TOS) was higher compared with the stable state, p<0.05 and control group, p<0.001. Multiple linear regression for the joint influence of inflammation, hypoxia and oxidative status during exacerbation showed almost 60% influence on the variability of beta CL concentrations. CONCLUSION Intensification of disease characteristic symptoms such as inflammation, hypoxia, protease/antiprotease imbalance and oxidative stress, during exacerbation episodes in COPD patients may also contribute to increased bone resorption.

Total bilirubin in young men and women: Association with risk markers for cardiovascular diseases

OBJECTIVE The aim of this study was to investigate whether high bilirubin concentration is a protective factor in cardiovascular disease (CAD) and how it correlates with parameters of oxidative stress in young males and females. METHODS The study comprised 628 healthy subjects of both genders, 18-22years of age. In fasting sera the concentration of total bilirubin (Tbil), parameters of cardiovascular risk and oxidative stress were determined. The results were analyzed by appropriate statistical methods. RESULTS We found no gender differences in body mass index (BMI), blood pressure and lipid profile between subjects with low and high Tbil level. Men with high Tbil had higher concentrations of albumin and uric acid (p<0.001) and lower of oxLDL (<0.05), while women had higher albumin (p<0.05) and lower TBARS (p<0.05). Significant positive correlation in men was found between Tbil, uric acid and albumin, while for glucose and TBARS this association was negative. In female significant positive correlation was between Tbil, HDL-C, fibrinogen, albumin and uric acid and negative between Tbil and TBARS. The high concentration of Tbil in men was independently associated with uric acid (p<0.05) and oxLDL (p<0.001), while in women it was independently associated with TBARS (p<0.05). After adjustment for traditional lipid parameters the predictive power of high bilirubin in men remained for uric acid (p<0.001) and TBARS in women (p<0.05). CONCLUSION These findings jointly support the concept that bilirubin via its antioxidant potential has a protective effect against cardiovascular disease in young male and female.

HDL 2 Particles are associated with hyperglycaemia, lower PON1 activity and oxidative stress in type 2 diabetes mellitus patients

OBJECTIVES In this study we examined the relationship of oxidative stress and hyperglycaemia to antioxidative capacity of high-density cholesterol (HDL-C) particles in type 2 diabetes mellitus (DM). DESIGN AND METHODS Oxidative stress status parameters (superoxide anion (O2(-)), superoxide dismutase (SOD) activity and paraoxonase (PON1) status were assessed in 114 patients with type 2 DM and 91 healthy subjects. HDL particle diameters were determined by non-denaturing polyacrylamide gradient (3-31%) gel electrophoresis. RESULTS Patients had significantly higher concentrations of oxidative stress parameter O2(-)(p<0.001) and antioxidative defence, SOD activity (p<0.001). Paraoxonase activity was significantly lower in diabetics (p<0.001). The PON1(192) phenotype distribution among study groups was not significantly different. HDL 3 phenotype was significantly prevalent among patients (p<0.001). Paraoxonase activity was significantly lower in patients with predominantly HDL 2 particles than in controls. CONCLUSIONS The results of our current study indicate that the diabetic HDL 2 phenotype is associated with hyperglycaemia, lower PON1 activity and elevated oxidative stress.

Dyslipidemia and oxidative stress in sarcoidosis patients

OBJECTIVES Sarcoidosis is an inflammatory disease characterised by enhanced production of reactive oxygen species and alterations in the circulating lipid profile. Both attributes are thought to play a role in its pathogenesis. However, current knowledge regarding the significance of blood oxidative stress/anti-oxidant defence as well as alterations in lipid status parameters in sarcoidosis is scarce. The aim of our study was to assess these parameters and their inter-relationships, as well as their potential for patient-control discrimination. DESIGN AND METHODS Oxidative stress status and anti-oxidant defence parameters were determined in serum and erythrocytes and lipid status parameters were assessed in the serum of 213 treated sarcoidosis patients and 90 controls. RESULTS Malondialdehyde, superoxide anion, total oxidant status, prooxidant-antioxidant balance and triglycerides were significantly higher whereas total anti-oxidant status, superoxide dismutase activity and HDL-cholesterol were significantly lower in sarcoidosis patients compared with controls. Total sulfhydryl group content was higher in patients compared with controls. Serum and erythrocyte malondialdehyde exhibited the strongest ability to predict disease presence. Elevated oxidative stress was characterised by higher clinical accuracy compared with lipid status abnormality. Some oxidative stress and lipid status markers were significantly associated in sarcoidosis. CONCLUSIONS Sarcoidosis is characterised by increased oxidative stress, diminished overall anti-oxidative protection and alterations in the circulating lipid profile. Both oxidative stress and lipid status parameters demonstrated the potential to discriminate sarcoidosis from controls which was particularly evident from the point of view of oxidative stress status parameters. Association between these parameters may indicate an increased risk for atherosclerosis development.

A hazardous link between malnutrition, inflammation and oxidative stress in renal patients.

BACKGROUND Atherosclerosis is the main cause of mortality in end stage renal disease (ESRD) patients. DESIGN AND METHODS Malnutrition, inflammation and diminished paraoxonase activity were used to calculate the sum of risk factors for atherosclerosis development in a cohort of 141 chronic renal disease patients. Kaplan-Meier survival analysis was implemented to assess risk of death. RESULTS Kaplan-Meier analysis (Log rank=12.06, P=0.0072) showed higher risk of death with increasing number of risk factors in haemodialysis patients. CONCLUSIONS Malnutrition in combination with inflammation and oxidative stress is associated with higher mortality in patients on long-term haemodialysis.