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Open access

Tatjana Cvetković, Predrag Vlahović, Vidosava đorđević, Lilika Zvezdanović, Dušica Pavlović, Gordana Kocić and Dušan Sokolović

The Significance of Urinary Markers in the Evaluation of Diabetic Nephropathy

Oxidative stress is considered to be a unifying link between diabetes mellitus (DM) and its complications, including nephropathy (DN). The aim of this study was to determine the parameters of oxidative injury of lipids and proteins as well as the activity of ectoenzymes in the urine of DN patients. The study included 40 individuals: 10 patients with type 2 diabetes mellitus and microalbuminuria (DMT2-MIA), 10 type 2 diabetic patients with macroalbuminuria (DMT2-MAA), 10 patients with type 1 diabetes and microalbuminuria (DMT1-MIA) and 10 age- and sex-matched healthy subjects (control). In the urine we determined TBA reactive substances (TBARS), reactive carbonyl groups (RCG), and the activity of ectoenzymes N-acetyl-β-d-glucosaminidase (NAG), plasma cell differentiation antigen (PC-1), aminopeptidase N (APN) and dipeptidyl peptidase IV (DPP IV). A higher concentration of TBARS in the urine was found in DMT2-MIA and DMT1-MIA, compared to the control group (p<0.001 and P<0.05). The urine concentration of RCD shows similar results with a significant elevation in the groups with DMT2-MAA and DMT1-MIA, compared to the DMT2-MIA (p<0.001) and control group (p<0.001). Activities of NAG, APN and DPPIV were significantly higher in the urine of DMT2-MAA, compared to the control (p<0.01). The activity of PC-1 was slightly increased in that group, but not significantly. In conclusion, the level of oxidative stress markers and activities of brush border ectoenzymes in the urine may be a useful non-invasive and easily repeatable test in DN.

Open access

Vidosava Đorđević, Tatjana Ristić, Vladan Ćosić, Predrag Vlahović, Lilika Zvezdanović and Gordana Đorđević

Inflammatory and Apoptotic Markers in Ischemic Heart Disease Patients

Ischemic heart disease is the most frequent cause of cardiovascular morbidity and mortality. It is developed on the basis of atherosclerosis which is today considered a chronic inflammatory disease. It is documented by an increase in inflammatory and immune biomarkers, such as C-reactive protein, fibrinogen, neopterin, leukocytes, lymphocytes and others, that are significantly changed in patients with unstable angina or acute myocardial infarction. CRP is mostly studied. Increased concentrations of CRP are associated with a series of risk factors. CRP may predict recurrent events and mortality independently of cardiac troponin levels, and it is also an independent predictor of a cardiovascular event after adjustment for traditional risk factors. Although CRP currently appears to be the most promising biological marker, there is still controversy regarding its use in clinical practice. Both necrotic and apoptotic cell death are documented during atherogenesis, however, limited data are available about apoptotic markers in ischemic heart disease patients. Increasing evidence supports the existence of apoptotic death initiated by ligation of membrane-bound death receptors or by release of cytochrome c from mitochondria, as well as their regulators in the heart. The studies of serum markers show that the apoptotic process is disregulated in ischemic heart disease patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is present in stable atherosclerotic lesions, is increased in vulnerable plaques, but its serum levels are reduced significantly in patients with unstable angina. Serum Fas concentrations are increased and FasL are decreased in subjects at high cardiovascular risk. The results of our study show significant changes in serum Fas, FasL, and Bcl-2 concentrations, and lymphocyte caspase-3 activity in different stages of ischemic heart disease. For now, there is evidence that statins are effective in the regulation of some apoptotic markers. The better understanding of the pathways of apoptosis and their regulation is promissing in yielding novel therapeutic targets for cardiovascular disease.

Open access

Dušan Lazarević, Vladimir Đorđević, Vladan Ćosić, Predrag Vlahović, Suzana Tošić-Golubović, Tatjana Ristić and Vidosava Đorđević

Increased Lymphocyte Caspase-3 Activity in Patients with Schizophrenia

A growing body of evidence indicates that cortical brain cells of schizophrenic patients are vulnerable to apoptosis. As apoptosis is an important mechanism in organism modeling during development, active since the early phase of intrauterine life, it could be involved in the pathogenesis of schizophrenia. To test this hypothesis, caspase-3 activity was determined in peripheral blood mono nuclear cells from 30 patients with schizophrenia and from 30 age and gender matched healthy subjects by a colorimetric commercially available kit. Consistent with increased susceptibility to apoptosis, caspase-3 activity in lymphocytes of patients with schizophrenia was significantly increased (0.111±0.055 μmol/mg protein, p<0.05) in comparison with those in the matched control group (0.086±0.030 μmol/mg protein). The highest activity was obtained in the group showing almost equally positive and negative symptoms (0.159±0.096 μmol/mg protein) and it was significantly higher (p<0.05) compared to the group with a relative predomination of positive symptoms (0.100±0.029 μmol/mg protein). Caspase-3 activity in patients receiving typical antipsychotic drugs (0.124± 0.071 μmol/mg protein) was not significantly different from that in patients treated with atypical antipsychotics (0.104±0.039 μmol/mg protein). To our knowledge to date, this has been the first demonstration that there is a significant increase in caspase-3 activity, determined in native cells, in patients with schizophrenia, indicating a dysregulated apoptotic mechanism in this disease.

Open access

Tatjana Ristić, Vladan Ćosić, Predrag Vlahović, Marina Deljanin-Ilić and Vidosava Đorđević

Could Lymphocyte Caspase-3 Activity Predict Atherosclerotic Plaque Vulnerability?

Apoptotic cell death may play a critical role in a variety of cardiovascular diseases, especially in those developing on the basis of atherosclerosis. The goal of this study was to compare the activity of caspase-3 in different forms of ischemic heart disease and to correlate caspase-3 activity with inflammatory and lipid markers as well as risk factors. This enzyme activity was determined in peripheral blood mononuclear cells (PBMC) of 30 patients with stable angina pectoris (SAP), 27 with unstable angina (USAP), 39 with acute ST-elevation myocardial infarction (STEMI) and 27 healthy volunteers by a colorimetric commercially available ELISA method. In the SAP group caspase-3 activity was 0.093±0.036 μmol/mg protein, in patients with STEMI it was 0.110±0.062 μmol/mg protein, and both values were insignificantly higher in comparison with controls (0.092±0.022 μmol/mg protein). In PBMC of USAP patients caspase-3 activity (0.122±0.062 μmol/mg protein) was significantly higher (p<0.05) compared to the control group. In SAP patients caspase-3 activity showed a significant positive correlation with triglicerydes (p<0.05). Caspase-3 activity may be a valid parameter for assessing the atherosclerotic plaque activity, and a new target for therapeutic intervention.

Open access

Vidosava Đorđević, Lilika Zvezdanović, Vladan Ćosić, Predrag Vlahović, Slavica Kundalić, Tatjana Jevtović-Stoimenov, Bojana Stamenković and Dragoslav Mitrović

Serum Levels and in Vitro Production of Th1- and Th2-Type Cytokines by Peripheral Blood Mononuclear Cells in Patients Suffering from Systemic Lupus Erythematosus

Th1-type and Th2-type cytokine profiles and adhesion molecules in the serum of patients suffering from systemic lupus erythematosus and the cytokine production by peripheral blood mononuclear cells (PBMC) were studied. Tumor necrosis factor-alpha (TNF-α), interferongamma (IFN-γ), interleukin-1β (IL-1β), IL-4, IL-10, IL-13, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured using ELISA technique in the sera of 16 systemic lupus erythematosus patients without vasculitis (SLE), 30 SLE patients with vasculitis (LV), and in 18 healthy controls. The cytokines were also measured in the culture media of unstimulated, concana valin-A (Con-A) and phorbol-12-myristate-13-acetate (PMA) stimulated PBMC. TNF-α serum levels were significantly elevated in both SLE and LV patients and those of IL-1β in SLE patients. TNF-α was also significantly increased in SLE compared to LV patients. Serum levels of all three Th-2 cytokines were significantly elevated in both SLE and LV patients compared to healthy controls. Serum IFN-γ and Th2 cytokine levels were significantly increased in patients with more active disease. Both ICAM-1 and VCAM-1 were significantly increased in SLE patients and only VCAM-1 in LV patients. ICAM-1 showed a significant correlation with IL-1β, IFN-γ, IL-4 and IL-10 in both patient groups. In the SLE group VCAM-1 correlated significantly only with ICAM-1, but in the LV group only with IL-1β and IFN-γ. Compared to healthy controls, basal TNF-α and IL-4 production by unstimulated PBMC derived from SLE patients were significantly increased. Con-A-stimulated PBMC of both SLE groups produced significantly more IFN-γ, IL-4 and IL-13 than Con-A-stimulated control cells. Con-A-stimulated cells derived from LV patients produced much more INF-γ than cells from SLE patients. PMA strongly stimulated INFγ, TNFα and IL-13 production by cells derived from both SLE groups but had no effect on IL-4 production. In addition, it had little if any effect on the production of INFγ and IL-13 by PBMC derived from healthy donors. These findings suggest that the altered pattern of cytokine production by PBMC may play an important role in the SLE pathophysiology, accounting for differences in the clinical expression of the disease. The differences in adhesion molecules production and their correlation with cytokines suggest ICAM-1 and VCAM-1 as useful markers in SLE patients stratification.

Open access

Nikola Z. Stefanović, Tatjana P. Cvetković, Radmila M. Veličković-Radovanović, Tatjana M. Jevtović-Stoimenov, Predrag M. Vlahović, Ivana R. Stojanović and Dušica D. Pavlović

Summary

Background: The primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients.

Methods: The study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-β-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage.

Results: The carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients’ genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes’ activities.

Conclusions: Our findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug’s tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress.