Biomedical subjects

Ewa Slominska

Publications and source records attributed to Ewa Slominska.

6 recordsLinked to original sources

PubMed2006

Interrelationship between uremic toxicity and oxidative stress.

Uremic syndrome is associated with several metabolic disturbances. Oxidative stress is an important factor involved in the pathologic mechanism of these changes. The goal of this study was to understand the relationship between oxidative stress markers and two compounds included among uremic toxins. Two independent studies were performed, one with 29 peritoneal dialysis patients and the other with 43 predialysis subjects. In both groups of patients, known oxidative stress markers, malonyldialdehyde (MDA) and carbonyl groups (CG) formation were measured. Additionally, in the predialysis group, glutathione in erythrocytes (GSH) was estimated. In peritoneal dialysis patients, the concentration of advanced glycation end products (AGEs) was found to be significantly increased and correlated with both markers of oxidative stress. In predialysis patients, the increment of newly described uremic toxin purine nucleotide end products (Me2PY and Me4PY) were found and significant correlation was observed between both compounds versus MDA (positive) and GSH (negative). This relationship was visible especially in patients with more advanced renal failure. CG concentration was within the normal values and did not show any correlation with estimated toxin concentrations. In summary, results of both studies suggest that the interrelationship between uremic toxicity and oxidative stress is an important component of uremic syndrome. Nevertheless, further complex studies are needed to elucidate closer pathogenic links.

Aged↗

PubMed2005

Role of mitochondria in the switch mechanism of the cell death mode from apoptosis to necrosis--studies on rho0 cells.

Detailed mechanisms of the switch of the cell death mode from apoptosis to necrosis remain to be solved, although the intracellular level of ATP and that of free radicals have been postulated to be the major factors involved in the mechanisms. In the present study menadione (MEN)-induced cell injury processes were studied using rho0 cells derived from human osteosarcoma 143B cells and parental rho+ cells co-treated with inhibitors of electron transfer chain of mitochondria or oligomycin, an inhibitor of ATP synthesis. Treatment of rho+ cells with 100 microM MEN induced apoptosis, which reached the maximum at 6 h, and was followed by an abrupt decrease thereafter, while necrotic cells (NC) increased continuously when they were judged by Annexin V and PI double staining. On the other hand, MEN induced apoptotic and necrotic changes much faster in rho0 cells compared to rho+ cells. The frequency to find apoptotic cells (AP) in the former cells was distinctly smaller than that to find NC judged by Annexin V and PI double staining. Electron microscopically, a major population of rho0 cells treated with MEN for 6 h consisted of intermediate cells, and a small number of AP co-existed. At 9 h of the treatment intermediate cells were exclusively seen, and AP were hardly detected. When parental rho+ cells were treated with MEN in the presence of oligomycin or oligomycin plus antimycin A both apoptotic and necrotic changes of the cells were distinctly accelerated. The intracellular level of superoxide in rho0 cells continuously increased after the MEN treatment, whereas that of ATP remained distinctly low before and after the MEN treatment compared to that in rho+ cells. These data suggest that the intracellular level of superoxide may be a key factor controlling the switch from apoptosis to necrosis.

Adenosine Triphosphate↗

PubMed2004

Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs.

Ischemia-reperfusion injury, a clinical problem during cardiac surgery, involves worsened adenosine trisphosphate (ATP) generation and damage to the heart. We studied carbon monoxide (CO) pretreatment, proven valuable in rodents but not previously tested in large animals, for its effects on pig hearts subjected to cardiopulmonary bypass with cardioplegic arrest. Hearts of CO-treated pigs showed significantly higher ATP and phosphocreatine levels, less interstitial edema, and apoptosis of cardiomyocytes and required fewer defibrillations after bypass. We conclude that treatment with CO improves the energy status, prevents edema formation and apoptosis, and facilitates recovery in a clinically relevant model of cardiopulmonary bypass surgery.

Adenosine Diphosphate↗

PubMed2004

Disturbances of purine nucleotide metabolism in uremia.

The increased concentration of adenosine triphosphate (ATP) in erythrocytes from patients with chronic renal failure (CRF) has been observed in many studies but the mechanism leading to these abnormalities still is controversial. It is believed that hyperphosphatemia and metabolic acidosis triggering enhanced reutilization of purine bases are the factors responsible for changes in erythrocyte nucleotide concentration. During the past decade we have performed several studies. A summary of the obtained results is presented. A high-performance liquid chromatography technique was used for the determination of plasma and intraerythrocyte nucleotide concentrations. Labeled adenine and adenosine were used for measuring adenine incorporation. In CRF patients treated conservatively increased concentrations of ATP levels and other nucleotides such as adenosine diphosphate were found. Adenosine monophosphate and hypoxanthine levels were lower than in controls. In hemodialyzed patients both ATP and adenosine monophosphate intraerythrocyte concentrations were higher than in controls. At the same time, adenosine monophosphate and hypoxantine level were comparable with levels in healthy people. The main pattern of nucleotides during hemodialysis remained unchanged, independent from the mode of therapy. The only exception was a decreased level of hypoxantine. Results of a consecutive study have suggested that the increased rate of adenine incorporation into the adenine nucleotide pool could be partially responsible for the increased ATP concentration in uremic erythrocytes. Last but not least, trying to elucidate the pathomechanism of adenine nucleotide disturbances in uremia, we have found that the concentration of N-methyl-2-pyridone-5-carboxamide (2PY), one of the end products of nicotinamide-adenine dinucleotide degradation, were enhanced in CRF patients to values that are potentially toxic. Our findings suggest that 2PY could be a novel uremic toxin. Disturbances of nucleotide metabolism are one of the important components of uremic syndrome.

Adenosine Triphosphate↗

PubMed2003

Decreased cardiac activity of AMP deaminase in subjects with the AMPD1 mutation--a potential mechanism of protection in heart failure.

OBJECTIVES: Possession of the C34T (Glu12Stop) nonsense mutation in the AMP-deaminase 1 (AMPD1) gene has been shown to be associated with improved prognosis in heart failure and ischemic heart disease. The most likely event leading to these clinical effects is a reduced capacity of the AMP deamination pathway and increased production of cardio-protective adenosine. However, since AMPD1 is predominantly expressed in skeletal muscle, the protective effects could be related not only to local cardiac changes, but also to a systemic mechanism. In the present study we evaluated the effect of the C34T mutation on cardiac AMP-deaminase activity and on the systemic changes in adenosine production. METHODS: The presence of the C34T mutation was assayed by single-stranded conformational polymorphism (SSCP). Analysis of the AMPD1 genotype and measurement of enzyme activities was performed on 27 patients with heart failure (HF). In addition, blood adenosine concentration was measured by liquid chromatography/mass spectrometry (LC/MS) in 21 healthy subjects with established AMPD1 genotype at rest and following exhaustive exercise. RESULTS: Cardiac AMP-deaminase activity in heterozygotes (C/T) was 0.59+/-0.02 nmol/min/g wet wt-about half of the activity found in normal wild-type (C/C) individuals (1.06+/-0.09 nmol/min/g wet wt, P=0.003). There were no significant differences in the activities of any other enzymes between subjects with the C/T or C/C genotype. Resting venous blood adenosine concentration was similar in subjects with C/C, C/T and homozygous for the mutated allele (T/T) genotype. Following exercise, a significant increase in adenosine was observed in T/T subjects (by 0.013+/-0.009 micromol/l, P=0.035) but not in C/C (0.003+/-0.009 micromol/l) or C/T (-0.002+/-0.011 micromol/l). CONCLUSIONS: Our findings indicate that the C34T mutation of AMPD1 leads to a decrease in cardiac enzyme activity of AMP-deaminase without changes in any other adenosine-regulating enzymes, highlighting the importance of local cardiac metabolic changes. Systemic (blood) changes in adenosine concentration were apparent only in homozygous subjects and therefore may play a relatively small part in cardio-protection.

AMP Deaminase↗

PubMed2003

N-methyl-2-pyridone-5-carboxamide: a novel uremic toxin?

BACKGROUND: N-methyl-2-pyridone-5-carboxamide (2PY) is one of the end products of nicotinamide-adenine dinucleotide (NAD) degradation. We recently found that serum 2PY concentrations in chronic renal failure (CRF) patients were enhanced to the values, which are potentially toxic. The aim of this study was to determine whether 2PY is an inhibitor of poly(ADP-ribose) polymerase, the nuclear enzyme that is highly involved in variety of physiologic events, including regulation of DNA replication and DNA repair. METHODS: High-performance liquid chromatography (HPLC) was used to determine 2PY and other NAD catabolite concentrations in serum of: nondialyzed patients; patients chronically hemodialyzed; patients after kidney transplantation; and healthy individuals (control group). Moreover, the effect of nicotinamide and 2PY on poly(ADP-ribose) polymerase (PARP-1) in vitro was studied. RESULTS: The serum nicotinamide, 2PY, and 4PY (N-methyl-4-pyridone-3-carboxamide) concentrations are many times elevated in nondialyzed CRF patients when compared with controls. The direct correlations were found between serum 2PY (as well as 4PY and nicotinamide) concentrations and serum creatinine concentration, and negative correlations between serum concentrations of these compounds and creatinine clearance. The concentration of 2PY decreases considerably after hemodialysis (HD) session, but elevates back 48 hours later. It permanently declines after kidney transplantation. Nicotinamide and 2PY significantly inhibit PARP-1 activity in vitro. CONCLUSIONS: Increased serum 2PY concentration, along with a deterioration of kidney function and its toxic properties (significant inhibition of PARP-1 by 2PY), suggest that it could be a novel uremic toxin.

Humans↗