Emerging Therapeutic Potential of Mesenchymal Stem/Stromal Cells in Preeclampsia.

PURPOSE OF REVIEW: Preeclampsia is a dangerous pregnancy condition affecting both the mother and offspring. It is a multifactorial disease with poorly understood pathogenesis, lacking effective treatments. Maternal immune response, inflammation and oxidative stress leading to endothelial dysfunction are the most prominent pathogenic processes implicated in preeclampsia development. Here, we give a detailed overview of the therapeutic applications and mechanisms of mesenchymal stem/stromal cells (MSCs) as a potential new treatment for preeclampsia. RECENT FINDINGS: MSCs have gained growing attention due to low immunogenicity, easy cultivation and expansion in vitro. Accumulating evidence now suggests that MSCs act primarily through their secretomes facilitating paracrine signalling that leads to potent immunomodulatory, pro-angiogenic and regenerative therapeutic effects. MSCs have been studied in different animal models of preeclampsia demonstrating promising result, which support further investigations into the therapeutic effects and mechanisms of MSC-based therapies in preeclampsia, steering these therapies into clinical trials.

Levels of oxidative stress biomarkers and bone resorption regulators in apical periodontitis lesions infected by Epstein-Barr virus.

AIM: To investigate whether apical periodontitis lesions infected by Epstein-Barr virus (EBV) exhibit higher levels of oxidative stress biomarkers [8-hydroxydeoxyguanosine (8-OHdG) and oxidized glutathione (GSSG)] and bone resorption regulators [receptor activator of nuclear factor (NF-κB) ligand (RANKL) and osteoprotegerin (OPG)] compared to EBV-negative periapical lesions and healthy pulp tissues. METHODOLOGY: The experimental group consisted of 30 EBV-positive and 30 EBV-negative periapical lesions collected in conjunction with apicoectomy. The pulp tissues of 20 impacted third molars were used as healthy controls. The qualitative and quantitative analysis of EBV was performed by nested and real-time polymerase chain reaction (PCR), respectively. The levels of RANKL and OPG were analysed by reverse transcriptase real-time PCR. The levels of 8-OHdG and GSSG were determined by enzyme-linked immunosorbent assay (ELISA). Mann-Whitney U-test and Spearman's correlation were used for statistical analysis. RESULTS: The levels of RANKL, OPG, 8-OHdG and GSSG were significantly higher in apical periodontitis lesions compared to healthy pulp controls (P = 0.001, P < 0.001, P < 0.001 and P < 0.05, respectively). RANKL and OPG mRNA expression was significantly higher in EBV-positive compared to EBV-negative periapical lesions (P < 0.05). There was no significant correlation between EBV copy numbers and levels of RANKL, OPG, 8OH-dG and GSSG in apical periodontitis. CONCLUSION: Levels of bone resorption regulators and oxidative stress biomarkers were increased in apical periodontitis compared to healthy pulp tissues. EBV-positive periapical lesions exhibited higher levels of RANKL and OPG compared to EBV-negative periapical lesions. EBV may contribute to progression of apical periodontitis via enhanced production of bone resorption regulators.

Novel Biomarkers of Heart Failure.

Although substantial improvements have been made in majority of cardiac disorders, heart failure (HF) remains a major health problem, with both increasing incidence and prevalence over the past decades. For that reason, the number of potential biomarkers that could contribute to diagnosis and treatment of HF patients is, almost exponentially, increasing over the recent years. The biomarkers that are, at the moment, more or less ready for use in everyday clinical practice, reflect different pathophysiological processes present in HF. In this review, seven groups of biomarkers associated to myocardial stretch (mid-regional proatrial natriuretic peptide, MR-proANP), myocyte injury (high-sensitive troponins, hs-cTn; heart-type fatty acid-binding protein, H-FABP; glutathione transferase P1, GSTP1), matrix remodeling (galectin-3; soluble isoform of suppression of tumorigenicity 2, sST2), inflammation (growth differentiation factor-15, GDF-15), renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL; kidney injury molecule-1, KIM-1), neurohumoral activation (adrenomedullin, MR-proADM; copeptin), and oxidative stress (ceruloplasmin; myeloperoxidase, MPO; 8-hydroxy-2'-deoxyguanosine, 8-OHdG; thioredoxin 1, Trx1) in HF will be overviewed. It is important to note that clinical value of individual biomarkers within the single time points in both diagnosis and outcome prediction in HF is limited. Hence, the future of biomarker application in HF lies in the multimarker panel strategy, which would include specific combination of biomarkers that reflect different pathophysiological processes underlying HF.

Insulin resistance in non-obese women with polycystic ovary syndrome: relation to byproducts of oxidative stress.

To get more insight into molecular mechanisms underlying oxidative stress and its link with insulin resistance, oxidative stress parameters, as well as, antioxidant enzyme activities were studied in young, non-obese women with polycystic ovary syndrome (PCOS). Study was performed in 34 PCOS women and 23 age and body mass index (BMI)-matched healthy controls. Plasma nitrotyrosine and malondialdehyde (MDA), representative byproducts of protein and lipid oxidative damage, were determined by enzyme immunoassay. Antioxidant enzyme activities, superoxide dismutase (SOD) and glutathione peroxidase (GPX) were studied spectrophotometrically. Insulin resistance was calculated using homeostasis assessment model (HOMA-IR). Plasma nitrotyrosine and MDA were increased, but only nitrotyrosine was significantly higher (p < 0.05) in PCOS women compared to controls. Uric acid (surrogate marker of × antine oxidase) was also significantly elevated in PCOS (p < 0.05). Both plasma SOD and GPX activity showed no statistically significant difference between PCOS and controls. Indices of insulin resistance (insulin and HOMAIR) were significantly higher in PCOS group and positively correlated with level of MDA (r = 0.397 and r = 0.523, respectively; p < 0.05) as well as GPX activity (r = 0.531 and r = 0.358, respectively; p < 0.05). Our results indicate that insulin resistance could be responsible for the existence of subtle form of oxidative stress in young, nonobese PCOS women. Hence, presence of insulin resistance, hyperinsulinemia and oxidative damage are likely to accelerate slow development of cardiovascular disease in PCOS.

Coffee consumption protects human lymphocytes against oxidative and 3-amino-1-methyl-5H-pyrido[4,3-b]indole acetate (Trp-P-2) induced DNA-damage: results of an experimental study with human volunteers.

Aim of the study was to investigate the impact of coffee on DNA-stability in humans. DNA-damage was monitored in lymphocytes of eight individuals with single cell gel electrophoresis assays before and after consumption of 600 ml coffee (400 ml paper filtered and 200 ml metal filtered/d) for five days. Under standard conditions, no alteration of DNA-migration was seen, but a strong reduction of DNA-migration attributable to endogenous formation of oxidised purines and pyrimidines was detected with restriction enzymes; furthermore DNA-damage caused by reactive oxygen radicals (H2O2 treatment) and by the heterocyclic aromatic amine 3-amino-1-methyl-5H-pyrido[4,3-b]indole-acetate was significantly reduced after coffee consumption by 17% and 35%, respectively. Also in in vitro experiments, inhibition of H2O2 induced DNA-damage was observed with coffee at low concentrations (

Identification of a glutathione S-transferase without affinity for glutathione sepharose in human kidney.

To identify kidney glutathione S-transferase (GST) isoenzyme, which does not bind to glutathione affinity column, biochemical characterization was performed by using an array of substrates and by measuring sensitivity to inhibitors. Immunological characterization was done by immunoblotting. Affinity flow-through GST exhibited activity towards 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole and cumene hydroperoxide, typical class alpha substrates and high sensitivity towards hematin, an alpha class inhibitor. It cross-reacted with antibodies against alpha class GST. Affinity flow-through GST in human kidney is an alpha class member.

Byproducts of oxidative protein damage and antioxidant enzyme activities in plasma of patients with different degrees of essential hypertension.

Despite evidence that essential hypertension (EH) is a state of increased oxidative stress, the data on oxidative protein modifications is lacking. Besides, the role of extracellular antioxidant enzymes in EH has not been systematically studied. Study was performed in 45 subjects with EH and 25 normotensive controls. Patients were divided into three groups according to the 2003 ESH/ESC guidelines (grade 1-3). Plasma protein reactive carbonyl derivatives (RCD) and SH-groups (as byproducts of oxidative protein damage) as well as antioxidant enzyme activities superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase were studied spectrophotometrically and correlated with blood pressure (BP). RCD levels were increased in EH patients compared to controls and correlated significantly with both systolic blood pressure (SBP) (r = 0.495, P<0.01) and diastolic blood pressure (DBP) (r = 0.534, P<0.01). Plasma SH-groups content was significantly lower in all patients with EH, with no correlation with BP. SOD and catalase activity in patients with grade 1 EH were similar to that of controls. Patients with grade 2 and 3 of EH had lower SOD and catalase activity. However, significant correlation with SBP and DBP was observed for catalase only (r = -0.331; P<0.05 and r = -0.365; P<0.05, respectively). EH patients exhibited higher plasma GPX activity compared to those in controls, and it correlated with SBP (r = 0.328; P<0.05). The results presented show that increased oxidative protein damage is present in all grades of EH. In mild hypertension extracellular antioxidant enzyme activities are not decreased, suggesting they are probably not critical in early EH, but could be important in moderate to severe EH.

Methods for the detection of antioxidants which prevent age related diseases: a critical review with particular emphasis on human intervention studies.

It is well documented that reactive oxygen species (ROS) are involved in the aetiology of age related diseases. Over the last decades, strong efforts have been made to identify antioxidants in human foods and numerous promising compounds have been detected which are used for the production of supplements and functional foods. The present paper describes the advantages and limitations of methods which are currently used for the identification of antioxidants. Numerous in vitro methods are available which are easy to perform and largely used in screening trials. However, the results of such tests are only partly relevant for humans as certain active compounds (e.g. those with large molecular configuration) are only poorly absorbed in the gastrointestinal tract and/or may undergo metabolic degradation. Therefore experimental models are required which provide information if protective effects take place in humans under realistic conditions. Over the last years, several methods have been developed which are increasingly used in human intervention trials. The most widely used techniques are chemical determinations of oxidised guanosine in peripheral blood cells or urine and single cell gel electrophoresis (comet) assays with lymphocytes which are based on the measurement of DNA migration in an electric field. By using of DNA-restriction enzymes (formamidopyrimidine DNA glycosylase and endonuclease III) it is possible to monitor the endogenous formation of oxidised purines and pyrimidines; recently also protocols have been developed which enable to monitor alterations in the repair of oxidised DNA. Alternatively, also the frequency of micronucleated cells can be monitored with the cytokinesis block method in peripheral human blood cells before and after intervention with putative antioxidants. To obtain information on alterations of the sensitivity towards oxidative damage, the cells can be treated ex vivo with ROS (H(2)O(2) exposure, radiation). The evaluation of currently available human studies shows that in approximately half of them protective effects of dietary factors towards oxidative DNA-damage were observed. Earlier studies focused predominantly on the effects of vitamins (A, C, E) and carotenoids, more recently also the effects of fruit juices (from grapes, kiwi) and beverages (soy milk, tea, coffee), vegetables (tomato products, berries, Brussels sprouts) and other components of the human diet (coenzyme Q(10), polyunsaturated fatty acids) were investigated. On the basis of the results of these studies it was possible to identify dietary compounds which are highly active (e.g. gallic acid). At present, strong efforts are made to elucidate whether the different parameters of oxidative DNA-damage correlates with life span, cancer and other age related diseases. The new techniques are highly useful tools which provide valuable information if dietary components cause antioxidant effects in humans and can be used to identify individual protective compounds and also to develop nutritional strategies to reduce the adverse health effects of ROS.

Evaluation of oxidative stress after repeated intravenous iron supplementation.

Parenteral iron has been recommended for the treatment of iron deficiency in the majority of maintenance hemodialyzed (HD) patients. However, iron supplementation and consequent over saturation of transferrin and high iron levels, may aggravate oxidative stress already present in these patients. This study aimed to further clarify the role of repeated intravenous iron therapy as a supplementary cause of oxidative stress in HD patients. Markers of free radical activities (carbonyl reactive derivatives, CRD, thiol groups, SH, malondialdehyde, MDA) and antioxidant enzyme activities (superoxide dismutase, SOD and glutathione peroxidase, GPX) were determined in plasma and red blood cells (RBC) of 19 hemodialysis patients given a total iron dose of 625 mg (ferrogluconat, Ferrlecit, 62.5 mg). Blood samples were taken before the first and after the last dose of iron. Twenty apparently normal subjects served as healthy controls. Before iron treatment, HD patients exhibited increased concentrations of MDA and CRD in plasma and red blood cells, accompanied with impaired antioxidant capacity. All patients responded to iron therapy with a significant increase in their serum ferritin, serum iron, hemoglobin, and red blood cells levels. However, iron treatment resulted in enhanced oxidative stress in plasma of HD patients, since significant increase in plasma MDA and CRD concentrations, together with a decrease in nonprotein SH groups levels were detected. Supplementation with iron did not significantly influence plasma SOD and GPX activities, nor did any of the red blood cell parameters tested. Our data show that, despite improvement in hematological parameters, an increase in iron stores due to supplementation could also contribute to increased free radical production in HD patients.

Glutathione S-transferase T1-1 activity upregulated in transitional cell carcinoma of urinary bladder.

OBJECTIVES: To perform a systematic functional investigation of different glutathione S-transferase (GST) classes, including GST class Theta (GSTT) member GSTT1-1, in transitional cell carcinoma (TCC) and the surrounding normal uroepithelium of the same individuals. Recently, it was suggested that GSTT1-1 might be an important risk modulator for TCC. METHODS: Tumor samples and surrounding normal uroepithelium were obtained from 24 patients with TCC of urinary bladder. The following substrates with differential specificities were used: 1-chloro-2,4-dinitrobenzene for overall GST activity; 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole for GST Alpha; 1,2-dichloro-4-nitro-benzene for GST Mu; 4-vinylpyridine for GST Pi 1-1(GSTP1-1); and 1,2-epoxy-3-(p-nitrophenoxy)propane for GSTT1-1. RESULTS: GSTP1-1 and GSTT1-1 activities were demonstrated in all uroepithelial and TCC samples, and GST Mu activity was detectable in 11 of 24 patients. In the tumor specimens, significant upregulation of all expressed GST subtypes was observed. The mean GSTP1-1 and GSTT1-1 level in TCC was increased 2-fold and 3.6-fold, respectively, compared with the mean level in the normal uroepithelium (P <0.001). Tumor GSTT1-1 activities correlated statistically significantly with the tumor stage (P <0.05). CONCLUSIONS: In tumors and adjacent normal uroepithelium of patients with TCC, three major cytosolic GST classes, Mu, Pi, and Theta, were expressed. Although the GST isoenzyme pattern in TCC was similar to that of the corresponding normal uroepithelium, during cancer progression a clear tendency toward an increase in all the GST subtypes expressed was noted. For the first time, distinct GSTT1-1 activity levels were demonstrated in human uroepithelium, as well as its pronounced upregulation in TCC.

Isoenzyme profile of glutathione S-transferases in human kidney.

Novel glutathione S-transferase (GST) isoenzymes, which do not bind to the glutathione (GSH) affinity column, were recently identified in dog kidney and dog renal cell lines. In humans, similar affinity flow-through GST has been previously found only in the urinary bladder. To ascertain whether these affinity flow-through GST isoenzymes also exist in the human kidney, we separated GST isoenzymes from five kidney samples on the basis of their affinity to GSH affinity resin. GSTs were further purified by anion exchange chromatography and chromatofocusing and characterized with specific substrates. Our results show that the human kidney has both affinity flow-through GST isoenzymes and those which bind tightly to the GSH affinity column. Purification of affinity-bound GST resulted in a rich profile of different isoenzymes with balanced expression of both anionic and cationic forms. Affinity flow-through GST was represented by one isoenzyme (pI-7.9) in all kidney samples tested, but one kidney specimen also contained another GST isoenzyme (pI-7.0). Our results for the first time show the presence of GST isoenzymes that do not bind to GSH-affinity resin in the human kidney. Although the assessment of similarity between the human kidney and urinary bladder affinity flow-through GST requires further elucidation, it can be speculated that these particular GSTs may play an important role in providing protection against the common carcinogens.

Alteration in plasma antioxidant capacity in various degrees of chronic renal failure.

AIM, PATIENTS AND METHODS: To obtain a more comprehensive profile of extracellular antioxidant capacity in chronic renal failure (CRF), markers of oxidative stress (malondialdehyde, MDA and hydrogen peroxide), protein SH groups (as an important chain-breaking antioxidant) and activity of antioxidant enzymes (glutathione peroxidase, [GPX], catalase and superoxide dismutase, [SOD]) were studied in plasma of 36 non-dialyzed patients with various degrees of CRF and 10 hemodialyzed (HD) patients. RESULTS: The results show that plasma MDA concentrations significantly increase with the severity of kidney dysfunction (r = -0.543, p < 0.01). A marked and profound fall in plasma thiol group levels was observed in all groups tested, independent of the degree of renal failure (r = 0.082, p > 0.05). Plasma SOD activity increased in CRF patients with the progression of renal insufficiency (r = -0.370, p < 0.05). On the other hand, plasma GPX activity decreased progressively in strong correlation with endogenous CCr (r = 0.712, p < 0.001). However, despite this imbalance between extracellular SOD and GPX activities, plasma concentration of hydrogen peroxide remained unchanged in non-dialyzed CRF patients. Catalase activity in non-dialyzed CRF patients was increased, suggesting the significant involvement of catalase in the regulation of plasma hydrogen peroxide level. CONCLUSION: In hemodialyzed patients significantly lower plasma catalase activity, associated with higher hydrogen peroxide levels, was found. It seems reasonable to assume that the imbalance in the activity of extracellular antioxidant enzymes in chronic renal failure may result in accumulation of free radical species, and in unscheduled oxidation of susceptible molecules.

[Chronic rupture of abdominal aortic aneurysms]. / Hronicna ruptura aneurizme abdominalne aorte.

INTRODUCTION: Rupture of abdominal aortic aneurysms (RAAA) can take place in one of the 4 following ways: 1. "Open" rupture in the free peritoneal cavity; 2. "Closed" rupture with formation of retroperitoneal haematoma; 3. Rupture into surrounding cavity structures, such as veins and bowels; 4. In rare cases rupture is effectively "sealed of" by the surrounding tissue reaction, and retroperitoneal haematoma is "chronically" contained [1]. The terms "sealed" [2], "spontaneously healed" [3], "leakig" [4] RAAA, were also used in the previous papers connected to this situation. The "sealed" rupture was first described by Szilagyi and associates in 1961 [2]. In their case the rupture was small and haemorrhage was effectively encircled by the tissue surrounding the aortic wall. The slow rate of blood loss contributed to the patient's haemodinamically stable condition. Christenson et al. reported a case of "spontaneously healed" RAAA [3]. Rosenthal and associates described 2 patients who had aortic aneuryms that ruptured several months before repair and contributed to the term "leaking AAA" [4], while Jones et al. introduced the term "chronic contained rupture" [1]. The aim of this paper is the presentation of 5 such patients. CASE REPORT: Between December 1, 1988 and May 30, 1997 411 patients with abdominal aortic aneurysms (AAA) have been operated at our institute. Of this number 137 (33%) had RAAA, while 5 patients (12%) had a contained RAAA (CRAAA). CRAAA were found in 3 male and two female patients, average age 62 years. All of them had a previously proved AAA and initial symptoms lasted for days or months before the admission. In all patients haematocrit, pulse rate and arterial tension during the admission, were normal. All typical signs of RAAA were absent in these patients. Patient 1. A 56-year-old man, smoker, with previous history of arterial hypertension had an isolated episode of abdominal pain and collapse 30 days before the admission. Physical examination revealed a pulsatile abdominal mass. Doppler ultrasonography identified an infrarenal AAA, with right lobular extraaneurysmal mass which displaced the inferior vena cava (ICV). Angiographically (Figure 1a) an unusual saccular intrarenal AAA was detected, while simultaneous cavography (Figure 1b) confirmed the-dislocated inferior vena cava to the right. The intraoperative finding showed infrarenal CRAAA with organized retroperitoneal haematoma between AAA, ICV and duodenum. After aortic cross clamping and aneurysmal opening, the rupture at the right posterior aneurysmal wall was discovered. The partial aneurysmactomy and aortobilliar bypass procedure with bifurcated knitted Dacron graft (16 x 8 mm), were performed. The patient recovered very well. After a 4-year follow-up period the graft is still patent. Patient 2. A 72-year-old woman with low back pain, fever and disuric problems was urgently admitted to the Institute of Urology and Nephrology. The standard urological examination (X-ray, intravenous pyelography, retrograde urography, kidney Duplex ultrasonography) excluded urological diseases. However, intrarenal AAA an a giant aneurysm of the right common iliac artery, were found. The proximal dilatation of the right excretory urinary system was also found by retrograde urography. The patient was transported to our Institute 20 days after the initial symptoms. Translumbar aortography (Figure 3) showed the right common iliac artery aneurysm and gave the false negative picture of normal abdominal aorta because of parietal thrombosis of AAA. The intraoperative finding showed chronic rupture of the posterior wall of the right common artery aneurysm. The retroperitoneal haematoma compressed the right ureter. Both aneurysm have been resected and replaced by bifurcated Dacron graft (16 x 8 mm). The patient recovered successfully. After a 2-year period of follow-up the graft is still patent. Patient 3. (ABSTRACT TRUNCATED)

Markers of oxidative stress after renal transplantation.

An increased degree of oxidative stress (OS) in chronic renal failure (CRF) and a possible role of free radicals in CRF have already been described. However, data on OS after renal transplantation are scarce. The aim of the present study was to estimate the degree of OS in renal transplant patients. The study included four groups: 1) 15 haemodialysis patients (HD group), 2) 11 renal transplant patients with stable function (SF group), 3) 12 renal transplant patients with chronic biopsy-proven rejection (CR group), and 4) 10 healthy controls (C group). Markers of OS (malondialdehyde and thiol group levels) and antioxidant activity (glutathione peroxidase and Cu,Zn-superoxide dismutase) were determined in plasma and in red blood cells of all examined individuals. After successful renal transplantation a significant improvement, but not normalization, of antioxidant enzyme activities accompanied by significantly reduced lipid peroxidation were found. In the CR group the degree of OS was increased, and our results suggest that OS may be a relevant pathophysiological factor for CR development.

Time course of renal glutathione levels in experimental Fanconi syndrome: an enzyme-based approach.

Time-dependent alterations in glutathione (GSH) concentration and the activities of several key enzymes of GSH metabolism were studied in a rat model of experimental Fanconi syndrome induced by i.p. injection of sodium maleate (400 mg/kg BW). The changes in the parameters tested were monitored 0, 2, 4, and 12 h after sodium maleate administration. A significant decrease in renal GSH level was observed 2 and 4 h after sodium maleate treatment (27% and 38% of control values, respectively). The renal GSH depletion did not appear to be due to the decreased production rate or to an increased degradation of the tripeptide. This suggestion is based on the findings that the activities of the GSH synthesis (gamma-glutamyl cysteine synthetase and glutathione reductase) and those of the catabolic pathways (gamma-glutamyl transpeptidase) were unaltered at the same time points. The unchanged activity of gamma-glutamyl transpeptidase also suggests preserved luminal membrane integrity in experimental Fanconi syndrome. The decreased activity of glutathione peroxidase, which utilizes GSH as a cosubstrate in the course of inactivation of free radicals, in the first hours after treatment could facilitate lipid peroxidation reactions in this model of acute renal failure. The observed changes in all parameters tested were transient, with recovery to baseline levels in a period of 12 h after sodium maleate administration. At the same time a pronounced functional impairment still existed. The beneficial effect of fast recovery of renal GSH level on the functional and morphological restitution in experimental Fanconi syndrome is suggested.

[Glutathione and enzymes associated with glutathione metabolism in adriamycin nephropathy]. / Glutation i kljucni enzimi metabolizma glutationa u adriamicinskoj nefropatiji.

Recent data have shown the protective effect of thiol groups on the progression of adriamycin-induced experimental nephropathy, in which reactive oxygen metabolites have been postulated to play an important role. To gain greater insight in the role of glutathione (GSH) in adriamycin-induced nephrosis, we studied changes in reduced GSH level and its associated enzymes in kidney tissue of rats undergoing chronic renal failure produced by i.v. infections of adriamycin (2 x 2 mg/kg b.w.). Kidney damage was characterized by increases in relative kidney weight and BUN levels. The results obtained revealed a 15% drop in renal GSH level in adriamycin-treated animals associated by a similar decrease in the gamma-glutamylcysteine synthetase activity. The activities of kidney glutathione reductase (GR) and glutathione peroxiase (GSH-Px) which are critical constituents of GSH-redox cycle, were significantly decreased (23 an 26%, respectively) in response to adriamycin treatment. Rat kidney glutathione-S transferase and gamma-glutamyl transpeptidase activities were not affected in adriamycin induced nephrosis. We propose that the impairment of renal antioxidant defense, characterized by combined drop in GSH, GR and GSH-Px levels, could permit enhanced free radical induced kidney damage in adriamycin-induced nephropathy.

Erythrocyte glutathione peroxidase and superoxide dismutase activities in different stages of chronic renal failure.

Antioxidant enzyme activities, glutathione peroxidase (GSH-Px) and Cu, Zn superoxide dismutase (SOD-1), were investigated in erythrocytes of non-dialyzed patients with varying degrees of chronic renal failure (CRF), and of patients on regular hemodialysis treatment. The results obtained have shown that GSH-Px and SOD-1 activities were significantly higher in erythrocytes from non-dialyzed CRF patients than in corresponding age-matched healthy controls. Antioxidant enzyme activities increase with the progression of chronic renal insufficiency, and the more pronounced augmentation in GSH-Px and SOD-1 activities were found in erythrocytes from the end-stage renal patients (with Ccr less than 20 ml/min). The increase of GSH-Px and SOD-1 activities seen in non-dialyzed CRF patients were abolished in patients undergoing regular hemodialysis treatment. We propose that the increased GSH-Px and SOD-1 activities could be a protective mechanism for the cells due to the hyperproduction of free radicals in chronic renal failure. The lowering of red blood cell antioxidant activity in uremic patients on chronic dialysis may contribute to the increased oxidative damage in uremia and in the development of uremic complications.

[Significance of laboratory tests for differential diagnosis of acute renal allograft rejection and acute cyclosporine nephrotoxicity]. / Znacaj laboratorijskih testova za diferencijalnu dijagnostiku akutnog odbacivanja transplantisanog bubrega i akutne ciklosporinske nefrotoksicnosti.

The most frequent causes of renal allograft function deterioration in early postransplantation period are aucte rejection (AR) and acute cyclosporine nephotoxicity (CyA NT). In order to contribute to noninvasive diagnostics in differential diagnosis of these two disorders, glomerular and tubular function in 40 patients during 2-3 weeks after renal transplantation, were followed-up. The results showed that ischaemia, during any act of transplantation provoked functional and structural disorders of renal allografts. During acute rejection serum creatinine level was increased diuresis, sodium and beta-2 microglobulin levels were decreased, whyle there was no significant change in the urinary enzymes ativity. In acute CyA NT there was significantly greater fractional excretion of sodium and beta-2 mikroblobulin, as well as activity of N-acetly-beta-d glukosaminidase and alkaline phosphatase in urine in comparison to other examined groups.

Glutathione and its associated enzymes in peripheral blood cells in different stages of chronic renal insufficiency.

Reduced glutathione (GSH) levels and glutathione reductase (GR) and glutathione S-transferase (GST) activities were investigated in the erythrocytes and lymphocytes of non-dialyzed patients with varying degrees of chronic renal insufficiency, and also of patients on regular hemodialysis treatment. GSH, GR and GST levels were higher in erythrocytes and lymphocytes of examined patients as compared to their corresponding age-matched healthy controls. A correlation was found between the degree of renal insufficiency and the above parameters tested. A routine hemodialysis did not significantly affect erythrocyte and lymphocyte GSH content and activities of its associated enzymes. The increased GSH levels as well as GSH-linked enzyme activities of blood cells in uremia may be a protective mechanism for the cells due to the accumulation of toxic, oxidizing, wastes in the blood as a result of the uremic state. This view is supported by the results ofin vitro experiments, which have shown that GR and GST activities of normal human lymphocytes are increased when incubated with plasma from uremic patients.