Search

Oxidative stress in patients with end-stage renal disease (ESRD) is associated with long-term cardiovascular complications. The cytosolic family of glutathione S-transferases (GSTs) is involved in the detoxication of various toxic compounds and antioxidant protection. GST omega class members, GSTO1 and GSTO2 possess, unlike other GSTs, dehydroascorbate reductase and deglutathionylation activities. The aim of this study was to clarify the role of genetic polymorphisms of GSTO1 (rs4925) and GSTO2 (rs156697) as risk determinants for ESRD development, as well as in the survival of these patients.A total of 199 patients and 199 healthy subjects were included in the study and genotyped for both GSTO1 and GSTO2 polymorphism. Protein thiol and carbonyl groups as markers of protein oxidative damage were determined spectrophotometrically. Cox proportional hazard model and Kaplan-Meier analysis were performed to investigate the role of GSTO1 and GSTO2 genetic polymorphism on mortality of ESRD patients during the follow-up period (36 month).Individuals carrying the variantGSTO polymorphisms have been shown to act as significant markers in assessing the risk of ESRD development and patients' survival.Oksidativni stres je kod pacijenata sa terminalnom slabošću bubrega (TSB) povezan sa brojnim kardiovaskularnim komplikacijama. Pored uloge u detoksikaciji, citosolne glutation transferaze (GST) poseduju i antioksidantnu aktivnost. Članovi GST klase omega, GSTO1 i GSTO2, katališu nekoliko reakcija koje nisu tipične za ostale GST, kao što su reakcija uklanjanja glutationa i dehidroaskorbat-reduktazna aktivnost. Cilj studije bio je da se ispita uloga polimorfizama gena GSTO1 (rs4925) i GSTO2 (rs156697) na razvoj terminalne bubrežne slabosti, kao i njihova uloga u preživljavanju ovih bolesnika.Osobe sa varijantnimPolimorfizam gena za GSTO je povezan sa povećanim rizikom za razvoj terminalne slabosti bubrega kao i sa preživljavanjem ovih bolesnika.

Summary Background: To get more insight into the effects of the most widely used antiepileptic drugs (AEDs) on the prooxidant/ antioxidant balance in epilepsy, a comparative analysis of the byproducts of oxidative damage and antioxidant de fense mechanisms was performed in patients with epilepsy treated with lamotrigine, carbamazepine and valproic acid. Methods: Byproducts of oxidative damage to proteins (reactive carbonyl derivatives, RCD and protein thiol groups, PSH), lipids (urinary isoprostanes, 8-epi-PGF2a) and DNA (urinary 8-hydroxy-2’-deoxyguanosine, 8-OHdG), as well as the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPX) were measured in 60 patients with newly diagnosed seizure (at illness onset and after 6 months of treatment with lamotrigine, carbamazepine or valproic acid) and in 20 healthy controls. Results: In patients with epilepsy, RCD, urinary 8-epi-PGF2a and 8-OHdG, together with SOD and GPX activities were significantly increased, while P-SH were only slightly decreased. After 6 months of treatment with AEDs, a decrease was observed in RCD, urinary 8-epi-PGF2a and 8-OHdG to values slightly higher or similar to the control, while P-SH remained unchanged. A decrease was also observed in SOD and GPX activities, although they remained significantly in creased compared to controls. Conclusions: The results of this study have shown that treatments with lamotrigine, carbamazepine and valproic acid affect the prooxidant/antioxidant balance in patients with epilepsy.

The Role of GSTM1 and GSTT1 Polymorphism in Patients with Renal Cell CarcinomaMembers of the glutathione S-transferase (GST) superfamily exhibit polymorphic expression. GSTs are investigated as biomarkers of risk for various cancers, including renal cell carcinoma (RCC). The aim of this study was to test the association betweenGSTM1andGSTT1polymorphism and susceptibility to RCC, independently or in conjunction with known risk factors. Genomic DNA was isolated from 182 controls and 76 patients with RCC.GSTM1andGSTT1genotypes were determined by multiplex PCR. Data obtained were analyzed with respect to RCC risk factors including smoking and occupational exposure. The frequency ofGSTM1-null genotype was higher in patients with RCC (60.5%) compared to controls (47.2%).GSTT1-null genotype was found in 28.6% controls and 27.6% of cases.GSTM1-null individuals exhibit 1.9-fold increased risk of RCC (95% CI: 1.06-3.33). The presence ofGSTT1active genotype was associated with increased risk of RCC in occupationally exposed subjects when unexposedGSTT1-null subjects were used as a comparison group (OR: 2.48; 95% CI: 1.05-5.86). No association was found between the inactive form ofGSTM1andGSTT1and smoking in RCC patients. In a Serbian cohort of patients, the presence of aGSTM1active genotype is protective against RCC, whereas aGSTT1active genotype increases RCC risk in occupationally exposed subjects.

Muscle-Invasive Transitional Cell Carcinoma of the Urinary Bladder is Associated with Down-Regulated CPP32 Expression and BCL-2 Positivity The objective was to get insight into the role of executive apoptotic enzyme caspase 3 (CPP32) and regulatory antiapoptotic protein Bcl-2 in the malignant phenotype of TCC. Samples were obtained from 84 TCC patients, who underwent transurethral resection, partial or radical cystectomy. Staging showed a superficial growth pattern in 41 patient, while other 43 showed invasive characteristics. Expression of CPP32 and Bcl-2 was determined by immunocytochemistry. Levels of expression were correlated with tumor stage and grade. Expression of CPP32 was positive in 80% of TCC patients. Low-, medium- and high positive status were observed in 18%, 24% and 38% of patients, respectively. There was a signifficant difference in the CPP32 expression between groups with superficial and invasive TCC tumors (p = 0.032), with frequency of CPP32 negative samples being higher and CPP32 high-positive samples being lower in patients with muscle-invasive tumors. Significant association was also found between CPP32 expression and tumor stage (p = 0.043). The positive rate of Bcl-2 protein expression was 48%. There was a statisticaly signifficant difference in the rate of Bcl-2 positivity between superficial and invasive TCC (p = 0.005), with frequency of Bcl-2 positive patients being higher in muscle-invasive TCC. Significant association was also found between Bcl-2 expression and both tumor grade (p=0.032) and stage (p=0.007). Muscle invasive TCC of the urinary bladder is associated with down-regulated expression of CPP32 and Bcl-2 positivity. Down-regulation of CPP32 and up-regulated Bcl-2 might, at least partially, play a role in the development of invasive characteristics of TCC.

Kratak sadr`aj: Jedan od etiolo{kih faktora za nastanak karcinoma bubrega svetlih }elija i karcinoma prelaznog epitela mokra}ne be{ike je izlo`enost potencijalnim kancerogenima. Karcinom bubrega svetlih }elija pripada tumorima sa visokim stepenom rezistencije na hemioterapiju, a karcinom prelaznog epitela mokra}ne be{ike grupi rekurentnih i multifokalnih tumora. Citosolne glutation S-transferaze (GST) su superfamilija enzima koji u zdravim }elijama imaju za{titnu ulogu od potencijalnih kancerogena, katali{u}i reakcije konjugacije elektrofilnih jedinjenja sa glutationom. Neki izoenzimi GST poseduju i hidroperoksidaznu aktivnost. Najbolje okarakterisane klase GST su Alfa (GSTA), Mi (GSTM), Pi (GSTP) i Teta (GSTT), a svaka od ovih klasa sadr`i vi{e razli~itih izoenzima. Uo~eno je nekoliko alelskih varijacija unutar razli~itih klasa, usled kojih GSTM1 nulti i GSTT1 nulti genotip imaju za posledicu odsustvo kataliti~ke aktivnosti. Kod osoba koje su homozigoti za GSTM1 nulti alel uo~en je zna~ajno ve}i rizik za nastanak karcinoma mokra}ne be{ike. Uticaj polimorfizma GSTT1 na pove}anu osetljivost za nastanak karcinoma bubrega svetlih }elija i karcinoma prelaznog epitela mokra}ne be{ike u velikoj meri zavisi od izlo`enosti odre|enim hemijskim agensima koji se metaboli{u pomo}u GSTT11. U procesu nastanka tumora bubrega dolazi do smanjenja ekspresije izoenzima, pripadnika GST klase alfa, sa posledi~nom promenom redoks statusa, {to pogoduje razvoju karcinoma bubrega svetlih }elija. Enzimska aktivnost GST pi je neizmenjena u karcinoma bubrega svetlih }elija i mo`e doprinositi hemorezistenciji ovih tumora. U nastanku malignog fenotipa karcinoma prelaznog epitela mokra}ne be{ike zna~ajnu ulogu ima pove}ana ekspresija razli~itih klasa GST. Pove}ana ekspresija GSTT1-1 i GSTP1-1 mo`e zna~ajno uticati na rast tumora, pomeranjem ravnote`e izme|u proi antioksidanasa ka redukovanom stanju, {to pogoduje inhibiciji apoptotskih puteva.