Povezanost polimorfizama glutation transferaza A1, M1, P1 i T1 sa pokazateljima oksidativnog stresa i kardiovaskularnim komplikacijama kod bolesnika sa terminalnom bubrežnom slabošću

Chronic kidney disease is described as a progressive and irreversible deterioration in kidney function. When there is less than 10% of nephron function pertained, the patients face endstage renal disease where renal replacement therapy is needed. Data show that hemodialysis is the most common method used to treat advanced and permanent kidney failure. Increased oxidative stress is a hallmark of end-stage renal disease (ESRD). Glutathione transferases (GST) are involved in the detoxification of xenobiotics and protection of oxidative damage. The role of polymorphic expression of GSTSs in end-stage renal disease development enhanced oxidative stress and prognosis of ESRD patients has emerged recently. The aim of this study was to test if the genetic polymorphism in antioxidant enzymes GSTA1, GSTM1, GSTP1 and GSTT1 is more frequent in ESRD patients than in control group, and if it modulates the levels of oxidative stress byproducts and cellular adhesion molecules in these patients. The association between GSTM1 and GSTT1 deletion polymorphisms as well as SNPs in GSTA1/rs3957357, GSTP1/rs1695 and rs1138272 genes with overall and causespecific cardiovascular mortality in patients with end-stage renal disease was also assessed. Furthermore, the predictive role of oxidative stress byproducts and adhesion molecules level was also tested. Individuals with either GSTM1-null or GSTP1*C/*T genotypes were at increased susceptibility towards ESRD development than individuals with GSTM1-active or GSTP1*C/*C genotypes (OR = 1.6, p = 0.024 and OR = 3.2, p = 0.001, respectively). This risk was even more increased when these genotypes were combined with other GST null/low activity genotypes. Polymorphic expression of GST gene influences the vulnerability to protein and lipid oxidation, as well as the levels of soluble cellular adhesion molecules in plasma of ESRD patients. The oxidative stress byproducts were even more increased in terms of combined GST genotypes. Regarding predictive role of GST genotypes, only GSTM1-null genotype in ESRD patients was found to be independent predictor of overall and cardiovascular mortality (overall: HR = 1.8, p = 0.009; cardiovascular: HR = 2.3, p = 0.006 and myocardial infarction: HR = 2.3, p = 0.035). Possible predictive role for the byproducts of oxidative stress was found for higher concentrations (above the median for each product) of MDA, AOPP, PAB and VCAM-1 regarding overall and cardiovascular survival. Comparison of two endothelial cells with different GSTM1 genotypes in terms of monocyte adhesion and reactive oxygen species production after incubation in uremic serum was not significantly different. Taken together, the results presented in this study suggest a possibility for GST genotypebased stratification of ESRD patients which could improve the attempts towards individualization of antioxidant treatment. Besides, determination of oxidative stress byproducts may permit the targeting of preventive and early intervention in high-risk patients to reduce their cardiovascular risk.Hronična bubrežna slabost se opisuje kao progresivno i ireverzibilno smanjenje bubrežne funkcije. Kada se funkcija bubrega smanji na ispod 10% od normalnih vrednosti, nastupa stanje koje se zove terminalna bubrežna slabost kada je neophodna primena terapije neke od meoda zamene bubrežne funkcije. Podaci pokazuju da je hemodijaliza najčešće primenjivan metod. Povećana produkcija slobodnih radikala i stanje oksidativnog stresa glavna su obeležja terminalne bubrežne slabosti. Glutation transferaze (GST) su enzimi koji su uključeni u procese eliminacije ksenobiotika i antioksidativne zaštite. Ipak do sada još uvek nije dovoljno ispitana njihova uloga u podložnosti za razvoj terminalne bubrežne slabosti, oksidativnog stresa kod ovih bolesnika kao i moguća prediktivna uloga. Imajući ovo u vidu, cilj ove teze bio je da se ispita veza između polimorfizama gena za GSTA1, GSTM1, GSTP1 i GSTT1 u podložnosti za razvoj terminalne bubrežne slabosti, kao i da se utvrdi da li polimorfna ekpresija glutation transferaza utiče na vrednosti produkata oksidativnog stresa i adhezionih molekula u plazmi bolesnika sa terminalnom bubrežnom slabošću. Takođe, jedan od ciljeva bio je i da se ispita da li polimorfizam GST gena može da ima prognostički značaj u smislu opšteg ili kardiovaskularnog preživljavanja kod ovih bolesnika. Dodatno, ispitan je i prediktivni značaj biohemijskih pokazatelja oksidativnog stresa i adhezionih molekula. Osobe koje su imale GSTM1-nulti i GSTP1*C/*T genotip imale su veću podložnost za razvoj terminalne bubrežne slabosti (OR = 1.6, p = 0.024 and OR = 3.2, p = 0.001, redom), koja je još više bila izražena kada su se ovi genotipovi kombinovali sa drugim GST nultim ili genotipovima smanjenih aktivnosti. Takođe, polimorfna ekspresija glutation transferaza kod bolesnika sa terminalnom bubrežnom slabošću utiče na nivo oksidativnog oštećenja proteina, lipida i adhezionih molekula. Produkti oksidativnog stresa su još više izraženi kod bolesnika kod kojih postoji kombinacija GST nultog ili genotipova smanjenih aktivnosti. U ovoj tezi je pokazano i da GSTM1-nulti genotip ima značajnu ulogu kao prediktor opšteg i kardiovaskularnog uzroka smrti (opšti uzrok smrti: HR = 1.8, p = 0.009; kardiovaskularni uzrok: HR = 2.3, p = 0.006 i infarct miokarda: HR = 2.3, p = 0.035). Takođe, pokazano je i da više vrednosti (iznad nivoa medijane vrednosti određene za svaki produkt pojedinačno) MDA, AOPP, PAB i VCAM-1 imaju prognostički značaj kod opšteg i kardiovaskularnog preživljanja u bolesnika sa terminalnom bubrežnom slabošću. Produkcija slobodnih radikala i adhezija monocita za endotelne ćelije nije se razlikovala između HUVEC sa GSTM1-aktivnim i GSTM1- nultim genotipom. Rezultati iz ove teze ukazuju da bolesnici sa terminalnom bubrežnom slabošću mogu da se stratifikuju prema GST genotipu sa ciljem unapređenja antioksidantne terapije. Takođe, merenje produkata oksidativnog stresa može da posluži da se odredi kod kojih bolesnika treba započeti rane preventivne mere da bi se smanjio rizik od kardiovaskularnih komplikacija

Glial cells, blood brain barrier and cytokines in seizures: Implications for therapeutic modalities

Epilepsy is a chronic, common, neurological disorder marked by transient, paroxysmal and hypersynchronous activity of the brain neurons, behaviorally manifested as seizures. It is developed through the process of epileptogenesis which alters neuronal excitability, establishes critical interconnections and develop neuronal hyperexcitability and degeneration, as well as the neuronal network reorganization as its main mechanisms. There are a number of different mechanisms of epileptogenesis, including neuroinflammation as a recently highlighted important novel mechanism. In this review paper, our focus will be to light up the latest findings about neuroinflammation as a pathogenic factor in epileptogenesis. Neuroinflammation is characterized by the structural and functional alteration of the CNS glial cells and peripherally derived immune cells with the presence of blood-brain barrier (BBB) dysfunction as main mechanisms. Disequilibrium in the CNS microenvironment is often followed by increased synthesis of proinflammatory cytokines (IL-6, IL-1β, TNF-α, IFN-γ) and chemokines. The interplay between glial alteration, BBB dysfunction, cytokines and chemokines establish a positive feedback cascade for further epileptogenesis. It is still unclear if neuroinflammation is causing epileptogenesis or whether in a consequence of that, but, there are clear findings about positive feedback between these two processes. This interconnection could be a helpful key to better target therapeutic treatment of neuroinflammation for providing beneficial effects for patients with epilepsy

GSTM1-null and GSTT1-active genotypes as risk determinants of primary open angle glaucoma among smokers

AIM: To evaluate glutathione transferase theta 1 and mu 1 (GSTT1 and GSTM1) polymorphisms as determinants of primary open angle glaucoma (POAG) risk, independently or in combination with cigarette smoking, hypertension and diabetes mellitus. METHODS: A case-control study with 102 POAG patients and 202 age and gender-matched controls was carried out. Multiplex-polymerase chain reaction method was used for the analysis of GSTM1 and GSTT1 polymorphisms. The differences between two groups were tested by the t-test or chi(2) test. Logistic regression analysis was used for assessing the risk for disease development. RESULTS: The presence of GSTM1-null genotype did not contribute independently towards the risk of POAG. However, individuals with GSTT1-active genotype were at almost two-fold increased risk to develop glaucoma (P=0.044) which increased up to 4.36 when combined with GSTM1-null carriers (P=0.024). When glutathione transferase (GST) genotypes were analyzed in association with cigarette smoking, hypertension and diabetes, only carriers of GSTT1-active genotype had significantly increased risk of POAG development in comparison with GSTT1-null genotype individuals with no history of smoking, hypertension and diabetes, respectively (OR=3.52, P=0.003; OR=10.02, P lt 0.001; OR=4.53, P=0.002). CONCLUSION: The results obtained indicate that both GSTM1-null and GSTT1-active genotypes are associated with increased POAG risk among smokers, suggesting potential gene-environment interaction in glaucoma development

Vitamin E-Bonded Membranes Do Not Influence Markers of Oxidative Stress in Hemodialysis Patients with Homozygous Glutathione Transferase M1 Gene Deletion

Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first study to use the vitamin E-bonded membranes (VEM) in patients with homozygousGSTM1gene deletion, and we aimed to determine the effect of VEM on oxidative and inflammatory status in HD patients with homozygousGSTM1gene deletion. Methods:GSTM1genotypes were determined by polymerase chain reaction (PCR) in 170 chronic HD patients. Those withGSTM1-nullgenotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VEM, while the other forty were dialyzed with high-flux same-surface polysulfone dialyzers. Markers of protein and lipid oxidative damage and inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined. Results: Seventy-five patients finished the study. There were no differences at baseline in markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, and thiol groups increased significantly in both groups, but without statistical significance between groups. SOD and C reactive protein (CRP) did not change significantly during the three-month period. IL-6 increased in the control group, and at the same time, decreased in the VEM group, but without statistical significance. Hemoglobin (Hb) value, red blood cells, erythropoiesis resistance index (ERI), serum ferritin and iron did not change significantly within or between groups. Regarding other laboratory parameters, proteins, albumins, triglycerides, serum phosphorus, serum bicarbonate and Kt/V showed significant improvements within groups but with no significant difference between groups. Conclusions: Our data shows that therapy with VEM over three months had no benefit over standard polysulfone membrane in decreasing by-products of oxidative stress and inflammation in dialysis patients lacking GSTM1 enzyme activity

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, GSM, 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

Povezanost polimorfizama glutation transferaza A1, M1, P1 i T1 sa pokazateljima oksidativnog stresa i kardiovaskularnim komplikacijama kod bolesnika sa terminalnom bubrežnom slabošću

Chronic kidney disease is described as a progressive and irreversible deterioration in kidney function. When there is less than 10% of nephron function pertained, the patients face endstage renal disease where renal replacement therapy is needed. Data show that hemodialysis is the most common method used to treat advanced and permanent kidney failure. Increased oxidative stress is a hallmark of end-stage renal disease (ESRD). Glutathione transferases (GST) are involved in the detoxification of xenobiotics and protection of oxidative damage. The role of polymorphic expression of GSTSs in end-stage renal disease development enhanced oxidative stress and prognosis of ESRD patients has emerged recently. The aim of this study was to test if the genetic polymorphism in antioxidant enzymes GSTA1, GSTM1, GSTP1 and GSTT1 is more frequent in ESRD patients than in control group, and if it modulates the levels of oxidative stress byproducts and cellular adhesion molecules in these patients. The association between GSTM1 and GSTT1 deletion polymorphisms as well as SNPs in GSTA1/rs3957357, GSTP1/rs1695 and rs1138272 genes with overall and causespecific cardiovascular mortality in patients with end-stage renal disease was also assessed. Furthermore, the predictive role of oxidative stress byproducts and adhesion molecules level was also tested. Individuals with either GSTM1-null or GSTP1*C/*T genotypes were at increased susceptibility towards ESRD development than individuals with GSTM1-active or GSTP1*C/*C genotypes (OR = 1.6, p = 0.024 and OR = 3.2, p = 0.001, respectively). This risk was even more increased when these genotypes were combined with other GST null/low activity genotypes. Polymorphic expression of GST gene influences the vulnerability to protein and lipid oxidation, as well as the levels of soluble cellular adhesion molecules in plasma of ESRD patients. The oxidative stress byproducts were even more increased in terms of combined GST genotypes. Regarding predictive role of GST genotypes, only GSTM1-null genotype in ESRD patients was found to be independent predictor of overall and cardiovascular mortality (overall: HR = 1.8, p = 0.009; cardiovascular: HR = 2.3, p = 0.006 and myocardial infarction: HR = 2.3, p = 0.035). Possible predictive role for the byproducts of oxidative stress was found for higher concentrations (above the median for each product) of MDA, AOPP, PAB and VCAM-1 regarding overall and cardiovascular survival. Comparison of two endothelial cells with different GSTM1 genotypes in terms of monocyte adhesion and reactive oxygen species production after incubation in uremic serum was not significantly different. Taken together, the results presented in this study suggest a possibility for GST genotypebased stratification of ESRD patients which could improve the attempts towards individualization of antioxidant treatment. Besides, determination of oxidative stress byproducts may permit the targeting of preventive and early intervention in high-risk patients to reduce their cardiovascular risk.Hronična bubrežna slabost se opisuje kao progresivno i ireverzibilno smanjenje bubrežne funkcije. Kada se funkcija bubrega smanji na ispod 10% od normalnih vrednosti, nastupa stanje koje se zove terminalna bubrežna slabost kada je neophodna primena terapije neke od meoda zamene bubrežne funkcije. Podaci pokazuju da je hemodijaliza najčešće primenjivan metod. Povećana produkcija slobodnih radikala i stanje oksidativnog stresa glavna su obeležja terminalne bubrežne slabosti. Glutation transferaze (GST) su enzimi koji su uključeni u procese eliminacije ksenobiotika i antioksidativne zaštite. Ipak do sada još uvek nije dovoljno ispitana njihova uloga u podložnosti za razvoj terminalne bubrežne slabosti, oksidativnog stresa kod ovih bolesnika kao i moguća prediktivna uloga. Imajući ovo u vidu, cilj ove teze bio je da se ispita veza između polimorfizama gena za GSTA1, GSTM1, GSTP1 i GSTT1 u podložnosti za razvoj terminalne bubrežne slabosti, kao i da se utvrdi da li polimorfna ekpresija glutation transferaza utiče na vrednosti produkata oksidativnog stresa i adhezionih molekula u plazmi bolesnika sa terminalnom bubrežnom slabošću. Takođe, jedan od ciljeva bio je i da se ispita da li polimorfizam GST gena može da ima prognostički značaj u smislu opšteg ili kardiovaskularnog preživljavanja kod ovih bolesnika. Dodatno, ispitan je i prediktivni značaj biohemijskih pokazatelja oksidativnog stresa i adhezionih molekula. Osobe koje su imale GSTM1-nulti i GSTP1*C/*T genotip imale su veću podložnost za razvoj terminalne bubrežne slabosti (OR = 1.6, p = 0.024 and OR = 3.2, p = 0.001, redom), koja je još više bila izražena kada su se ovi genotipovi kombinovali sa drugim GST nultim ili genotipovima smanjenih aktivnosti. Takođe, polimorfna ekspresija glutation transferaza kod bolesnika sa terminalnom bubrežnom slabošću utiče na nivo oksidativnog oštećenja proteina, lipida i adhezionih molekula. Produkti oksidativnog stresa su još više izraženi kod bolesnika kod kojih postoji kombinacija GST nultog ili genotipova smanjenih aktivnosti. U ovoj tezi je pokazano i da GSTM1-nulti genotip ima značajnu ulogu kao prediktor opšteg i kardiovaskularnog uzroka smrti (opšti uzrok smrti: HR = 1.8, p = 0.009; kardiovaskularni uzrok: HR = 2.3, p = 0.006 i infarct miokarda: HR = 2.3, p = 0.035). Takođe, pokazano je i da više vrednosti (iznad nivoa medijane vrednosti određene za svaki produkt pojedinačno) MDA, AOPP, PAB i VCAM-1 imaju prognostički značaj kod opšteg i kardiovaskularnog preživljanja u bolesnika sa terminalnom bubrežnom slabošću. Produkcija slobodnih radikala i adhezija monocita za endotelne ćelije nije se razlikovala između HUVEC sa GSTM1-aktivnim i GSTM1- nultim genotipom. Rezultati iz ove teze ukazuju da bolesnici sa terminalnom bubrežnom slabošću mogu da se stratifikuju prema GST genotipu sa ciljem unapređenja antioksidantne terapije. Takođe, merenje produkata oksidativnog stresa može da posluži da se odredi kod kojih bolesnika treba započeti rane preventivne mere da bi se smanjio rizik od kardiovaskularnih komplikacija

Glial cells, blood brain barrier and cytokines in seizures: Implications for therapeutic modalities

info:eu-repo/semantics/publishe