RESUMEN
Although disturbance of redox homeostasis might be responsible for COVID-19 cardiac complications, this molecular mechanism has not been addressed yet. We have proposed modifying the effects of antioxidant proteins polymorphisms (superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GPX1), glutathione peroxidase 3 (GPX3) and nuclear factor erythroid 2-related factor 2, (Nrf2)) in individual susceptibility towards the development of cardiac manifestations of long COVID-19. The presence of subclinical cardiac dysfunction was assessed via echocardiography and cardiac magnetic resonance imaging in 174 convalescent COVID-19 patients. SOD2, GPX1, GPX3 and Nrf2 polymorphisms were determined via the appropriate PCR methods. No significant association of the investigated polymorphisms with the risk of arrhythmia development was found. However, the carriers of variant GPX1*T, GPX3*C or Nrf2*A alleles were more than twice less prone for dyspnea development in comparison with the carriers of the referent ones. These findings were even more potentiated in the carriers of any two variant alleles of these genes (OR = 0.273, and p = 0.016). The variant GPX alleles were significantly associated with left atrial and right ventricular echocardiographic parameters, specifically LAVI, RFAC and RV-EF (p = 0.025, p = 0.009, and p = 0.007, respectively). Based on the relation between the variant SOD2*T allele and higher levels of LV echocardiographic parameters, EDD, LVMI and GLS, as well as troponin T (p = 0.038), it can be proposed that recovered COVID-19 patients, who are the carriers of this genetic variant, might have subtle left ventricular systolic dysfunction. No significant association between the investigated polymorphisms and cardiac disfunction was observed when cardiac magnetic resonance imaging was performed. Our results on the association between antioxidant genetic variants and long COVID cardiological manifestations highlight the involvement of genetic propensity in both acute and long COVID clinical manifestations.
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Antioxidantes , COVID-19 , Humanos , Síndrome Post Agudo de COVID-19 , Factor 2 Relacionado con NF-E2 , COVID-19/diagnóstico por imagen , COVID-19/genética , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa GPX1 , Superóxido Dismutasa/metabolismo , EcocardiografíaRESUMEN
In SARS-CoV-2 infection, excessive activation of the immune system intensively increases reactive oxygen species levels, causing harmful hyperinflammatory and oxidative state cumulative effects which may contribute to COVID-19 severity. Therefore, we assumed that antioxidant genetic profile, independently and complemented with laboratory markers, modulates COVID-19 severity. The study included 265 COVID-19 patients. Polymorphism of GSTM1, GSTT1, Nrf2 rs6721961, GSTM3 rs1332018, GPX3 rs8177412, GSTP1 rs1695, GSTO1 rs4925, GSTO2 rs156697, SOD2 rs4880 and GPX1 rs1050450 genes was determined with appropriate PCR-based methods. Inflammation (interleukin-6, CRP, fibrinogen, ferritin) and organ damage (urea, creatinine, transaminases and LDH) markers, complete blood count and coagulation status (d-dimer, fibrinogen) were measured. We found significant association for COVID-19 progression for patients with lymphocytes below 1.0 × 109/L (OR = 2.97, p = 0.002). Increased IL-6 and CRP were also associated with disease progression (OR = 8.52, p = 0.001, and OR = 10.97, p < 0.001, respectively), as well as elevated plasma AST and LDH (OR = 2.25, p = 0.021, and OR = 4.76, p < 0.001, respectively). Of all the examined polymorphisms, we found significant association with the risk of developing severe forms of COVID-19 for GPX3 rs8177412 variant genotype (OR = 2.42, p = 0.032). This finding could be of particular importance in the future, complementing other diagnostic tools for prediction of COVID-19 disease course.
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COVID-19 , Humanos , COVID-19/genética , SARS-CoV-2 , Genotipo , Polimorfismo Genético , Fibrinógeno/genética , Glutatión Peroxidasa/genética , Glutatión Transferasa/genéticaRESUMEN
Background and Objectives: Oxidative stress induced by increased reactive oxygen species (ROS) production plays an important role in carcinogenesis. The entire urinary tract is continuously exposed to numerous potentially mutagenic environmental agents which generate ROS during their biotransformation. In first line defense against free radicals, antioxidant enzymes superoxide dismutase (SOD2) and glutathione peroxidase (GPX1) both have essential roles. Altered enzyme activity and decreased ability of neutralizing free oxygen radicals as a consequence of genetic polymorphisms in genes encoding these two enzymes are well described so far. This study aimed to investigate the association of GPX1 (rs1050450) and SOD2 (rs4880) genetic variants with the urothelial bladder cancer (UBC) risk independently and in combination with smoking. Furthermore, we aimed to determine whether the UBC stage and pathological grade were influenced by GPX1 and SOD2 polymorphisms. Material and Methods: The study population included 330 patients with UBC (mean age 65 ± 10.3 years) and 227 respective controls (mean age 63.4 ± 7.9 years). Single nucleotide polymorphism (SNP) of GPX1 (rs1050450) was analyzed using the PCR-RFLP, while SOD2 (rs4880) SNP was analyzed using the q-PCR method. Results: Our results showed that UBC risk was significantly increased among carriers of at least one variant SOD2 Val allele compared to the SOD2 Ala16Ala homozygotes (OR = 1.55, p = 0.03). Moreover, this risk was even more pronounced in smokers with at least one variant SOD2 Val allele, since they have even 7.5 fold higher UBC risk (OR = 7.5, p < 0.001). Considering GPX1 polymorphism, we have not found an association with UBC risk. However, GPX1 genotypes distribution differed significantly according to the tumor stage (p Ë 0.049) and pathohistological grade (p Ë 0.018). Conclusion: We found that SOD2 genetic polymorphism is associated with the risk of UBC development independently and in combination with cigarette smoking. Furthermore, we showed that GPX1 genetic polymorphism is associated with the aggressiveness of the disease.
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Antioxidantes , Neoplasias de la Vejiga Urinaria , Humanos , Persona de Mediana Edad , Anciano , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa GPX1 , Especies Reactivas de Oxígeno , Polimorfismo de Nucleótido Simple/genética , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Genotipo , Neoplasias de la Vejiga Urinaria/genética , Radicales Libres , Predisposición Genética a la Enfermedad , Estudios de Casos y ControlesRESUMEN
Background and Objectives: In the development of type 2 diabetes mellitus (T2DM) and its complications, genetic and environmental factors play important roles. Diabetic nephropathy (DN), one of the major microangiopathic chronic diabetic complications, is associated with an increased risk of major cardiovascular events and all-cause mortality. The present study was designed to investigate the possible modifying effect of glutathione transferase polymorphisms (GSTM1, GSTT1, GSTP1 rs1138272/rs1695, GSTO1 rs4925 and GSTO2 rs156697) in the susceptibility to T2DM and diabetic nephropathy. Materials and Methods: GSTM1 and GSTT1 deletion polymorphisms were determined by multiplex PCR, whereas GSTO1, GSTO2, and GSTP1 polymorphisms were determined by the real-time PCR in 160 T2DM patients and 248 age- and gender-matched controls. Advanced glycation end products (AGEs) were measured by ELISA. Results: Among six investigated GST polymorphisms, a significant association between the GST genotypes and susceptibility for development of diabetes mellitus was found for the GSTM1, GSTT1, GSTP1 (rs1138272) and GSTO1 polymorphisms. When the GST genotypes' distribution in diabetes patients was assessed in the subgroups with and without diabetic nephropathy, a significant association was found only for the GSTO2 rs156697 polymorphism. Diabetic patients, carriers of the GSTM1 null, GSTT1 null and variant GSTO1*AA genotypes, had significantly increased levels of AGEs in comparison with carriers of the GSTM1 active, GSTT1 active and referent GSTO1*CC genotypes (p < 0.001, p < 0.001, p = 0.004, respectively). Conclusions: The present study supports the hypothesis that GST polymorphisms modulate the risk of diabetes and diabetic nephropathy and influence the AGEs concentration, suggesting the potential regulatory role of these enzymes in redox homeostasis disturbances.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , Glutatión Transferasa/genética , Genotipo , Productos Finales de Glicación Avanzada , Factores de RiesgoRESUMEN
Current data suggest that aristolochic acid (AA) exposure is a putative cause of Balkan endemic nephropathy (BEN), a chronic kidney disease strongly associated with upper tract urothelial carcinoma. The cellular metabolism of AA is associated with the production of reactive oxygen species, resulting in oxidative distress. Purpose: Therefore, the aim of this study was to analyze individual, combined and cumulative effect of antioxidant gene polymorphisms (Nrf2 rs6721961, KEAP1 rs1048290, GSTP1AB rs1695, GSTP1CD rs1138272, GPX3 rs8177412 and MDR1 rs1045642), as well as GSTP1ABCD haplotypes with the risk for BEN development and associated urothelial cell carcinoma in 209 BEN patients and 140 controls from endemic areas. Experimental method: Genotyping was performed using polymerase chain reaction (PCR) and PCR with confronting two-pair primers (PCR-CTTP) methods. Results: We found that female patients carrying both variant GPX3 rs8177412 and MDR1 rs1045642 genotypes in combination exhibited significant risk towards BEN (OR 1 = 3.34, 95% CI = 1.16-9.60, p = 0.025; OR 2 = 3.79, 95% CI = 1.27-11.24, p = 0.016). Moreover, significant association was determined between GPX3rs8174412 polymorphism and risk for urothelial carcinoma. Carriers of variant GPX3*TC + CC genotype were at eight-fold increased risk of BEN-associated urothelial tumors development. There was no individual or combined impact on BEN development and BEN-associated tumors among all examined polymorphisms. The haplotype consisting of variant alleles for both polymorphisms G and T was associated with 1.6-fold increased risk although statistically insignificant (OR = 1.64; 95% CI = 0.75-3.58; p = 0.21). Conclusions: Regarding GPX3 rs8177412 polymorphism, the gene variant that confers lower expression is associated with significant increase in upper urothelial carcinoma risk. Therefore, BEN patients carrying variant GPX3 genotype should be more frequently monitored for possible upper tract urothelial carcinoma development.
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Nefropatía de los Balcanes , Carcinoma de Células Transicionales , Enfermedades Renales , Neoplasias de la Vejiga Urinaria , Humanos , Femenino , Neoplasias de la Vejiga Urinaria/genética , Nefropatía de los Balcanes/genética , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Glutatión Peroxidasa/genéticaRESUMEN
Using comprehensive analysis of heart rate (HRV) and blood pressure (BPV) short-term variability we estimated the time course of changes of autonomic nervous system remodeling in two stages of doxorubicin-induced cardiomyopathy (DCM). We also investigated the level of gene expression of cardiac ß-1 (ß-1AR) and ß-2 (ß-2AR) adrenoceptors. Experiments were performed in adult male Wistar rats equipped with indwelling catheters for BP recording and blood withdrawal. A 15 mg/kg total cumulative dose of doxorubicin was injected i.p. to rats to induce DCM or saline for control (n=18). Rats were assessed for general toxicity, cardiovascular hemodynamic and echocardiography before treatment (n=6), 35 days (DOX35; n=6) and 70 days (DOX70; n=6) post-treatment. HRV was evaluated by spectral analysis, Poincaré plots, sample and approximate entropy. Expression of ß-1AR and ß-2AR mRNA was evaluated by RT-qPCR. Doxorubicin-treated rats exhibited poor general condition and lower survival than saline-treated rats. In DOX35 rats, there were no echocardiography signs of decompensation, no increase in serum cardiac troponins, but there was an increase of HRV and decrease of HR complexity. In these rats typical microscopic signs of cardiotoxicity were seen along with over-expression of ß-1AR mRNA. 70 days post-treatment echocardiography revealed signs of decompensation and serum cardiac troponin T was increased. At this stage BPV decreased. In conclusion, HRV increase matches transient over-expression of cardiac ß-1AR mRNA in compensate stage of DCM while decompensate stage of DCM is characterized by a decrease of BPV and no changes in ß-1AR and ß-2AR gene expression.
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Antibióticos Antineoplásicos/toxicidad , Cardiomiopatías/inducido químicamente , Doxorrubicina/toxicidad , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Animales , Presión Sanguínea/efectos de los fármacos , Cardiomiopatías/genética , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Ecocardiografía , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Miocardio/metabolismo , Miocardio/patología , Ratas WistarRESUMEN
INTRODUCTION: Overall survival of patients with end-stage renal disease (ESRD) remains poor. Oxidative stress is one of the major risk factors associated with mortality in this patient group. As glutathione S-transferases (GST) are well-established antioxidants, we hypothesized that a model including GST gene polymorphisms, oxidative damage byproducts and cell adhesion markers has a prognostic role in ESRD patient survival. METHODS: A prospective study of 199 patients with ESRD on haemodialysis was conducted. GST genotype, oxidative stress byproducts and cell adhesion molecules were measured in plasma. Multivariate Cox regression and Kaplan-Meier survival analyses were performed to test the predictive ability of these parameters in the 8-year follow-up period. RESULTS: GSTM1-null genotype was associated with significantly shorter overall (HR 1.6, p = 0.018) and cardiovascular-specific (HR 2.1, p = 0.010) survival. Oxidative stress byproducts (advanced oxidation protein products [AOPP], prooxidant-antioxidant balance [PAB], malondialdehyde [MDA]) and cell adhesion molecules (soluble vascular cell adhesion molecule-1 [sVCAM-1] and soluble intercellular adhesion molecule-1 [sICAM-1]) demonstrated a significant predictive role in terms of overall and cardiovascular survival. When 6 biomarkers (GSTM1 genotype, high AOPP/PAB/MDA/-sVCAM-1/sICAM-1) were combined into a scoring model, a significantly shorter overall and cardiovascular survival was observed for patients with the highest score (p < 0.001). CONCLUSION: We identified a novel panel of biomarkers that can be utilized in predicting survival in ESRD patients. This biomarker signature could enable better monitoring of patients and stratification into appropriate treatment groups.
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Enfermedades Cardiovasculares/mortalidad , Glutatión Transferasa/genética , Fallo Renal Crónico/mortalidad , Diálisis Renal , Anciano , Biomarcadores/análisis , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Toma de Decisiones Clínicas , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Molécula 1 de Adhesión Intercelular/metabolismo , Estimación de Kaplan-Meier , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/genética , Fallo Renal Crónico/terapia , Masculino , Malondialdehído/sangre , Malondialdehído/metabolismo , Persona de Mediana Edad , Estrés Oxidativo , Selección de Paciente , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo/métodos , Molécula 1 de Adhesión Celular Vascular/sangre , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Background: Experimental data show that superoxide dismutase 2 (SOD2) is involved in ochratoxin (OTA)-induced nephrotoxicity, whereas clinical data indicate the role of SOD2 rs4880 or glutathione peroxidase 1 (GPX1) rs1050450 polymorphisms in end-stage renal disease and urothelial carcinoma risk, known to be the major complications of Balkan endemic nephropathy (BEN). Therefore, we hypothesized that SOD2 and GPX1 gene polymorphisms would influence the risk of BEN and its associated tumors. Materials and Methods: The study was conducted in 207 BEN patients and 86 controls from endemic areas. Results: Individuals with both copies of variant SOD2 allele, known for lower mitochondrial antioxidant protection, are at a significantly higher BEN risk (OR = 2.6, p = 0.021). No association was observed between GPX1 gene polymorphism and BEN risk. Combining SOD2 and GPX1 genotypes did not alter the risk of BEN development. Regarding the risk of urothelial tumors in BEN patients, none of the polymorphisms studied was significantly associated with the risk of these tumors. Conclusions: Polymorphism in SOD2 rs4880 gene affects the risk of BEN development. Hence, SOD2 genotyping could, together with a panel of other enzymes, be used as a biomarker of susceptibility in BEN areas.
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Nefropatía de los Balcanes/genética , Glutatión Peroxidasa/genética , Polimorfismo Genético/genética , Superóxido Dismutasa/genética , Anciano , Anciano de 80 o más Años , Nefropatía de los Balcanes/epidemiología , Nefropatía de los Balcanes/fisiopatología , Biomarcadores/análisis , Biomarcadores/sangre , Bosnia y Herzegovina/epidemiología , Femenino , Glutatión Peroxidasa/sangre , Humanos , Masculino , Serbia/epidemiología , Superóxido Dismutasa/sangre , Glutatión Peroxidasa GPX1RESUMEN
Glutathione S-transferases (GSTs), a superfamily of multifunctional enzymes, play an important role in the onset and progression of renal cell carcinoma (RCC). However, novel GST omega class (GSTO), consisting of GSTO1-1 and GSTO2-2 isoenzymes, has not been studied in RCC yet. Two coding single nucleotide polymorphisms (SNPs) supposedly affect their functions: GSTO1*C419A (rs4925) causing alanine to aspartate substitution (*A140D) and GSTO2*A424G (rs156697) causing asparagine to aspartate substitution (*N142D), and have been associated with several neurodegenerative diseases and cancers. Functional relevance of yet another GSTO2 polymorphism, identified at the 5' untranslated (5'UTR) gene region (GSTO2*A183G, rs2297235), has not been clearly discerned so far. Therefore, we aimed to assess the effect of specific GSTO1 and GSTO2 gene variants, independently and in interaction with established risk factors (smoking, obesity and hypertension) on the risk for the most aggressive RCC subtype, the clear cell RCC (ccRCC). Genotyping was performed in 239 ccRCC patients and 350 matched controls, while plasma levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, were determined by ELISA. As a result, combined effect of all three variant genotypes exhibited almost 3-fold risk of RCC development. Additionally, this association was confirmed at the haplotype level [variant GSTO1*A/GSTO2*G (rs156697)/GSTO2*G (rs2297235) haplotype], suggesting a potential role of those variants in propensity to RCC. Regarding the gene-environment interactions, variant GSTO2*G (rs156697) homozygous smokers are at higher ccRCC risk. Association in terms of oxidative DNA damage was found for GSTO2 polymorphism in 5'UTR and 8-OHdG. In conclusion, the concomitance of GSTO polymorphisms may influence ccRCC risk.
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Carcinoma de Células Renales/genética , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Neoplasias Renales/genética , Polimorfismo de Nucleótido Simple/genética , 8-Hidroxi-2'-Desoxicoguanosina , Estudios de Casos y Controles , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Femenino , Haplotipos/genética , Humanos , Hipertensión/genética , Masculino , Persona de Mediana Edad , Obesidad/genética , Factores de RiesgoRESUMEN
Multifunctional enzymes glutathione transferases (GSTs) are involved in the development of chemoresistance, thus representing a promising target for a novel approach in cancer treatment. This superfamily of polymorphic enzymes exhibits extraordinary substrate promiscuity responsible for detoxification of numerous conventional chemotherapeutics, at the same time regulating signaling pathways involved in cell proliferation and apoptosis. In addition to upregulated GST expression, different cancer cell types have a unique GST signature, enabling targeted selectivity for isoenzyme specific inhibitors and pro-drugs. As a result of extensive research, certain GST inhibitors are already tested in clinical trials. Catalytic properties of GST isoenzymes are also exploited in bio-activation of specific pro-drugs, enabling their targeted accumulation in cancer cells with upregulated expression of the appropriate GST isoenzyme. Moreover, the latest approach to increase specificity in treatment of solid tumors is development of GST pro-drugs that are derivatives of conventional anti-cancer drugs. A future perspective is based on the design of new drugs, which would selectively target GST overexpressing cancers more prone to developing chemoresistance, while decreasing side effects in off-target cells.
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Inhibidores Enzimáticos/uso terapéutico , Glutatión Transferasa/antagonistas & inhibidores , Glutatión Transferasa/metabolismo , Animales , Resistencia a Antineoplásicos , Humanos , Profármacos/uso terapéutico , Unión ProteicaRESUMEN
PURPOSE: Menopause is frequently associated with an increase in visceral fat, thus modifying redox status by promoting oxidative damage and decreasing antioxidant defense systems. It is known that at higher concentrations estradiol has some antioxidant properties, while its decline in postmenopause is associated with pro-oxidant effects. However, the role of follicle stimulating hormone (FSH) in antioxidant defense in postmenopausal women is still not well elucidated. Therefore, we aimed to evaluate the potential complex association between visceral obesity, FSH and enzymatic antioxidant defense as measured by glutathione peroxidase (GPx) in postmenopausal women. METHODS: A total of 150 postmenopausal women (mean age 56.6 ± 4.8 years), among them 50 normal weight and 100 overweight/obese, were included. GPx activity, FSH, luteinizing hormone, estradiol, total testosterone, cardiometabolic and anthropometric parameters, were determined. RESULTS: With increasing tertiles of serum FSH levels, significant increase in GPx activity (P = 0.005) was found. Also, the highest number of overweight/obese subjects were in the group with the lowest FSH values (χ 2 = 14.9, P < 0.001). After multiple linear regression analysis, the relationship between GPx and FSH disappeared, whereas only higher waist circumference (ß = -0.218, P = 0.045) predicted lower FSH level (adjusted R 2 = 0.227). CONCLUSION: Higher GPx activity is associated with higher FSH level, but abdominal obesity may be the underlying determinant of this relationship.
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Hormona Folículo Estimulante/sangre , Glutatión Peroxidasa/sangre , Obesidad Abdominal/sangre , Posmenopausia/sangre , Presión Sanguínea/fisiología , Estradiol/sangre , Femenino , Humanos , Resistencia a la Insulina/fisiología , Hormona Luteinizante/sangre , Persona de Mediana Edad , Circunferencia de la Cintura/fisiologíaRESUMEN
PURPOSE: Purpose: Urothelial bladder cancer (UBC) is the most common malignancy of urinary tract in the developed world. In metastatic UBC, systemic chemotherapy still remains the mainstay of initial treatment. Inter-individual differences in treatment outcome partially may be the consequence of genetic variations in enzymes that modulate oxidative stress. Therefore, we aimed to determine the potential prognostic role of single nucleotide polymorphism (SNP) of the two antioxidant enzymes glutathione peroxidase 1 (GPX1) and superoxide dismutase 2 (SOD2) in metastatic UBC patients treated with cisplatin-based chemotherapy. METHODS: Methods: This prospective single-center hospital-based case-control study included 33 patients with metastatic UBC treated with cisplatin-based chemotherapy and 227 healthy controls. GPX1 SNP (rs1050450) was assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and SOD2 SNP (rs4880) was determined by quantitative PCR (q-PCR). Overall survival (OS) was evaluated using KaplanMeier survival analysis during 2-year follow up period, with the log-rank test for prognostic significance. RESULTS: Results: No significant difference was observed in the distributions of GPX1 and SOD2 gene variants between patients and controls (pË0.05). Regarding GPX1 polymorphism, no impact of GPX1 polymorphism on OS could be demonstrated (pË0.05). Finally, Kaplan-Meier survival analysis showed no association between SOD2 polymorphism and OS (pË0.05). CONCLUSIONS: Conclusions: No association was found between polymorphism of GPX1 and SOD2 and OS in patients with metastatic urothelial bladder cancer treated with cisplatin-based chemotherapy.
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Glutatión Peroxidasa/genética , Superóxido Dismutasa/genética , Neoplasias de la Vejiga Urinaria/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Casos y Controles , Cisplatino/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Serbia/epidemiología , Análisis de Supervivencia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/mortalidad , Glutatión Peroxidasa GPX1RESUMEN
PURPOSE: Presence of metastasis in sentinel lymph node (SLN) is considered to be the most important factor in terms of patient survival. The main aim of this study was to identify predictors of positive SLN in Serbian patients with melanoma. METHODS: This retrospective study was conducted on 147 patients. Univariate chi-square and univariate logistic regression analyses were used to identify the association between prognostic factors and positive SLN. Receiver Operating Characteristics (ROC) was conducted to find the Breslow thickness cutoff point at which to perform SLN biopsy (SLNB). Kaplan-Meier analysis was used to evaluate disease-free survival (DFS), and log rank test was applied to compare differences between groups. RESULTS: Breslow thickness and Clark level (p≤0.05), presence of ulceration and a high mitotic rate (>6 mitoses/mm2) (p<0.001) were significant independent predictors of SLN metastasis. ROC curve showed that Breslow thickness of 2.8 mm was the most suitable cutoff point for SLN positivity (sensitivity 86%, specificity 67%). Furthermore, Breslow thickness and presence of ulceration were found to be associated with DFS (p<0.05). CONCLUSIONS: Patients with Breslow thickness ≥2.8 mm, ulceration, and high mitotic rate are at higher risk for SLN metastasis. In addition, high Breslow thickness and presence of ulceration are associated with decreased DFS. These results indicate that multiple selection criteria should be used when performing and predicting SLN metastasis and disease recurrence.
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Melanoma/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Pronóstico , Ganglio Linfático Centinela/patología , Neoplasias Cutáneas/diagnóstico , Adulto , Femenino , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Melanoma/epidemiología , Melanoma/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Biopsia del Ganglio Linfático Centinela , Serbia/epidemiología , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
PURPOSE: Since several studies have proposed that epithelial ovarian cancer should not be considered as a single disease entity and that it results from an accumulation of genetic changes, we aimed to assess the polymorphic expression of major cytosolic glutathione S-transferases (GSTM1, T1, A1 and P1) with respect to ovarian cancer susceptibility and aggressiveness. METHODS: This case-control study was conducted on 93 newly diagnosed epithelial ovarian cancer patients and 178 healthy matched controls. The multiplex polymerase chain reaction (PCR) was used to detect homozygous deletions of GSTM1 and GSTT1 genes. Analysis of the single nucleotide polymorphism (SNP) GSTA1 C69T was performed using PCR-restriction fragment length polymorphism (RFLP), while for SNP GSTP1 Ile105Val real-time PCR was used. RESULTS: No significant association to ovarian cancer risk was found for individual GSTM1, GSTA1 and GSTP1 genotypes (p>0.05). However, the carriers of GSTT1-active genotype were at 2-fold higher risk of ovarian cancer development (95%CI: 1.00-4.01, p=0.049), which was even more elevated in the subgroup of patients with positive family history of cancer. Moreover, the frequency of all three GST genotypes that might be associated to ovarian cancer risk (GSTT1-active, GSTA1-active and GSTP1-referent) was significantly higher in patients than in the control group (p=0.042). Even more, patients who were carriers of combination of these three genotypes represented over 64% of the total number of patients within any of the International Federation of Gynecology and Obstetrics (FIGO) stages of ovarian cancer. CONCLUSIONS: This study provides supportive evidence that GSTs might affect both susceptibility and progression of ovarian cancer.
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Predisposición Genética a la Enfermedad , Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/genética , Polimorfismo de Nucleótido Simple , Carcinoma Epitelial de Ovario , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Neoplasias Glandulares y Epiteliales/enzimología , Neoplasias Glandulares y Epiteliales/etiología , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/etiología , RiesgoRESUMEN
Balkan endemic nephropathy (BEN) is a chronic familial form of interstitial nephritis that might eventually lead to end stage renal disease. This nephropathy affects individuals living along of the Danube River and its tributaries in Serbia, Bosnia, Croatia, Bulgaria and Romania. The increased incidence of urinary tract tumors in the BEN areas is well described, but its specific genetic predisposition is still unclear. Certain nephrocarcinogenic compounds, including those associated with BEN, are metabolized by glutathione S-transferase (GST) superfamily of phase II detoxication enzymes. Importantly, the GST-mediated detoxification may result in formation of more toxic compounds. We examined the association of common GST polymorphisms and bladder cancer (BC) risk in individuals from BEN areas in Serbia. A hospital-based case-control study included 201 BC cases (67 from BEN region) and 122 controls. Each polymorphism was identified by a PCR-based method. Individuals from BEN region with low-expression GSTA1 genotype (AB+BB) exhibited a 2.6-fold higher BC risk compared to those with GSTA1 (AA) genotype who were from non-BEN region (OR = 2.60, p = 0.015). In contrast, carriers of GSTM1-active genotype from BEN region had a 2.9-fold increased BC risk compared to those with GSTM1-active genotype from non-BEN region (OR = 2.90, p = 0.010). Likewise, carriers with GSTT1-active genotype from BEN region exhibited 2.1-fold higher BC risk compared to those from non-BEN region with GSTT1-active genotype (OR = 2.10, p = 0.027). Thus, common polymorphisms in GSTA1, GSTM1 and GSTT1 are associated with susceptibility to BC in individuals from BEN areas of Serbia.
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Nefropatía de los Balcanes/genética , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Polimorfismo Genético , Neoplasias de la Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/genética , Estudios de Casos y Controles , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , SerbiaRESUMEN
BACKGROUND: Glutathione S-transferase omega-1 and 2 have a unique range of enzymatic activities, including the regeneration of ascorbate by their dehydroascorbate reductase activities. Because these enzymes could have a protective role from oxidative damage in the lens, the question of whether the two coding glutathione S-transferase omega polymorphisms confer the risk of age-related cataract was addressed. METHODS: rs4925 (Ala140Asp) of glutathione S-transferase omega-1 and rs156697 (Asn142Asp) of glutathione S-transferase omega-2 polymorphisms in 100 patients with age-related cataract and 130 controls were assessed. RESULTS: Presence of one mutant GSTO1*Asp or GSTO2*Asp allele did not contribute independently towards the risk of cataract; however, homozygous carriers of GSTO1*Asp/GSTO2*Asp haplotype demonstrated 3.42-fold enhanced risk of cataract development (95% confidence interval = 0.84-13.93; P = 0.086). When GSTO genotype was analysed in association with smoking or professional exposure to ultraviolet irradiation, carriers of at least one mutant GSTO2*Asp allele had increased risk of cataract development in comparison with individuals with wild-type GSTO2*Asn/Asn with no history of smoking or ultraviolet exposure (odds ratio = 6.89, 95% confidence interval = 1.81-16.21, P = 0.005; odds ratio = 4.10, 95% confidence interval = 1.23-13.74, P = 0.022, respectively). Regarding the distribution of particular glutathione S-transferase omega genotype and cataract type, the highest frequency of mutant GSTO2*Asp allele was found in patients with nuclear cataract. CONCLUSION: The results indicate that mutant GSTO2*Asp genotype is associated with increased risk of age-related cataract in smokers and ultraviolet-exposed subjects, suggesting a role of inefficient ascorbate regeneration in cataract development.
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Catarata/genética , Glutatión Transferasa/genética , Cristalino/efectos de la radiación , Polimorfismo de Nucleótido Simple , Traumatismos por Radiación/genética , Fumar/genética , Rayos Ultravioleta/efectos adversos , Anciano , Envejecimiento , Alelos , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Técnicas de Genotipaje , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Factores de RiesgoRESUMEN
OBJECTIVE: Although C-reactive protein (CRP) is among the best cardiovascular disease risk predictors, data regarding the association of CRP and menopause are controversial. In this study, we measured CRP by a high-sensitivity method (hsCRP), cholesterol, lipoproteins, and triglycerides in normal and overweight postmenopausal women. METHODS: Body weight, height, waist circumference (WC), hsCRP, total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides, and lipoprotein (a) were measured in 30 normal weight and 60 overweight healthy postmenopausal women. RESULTS: Significantly higher triglyceride and hsCRP levels (P = 0.005 and P < 0.001 respectively), together with lower HDL-c levels (P = 0.001) were found in overweight compared to normal weight women. In the overweight group, positive correlations of hsCRP were observed with age, body mass index and WC (P = 0.016, P = 0.001, and P < 0.001, respectively) and a negative correlation was observed with HDL-c (P = 0.007). In the normal weight group, positive correlations were found for hsCRP with age and WC (P = 0.023 and P = 0.014, respectively). WC was the best predictor of hsCRP level in both groups (P < 0.001). CONCLUSION: Elevated hsCRP levels in conjunction with abnormal lipid profiles may be strongly associated with weight gain in postmenopausal women. Efforts to reduce obesity and inflammation in this group may help correct abnormal levels of hsCRP and lipids.
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Proteína C-Reactiva/metabolismo , Menopausia/sangre , Obesidad/sangre , Anciano , Antropometría , Biomarcadores/sangre , Femenino , Voluntarios Sanos , Humanos , Inflamación/sangre , Lípidos/sangre , Persona de Mediana Edad , Aumento de PesoRESUMEN
Invasive plant species (IPS) have many characteristics that are necessary for successful phytoremediation and the accumulation of large amounts of potentially toxic elements (PTEs). The most common IPS from the source of the Sava River are Reynoutria japonica, Solidago canadensis and Impatiens glandulifera. Considering that the riparian soils of the Sava River are classified as moderately polluted, this study investigated their enrichment with PTEs (As, B, Cd, Cr, Cu, Ni, Pb, Zn) and the potential for accumulation of these elements in roots and leaves of the most common IPS. The soil and plant samples were prepared using the wet digestion method in CEM Mars 6 microwave oven. The content of PTEs in soil and plant samples was determined by ICP-OES. The results showed a moderate to very high enrichment of Cu in the soils. Impatiens glandulifera has the highest uptake capacity in leaves and phytoextraction ability of B, Cd, Cu and Zn. Reynoutria japonica has some potential for phytoextraction of Pb, Zn and especially B, while Solidago canadensis has potential for phytoextraction of B and Zn, while excluding Cr and Cu. The analyzes have shown that the studied species are not suitable for bioindication of PTEs in the riparian soils of the Sava River. Considering the enrichment of soils with Cu, Impatiens glandulifera is the most suitable species for phytoremediation of these elements among the studied species.
RESUMEN
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, GSTT1, 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.
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Glutatión Transferasa/genética , Fallo Renal Crónico/genética , Estrés Oxidativo/genética , Diálisis Renal/efectos adversos , Anciano , Biomarcadores , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
BACKGROUND: To assess the prognostic significance of four inflammatory markers (TNF-α, high sensitive C-reactive protein (hs-CRP), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1)) in chronic heart failure (CHF) patients with respect to individual outcomes, especially disease exacerbation and mortality. METHODS: Plasma adhesion molecules, ICAM-1, and VCAM-1, together with TNF-α and hs-CRP were determined in 120 CHF patients and 69 healthy controls. Endothelial function was also estimated by flow-mediated brachial artery dilatation. RESULTS: Increased levels of all investigated inflammatory markers were found in CHF patients compared to controls, with the rise more pronounced in New York Heart association (NYHA) functional IV class. Significant correlations were obtained for VCAM-1 and brain natriuretic peptide (r = 0.191; P = 0.038), as well as, ICAM-1 and endothelium-dependent vasodilatation (r = -0.235; P = 0.01). Kaplan-Meier analysis showed disease exacerbation in patients with TNF-α levels >2.78 pg/ml significantly shorter compared to those with TNF-α levels <2.78 pg/ml (log-rank test = 8.270; P = 0.004), while similar association was observed for patients with hs-CRP levels >4.76 mg/l (log-rank test = 5.052; P = 0.025) and VCAM-1 levels >1200 ng/l (log-rank test = 5.45; P = 0.020) with respect to mortality. Cox regression analysis demonstrated only VCAM-1 (HR = 4.7; 95% confidence interval (CI): 1.1-18.7; P = 0.030) as independent death predictor, while TNF-α was associated with disease exacerbation (HR = 8.2; 95%CI: 1.1-23.0; P = 0.045). CONCLUSIONS: VCAM-1 appears to be useful in risk stratification of CHF patients and in screening, to identify subjects at risk for heart failure related events.