RESUMEN
The tumor microenvironment is affected by reactive oxygen species and has been suggested to have an important role in ovarian cancer (OC) tumorigenesis. The role of glutathione transferases (GSTs) in the maintenance of redox balance is considered as an important contributing factor in cancer, including OC. Furthermore, GSTs are mostly encoded by highly polymorphic genes, which further highlights their potential role in OC, known to originate from accumulated genetic changes. Since the potential relevance of genetic variations in omega-class GSTs (GSTO1 and GSTO2), with somewhat different activities such as thioltransferase and dehydroascorbate reductase activity, has not been clarified as yet in terms of susceptibility to OC, we aimed to investigate whether the presence of different GSTO1 and GSTO2 genetic variants, individually or combined, might represent determinants of risk for OC development. Genotyping was performed in 110 OC patients and 129 matched controls using a PCR-based assay for genotyping single nucleotide polymorphisms. The results of our study show that homozygous carriers of the GSTO2 variant G allele are at an increased risk of OC development in comparison to the carriers of the referent genotype (OR1 = 2.16, 95% CI: 0.88-5.26, p = 0.08; OR2 = 2.49, 95% CI: 0.93-6.61, p = 0.06). Furthermore, individuals with GST omega haplotype H2, meaning the concomitant presence of the GSTO1*A and GSTO2*G alleles, are more susceptible to OC development, while carriers of the H4 (*A*A) haplotype exhibited lower risk of OC when crude and adjusted haplotype analysis was performed (OR1 = 0.29; 95% CI: 0.12-0.70; p = 0.007 and OR2 = 0.27; 95% CI: 0.11-0.67; p = 0.0054). Overall, our results suggest that GSTO locus variants may confer OC risk.
Asunto(s)
Alelos , Predisposición Genética a la Enfermedad , Glutatión Transferasa , Neoplasias Ováricas , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Neoplasias Ováricas/genética , Glutatión Transferasa/genética , Persona de Mediana Edad , Genotipo , Adulto , Anciano , Estudios de Casos y Controles , Frecuencia de los GenesRESUMEN
Background and Objectives: Despite improvements in screening programs, a large number of patients with colorectal cancer (CRC) are diagnosed in an advanced disease stage. Previous investigations imply that glutathione transferases (GSTs) might be associated with the development and progression of CRC. Moreover, the detoxification mechanism of oxaliplatin, which represents the first line of treatment for advanced CRC, is mediated via certain GSTs. The aim of this study was to evaluate the significance of certain GST genetic variants on CRC prognosis and the efficacy of oxaliplatin-based treatment. Materials and Methods: This prospective study included 523 patients diagnosed with CRC in the period between 2014 and 2016, at the Digestive Surgery Clinic, University Clinical Center of Serbia, Belgrade. Patients were followed for a median of 43.47 ± 17.01 months (minimum 1-63 months). Additionally, 109 patients with advanced disease, after surgical treatment, received FOLFOX6 treatment as a first-line therapy between 2014 and 2020. The Kaplan-Meier method was used to analyze cumulative survival, and the Cox proportional hazard regression model was used to study the effects of different GST genotypes on overall survival. Results: Individuals with the GSTM1-null genotype and the GSTP1 IleVal+ValVal (variant) genotype had significantly shorter survival when compared to referent genotypes (GSTM1-active and GSTP1 IleIle) (log-rank: p = 0.001). Moreover, individuals with the GSTM1-null genotype who received 5-FU-based treatment had statistically significantly shorter survival when compared to individuals with the GSTM1-active genotype (log-rank: p = 0.05). Conclusions: Both GSTM1-null and GSTP1 IleVal+ValVal (variant) genotypes are associated with significantly shorter survival in CRC patients. What is more, the GSTM1-null genotype is associated with shorter survival in patients receiving FOLOFOX6 treatment.
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Adenocarcinoma , Neoplasias Colorrectales , Gutatión-S-Transferasa pi , Glutatión Transferasa , Polimorfismo Genético , Humanos , Gutatión-S-Transferasa pi/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/tratamiento farmacológico , Glutatión Transferasa/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Serbia , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Genotipo , Pronóstico , Estimación de Kaplan-Meier , Compuestos Organoplatinos/uso terapéutico , Leucovorina/uso terapéutico , Oxaliplatino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Modelos de Riesgos Proporcionales , AdultoRESUMEN
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
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
It is becoming increasingly evident that oxidative stress has a supporting role in pathophysiology and progression of primary open angle glaucoma (POAG). The aim of our study was to assess the association between polymorphisms in genes encoding enzymes involved in redox homeostasis, mitochondrial superoxide dismutase (SOD2), glutathione peroxidase (GPX1) and glutathione transferases (GSTs) with susceptibility to POAG. Single nucleotide polymorphisms in GST omega (GSTO1rs4925, GSTO2 rs156697), pi 1 (GSTP1 rs1695), as well as GPX1 (rs1050450) and SOD2 (rs4880) were determined by quantitative polymerase chain reaction (qPCR) in 102 POAG patients and 302 respective controls. The risk for POAG development was noted in carriers of both GSTO2*GG and GSTO1*AA variant genotypes (OR = 8.21, p = 0.002). Individuals who carried GPX1*TT and SOD2*CC genotypes had also an increased risk of POAG development but without significance after Bonferroni multiple test correction (OR = 6.66, p = 0.005). The present study supports the hypothesis that in combination, GSTO1/GSTO2, modulate the risk of primary open angle glaucoma.
Asunto(s)
Glaucoma de Ángulo Abierto/genética , Glutatión Peroxidasa/genética , Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Polimorfismo de Nucleótido Simple/genética , Superóxido Dismutasa/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Técnicas de Genotipaje , Glaucoma de Ángulo Abierto/diagnóstico , Humanos , Presión Intraocular/fisiología , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Glutatión Peroxidasa GPX1RESUMEN
Background and Objectives: Mounting evidence implicates oxidative damage in prostate carcinogenesis, contributing to modifications of macromolecules that drive cellular malignant transformation. Functional single-nucleotide polymorphisms (SNPs) of enzymes involved in redox homeostasis can disrupt pro-oxidant-antioxidant balance, leading to accumulation of reactive oxygen species and oxidative damage. We investigated the potential role of genetic polymorphisms of antioxidant enzymes glutathione peroxidase 1 (GPX1 rs1050450) and superoxide dismutase 2 (SOD2 rs4880) and regulatory antioxidant protein nuclear factor erythroid 2-related factor 2 (Nrf2 rs6721961) in the susceptibility to prostate cancer development (PC) and prognosis. Materials and Methods: We conducted a case-control study consisting of 235 patients with PC and 240 controls. Gene polymorphisms were determined by quantitative polymerase chain reaction (qPCR) and polymerase chain reaction with confronting two-pair primers (PCR-CTTP) methods. Multiple risk models were composed to inspect the separate and mutual effect of multiple genes and in combination with acquired contributory factors on the risk of PC development. Results: Independently, carriers of at least one SOD2*C allele had increased risk of PC development, which was significantly further amplified in advanced statistical models. When tested in combination, individuals with both SOD2*C allele and Nrf2*C/C genotype were also at increased risk of PC development, which was augmented when combined with acquired contributory factors. During the mean 75 ± 25 months of follow-up, investigated gene polymorphisms did not affect overall survival. Conclusion: Our results suggest that these gene polymorphisms could be used as risk biomarkers of PC evolution.
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Antioxidantes , Neoplasias de la Próstata , Humanos , Masculino , Biomarcadores , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Factor 2 Relacionado con NF-E2/genética , Polimorfismo de Nucleótido Simple/genética , Neoplasias de la Próstata/genética , Especies Reactivas de Oxígeno , Glutatión Peroxidasa GPX1RESUMEN
The possible cardioprotective effects of translocator protein (TSPO) modulation with its ligand 4'-Chlorodiazepam (4'-ClDzp) in isoprenaline (ISO)-induced rat myocardial infarction (MI) were evaluated, alone or in the presence of L-NAME. Wistar albino male rats (b.w. 200-250 g, age 6-8 weeks) were divided into 4 groups (10 per group, total number N = 40), and certain substances were applied: 1. ISO 85 mg/kg b.w. (twice), 2. ISO 85 mg/kg b.w. (twice) + L-NAME 50 mg/kg b.w., 3. ISO 85 mg/kg b.w. (twice) + 4'-ClDzp 0.5 mg/kg b.w., 4. ISO 85 mg/kg b.w. (twice) + 4'-ClDzp 0.5 mg/kg b.w. + L-NAME 50 mg/kg b.w. Blood and cardiac tissue were sampled for myocardial injury and other biochemical markers, cardiac oxidative stress, and for histopathological evaluation. The reduction of serum levels of high-sensitive cardiac troponin T hs cTnT and tumor necrosis factor alpha (TNF-α), then significantly decreased levels of serum homocysteine Hcy, urea, and creatinine, and decreased levels of myocardial injury enzymes activities superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as lower grades of cardiac ischemic changes were demonstrated in ISO-induced MI treated with 4'-ClDzp. It has been detected that co-treatment with 4'-ClDzp + L-NAME changed the number of registered parameters in comparison to 4'-ClDzp group, indicating that NO (nitric oxide) should be important in the effects of 4'-ClDzp.
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Benzodiazepinonas/farmacología , Proteínas Portadoras/metabolismo , Infarto del Miocardio/prevención & control , NG-Nitroarginina Metil Éster/farmacología , Estrés Oxidativo/efectos de los fármacos , Receptores de GABA-A/metabolismo , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Inhibidores Enzimáticos/farmacología , Glutatión Peroxidasa/metabolismo , Homocisteína/sangre , Isoproterenol , Masculino , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/metabolismo , Miocardio/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Ratas Wistar , Superóxido Dismutasa/metabolismo , Troponina T/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The aim of this study was to test the hypothesis that subchronic co-application of vitamins B6 and folic acid (FA) could affect heart failure (HF) induced by monocrotaline (MCT), with the modulation of oxidative stress parameters and cardiometabolic biomarkers. Biochemical and histomorphometric analyses were assessed in blank solution-exposed controls (C1 physiological saline 1 mL/kg, 1 day, n = 8; C2 physiological saline 1 mL/kg, 28 days, n = 8), MCT-induced HF (MCT 50 mg/kg, n = 8), B6+FA (vitamin B6 7 mg·kg-1·day-1, FA 5 mg·kg-1·day-1; n = 8), and MCT+B6+FA (MCT 50 mg/kg, vitamin B6 7 mg·kg-1·day-1, FA 5 mg·kg-1·day-1; n = 8) in male Wistar albino rats (body mass 160 g at the start). Superoxide dismutase and glutathione peroxidase activities, thiol-, carbonyl groups, and nitrotyrosine were determined in cardiac tissue. Echocardiography was performed to confirm MCT-induced HF. The right ventricular wall hypertrophy, accompanied with significant increase of troponin T and preserved renal and liver function, has been shown in MCT-induced HF. However, these effects were not related to antioxidant effects of vitamin B6 and FA, since several parameters of oxidative stress were more pronounced after treatment. In this study, co-application of vitamins B6 and FA did not attenuate hypertrophy of the right ventricle wall but aggravated oxidative stress, which is involved in HF pathogenesis.
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Ácido Fólico/administración & dosificación , Ácido Fólico/farmacología , Insuficiencia Cardíaca/metabolismo , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Vitamina B 6/administración & dosificación , Vitamina B 6/farmacología , Animales , Biomarcadores/metabolismo , Electrocardiografía/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/fisiopatología , Masculino , Monocrotalina/efectos adversos , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Heart failure (HF) is one of the major cardiovascular causes of death worldwide. In this study, we explored the effects of folic acid (FA) on cardiometabolic, oxidative stress biomarker changes, and the activity of proliferation marker Ki67 in monocrotaline-induced HF. The research was conducted during a 4 week period using five experimental groups (eight animals per group): blank solution exposed controls (C1: 1 mL/kg physiological saline, 1 day; C2: 1 mL/kg physiological saline, 28 days), monocrotaline (MCT) induced HF (50 mg/kg MCT), FA (5 mg·kg-1·day-1 FA), and MCT+FA (50 mg/kg MCT, 5 mg·kg-1·day-1 FA). Superoxide dismutase and glutathione peroxidase activities together with total glutathione and parameters of oxidative damage of proteins were determined in cardiac tissue as well as cardiometabolic parameters in plasma or serum. The total glutathionylation was determined by Western blot and proliferation marker Ki67 was assessed by immunohistochemistry. The right ventricular (RV) wall hypertrophy and Ki67 positivity, accompanied by a significant increase of troponin T, has been shown in MCT-induced HF. The antioxidant effect of FA was reflected through superoxide dismutase activity, reduced Ki67 positivity in the RV wall, and a slightly decreased total glutathionylation level.
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Antioxidantes/farmacología , Metabolismo Energético/efectos de los fármacos , Ácido Fólico/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Glutatión/metabolismo , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Masculino , Monocrotalina , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Wistar , Remodelación Ventricular/efectos de los fármacosRESUMEN
Background and Objectives: One of the most frequent genetic alterations reported to date in prostate cancer (PC) is aberrant methylation of glutathione transferase P1 (GSTP1). Taking into consideration the involvement of oxidative stress in PC pathogenesis and recent advances in scientific understanding of the role of GSTP1*Ala114Val rs1138272 polymorphism in carcinogenesis, we hypothesized that this single-nucleotide polymorphism (SNP) influences the risk of PC independently of, or in combination with, other GST polymorphisms, including GSTP1*IIe105Val rs1695 or GSTM1 and GSTT1 deletion polymorphisms. Materials and Methods: Genotyping was performed in 237 PC cases and in 236 age-matched controls by multiplex polymerase chain reaction (PCR) for deletion of GST polymorphisms and by quantitative PCR for SNPs. Results: We found that carriers of either GSTP1*Val (rs1138272) or GSTP1*Val (rs1695) variant alleles had a PC risk compared to individuals with both referent alleles (OR = 4.93, 95%CI: 2.89-8.40, p < 0.001 and OR = 1.8, 95%CI: 1.19-2.73, p = 0.006, respectively). Additionally, in a haplotype analysis we found that individuals with GSTP1*C haplotype, represented by both variant alleles (GSTP1*Val rs1695 + GSTP1*Val rs1138272), had a 5.46 times higher risk of PC development compared to individuals with the most frequent haplotype (95%CI = 2.56-11.65, p < 0.001), suggesting a potential role of those variants in PC susceptibility. A regression analysis on the number of risk-associated alleles per individual (GSTM1*active, GSTT1*null, GSTP1*Val rs1695 and GSTP1*Val rs1138272) showed a significant increase in the risk of developing PC, from 3.65-fold in carriers of two risk alleles (95%CI = 1.55-8.61, p = 0.003) to an approximately 12-fold increase in carriers of all four risk alleles (95%CI = 3.05-44.93, p < 0.001). Conclusion: Prostate cancer may be influenced by multiple glutathione transferase (GST) polymorphic genes, especially GSTP1, highlighting the role of gene-gene interactions in human susceptibility to this cancer.
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Gutatión-S-Transferasa pi/análisis , Polimorfismo Genético/genética , Neoplasias de la Próstata/genética , Anciano , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Gutatión-S-Transferasa pi/sangre , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/fisiopatología , Ajuste de Riesgo/métodos , SerbiaRESUMEN
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Glutatión Transferasa/antagonistas & inhibidores , Glutatión Transferasa/metabolismo , Animales , Resistencia a Antineoplásicos , Humanos , Profármacos/uso terapéutico , Unión ProteicaRESUMEN
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.
Asunto(s)
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 OF REVIEW: This review aims to provide a brief description of the complex etiology of autism spectrum disorders (ASD), with special emphasis on the recent findings of impaired redox control in ASD, and to suggest a possible model of oxidative stress-specific gene-environment interaction in this group of disorders. RECENT FINDINGS: Recent findings point out to the significance of environmental, prenatal, and perinatal factors in ASD but, at the same time, are in favor of the potentially significant oxidative stress-specific gene-environment interaction in ASD. Available evidence suggests an association between both the identified environmental factors and genetic susceptibility related to the increased risk of ASD and the oxidative stress pathway. There might be a potentially significant specific gene-environment interaction in ASD, which is associated with oxidative stress. Revealing novel susceptibility genes (including those encoding for antioxidant enzymes), or environmental factors that might increase susceptibility to ASD in carriers of a specific genotype, might enable the stratification of individuals more prone to developing ASD and, eventually, the possibility of applying preventive therapeutic actions.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Interacción Gen-Ambiente , Estrés Oxidativo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/genética , Niño , Daño del ADN , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Humanos , Exposición Materna/estadística & datos numéricos , Oxidación-Reducción , Embarazo , Efectos Tardíos de la Exposición Prenatal/epidemiología , Efectos Tardíos de la Exposición Prenatal/genéticaRESUMEN
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.
Asunto(s)
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.