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1.
Urologiia ; (4): 84-89, 2020 Sep.
Artigo em Russo | MEDLINE | ID: mdl-32897019

RESUMO

Genetic factors cause various forms of male infertility in 30-50% of cases. The role of oxidative stress in male infertility has been broadly recognised, and the search for a new marker to determine the redox environment in semen has gained considerable interest. AIM: to establish the association of two polymorphic loci Ile105Val, Ala114Val of the GSTP1 gene (glutathione transferase class pi-1) with the parameters of oxidative stress in men with infertility. MATERIALS AND METHODS: the main study group consisted of 160 men of reproductive age with infertility (mean age - 29,9+/-5,3 years). The control group included 104 practically healthy men with realized reproductive function (average age - 30,2+/-3,6 years). Molecular and genetic study of polymorphisms of the GSTP1 gene was performed by using real-time PCR. The material for the study was DNA samples, the extraction of which was carried out from samples of whole venous blood. The components of lipid peroxidation and antioxidant protection were determined in the blood and ejaculate using spectrophotofluorometric METHOD: s. Resalts: While analyzing the frequency of occurrence of the Ile105Val polymorphism of the GSTP1 gene in men with infertility and fertile men, statistically significant differences were found at (2=7,487; p=0,024). No significant differences were found between the groups (2=3,823; p=0,14), when were compared the frequency distribution of the genotypes of the Ala114Val polymorphism of the GSTP1 gene in men diagnosed with infertility and fertile patients. In men with infertility, carriers of the GSTP1(Ile105Val) heterozygous polymorphism, associations of the studied gene were established with an increase in GSH activity by 7% and a decrease in GR by 20% in blood and a decrease in SOD activity by 8% in the ejaculate, in contrast, fertile men, carriers of heterozygous polymorphism GSTP1(Ile105Val), which have associations with an increase in total AOA blood by 20% and with a decrease in GPO activity by 24% in the ejaculate. In men with infertility, carriers of the heterozygous polymorphism of GSTP1(Ala114Val), associations of the studied gene were established with a decrease in -tocopherol concentration by 15%, an increase in GPO activity by 25% in blood and a decrease in SOD activity by 7% in ejaculate, in contrast, fertile men, carriers of heterozygous polymorphism GSTP1(l114Val), which have associations with an increase in the concentration of DK in blood by 19% and with a decrease in GST activity by 32% in the ejaculate. CONCLUSION: identification of carriers of polymorphic loci Ile105Val, Ala114Val GSTP1, as well as determination of enzymes of the thiol disulfide system can be recommended for additional assessment of the risk of reproductive disorders in men.


Assuntos
Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Infertilidade Masculina , Adulto , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Infertilidade Masculina/genética , Masculino , Estresse Oxidativo , Polimorfismo Genético , Adulto Jovem
2.
Nat Commun ; 11(1): 4467, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948751

RESUMO

Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.


Assuntos
Fibrose/genética , Predisposição Genética para Doença/genética , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Nefropatias/genética , Idoso , Animais , Apoptose , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Nefropatias Diabéticas , Modelos Animais de Doenças , Feminino , Fibrose/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Inflamação , Rim/lesões , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Transdução de Sinais , Proteína Smad3/metabolismo , Proteína Supressora de Tumor p53/metabolismo
3.
Medicine (Baltimore) ; 99(36): e21918, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899025

RESUMO

Schizophrenia (SCZ) is a chronic disability disorder related to oxidative stress. Glutathione S-transferase (GST) is a group enzyme that protects cells and tissues from oxidative stress damage. Among GSTs, GSTT1 and GSTM1 have well defined genetic polymorphisms. The purpose of our research was to explore the correlation between GSTT1 and GSTM1 polymorphism and SCZ risk in Chinese Han population.A total of 650 subjects (386 SCZ patients and 264 healthy individuals) were included in this case-control designed study. The GSTT1 and GSTM1 polymorphisms were analyzed by multiplex polymerase chain reaction (PCR). We explored the relationship between these 2 polymorphisms and the risk of SCZ.We found that the GSTT1 null genotype had a protective effect on the development of SCZ [odds ratio (OR) = 0.601, 95% confidence interval (95% CI) = 0.412-0.986, P = .031]. We also found that the combination of null genotypes of the GSTT1 and GSTM1 genes was made at a lower risk of SCZ (OR = 0.452, 95% CI = 0.238-0.845, P = .028). However, we found no correction between Positive and Negative Syndrome Scale score (PANSS) and GSTM1, GSST1 genotypes in SCZ patients.Our finding revealed that GSTT1 null polymorphisms may be related to the reduced risk of SCZ in Chinese Han population, and this risk was further reduced with the combination of GSTT1 null polymorphisms and GSTM1 null polymorphisms.


Assuntos
Glutationa Transferase/genética , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco
4.
Nat Commun ; 11(1): 4071, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792491

RESUMO

Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.


Assuntos
Glutationa Transferase/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Caspase 8/genética , Caspase 8/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glutationa Transferase/genética , Homeostase/genética , Homeostase/fisiologia , Imuno-Histoquímica , Masculino , Microglia/citologia , Microglia/metabolismo , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Fagocitose/genética , Fagocitose/fisiologia , Processamento de Proteína Pós-Traducional , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Remielinização/genética , Remielinização/fisiologia
5.
Int J Nanomedicine ; 15: 5005-5016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764932

RESUMO

Background and Aim: With the wide applications of chitosan and gold nanoparticles in drug delivery and many consumer products, there is limited available information about their effects on drug-metabolizing enzymes (DMEs). Changes in DMEs could result in serious drug interactions. Therefore, this study aimed to investigate the effects of exposure to chitosan or gold nanoparticles on hepatic Phase I and II DMEs, liver function and integrity, oxidative damage and liver architecture in male rats. Methods: Animals were divided into three equal groups: a control group, a group treated with chitosan nanoparticles (200 mg/kg, 50±5 nm) and a group treated with gold nanoparticles (4 mg/kg, 15±5 nm). Rats were orally administered their respective doses daily for 10 days. Results: Both chitosan and gold nanoparticles decreased the body weights by more than 10%. Gold nanoparticles reduced the activities of antioxidants (superoxide dismutase and catalase), and reduced glutathione level and elevated the malondialdehyde level in the liver. Gold nanoparticles caused significant reductions in CYP1A1, CYP2E1, quinone oxidoreductase1, and glutathione S-transferase and elevated CYP2D6 and N-acetyl transferase2. Chitosan elevated CYP2E1 and CYP2D6 and reduced UDP-glucuronosyltransferase 1A1. Both nanoparticles disturbed the architecture of the liver, but the deleterious effects after gold nanoparticles treatment were more prominent. Conclusion: Taken together, gold nanoparticles severely perturbed the DMEs and would result in serious interactions with many drugs, herbs, and foods.


Assuntos
Antioxidantes/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inativação Metabólica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas Metálicas/efeitos adversos , Animais , Catalase/genética , Catalase/metabolismo , Quitosana/química , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Interações Medicamentosas , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Glutationa/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Ouro/química , Ouro/farmacocinética , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Nanopartículas Metálicas/química , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
6.
Medicine (Baltimore) ; 99(34): e21732, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846793

RESUMO

BACKGROUND: We performed an updated meta-analysis to clarify the relationship between glutathione S-transferase Mu and theta (GSTM1 and GSTT1, respectively) null/positive genotypes and asthma. METHODS: We performed a literature search using PubMed and Web of Science databases in August 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the role of GSTM1 and GSTT1 genotypes in the risk of asthma. RESULTS: Overall, we found a significant association with asthma risk in the general population for both the GSTM1 genotype (OR = 1.21; 95% CI: 1.07-1.35; P < .001; I = 69.5%) and the GSTT1 genotype (OR = 1.61; 95% CI: 1.30-2.00; P < .001; I = 83.6%). Moreover, significant associations between both genotypes and asthma risk were also found by age stratification. Furthermore, for GSTM1 we found significant associations in populations living in Asia, Europe, and Russia, but not in Africa. Conversely, for GSTT1, we found a significantly increased risk in populations living in Asia, Europe, Africa, and Russia. In addition, a significant association was found for both genotypes with a sample size <500, but not a sample size >2000. CONCLUSION: Our meta-analysis provides evidence that GSTM1 and GSTT1 genotypes could be used as asthma-associated biomarkers.


Assuntos
Asma/genética , Glutationa Transferase/genética , Fatores Etários , Grupos de Populações Continentais , Predisposição Genética para Doença , Genótipo , Humanos , Fatores de Risco , Fatores Sexuais
7.
Mar Pollut Bull ; 156: 111080, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32510351

RESUMO

Various xenobiotics are constantly being released and accumulated into the aquatic environments and consequently, the aquatic organisms are continuously being exposed to exogenous stressors. Among various xenobiotic detoxifying enzymes, Glutathione S-transferase (GST) is one of the major xenobiotic detoxifying enzyme which is widely distributed among living organisms and thus, understanding of the nature of GSTs is crucial. Previous studies have shown GST activity in response to various xenobiotics yet, full identification of GSTs in marine invertebrates is still limited. This review covers information on the importance of GSTs as a biomarker for emerging chemicals and their response to wide ranges of environmental pollutants as well as in-depth phylogenetic analysis of marine invertebrates, including recently identified GSTs belonging to rotifers (Brachionus spp.) and copepods (Tigriopus japonicus and Paracyclopina nana), with unique class-specific features of GSTs, as well as a new suggestion of GST evolutionary pathway.


Assuntos
Copépodes , Rotíferos , Animais , Ecotoxicologia , Glutationa Transferase/genética , Filogenia
8.
Environ Sci Pollut Res Int ; 27(25): 31269-31277, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32488710

RESUMO

Esophageal cancer is the eighth most common cancer and the sixth most frequent cause of cancer mortality worldwide. Exposure to polycyclic aromatic hydrocarbons formed by incomplete combustion of organic matter is an important risk factor. Genetic polymorphisms in genes encoding PAH-metabolizing enzymes like glutathione S-transferases (GSTM1, GSTP1, GSTT1) which conjugate glutathione to PAHs for reduction of oxidative stress may affect an individual's response to PAH exposure. Genomic DNA from 50 esophageal squamous cell carcinoma patients extracted from peripheral blood. PCR-RFLP technique was employed to determine GSTM1, GSTT1, and GSTP1 polymorphisms. Aberrant promoter methylation of CDKN2A was applied by methylation-specific PCR technique. Concentration of urinary 1-hydroxypyrene was determined using a HPLC system. About 38.7% showed the null GSTM1 genotype (54% cases and 13% controls), 23.7% showed GSTT1 null genotype (30% cases and 13% controls), and 62.5% were GSTP1 A/A genotype (66% cases and 56% controls). Polymorphic variants of GSTM1 and GSTT1 were significantly associated with aberrant methylation of CDKN2A gene. The null state of GSTT1 was significantly associated with high concentrations of 1-OHP in urea (p < 0.01). There was significant association between methylated states of CDKN2A and high concentrations of 1-OHP in urine (p < 0.01). We identified significant association between polymorphism of GSTs genes and epigenetic silencing of tumor suppressor gene CDKN2A in esophageal squamous cell carcinoma.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Estudos de Casos e Controles , Epigênese Genética , Genes p16 , Predisposição Genética para Doença , Genótipo , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Humanos , Polimorfismo Genético , Fatores de Risco
10.
Environ Toxicol ; 35(10): 1091-1099, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32485069

RESUMO

Various pollutants co-exist in the aquatic environment such as carbamazepine (CBZ) and copper (Cu), which can cause complex effects on inhabiting organisms. The toxic impacts of the single substance have been studied extensively. However, the studies about their combined adverse impacts are not enough. In the present study, zebrafish were exposed to environmental relevant concentrations of CBZ (1, 10, and 100 µg/L), Cu (0.5, 5, and 10 µg/L) and the mixtures (1 µg/L CBZ + 0.5 µg/L Cu, 10 µg/L CBZ + 5 µg/L Cu, 100 µg/L CBZ + 10 µg/L Cu) for 45 days, the effects on nervous and antioxidant systems of zebrafish were investigated. The results demonstrated that, in comparison with single exposure group, the combined presence of CBZ and Cu exacerbated the effect of antioxidant system (the ability of inhibition of hydroxyl radicals (IHR), superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST)) but not nervous system (Acetylcholinesterase [AChE]). The qPCR results supported the changes of corresponding enzymes activities. Hepatic histopathological analysis verified the results of biomarkers. Our work illustrated that the toxicity of mixed pollutants is very complicated, which cannot simply be inferred from the toxicity of single pollutant, and calls for more co-exposure experiments to better understanding of the co-effects of pollutants on aquatic organisms.


Assuntos
Antioxidantes/metabolismo , Carbamazepina/toxicidade , Cobre/toxicidade , Sistema Nervoso/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Biomarcadores/metabolismo , Catalase/genética , Catalase/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Sistema Nervoso/enzimologia , Sistema Nervoso/metabolismo , Estresse Oxidativo/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
12.
Aquat Toxicol ; 224: 105480, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32417752

RESUMO

The calanoid copepod, Acartia tonsa, is relatively sensitive to marine pollution. Glutathione S-transferase (GST) multifunctional enzyme, as a biomarker, play an important role in detoxification metabolism of exogenous substances. In the present study, GST-theta and GST-mu class homology genes (designated as AtGSTT1 and AtGSTM2) were identified and characterized from A. tonsa. The coding sequence of AtGSTT1 comprised 726 bp and encoded a putative protein of 241 amino acid residues. AtGSTM2 contained an open reading frame of 678 bp that encoded a putative 227 amino acid polypeptide. Both proteins contained a conserved GST-N domain and a GST-C domain. Structural analysis revealed the characteristic N-terminal G-site. Three-dimensional structure analysis showed that AtGSTT1 and AtGSTM2 have two typical domains of GST family: The ßαßαßßα topology structure at the N- terminus and the superhelical structure at the C- terminus. Subsequently, the expression levels of the two GST genes were detected in A. tonsa using real-time quantitative PCR after exposure to 1,2-dimethylnaphthalene (C2-NAPH) at different concentrations (0.574, 5.736 and 57.358 µg/L) for 24, 48, 72, and 96 h. AtGSTT1 mRNA expression was significantly up-regulated in a time-dependent manner and the highest mRNA expression occurred at 5.736 µg/L C2-NAPH exposure for 96 h. AtGSTM2 mRNA expression peaked at 72 h in 0.574 µg/L and 5.736 µg/L dose groups. The expression level of AtGSTM2 showed an increasing trend in a time-dependent manner at 57.358 µg/L of C2-NAPH. These results suggested that GST genes may play an important role in protecting A. tonsa from C2-NAPH pollution, and provide a theoretical basis for further study on the molecular mechanism of polycyclic aromatic hydrocarbon (PAHs) pollution on zooplankton.


Assuntos
Copépodes/efeitos dos fármacos , Monitoramento Ambiental/métodos , Glutationa Transferase/genética , Naftalenos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Sequência de Bases , Clonagem Molecular , Copépodes/enzimologia , Copépodes/genética , DNA Complementar/genética , Relação Dose-Resposta a Droga , Glutationa Transferase/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , RNA Mensageiro/genética , Testes de Toxicidade Aguda
13.
Adv Clin Exp Med ; 29(5): 623-628, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32407610

RESUMO

The direct causes of idiopathic carpal tunnel syndrome (CTS) still remain obscure. It has been suggested that the pathology of tendons and other connective tissue structures within the carpal tunnel may be involved in its etiology. The objective of this study was to review the literature about the potential role of genetic factors in the etiology of CTS. Three different mechanisms are suspected to be involved in genetic predisposition to CTS: collagen synthesis, collagen degradation and protection against oxidative stress effect in connective tissue. Several gene groups are involved in the regulation and modulation of these mechanisms, and the research reviewed in this study showed their possible effect on the development of CTS. Variants within the COL1A1, COL5A1 and COL11A1 genes - encoding the synthesis of minor collagen subtypes - may potentially be involved, as they alter the mechanical properties of tendons and other connective tissue structures within the carpal tunnel. The collagen within connective tissue structures is also remodeled by matrix metalloproteinases (MMPs), so variants of these genes have also been investigated for their possible role in the risk of CTS development. Next, the variants of genes encoding glutathione S-transferase (GST) synthesis were found to be involved in the etiology of CTS. The findings from the abovementioned studies provide reliable information on the potential role of genetic risk factors in the development of CTS.


Assuntos
Síndrome do Túnel Carpal/etiologia , Síndrome do Túnel Carpal/genética , Colágeno/genética , Glutationa Transferase/genética , Tecido Conjuntivo , Predisposição Genética para Doença , Humanos , Polimorfismo Genético
14.
Nat Commun ; 11(1): 2456, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415123

RESUMO

Anthocyanin pigments furnish a powerful visual output of the stress and metabolic status of Arabidopsis thaliana plants. Essential for pigment accumulation is TRANSPARENT TESTA19 (TT19), a glutathione S-transferase proposed to bind and stabilize anthocyanins, participating in their vacuolar sequestration, a function conserved across the flowering plants. Here, we report the identification of genetic suppressors that result in anthocyanin accumulation in the absence of TT19. We show that mutations in RDR6, SGS3, or DCL4 suppress the anthocyanin defect of tt19 by pushing carbon towards flavonoid biosynthesis. This effect is not unique to tt19 and extends to at least one other anthocyanin pathway gene mutant. This synergy between mutations in components of the RDR6-SGS3-DCL4 siRNA system and the flavonoid pathway reveals genetic/epigenetic mechanisms regulating metabolic fluxes.


Assuntos
Antocianinas/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Carbono/metabolismo , RNA Replicase/metabolismo , RNA Interferente Pequeno/metabolismo , Ribonuclease III/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Sequência de Bases , Regulação da Expressão Gênica de Plantas , Genes Supressores , Genótipo , Glutationa Transferase/genética , Mutação/genética , Fenótipo , Pigmentação/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Plântula/crescimento & desenvolvimento , Açúcares/metabolismo
15.
Mutat Res ; 852: 503167, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32265040

RESUMO

Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.


Assuntos
Angiotensinogênio/genética , Reparo do DNA , Instabilidade Genômica , Lactoilglutationa Liase/genética , Proteínas dos Microfilamentos/genética , Insuficiência Renal Crônica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiotensinogênio/metabolismo , Estudos de Casos e Controles , Ensaio Cometa , Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Lactoilglutationa Liase/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Testes para Micronúcleos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/genética , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
16.
Science ; 368(6493)2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32273397

RESUMO

Fusarium head blight (FHB), a fungal disease caused by Fusarium species that produce food toxins, currently devastates wheat production worldwide, yet few resistance resources have been discovered in wheat germplasm. Here, we cloned the FHB resistance gene Fhb7 by assembling the genome of Thinopyrum elongatum, a species used in wheat distant hybridization breeding. Fhb7 encodes a glutathione S-transferase (GST) and confers broad resistance to Fusarium species by detoxifying trichothecenes through de-epoxidation. Fhb7 GST homologs are absent in plants, and our evidence supports that Th. elongatum has gained Fhb7 through horizontal gene transfer (HGT) from an endophytic Epichloë species. Fhb7 introgressions in wheat confers resistance to both FHB and crown rot in diverse wheat backgrounds without yield penalty, providing a solution for Fusarium resistance breeding.


Assuntos
Resistência à Doença/genética , Epichloe/genética , Fusarium/patogenicidade , Transferência Genética Horizontal , Glutationa Transferase/genética , Doenças das Plantas/microbiologia , Triticum/genética , Triticum/microbiologia , Clonagem Molecular , Melhoramento Vegetal , Poaceae/genética
17.
BMC Med Genet ; 21(1): 55, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32188413

RESUMO

BACKGROUND: Glutathione S-transferases play a key role in the detoxification of persistent oxidative stress products which are one of several risks factors that may be associated with many types of disease processes such as cancer, diabetes, and hypertension. In the present study, we characterize the null genotypes of GSTM1 and GSTT1 in order to investigate the association between them and the risk of developing essential hypertension. METHODS: We conducted a case-control study in Burkina Faso, including 245 subjects with essential hypertension as case and 269 control subjects with normal blood pressure. Presence of the GSTT1 and GSTM1 was determined using conventional multiplex polymerase chain reaction followed by gel electrophoresis analysis. Biochemical parameters were measured using chemistry analyzer CYANExpert 130. RESULTS: Chi-squared test shows that GSTT1-null (OR = 1.82; p = 0.001) and GSTM1-active/GSTT1-null genotypes (OR = 2.33; p <  0.001) were significantly higher in cases than controls; the differences were not significant for GSTM1-null, GSTM1-null/GSTT1-active and GSTM1-null/GSTT1-null (p > 0.05). Multinomial logistic regression revealed that age ≥ 50 years, central obesity, family history of hypertension, obesity, alcohol intake and GSTT1 deletion were in decreasing order independent risk factors for essential hypertension. Analysis by gender, BMI and alcohol showed that association of GSTT1-null with risk of essential hypertension seems to be significant when BMI < 30 Kg/m2, in non-smokers and in alcohol users (all OR ≥ 1.77; p ≤ 0.008). Concerning GSTT1, GSTM1 and cardiovascular risk markers levels in hypertensive group, we found that subjects with GSTT1-null genotype had higher waist circumference and higher HDL cholesterol level than those with GSTT1-active (all p <  0.005), subjects with GSTM1-null genotype had lower triglyceride than those with GSTM1-active (p = 0.02) and subjects with the double deletion GSTM1-null/GSTT1-null had higher body mass index, higher waist circumference and higher HDL cholesterol than those with GSTM1-active/GSTT1-active genotype (all p = 0.01). CONCLUSION: Our results confirm that GSTT1-null genotype is significantly associated with risk of developing essential hypertension in Burkinabe, especially when BMI < 30 Kg/m2, in non-smokers and in alcohol users, and it showed that the double deletion GSTM1-null/GSTT1-null genotypes may influence body lipids repartition.


Assuntos
Hipertensão Essencial/genética , Glutationa Transferase/genética , Polimorfismo Genético , Deleção de Sequência , Adulto , Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/epidemiologia , Índice de Massa Corporal , Burkina Faso/epidemiologia , Estudos de Casos e Controles , Hipertensão Essencial/sangue , Hipertensão Essencial/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos/sangue , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar/sangue , Fumar/epidemiologia
18.
PLoS One ; 15(3): e0216147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155154

RESUMO

BACKGROUND: Fourteen previous meta-analyses have been published to analyze the polymorphisms of individual GSTM1 present/null, GSTT1 present/null, and GSTP1 IIe105Val on breast cancer (BC) risk. However, their meta-analyses did not explore the combined effects of the three genetic polymorphisms on BC risk. In addition, they did not evaluate the credibility of statistically significant associations. Furthermore, a multitude of new articles have been published on these themes, and therefore a meta-analysis and re-analysis of systematic previous meta-analyses were performed to further explore these issues. OBJECTIVES: To determine the association between the individual and combined effects of GSTM1, GSTT1, and GSTP1 polymorphisms on breast cancer risk. METHODS: Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were applied to estimate the association between individual and combined effects of GSTM1, GSTT1, and GSTP1 polymorphisms on BC risk. To evaluate the credibility of statistically significant associations in the current and previous meta-analyses, we applied the the false-positive report probabilities (FPRP) test and the Venice criteria. RESULTS: 101 publications were selected to evaluate the individual and combined effects of GSTM1, GSTT1 and GSTP1 polymorphisms on BC risk. Overall, statistically significant elevated BC risk was found in any individual and combined effects of GSTM1 present/null, GSTT1 present/null, and GSTP1 IIe105Val polymorphisms. However, when we restricted studies only involving with high-quality, matching, HWE, and genotyping examination performed blindly or with quality control, significantly increased BC risk was only found in overall population for GSTM1 null genotype, among all populations, Caucasians, and postmenopausal women for the combined effects of GSTM1 and GSTT1 polymorphisms, and in overall analysis for the combined effects of GSTM1, GSTT1, and GSTP1 IIe105Val polymorphisms. Further, less-credible positive results were identified when we evaluated the credibility of positive results of the current and previous meta-analyses. CONCLUSIONS: This meta-analysis indicates that the individual and combined effects of GSTM1, GSTT1 and GSTP1 polymorphisms may be not associated with increased BC risk.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Polimorfismo de Nucleotídeo Único/genética , Feminino , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Probabilidade , Viés de Publicação , Fatores de Risco
19.
Int Endod J ; 53(7): 895-904, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32216135

RESUMO

AIM: To investigate the possible association between TNFα (-308 G/A) and IL-1ß (-511 C/T) single nucleotide polymorphisms (SNPs) and GSTT and GSTM deletion polymorphisms and risk of apical periodontitis (AP) development, and determine the association of different genotypes with the presence of herpesviral infection in AP. METHODOLOGY: The study included 120 periapical lesions and 200 control samples. Gene polymorphism analysis was performed using either polymerase chain reaction (PCR) or PCR/ restriction fragment length polymorphism (RFLP). Relative gene expression of TNF-α and IL-1ß was analysed using reverse transcriptase - real-time PCR. The presence of Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) was assessed by nested PCR. Chi-square and Fisher's exact tests and logistic regression analyses were done for polymorphisms, whilst Mann-Whitney U-test was performed for the expression analysis. The expected frequency of variants was analysed by the Hardy-Weinberg equilibrium test. RESULTS: TNF-α (-308 G/A) SNP increased AP susceptibility for heterozygous (odds ratio (OR) = 1.72, 95% confidence interval (CI) = 1.06-2.80, P = 0.027) and homozygous (OR = 8.55, 95% CI = 1.77-41.36, P < 0.001) carriers of the variant A allele. On the other hand, IL-1ß (-511 C/T) polymorphism exerted a protective effect both in heterozygotes (OR = 0.540, 95% CI = 0.332-0.880, P = 0.013) and homozygotes (OR = 0.114, 95% CI = 0.026-0.501, P < 0.001). In addition, GSTM1 and GSTT1 null genotypes separately, as well as concomitantly, were associated with an increased risk for AP development (P < 0.001). The null GSTT1 genotype increased approximately twice the risk of Epstein-Barr infection (EBV) in AP (OR = 2.17, 95% CI = 1-4.71, P = 0.048), whilst TNF-α SNP decreased it, both in heterozygotes (OR = 0.20, 95% CI = 0.08-0.48, P < 0.001) and AA homozygotes (OR = 0.07, 95% CI = 0.01-0.37, P = 0.001). CONCLUSIONS: GSTM and GSTT deletion polymorphisms, as well as TNFα (-308 G/A) SNP, are associated with increased risk, whereas IL-1ß (-511 C/T) polymorphism decreases the risk of AP development. GSTT and TNFα polymorphisms also appear to modulate the risk of EBV infection in Serbian patients with AP.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Glutationa Transferase/genética , Interleucina-1beta/genética , Periodontite Periapical/genética , Fator de Necrose Tumoral alfa/genética , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Herpesvirus Humano 4 , Humanos , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único
20.
PLoS One ; 15(3): e0230282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160243

RESUMO

Cloning and expression of a desired gene is indispensable in molecular biology studies. Expression vectors, in this regard, should offer much needed flexibility and choice of cloning strategies for both in vivo and in vitro protein expression experiments. Furthermore, availability of option to choose from various reporter tags allows one to be flexible during designing of an experiment in a more relevant manner. Thus, the need of a versatile expression system cannot be ignored. Although several different expression vectors are available for gene expression in mycobacteria, they lack the required versatility of expression and the inclusion of reporter tags. We here present the construction of a set of nine E. coli-Mycobacterium shuttle plasmids, which offer a combination of three mycobacterial promoter systems (heat shock inducible-hsp60, tetracycline-, and acetamide-inducible) along with three polypeptide tags (Green Fluorescent Protein (GFP), Glutathione S-transferase (GST) and hexa-histidine tag). These vectors offer the cloning of a target gene in all the nine given vectors in parallel, thus allowing the generation of recombinant plasmids that will express the target gene from different promoters with different tags. Here, while the hexa-histidine and GST tags can be used for protein purification and pull-down experiments, the GFP-tag can be used for protein localization within the cell. Additionally, the vectors also offer the choice of positioning of the reporter tag either at the N-terminus or at the C-terminus of the expressed protein, which is achieved by cloning of the gene at any of the two blunt-end restriction enzyme sites available in the vector. We believe that these plasmids will be extremely useful in the gene expression studies in mycobacteria by offering the choices of promoters and reporters. Our work also paves the way to developing more such plasmids with other tags and promoters that may find use in mycobacterial biology.


Assuntos
Engenharia Genética/métodos , Vetores Genéticos/genética , Mycobacterium/genética , Escherichia coli/genética , Genes Reporter , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Histidina/genética , Histidina/metabolismo , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Regiões Promotoras Genéticas , Ativação Transcricional
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