GSTM1 Research Articles

Molecular Approach of Oxidative Stress and Bronchopulmonary Dysplasia - Relationship of GSTM1 and GSTT1 Genes.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease, with its own clinical, radiological and histopathological characteristics, which mainly affects premature newborns, resulting from a combination of factors that include immaturity, inflammation and lung injury, in addition to therapy with mechanical ventilation and exposure to high concentrations of oxygen. However, even with advances in care for critically ill newborns, BPD continues to be a challenge for the care team and family members. This has been identified as one of the most important causes of morbidity and mortality due to prematurity, and can have significant impacts on the quality of life of the affected patients. While interactions between the risk factors associated with BPD characterize it as multifactorial, its real pathogenesis still remains uncertain, as some newborns, despite having similar risk factors, do not develop it, suggesting, therefore, that susceptibility to BPD is genetically determined. Genetic variants in the Glutathione S-Transferase Mu-1/Glutathione S-Transferase Theta-1-null (GSTM1/GSTT1) genes may be associated with a greater risk of developing BPD in premature newborns, as they affect the function of glutathione S-transferases (GSTs) enzymes and, consequently, the body's ability to eliminate toxic or harmful pro-inflammatory substances. GSTM1/GSTT1-null individuals, due to the absence of gene expression, present loss of enzymatic activity of the respective GST enzymes, triggering failures in the detoxification process and the consequent development of numerous diseases resulting from oxidative damage such as infertility, chronic kidney disease, eryptosis, retinopathy of prematurity, necrotizing enterocolitis, periventricular leukomalacia, intraventricular hemorrhage. The objective of this narrative review is to highlight the role of genetic variants in the GSTM1/GSTT1 genes in the onset of bronchopulmonary dysplasia.

Alterations in the expression of genes involved in the mitochondrial apoptotic pathway upon exposure to lead oxide nanoparticles

Introduction. Lead production technologies pollute the air with aerosol nanoparticles, including those of lead oxide (PbO NPs). Lead can cause oxidative stress that leads to cell death. Experimental studies of effects of PbO NPs at the gene transcription level will expand our knowledge of the mechanisms of PbO NP toxicity and improve assessment of health risks for the population exposed to them. The purpose was to study the expression of genes involved in antioxidant protection and apoptosis following subchronic inhalation exposure of lead nanoparticles to rats. Materials and methods. Female albino rats were exposed to PbO NPs in an inhalation chamber at a concentration of 1.55 ± 0.06 mg/m3, 4 hours a day, 5 days a week for 1 month; the control group breathed clean air in a similar chamber. After exposure cessation, RNA was isolated from fragments of the olfactory bulb, cerebellum, lung, and liver. Expression of the P53, BAX, BCL-2, GSTM1, GSTP1, and SOD2 genes was determined by quantitative real-time PCR. The data was analyzed using the Mann-Whitney test. Results. In the olfactory bulb, BCL-2 gene expression was significantly lower, while that of P53 was higher in the exposed rodents compared to the controls. In the cerebellum of the exposed animals, BAX and P53 genes expression was statistically higher and lower than in the control group, respectively. BCL-2 gene expression in the liver was significantly lower in the exposed group. Limitations. The experiment involved only female rats, so it does not take into account sex differences and considers only gene expression, neglecting post-translational mechanisms and protein expression. Conclusion. Inhalation exposure to PbO NPs at the concentration of 1.55 ± 0.06 mg/m3 causes changes in the expression of genes associated with mitochondrial apoptosis in the brain and liver, but not in the lungs of laboratory rats.

Impact of genetic polymorphisms on associations between crude oil exposure and health effects among Coast Guard Deepwater Horizon responders

The U.S. Coast Guard led a clean-up response to the Deepwater Horizon (DWH) oil spill, the largest marine oil spill in history. Studies from the Deepwater Horizon Coast Guard Cohort (DWH-CG) have shown associations between crude oil exposure and various acute symptoms and longer-term health outcomes. Evidence has suggested genetic polymorphisms in metabolizing genes could modify the toxicity of crude oil and its components, which could impact health effects in responders exposed to crude oil. We applied log-binomial regression to calculate prevalence ratios (PRs) and 95 % confidence intervals (CIs) in the relationship between crude oil exposure (categorized to never, low, and high) and four acute symptoms (cough, shortness of breath/wheeze, skin rash/itching, headache) and to calculate risk ratios (RR) and 95 % CIs in the relationship between crude oil exposure and incidence of hypertension and asthma in the DWH-CG cohort. Effect modification by polymorphisms in 6 metabolizing genes [Cytochrome P450 family 2 subfamily E member 1 (CYP2E1), Glutathione S-Transferase Mu 1 (GSTM1), Glutathione S-Transferase Theta 1 (GSTT1), Epoxide Hydrolase 1 (EPHX1), NADPH quinone oxidoreductase-1 (NQO1), and Myeloperoxidase (MPO)] was evaluated. Results were stratified into wildtype and variant [i.e., those with at least one variant allele] for each gene. There was evidence of effect modification in the relationship between crude oil exposure and asthma by CYP2E1 [wildtype (RRHigh vs never/low, 95 % CI = 1.18, 0.99–1.42); variant (RRHigh vs never/low, 95 % CI = 2.27, 1.26–4.10); pinteraction = 0.04] and headache by NQO1 [wildtype (PRHigh vs never/low, 95 % CI = 2.1, 1.88–2.34); variant (PRHigh vs never/low, 95 % CI = 1.44, 1.07–1.94); pinteraction = 0.04]. Our study indicated the potential effect modification by metabolizing genotype in the relationship between crude oil exposure and headaches or asthma. These findings underscore the importance of considering potential genetic susceptibility among oil spill responders. Genotype variations, which are revealed only via specialized testing and thus not readily apparent, may contribute to differential vulnerability to the health effects associated with oil spill exposures.

Lung cancer, platinum analog-based frontline treatment and pharmacogenetic limitations.

Lung cancer has the highest mortality rate among all the highly prevalent neoplasia globally. The major concern with its frontline treatment-cisplatin, is the rapid progression of chemoresistance and multi-organ-based toxicities including hearing loss and tinnitus, nephrotoxicity, hepatotoxicity and myelosuppression including anemia and neutropenia. In this review, studies concluding the association of single nucleotide polymorphisms (SNP) in disparate genes with aforementioned toxicity points are summarized to observe the pharmacogenomic pattern. Especially, SNPs in ATP7B, ERCC-1, ERCC-2, MATE-1, OCT-2, ABCB-1, ABCC-1, ABCG-2, ABCC-2, SLC22A, ERCC-5, BRCA-1, GSTM-3, GSTM-4 and GSTM-5 genes appear to be associated with the therapeutic response and/or adverse effects of cisplatin. We recommend utilizing this information to minimize the risk of treatment failure due to chemoresistance and adverse effects on other organs.

The influence of host genotype and gut microbial interactions on feed efficiency traits in pigs.

Feed efficiency and growth performance are economically important traits in pigs. Precious studies have been revealed that both genetics and gut microbes could influence host phenotypes, however, the mechanisms by which they affect pig growth and feed efficiency remain poorly understood. In this study, 361 crossbred Duroc × (Landrace × Yorkshire) commercial pigs were genotyped using GeneSeek Porcine SNP50K BeadChip, and the microbiotas from fecal samples were acquired using microbial 16S rRNA gene sequencing technology to investigate the impact of host genetics and gut microorganisms on growth and feed efficiency. The results showed that the heritability and enterobacterial force ranged from 0.27 to 0.46 and 0 to 0.03, respectively. Genome-wide association studies (GWAS) identified seven significant SNPs to be associated with growth and feed efficiency, and several genes, including AIF1L, ASS1, and QRFP were highlighted as candidates for the analyzed traits. Additionally, microbiome-genome-wide association studies GWAS revealed potential links between CCAR2, EGR3, GSTM3, and GPR61 genes and the abundance of microorganisms, such as Trueperella, Victivallis, and Erysipelatoclostridium. In addition, six microbial genera linked to growth and feed efficiency were identified as follows Lachnospiraceae_UCG-005, Prevotellaceae_UCG-003, Prevotellaceae_NK3B31_group, Prevotella_1, Prevotella_9, and Veillonella. Our findings provide novel insights into the factors influencing host phenotypic complexity and identify potential microbial targets for enhancing pig feed efficiency through selective breeding. This could aid in the development of strategies to manipulate the gut microbiota to optimize growth rates and feed efficiency in pig breeding.

Analysis of glutathione Stransferase mu class 5 gene methylation as a prognostic indicator in low-grade gliomas.

Low-grade gliomas (LGG) are a variety of brain tumors that show different clinical outcomes. The methylation of the GSTM5 gene has been noted in the development of LGG, however, its prognostic importance remains uncertain. The objective of this study was to examine the correlation between GSTM5 DNA methylation and clinical outcomes in individuals diagnosed with LGG. Analysis of GSTM5 methylation levels in LGG samples was conducted using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. The overall survival based on GSTM5 methylation status was evaluated using Kaplan-Meier curves. The DNA methylation heatmap for particular CpG sites in the GSTM5 gene was visualized using the "pheatmap" R package. The study analyzed that LGG tumors had higher levels of GSTM5 methylation than normal tissues. There was an inverse relationship discovered between GSTM5 expression and methylation. LGG patients with hypermethylation of GSTM5 promoter experienced a positive outcome. Age, grade, and GSTM5 methylation were determined as independent prognostic factors in LGG through both univariate and multivariate Cox regression analyses. Methylation of GSTM5 DNA, specifically at certain CpG sites, is linked to a positive outlook in patients with LGG. Utilizing the "pheatmap" R package to visualize GSTM5 methylation patterns offers important information for identifying prognostic markers and therapeutic targets in low-grade gliomas.

Pharmacogenetic assessment of cytostatic therapy efficacy depending on the polymorphism of T1 and M1 glutathione-S-transferase genes in breast cancer patients

Aim. To study the effect of deletion polymorphism of the GST genes (GSTT1, GSTM1) on chemotherapy (CT) efficacy in women diagnosed with breast cancer (BC) in the Primorsky Krai. Materials and methods. The study involved 132 women with breast cancer aged 23 to 79 years (mean age 48 ± 13 years) who received chemotherapy treatment. The detection of deletion (null) genotypes of GSTM1 and GSTT1 was carried out using multiplex PCR followed by an analysis of the melting curves of the reaction products. Results. Relapse-free survival (RFS) of BC patients with the “null” GSTT1 genotype was statistically significantly higher (116.7 months (9.6 years) versus 75.8 months (6.2 years)) than in patients with the “normal” GSTT genotype. Thus, in the case of the GSTT1“null” genotype, the risk of disease relapse decreased by 2.4 times (HR = 0.418, CI = 0.191–0.915, p = 0.024). Similar to GSTT1, the DFS of patients with the GSTM1 null genotype increased from 72.7 months (6 years) to 76.1 months (6.3 years). At the same time, the risk of disease relapse in carriers of the “null” GSTM1 genotype decreased by 1.7 times (HR = 0.596, CI = 0.369–0.964, p = 0.033) compared with that in carriers of the “normal” GSTM1 genotype. Conclusions. Deletion polymorphism of the GSTT1 and GSTM1 genes has a significant impact on chemotherapy efficacy in breast cancer patients. Carriers of “null” genotypes demonstrated a higher RFS and a lower risk of developing disease relapse. Further research in this direction and validation of the data obtained may contribute to individualizing the treatment of breast cancer patients, optimizing chemotherapy regimens, and reducing the number of adverse events.

Clinical Value of Urinary Wilms' Tumour-1 and Mu-Glutathione S-Transferase Gene Expression in Kidney Injury in Type 2 Diabetes Mellitus.

To investigate the diagnostic value of urinary Wilms' tumour-1 (WT-1) and mu-glutathione S-transferase (Mu-GST) gene expression for detecting kidney injury in type 2 diabetes mellitus (T2DM). Patients treated between October 2022 and June 2023 were divided into two groups: a diabetic nephropathy (DN) group (105 patients) and a diabetes mellitus (DM) group (100 patients). Additionally, 100healthy individuals undergoing routine medical check-ups were selected as the control group. The urinary albumin/creatinine ratio (ACR), as well as urinary WT-1 and Mu-GST expression levels, were measured. The sensitivity and specificity of these markers for predicting renal injury were evaluated. The levels of ACR, WT-1 and Mu-GST in the DN group were significantly higher than those in the DM and control groups. The ACR in the DM group was also significantly higher than that in the control group (P < 0.05), and WT-1 and Mu-GST gene expression levels demonstrated a positive correlation with ACR (r = 0.391 and 0.342, respectively). The sensitivity and specificity of WT-1 were 74% and 95%, respectively, whereas those of Mu-GST were 70% and 96%, respectively. The combined detection of WT-1 and Mu-GST yielded a sensitivity of 82% and a specificity of 97%. The levels of WT-1 and Mu-GST gene expression are closely related to T2DM kidney injury, helping to identify the location of kidney injury to some extent, which provides valuable information for the clinical diagnosis and treatment of kidney injury.

A Comment on ‘Clinical Value of Urinary Wilms’ Tumour-1 and Mu-Glutathione S-Transferase Gene Expression in Kidney Injury in Type 2 Diabetes Mellitus: Important Considerations for Clinical Application’ [Letter]

A Comment on ‘Clinical Value of Urinary Wilms’ Tumour-1 and Mu-Glutathione S-Transferase Gene Expression in Kidney Injury in Type 2 Diabetes Mellitus: Important Considerations for Clinical Application’ [Letter]

Associations of GST Gene Polymorphisms and GST Enzyme Activity with the Development of Noise-Induced Hearing Loss in Chinese Han Males

Introduction: In noise-induced hearing loss (NIHL), glutathione S-transferases (GSTs) play a pivotal role as antioxidants in cochlear protection. Nevertheless, the variability in population and environmental factors complicates the interpretation of research findings on the association among GST gene polymorphism, GST enzyme activity, and NIHL, leading to inconsistent results. To explore the potential correlation between them, we took a cross-sectional survey. Methods: For workers with NIHL, standard 1:1 propensity score matching was applied to create a highly comparable control group. Multiplex PCR was used to detect GSTT1 and GSTM1 gene deletions, PCR-restriction fragment length polymorphism was used to detect the GSTP1 rs1695 gene polymorphism, and a GST assay kit was used to measure total plasma GST activity. Furthermore, we analyzed the relationship among GST gene polymorphism, GST enzyme activity, and NIHL. Results: This study included 144 workers with NIHL and 144 workers with normal hearing. The GSTM1 null genotype was significantly higher among workers with NIHL than controls (64.6% vs. 49.3%), regression analysis revealed a significant correlation between GSTM1 null genotype and elevated susceptibility to NIHL (p = 0.013). Workers with NIHL had significantly lower GST activity than healthy controls (p < 0.05). GST enzymes were not affected by GSTT1, GSTM1, or GSTP1 polymorphisms. Conclusion: GSTM1 null genotype but not GSTM1 alone may confer susceptibility to NIHL, and serum GST enzyme activity is linked to NIHL.

Effect of donor GSTM3 rs7483 genetic variant on tacrolimus elimination in the early period after liver transplantation.

Glutathione S-transferase mu (GSTM) belongs to the group of phase II drug-metabolizing enzymes, and the GSTM1 genetic variant has been reported to have a potential association with the metabolism of immunosuppressive drug after renal transplantation. The effect of donor and recipient GSTMs genetic variants on tacrolimus (Tac) metabolism was the focus of our investigation in this study. A total of 203 liver transplant patients were recruited for the study. In the training set (n=110), twenty-one SNPs in five genes (GSTM1-5) were genotyped by the drug-metabolizing enzymes and transporter (DMET) microarray. CYP3A5 rs776746 and GSTM3 rs7483 were genotyped using a Mass ARRAY platform in the validating set (n=93). Tac C/D ratios of donor GSTM3 rs7483 AA carriers were significantly lower than those with the G allele at weeks 1, 2, 3 and 4 after liver transplantation (LT). Multivariate analysis was conducted on the training set and validating set, donor and recipient CYP3A5 rs776746, donor GSTM3 rs7483 and total bilirubin were identified as independent predictors of Tac C/D ratios in the early period after LT. Combining CYP3A5 rs776746 and donor GSTM3 rs7483 genotypes, Tac C/D ratios were observed to be increasingly lower with increasing numbers of alleles associated with fast metabolism. Moreover, the risk of a supratherapeutic C0 (Tac > 15 ug/L) was significantly higher for poor metabolizers than the other groups at week 1 after LT. There was a significant association between the donor GSTM3 rs7483 genetic variant and Tac metabolism in the early period after LT. Genotype classification might have a better predictive ability of the initial Tac doses.

The moderation effect of GSTM1/GSTT1 gene polymorphisms on the association of sperm mitochondrial DNA copy number and sperm mobility

Oxidative stress (OS) is believed to be a significant factor in the decline of semen quality, with mitochondrial DNA copy number (mtDNAcn) serving as a sensitive biomarker for both semen quality and mitochondrial dysfunction resulting from oxidative stress. While glutathione S-transferases (GSTs) are commonly known as ‘antioxidant’ enzymes, there is ongoing debate regarding the relationship between GST genotypes and semen quality. In a study involving 568 male volunteers from the outpatient department of Puyang Reproductive Medicine Center, sperm mtDNAcn, semen quality, and GSTM1/GSTT1 genotypes were analyzed to investigate the potential link between GSTM1/GSTT1 gene variations and semen quality, as well as the impact of GSTs gene variations on the connection between sperm mtDNAcn and semen quality. Adjusting for variables such as age, BMI, smoking, and alcohol consumption, it was found that mtDNAcn was significantly correlated with decreased sperm concentration and total sperm count (b = − 0.109, − 0.128, respectively; P = 0.002, 0.001, respectively). GSTM1 was associated with progressive motility (OR 0.390, 95% CI 0.218, 0.697), Straight line velocity (VSL) (OR = 0.606, 95% CI 0.385, 0.953), and Straightness (STR) (OR 0.604, 95% CI 0.367, 0.994), while GSTT1 was linked to progressive motility (OR 0.554, 95% CI 0.324, 0.944) and Beat crossover frequency (OR 0.624, 95% CI 0.397, 0.982). The GSTT1 was found to moderate the relationship between mtDNAcn and sperm motility parameters linearity (LIN), STR, and Wobble (WOB), with additive interaction effects observed between GSTT1 and mtDNAcn on LIN, STR, and WOB (P for interaction = 0.008, 0.034, 0.010, respectively). Overall, this study suggests that GSTT1 and GSTM1 gene variations may play a role in sperm motility, with GSTT1 potentially influencing the impact of oxidative stress on sperm motility.

Association of polymorphic variants of the GSTP1 and GSTM1 genes with signs of tunnel syndromes in patients with vibration disease (pilot study)

Introduction. The data on the association between GSTs gene variants and the risk of developing carpal tunnel syndrome (CTS) determine the feasibility of studying the relationship with changes in the nerve structure of the upper limbs identified by ultrasound examination in patients with vibration disease (VD). The aim of the study was to investigate the association of polymorphic variants of the GSTP1 and GSTM1 genes with signs of tunnel syndromes in VD patients. Materials and methods. Polymorphic variants of the GSTP1 (rs1695 and rs1138272) and GSTM1 genes in one hundred forty male VD patients were studied using PCR-RT method. High-resolution ultrasonography parameters were used to evaluate the morphological structure of the peripheral nerves of the upper limbs in patients, including the cross-sectional area (CSA) of the peripheral nerves. Results. A significant gain in CSA maximum of the median nerve was found in carriers of the GSTM1–/– genotype relative to those in the GSTM1+ polymorphic variant of the GSTM1 gene (p=0.014). At the same time, AG-GSTP1 (Ile105Val) heterozygote carriers were less resistant to vibration exposure compared to the AA homozygote ones. The AG carriers had a shorter period of vibration exposure (p=0.017), which was observed against the background of a pronounced tendency to a decrease in the period of vibration exposure at the time of VD diagnosis (p=0.034). Limitations. Limitations include the small number of examined patients and the analysis of associations of polymorphic variants of GSTs genes only with CSA values without taking into account the clinical and functional status of patients. Conclusion. The results obtained indicate that GSTs genes involved in protection against oxidative stress, may be associated with the development of CTS in VD patients. Further investigations are needed involving a larger number of VD patients with simultaneous analysis of the morphological structure of peripheral nerves, as well as of electrophysiological and clinical studies.

Comparative analysis of transcriptomics of Fasciola hepatica at different developmental stages.

This study explored the transcriptome differences in Fasciola hepatica at different developmental stages and identified functional genes related to growth and development during juvenile stages. DNBSEQ eukaryotic strand-specific transcriptome resequencing technology was used to sequence the transcriptomes of Fasciola hepatica eggs, juveniles, and adults. Additionally, the genes that were highly expressed during the juvenile stage were validated using qRT-PCR. The Q20 values of all three phases of sequencing were above 98%, and the Q30 values were above 94%. The differentially expressed genes (DEGs) in pairwise comparisons were analyzed by GO functional classification and the KEGG pathway database. Many immune-, growth-, and development-related pathways were found, which might be related to cell proliferation, development, and host immune evasion by Fasciola hepatica. In addition, five DEGs with high expression levels during the juvenile stage were identified: Cathepsin B, Glutathione S-transferase mu, heat shock protein 67B2, Kunitz-CH, and Legumain. Validation analyses revealed that these genes play key roles in maintaining normal growth, development, and immunological processes in liver Fasciola hepatica. RNA-seq was used to analyze the biological characteristics of the DEGs at different developmental stages concerning GO functional classification and KEGG metabolic pathways. Five DEGs with high expression during the juvenile stage were identified. These genes are related to the growth, development, and immune function of Fasciola hepatica, which provides a theoretical basis for subsequent research on the proteomics of Fasciola hepatica and the screening of candidate genes for early diagnosis.

Influence of Genetic Polymorphisms on the Age at Cancer Diagnosis in a Homogenous Lynch Syndrome Cohort of Individuals Carrying the MLH1:c.1528C>T South African Founder Variant.

Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan-Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini-Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01-4.08], p = 0.034 and Adj HR: 1.53 [1.09-2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48-0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06-2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37-0.73], and Adj HR: 0.51 [CI: 0.36-0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene.

Natural Compounds That Activate the KEAP1/Nrf2 Signaling Pathway as Potential New Drugs in the Treatment of Idiopathic Parkinson's Disease.

Recently, a single-neuron degeneration model has been proposed to understand the development of idiopathic Parkinson's disease based on (i) the extremely slow development of the degenerative process before the onset of motor symptoms and during the progression of the disease and (ii) the fact that it is triggered by an endogenous neurotoxin that does not have an expansive character, limiting its neurotoxic effect to single neuromelanin-containing dopaminergic neurons. It has been proposed that aminochrome is the endogenous neurotoxin that triggers the neurodegenerative process in idiopathic Parkinson's disease by triggering mitochondrial dysfunction, oxidative stress, neuroinflammation, dysfunction of both lysosomal and proteasomal protein degradation, endoplasmic reticulum stress and formation of neurotoxic alpha-synuclein oligomers. Aminochrome is an endogenous neurotoxin that is rapidly reduced by flavoenzymes and/or forms adducts with proteins, which implies that it is impossible for it to have a propagative neurotoxic effect on neighboring neurons. Interestingly, the enzymes DT-diaphorase and glutathione transferase M2-2 prevent the neurotoxic effects of aminochrome. Natural compounds present in fruits, vegetables and other plant products have been shown to activate the KEAP1/Nrf2 signaling pathway by increasing the expression of antioxidant enzymes including DT-diaphorase and glutathione transferase. This review analyzes the possibility of searching for natural compounds that increase the expression of DT-diaphorase and glutathione transferase through activation of the KEAP1/Nrf2 signaling pathway.

Association of polymorphism of the glutathione-s-transferase M1 gene and tumor necrosis factor alpha with the formation and size of decay cavities in patients with pulmonary tuberculosis

The aim. To study the association of polymorphic variants of the GSTM1 (E/D) and TNF-s (308G&gt;A (rs1800629) genes with the formation of decay cavity sizes in patients with pulmonary tuberculosis.Material and methods. The study group is represented by 335 patients suffering from pulmonary tuberculosis (212 people were diagnosed with pulmonary tuberculosis for the first time; 123 people with chronic pulmonary tuberculosis) aged 18 to 65 years; receiving an intensive phase of chemotherapy. To conduct molecular genetic studies; 335 people had whole blood taken from a vein into a test tube with EDTA. Genomic DNA was isolated using Arrow Blood DNA 500 reagent kits from whole blood (at the NorDiag Arrow station). After; the polymerase chain reaction was staged in real time using sets of reagents for genotyping SNPs: GSTM1 (E/D) and TNF-s (–308G&gt;A (rs1800629).Results and discussion. In patients with pulmonary tuberculosis; the genotype DD of the gene GSTM1 (E/D) and the genotype GG of the gene TNF-s –308G&gt;A (rs1800629) is most often associated with the formation of the size of decay cavities.Conclusion. It is advisable to introduce genotyping of the GSTM1 and TNF-s genes into the practice of a phthisiologist in order to predict the probability of the formation of the size of decay cavities in patients with pulmonary tuberculosis.

Intraindividual variability of semen quality, proteome, and sncRNA profiles in a healthy cohort of young adults.

Within-subject variability of semen parameters and molecular components of ejaculates in young men remains poorly understood. To investigate intraindividual variability (IIV) of semen parameters and molecular markers in repeated ejaculates from young men. Semen parameters were assessed in samples collected 6-8 days apart from 164 18-19-year old participants of the Russian Children's Study, a prospective cohort. Subsets of paired samples were used for label-free quantitation and targeted mass-spectrometry of proteins in seminal plasma (SP) and seminal extracellular vesicles (EVs), and for small non-coding RNA (sncRNA) profiling in EVs and spermatozoa using RNA-seq. The mean difference between two ejaculates, within-subject variation, intraclass correlation, and concordance correlation were used to assess IIV for all parameters. Low variability with high reproducibility and high reliability was considered if CVw<15% and ICC>0.90, respectively. Analytical variability was low for all investigated parameters in technical replicates. IIV was assessed for basic semen parameters and proteins in SPs and EVs: 319 and 777 proteins, respectively, using untargeted analysis; 9 and 10 proteins using targeted quantification. We also described the IIV for sncRNA, including microRNA, piwi-interacting RNA, tRNA, and tRNA-derived small RNA (tsRNA) in EVs (409 sncRNA and 78 tsRNA) and in spermatozoa (265 sncRNA and 15 tsRNA). We identified 22 and 27 non-overlapping proteins in SP and EVs, respectively, and 46 and 9 sncRNA, including 5 and 0 tsRNA in seminal EVs and spermatozoa, respectively, with low variability. The fatty acid synthase (FAS) had the lowest IIV in both media in targeted protein quantification. We identified a number of proteins and sncRNA with low variability among 111 proteins, 176 sncRNA, and 12 tsRNA which were previously suggested as biomarkers of male fertility and reproductive outcomes: lactotransferrin, cysteine-rich secretory protein 3, alpha-1-antichymotrypsin, epididymal sperm-binding protein 1, glutathione S-transferase Mu 3, alpha-1-acid glycoprotein 2, serum amyloid P-component, aminopeptidase N, neprilysin, FAS, and miR-10b-3p, miR-122-5p, miR-205-5p, miR-222-3p, miR-34c-5p, miR-509-3-5p, miR-888-5p, miR-892a, miR-363-3p, miR-941, miR-146a-5p, miR-744-5p. These molecules have low IIV and may be promising candidate biomarkers of male fertility and reproductive health.

Null polymorphism of the GSTM1 and GSTT1 genes in susceptibility to colorectal tumorigenesis: systematic review with meta-analysis

Objective: To assess if GSTT1 and GSTM1 null polymorphisms increase susceptibility to colorectal cancer. Methods: A search was conducted in PubMed, SciELO, BVS, and Medline databases. Forty articles were selected, totaling 12,698 cases and 19,517 controls. Odds ratios with 95% confidence intervals were used, and p-values &lt;0.05 were considered significant. The Dersimonian-Laird method was applied for p-values &lt;0.05, and the Mantel-Haenszel method was used otherwise. All p-values were two-tailed with an alpha value of 0.05 determined a priori. STATA 16.0 software was utilized. Result: A higher risk of colorectal cancer was shown in the general population for the GSTM1 null genotype (OR=1.11; 95%CI [1.03, 1.19]; P&lt;0.01). No significant risk was observed for GSTT1 or the GSTM1/GSTT1 null combination (OR=1.09; 95%CI [0.98, 1.22]; P&lt;0.01 and OR=1.13; 95%CI [0.89, 1.43]; P&lt;0.01, respectively). In subgroup analysis, increased colorectal cancer risk was found for Asians with the GSTM1 null genotype (OR=1.10; 95%CI [1.02, 1.20]; P=0.02) and GSTM1/GSTT1 null combination (OR=1.49; 95%CI [1.03, 2.15]; P&lt;0.01). Conclusion: The findings suggest that the GSTM1 null polymorphism and the GSTM1/GSTT1 null combination are potential susceptibility factors for colorectal cancer, particularly in the Asian population.

Associations of polymorphisms of glutathione-S-transferase and N-acetyltransferase 2 genes in children with acute lymphoblastic leukemia

The development of personalized medicine is inextricably linked with the study of the patient’s genetic profile, which determines not only the features of the course of the disease, but also the risks of its occurrence. Purpose. The aim of the work was to study possible associations between the genetic polymorphisms GSTT1, GSTM1, NAT2 and predisposition to the development of acute lymphoblastic leukemia in children of the East Siberian region. Material and methods. A total of 82 children with acute lymphoblastic leukemia and 227 healthy volunteers with no history of hematological pathology were examined. Deletion polymorphisms in the glutathione S-transferase GSTT1 and GSTM1 genes were detected by polymerase chain reaction (PCR) with electrophoretic detection of amplification products in agarose gel; the type of acetylation was determined by genotyping SNP rs1495741 of the NAT2 gene by conducting a polymerase chain reaction in real time. The material for the study was DNA samples isolated from buccal epithelium samples. Results. Statistical processing allowed us to draw the following conclusions: the rate of acetylation of xenobiotics does not affect the risk of acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. Conclusion. There is no associative relationship between deletions in the GSTM1 and GSTT1 genes and the risk of developing acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. It was found that the risk of developing acute lymphoblastic leukemia in children was significantly higher with the variant of combinations of alleles of the rapid type of NAT2 acetylation and normal activity of GSST1 and GSTM1 (G/G, active, active).