GSTM1 Research Articles

The ameliorative mechanism of Lactiplantibacillus plantarum NJAU-01 against D-galactose induced oxidative stress: a hepatic proteomics and gut microbiota analysis.

Probiotic intervention is an effective strategy to alleviate oxidative stress-related diseases. Our previous studies found that Lactiplantibacillus plantarum NJAU-01 (NJAU-01) exhibited antioxidant effects in a D-galactose (D-gal)-induced aging mouse model. However, the underlying mechanism remains to be unveiled. This study was aimed to investigate the ameliorative effect and mechanism of NJAU-01 against oxidative stress induced by D-gal. The results showed that NJAU-01 could reverse the tendency of a slow body weight gain induced by D-gal. NJAU-01 relieved hepatic oxidative stress via increasing the hepatic total antioxidant capacity and antioxidant enzyme activities including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). Moreover, the malondialdehyde (MDA) level was reversed after NJAU-01 supplementation. The proteomic results showed that there were 201 differentially expressed proteins (DEPs) between NJAU-01 and D-gal groups. NJAU-01 regulated the expressions of glutathione S-transferase Mu 5 (Gstm5), glutathione S-transferase P2 (Gstp2) and NADH dehydrogenase 1α subcomplex subunit 7 (Ndufa7) related to oxidative stress, and autophagy protein 5 (Atg5) and plasma alpha-L-fucosidase (Fuca2) involved in autophagy, etc. 16S rDNA sequencing results showed that NJAU-01 supplementation could regulate the gut microbiota dysbiosis induced by D-gal via increasing the relative abundances of the phylum Firmicutes and the genus Lactobacillus and reducing the relative abundances of the phylum Bacteroidetes and the genera Lachnospiraceae_NK4A136_group as well as Prevotellaceae_UCG-001, etc.. Spearman correlation analysis results showed that the altered gut microbiota composition had a significant correlation with antioxidant enzyme activities and the DEPs related to oxidative stress. Overall, NJAU-01 alleviated hepatic oxidative stress induced by D-gal via manipulating the gut microbiota composition and hepatic protein expression profile.

Describing the Glutathione S-transferase Mu and Tumor Protein 53 Expression Profiles in Brain Tumor Tissue

Describing the Glutathione S-transferase Mu and Tumor Protein 53 Expression Profiles in Brain Tumor Tissue

Unveiling the etiological impact of GST-M1, GST-T1, and P53 genotypic variations on brain carcinogenesis.

Functional variants of glutathione-S-transferase (GST)-M1, GST-T1, p53 might modulate brain cancer risk by altering the rate of metabolism and clearance of carcinogens from the brain tissue. In this study, the role of GST-M1, GST-T1, p53 polymorphisms on brain tumor was investigated. Brain tumor tissues of 143 patients were obtained from the Gulhane Training and Research Hospital, Department of Neurosurgery between 2019 and 2020. In the xenobiotic mechanism, the null allele frequency in the GST-T1, GST-M1 gene regions of Phase II enzymes by qPCR method were investigated. Single nucleotide polymorphism encoding Arg/Pro conversion in the p53 gene region was analyzed in 120 cases by sequence analysis method. The data were analyzed statistically with patient's demographic and clinical data. GST-M1, GST-T1, p53 genotypes of the patient group were determined. The most frequent genotype was null genotype (0/0) for GST-M1 (χ2 = 39.756, p < 0.001). GST-M1 genotype frequencies were 30.8%, 23.1%, 44.3% for 1/1, 1/0, 0/0, respectively. The most frequent genotype was GST-T1 1/1 following by GST-T1 1/0 (χ2 = 0.335, p = 0.846). GST-T1 genotype frequencies were 64.3%, 30.8%, 4.9% for 1/1, 1/0, 0/0, respectively. GST-M1 null genotype might be associated with the development of brain tumors. Genotype distribution obtained in p53 exon 4 codon 72; Arg/Arg was determined as 31 (25.8%), Arg/Pro 70 (58.3%), and Pro/Pro 19 (15.8%) in the case group, while there were 18 (38.3%), 23 (48.9%), and 6 (12.8%) respectively in the control group. However, the genotype distribution of p53 exon 4 codon 72 among tumorous tissue did not significantly vary from healthy control tissues (χ²=2.536, p = 0.281). The null allele frequency encountered in the GST-M1, GST-T1 gene regions is consistent with the rates in the gene pool called Caucasian in the literature. GST-M1 gene polymorphism may play a crucial role in brain carcinogenesis in Turkish patients. This study based on clinical data is thought to help to understand the important epidemiological features of brain tumors.

Study on the association of Glutathione S-transferase Mu 1 (GSTM1) gene polymorphism with acute decompensated heart failure with reduced ejection fraction

The most frequent cause of hospitalization in adults over 65 in Western nations is acute decompensation of heart failure (ADHF). Due to the high death rate, it places a heavy load on healthcare systems as well as people. The present study’s objective was to ascertain the connection between polymorphisms in the Glutathione S-transferase Mu 1 (GSTM1) gene and heart-failure-reduced ejection fraction (HFrEF) patients. Sixty patients with a mean age of 25–94 were taken from both genders after the clinical diagnosis by a specialist to cases who were referred to the Ibn Al-Baitar Specialized Center for Cardiac Surgery and Ramadi Teaching Hospital, and thirty apparently healthy people were taken as a control. Blood and serum containing EDTA were drawn from sick and healthy people to extract DNA for multiplex PCR detection of the GSTM1 polymorphism. The GSTM1 genotype was found in 23 (38.33%) and the null gene in 37 (61.66%) of the 60 ADHF patients. Of 30 healthy people, 8 (26.66%) had the GSTM1 gene and 22 (73.33%) had the null gene. According to the present study, the etiology of acute decompensated heart failure (ADHF) and the antioxidant null gene (GSTM1) are related. The present study has been achieved to determine the relationship between the presence of the antioxidant gene (GSTM1) and the incidence of ADHF with reduced ejection fraction for research and therapeutic purposes, which opens new spaces in the treatment of the mentioned condition.

Buspirone Enhances Cell Survival and Preserves Structural Integrity during Oxidative Injury to the Retinal Pigment Epithelium.

Chronic oxidative stress impairs the normal functioning of the retinal pigment epithelium (RPE), leading to atrophy of this cell layer in cases of advance age-related macular degeneration (AMD). The purpose of our study was to determine if buspirone, a partial serotonin 1A (5-HT1A) receptor agonist, protected against oxidative stress-induced changes in the RPE. We exposed differentiated human ARPE-19 cells to paraquat to induce oxidative damage in culture, and utilized a mouse model with sodium iodate (NaIO3)-induced oxidative injury to evaluate the effect of buspirone. To investigate buspirone's effect on protective gene expression, we performed RT-PCR. Cellular toxicities and junctional abnormalities due to paraquat induction in ARPE-19 cells and buspirone's impact were assessed via WST-1 assays and ZO-1 immunostaining. We used spectral-domain optical coherence tomography (SD-OCT) and ZO-1 immunostaining of RPE/choroid for structural analysis. WST-1 assays showed dose-dependent protection of viability in buspirone-treated ARPE-19 cells in culture and preservation of RPE junctional integrity under oxidative stress conditions. In the NaIO3 model, daily intraperitoneal injection (i.p.) of buspirone (30 mg/kg) for 12 days improved the survival of photoreceptors compared to those of vehicle-treated eyes. ZO-1-stained RPE flat-mounts revealed the structural preservation of RPE from oxidative damage in buspirone-treated mice, as well as in buspirone-induced Nqo1, Cat, Sqstm1, Gstm1, and Sod2 genes in the RPE/choroid compared to untreated eyes. Since oxidative stress is implicated in the pathogenesis AMD, repurposing buspirone, which is currently approved for the treatment of anxiety, might be useful in treating or preventing dry AMD.

A positive correlation between mutated gene of sickle cell anemia and glucose-6-phosphate dehydrogenase among gond tribes of Chhattisgarh, India

BackgroundGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy affecting millions of individuals worldwide. It is believed that the prevalence of G6PD deficiency in different ethnic populations increases its association with other pathological conditions especially sickle cell anemia (SCA), as they both are well-known adaptations against malaria. Thus, the present study aims to determine the frequency of G6PD deficiency among SCA patients and the association between them in the tribal community (Gond) of Chhattisgarh, India. MethodA total of 810 samples from three different age groups i.e., 10–20, 21–30, and 31–40 years were collected from the tribal community (Gond) of Kabirdham district of Chhattisgarh. The frequency of SCA was determined by a slide test followed by cellulose acetate paper electrophoresis and G6PD deficiency by methemoglobin reduction test. Glutathione-S-Transferase (GST) gene polymorphism in sickle celled individuals and variant analysis in G6PD deficient individuals were analyzed by RT-PCR. ResultsThe frequency of SCA and G6PD deficiency was reported at 9.75% and 17.16% respectively and a high degree of positive correlation between SCA and G6PD deficiency was also found (HbSS-G6PD deficient: r = 0.84, p = .356; HbAS-G6PD deficient: r = 0.89, p = .345). Results of the GST gene revealed that GSTM1 and GSTT1 genes are present in almost all sickled individuals while GSTP1 and GSTP1a exist in the mutated form in a maximum percentage of individuals. G6PD variant analysis also showed that 70% and 60% of individuals have mutated Mahidol and Union variants respectively, while none of the individuals have mutated Chinese variants. ConclusionA high degree of correlation between SCA and G6PD was reported among Gond tribes of Chhattisgarh, India with a high degree of mutated GSTP1, GSTP1a, Mahidol, and Union variants. The study makes it possible to take specific preventive measures concerning the medication of anti-oxidizing drugs.

GST polymorphism as a predictive biomarker for modulating the susceptibility to chronic obstructive pulmonary disease: A North Indian study.

Chronic obstructive pulmonary disease (COPD) is commonly characterized by shortness of breath, coughing or expectoration. Smoking is the leading cause of COPD development, but only a small percentage of smokers develop symptoms, implying a genetic component. Glutathione S-transferase enzymes are responsible for detoxifying cigarette smoke components. The role of glutathione S-transferase T1 (GSTT1) and glutathione S-transferase M1 (GSTM1) gene polymorphism was assessed with COPD susceptibility and associated clinical parameters in the North Indian population. This was a cross-sectional study involving 200 COPD patients and 200 healthy individuals, with peripheral blood sampling and adequate questionnaires. Multiplex PCR was used for genotyping GSTT1 and GSTM1 gene polymorphism. Logistic regression was used to calculate the odds ratio and 95% confidence intervals to assess the COPD risk and GST polymorphisms. The GSTT1 gene deletion rate was higher in COPD cases (34.5%) than in healthy individuals (20.5%). A statistical relationship between the GSTT1(-) null genotype and COPD risk was observed (odds ratio=2.04, 95% CI=1.30-3.20, P=0.0019). After adjusting for covariates like age, sex and smoking status, a significant association was found for GSTT1(-) null genotype and COPD risk (adjusted odds ratio=2.90, 95% CI=1.43-5.87, P=0.003). The GSTT1(-) genotype was also significantly correlated with clinical parameters for COPD risk. Another primary observation was that females with the GSTT1(-) null genotype were more vulnerable to COPD than males with the same gene deletion. The GSTT1(-) null genotype strongly correlates with COPD development, while no association was observed in the GSTM1(-) null genotype in the North Indian population.

GPX3 Variant Genotype Affects the Risk of Developing Severe Forms of COVID-19.

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.

Potential role of glutathione S‑transferase M1 gene polymorphism in kidney calcium oxalate stone formation.

The purpose of this study was to look into the effects of glutathione S-transferase M1 (GSTM1) gene polymorphism on the formation of kidney calcium oxalate stones. A total of 159 patients with kidney calcium oxalate stones were included in this study as a case group. One hundred and three healthy individuals were included in the control group. The age, gender, and levels of calcium (Ca), uric acid (UA), creatinine (Cr), and urinary creatinine (Ucr) are tracked. Peripheral blood samples are used to perform a polymerase chain reaction to identify the glutathione S-transferase (GST) gene polymorphism (PCR). A commercial kit was used in this study to measure the levels of malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (T-AOC), and 8-hydroxydeoxyguanosine (8-OHdG) in peripheral blood. There was no difference in age or gender distribution between the case and control groups (P > 0.05). The Cr, Ucr, Ca, UA, 8-OHdG, MDA, NO, and T-AOC in the case group were significantly higher than those in the control group (P < 0.001). The Hardy-Weinberg genetic equilibrium test showed no difference between the case group (P = 0.23) and the control group (P = 0.09). In the case group, the 8-OHdG and NO in GSTM1 null genotype were significantly higher than those in GSTM1 genotype(P < 0.05), but there was no significant difference in MDA and T-AOC (P > 0.05). Multivariate regression analysis showed that the GSTM1 null genotype was positively correlated with 8-OHdG (P < 0.001) and NO (P < 0.001). GSTM1 gene polymorphism might be a detecting risk factor for kidney calcium oxalate stone formation. ChiCTR2100051300.

Changes in the expression of oxidative stress genes in toxic hepatitis of different etiologies and their correction

The study aims to study of changes in transcriptional activity of oxidative stress genes in acute toxic hepatitis. Materials and methods. The study material was white mongrel male rats weighing 180-200 grams. The studied toxicants were: carbon tetrachloride, ethanol, acetaminophen. As hepatoprotectors were introduced: oxymethyluracil, ademethionine and ethylmethylhydroxypyridine succinate. RNA was isolated, which was subjected to reverse transcription. RT-PCR was performed using a real-time PCR system in the presence of SYBR Green. GAPDH was used as a normalized control. The expression of the studied genes was evaluated by PCR analysis using pre-selected primers. Statistical significance was checked using IBM SPSS Statistics software. Results. In comparison of experimental groups, statistically significant differences were found in the level of expression of the CASP7 gene. Transcriptional activity of the CHEK gene (k=11.25; p=0.024). The GCLC gene (k=21.70; p=0.001) reached its minimum value of -3.6 [-3.72; -3.32] in the Mexidol group. The multiplicity of expression of the GSTM1 gene (k=15.54; p=0.004) had the highest value -0.14 [-1.11; 1] in the group that did not receive TCM. The NQO1 gene achieved its statistical significance in a 72-hour experiment (p=0.005). Statistical analysis of the RIPK gene showed significant differences. The expression level of the GSTP1 gene (k=10.39; p=0.034) reached its maximum value in the untreated group of 0.03 [-0.74; 0.48]. Expression of the NFE2L2 gene with acetaminophen administration showed the following results (k=13.64; p=0.009). Glutathione activity (k=10.29; p=0.036) reached its minimum value in the group receiving Mexidol -1.6 [-1.7; -1.29]. The multiplicity of superoxide dismutase expression showed statistical significance (p=0.003). Conclusions. Markers of the clinical course, prognosis and outcomes of toxic hepatitis were found. These data make it possible to determine the severity of the disease at the stage of early molecular response, when active clinical symptoms have not yet developed, which makes it possible to prescribe targeted therapy and adjust treatment tactics.

Copy Number Variation in the GSTM1 and GSTT1 Genes and the Risk of Liver Cirrhosis in Eastern Ethiopia.

Polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) can cause an entire gene deletion. The current methodology can accurately identify GSTM1 and GSTT1 copy number variants (CNVs), which may shed light on the true contribution of each gene copy to the cellular detoxification process and disease risk. Because liver cirrhosis is becoming a critical worldwide health issue, this study determined the CNVs of GSTM1 and GSTT1 and their relationship to the risk of liver cirrhosis. In this study, we compared 106 patients with liver cirrhosis to 104 healthycontrols. Real-time PCR was used to identify the CNVs of GSTM1 and GSTT1. Logistic and linear regression models were used to estimate the relationship between liver cirrhosis and clinical chemistry variables with the CNVs, respectively. In 3.3% of the study participants, >2 copies of the GSTM1 or GSTT1 genes were detected. GSTT1 carriers had a significantly lower risk of liver cirrhosis (p<0.05) compared with individuals who had homozygous deletion (adjusted odds ratio (AOR) = 0.47; 95% CI: 0.25, 0.86). This risk reduction was significant (p<0.05) in patients with a single copy of the GSTT1 gene (AOR = 0.48; 95% CI: 0.25, 0.91). Those with ≥2 copies of combined GSTM1 and GSTT1 also had a significantly (p<0.05) lower risk of developing liver cirrhosis compared with double null genotypes (AOR = 0.38; 95% CI: 0.16, 0.91, p trend <0.001). Moreover, ≥2 copies of combined GSTM1 and GSTT1 genes were associated with a substantial decrease in alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels, respectively. A single copy number of GSTT1, and ≥2 copies of combined GSTM1 and GSTT1 genes were associated with a reduced risk of liver cirrhosis in Ethiopians. These findings underscore the importance of gene-environment interactions in the multifactorial development of liver cirrhosis.

Prognosis of the risk progression of post-inflammatory pneumofibrosis in children with chronic nonspecific lung diseases

Introduction. Pneumofibrosis (PF) is a morphological outcome of acute and chronic lung diseases, the progression of which leads to organ deficiency.Aim. Development of a prognostic algorithm for assessing the risk of progression of post-inflammatory PF in children with chronic nonspecific lung diseases (CNSLD).Materials and methods. The examination of 52 children with CNSLD with focal post-inflammatory PF was conducted, of which 26 children with progressive PF and 26 children with non-progressive PF. The children were selected according to the “case-control” scheme. The patients had a dynamic clinical and laboratory examination with multispiral computed tomography of the lungs. Determination of the “zero” genotypes of the detoxification genes GSTM1, GSTT1 was carried out by means of polymerase chain reaction. The odds ratio indicator was used to assess the relative risk.Results. Based on the analysis of medico-social, clinical characteristics and genetic polymorphism, an individual prognostic algorithm for the risk of progression of post-inflammatory PF in children with CNSLD was developed. The algorithm includes the calculation of the total score (TS) of 7 medical and social indicators (living in an urban area; the presence of passive smoking; the duration of a pulmonological history of 4-9 years; the presence of congenital lung malformation; the number of acute respiratory infections (ARI) 4 or more times/year; the duration of ARI 11 days or more; taking antibiotics for more than 3 once/year) and the presence of deletions in the detoxification genes GSTM1 and GSTT1. With a value of TS 6.97 or more, a high risk of progression of PF is predicted, with TS 3.47-6.96 points, a moderate risk of progression of PF is diagnosed, with TS 3.46 or less points, a minimal risk of progression of PF.Conclusion. The proposed algorithm allows predicting the risk of progression of post-inflammatory PF in children with CNSLD at the stage of early diagnosis and will prevent the spread of the process in the lungs with the help of preventive measures and preventive therapy, which will increase the duration and improve the quality of life of the patient.

In Vitro Enzyme Kinetics and NMR-Based Product Elucidation for Glutathione S-Conjugation of the Anticancer Unsymmetrical Bisacridine C-2028 in Liver Microsomes and Cytosol: Major Role of Glutathione S-Transferase M1-1 Isoenzyme.

This work is the next step in studying the interplay between C-2028 (anticancer-active unsymmetrical bisacridine developed in our group) and the glutathione S-transferase/glutathione (GST/GSH) system. Here, we analyzed the concentration- and pH-dependent GSH conjugation of C-2028 in rat liver microsomes and cytosol. We also applied three recombinant human GST isoenzymes, which altered expression was found in various tumors. The formation of GSH S-conjugate of C-2028 in liver subfractions followed Michaelis-Menten kinetics. We found that C-2028 was conjugated with GSH preferentially by GSTM1-1, revealing a sigmoidal kinetic model. Using a colorimetric assay (MTT test), we initially assessed the cellular GST/GSH-dependent biotransformation of C-2028 in relation to cytotoxicity against Du-145 human prostate cancer cells in the presence or absence of the modulator of GSH biosynthesis. Pretreatment of cells with buthionine sulfoximine resulted in a cytotoxicity decrease, suggesting a possible GSH-mediated bioactivation process. Altogether, our results confirmed the importance of GSH conjugation in C-2028 metabolism, which humans must consider when planning a treatment strategy. Finally, nuclear magnetic resonance spectroscopy elucidated the structure of the GSH-derived product of C-2028. Hence, synthesizing the compound standard necessary for further advanced biological and bioanalytical investigations will be achievable.

BPDE-DNA adduct formation and alterations of mRNA, protein, and DNA methylation of CYP1A1, GSTP1, and GSTM1 induced by benzo[a]pyrene and the intervention of aspirin in mice.

Benzo[a]pyrene (B[a]P), one typical environmental pollutant, the toxicity mechanisms, and potential prevention remain perplexing. Available evidence suggests cytochrome P450 1A1 (CYP1A1) and glutathione S-transferases (GSTs) metabolize B[a]P, resulting in metabolic activation and detoxification of B[a]P. This study aimed to reveal the impact of B[a]P exposure on trans-7,8-diol-anti-9,10-epoxide DNA (BPDE-DNA) adduct formation, level of CYP1A1, glutathione S-transferase pi (GSTP1) and glutathione S-transferase mu1 (GSTM1) mRNA, protein and DNA methylation in mice, and the potential prevention of aspirin (ASP). This study firstly determined the BPDE-DNA adduct formation in an acute toxicity test of a large dose in mice induced by B[a]P, which subsequently detected CYP1A1, GSTP1, and GSTM1 at levels of mRNA, protein, and DNA methylation in the organs of mice in a subacute toxicity test at appropriate doses and the potential prevention of ASP, using the methods of real-time quantitative PCR (QPCR), western blotting, and real-time methylation-specific PCR (MSP), respectively. The results verified that B[a]P induced the formation of BPDE-DNA adduct in all the organs of mice in an acute toxicity test, and the order of concentration of which was lung > kidney > liver > brain. In a subacute toxicity test, following B[a]P treatment, mice showed a dose-dependent slowdown in body weight gain and abnormalities in behavioral and cognitive function and which were alleviated by ASP co-treatment. Compared to the controls, following B[a]P treatment, CYP1A1 was significantly induced in all organs in mice at mRNA level (P < 0.05), was suppressed in the lung and cerebrum of mice at protein level, and inhibited at DNA methylation level in the liver, lung, and cerebrum, whereas GSTP1 and GSTM1 at mRNA, protein, and DNA methylation levels showed organ-specific changes in mice following B[a]P treatment, which was generally alleviated by ASP intervention. In conclusion, B[a]P induced BPDE-DNA adduct formation in all organs in mice and altered the mRNA, protein, and DNA methylation levels in CYP1A1, GSTP1, and GSTM1 in an organ-dependent pattern, which could be related to the organ toxicity and mechanism of B[a]P. ASP intervention may be an effective measure to prevent B[a]P toxicity. The findings provide scientific evidence for further study on the organ toxicity and mechanisms of B[a]P.

Polymorphism of Free Radicals Detoxification Genes GSTM1 and GSTT1 is Associated to Prostate Cancer Risk in men: Case Study in Benin

Polymorphism of Free Radicals Detoxification Genes GSTM1 and GSTT1 is Associated to Prostate Cancer Risk in men: Case Study in Benin

Study of glutathione-S-transferase (GST) T1 and M1 genes in aluminum industry workers with comorbid cardiovascular pathology

Introduction. Employees of the main professions of aluminum production have a high level of professional and production-related pathology, primarily diseases of the circulatory system associated with the long-term influence of vasotoxic factors on the body. The pathogenetic course of angiopathies does not proceed in isolation, it is predetermined by chronic fluoride intoxication and hereditary component. The establishment of associations determined on the basis of studying the polymorphism of glutathione-S-transferase genes with the risk of developing comorbid cardiovascular pathology makes it possible to use genetic analysis in its early diagnosis.&#x0D; The study aims to explore the polymorphism of GST genes in aluminum industry workers with comorbid cardiovascular pathology.&#x0D; Materials and methods. The authors have carried out the study using clinical and molecular genetic diagnostic methods in workers of the main professions engaged in the production of aluminum, with chronic occupational intoxication with fluorine compounds and persons with individual signs of fluoride exposure to the skeleton (comparison group). By detecting extended deletions in the loci of the GSTT1 and GSTM1 genes, the researchers have assessed the association of the studied genotypes with the risk of chronic intoxication and atherosclerosis.&#x0D; Results. In the cohort of patients (36.58%) and in the comparison group (16.98%), the authors have revealed a combined form of cardiomyopathy complicated by coronary atherosclerosis, coronary heart disease. Also, scientists have established significant differences in the frequency distribution of genotypes of GST genes. Homozygous polymorphism GSTT1 0/0 is a risk factor for the development of occupational pathology against the background of the predominance of the normal genotype GSTM1+. Predictors (GSTT1 0/0, GSTM1 0/0) of the risk of atherosclerosis associated with hypertension in persons with chronic fluoride intoxication were determined.&#x0D; Conclusion. The association of GST genes with the development of comorbid cardiovascular pathology was determined in the structure of professional and production-related pathology in aluminum industry workers.&#x0D; Ethics. We have conducted the study of employees at the aluminum plant on a voluntary basis with the written consent of the examined persons on the basis of a specialized clinic of the Research Institute of Complex Problems of Hygiene and Occupational Diseases in accordance with the Ethical principles of conducting scientific and medical research with human participation ("Rules of Clinical Practice in the Russian Federation", Order of the Ministry of Health of the Russian Federation No. 266, 2003; Helsinki Declaration of the World Medical Association "Ethical principles of conducting scientific medical research with human participation", 2013).

Применение молекулярно-генетических предикторов и машинного обучения в оценке токсичности химических веществ

Toxic hepatites is an important public health issue in Russia. They have diverse etiologies, including industrial toxins, drugs, and ethanol, leading to significant differences in pathogenesis at the molecular and genetic level. This study aimed to analyze genes involved in the response to toxic liver injury of different origins and to establish a model to predict the etiology of toxic hepatitis. To model acute toxic hepatitis, outbred white male rats weighing 180–200 g were used. They were divided into four groups: control group, tetrachloromethane group, paracetamol group, and ethanol group. 24 h and 72 h after toxicant administration rats were anesthetized and mRNA levels of Chek1, Gclc, Gstm1, Gstp1, Gstt1, Nfe2l2, Nqo1, and Ripk1 genes in liver homogenate were studied. Analysis of the expression of these genes showed that the expression profile varies depending on the etiology of toxic hepatitis. In tetrachloromethane poisoning, there was a marked increase in gene expression of Nqo1 (p?=?0.001), Gstm1 (p?=?0.037), and a decrease in gene expression of Nfe2l2 (p?=?0.004), Ripk1 (p?=?0.004). However, liver exposure to paracetamol and its metabolites resulted in decreased Gstm1 gene expression (p?=?0.001) and increased Nfe2l2 (p?=?0.009), Gclc (p?=?0.001), and Chek1 (p?=?0.011) gene expression. No significant changes in the expression of these genes are found in alcohol intoxication. A model was constructed to predict the etiology of toxic hepatitis on the basis of gene expression indices. Keywords: acute toxic hepatitis, paracetamol, tetrachloromethane, ethanol, gene expression.

Abstract 035: Early Depletion Of Activated Neutrophils Ameliorates Ang Ii-induced Hypertension In Gstm1 Deficient Mice

Background: Glutathione-S-transferase Mu1( Gstm1 ) gene encodes an enzyme that functions in the detoxification of electrophilic compounds. The common GSTM1 deletion variant in humans is associated with increased risks of chronic kidney disease progression. We reported that deletion of Gstm1 in mice increases oxidative stress, kidney inflammation and injury in angiotensin II induced hypertension (Ang II-HTN). Bone marrow cross-transplantation suggested a chemotaxis signal originating from the kidney. Moreover, we recently found that global deletion of Gstm1 significantly increased neutrophil chemotaxis response to CXCL1 and CXCL2 in vitro and kidney neutrophil populations early in Ang II-HTN by day 4. To test whether early activation of neutrophil mediates inflammation and kidney injury in Gstm1 KO mice, we depleted neutrophils using Ly6G antibody. Methods: Gstm1 KO male mice (12 weeks old) on 129S6 background were used for the study. After a 2-week training period, baseline systolic blood pressure (SBP) was measured by tail cuff daily for 2 weeks. For neutrophil depletion, Ly6G antibody (1A8, BioXcell ) (n=3) or control IgG (2A3)(n=2) were injected IP (200 μg/mouse) at 48hr and 24hr before Ang II mini-osmotic pump was implanted (1000 ng/kg/minute). A third IP injection was performed at day 4 after the Ang II. SBP was measured for 8 days during Ang II-HTN. FACS analysis was performed at day 8 post Ang II to determine the efficiency of neutrophil depletion. Results: Compared to control IgG, Ly6G antibody significantly depleted neutrophil populations in the kidney, bone marrow, and spleen by 95%, 97%, and 93%, respectively. Baseline SBP was similar between the two groups (129.5 ± 6.7 vs 128.3 ± 0.8 mm Hg, p = 0.9). In Ang II-HTN, depletion of neutrophils with Ly6G antibody in Gstm1 KO mice resulted in a trend in decrease in SBP compared to control antibody (154.7 ± 17.9 vs 182.6 ± 2.6 mm Hg; p = 0.13). Conclusion: Loss of Gstm1 activates neutrophils early in Ang II-HTN. Successful depletion of neutrophils in Gstm1 KO mice decreased blood pressure in response to Ang II. Further studies are underway to confirm the pressor response and to determine whether depletion of neutrophils early in Ang II-HTN can ameliorate kidney inflammation and injury in GSTM1 deficiency.

Glutathione S-transferase M1 and T1 gene polymorphisms in psoriasis patients: a pilot case-control study

Background The exact etiology of psoriasis remains unknown; nevertheless, it has been found that oxidative stress plays a vital role. Among the multiple antioxidant enzymes, genetic polymorphisms in the Glutathione S-Transferases (GSTs) led to an imbalance in the antioxidant system, resulting in increased levels of reactive oxygen species. Accordingly, the polymorphism in these genes could increase the susceptibility to psoriasis. Objectives To assess the association between Glutathione S-Transferase M1 (GSTM1) and Glutathione S Transferase Theta-1 (GSTT1) gene polymorphisms in psoriasis patients compared to healthy controls. Methods A total of 200 participants, 100 psoriasis cases who were assessed by the Psoriasis Area and Severity Index (PASI), and 100 healthy controls were included. DNA extraction was done followed by multiplex PCR to detect genetic polymorphism in the GSTM1 and GSTT1 genes, Finally, the relation between the presence of polymorphism and the severity of psoriasis was estimated. Results The null genotype frequency of GSTM1 and GSTT1 was 76.0% and 58.0%, respectively among psoriasis patients, while it was 58.0% and 55.0%, respectively among healthy controls. There was a significantly higher risk for psoriasis in patients with the null genotype GSTM1 (OR=2.293) as compared to controls. On the other hand, there was no statistically significant relation between their polymorphisms and family history, psoriasis severity, and PASI score. Conclusion The null genotype GSTM1 could increase the risk of psoriasis susceptibility especially among males.

Single-neuron neurodegeneration as a degenerative model for Parkinson's disease.

The positive effect of levodopa in the treatment of Parkinson's disease, although it is limited in time and has severe side effects, has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons. Successful preclinical studies with coenzyme Q10, mitoquinone, isradipine, nilotinib, TCH346, neurturin, zonisamide, deferiprone, prasinezumab, and cinpanemab prompted clinical trials. However, these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease, despite its severe side effects after 4-6 years of chronic treatment. The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson's disease treatment is a big problem. In our opinion, the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, that induce a very fast, massive and expansive neurodegenerative process, which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons. The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson's patients is due to (i) a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron, (ii) a neurotoxic event that is not expansive and (iii) the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons. The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome, since it (i) is generated within neuromelanin-containing dopaminergic neurons, (ii) does not cause an expansive neurotoxic effect and (iii) triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson's disease. In conclusion, based on the hypothesis that the neurodegenerative process of idiopathic Parkinson's disease corresponds to a single-neuron neurodegeneration model, we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2. It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.