GSTT1 Research Articles

In Vitro Low-Bortezomib Doses Induce Apoptosis and Independently Decrease the Activities of Glutathione S-Transferase and Glutathione Peroxidase in Multiple Myeloma, Taking into Account the GSTT1 and GSTM1 Gene Variants.

Multiple myeloma (MM) is a malignancy derived from plasma cells. Bortezomib affects the concentration of reduced glutathione (GSH) and the activity of glutathione enzymes. The aim of our study was to analyze deletion (null/present) variants of GSTT1 and GSTM1 genes and their association with the levels of glutathione and its enzymes in bortezomib-treated cell cultures derived from MM patients. This study included 180 individuals (80 MM patients and 100 healthy blood donors) who were genotyped via multiplex PCR (for the GSTT1/GSTM1 genes). Under in vitro conditions, MM bone marrow cells were treated with bortezomib (1-4 nM) to determine apoptosis (via fluorescence microscopy), GSH concentration, and activity of glutathione enzymes (via ELISA). Bortezomib increased the number of apoptotic cells and decreased the activity of S-glutathione transferase (GST) and glutathione peroxidase (GPx). We found significant differences in GST activity between 1 nM (GSTT1-null vs. GSTT1-present), 2 nM (GSTT1-null vs. GSTT1-present), and 4 nM (GSTM1-null vs. GSTM1-present) bortezomib: 0.07 vs. 0.12, p = 0.02; 0.06 vs. 0.10, p = 0.02; and 0.03 vs. 0.08, p = 0.01, respectively. Bortezomib affects the activities of GST and GPx. GST activity was associated with GSTT1 and GSTM1 variants but only at some bortezomib doses.

Combined genetic polymorphisms of the GSTT1 and NRF2 genes increase susceptibility to cisplatin-induced ototoxicity: A preliminary study

ObjectiveThe genotype-phenotype relationship in cisplatin-induced ototoxicity remains unclear. By assessing early shifts in distortion product otoacoustic emission (DPOAE) levels after initial cisplatin administration, we aimed to discriminate patients’ susceptibility to cisplatin-induced ototoxicity and elucidate their genetic background. Study DesignA prospective cross-sectional study. SettingTertiary referral hospital in Japan. PatientsTwenty-six patients with head and neck cancer were undergoing chemoradiotherapy with three cycles of 100 mg/m2 cisplatin. InterventionsRepetitive pure-tone audiometry and DPOAE measurements, and blood sampling for DNA extraction were performed. Patients were grouped into early ototoxicity presence or absence based on whether DPOAE level shifts exceeded the corresponding reference limits of the 21-day test interval. Main Outcome MeasuresHearing thresholds after each cisplatin cycle, severity of other adverse events, and polymorphisms in cisplatin-induced ototoxicity-associated genes were compared. ResultsEarly ototoxicity was present in 14 and absent in 12 patients. Ototoxicity presence on DPOAEs was associated with greater progression of hearing loss in frequencies ≥2 kHz throughout therapy and with higher ototoxicity grades compared with ototoxicity absence. Ototoxicity was further associated with grade ≥2 nausea. Ototoxicity presence was genetically associated with the GSTT1 null genotype and G-allele of NFE2L2 rs6721961, whereas ototoxicity absence was associated with the GSTM1 null genotype. Dose-dependent progression of hearing loss was the greatest in the combined genotype pattern of GSTT1 null and the T/G or G/G variants of rs6721961. ConclusionEarly DPOAE changes reflected genetic vulnerability to cisplatin-induced ototoxicity. Hereditary insufficiency of the antioxidant defense system causes severe cisplatin-induced hearing loss and nausea.

Impact of GSTT1 AND GSTM1 variants and hair mercury concentration in maternal blood pressure among coastal pregnant women in Central Java, Indonesia

The GSTT1 and GSTM1 genes have a role in mercury metabolism and excretion, as well as blood pressure response, impacting birth outcomes. The present study assesses whether GSTT1 and GSTM1 deletion variants and maternal hair Hg concentration are associated with blood pressure and birth outcomes among the Indonesian coastal pregnant mother population. A cross-sectional study was conducted on 139 pregnant women in the Jepara coastal area of Central Java, Indonesia. Maternal characteristics during pregnancy, including blood pressure and birth outcomes, were collected. GSTT1 and GSTM1 gene variants were detected using polymerase chain reaction (PCR). Hair Hg levels were measured using the reducing-vaporization mercury analyzer. The mean maternal hair Hg concentration was 0.727±0.558 μg/g. GSTT1 genotype homozygous deletion was found in 41.7% of subjects, while no GSTM1 deletion was found. No statistically significant difference was found between deletion and non-deletion groups for hair Hg. GSTT1 deletion genotype shows protection but is inconclusive toward diastolic hypertension (p=0.048, OR 0.285, CI 0.077–1.052) and insignificant with birth outcomes (all p>0.05). High hair Hg concentration and positive history of cardiovascular diseases increase the risk of systolic and diastolic hypertension during pregnancy with OR 6.871 (CI 95% 1.445–32.660) and 8.518 (CI 95% 2.126–34.125), respectively, while not in birth outcomes. Maternal Hg exposure and history of cardiovascular diseases are independent risk factors for pregnant hypertension, whereas the GSTT1 homozygous deletion genotype has no role in diastolic hypertension and birth outcomes among the Indonesian coastal pregnant mother population.

Association of polymorphic variants of genes of xenobiotic biotransformation enzymes with susceptibility to pulmonary tuberculosis, taking into account gender features

Aim of the study was to investigate susceptibility to pulmonary tuberculosis in men and women depending on polymorphism of genes of xenobiotic biotransformation enzymes NAT2 (590G> A (rs1799930)), CYP2E1 (9896C> G (rs2070676)), ABCB1 (3435T> C (rs1045642)), GSTM1 (E/D) and GSTT1 (E/D). Material and methods. The study included 335 patients with pulmonary tuberculosis aged 18 to 65 years (212 patients with newly diagnosed pulmonary tuberculosis and 123 people with chronic pulmonary tuberculosis receiving intensive phase of chemotherapy). Statistical data processing was carried out on a personal computer using IBM SPSS Statistics 26 and MS Excel 2013 software packages. The control group consisted of relatively healthy individuals without chronic diseases. Genotyping of polymorphisms NAT2 (590G>A (rs1799930)), CYP2E1 (9896C>G (rs2070676)), ABCB1 (3435T>C (rs1045642)) and extended deletions GSTM1 (E/D), GSTT1 (E/D) was performed using real time PCR. Results. It has been established that the genotype EЕ of GSTT1 gene identified in 89.1 % men was statistically significantly associated with increased susceptibility to pulmonary tuberculosis, while the genotype DD of the GSTT1 gene (10.9 % cases) was associated with reduced susceptibility. A similar trend is observed in women: the greatest susceptibility to pulmonary tuberculosis is characteristic for the genotype ЕЕ GSTT1 gene (87.2 %), the least (12.8 %) – for the DD genotype. Conclusions. It is advisable to introduce genotyping of genes of xenobiotic biotransformation enzymes into the practice of a phthisiologist in order to develop measures to improve the effectiveness of prevention and treatment of patients with pulmonary tuberculosis.

Are changes in olanzapine-induced liver enzyme levels associated with GSTT1, GSTM1, GSTP1, and OGG1 gene polymorphisms?

Olanzapine treatment sometimes produces transient liver biochemistry abnormalities, and such drug-induced liver injuries are mainly monitored by measuring blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), whereas alpha-glutathione-S-transferase (α-GST) is not routinely measured in clinics, even though it can serve as an earlier and more specific biomarker of liver damage. Susceptibility to drug-induced liver injury can much depend on the gene polymorphisms regulating the activity of DNA detoxification and repair enzymes. The aim of this study was to evaluate which of the three liver enzymes - α-GST, ALT, and AST - is the most sensitive biomarker of olanzapine-induced liver injury and how their blood levels are affected by the GSTT1, GSTM1, GSTP1, and OGG1 gene polymorphisms in 30 olanzapine-treated patients. Contrary to our hypothesis, the increase in serum α-GST levels was not significantly greater than that of the transaminases. ALT turned out to be an earlier biomarker of liver injury than the other two enzymes. No significant association was found between gene polymorphisms and liver enzyme levels, save for GSTP1 Ile/Val + Val/Val and ALT, which points to this genotype as a risk factor for drug-induced liver injury. Future studies might help to identify the underlying mechanisms of transient liver enzyme increase associated with this genotype.

Comprehensive analysis of DNA methylation gene expression profiles in GEO dataset reveals biomarkers related to malignant transformation of sinonasal inverted papilloma

BackgroundDNA methylation may be involved in the regulation of malignant transformation from sinonasal inverted papilloma (SNIP) to squamous cell carcinoma (SCC). The study of gene methylation changes and screening of differentially methylated loci (DMLs) are helpful to predict the possible key genes in the malignant transformation of SNIP-SCC.Materials and methodsMicroarray dataset GSE125399 was downloaded from the Gene Expression Omnibus (GEO) database and differentially methylated loci (DMLs) were analyzed using R language (Limma package). ClusterProfiler R package was used to perform Gene Ontology (GO) analysis on up-methylated genes and draw bubble maps. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and its visualization analysis were analyzed to speculate the possible key Genes in SNIP-SCC malignant transformation. Subsequently, SNIP cases archived in our department were collected, tissue microarray was made, and immunohistochemical staining was performed to analyze the expression levels of UCKL1, GSTT1, HLA-G, MAML2 and NRGN in different grades of sinonasal papilloma tissues.ResultsAnalysis of dataset GSE125399 identified 56 DMLs, including 49 upregulated DMLs and 7 downregulated DMLs. Thirty-one genes containing upregulated DNA methylation loci and three genes containing downregulated DNA methylation loci were obtained by methylation microarray annotation analysis. In addition, KEGG pathway visualization analysis of 31 up-methylated genes showed that there were four significantly up-methylated genes including UCKL1, GSTT1, HLA-G and MAML2, and one significantly down-methylated gene NRGN. Subsequently, compared with non-neoplasia nasal epithelial tissues, the expression of HLA-G and NRGN was upregulated in grade I, II, III and IV tissues, while the expression of MAML2 was lost. The protein expression changes of MAML2 and NRGN were significantly negatively correlated with their gene methylation levels.ConclusionsBy analyzing the methylation dataset, we obtained four up-regulated methylation genes UCKL1, GSTT1, HLA-G and MAML2 and one down-regulated gene NRGN. MAML2, a tumor suppressor gene with high methylation modification but loss of protein expression, and NRGN, a tumor gene with low methylation modification but upregulated protein expression, can be used as biological indicators to judge the malignant transformation of SNIP-SCC.

Association of Oral Submucous Fibrosis Risk with GSTM1 and GSTT1 Gene Polymorphisms.

To determine the association of GSTM1 and GSTT1 polymorphisms with oral submucous fibrosis (OSF). A case-control study. Place and Duration of the Study: Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore and Oral and Maxillofacial Surgery Department, de Montmorency, College of Dentistry/ Punjab Dental Hospital, Lahore, Pakistan, from 1st April 2019 to 31st April 2020. OSF patients were diagnosed with different clinical staging of mouth opening by Vernier caliper with the help of a professional dentist in the Department of Oral and Maxillofacial, de Montmorency, College of Dentistry, Lahore. One hundred and eight blood samples of OSF patients and 108 samples of normal controls were collected. Genomic DNA was obtained from whole-blood extraction. Multiplex PCR amplification using GSTM1, GSTT1, and β -Globin gene primers was performed. GSTM1 and GSTT1 null genotypes frequencies were found in 43.5% (47/108) and 13.9% (15/108) of controls, whereas 54.6% (59/108) and 25.9% (28/108) of OSF patients, respectively. OSF patients had a greater frequency rate of GSTM1 and GSTT1 null genotypes than controls [OR 1.56, 95% CI 0.91-2.67 (p=0.13)]and [OR 2.17, 95% CI 1.08-4.34 (p=0.04)], respectively. The GSTT1 genotype was found statistically significant with OSF (p=0.05), and risk was also determined. The cumulative effect of null genotypes of GSTM1/GSTT1 did not show any association with the controls and in OSF patients. Proportions of active and null alleles of the patient group were; 86.1%/13.9%; and in control, it was 92.6%/7.4% (OR = 2.01; CI: 0.82-4.97; p=0.18), respectively. The study determined a statistically significant association of GSTT1 gene polymorphism with OSF. Oral submucous fibrosis, GSTM1, GSTT1, Gene polymorphisms, Genetic risk.

Genotoxicity in humans exposed to arsenic, lithium, and boron in drinking water in the Bolivian Andes-A cross sectional study.

Elevated concentrations of arsenic, lithium and boron in drinking water have already been reported in Bolivia. Arsenic is known to cause genotoxicity but that caused by lithium and boron is less well known. The aim of the present cross-sectional study was to evaluate potential genotoxic effects of exposure to arsenic, while considering exposure to lithium and boron and genetic susceptibility. Women (n = 230) were recruited in villages located around Lake Poopó. Exposure to arsenic was determined as the sum of concentrations of arsenic metabolites inorganic arsenic, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in urine. Exposure to lithium and boron was determined based on their concentrations in urine. Genetic susceptibility was determined by GSTM1 (glutathione S-transferase-mu-1) and GSTT1 (glutathione S-transferase-theta-1) null genotypes and AS3MT (Arsenite Methyltransferase) rs3740393. Genotoxicity was measured in peripheral blood leukocytes using the comet assay. The geometric means of arsenic, lithium, and boron concentrations were 68, 897, and 3972 μg/L, respectively. GSTM1 and GSTT1 null carriers had more DNA strand breaks than gene carriers (p = .008, p = .005). We found no correlation between urinary arsenic and DNA strand breaks (rS = .03, p = .64), and only a weak non-significant positive association in the adjusted multivariate analysis (β = .09 [-.03; .22], p = .14). Surprisingly, increasing concentrations of lithium in urine were negatively correlated with DNA strand breaks (rS = -.24, p = .0006), and the association persisted in multivariate analysis after adjusting for arsenic (β = -.22 [-.36; -.08], p = .003). We found no association between boron and DNA strand breaks. The apparent protective effect of lithium merits further investigation.

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.

Neural network technologies in prediction the effectiveness of treatment of patients with pulmonary tuberculosis

The study used predicting the effectiveness of treatment of patients with pulmonary tuberculosis using neural network technologies. The most optimal neural network model was obtained, which allows predicting the effectiveness of treatment with a forecast accuracy of at least 78.4%. As a result of constructing a neural network model, the most significant «input» parameters of the neural network were identified: the presence of hepatotoxic reactions, the level of IL-1ß, IL-6, IL-4, IL-10, IFN-γ, C-reactive protein before the start of the intensive phase of chemotherapy, the presence of antibiotic resistance, the presence of mycobacterium tuberculosis before the appointment of a specific chemotherapy by seeding, the volume of lung tissue damage, the chemotherapy regimen, the clinical form of pulmonary tuberculosis, as well as the genotype of ЕЕ gene GSTT1.

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.

Abstract B051: GSTT2 modulates the bladder tumor environment and response to BCG Immunotherapy

Abstract The purpose of this study was to elucidate the impact of Glutathione -S-transferase Theta 2 (GSTT2) loss on the response of bladder tumors to Mycobacterium Bovis, Bacillus Calmette Guerin (BCG) immunotherapy. GSTT2 gene expression is controlled by a promoter deletion that occurs frequently in 25-29% of Asians and 41% of Caucasians. The GSTT2 promoter deletion correlated with better response to BCG therapy in a retrospective analysis of patients who received less BCG therapy. To understand this response, we generated GSTT2 knockout mice to elucidate the role of GSTT2 in BCG immunotherapy. Female C57BL/6J mice from GSTT2 wildtype (WT) and KO backgrounds were orthotopically implanted with MB49-PSA cells (murine MB49 cells secreting human PSA). To view the impact of GSTT2 loss on BCG immunotherapy, mice were treated with only 4 instillations of BCG Tokyo. This therapeutic schedule would not result in a high cure rate and but was chosen as we expected it to provide insights into the anti-tumor response. Mice were treated weekly with intravesical BCG Tokyo instillations and tumor growth was monitored by urinary PSA secretion. Final tumor presence was confirmed by real-time PCR analysis of PSA gene expression. One day after the last instillation the bladders (n=7) were harvested for single cell RNA sequencing (Parse Biosciences). Cell clusters were identified by their gene expression profiles. The response to BCG in terms of the cure rate was similar in KO and WT mice (cure rate of 18-20%) but several genes were differentially expressed. Genes with a Log2FC value of +1.5 in KO mice (Peak1, Rpph1, Gphn and Gm19551) and -1.5 in KO (Rora, Tshz2, Sh3gl2, Ankfn1, Rbms3, Naaladl2, Prkn, Mecom, Fmo5, Saa3, Tmprss2, C3, Gm10800 and Gm10801) relative to WT mice were examined. Based on the literature, these genes either block tumor progression (Rora, Tshz2, Sh3gl2 and Gphn); promote tumor progression (Ankfn1, Rbms3, Naaladl2, Prkn, Mecom, Fmo5, Tmprss2, Saa3, C3, Peak1, Rpph1) or modulate immune cells (C3, Saa3 and Rpph1). The majority of these genes were not previously associated with bladder cancer. Interrogation of the TCGA database showed that high expression of Gphn, Peak1 and GSTT2 correlated with poorer outcomes in bladder cancer patients in terms of disease-free survival (HR=1.9 log rank p=0.00038). While expression of the genes downregulated in KO mice and GSTT2 resulted in better outcomes with lower expression of all the genes (HR=1.4, log rank p=0.042). This data indicates that the loss of GSTT2 expression impacts the response of tumors to BCG immunotherapy, primarily by modulating the expression of genes associated with cancer progression and the expression of genes in multiple cell types. Given the common loss of GSTT2 expression in man this gene may be a parameter that should be evaluated in further detail in patients receiving BCG immunotherapy. Citation Format: Ratha Mahendran, Mugdha Vijay Patwardhan, Qin Kane Toh, Edmund Chiong. GSTT2 modulates the bladder tumor environment and response to BCG Immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B051.

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.

GSTT1 as a Predictive Marker and Enhancer for Osteogenic Potential of Human Adipose-Derived Stromal/Stem Cells.

Adipose-derived stromal/stem cells (ASCs) have been extensively studied as cell sources for regenerative medicine for bone because of their excellent proliferative capacity and the ability to obtain a large number of cells with minimal donor morbidity. On the other hand, the differentiation potential of ASCs is generally lower than that of bone marrow-derived stromal/stem cells and varies greatly depending on donors. In this study, we mined a marker that can predict the osteogenic potential of ASC clones and also investigated the usefulness of the molecule as the enhancer of osteogenic differentiation of ASCs as well as its mechanism of action. Through RNA-seq gene analysis, we discovered that GSTT1 (Glutathione S-transferase theta-1) was the most distinguished gene marker between highly osteogenic and poorly osteogenic ASC clones. Knockdown of GSTT1 in high osteogenic ASCs by siGSTT1 treatment reduced mineralized matrix formation. On the other hand, GSTT1 overexpression by GSTT1 transfection or GSTT1 recombinant protein treatment enhanced osteogenic differentiation of low osteogenic ASCs. Metabolomic analysis confirmed significant changes of metabolites related to bone differentiation in ASCs transfected with GSTT1. A high total antioxidant capacity, low levels of cellular reactive oxygen species, and increased GSH/GSSG ratios were also detected in GSTT1-transfected ASCs. When the in vivo effect of GSTT1-transfected ASCs on bone regeneration was investigated with segmental long-bone defect model in rats, bone regeneration was significantly better after implantation of GSTT1-transfected ASCs compared with that of control vector-transfected ASCs. In conclusion, GSTT1 can be a useful marker to screen the highly osteogenic ASC clones and also a therapeutic factor to enhance the osteogenic differentiation of poorly osteogenic ASC clones. © 2023 American Society for Bone and Mineral Research (ASBMR).

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.

Short-term ozone exposure and serum neural damage biomarkers in healthy elderly adults: Evidence from a panel study

BackgroundAlthough converging lines of research have pointed to the adverse neural effects of air pollution, evidence linking ozone (O3) and neural damage remains limited. ObjectivesTo investigate the subclinical neural effects of short-term ozone (O3) exposure in elderly adults. MethodsA panel of healthy elderly individuals was recruited, and five repeated measurements were conducted from December 2018 to April 2019 in Xinxiang, China. Serum neural damage biomarkers, including brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), neuron-specific enolase (NSE), protein gene product 9.5 (PGP9.5), and S100 calcium-binding protein B (S100B) were measured at each follow-up session. Personal O3 exposure levels were calculated based on outdoor monitoring and sampling times. A linear mixed-effects model was adopted to quantify the acute effect of O3 on serum neural damage biomarkers. Stratification analysis based on sex, education level, physical activity, and glutathione S-transferases (GST) gene polymorphism analysis was performed to explore their potential modifying effects. ResultsA total of 34 healthy volunteers aged 63.7 ± 5.7 y were enlisted and completed the study. The concentration of the daily maximum 8-h average O3 (O3-8h) ranged from 19.5 to 160.5 μg/m3 during the study period. Regression analysis showed that short-term O3 exposure was associated positively with serum concentrations of neural damage biomarkers. A 10 μg/m3 increase in O3-8h exposure was associated with an increment of 74 % (95 % CI:1 %–146 %) and 197 % (95 % CI:39 %–356 %) in BDNF (lag 2 d) and NfL (lag 1 d), respectively. The stratification results suggest that males, people with lower education levels, lower physical activity, and GST theta 1 (GSTT1)-sufficient genotype might be marginally more vulnerable. ConclusionsThis study provides new evidence for the neural damage risk posed by O3 exposure, even at relatively low concentrations, which, therefore, requires that stringent air quality standards be developed and implemented.

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.

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.