GSTM1 Research Articles

Genetic factors of toxic effects development in pollution liquidators of the former factory with mercury electrolysis technology

Introduction. According to genetic factors, it is possible to determine the degree of manifestation of the toxic effects of mercury. The latter justifies the assessment of the genetic status of the exposed contingent in order to identify hypersensitive individuals in whom adverse health effects can be realized when exposed to relatively low levels of the toxicant. The study aims to research the distribution of genotypes of some polymorphic variants of genes of the xenobiotic biotransformation system, heat shock proteins and tumor necrosis factor in the contingent involved in liquidation measures, as well as to identify individuals with a high prognostic risk of toxic effects due to exposure to mercury. Materials and methods. We conducted genotyping of 231 people (men only): 193 employees of the Ministry of Emergency Situations (MES) of Russia in the Irkutsk Region and 38 employees of the Federal Environmental Operator (FEO) involved in the elimination of mercury pollution at the industrial site of the mercury electrolysis plant and adjacent facilities on the territory of a former chemical plant in Eastern Siberia. The researchers used real-time PCR and PCR-RFLP methods to study polymorphic variants of the genes CYP1A1 (rs1048943), GSTP1 (rs1695 and rs1138272), TNF-α (rs1800629) and HSPA1B (rs1061581). Results. For the polymorphism of the GSTP1 gene (rs1695), we have identified an increase in the frequency of AG genotypes (p=0.043) and a decrease in the frequency of GG genotypes (p=0.048) in employees of the MES compared to those from the FEO group. The researchers didn’t detect carriers of the TT genotype for the polymorphic locus GSTP1 (rs1138272) in both examined groups. There was the carriage of the rare GG-CYP1A1 homozygote only in one MES employee. We found that 33 MES employees and 3 examined from the FEO group who are carriers of the GG-HSPA1B (+1267A/G) genotype have a high predictive risk of developing toxic effects due to mercury exposure. The experts discussed the data obtained with the results of genotyping of former mercury electrolysis shop workers who were chronically exposed to metallic mercury vapor. The experts have reviewed the data obtained from the results of genotyping of former employees of the mercury electrolysis shop who were chronically exposed to metallic mercury vapor Limitations. The limitations, first of all, should include the number of examined individuals in the FEO group, as well as the lack of data on deletion polymorphisms of the GSTT1 and GSTM1 genes, potentially having a significant role in the toxicokinetics of mercury. Conclusion. The study has revealed 36 carriers of the GG genotype of the polymorphic locus +1267A/G of the HSPA1B gene associated with a high prognostic risk of toxic effects associated with exposure to mercury among the employees of the Ministry of Emergency Situations (MES) and the FEO involved in liquidation work. Taking into account the forthcoming volume and duration of work related to the demercurization of the territory of the former factory with mercury electrolysis technology and the surrounding area it is advisable to take into account the results obtained when monitoring the health status of the liquidators. Ethics. We have received voluntary informed consent, approved by the Committee on Biomedical Ethics (Protocol No. 6 of 10.03.2020), from each employee being examined.

Application of an antibody microarray for serum protein profiling of coronary artery stenosis

Protein expression profiling in the serum is used to identify novel biomarkers and investigate the signaling pathways in various diseases. The aim of the present study was to evaluate serum biomarkers associated with coronary artery stenosis resulting from atherosclerosis.The study included 4 groups of subjects: group A and B with and without coronary lesions, respectively, were selected from a previously reported cohort study on coronary atherosclerosis, control group C comprised of asymptomatic subjects and group D was used for independent validation of the microarray data by ELISA. Labeled serum proteins were profiled by an Explorer antibody array, which included 656 specific antibodies in two replicates (FullMoon Biosystems, USA). Cadherin-P, interleukin-5, glutathione S-transferase Mu, and neuronal nitric oxide synthase were sex-independently increased in Group A compared with those in group B. The microarray data on cadherin-P were externally validated in an independent group D using ELISA. Fibroblast growth factor-1, FGF-2, collagen II, granulocyte-macrophage colony-stimulating factor, IL-1 alpha, angiopoietin-2, granulocyte colony-stimulating factor, lymphocyte cell-specific protein tyrosine kinase, and IkappaB kinase b were increase in men in group A compared with group B. Cyclin-dependent kinase 1, DNA fragmentation factor subunit alpha DFF45/ICAD, adenovirus type 2 E1A, calponin, ADP-ribosylation factor-6, muscle-specific actin, thyroid hormone receptor alpha, and alpha-methylacyl-CoA racemase were specifically increased in women in Group A compared with group B. Alterations in the levels of specific proteins may point to the signaling pathways contributing to coronary atherosclerosis, and these proteins will be useful biomarkers for the progression of cardiovascular diseases.

Effects of 4-n-nonylphenol in liver of male and female viviparous fish (Poecilia vivipara)

4-n-Nonylphenol (NP) is one of the most toxic alkylphenols found in the environment. To evaluate the transcriptional effects of NP in the viviparous fish Poecilia vivipara, a hepatic transcriptome and qPCR analysis of genes were carried out. Guppies separated by sex were injected with two doses of NP (15 μg/g and 150 μg/g) or peanut oil (control). After 24 h, analysis of transcriptional level of Aryl Hydrocarbon Receptor (AhR), Estrogen Nuclear Receptor Alpha (ESR1), Pregnane X Receptor (PXR), Cytochromes P450 (CYP1A, CYP2K1 and CYP3A30), Glutathione S-transferase A3 and Mu 3 (GSTa3 and GSTMu3), SRY-Box Transcription Factor 9 (SOX9), Vitellogenin-1 (VIT), ATP Binding Cassette Subfamily C Member 1 (ABCC1), Multidrug Resistance-Associated Protein 2 (MRP2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1) was evaluated. 205,046 transcripts were assembled and protein prediction resulted in 203,147 predicted peptides. In females, no significant changes were detected in the transcription of some phase I biotransformation and ABC transporter genes. AhR, PXR, GSTa3 and SOX9 genes where higher in the lower dose group (15 μg/g) compared to control. In male fish, no changes were observed in the transcript levels of the nuclear receptors, in endocrine disruption and phase I biotransformation genes. GSTa3 showed lower transcription in fish treated with both doses. ABCC1 was higher in guppies treated with the lower dose while MRP2 showed less transcripts. This short-term and low-dose exposure to NP caused changes that could serve as early indicators of deleterious processes. These results indicate P. vivipara as a good sentinel in biomonitoring programs.

Frequency of polymorphic loci of GSTM1 and GSTT1 modifier genes in the genotype of children with pyelonephritis and congenital urinary malformations

IntroductionThe growing number, prevalence, numerous complications, and deaths in patients with congenital anomalies of the kidney and urinary tract (CAKUT) indicate the high relevance of the declared topic. Currently, clinical medicine is actively engaged in research on the cellular and molecular mechanisms that cause the appearance of these diseases.AimThe aim of the work is to study genetic markers of CAKUT and the tendency to a more severe course of pyelonephritis in young children.Material and methodsUsing the multiplex polymerase chain reaction method, 50 children with pyelonephritis were examined for the presence of deletion alleles of the glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) genes.Results and discussionAs a result, 35 children were diagnosed with certain CAKUT. A statistically significant associative relationship between the development of pyelonephritis in a child and the presence of a null allele GSTM1 0/0 in its genotype and a high probability of CAKUT with quantitative and positional anomalies and impaired formation and differentiation of renal tissue in carriers of null alleles GSTT1 0/0, GSTM1 0/0 in their combination was revealed.ConclusionsThe fact that different forms of abnormalities are detected in members of the same family suggests that certain genetic mutations can potentially lead to CAKUT syndrome, but the final phenotype of the renal system depends either on the genetic background or on environmental factors.

Copper metabolism patterns and tumor microenvironment characterization in colon adenocarcinoma.

Copper participates in biological processes such as oxygen metabolism and iron uptake, and is a key factor in immune regulation. Based on the transcription data, mutation data and clinical data of colon adenocarcinoma (COAD) patients from The Cancer Genome Atlas (TCGA) database and Gene Expression Profiling Interactive Analysis (GEPIA2) database, the expression and mutation of copper metabolization-related genes in COAD patients and their correlation with tumor immune microenvironment were analyzed. Copper metabolization-related genes (CMRGs) were used to construct COAD subtypes and prognostic risk models for COAD patients. Furthermore, Kaplan-Meier (K-M) curve and receiver operating characteristic (ROC) curve were used to analyze the clinical value of COAD subtypes and genotyping models in distinguishing clinical characteristics of patients, and the immune infiltration of patients with different genotypes was analyzed. Finally, the clinical tissue samples from COAD patients were used to analyze the mRNA expression of genes in risk model between tumor and normal tissues by the method of Polymerase Chain Reaction (PCR). Of the 479 CMRGs, 68 genes were differentially expressed in normal and tumor tissues of COAD patients in TCGA and GEPIA2. Two subtypes with different clinical and immunological characteristics were identified by using 482 genes related to copper metabolism. Finally, a prognostic risk model consisting of five CMRGs was constructed, which could not only predict the prognosis of patients, but also correlated with COAD subtypes. In addition, some genes (glutathione S-transferase mu 1, cyclin D1and cytochrome P450 family 2 subfamily S member 1) in risk model was show significant difference between normal and tumor tissues. The COAD subtypes identified by CMRGs can help clinically distinguish patients with different prognosis and tumor progression, and the risk score can assist in clinical evaluation of patient prognosis, serving as a valuable biomarker for COAD immunotherapy.

Worldwide Systematic Review of GSTM1 and GSTT1 Null Genotypes by Continent, Ethnicity, and Therapeutic Area.

Glutathione S-transferase Mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) enzymes are glutathione-S-transferases with broad significance for susceptibility or resistance to multifactorial human diseases, as well as detoxification of environmental chemicals and drugs. Moreover, some individuals may have a complete deletion of GSTM1 and GSTT1 genes, which can contribute to patient-to-patient variability in drug safety and efficacy. GSTM1 and GSTT1 gene deletion frequencies can vary according to ethnicity and continental origin of the studied population with implications for achieving the goal of precision/personalized medicine in clinical practice. We report here a worldwide systematic review of the null genotypes in these two clinically important genes by continents, ethnicities, and therapeutic areas (TAs). Searches were performed in the PubMed database covering the period from 1992 to 2020. Out of the 1925 articles included, most studies analyzed European individuals, corroborating the literature failure for not adequately considering the non-European ethnicities. The frequency of GSTM1 and GSTT1 null genotypes was higher in patients than in healthy volunteers. Conversely, in East Asians, higher frequencies of the null genotypes were observed in healthy volunteers than patients. Oncology was the most intensively studied TA (57% of the articles) in relation to GSTM1 and GSTT1. In all, these results demonstrate that there is an important gap in the literature in terms of failure to consider a broader range of populations, as well as diseases wherein GSTM1 and GSTT1 variations have clinical and biological implications. To achieve precision/personalized medicine on a global/worldwide scale, with equity and inclusiveness, this knowledge/research gap ought to be remedied in studies of GSTM1 and GSTT1 null genotypes. To the best of our knowledge, this is the largest systematic review conducted to date addressing the GSTM1 and GSTT1 null genotypes worldwide. The analyses from the 1925 articles highlighted the current knowledge gaps in different TAs, ethnicities, and populations. Filling these gaps is of importance, given the role these genes play in relation to the metabolism of substances to which we have frequent contact with, the associations observed between their deletion and diseases such as cancer, in addition to the interethnic differences observed for the deletion frequencies of these genes.

Pangenomic analysis of Chinese gastric cancer

Pangenomic study might improve the completeness of human reference genome (GRCh38) and promote precision medicine. Here, we use an automated pipeline of human pangenomic analysis to build gastric cancer pan-genome for 185 paired deep sequencing data (370 samples), and characterize the gene presence-absence variations (PAVs) at whole genome level. Genes ACOT1, GSTM1, SIGLEC14 and UGT2B17 are identified as highly absent genes in gastric cancer population. A set of genes from unaligned sequences with GRCh38 are predicted. We successfully locate one of predicted genes GC0643 on chromosome 9q34.2. Overexpression of GC0643 significantly inhibits cell growth, cell migration and invasion, cell cycle progression, and induces cell apoptosis in cancer cells. The tumor suppressor functions can be reversed by shGC0643 knockdown. The GC0643 is approved by NCBI database (GenBank: MW194843.1). Collectively, the robust pan-genome strategy provides a deeper understanding of the gene PAVs in the human cancer genome.

Association of Polymorphic Gene Variants of Xenobiotic Biotransformation Enzymes with Lung Tissue Destruction in Tuberculosis Patients

The objective: to investigate the association of polymorphic gene variants of xenobiotic biotransformation enzymes (NAT2, CYP2E1, ABCB1, GSTM1, GSTT1) and cytokines (IL1B, IL-4, IL-10, TNF) with lung tissue destruction in pulmonary tuberculosis patients.Subjects and Methods. An ethnically homogeneous population sample of unrelated individuals of Slavic nationalities (mainly Russians) living in Kursk Oblast suffering from new pulmonary tuberculosis was examined.Results. New pulmonary tuberculosis with no destructive changes in the lungs was associated with the EE genotype of the GSTM1 gene (p < 0.0001) in 89.5%, while the DD genotype of the GSTM1 gene (p < 0.0001) was associated with the presence of destructive changes in the lungs in 56.1% of cases; the dominant GG genotype of the TNF-α gene was associated with destructive changes in the lungs in 93.3% (p = 0.027), and the recessive GA genotype of the TNF-α gene was associated with no destructive changes in the lungs in 71.9% (p = 0.027).

Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. Combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD.

An updated analysis on the association of GSTM1 polymorphism and smoking exposure with the increased risk of coronary heart disease.

ObjectiveTo undertake a meta-analysis to investigate if there is an association between the glutathione S-transferase mu 1 (GSTM1) gene polymorphism, coronary artery disease (CAD) susceptibility and smoking.MethodsElectronic databases, including PubMed®, Web of Science and Embase®, were searched for relevant case–control studies. Data were extracted and the odds ratio (OR) was calculated and appropriate statistical methods were used for the meta-analysis.ResultsThe analysis included eight studies with a total of 1880 cases with CAD and 1758 control subjects. The results of this meta-analysis demonstrated that there is no association between the GSTM1 null and CAD (OR 1.24, 95% confidence interval [CI] 1.00, 1.55). An increased risk of CAD was observed in the smoking population with the GSTM1 null genotype (OR 1.48, 95% CI 1.02, 2.15). Subgroup analyses of geographical region, genotyping method and publication language category demonstrated potential relationships among gene polymorphism, smoking and CAD.ConclusionsBased on the current literature, the GSTM1 null genotype was associated to CAD in the smoking population. The interaction between smoking and GSTM1 polymorphism may contribute to the susceptibility of CAD.

Effects of genetic polymorphisms of GSTM1, GSTT1, and GSTP1 genes on blood metal levels in non-ferrous metal alloy smelter operators

Heavy metal ions are known to induce generation of a large number of reactive oxygen species (ROS). Glutathione S-transferases (GSTs) play an important role in adaptation and response to oxidative stress. GSTM1, GSTT1, and GSTP1 genes have numerous described polymorphisms, the most significant being GSTM1, GSTT1, and GSTP1 Ile105Val deletion ones. Our objective was to study the relationship between the genetic polymorphism of GSTM1, GSTT1, GSTP1 genes and blood levels of metals in smelter operators engaged in crude lead refining. We examined 55 male lead-refining furnace operators working at a non-ferrous metal alloy plant. Blood metal concentrations were measured by inductively coupled plasma mass spectrometry. GSTM1 and GSTT1 deletion polymorphisms were determined using real-time SYBR Green qPCR and that of GSTP1 Ile105Val – using a commercial SNP Screening Kit. Statistical data processing was carried out using the Mann – Whitney U-test. Blood levels of industry-specific metals were not statistically different between the workers with GSTT1 and GSTP1 genotypes. We established, however, that men with the null genotype of GSTM1 had significantly higher blood arsenic levels. Our findings indicate that a high blood arsenic level associated with occupational exposure may be attributed to the GSTM1 null genotype. This observation can be used to identify the most vulnerable groups of individuals at risk of overexposure to arsenic.

Abstract 128: Loss Of Gstm1 Augments Kidney Neutrophil Population In Angii-induced Hypertension

Background: Glutathione-S-transferase Mu1( Gstm1 ) gene, a member of Glutathione-S-transferases (GST) superfamily, 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 (CKD) progression and incident end stage kidney failure. We reported that deletion of Gstm1 increases oxidative stress, kidney inflammation and injury in angiotensin II induced hypertension (Ang II-HTN) in mice. At 4 weeks of Ang II-HTN, neutrophils, CD4+T cells, and F4/80+ cells were significantly increased in Gstm1 knockout (KO) kidney. While a link between oxidative stress and immune activation in hypertension has been well documented, the molecular mechanism by which Gstm1 regulates immune cell activation in hypertension is unknown. Methods: To further characterize the inflammatory response in GSTM1 deficiency, Gstm1 KO and wild-type (WT) male mice at ~ 12 weeks of age were subjected to Angiotensin II at 1000 ng/kg per minute for 4 days via a mini osmotic pump. The kidney cells and bone marrow cells were isolated for flow cytometry analysis. Results: At baseline, there were no differences in inflammatory cell populations including neutrophils between WT and Gstm1 KO mice. At Day 4 of Ang II-HTN, Gstm1 KO kidneys exhibited about a 2.3 fold increase in neutrophil population (CD45 + Ly6G + CD11b + ), compared to WT control mice (10 WT and 8 Gstm1 KO mice, p=0.0075). Interestingly, CD45+ bone marrow cells isolated from both Gstm1 KO and WT mice have similar percentile of neutrophil populations ; however, neutrophils in Gstm1 KO bone marrow express relatively higher levels of CXCR2. Unlike at 4 weeks, there was no difference in other inflammatory cells at Day 4. Conclusion: Deletion of Gstm1 increases renal neutrophil population early in Ang II-HTN and CXCR2 expression in bone marrow neutrophils. Gstm1 may play a role in regulating neutrophil migration and recruitment. Further studies are needed to delineate whether GSTM1 deficiency drives kidney injury via early neutrophil migration, which could shed light on potential therapeutic target for CKD progression in those genetically susceptible.

Влияние генетического полиморфизма генов GSTM1, GSTT1 и GSTP1 на содержание металлов в крови у плавильщиков производства сплавов цветных металлов

Heavy metal ions are known to induce generation of a large number of reactive oxygen species (ROS). Glutathione S-transferases (GSTs) play an important role in adaptation and response to oxidative stress. GSTM1, GSTT1, and GSTP1 genes have numerous described polymorphisms, the most significant being GSTM1, GSTT1, and GSTP1 Ile105Val deletion ones. Our objective was to study the relationship between the genetic polymorphism of GSTM1, GSTT1, GSTP1 genes and blood levels of metals in smelter operators engaged in crude lead refining. We examined 55 male lead-refining furnace operators working at a non-ferrous metal alloy plant. Blood metal concentrations were measured by inductively coupled plasma mass spectrometry. GSTM1 and GSTT1 deletion polymorphisms were determined using real-time SYBR Green qPCR and that of GSTP1 Ile105Val – using a commercial SNP Screening Kit. Statistical data processing was carried out using the Mann – Whitney U-test. Blood levels of industry-specific metals were not statistically different between the workers with GSTT1 and GSTP1 genotypes. We established, however, that men with the null genotype of GSTM1 had significantly higher blood arsenic levels. Our findings indicate that a high blood arsenic level associated with occupational exposure may be attributed to the GSTM1 null genotype. This observation can be used to identify the most vulnerable groups of individuals at risk of overexposure to arsenic.

PREDICTIVE MODELING OF N-ACETYL TRANSFERASE 2 SINGLE NUCLEOTIDE POLYMORPHISMS AND BREAST CANCER RISK USING IN-SILCO APPROACHES

N-acetyltransferase 2, also known as arylamine N-acetyltransferase, commonly known as NAT2. The objective of this study was to identify non-synonymous SNPs of NAT2 and their association with breast cancer using computational analysis. For this purpose, different online tools like SIFT, Polyphen, Polyphen-2, fuNTRp, SNAP2 (to identify pathogenic SNPs), SNP&GO, PhD-SNP, PredictSNP, MAPP, SNAP, MetaSNP, PANTHER (disease associated SNPs), Mu-Pro, I-Mutant, and CONSURF (to check protein stability) were used. Post-translational modifications (PTMs) were detected by Musitedeep, Protein secondary structure by SOPMA, and protein to protein interaction by STRING. Nineteen SNPs having rsIDs (rs1435840670, rs747536177, rs753310036, rs1175197943, rs1805158,rs1019316375, rs201345576, rs1476310549, rs72466458, rs201080763, rs746734312, rs561124342, rs549917500, rs1383708687, rs4986996, rs559660817, rs1344597702, rs749948990, and rs148566670) showing mutations on Y6H, G11V, F37S, H43P, R64W, G65D, W67R, W67C, C68Y, N72S, G83S, G83A, H107Q, V112M, D122N, D122G, C223W, G230V, and L275M, respectively found to be completely deleterious. The PTMs found were Glycosylation at amino acid number 125; Ubiquitination at 256 and 282, Acetylation at 272; Hydroxylation at 281, and Phosphorylation at 287. The protein secondary structure consisted of Alpha helix (Hh) 80 is (27.59%), Extended strand (Ee) 65 is (22.41%), Beta turn (Tt) 21 is 7.24% and Random coil (Cc) 124 is (42.76%). Protein-protein interaction analysis revealed that it has strong interaction with Myeloperoxidase, Xanthine dehydrogenase, Liver carboxylesterase 1, Glutathione S-transferase Mu 1, and with cytochrome family. Based on these results, it is concluded that these SNPs found in NAT2 are involved in breast cancer. Further in vitro and in vivo analysis should be performed to conduct these interactions.

GSTM1 and GSTT1 Gene Polymorphisms with Gallbladder Carcinoma

In order to explore the relationship between GSTM1 and GSTT1 gene polymorphisms and gallbladder cancer, so as to find a better treatment and prevention of gallbladder cancer and improve the treatment effect. In this paper, 247 patients with gallbladder cancer were selected for the experiment, including 187 male patients and 60 female patients. The total number of patients was randomly divided into two groups, namely the case group and the control group. The patients in normal condition and after treatment of tumor tissue and adjacent non-tumor tissue gene detection, and then through the logistic regression model to analyze the data. After the experiment, we found that the frequency ratio of GSTM1 and GSTT1 in gallbladder cancer patients before treatment was 57.33% and 52.37%, which was very high, which was very disadvantageous in gene detection. However, after treatment, the frequency of deletion of the two genes was 45.73% and 51.02%, which was significantly reduced. The reduced gene ratio is very beneficial to the observation of gallbladder cancer. Therefore, the surgical treatment of gallbladder cancer before the first drug after gene testing, in the understanding of various principles, will have twice the result with half the effort.

GSTM2 is a key molecular determinant of resistance to SG-ARIs.

Prostate cancer (PCa) continues to threaten men's health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in naïve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.

The Leucocyte Telomere Length, GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease.

Simple SummaryChronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress, both in the airways and blood, and in other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). We explored the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1 and GSTT1, we genotyped 152 COPD patients and 131 non-affected controls, while for TL, we assessed 91 patients and 88 controls. There was a significant difference in GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); and in controls, the opposite occurred (31,354 bp vs. 17,800 bp, p = 0.020). According to our results GSTM1, but not GSTT1, null genotypes might play role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.

Do Polymorphisms of the TERT, GSTM1, and GSTT1 Genes Increase Laryngeal Cancer Susceptibility in Smokers of Romanian Descent?

Background and Objectives: The aim of this study was to investigate the association between smoking status and single-nucleotide polymorphism in candidate genes that had a known association with smoking-related tumors in previous studies and to explore their link to laryngeal cancer risk in a population of northern Romanian descent. The genes selected have key functions in xenobiotic metabolism (GSTs: the glutathione S-transferases family: GSTM1 and GSTT1) and chromosomal management (TERT). Materials and Methods: The genotype frequencies of TERTRs2736100 and the GST subfamilies (GSTM1 and GSTT1) were determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The relationship between the polymorphisms and the risk of laryngeal cancer was analyzed in a retrospective case–control study of 92 laryngeal cancer cases and 101 controls, all of whom were smokers. Results: Subjects presenting the GSTT1-null variant had a two-fold increase in risk (OR = 2.05, 95% CI = 1.07–3.95, p = 0.02). While no individual risk was observed for the TERTRs2736100 polymorphism, stratification based on gender revealed a nine-fold increase in risk for carriers of the “C” allele in the heterozygote variant who were male (OR = 9, 65% CI = 3.51–26.51, p = 0.0000). Conclusions: The results showed that the GSTT1-null genotype and the mutant heterozygote variant of TERTRs2736100 genes may play a significant role in laryngeal cancer susceptibility in subjects of northern Romanian descent. There may be no association between the susceptibility to laryngeal carcinoma and the GSTM1 polymorphism. The results could not confirm the carcinogenic influence smoking has on laryngeal cancer development for the studied polymorphisms.

Oxidative-Stress Related Gene Polymorphism in Endometriosis-Associated Infertility.

Background and Objectives: Endometriosis is a benign inflammatory disease associated with infertility and chronic pelvic pain, estimated to affect 7–10% of reproductive-age women, with the possibility of malignant transformation. Recent studies focus on oxidative stress and genetic mutations as risk factors in the pathophysiology of endometriosis-associated infertility. Materials and Methods: This case-control study is the first in Eastern European women that aimed to investigate four genes’ genetic polymorphisms that encode antioxidant enzymes involved in oxidative stress (glutathione peroxidase 1, GPX1 198Pro > Leu, catalase CAT-262C > T, glutathione S-transferase M1, and T1 null genotype) and their association with endometriosis-related infertility. We compared 103 patients with endometriosis-associated infertility with 102 post-partum women as the control group. Results: The endometriosis group had a mean age of 34.5 +/− 6.12 years, while the control group’s mean age was 35.03 +/− 5.95 years. For CAT-262C > T polymorphism, the variant genotypes were significantly more frequent in the endometriosis group. Moreover, for the GPX1 198Pro > Leu, the endometriosis group had significantly more frequent CT and TT genotypes. The null genotype of GSTM1 was detected significantly higher in the endometriosis group. No significant differences were found in the frequency of GSTT1 between the two groups. This study suggests that GPX1 198Pro > Leu, CAT-262C > T, and GSTM1 polymorphisms may be risk factors and that the association between the GSTM1-GSTT1 null genotype may play a significant role in endometriosis-associated infertility. Moreover, this study suggests that the GSTT1 null genotype does not influence the disease. Visual identification of endometriotic lesions with microscopic confirmation is the accepted gold standard for diagnosing endometriosis, but general anesthesia and laparoscopy are required. Conclusions: In this regard, a panel of genetic or laboratory markers is needed for the early diagnostics of this prevalent disease, especially in the case of young patients with future pregnancy intention.

Effects of cereblon on stress-activated redox proteins and core behavior

The mechanisms underlying the vulnerability and resilience of an individual to stress are only partly understood. Response to stress is determined by behavioral and biochemical changes in the brain. Chronic ultra-mild stress (CUMS) induces an anhedonic-like state in mice that resembles symptoms of human depression. This study reports the role of cereblon (CRBN) in regulating the metabolic and antioxidant status of neuronal tissues in the mouse model of CUMS. Intriguingly, Crbn−/− (KO) mice showed resilient responsiveness, both at the behavioral and proteomic levels. Several core behaviors were also differentially altered by CUMS in KO mice. Liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based proteome analysis of whole brain lysate (WBL) showed an enriched chaperonic, metabolic, and antioxidant status in the brains of KO subjects, including several members of DNAJ chaperones, creatine kinase, quinone oxidoreductase, superoxide dismutase (SOD1), glutathione S-transferase Mu (GSTM), peroxiredoxin-6 (PRDX6), and thioredoxin. Pathological phosphorylation as characterized by aggregation of tau and α-synuclein (α-syn) was significantly reduced in the neuronal tissues of KO mouse model of CUMS as compared to wild type (WT) mice. Furthermore, significantly increased SOD1 activity and reduced lipid peroxidation were observed in Crbn-KO systems. Integrated signaling pathways were also identified in CRBN-specific sub-networks constructed from protein-protein interaction analysis by STRING. The present study highlights the roles of CRBN in regulating the stress response (SR) and reshaping metabolic status in the brains of mice exposed to CUMS. A better understanding of the molecular mechanisms of depression and neurodegeneration can improve the development of novel treatments.