Association of glutathione peroxidase-1 （GPx-1） rs1050450 Pro198Leu and Pro197Leu polymorphisms with cardiovascular risk：a meta-analysis of ob-servational studies

Objective To clarify the association between rs1050450 polymorphism in Glutathione peroxidase-1 （GPx-1） and the risk of cardi-ovascular diseases （CVD） by performing a meta-analysis of published studies. There is growing evidence from different study types for an association of the GPx-1 polymorphism and cardiovascular outcomes, but observational studies have so far shown inconsistent results. Me-thods Relevant publications were searched through PubMed, Embase database databases and the Cochrane Library. We used odds ratios （ORs） with 95%confidence intervals （CIs） to assess the strength of association under the best genetic model. Both Q statistic and the I2 were used to check heterogeneity. Meta-regression analysis was performed to explore heterogeneity source. Sensitivity analysis, cumulative me-ta-analysis analysis and publication bias were used to test the reliability of the results. Results Data were available from two cohort studies and 8 case-control studies involving 1,430 cases and 3,767 controls. The pooled ORs for overall CVD risk was 1.36 with 95%CI：1.08-1.70 under a co-dominant model, and that for East Asian subgroup was 1.84 （95%CI：1.39-2.43）. Substantial heterogeneity for ORs were de-tected among all the included studies, mainly caused by ethnic differences between East Asian and non-East Asian populations. Although Egger＇s regression test suggested no statistical significant publication bias, Begg＇s funnel plot exhibited obvious asymmetry. The statistical significance disappeared after adjusting for potential publication bias in the overall studies. However, no substantial publication bias was found in the East Asian subgroup. Conclusions GPx-1 gene Pro198Leu and Pro197Leu polymorphisms considerably increased the risk of CVD in the East Asian population. Large-scale investigations are needed to confirm the results in different ethnicities.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis

BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple biological processes,including cellular senescence,apoptosis,sugar and lipid metabolism,oxidative stress,and inflammation.AIM To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.METHODS This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)testing.C57BL/6 mice were also intraperitoneally pretreated with SIRT1,p53,or glutathione peroxidase 4(GPX4)inducers and inhibitors and injected with lipopolysaccharide(LPS)/D-galactosamine(D-GalN)to induce ALF.Gasdermin D(GSDMD)^(-/-)mice were used as an experimental group.Histological changes in liver tissue were monitored by hematoxylin and eosin staining.ALT,AST,glutathione,reactive oxygen species,and iron levels were measured using commercial kits.Ferroptosis-and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction.SIRT1,p53,and GSDMD were assessed by immunofluorescence analysis.RESULTS Serum AST and ALT levels were elevated in patients with ALF.SIRT1,solute carrier family 7a member 11(SLC7A11),and GPX4 protein expression was decreased and acetylated p5,p53,GSDMD,and acyl-CoA synthetase long-chain family member 4(ACSL4)protein levels were elevated in human ALF liver tissue.In the p53 and ferroptosis inhibitor-treated and GSDMD^(-/-)groups,serum interleukin(IL)-1β,tumour necrosis factor alpha,IL-6,IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated.In mice with GSDMD knockout,p53 was reduced,GPX4 was increased,and ferroptotic events(depletion of SLC7A11,elevation of ACSL4,and iron accumulation)were detected.In vitro,knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels,the cytostatic rate,and GSDMD expression,restoring SLC7A11 depletion.Moreover,SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group,accompanied by reduced p53,GSDMD,and ACSL4,and increased SLC7A11 and GPX4.Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalNinduced in vitro and in vivo models.CONCLUSION SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Glutathione S-transferase M1 and T1 Gene Deletion Associated with Increased Susceptibility to Nasopharyngeal Carcinoma

Objective： To evaluate the association of Glutathione S-transferase （GST） M1 and T1 genetic polymorphisms and susceptibility to nasopharyngeal carcinoma （NPC） in a high risk area of Guangxi Zhuang Autonomous Region （province）, Southwest of China. Methods： A case-control study was conducted to investigate the genetic polymorphisms of these enzymes （GSTM1 and GSTT1 null genotypes）. A total of 127 NPC cases and 207 controls were recruited. Results： GSTM1 and GSTT1 null genotype frequencies were higher among NPC patients at a level of statistical significance （P〈0.005; P〈0.001 respectively）, and both GSTM1 and GSTT1 null genotype were even more significant （P〈0.001）. Conclusion： NPC is the most common cancer in Guangxi. GST enzymes are involved in the detoxification of many environmental carcinogens. Homozygous deletions of GSTM1 and GSTT1 have been associated with several types of cancer. The risk to develop NPC has been associated with environmental factors such as cigarette smoking and EB virus infection. The present results indicate that the GSTM1 and GSTT1 deletion polymorphisms are associated with an increase risk of susceptibility to NPC, and both detoxific enzyme genes deletion is more important than a single gene deletion for the susceptibility to NPC.

Increased oxidative damage of sperm and seminal plasma in men with idiopathic infertility is higher in patients with glutathione S-transferase Mu-1 null genotype

Aim： To examine whether a relationship exists between glutathione S-transferase Mu-1 （GSTM1） gene polymorphism and the susceptibility of sperm and seminal plasma from patients with idiopathic infertility to oxidative stress. Methods： Fifty-two men with idiopathic infertility and 60 healthy fertile men were recruited to this study. GSTM1 gene polymorphism was determined by polymerase chain reaction （PCR） and both the infertile and control individuals were divided into GSTM1 null and GSTM1 positive groups according to their GSTM1 gene structure. We compared reactive oxygen species （ROS） generation, malondialdehyde （MDA）, protein carbonyls and glutathione （GSH） concentrations, and glutathione S-transferase （GST） activity in seminal plasma and spermatozoa from infertile patients and controls with respect to GSTM1 genotype. Results： Significantly higher levels of oxidative stress and damage markers were found in idiopathic infertile men with the GSTM1 null genotype compared with those with the GSTM1 positive genotype. There was no significant difference in genotype distribution for theGSTM1 variant between the idiopathic infertile subjects and fertile subjects. Patients with the GSTM1 null genotype also had lower sperm concentrations than those with GSTM1 positive genotype. Conclusion： Our results suggest that the susceptibility of sperm and seminal plasma to oxidative stress is significantly greater in idiopathic infertile men with the GSTM1 null genotype compared with those possessing the gene. Therefore, in patients with idiopathic infertility, GSTM1 polymorphism might be an important source of variation in susceptibility of spermatozoa to oxidative damage.

Polymorphism of glutathione S-transferase mu 1 and theta 1 genes and hepatocellular carcinoma in southern Guangxi, China

AIM: Glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genes are involved in the metabolism of a wide range of carcinogens, but deletions of the genes are commonly found in the population. The present study was undertaken to evaluate the association between GSTM1 and GSTT1 gene polymorphisms and hepatocellular carcinoma (HCC) risk. METHODS: The genetic polymorphisms were studied at an aflatoxin highly contaminated region in Guangxi, China. Pdymerase chain reaction (PCR) technique was used to detect the presence or absence of the GSTM1 and GSTT1 genes in blood samples. The case group was composed of 181 patients of HCC identified by the pathologists and the control group was composed of 360 adults without any tumor. RESULTS: The frequencies of GSTM1 and GSTT1 null genotypes in the control were 47.8% and 42.7%, while those in the HCC group were 64.6% and 59.7%, respectively. The differences between HCC group and control group were very significant (P<0.01). GSTM1 and GSTT1 combined null genotypes in HCC group and control group were 38.2% and 18.5% respectively, and the difference was significant (P<0.05). CONCLUSION: The GSTM1 and GSTT1 null genotypes are associated with an increased risk of HCC in a special geographic environment. Combination of the two null genotypes in an individual is substantially increased twice the risk of HCC.

Glutathione S-transferase M1 polymorphism and esophagealcancer risk:An updated meta-analysis based on 37 studies

AIM: To evaluate the relationship between glutathione S-transferase M1(GSTM1) polymorphism and susceptibility to esophageal cancer(EC).METHODS: A comprehensive search of the United States National Library of Medicine Pub Med database and the Elsevier, Springer, and China National Knowledge Infrastructure databases for all relevant studies was conducted using combinations of the following terms: "glutathione S-transferase M1", "GSTM1", "polymorphism", and "EC"(until November 1, 2014). The statistical analysis was performed using the SAS software(v.9.1.3; SAS Institute, Cary, NC, United States) and the Review Manager software(v.5.0; Oxford, England); crude odds ratios(ORs) with 95% confidence intervals(CIs) were used to assess the association between the GSTM1 null genotype and the risk of EC.RESULTS: A total of 37 studies involving 2236 EC cases and 3243 controls were included in this metaanalysis. We observed that the GSTM1 null genotype was a significant risk factor for EC in most populations(OR = 1.33, 95%CI: 1.12-1.57, P_(heterogeneity) < 0.000001, and I2 = 77.0%), particularly in the Asian population(OR = 1.53, 95%CI: 1.26-1.86, P_(heterogeneity)< 0.000001, and I2 = 77.0%), but not in the Caucasian population(OR = 1.02, 95%CI: 0.87-1.19, P_(heterogeneity) = 0.97, and I2 = 0%).CONCLUSION: The GSTM1 null polymorphism may be associated with an increased risk for EC in Asian but not Caucasian populations.

Genetic polymorphism of glutathione S-transferase T1 gene and susceptibility to idiopathic azoospermia or oligospermia in northwestern China

Aim： To investigate the association of glutathione S-transferase T1 （GSTT1） gene polymorphism in patients with idiopathic azoospermia or oligospermia in the northwestern China population. Methods： In the case-control study, GSTT1 genotypes were identified by multiplex polymerase chain reaction （PCR） with peripheral blood DNA samples from 78 patients with idiopathic azoospermia, 103 patients with idiopathic oligospermia and 156 age-matched controls with normal sperm concentration and motility, according to the criteria adapted from World Health Organization guidelines. All of the patients and controls were from northwestern China. Results： There is a significant association between GSTT1 null genotype with idiopathic azoospermia risk （odds ratio [OR]： 2.36, 95% confidence interval [CI]： 1.33-4.20, P = 0.003） or idiopathic oligospermia risk （OR： 2.00, 95% CI： 1.17-3.27, P = 0.010）. Conclusion： GSTT1 null genotype is a predisposing risk factor for sporadic idiopathic azoospermia or oligospermia in northwestern China. （Asian J Androl 2008 Mar; 10： 266-270）

A systemic review of glutathione S-transferase P1 Ile105Val polymorphism and colorectal cancer risk

Objectives： To investigate the correlation between glutathione S-transferase P1 （GSTP1） Ilel05Val polymorphism and colorectal cancer （CRC） risk. Methods： Studies were identified to investigate the association between GSTP1 Ilel05Val polymorphism and CRC risk. Systematic computerized searches of the PubMed, Chinese National Knowledge Infrastructure, WANFANG and SinoMed were performed. Summary odds ratios （OR） and 95% confidence intervals （95 % CI） were used to measure GSTP 1 Ile 105Val polymorphisms and CRC risk. Results： A total of 23 retrospective studies were included in the meta-analysis. During all studies including 6,981 cases and 8,977 controls, sample sizes ranged from 146 to 2,144. Overall, the pooled results revealed that lie 105Val polymorphism was not associated with CRC risk and confused results were found in subgroup analyses. Further meta-analyses were conducted after excluding low-quality studies. GSTP1 Ilel05Val is associated with increased risk of CRC limited in studies with matched control. There was no significant heterogeneity in all genetic comparisons, but heterogeneity existed in subgroup analyses of heterozygous and dominant comparisons. The meta-regression analyses indicated that matched controls were the significant factor influencing between-study heterogeneity in all possible influential factors including published year, ethnicity, source of control, sample size, Hardy-Weinberg equilibrium （HWE） in control and matched controls. Sensitivity analysis revealed the pooled ORs were not changed before and after removal of each single study in all genetic comparisons, indicating the robustness of the results. Conclusions： GSTP1 Ilel05Val might be associated with increased risk of CRC. However, more high- quality case-control studies should be performed to confirm the authenticity of our conclusion.

STUDY OF THE DELETION MUTATION OF GLUTATHIONE S TRANSFERASE M1 GENE AND ITS ROLE IN SUSCEPTIBILITYTO HEPATOCELLULAR CARCINOMA

Objection: To investigate the glutathione S transferase M1 (GSTM1) gene inherent deletion and its relation to prevalence of hepatocellular carcinoma (HCC) in Guangxi, China. Methods: The GSTM1 gene polymorphism of 120 HCC patients and 100 healthy subjects both from the same high aflatoxin B1 (AFB1) contaminated area were detected using PCR technique with special primers. Another 40 patients from AFB1 low risk area were also tested. Results: In HCC high risk area, it was found that the frequencies of GSTM1 null genotype in HCC patients and healthy subjects were 59% and 51% respectively, with no significant difference. However, the frequency of GSTM1-null genotype in control group from AFB1 low risk area was lower than those from high risk area (P<0.01). Conclusion: Populations in this HCC endemic region show a higher rate of GSTM1-null genotype, which may be partially responsible for the susceptibility to AFB1 induced HCC. But the detoxification effect of GSTM1 alone is not sufficient to resist the genetic toxicity of AFB1, especially in those people who expose to excess AFB1. The GSTM1 gene deletion would not be suitable as an independent predictor of susceptibility to HCC.

Association of glutathione S-transferase T1 and M1 gene polymorphisms with ischemic stroke risk in the Chinese Han population

Atherosclerosis plays an important role in ischemic stroke, and oxidative stress participates in the entire process of atherosclerosis. Glutathione S-transferase （GST） acting with other antioxidant enzymes can eliminate reactive oxygen species and protect cells against oxidative damage. To assess the association of glutathione S-transferase （GSTT1 and GSTM1） gene polymorphisms with ischemic stroke in the Chinese Han population, the present study selected 315 patients with ischemic stroke and 210 healthy controls for comparison. GSTT1 and GSTM1 genotypes were determined using polymerase chain reactions, electrophoresis and imaging analysis. No obvious evidence of GSTTI-nulI, GSTMI-null and GSTTI/GSTMI-double null genotype distribution differences was found between case and control groups or between genders. Subgroup analysis showed that the risk of stroke was increased when hypertension was accompanied by GSTTl-null （odds ratio （OR） = 2.996, P 〈 0.001） and GSTMl-null （OR = 3.680, P 〈 0.001 ） genotypes; diabetes mellitus was accompanied by GSTTI-null （OR = 1.860, P = 0.031） and GSTMI-null （OR = 2.444, P = 0.002） genotypes, and smokers showed a GSTTl-null genotype （OR = 2.276, P = 0.003）. GSTT1- and GSTMl-null genotypes may interact synergistically with hypertension, diabetes mellitus and smoking to increase the incidence risk of ischemic stroke.

Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion

ATP-binding cassette（ABC） transporters ABCC1（MRP1）,ABCB1（P-gp）,and ABCG2（BCRP） contribute to chemotherapy failure.The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug（NSAID）,sulindac sulfide,to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux.Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs.NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines,as well as a large panel of standard tumor cell lines.Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate（GSH） transport in isolated membrane vesicles and intact cells.Selective reversal of multi-drug resistance（MDR）,decreased efflux of doxorubicin,and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID,indomethacin,in resistance selected and engineered cell lines expressing ABCC 1,but not ABCB 1 or ABCG2.Sulindac sulfide also inhibited transport of leukotriene C_4 into membrane vesicles.Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines,including all melanoma lines tested（7-7）.Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells,while the glutathione synthesis inhibitor,BSO,selectively increased sensitivity to sulindac sulfide induced cytotoxicity.Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations.ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide,and in combination with chemotherapeutic drugs that induce oxidative stress.

Rethinking de novo immune hepatitis,an old concept for liver allograft rejection:relevance of glutathione S-transferase T1 mismatch

Antibody-mediated rejection(AMR) in liver transplantation has long been underestimated. The concept of the liver as an organ susceptible to AMR has emerged in recent years, not only in the context of the major histocompatibility complex with the presence of HLA donor-specific antibodies, but also with antigens regarded as "minor", whose role in AMR has been demonstrated. Among them, antibodies against glutathione S-transferase T1 have been found in 100% of patients with de novo autoimmune hepatitis(dn AIH) when studied. In its latest update, the Banff Working Group for liver allograft pathology proposed replacing the term dn AIH with plasma cell(PC)-rich rejection. Antibodies to glutathione S-transferase T1(GSTT1) in null recipients of GSTT1 positive donors have been included as a contributory but nonessential feature of the diagnosis of PC-rich rejection. Also in this update, non-organ-specific anti-nuclear or smooth muscle autoantibodies are no longer included as diagnostic criteria. Although initially found in a proportion of patients with PC-rich rejection, the presence of autoantibodies is misleading since they are not diseasespecific and appear in many different contexts as bystanders. The cellular types and proportions of the inflammatory infiltrates in diagnostic biopsies have been studied in detail very recently. PC-rich rejection biopsies present a characteristic cellular profile with a predominance of T lymphocytes and a high proportion of PCs, close to 30%, of which 16.48% are Ig G4+. New data on the relevance of GSTT1-specific T lymphocytes to PC-rich rejection will be discussed in this review.

Integrative Modeling of Oxidative Stress and C1 Metabolism Reveals Upregulation of Formaldehyde and Downregulation of Glutathione

This research provides, to the authors’ knowledge, the first integrative model of oxidative stress and C1 metabolism in plants. Increased oxidative stress can cause irreversible damage to photosynthetic components and is harmful to plants. Perturbations at the genetic level may increase oxidative stress and upregulate antioxidant systems in plants. One of the key mechanisms involved in oxidative stress regulation is the ascorbate-glutathione cycle which operates in chloroplasts as well as the mitochondria and is responsible for removal of reactive oxygen species (ROS) generated during photosynthetic operations and respiration. In this research, the complexity of molecular pathway systems of oxidative stress is modeled and then integrated with a previously developed in silico model of C1 metabolism system. This molecular systems integration provides two important results: 1) demonstration of the scalability of the CytoSolve&#174?Collaboratory&#153, a computational systems biology platform that allows for modular integration of molecular pathway models, by coupling the in silico model of oxidative stress with the in silico model of C1 metabolism, and 2) derivation of new insights on the effects of oxidative stress on C1 metabolism relative to formaldehyde (HCHO), a toxic molecule, and glutathione (GSH), an important indicator of oxidative homeostasis in living systems. Previous in silico modeling of C1 metabolism, without oxidative stress, observed complete removal of formaldehyde via formaldehyde detoxification pathway and no change in glutathione concentrations. The results from this research of integrative oxidative stress with C1 metabolism, however, demonstrate significant upregulation of formaldehyde concentrations, with concomitant downregulation and depletion of glutathione. Sensitivity analysis indicates that kGSH-HCHO, the rate constant of GSH-HCHO binding, VSHMT, the rate of formation of sarcosine from glycine, and , the rate of superoxide formation significantly affect formaldehyde homeostasis in the C1 metabolism. Future research may employ this integrative model to explore which conditions initiate oxidative stress and the resultant upregulation and downregulation of formaldehyde and glutathione.

Oxidative stress regulated heme-oxygenase-1 and glutathione S-transferase-m1 gene expression changes in cell lines exposed to melanins

To investigate the effects of oxidative stress on substantia nigra neuronal degeneration and death in patients with Parkinson＇s disease, we treated neuroblastoma cells （SK-N-SH） and glioma cells with Fenton＇s reagent, iron chelating agent, neuromelanin and dopamine melanin. We investigated the changes in expression of nine oxidative stress-related genes and proteins. The levels of mRNAs for heme-oxygenase-1 and glutathione S-transferase-ml were significantly reduced in SK-N-SH cells exposed to oxidative stress, and increased in glial cells treated with deferoxamine. These results revealed that SK-N-SH neurons react sensitively to oxidative stress, which implies different outcomes between these two types of cells in the substantia nigra. Moreover, the influences of neuromelanin and dopamine melanin on cell function are varied, and dopamine melanin is not a good model for neuromelanin.

T-cell allorecognition of donor glutathione S-transferase T1 in plasma cell-rich rejection

AIM To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts.METHODS The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1(GSTT1) alleles(don+/rec-), and 4 were matched(don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection(former de novo immune hepatitis). For the detection of specific Tlymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ.RESULTS Activation of CD8^+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection(3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4^+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides(1.45%-5.18%). Highly unexpected was the finding of a double positive CD4^+CD8^(low) T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4^+CD8^(low) cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides. CONCLUSION Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.

Association among Serum Organochlorine Pesticide Residues, Glutathione S-Transferase M1 Genetic Polymorphism and Female Breast Cancer

Background: The purpose of this study was to evaluate the association among serum organochlorine pesticide residues, glutathione S-transferase M1 genetic polymorphism and female breast cancer. Methods: A 1:1 matched case-control study of 140 newly diagnosed breast cancer patients and 140 non-cancer female patients who consulted the five largest hospitals in the Tangshan city from September 2006 to October 2007. Results: The result showed higher risk of breast cancer among subjects with higher levels of serum DDT and HCH residue, the OR was 3.18 (95%CI, 1.11 - 9.07) and 5.02 (95%CI, 1.64 - 16.56).The value of ORe associated with single environmental factor DDT high residues, and ORg associated with single GSTM1 deletion genotype were respectively 3.86 (1.20 - 12.47) and 1.34 (0.36 - 5.08). The OReg associated with combined action of two factors was 5.59 (1.63 - 18.90), and the value of interaction parameters (γ) equaled 1.24. The value of ORe associated with single environmental factor HCH higher residue and ORg associated with single GSTM1 deletion genotype were respectively 2.73 (0.84 - 8.87) and 1.48 (0.49 - 4.60). The value of OReg associated with combined action of two factors was 3.87 (1.18 - 12.68), and γ equaled 1.38. Conclusion: The results indicated that breast cancer occurrence was the combined result of environmental and genetic factors. The concurrent action of GSTM1 deletion genotype and DDT/HCH enhanced the risk of breast cancer.

Genetic dissection of glutathione S-transferase omega-1:identification of novel downstream targets and Alzheimer's disease pathways

Alzheimer's disease(AD)is affected by genetic factors.Polymorphisms in the glutathione S-transfe rase omega-1(Gsto1)gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD.Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to chara cterize the mechanisms underlying regulation of Gstol variation regulation and to identify network membe rs that may contribute to AD risk or progression.Allele-specific assays confirmed that variation in Gstol expression is controlled by cis-expression quantitative trait loci.We found that Gstol mRNA levels were related to several central nervous system traits,such as glial acidic fibrillary protein levels in the caudate putamen,co rtical gray matter volume,and hippocampus mossy fiber pathway volume.We identified 2168 genes whose expression was highly correlated with that of Gsto1.Some genes were enriched for the most common neurodegenerative diseases.Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD,such as APP,Grin2 b,Ide,and Psenen.To evaluate the relationships between Gstol and candidate network members,we transfected astrocytes with Gstol siRNA and assessed the effect on putative downstream effecto rs.We confirmed that knockdown of Gstol had a significant influence on Pa2g4 expression,suggesting that Pa2g4 may be a downstream effector of Gstol,and that both genes intera ct with other genes in a network during AD pathogenesis.

Frequency of Null Phenotypes of Glutathione S-Transferase M1 and T1 among the Populations of Tabuk (Northwestern Part of Saudi Arabia)

Background: The variability in the distribution of the null phenotypes of GSTM1 and GSTT1, due to total or partial gene deletion resulting in the lack of the active enzyme, has been reported in different populations, especially in ethnically well-defined groups but not in Tabuk. This study investigated the variability in the distribution of the null phenotypes of GSTM1 and GSTT1 in the population of Tabuk (northwestern part of Saudi Arabia). Method: This study was conducted on 200 subjects of Tabuk—northwestern part of Saudi Arabia among which 100 were chronic smokers and 100 were nonsmokers. The subjects were reporting to hospital for routine checkup. All were without past history of any chronic disease and no significant abnormality. GST genotyping was done by multiplex PCR-based methods. The smoker and control groups were compared using a chi-square test with P GSTM1 deletion homozygosity of 14% and 1% was reported among non smokers and smokers, respectively whereas GSTT1 deletion homozygosity of 28% and 6% was reported among non smokers and smokers, respectively. Our results indicate that there are major differences in allelic distribution of GSTM1 and GSTT1 genes between the two groups investigated. Combined analysis of both genes revealed that 15% of smokers and non smokers harbor the deleted genotype of GSTM1 and 34% of smokers and non smokers harbor the deleted genotype of GSTT1 with significant differences. Conclusion: This study enables selecting subgroups among the general population who are more susceptible to DNA damage and will help genetic studies on the association of GST polymorphisms with disease risks and drug effects in Arab population. Studies with a larger sample size are needed to evaluate and confirm the validity of our results.

硫氢化钠增加高糖高脂条件下小鼠心房肌细胞系HL-1谷胱甘肽合成

目的研究硫氢化钠(NaHS)是否通过调节谷胱甘肽(GSH)的合成,降低活性氧自由基(ROS)产生,改善小鼠2型糖尿病心肌病(DCM)。方法将小鼠心房肌细胞系HL-1分为对照组、高葡萄糖(HG:40 mmol/L)和棕榈酸(Pal:500μmol/L)处理组;以及硫氢化钠(NaHS,100μmol/L)、DL-炔丙基甘氨酸[PPG,胱硫醚γ裂解酶(CSE)抑制剂,1 mmol/L]和N-乙酰-L-半胱氨酸(NAC,ROS抑制剂,5 mmol/L)处理72 h组。Western blot检测CSE和谷胱甘肽合成酶(GSS)的表达;二氢乙锭(DHE)和二氯氟甲烷(DCFH)检测ROS含量;免疫共沉淀检测核因子红细胞系2相关因子2(Nrf2)泛素化水平及Nrf2与肌肉特异性环指蛋白1(Murf1)的相互作用。结果与对照组比高糖高脂处理HL-1细胞后CSE、溶质载体家族7成员11(SLC7A11)、谷氨酸半胱氨酸连接酶催化亚基C(GCLC)、谷氨酸半胱氨酸连接酶修饰亚基M(GCLM)、谷胱甘肽合成酶(GSS)的表达水平下降,而NaHS能恢复其表达。高糖高脂组ROS含量高于NaHS组。与NaSH组比高糖高脂条件下Murf1与Nrf2的相互作用增加,Nrf2泛素化水平明显增加。结论硫氢化钠减轻Nrf2的泛素化,增加GSH合成关键酶的表达。

Anticancer Drug Resistance of HeLa Cells Transfected With Rat Glutathione S-transferase pi Gene

To establish a cytologic expressing system of rat glutathione S-transferase pi (GST-pi) cDNA for detecting the resistance of HeLa cells to anticancer drugs. Methods The assessment was made with various anticancer drugs (adriamycin, mitomycin, cisplatinum and vincristine) that showed different cytotoxicities in transfectant HeLa cells with pSV-GT containing rat GST-pi cDNA (HeLa/pSV-GT) or control pSV-neo (HeLa/pSV-neo). Expression levels of GST-pi mRNA in HeLa/pSV-GT and HeLa/pSV-neo were measured by in situ hybridization using Digoxin-labelled cDNA probe. Results HeLa/pSV-GT expressed significantly high degree of GST-pi mRNA, whereas both HeLa/pSV-neo and HeLa cells had very low expression. Cytotoxicities of HeLa/pSV-GT and HeLa/pSV-neo with 4 anticancer drugs were measured by MTT assay. Drug concentrations for yielding 50% inhibition (IC50) in HeLa/pSV-GT by adriamycin, mitomycin and cisplatinum were 70.13 靏/mL, 10.95 靏/mL and 16.52 靏/mL, respectively. In contrast, IC50 in HeLa/pSV-neo was 10.34 靏/mL, 7.48 靏/mL and 13.70 靏/mL, respectively. The cytotoxicities of vincristine on both HeLa/pSV-GT and HeLa/pSV-neo were not significantly different. Conclusions Our findings suggest that HeLa/pSV-GT containing rat GST-pi cDNA is resistant to some anticancer drugs due to overexpression of GST-pi. Also, HeLa/pSV-GT cell line could serve as a useful cytogenetic model for further research.