Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders

Objective: The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls. Methods: The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model. Results: GSH levels were significantly reduced and, conversely, GPx activity was higher among patients than controls. GCLC_GAG-7/9 genotype (OR = 4.3, 95%CI = 1.40-14.31, p = 0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR = 6.09, 95%CI = 1.93-22.59, p = 0.003) were found to be risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or metabolic ratio. Conclusions: GCLC variants were associated with the oxidative stress profile of patients with psychotic disorders, raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.

Factors influencing bilirubin elevation and its correlation with UGT1A1 gene polymorphism in the early postoperative period of transjugular intrahepatic portosystemic shunt / 中华肝脏病杂志

Objective: To investigate the factors influencing total bilirubin elevation and its correlation with UGT1A1 gene polymorphism in the early postoperative period of transjugular intrahepatic portosystemic shunt (TIPS). Methods: 104 cases with portal hypertension and esophageal variceal hemorrhage (EVB) treated with elective TIPS treatment were selected as the study subjects and were divided into a bilirubin-elevated group and a normal bilirubin group according to the total bilirubin elevation level during the early postoperative period. Univariate analysis and logistic regression were used to analyze the factors influencing total bilirubin elevation in the early postoperative period. PCR amplification and first-generation sequencing technology were used to detect the polymorphic loci of the UGT1A1 gene promoter TATA box, enhancer c.-3279 T > G, c.211G > A, and c.686C > A. Logistic regression was used to analyze the correlation of four locus alleles and genotypes with elevated total bilirubin in the early postoperative period. Results: Among the 104 cases, 47 patients were in the bilirubin elevated group, including 35 males (74.5%) and 12 females (25.5%), aged (50.72 ± 12.56) years. There were 57 cases in the normal bilirubin group, including 42 males (73.7%) and 15 females (26.3%), aged (51.63 ± 11.10) years. There was no statistically significant difference in age (t = -0.391, P = 0.697) and gender (χ(2) = 0.008, P = 0.928) between the two groups of patients. Univariate analysis revealed that preoperative alanine transaminase (ALT) level (χ(2) = 5.954, P = 0.015), total bilirubin level (χ(2) = 16.638, P < 0.001), MELD score (χ(2) = 10.054, P = 0.018), Child-Pugh score (χ(2) = 6.844, P = 0.022), and postoperative portal vein branch development (χ(2) = 6.738, P = 0.034) were statistically significantly different between the two groups. Logistic regression analysis showed that preoperative ALT level, total bilirubin level, and portal vein branch development after TIPS were correlated with the elevated total bilirubin in the early postoperative period. The polymorphism of the c.211G > A locus of the UGT1A1 gene correlation had elevated total bilirubin in the early postoperative period of TIPS. The risk of elevated total bilirubin was increased in the population carrying allele A (P = 0.001, OR = 4.049) in the early postoperative period. Allelic polymorphisms in the TATA box promoter region and enhancer c.-3279 T > G and c.686C > A had no statistically significant difference between the bilirubin-elevated group and the normal bilirubin group. Conclusion: The preoperative ALT level, total bilirubin level, and portal vein branch development are correlated with the elevated total bilirubin in early postoperative patients. The polymorphisms of the UGT1A1 gene and enhancer c.211G > A are correlated with the occurrence of elevated total bilirubin in the early postoperative period of TIPS. Allele A carrier may have a higher risk of elevated total bilirubin in the early postoperative period.

Asociación entre el síndrome metabólico y los niveles de transaminasas / Association between metabolic syndrome and transaminase levels

RESUMEN Introducción: En la patología del síndrome metabólico, de acuerdo con distintas investigaciones y la práctica clínica se han visto manifestaciones de daño hepático. Objetivo: Estimar la prevalencia de transaminasas elevadas (alanina aminotransaminasa y aspartato aminotransaminasa) y determinar su asociación con síndrome metabólico. Métodos: Estudio transversal con procedimientos analíticos. Análisis secundario de los datos generados por el registro electrónico en salud de un policlínico ocupacional. La variable principal fue el diagnóstico del síndrome metabólico. Para definir aspartato aminotransaminasa elevada se consideraron valores > 30 U/L en mujeres y valores > 36 U/L en hombres. Para alanina aminotransaminasa, se consideraron valores > 30 U/L en mujeres y valores > 40 U/L en hombres. Resultados: La prevalencia de síndrome metabólico fue de 21,82 %, de aspartato aminotransaminasa elevada fue del 10,30 % y alanina aminotransaminasa elevada del 16,67 %. En la regresión múltiple, se ajustó por las covariables confusoras sexo, edad, ocupación, índice de masa corporal, fumar, alcohol y actividad física. Se observó que los pacientes con aspartato aminotransaminasa elevada tenían 128 % mayor frecuencia de síndrome metabólico, respecto a quienes no presentaban valores elevados (razón prevalencia= 2,28; IC95 %: 1,64 - 3,17; p< 0,001). Se encontró que los pacientes con alanina aminotransaminasa elevada tenían 148 % mayor frecuencia de presentar síndrome metabólico respecto a quienes no presentaban valores elevados (razón prevalencia= 2,48; IC95 %: 1,77 - 3,47; p< 0,001). Conclusiones: Existe asociación entre las transaminasas hepáticas elevadas y la presencia de síndrome metabólico.

ABSTRACT Introduction: In the pathology of metabolic syndrome, manifestations of liver damage have been seen in different investigations and in clinical practice. Objective: To estimate the prevalence of elevated transaminases (alanine aminotransaminase and aspartate aminotransaminase), and to determine their association with metabolic syndrome. Methods: Cross-sectional with analytical procedure study. Secondary analysis of data generated by the electronic health record of an occupational polyclinic. The main variable was the diagnosis of metabolic syndrome. To define elevated aspartate aminotransaminase, values > 30 U/L in women and values > 36 U/L in men were considered. For alanine aminotransaminase, values > 30 U/L in women and values > 40 U/L in men were considered. Results: The prevalence of metabolic syndrome was 21.82%, elevated aspartate aminotransaminase was 10.30% and elevated alanine aminotransaminase was 16.67%. In multiple regression, we adjusted for the confounding covariates of sex, age, occupation, body mass index, smoking, alcohol and physical activity. It was observed that patients with elevated aspartate aminotransaminase had a 128% higher frequency of presenting metabolic syndrome, compared to those without elevated values (reason prevalence= 2.28; 95% CI: 1.64-3.17; p< 0.001). On the other hand, it was found that patients with elevated alanine aminotransaminase had a 148% higher frequency of presenting metabolic syndrome compared to those without elevated values (reason prevalence= 2.48; 95% CI: 1.77 - 3.47; p< 0.001). Conclusions: There is an association between elevated hepatic transaminases and the presence of metabolic syndrome.

Influência de polimorfismos nos genes antioxidantes GSTM1, GSTT1 e GSTP1 no desenvolvimento de complicações oftalmológicas em diabéticos tipo 2 / Influence of polymorphisms in the GSTM1, GSTT1, and GSTP1 antioxidant genes on the development of ophthalmic complications in persons with type 2 diabetes

Introdução: A diabetes tipo 2 (DM2) é uma desordem metabólica ocasionada pela disfunção das células beta pancreáticas que interferem na produção de insulina e/ou pela resistência dos órgãos alvos a esse hormônio. Níveis elevados de radicais livres em conjunto com o declínio das defesas antioxidantes presente na DM2 podem ocasionar danos a organelas celulares, promovendo complicações da doença. As glutationas S- transferases (GST) são as principais enzimas antioxidantes que participam da defesa celular contra o estresse oxidativo. Os polimorfismos nos genes que codificam essas enzimas podem acarretar o surgimento de complicações oftalmológicas em diabéticos. Este trabalho avaliou a influência dos polimorfismos nos genes GST no desenvolvimento de doenças como a catarata e o glaucoma em pacientes com DM2 na Grande Vitória (ES). Metodologia: Os polimorfismos dos genes GSTM1 e GSTT1 foram investigados através da técnica de PCR multiplex. Para o gene GSTP1 utilizou-se a técnica PCR- RFLP. A análise estatística foi realizada através do teste exato de Fisher ou do teste do qui-quadrado com P-valor < 0.05. Resultados: Não foi encontrada relação entre os polimorfismos nos genes GSTM1, GSTT1 e GSTP1 e o surgimento de doenças como glaucoma e catarata em pacientes com DM2. Conclusão: Nossos dados sugerem que os polimorfismos nulos nos genes GSTM1 e GSTT1 e o polimorfismo Ile105Val no gene GSTP1 não estão associados com a suscetibilidade individual para o desenvolvimento de complicações oftalmológicas em pacientes com DM2. (AU)

Introduction: Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused by beta cell dysfunction that interferes with insulin production and/or by the resistance of target organs to this hormone. An increase in free radicals together with a decline in antioxidant defenses, present in T2DM, can damage cellular organelles and promote the occurrence of disease complications. Glutathione S-transferases (GSTs) are the main antioxidant enzymes involved in cellular defense against oxidative stress, and polymorphisms in genes encoding GSTs can lead to ophthalmic complications in persons with diabetes. In this study, we evaluated the influence of GST polymorphisms on the development of diseases such as cataract and glaucoma in patients with T2DM in Grande Vitória, Espírito Santo, Brazil. Methods: GSTM1 and GSTT1 polymorphisms were investigated using a multiplex PCR technique. PCR-RFLP was used for the GSTP1 gene. Statistical analysis was performed with Fisher's exact test or the chi-square test, with P-value <0.05. Results: There was no relationship between GSTM1, GSTT1, or GSTP1 polymorphisms and the occurrence of diseases such as glaucoma and cataract in patients with T2DM. Conclusion: Our data suggest that the GSTM1 and GSTT1 null polymorphisms and the ile105Val polymorphism in the GSTP1 gene are not associated with individual susceptibility to the development of ophthalmic complications in persons with T2DM. (AU)

Expressions of glutathione S-transferases M1 and glutathione S-transferases M2 in follicular thyroid carcinoma and their significances / 肿瘤研究与临床

Objective:To investigate the expressions of glutathione S-transferases M1 (GSTM1) and glutathione S-transferases M2 (GSTM2) in follicular thyroid carcinoma (FTC) and their clinical significances.Methods:Gene expression profile of GSE82208 generated from 52 human thyroid samples, including 27 cases of FTC and 25 cases of follicular adenoma (FA) were collected from Gene Expression Omnibus (GEO) database. The gene matrix data were extracted and analyzed, and then differentially expressed genes (DEG) between FTC and FA were identified by using Limma package. Immunohistochemical SABC method was used to detect the expression levels of GSTM1 and GSTM2 proteins in FTC tissues and FA tissues collected from 56 FTC samples and 56 FA samples in Dandong First Hospital of Liaoning Province from January 2000 to December 2020. The relationship between GSTM1 and GSTM2 was analyzed; the association of expression levels of GSTM1 and GSTM2 with the clinicopathological factors of FTC patients was also analyzed.Results:Based on the GEO database, a total of 40 DEG were identified, including 9 up-regulated DEG (GSTM1, GSTM2, COL6A2, CUX2, CLUH, TSC2, OGDHL, ACADVL, SDHA) and 31 down-regulated DEG in FTC. The immunohistochemistry results of samples resected showed that the positive rates of GSTM1 and GSTM2 proteins in FTC tissues were higher than those in FA tissues [71.4% (40/56) vs. 23.2% (13/56), 80.4% (45/56) vs. 14.3% (8/56)], and differences were statistically significant ( χ2 values were 26.11 and 49.03, both P < 0.01). The expressions of GSTM1 and GSTM2 in FTC tissues were correlated with clinical staging, invasion degree and distant metastasis (all P < 0.05), but not with gender, age and tumor diameter (all P>0.05). There was a positive correlation between GSTM1 and GSTM2 proteins expressions in FTC ( r = 0.384, P = 0.004). Conclusions:The expression levels of GSTM1 and GSTM2 in FTC are increased. The interaction between GSTM1 and GSTM2 proteins can be involved in the development and progression of FTC.

Effect of molecular weight of polyethylene glycol on pharmacokinetics of baicalin / 药学学报

The aim of this study was to investigate the effects of polyethylene glycol (PEGs) with different molecular weights (MW: 400, 1 000, 4 000) on the pharmacokinetics of baicalin, and preliminarily analyze its mechanism. Rats were gavaged with baicalin (168 mg·kg-1) + aqueous solution or baicalin + PEGs solution and plasma samples were collected from 0 to 24 h after administration. The concentration of baicalin and its main metabolite baicalein 6-O-β-D-glucuronide (B6G) were determined at different time points by UPLC-MS/MS, and the pharmacokinetic parameters were calculated with DAS 3.0 software. The results showed that PEGs with different molecular weights could effectively increase the AUC0-t of baicalin and B6G, increase the Cmax, and prolong the t1/2, effectively increasing the concentration of baicalin and B6G in vivo. The mechanism may be by promoting the activity of uridine diphosphate glucuronosyl-transferases 1A8 (UGT1A8) and 1A9 (UGT1A9), thereby increasing the transformation rate of baicalin and B6G. The rate of metabolism of B6G was faster than that of baicalin, suggesting that PEGs had a higher affinity for UGT1A8, and PEG400 had the most significant effect. The purpose of this study was to provide a basis for the clinical safe use of baicalin and other flavonoids and the design of new dosage forms with the participation of PEGs. The animal experiment protocol in this study was approved by the Experimental Animal Ethics Committee of Guizhou Medical University.

Combined GSTM1 and GSTT1 null genotypes are strong risk factors for atherogenesis in a Serbian population

Abstract Oxidative stress (OS) plays an important role in atherogenesis and since glutathione S-transferases (GSTs) provide protection against OS, we have tested the hypothesis that deletion polymorphisms in two GSTs (GSTM1 and GSTT1) may affect the risk of developing atherosclerosis. A total of 382 individuals (200 patients with atherosclerosis and 182 healthy controls) were included in this association study. Genomic DNA was isolated from peripheral blood cells or from buccal epithelial cells and genotyping was performed using multiplex-PCR or real-time PCR methods. GSTM1 null genotype was significantly more frequent in atherosclerotic patients than in controls (52.0% vs 34.1%) and individuals with the GSTM1 null genotype had an approximately 2-fold increase in atherosclerosis risk (OR: 2.1, 95%CI=1.39-3.17, P=0.0004). GSTT1 null genotype alone did not show a statistically significant effect on atherosclerosis risk modulation, but the association approached significance (OR: 1.57, 95%CI=0.94-2.64, P=0.08). The combined analysis showed that the presence of both genes had a protective effect against atherosclerosis (OR=0.55, 95%CI=0.37-0.83, P=0.005) while double null genotypes led to a robust atherosclerosis risk increase (OR: 8.14, 95%CI= 2.41-27.51, P < 0.0001). This study demonstrated that the GSTM1 null and combined GSTM1/GSTT1 null genotypes are susceptibility factors for development of atherosclerosis in a Serbian population.

Polymorphism of glutathione S-transferase M1 and T1 genes and susceptibility to psoriasis disease: A study from North India

Background: Increased oxidative stress and resulting inflammation has been emphasized as a factor in the pathogenesis of many diseases including psoriasis. Glutathione S-transferases (GSTs) protect against oxidative stress, inflammation, and genotoxicity. Polymorphisms in the GST genes may lead to an imbalance in pro- and antioxidant systems resulting in the increased production of reactive oxygen species that could influence the pathogenesis of psoriasis. Aim: The aim of this study was to investigate the association between GSTs (GSTM1 and GSTT1) gene polymorphism in patients with chronic plaque psoriasis as a factor in the susceptibility and development of psoriasis. Materials and Methods: We assessed 128 patients with psoriasis and 250 age- and sex-matched healthy controls. Genomic DNA was extracted from peripheral blood by the phenol chloroform method. The null GSTT1 and GSTM1 genotypes were identified by multiplex polymerase chain reaction (PCR) method. Results: The null genotype of GSTM1 and GSTT1 was seen in 45.3% and 40.6% in psoriasis patients whereas in the controls it was 34.4% and 20.0%, respectively. A significant association was seen between the null alleles of the GSTT1 (OR = 2.74) and GSTM1 (OR = 1.58) alone or in combination with tobacco use (P < 0.001) and psoriasis risk. The presence of both null genotypes of GSTM1 and GSTT1 further increased the risk of psoriasis (OR = 3.52) when compared with the positive genotypes of GSTM1 and GSTT1. Limitations: A major limitation of this study was the small sample size. A large epidemiological study is necessary to confirm these findings. Conclusions: The null genotype of GSTT1 is a strong predisposing factor for psoriasis in North India.

Asociación entre polimorfismos de Glutation s-transferasa y cáncer cérvico uterino / Association between polymorphisms of Glutathione s-transferase and cervical cancer

Introducción: entre los factores de riesgo que favorecen la aparición de las lesiones cérvico uterinas, se encuentran la infección por virus de papiloma humano, la promiscuidad, el uso de anticonceptivos orales y el hábito de fumar. No obstante, varias investigaciones refieren que los polimorfismos genéticos podrían contribuir al desarrollo y progresión del cáncer cérvico uterino. Objetivo: identificar en la bibliografía revisada, la frecuencia de asociación de los polimorfismos de Glutation s - transferasa con el cáncer cérvico uterino y con factores de riesgo que inciden en la patología. Métodos: se realizó una extensa revisión de la literatura especializada a través de los buscadores en base de datos de PubMed, EBSCO, NCBI y BVS. Resultados: se constató la variabilidad en los reportes de las frecuencias alélicas de los genotipos GSTM1 y T1 en distintas poblaciones. Se corroboró en varios estudios revisados el hallazgo de asociación entre los genotipos GSTM1 y T1 nulos y cáncer cérvico uterino y, de igual forma con el consumo de tabaco y anticonceptivos orales por tiempo prolongado. Conclusiones: la bibliografía sobre el tema pone en evidencia que los genes que codifican la enzima Glutation s - transferasa intervienen en la protección celular contra los efectos citotóxicos, de manera que cuando éstos presentan alteración se afecta la actividad enzimática, lo que predispone a una mayor susceptibilidad al cáncer(AU)

Introduction: Among risk factors that lead to uterine cervix lesions we can find the human papilloma virus infection, promiscuity, use of oral contraceptive and smoking habit. However, several researches refer that genetic polymorphism could be related to the development and progression of the uterine cervix cancer. Objective: Identify the association of glutathione S- transferases polymorphism with uterine cervix cancer and risk factors relate with this disease, in the revise bibliography. Method: An extensive review was made of the specialized literature using web search in database PubMed, EBSCO, NCBI and BVS. Result: The variability of the allelic frequency of the GSTM1 and T1 genotypes in different populations was confirmed. Besides the association between null GSTM1 and T1 with uterine cervix cancer was corroborated. In addition, this association with smoking habit and the use of oral contraceptive for long time was corroborated. Conclusions: Consulted bibliography shows that genes encoding glutahione S- transferases enzyme contribute to the cellular protection against cytotoxic effects, therefore, alterations in these genes affect the enzymatic activity lead to a major susceptibility to suffer cancer(AU)

The Role of N-Acetyl Transferases on Isoniazid Resistance from Mycobacterium tuberculosis and Human: An In Silico Approach / 결핵및호흡기질환

BACKGROUND: N-acetyl transferase (NAT) inactivates the pro-drug isoniazid (INH) to N-acetyl INH through a process of acetylation, and confers low-level resistance to INH in Mycobacterium tuberculosis (MTB). Similar to NAT of MTB, NAT2 in humans performs the same function of acetylation. Rapid acetylators, may not respond to INH treatment efficiently, and could be a potential risk factor, for the development of INH resistance in humans. METHODS: To understand the contribution of NAT of MTB and NAT2 of humans in developing INH resistance using in silico approaches, in this study, the wild type (WT) and mutant (MT)-NATs of MTB, and humans, were modeled and docked, with substrates and product (acetyl CoA, INH, and acetyl INH). The MT models were built, using templates 4BGF of MTB, and 2PFR of humans. RESULTS: On the basis of docking results of MTB-NAT, it can be suggested that in comparison to the WT, binding affinity of MT-G207R, was found to be lower with acetyl CoA, and higher with acetyl-INH and INH. In case of MT-NAT2 from humans, the pattern of score with respect to acetyl CoA and acetyl-INH, was similar to MT-NAT of MTB, but revealed a decrease in INH score. CONCLUSION: In MTB, MT-NAT revealed high affinity towards acetyl-INH, which can be interpreted as increased formation of acetyl-INH, and therefore, may lead to INH resistance through inactivation of INH. Similarly, in MT-NAT2 (rapid acetylators), acetylation occurs rapidly, serving as a possible risk factor for developing INH resistance in humans.

The effects of HtrA on the expression and biological activity of GTFs of Streptococcus mutans isolated from children with high cario-susceptibility / 实用口腔医学杂志

Objective:To compare the expression and biological activity of glucosyl transferases (GTFs)of Streptococcus mutans (S.mutans)under normal outside environment between high temperature requirment serine proteinase A(HtrA)-deficient strains and high virulent strains isolated from children with high cario-susceptibility.Methods:The HtrA-deficient strains and high virulent strains of S.mutans were obtained by preliminary study.The strains were reanimated and incubated in BHI medium to exponential phase at tenth hour.The expression of gtfB,gtfC and gtfD were detected by real-time RT-PCR.The biological activity of the GTFs were detected by entong sulfuric acid method and Western Blot.Results:The expression of gtfs and GTFs in the HtrA-deficient strains was higher than those of high virulent strains,but the biological activity of the GTFs was lower.Conclusion:The HtrA gene plays an important regulatory role in the process of the GTFs expression of S.mutans isolated from children with high cario-susceptibility.

Glutathione S transferase (GSTP 1, GSTM 1, and GSTT 1) gene polymorphisms in Egyptian patients with acute myeloid leukemia.

BACKGROUND: The super family of glutathione S‑transferases (GSTs) is composed of multiple isoenzymes with significant evidence of functional polymorphic variation. GSTs detoxify potentially mutagenic and toxic DNA‑reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Polymorphisms within the phase II metabolizer enzymes GST T1, GST M1, and GST P1 affect the body’s ability to detoxify a range of potential leukemogens encountered in the environment. AIM OF WORK: To address how differences in the human GST isoenzyme expression patterns influence cancer susceptibility, prognosis, and treatment. PATIENTS AND METHODS: A total of 50 patients with acute myeloid leukemia (AML), as well as 50 age and sex matched apparently healthy volunteers were genotyped for GSTP 1, GSTM 1, and GSTT 1 gene polymorphisms using polymerase chain reaction‑restriction fragment length polymorphism (PCR‑RFLP) and conventional polymerase chain reaction (PCR), respectively. RESULTS: For GSTP1 313 A → G (GSTP1 Ile105Val) polymorphism, It was found that the wild genotype (AA) was significantly higher among control subjects (P value = 0.0277), while the frequency of heteromutant genotype (AG) and mutant G allele (AG + GG) was significantly higher among patients (P value = 0.0402, P value = 0.0277, respectively). For GSTM1 and GSTT1gene, we found statistically significantly higher frequency among patients regarding homozygous gene deletion (P value = 0.0005). CONCLUSION: We demonstrated that GSTM1 null or GSTT1 null genotypes may be considered independent risk factors for AML with no impact on prognosis and GSTP1 * 105 genotype is a prognostic factor, adding independent information to the routine laboratory parameters and cytogenetic and molecular alterations of the tumor cells.

Aβ25-35 induce endoplasmic reticulum stress and apoptosis of rat cardiomyocytes / 中国医师杂志

Objective To investigate the effects of amyloid-β (Aβ)25-35 on endoplasmic reticulum (ER) stress and apoptosis in cultured rat cardiomocytes,and to elucidate the role of ER stress in the injury of cardiomocytes induced by Aβ25-35.Methods The isolated rat myocardial cells were cultured in vitro.Following stimulation of Aβ25-35 with different dose,the survival ratio was observed with methyl thiazolyl tetrazolium (MTT) method.Hoechst33258 staining was used to observe the morphology of apoptotic changes.The percentage of apoptotic cardiomyocytes was quantified with flow cytometry.The expressions of ER stree proteins,including X box-binding protein-1 (XBP-1),glucose-regulated protein 78 (GRP78),and CCAAT/enhancer-binding protein homologous protein (CHOP) were measured with Western blot.The cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) were measured with Western blot.Results Aβ25-35 decreased the survival ratio and induced the apoptosis of cultured rat cardiomocytes in dose-dependent mode.Meanwhile,Aβ25-35 increased the expressions of ER stree proteins,including XBP-1,GRP78,and CHOP.Aβ25-35 increased the expressions of cleaved caspase-3 and cleaved PARP.Conclusions Aβ25-35 could induce the apoptosis of rat cardiomyocytes,which were involved in ER stress possibly.This study might provide a new strategy for clinical treatment of Alzheimer's disease (AD)-associated myocardial injury.

Meta-analysis of the association between GSTT1 and the susceptibility to colorectal cancer among ;Chinese population / 国际肿瘤学杂志

Objective To assess the association between glutathione S-transferase T1 (GSTT1 )gene and the susceptibility of colorectal cancer among Chinese population.Methods Clinical controlled trials of the association between GSTT1 and the susceptibility of colorectal cancer among Chinese population were searched in PubMed,EMBase,Cochrane Library,China Biology Medicine disc,VIP database,China National Knowledge Infrastructure and Wanfang database.According to the inclusion and exclusion criteria,data extraction and quali-ty assessment were done by two researchers independently.Outcomes were pooled with RevMan 5.1 .Results 326 studies were found and 10 clinical controlled trails including 2 983 cases of colorectal cancer and 4 386 cases of healthy objects were included in this analysis.The results of Meta-analysis showed that the lack of GSTT1 gene is associated with colorectal cancer susceptibility (RR =1 .11 ,95%CI:1 .06-1 .17,Z =4.26,P <0.000 1 ). Conclusion The loss of GSTT1 increase the risk of colorectal cancer among Chinese population.

Impact of GSTM1 and GSTP1 polymorphism on lung cancer patients treated with platinum-based chemotherapy / 重庆医学

Objective To investigate the relationship between glutathione S-transferases P1(GSTP1)Ile105Val and glutathione S-transferases M1(GSTM1)single nucleotide polymorphisms(SNP) and the sensitivity to chemotherapy among patients with ad-vanced non-small cell lung cancer(NSCLC) .Methods We used gene sequencing analysis to determine the SNP of GSTP1 Ile105Val and PCR analysis to GSTM1 in DNA from peripheral lymphocytes of NSCLC patients .Totally 89 patients with NSCLC were trea-ted with platinum-based chemotherapy ,and clinical response was evaluated after 2 cycles .The association between GSTP1 Ile105Val and GSTM1 SNP and chemosensitivity were analyzed .Results The overall response rate was 29 .2% .Chemotherapy re-sponse did not show statistically significant differences between the wild genotypes and the variant genotypes for the GSTP1 Ile105Val and GSTM1 gene(P>0 .05) .Conclusion The polymorphisms of GSTP1 Ile105Val and GSTM1 may be not associated with sensitivity to chemotherapy in NSCLC patients .

Genetic Polymorphisms of Glutathione S-transferase M1 and T1 and Evaluation of Oxidative Stress in Patients with Non-small Cell Lung Cancer / 中国医科大学学报

Objective To investigate the genetic polymorphisms of the glutathione S-transferase M1 and T1 genes(GSTM1 and GSTT1),and eval-uate the oxidative damage in patients with non-small lung cancer(N-SCLC). Methods A total of 110 patients with N-SCLC and 100 healthy indi-viduals were recruited in this case-control study. Multiplex polymerase chain reaction(PCR)analysis was used to identify the genotypes. The activi-ty of malondialdehyde(MDA),nitric oxide(NO),and the total antioxidant capacity(T-AOC)were detected by spectroscopic analysis using assay kits. Results The frequencies of the GSTM1,T1,and GSTM1/T1 null genotypes in the patient group were significantly higher than those in control group(OR1=2.071,P1=0.009;OR2=1.900,P2=0.024;OR3=3.258,P3=0.003). The activity of MDA and NO were obviously higher in the pa-tient group compared with the control group(P<0.001),and T-AOC was obviously lower in patient group than those in control group(P<0.001). The activity of MDA,and NO were higher but the T-AOC were lower in patients with GSTM1,T1 and GSTM1/T1 null genotypes than those in pa-tients with GSTM1,T1 and GSTM1/T1 present genotypes(P<0.001). Conclusion Our results suggest that oxidative damage may play a impor-tant role in patients with N-SCLC,and the N-SCLC patients with GSTM1and GSTT1deletion genotypes are more susceptible to oxidative damage.

Toxicological and biochemical analysis of the susceptibility of sylvatic Triatoma infestans from the Andean Valley of Bolivia to organophosphate insecticide

To increase our knowledge of the natural susceptibility of Triatoma infestans to an organophosphate insecticide, we performed toxicological and biochemical studies on three sylvatic populations from Bolivia and two populations from domestic dwellings from Bolivia and Argentina. Fifty-per-cent lethal doses (LD50) were determined based on the topical application of fenitrothion on first instar nymphs and mortality was assessed at 24 h. Both type of populations exhibited LD50ratios significantly higher than 1 with a range of the values (1.42-2.47); the maximum value were found in a sylvatic (-S) population, Veinte de Octubre-S. Samples were biochemically analysed using a glutathione S-transferase activity assay. The highest significant activity was obtained for Veinte de Octubre-S and the lowest activity was obtained for the reference population (102.69 and 54.23 pmol per minute per mg of protein respectively). Two out of the three sylvatic populations (Veinte de Octubre-S and Kirus Mayu-S) exhibited significantly higher glutathione S-transferase activity than that of the reference population. Based on this analysis of the natural susceptibility of this organism to organophosphate insecticides, continental and focal surveys of organophosphate susceptibility should be conducted to evaluate the evolution and distribution of this phenomenon.

Relationship of DNA methylation, mRNA transcription and protein expression of glutathione-S-transferases-P1 gene and coal-pollution-borne endemic arsenism / 中国地方病学杂志

Objective To investigate DNA methylation in the promoter region,mRNA transcription and protein expression of glutathione-S-transferases-P1 (GSTP1) gene and their relation with arsenism.Methods In endemic coal-pollution-borne arsenism area,Jiaole village of Xinren county,Guizhou province,according to the diagnostic criteria of endemic arsenism(WS/T 211-2001),123 cases with endemic arsenism were selected and divided into three groups (mild arsenism group:42 cases,moderate arsenism group:41 cases and severe arsenism group:40 cases).Forty seven residents were selected as controls in a village about 12 km away from the endemic arsenism area.With the informed consent principle,peripheral blood of all respondents was collected in order to analyze DNA methylation and check mRNA.DNA methylation of GSTP1 gene promoter region in peripheral blood was assayed by PCR,and GSTP1 mRNA expression was assayed using real-time quantitative PCR.In addition,other cutaneous specimens originated from 53 cases with arsenism that accepted surgical treatment voluntarily were taken.Of these specimens,general pathological changes were 28 cases,precancerous 20 cases and cancerous 5 cases.Skin tissues of 15 cases of non-tumor surgery patients without abnormal pathological changes were as control group.GSTP1 protein expression in the skin tissue was detected using immunohistochemistry (IHC).Results Among different groups of arsenic poisoning,the positive rate of DNA methylation of GSTP1 gene was 28.57％(12/42) in the mild group,57.10％ (23/41) in the moderate group and 65.00％ (26/40) in the severe group.Compared with the control group (6.38％,3/47),the difference was statistically significant (x2 =7.792,26.000,33.412,all P ＜ 0.01).Among different groups of arsenic poisoning diagnosed by dermapathology,the positive rate of DNA methylation of GSTP1 gene was 21.43％(6/28) in the general pathological change group,50.00％(10/20) in the precancerous group and 80.00％(4/5) in the cancerous group.Compared with the control group(6.67％,1/15),the difference was statistically significant (x2 =3.562,7.468,10.756,all P ＜ 0.05).It showed that the positive rate of DNA methylation of GSTP1 gene increased with aggravation of the disease and dermatic lesion of arsenism (tendency x2 =38.239,x2 =13.659,all P ＜ 0.01).Compared with the control group(0.184 26),the expressions of GSTP1 mRNA in peripheral blood in moderate (0.087 77) and severe arsenic poisoning groups (0.056 93) were significantly reduced(all P ＜0.01),and that of severe group was significantly lower than that of the moderate group (P ＜ 0.01) ; compared with the control group(0.338 45) and the general lesion group(0.276 74),GSTP1 mRNA expression was significantly reduced in precancerous lesion group(0.104 81) and cancerous group(0.043 70),in which the cancerous group was significantly lower than that of the precancerous lesions.The difference of skin tissue GSTP1 protein expression rate between groups was statistically significant (x2 =20.948,P ＜ 0.05),in which the difference between the precancerous lesion group(65.00％,13/20),the cancer group (40.00％,2/5) and the control group(100.00％,15/15)was statistically significant (x2 =12.183,11.778,P ＜ 0.01).Spearman correlation analysis showed that the degree of skin lesion and the level of GSTP1 protein expression was negatively correlated (r =-0.520,P ＜ 0.05).Groups were divided according to DNA methylation of GSTP1 gene,and the mRNA and protein expression of GSTP1 in methylation group(0.038 40,57.14％) was significantly lower compared with that of unmethylated group(0.187 07,95.74％; Z =9.032,x2 =23.134,all P ＜ 0.01).Conclusions Arsenism may lead to DNA methylation of human GSTP1 gene promoter region,thereby inhibiting expression of mRNA and protein.GSTP1 gene plays an important role in arsenism or carcinogenic process.

Regulation of Acrylamide Induced µ-Class Glutathione-S-Transferases in Mice Testis by the Treatment of Hybanthus Enneaspermus Active Principles.

The present study was aimed to analyse the effect of acrylamide and Hybanthus enneaspermus leaf extract active principles on mice testis glutathione-s-transferases (GST; EC 2.5.1.18). These enzymes play a role in biotransformation of electrophilic compounds that cause damage to cells by conjugating with the substrate glutathione. Hybanthus enneaspermus, a spade flower, is an erect shrub of violaceae family, having free radical scavenging activity. Acrylamide is a known neurotoxicant that cause damage to almost all cells including liver, testis, brain and kidney. The GSTs purified from mice testis using glutathionyl linked agarose affinity chromatography were analyzed by using SDS-PAGE and were resolved into four sub units i.e. Yc, Yb, Yβ &Yδ. Also these subunits expression were confirmed by western blot analysis. During experimentation to analyze the effect of Hybanthus enneaspermus active principle (HE) mice were subjected to both acrylamide (AC) and also mixture of HE and AC. This exposure significantly altered the specific activity of mice GSTs in testis. Polyclonal antibodies produced against purified GSTs of mice testis on immunoblot analysis showed significant increase of μclass GSTs (Yb & Yβ) based on dose and time dependent manner. Therefore the present research of Hybanthus enneaspermus treatment on mice testis showed that, regulation of synthesis of μ-GSTs was depending on the dose of acrylamide concentration and also the active principles of HE. Hence it is proposed that μ-GSTs may be used as tumour markers for testis carcinoma, since their production is variable due to the increased dose concentration of synthetic chemical acrylamide and its regulation by plant product, HE.

Relationship between glutathione S-transferase GSTO 1 Glu155 △Glu genetic polymorphism and arsenic poisoning caused by coal-burning / 中国地方病学杂志

ObjectiveTo investigate glutathione S-transferase GSTO 1 Glu155△Glu genetic polymorphism and risks of arsenic poisoning caused by coal-burning in Guizhou.Methods GSTO1 Glu155 △Glu gene polymorphism was analyzed by polymerase chain reaction-with confronting two-pair primers among one hundred and thirty arsenic poisoning patients and one hundred and thirty healthy controls.The results were verified by DNA sequencing.The association between different genotypes and arsenic poisoning was analyzed by unconditional Logistic regression model.ResultsThe results of Glu/Glu and Glu/△Glu genotype detected by this method were consistent with those of DNA sequencing.The frequencies of GSTO1 Glu/Glu genotype and Glu/△Glu genotype were 94.85％(92/97) and 5.15％(5/97) in the patients,99.15％(117/118) and 0.85％(1/118) in the controls,respectively.The difference was statistically significant(x2 =3.896,P ＜ 0.05).△Glu/△Glu genotype was not found in both patients and controls.After age and sex adjusting,GSTO1 Glu155 △Glu polymorphism was found to be a risk factor of arsenic poisoning [odds ratio (OR) =1.85,95％ confidence interval (CI):1.39 - 17.48].ConclusionsThe study finds that GSTO1 Glu 155 △ Glu polymorphism is associated with risk of arsenic poisoning.The relationship between them should be further studied through increasing sample size.