Elevated Reactive Oxygen Species but not Glutathione Regulate Mercury Resistance to AML-2/DX100 Cells

The multidrug resistance-associated protein (MRP1) mediates cellular efflux of various xenobiotics and cellular resistance to heavy metals. Previously we reported that MRP1 mediates resistance to mercury exposure and possible mechanism mediating MRP1 expression after mercury exposure. This study was designed to investigate the role of reactive oxygen species (ROS) and glutathione on the resistance of AML-2/DX100 cells to mercuric chloride. The MRP1 overexpressing cells (AML-2/DX100) cells showed less scavenging activity to ROS induced by mercury while no difference in the basal glutathione levels between AML-2/WT and AML-2/DX100 cells. Mercury induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) but not c-jun-N-terminal kinase in AML-2/DX100 cells. The specific inhibitor for p38 MAPK and ERK, and antioxidant decreased the production of MRP1 and therefore resistance of AML-2/DX100 cells against mercury exposure. These results suggest that induction of ROS and downstream p38 MAPK and ERK were involved in the resistance of cells to mercury by expression MRP1 in AML-2/DX100 cells.     

Glutathione‐S‐transferase‐oxidative stress relationship in the internal spermatic vein blood of infertile men with varicocele

This study aimed to assess glutathione‐S–transferase (GST) enzyme‐ oxidative stress (OS) relationship in the internal spermatic vein (ISV) of infertile men associated with varicocele (Vx). Ninety five infertile oligoasthenoteratozoospemic (OAT) men associated with Vx were subjected to history taking, clinical examination and semen analysis. During inguinal varicocelectomy, GST, malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated in the blood samples drawn from ISV and median cubital veins. The mean levels of GST, GPx were significantly decreased and the mean level of GPx was significantly increased in the ISV compared with the peripheral blood. The mean level of GST and GPx in the ISV was significantly decreased, and the mean level of MDA was significantly increased in Vx grade III compared with Vx grade II cases. There was nonsignificant difference in the mean level of GST in the ISV in unilateral Vx cases compared with bilateral Vx cases. There was significant positive correlation of GST with sperm count, sperm motility, GPx and significant negative correlation with sperm abnormal forms, MDA. It is concluded that ISV of infertile men associated with Vx has decreased levels of GST compared with peripheral venous circulation that is correlated with both OS and Vx grade.     

GST－π在食管癌及癌前病变组织中的表达意义

用人体胎盘型谷胱甘肽－Ｓ转移酶（ＧＳＴ－π）抗体，按ＡＢＣ免疫组织化学技术，检测了５０例食管癌、６８例癌前病变组织和５１例正常对照组织。结果表明：正常食管组织ＧＳＴ－π阳性率为３．９％；不典型增生组织为７７．９％；食管癌组织为８６．０％。不典型增生组织中ＧＳＴ－π阳性率随不典型增生程度增著而增加。同此可见，ＧＳＴ－π在食管癌及癌前病变组织中的表达为研究其发病机理和早期诊断提供了新的酶学指标，可以作为食管癌早期诊断的标志酶之一。     

Effects of In Vitro Ethanol and Fetal Ethanol Exposure on Glutathione Stimulation of N-Methyl-D-Aspartate Receptor Function

The present studies investigated the effects of glutathione (GSH; γ-glutamylcysteinylglycine) and its oxidized form (GSSG) on neuronal N -methyl-D-aspartate (NMDA) receptor activation in both acute and chronic preparations of ethanol exposure. It was demonstrated using fura-2-loaded dissociated brain cells from newborn rat pups that both GSH and GSSG (0–4 mM) produced concentration-dependent increases in intracellular calcium similar to those produced by NMDA and other agonists of the NMDA receptor. GSH-stimulated calcium entry was not inhibited by low intoxicating concentrations of ethanol, which contrasts with ethanol's typical inhibitory effect on NMDA-stimulated receptor activation. Behavioral studies in adult rats demonstrated that ethanol-induced sleep times were significantly decreased when 10 μl of GSSG (20 mM) were administered intracere-broventricularly approximately 5 min before an intraperitoneal injection of 20% (w/v) ethanol (3 g/kg). These findings suggest that the less potent effect of ethanol on GSH-stimulated calcium entry as well as the reduction in ethanol-induced sleep times may be related to the presence of glycine in the peptide. The glycine found in GSH may activate the glycine site and block or reduce ethanol's action on this site. It appears that although GSH may play an important role in the activation of the NMDA receptor, this action does not involve a process that is sensitive to acute ethanol exposure. In contrast, when rat pups were chronically exposed to ethanol via prenatal exposure before the fura-2 preparation, increases in NMDA- and GSH-stimulated calcium entry were significantly decreased relative to those in pair-fed and ad libitum-fed controls. Thus, chronic in utero exposure to ethanol may alter the NMDA-receptor complex, such that calcium entry mediated by NMDA or GSH activation is significantly reduced.     

NADPH Oxidase Accounts for Changes in Cerebrovascular Redox Status in Hindlimb Unweighting Rats

ObjectiveThe roles of cerebrovascular oxidative stress in vascular functional remodeling have been described in hindlimb-unweighting (HU) rats. However, the underlying mechanism remains to be established.
MethodsWe investigated the generation of vascular reactive oxygen species (ROS),Nox2/Nox4 protein and mRNA levels, NADPH oxidase activity, and manganese superoxide dismutase (MnSOD) and glutathione peroxidase-1 (GPx-1) mRNA levels in cerebral and mesenteric smooth muscle cells (VSMCs) of HU rats.
ResultsROS production increased in cerebral but not in mesenteric VSMCs of HU rats compared with those in control rats.Nox2 and Nox4 protein and mRNA levels were increased significantly but MnSOD/GPx-1 mRNA levels decreased in HU rat cerebral arteries but not in mesenteric arteries. NADPH oxidases were activated significantly more in cerebral but not in mesenteric arteries of HU rats. NADPH oxidase inhibition with apocynin attenuated cerebrovascular ROS production and partially restored Nox2/Nox4 protein and mRNA levels, NADPH oxidase activity, and MnSOD/GPx-1 mRNA levels in cerebral VSMCs of HU rats.
ConclusionThese results suggest that vascular NADPH oxidases regulate cerebrovascular redox status and participate in vascular oxidative stress injury during simulated microgravity.     

Effect of DASH diet on oxidative stress parameters: A systematic review and meta-analysis of randomized clinical trials

Background and aimsOxidative stress (OS) is one of the main risk factors for several chronic diseases. The Dietary Approaches to Stop Hypertension (DASH) contain many antioxidants and may contribute to managing OS.ObjectiveTo perform a systematic review and meta-analysis to examine the impacts of the DASH diet on OS parameters.MethodsA comprehensive electronic search in MEDLINE, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials was performed through September 2020 to find related studies evaluating the impact of the DASH diet on OS parameters. Standardized mean differences were pooled using random-effects meta-analysis.ResultsEight studies with a total of 317 subjects met our inclusion criteria. Four studies included in meta-analysis model with 200 participants (100 in treatment and 100 in control group). The DASH diet was associated with a statistically significant decrease in malondialdehyde (MDA) (SMD: −0.53; 95% CI: −0.89, −0.16; I² = 42.1%), and a significant increase in glutathione (GSH) (SMD: 0.83; 95% CI: 0.36, 1.03; I² = 42.1%). Meta-analysis found no statistically significant effect of DASH diet on nitric oxide (NO) (SMD: −1.40; 95% CI: −0.12, 1.93; I² = 92.6%) or total antioxidant capacity (TAC) levels (SMD: 0.95; 95% CI: −0.10, 1.99; I² = 87.6%).ConclusionOur results demonstrated that a DASH diet could significantly increase GSH and decrease MDA levels. Furthermore, there is a trend to improve TAC, NO, and f2-isoprostanes by the adherence to the DASH diet. However, long-term, large sample size and well-designed randomized clinical trials are still needed to draw concrete conclusions about DASH diet’s effects on OS parameters.     

Association between Glutathione S-Transferase T1, M1, and P1 Genotypes and the Risk of Colorectal Cancer

Glutathione S-transferases (GSTs) are enzymes which play an important role in the neutralization of toxic compounds and eradication of electrophilic carcinogens. Genetic polymorphisms within the genes encoding for GSTs may therefore cause variations in their enzyme activity, which may in turn influence the interindividual susceptibility to cancers. In this study, we aimed to investigate the association between genetic polymorphisms of GSTT1, GSTM1, and GSTP1 and the risk of colorectal cancer (CRC) in 264 cases and 317 controls in a Chinese population. Genotyping was performed by using multiplex PCR (for GSTT1 and GSTM1) and PCR-RFLP (for GSTP1) methods. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Our results showed that individuals with GSTT1 and GSTM1 null genotypes exhibited a higher risk of CRC (GSTT1, OR,1.66; 95% CI, 1.20-2.31, P=0.003; GSTM1, OR,1.57; 95% CI,1.13-2.18, P=0.007), while no association was observed for GSTP1 (P_heterozygous=0.790 or P_variant=0.261). Furthermore, individuals who simultaneously carried the null genotypes for both GSTT1 and GSTM1 showed a stronger risk association (OR, 1.95; 95% CI, 1.33-2.85; P<0.001). In conclusion, the GSTT1 and GSTM1 polymorphisms, but not GSTP1, may modulate the CRC risk among Chinese.

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Chronic methylphenidate induces increased quinone production and subsequent depletion of the antioxidant glutathione in the striatum

BackgroundMethylphenidate (Ritalin®) is a psychostimulant used chronically to treat attention deficit hyperactivity disorder. Methylphenidate acts by preventing the reuptake of dopamine and norepinephrine, resulting in an increase in these neurotransmitters in the synaptic cleft. Excess dopamine can be autoxidized to a quinone that may lead to oxidative stress. The antioxidant, glutathione helps to protect the cell against quinones via conjugation reactions; however, depletion of glutathione may result from excess quinone formation. Chronic exposure to methylphenidate appears to sensitize dopaminergic neurons to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We hypothesized that oxidative stress caused by the autooxidation of the excess dopamine renders dopaminergic neurons within the nigrostriatal pathway to be more sensitive to MPTP.MethodsTo test this hypothesis, male mice received chronic low or high doses of MPH and were exposed to saline or MPTP following a 1-week washout. Quinone formation in the striatum was examined via dot blot, and striatal GSH was quantified using a glutathione assay.ResultsIndeed, quinone formation increased with increasing doses of methylphenidate. Additionally, methylphenidate dose-dependently resulted in a depletion of glutathione, which was further depleted following MPTP treatment.ConclusionsThus, the increased sensitivity of dopamine neurons to MPTP toxicity following chronic methylphenidate exposure may be due to quinone production and subsequent depletion of glutathione.