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Objective: This study aimed to investigate the combined effects of caffeine and Alpha Lipoic Acid (ALA) on oxidative stress, due to chronic hyperglycemia, in a model of diabetic rats induced with streptozotocin (STZ) (in silico and in vivo approaches). Material and Methods: This In silico study investigated the interaction between caffeine and ALA against insulin receptors and enzymes of Glutathione Peroksidase-1 (GPx-1), with molecular docking. Male, Wistar rats were included using a quasi-experimental research design, with post-test only and a control group (in vivo). This study measured the end result of a 6-week-induction on body weight, fasting blood glucose, Malondialdehyde (MDA) and GPx-1 enzyme from 25 rats. Results: Molecular docking found the interactions of caffeine and GPx-1 consisting of an energy bond of -5,06 kcal/mol, hydrogen and hydrophobic bond. Additionally, it showed the interaction of ALA and GPx-1 containing an energy bond of -5.16 kcal/mol, hydrogen bonding and hydrophobicity. However, there were no significant difference in body weight, fasting blood glucose, MDA and GPx-1 levels of the ALA-caffeinated diabetic rats compared to diabetic rats. Conclusion: Caffeine and ALA have the potential to activate GPx-1 enzymes (in silico study). However, the use of a caffeine and ALA combination resulted in no significant difference in fasting blood glucose and oxidative stress conditions when compared to diabetic rats without additional induction (in vivo study).

Objectives: This study aimed to investigate the role of eldecalcitol in the progression of oral squamous cell carcinoma and to explore the related mechanism. Materials and Methods: The effects of eldecalcitol on the proliferation, cell cycle, apoptosis, and migration of oral cancer cells (SCC‐15 and CAL‐27) were evaluated with cell counting kit‐8, flow cytometry, quantitative real‐time polymerase chain reaction, western blotting, and scratch assay. Mouse xenograft tumor model was established to further confirm the role of eldecalcitol in the progression of oral cancer. Immunohistochemistry, quantitative real‐time polymerase chain reaction, and western blotting were used to detect glutathione peroxidase‐1 expression in oral cancer tissue and cells treated with eldecalcitol. Results: Eldecalcitol was found to inhibit the proliferation and migration of SCC‐15 and CAL‐27 cells significantly, block the cell cycle in the G0/G1 phase, and enhance the apoptosis. In addition, glutathione peroxidase‐1 was downregulated by eldecalcitol and acted as an important medium of eldecalcitol in inhibiting the proliferation and migration of SCC‐15 and CAL‐27 cells, as well as promoting their apoptosis. Conclusions: Eldecalcitol may inhibit the progression of oral cancer by suppressing the expression of glutathione peroxidase‐1, which may provide new insight into the application of eldecalcitol as a potential anti‐cancer drug. [ABSTRACT FROM AUTHOR]

Introduction:In this study, we investigated the etiopathogenesis of allergic rhinitis by analyzing the polymorphisms including GPx-1 Pro198Leu, CAT-262 C/T, and MnSOD Ala16Val.Methods:The diagnosis of allergic rhinitis was diagnosed by clinical history, examination, serum total immunoglobulin E levels and skin prick test. Five mL of peripheral blood from patients and individuals constituting the control group was taken into EDTA tubes. DNA isolation from whole blood samples was performed according to the Poncz method.Results:Because of this study; for the Pro198Leu polymorphism of the GPX1; was concluded with 95% confidence that the presence of the Leu allele increased the susceptibility to allergic rhinitis 1.092 times. However, this increase was not found to be statistically significant. For the -262 C/T polymorphism of the CAT gene; was concluded with 95% confidence that the presence of the T-allele increased the susceptibility to allergic rhinitis 27,064 times. This increase was found to be statistically significant. For Ala16Val polymorphism of the Mn-SOD gene; was concluded with 95% confidence that the presence of the Ala allele increased the susceptibility to allergic rhinitis 25,791 times. This increase was found to be statistically significant.Conclusion:A significant relationship was found between allergic rhinitis and the genotypes and the frequencies of alleles in the polymorphisms of the MnSOD and CAT genes. However, no significant relationship was found between allergic rhinitis and the polymorphisms of the GPx-1 gene.

Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus. [ABSTRACT FROM AUTHOR]

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Background: Incomplete combustion of wood releases toxic chemicals. Exposure to these chemicals during charcoal production can modulate redox status of cellular system which may further lead to genomic instability and of antioxidant enzymes. Genetic polymorphism may alter the functioning properties of these enzymes and modulate the response to oxidative stress. Methods: In this study, we analyzed the link between genetic polymorphism and enzyme activity for antioxidant enzymes: MnSOD and GPx-1 in charcoal workers and control population. This study included 77 charcoal workers and 79 demographically matched healthy control subjects. This association was studied using multiple linear regression, adjusted for confounding factors viz. age, consumption habits and exposure duration. Results: SOD activity was lower for TT genotype (3.47 ± 0.66; 5.92 ± 1.08) versus CC genotype (3.47 ± 0.66; 6.67 ± 1.60) in control and charcoal workers respectively. Significant lower GPx-1 activity was found in leu/leu genotype (7.25 ± 0.38; 3.59 ± 0.57) when compared to pro/pro genotype (7.78 ± 0.59; 4.28 ± 0.71) and pro/leu genotype (8.48 ± 0.34; 4.30 ± 0.76) in control population and charcoal workers respectively. A significant difference in the levels of 1-Hydroxypyrene (biomarker of exposure) and SOD and GPx-1 activity (biomarkers of oxidative stress) was evident in exposed group in comparison to the control one. Conclusion: Collectively, our findings suggested that PAH influenced the mode of action of SOD and GPx-1 which were impacted by polymorphism in SOD and GPx-1 gene. Hence, polymorphism of MnSOD and GPx-1 genes were found to play a modulatory role in human susceptibility to oxidative damage induced by wood smoke in charcoal workers. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we investigated the etiopathogenesis of allergic rhinitis by analyzing the polymorphisms including GPx-1 Pro198Leu, CAT-262 C/T, and MnSOD Ala16Val. Methods: The diagnosis of allergic rhinitis was diagnosed by clinical history, examination, serum total immunoglobulin E levels and skin prick test. Five mL of peripheral blood from patients and individuals constituting the control group was taken into EDTA tubes. DNA isolation from whole blood samples was performed according to the Poncz method. Results: Because of this study; for the Pro198Leu polymorphism of the GPX1; was concluded with 95% confidence that the presence of the Leu allele increased the susceptibility to allergic rhinitis 1.092 times. However, this increase was not found to be statistically significant. For the -262 C/T polymorphism of the CAT gene; was concluded with 95% confidence that the presence of the T-allele increased the susceptibility to allergic rhinitis 27,064 times. This increase was found to be statistically significant. For Ala16Val polymorphism of the Mn-SOD gene; was concluded with 95% confidence that the presence of the Ala allele increased the susceptibility to allergic rhinitis 25,791 times. This increase was found to be statistically significant. Conclusion: A significant relationship was found between allergic rhinitis and the genotypes and the frequencies of alleles in the polymorphisms of the MnSOD and CAT genes. However, no significant relationship was found between allergic rhinitis and the polymorphisms of the GPx-1 gene. [ABSTRACT FROM AUTHOR]

Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation forms of the FMR1 gene, resulting in a progressive development of tremor, ataxia and neuropsychological problems. The disease is caused by an expanded CGG repeat in the FMR1 gene, leading to an RNA gain-of-function toxicity mechanism. In order to study the pathogenesis of FXTAS, new inducible transgenic mouse models have been developed that expresses either 11CGGs or 90CGGs at the RNA level under control of a Tet-On promoter. When bred to an hnRNP-rtTA driver line, doxycycline (dox) induced expression of the transgene could be found in almost all tissues. Dox exposure resulted in loss of weight and death within 5 d for the 90CGG RNA expressing mice. Immunohistochemical examination of tissues of these mice revealed steatosis and apoptosis in the liver. Decreased expression of GPX1 and increased expression of cytochrome C is found. These effects were not seen in mice expressing a normal sized 11CGG repeat. In conclusion, we were able to show in vivo that expression of an expanded CGG-repeat rather than overexpression of a normal CGG-repeat causes pathology. In addition, we have shown that expanded CGG RNA expression can cause mitochondrial dysfunction by regulating expression levels of several markers. Although FTXAS patients do not display liver abnormalities, our findings contribute to understanding of the molecular mechanisms underlying toxicity of CGG repeat RNA expression in an animal model. In addition, the dox inducible mouse lines offer new opportunities to study therapeutic interventions for FXTAS.

Stroke is a medical condition characterized by a sudden, localized neurological impairment caused by damage to the central nervous system due to either a blockage or bleeding in the blood vessels. This process leads to increased oxidation, which can exacerbate brain damage. Flavonoids are compounds that are widely found in nature and are considered to have numerous health benefits. 7,8-dihydroxyflavone (7,8-DHF) is a flavonoid that has tropomyosin receptor kinase B agonist activity. However, the other beneficial activities of 7,8-DHF remain to be explored, particularly in neuron-related diseases. The present study aimed to explore 7,8-DHF as an antioxidant agent using in vivo and in silico analyses. An in vivo experiment was conducted using Rattus novergicus, in which ischemia-reperfusion brain injury was induced. A total of 30 rats were divided into the sham-operated, control and treatment groups. The treatment groups were administered doses of 10, 20 and 50 mg/kg body weight of 7,8-DHF orally, once daily for a duration of 14 days following the induction of ischemia-reperfusion brain injury. Subsequently, blood and brain tissues were collected for the examination of nuclear factor E2-related factor 2 (Nrf2) expression, glutathione peroxidase-1 (GPX-1) expression and the malondialdehyde (MDA) level. Molecular docking analysis and dynamic simulations of 7,8-DHF and Kelch like ECH-associated protein 1 (Keap1) protein interactions were performed using AutoDock Vina and AMBER. The visualization of the interaction was performed using ChimeraX and Discovery Studio. The drug-like properties of 7,8-DHF were predicted using the SwissADME web server, and the bioactivity of the compounds was evaluated using the PASS online server. The results revealed that 7,8-DHF exhibits antioxidant activity through the inhibition of Keap1, thereby increasing Nrf2 and GPX-1 expression and decreasing the levels of MDA. In silico analysis revealed that 7,8-DHF can bind Keap1 protein, thereby disrupting the interaction between Nrf2 and Keap1. Molecular dynamics also demonstrated that 7,8-DHF has good stability compared to the control. On the whole, as demonstrated in the present study 7,8-DHF has promising biological activity as an antioxidant agent in the rat model of ischemia-reperfusion brain injury. Further studies on the effects of 7,8-DHF are required to clarify its potential as a novel therapeutic agent for cerebral infarction. [ABSTRACT FROM AUTHOR]

Introduction: Kanamycin therapy in Multi-Drug Resistance Tuberculosis (MDR-TB) patients increases the possibility of sensorineural hearing loss through increasing the level of Reactive Oxygen Species (ROS) production in cochlea, particularly in hair cells. In normal state, ROS is detoxicated by numerous antioxidant enzymes, including glutathione peroksidase-1 (GPx-1). Imbalance of antioxidant enzymes and ROS production leads to death of hair cells and eventually sensorineural hearing loss. Objective: This study aimed to observe the association of GPx-1 level and sensorineural hearing loss in MDR-TB patients with Kanamycin therapy. Method: This study was a prospective observational study conducted at Dr. Hasan Sadikin General Hospital, Bandung, Indonesia, between February to April 2017. 17 patients were included into the study with pre- and post-kanamycin therapy examination within 3 weeks duration using pure tone audiometry and serum level of GPx-1. Statistic analysis was done using Mann Whitney test with significant level of p < 0.05. Result: A significant reduction of GPx-1 level in 3 weeks period after the initial Kanamycin administration was found in the study; p <0.001. Furthermore, there was a significant alteration in the hearing threshold on frequency of 500-800 Hz after Kanamycin administration; p < 0.05. There was a significant association between GPx-1 level and sensorineural hearing loss in Kanamycin therapy; p < 0.05. Conclusion: Sensorineural hearing loss in patient with history of Kanamycin therapy was associated with level of GPx-1 degradation. [ABSTRACT FROM AUTHOR]

Introduction: Systemic Lupus Erythematous (SLE) is a disease characterized by the involvement of antibodies in the immune system-mediated inflammation, including the auditory system. One of the things that causes hearing loss in SLE is the occurrence of vasculitis and the process of oxidative stress which results in decreasing the activity of Glutathione Peroxidase (GPx) which is one of the important antioxidants in the human body against ROS. Provision of Prednisone therapy in SLE patients with hearing loss will improve hearing. It is expected that there will be an increase in GPx-1 levels along with hearing improvement in SLE patients with hearing loss after receiving prednisone. Objective: To determine the correlation of hearing threshold with changes of serum GPx-1 levels in systemic lupus erythematosus patients who receiving prednisone therapy. Method: A comparative analytic study conducted with pre-post design which analyzed the correlation between elevated serum GPx-1 levels and hearing threshold of SLE patients receiving prednisone therapy. Results: This study found significant changes in GPx-1 levels after SLE patients with hearing loss received prednisone therapy. Comparison of serum GPx-1 levels of SLE patients who experience sensorineural hearing loss before and after prednisone therapy. The statistical test used is the Wilcoxon test and significant if p value <0.05. Comparative test of GPx-1 levels showed a significant number (p <0.001) with increase difference about 3.69U/g Hb. There is significant correlation between the increased serum GPx-1 levels with a decreased hearing threshold shown at high-frequency frequencies at 10,000 Hz and 14,000 Hz (p <0.05). Conclusion: There is a correlation between improved hearing threshold in increased serum GPx-1 levels in patients receiving prednisone therapy. [ABSTRACT FROM AUTHOR]

Endothelial progenitor cells (EPCs) are a group of heterogeneous cells in bone marrow (BM) and blood. Ischaemia increases reactive oxygen species (ROS) production that regulates EPC number and function. The present study was conducted to determine if ischaemia‐induced ROS differentially regulated individual EPC subpopulations using a mouse model concomitantly overexpressing superoxide dismutase (SOD)1, SOD3 and glutathione peroxidase. Limb ischaemia was induced by femoral artery ligation in male transgenic mice with their wild‐type littermate as control. BM and blood cells were collected for EPCs analysis and mononuclear cell intracellular ROS production, apoptosis and proliferation at baseline, day 3 and day 21 after ischaemia. Cells positive for c‐Kit+/CD31+ or Sca‐1+/Flk‐1+ or CD34+/CD133+ or CD34+/Flk‐1+ were identified as EPCs. ischaemia significantly increased ROS production and cell apoptosis and decreased proliferation of circulating and BM mononuclear cells and increased BM and circulating EPCs levels. Overexpression of triple antioxidant enzymes effectively prevented ischaemia‐induced ROS production with significantly decreased cell apoptosis and preserved proliferation and significantly increased circulating EPCs level without significant changes in BM EPC populations, associated with enhanced recovery of blood flow and function of the ischemic limb. These data suggested that ischaemia‐induced ROS was differentially involved in the regulation of circulating EPC population. [ABSTRACT FROM AUTHOR]

Oxidative stress-induced apoptosis is an important pathological process in renal ischemia/reperfusion injury (RIRI). Theaflavin (TF) is the main active pigment and polyphenol in black tea. It has been widely reported because of its biological activity that can reduce oxidative stress and protect against many diseases. Here, we explored the role of theaflavin in the pathological process of RIRI. In the present study, the RIRI model of 45 min ischemia and 24 h reperfusion was established in C57BL/6 J male mice, and theaflavin was used as an intervention. Compared with the RIRI group, the renal filtration function, renal tissue damage and antioxidant capacity of the theaflavin intervention group were significantly improved, while the level of apoptosis was reduced. TCMK-1 cells were incubated under hypoxia for 48 h and then reoxygenated for 6 h to simulate RIRI in vitro. The application of theaflavin significantly promoted the translocation of p53 from cytoplasm to nucleus, upregulated the expression of glutathione peroxidase 1 (GPx-1) in cells, and inhibited oxidative stress damage and apoptosis. Transfection with p53 siRNA can partially inhibit the effect of theaflavin. Thus, theaflavin exerted a protective effect against RIRI by inhibiting apoptosis and oxidative stress via regulating the p53/GPx-1 pathway. We conclude that theaflavin has the potential to become a candidate drug for the prevention and treatment of RIRI. [Display omitted] • Theaflavin exerts beneficial effects in renal ischemia/reperfusion injury. • Theaflavin can inhibit the overproduction of reactive oxygen species in renal cells induced by hypoxia reperfusion. • Theaflavin can alleviate apoptosis induced by H/R or RIRI. • Theaflavin promote the translocation of p53 from cytoplasm to nucleus and activate the p53/GPx-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress is a condition in which the balance is disrupted between reactive oxygen species (ROS) and antioxidant. Glutathione peroxidase 1(GPX-1), as one of the antioxidant enzyme remove the ROS in a continuous process. One of the functional polymorphism of GPX1 gene is Pro198Leu polymorphism. The aim of this study was to study the association between GPX-1 Pro198Leu polymorphism with the risk of colorectal cancer. Materials & Methods: in this case-control study, 130 patients with colorectal cancer were compared with 170 healthy subjects. Genomic DNA was extracted from peripheral blood leukocytes. Determination of DNA genotyping in GPX-1 Pro198Leu polymorphism were performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The χ2-test was used for statistical analyses. Results: The GPX1 genotype frequencies were 64% for CC, 24% for CT and 12% for TT in control group, and 60% for CC, 30% for CT and 12% for TT among the patients. The C allele frequency in cases and controls including 0.75 and 0.76 and T allele frequency was including 0.25 and 0.24. Based on these data, there was no significant differences in the GPX1 Pro198Leu genotypes and allele frequencies between cases and controls (P=0.2). Conclusion: The result of this study suggested that GPX-1 Pro198Leu polymorphism could not be a risk factor for colorectal cancer. However, studies in larger populations are needed in order to confirm the results.

Background: Intracellular antioxidant response to high glucose is mediated by Cu/Mn-superoxide dismutases (SOD-1/SOD-2), catalase (CAT) and glutathione peroxidases (GPx), particularly glutathione peroxidase-1 (GPx-1). Although oscillating glucose can induce a more deleterious effect than high glucose on endothelial cells, the mechanism by which oscillating glucose exerts its dangerous effects is incompletely understood; however, the involvement of oxidative damage has been generally accepted. In this study we sought to determine whether oscillating glucose differentially modulates antioxidant response, and to elucidate the potential regulatory mechanisms exerted by the microRNA-185 (miR-185). Methods: Human endothelial cells were exposed for 1 week to constant and oscillating high glucose. SOD-1, SOD-2, CAT and GPx-1, as well as two markers of oxidative stress [8-hydroxy-2'-deoxyguanosine (8-OHdG) and the phosphorylated form of H2AX (?-H2AX)] were measured at the end of the experiment. Intracellular miR-185 was measured and loss-of function assays were performed in HUVEC. Bioinformatic tool was used to predict the link between miR-185 on 3'UTR of GPx-1 gene. Luciferase assay was performed to confirm the binding on HUVEC. Results: After exposure to constant high glucose SOD-1 and GPx-1 increased, while in oscillating glucose SOD-1 increased and GPx-1 did not. SOD-2 and CAT remained unchanged under both conditions. A critical involvement of oscillating glucose-induced miR-185 in the dysregulation of endogenous GPx-1 was found. Computational analyses predict GPx-1 as miR-185's target. HUVEC cultures were used to confirm glucose's causal role on the expression of miR-185, its target mRNA and protein and finally the activation of antioxidant response. In vitro luciferase assays confirmed computational predictions targeting of miR-185 on 3'-UTR of GPx-1 mRNA. Knockdown of miR-185, using anti-miR-185 inhibitor, was accompanied by a significant upregulation of GPx-1 in oscillating glucose. 8-OHdG and ?-H2AX increased more in oscillating glucose than in constant high glucose. Conclusions: Glucose oscillations may exert more deleterious effects on the endothelium than high glucose, likely due to an impaired response of GPx-1, coupled by the upregulation of miR-185. [ABSTRACT FROM AUTHOR]

Reactive oxygen species are involved in the pathogenesis of type 2 diabetes mellitus (T2DM). Catalase and Glutathione peroxidase-1 are antioxidant enzymes and the activity of them is essential for the protection against damage caused by reactive oxygen species. The aim of this study was to investigate the association between genetic polymorphisms of CAT gene (rs7943316) and GPx-1 gene (rs1050450) in patients with type 2 diabetes. In this case-control study, a total of 120 Iranian patients with T2DM and 120 healthy individuals as control were included. Genotypes were determined by PCR-RFLP. A significant difference was found between genotyping distribution of CAT (-21 A/T) polymorphism.The frequency of TT genotype was increased in patients compared to controls and we observed a statistically significant difference ( OR = 1.797, 95% CI = 0.975-3.318, P = 0.044). Distribution of genotypes did not differ for GPx-1 (198 C/T) polymorphism between the cases and controls subjects. This study indicated that CAT rs7943316 genotype (TT) was associated with an increased risk of T2DM. No evidence was found to support an association between GPx-1 (198 C/T) polymorphism and T2DM. [ABSTRACT FROM AUTHOR]

Both endogenous factors (genomic variations) and exogenous factors (environmental exposures, lifestyle) impact the balance of reactive oxygen species (ROS). Variants of the ND3 (rs2853826; G10398A) gene of the mitochondrial genome, manganese superoxide dismutase ( MnSOD; rs4880 Val16Ala) and glutathione peroxidase ( GPX-1; rs1050450 Pro198Leu), are purported to have functional effects on regulation of ROS balance. In this study, we examined associations of breast and prostate cancer risks and survival with these variants, and interactions between rs4880-rs1050450, and alcohol consumption-rs2853826. Nested case-control studies were conducted in the Breast and Prostate Cancer Cohort Consortium (BPC3), consisting of nine cohorts. The analyses included over 10726 post-menopausal breast and 7532 prostate cancer cases with matched controls. Logistic regression models were used to evaluate associations with risk, and proportional hazard models were used for survival outcomes. We did not observe significant interactions between polymorphisms in MnSOD and GPX-1, or between mitochondrial polymorphisms and alcohol intake and risk of either breast (p-interaction of 0.34 and 0.98, respectively) or prostate cancer (p-interaction of 0.49 and 0.50, respectively). We observed a weak inverse association between prostate cancer risk and GPX-1 Leu198Leu carriers (OR 0.87, 95% CI 0.79-0.97, p = 0.01). Overall survival among women with breast cancer was inversely associated with G10398 carriers who consumed alcohol (HR 0.66 95% CI 0.49-0.88). Given the high power in our study, it is unlikely that interactions tested have more than moderate effects on breast or prostate cancer risk. Observed associations need both further epidemiological and biological confirmation. [ABSTRACT FROM AUTHOR]

Abstract: As there is strong evidence for inflammation and oxidative stress in depression, the aim of this study was to elucidate the relationship between oxidative imbalance and cellular immune response and to ask whether these processes are linked with iron metabolism in depressed patients. Blood was collected from patients diagnosed with recurrent depressive disorder (n=15) and from healthy controls (n=19). Whole-blood reduced glutathione (GSH), erythrocyte superoxide dismutase (SOD-1), glutathione peroxidase (GPx-1), glutathione reductase, malondialdehyde (MDA), and methemoglobin (MetHb) and plasma H2O2 were assayed spectrophotometrically. The serum heme oxygenase 1 (HO-1), cytokine, neopterin, and iron statuses were measured by ELISA. DNA damage was analyzed by comet assay. Serum concentrations of ferritin and soluble transferrin receptor were assayed by ELISA. MetHb saturation was analyzed spectrophotometrically in red blood cell hemolysate. The erythron variables were measured using a hematological analyzer. We observed a significant decrease in GPx-1 and SOD-1 activities and decreased levels of HO-1 and GSH in depressed patients compared to controls. Conversely, compared with controls, we found increased concentrations of MDA and H2O2 and more DNA damage in depressed patients. Furthermore, the levels of the proinflammatory cytokine interleukin-6 and of neopterin were increased in depressed patients along with decreased hemoglobin and hematocrit. A strong association between antioxidant defense, cytokine levels, and iron homeostasis was also revealed. These findings show that depression is associated with increased oxidative stress, inflammation, and restrictions on the available iron supply for red blood cell production. Furthermore, decreased antioxidant defense correlates with an increased cellular inflammatory response, whereas both concur with erythron and iron status, the latter explained by significant canonical correlations with the set of free radical scavenging enzymes and proinflammatory enzymes. The strong links between immune function, oxidative stress, and iron homeostasis suggest the presence of a self-sustaining multipathway mechanism that may progressively worsen, i.e., throughout accumulation of oxidative damage, producing the functional and structural consequences associated with depression. Hence, identifying viable therapeutic strategies to tackle oxidative stress and accompanying physiological disturbances, including inflammation and anemia, of chronic disease provides more opportunities for the treatment and, ultimately, prevention of depression. [Copyright &y& Elsevier]

Giant cell tumor of bone (GCTB) is a benign tumor with a tendency for local recurrence. Secondary malignant GCTB is rare, occurring in less than 2 % of GCTB cases. Mechanisms of malignant transformation of GCTB remain unclear. We examined 43 cases of GCTB (38 conventional cases, two lung implantation cases, and three secondary malignant cases) for p53 gene mutations and for loss of heterozygosity (LOH) of p53 when corresponding normal tissue was available. In addition, to elucidate the possible involvement of p53, GPX-1, cyclinD1, and Ki-67 in malignant transformation of GCTB, we assessed the expression of these proteins by immunohistochemistry. Mutations or LOH of p53 were found in all three malignant cases, which also showed p53 overexpression. Non-synonymous p53 mutations were detected in seven of 38 conventional cases (18 %), although none of these showed p53 overexpression, defined as more than 10 % of cells being positive. LOH at the p53 locus was detected in eight of 37 informative cases, although this was not associated with p53 overexpression in conventional GCT. Expression of GPX-1 was higher in the recurrent group, which included metastatic and malignant cases, and patients with high GPX-1 expression were at greater risk for early relapse. We also observed a positive correlation between high p53 expression and high GPX-1 expression in GCTB. Given that GPX-1 is shown to be a target of p53, these results suggest that p53 mutations play a role in tumor recurrence and malignant transformation of GCTB through interactions with GPX-1. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder in which the nigro-striatal dopaminergic (DAergic) neurons have been selectively lost. Due to side effects of levodopa, a dopamine precursor drug, recently cell replacement therapy for PD has been considered. Lack of sufficient amounts of, embryos and ethical problems regarding the use of dopamine-rich embryonic neural cells have limited the application of these cells for PD cell therapy. Therefore, many investigators have focused on using the pluripotent stem cells to generate DAergic neurons. This study is aimed first to establish a mouse embryonic stem (mES) cell line that can stably co-express Nurr1 (Nuclear receptor subfamily 4, group A, member 2) transcription factor in order to efficiently generate DAergic neurons, and glutathione peroxidase-1 (GPX-1) to protect the differentiated DAergic-like cells against oxidative stress. In addition to genetic engineering of ES cells, the effect of Beta-boswellic acid (BBA) on DAergic differentiation course of mES cells was sought in the present study. To that end, the feeder-independent CGR8 mouse embryonic stem cells were transduced by Nurr1- and GPX-1-harboring Lentiviruses and the generated Nurr1/GPX-1-expresssing ES clones were characterized and verified. Gene expression analyses demonstrated that BBA treatment and overexpression of Nurr1 has a synergistic effect on derivation of DAergic neurons from Nurr1/GPX-1-expressing ES cells. The differentiated cells could exclusively synthesize and secrete dopamine in response to stimuli. Overexpression of GPX-1 in genetically engineered Nurr1/GPX-1-ES cells increased the viability of these cells during their differentiation into CNS stem cells. In conclusion, the results demonstrated that Nurr1-overexpressing feeder-independent ES cells like the feeder-dependent ES cells, can be efficiently programmed into functional DAergic neurons and additional treatment of cells by BBA can even augment this efficiency. GPX-1 overexpression in Nurr1/GPX-1-ES cells increases the viability of differentiated CNS stem-like cells. The result of this study may have impact on future stem cell therapy of PD. [Copyright &y& Elsevier]

lthough melatonin lowers blood pressure in spontaneously hypertensive rats (SHR), its effect following antenatal and postpartum supplementation on the subsequent development of hypertension in SHR pups remains unknown. To investigate this, SHR dams were given melatonin in drinking water (10 mg/kg body weight/day) from day 1 of pregnancy until day 21 postpartum. After weaning, a group of male pups continued to receive melatonin till the age of 16 weeks (Mel-SHR), while no further melatonin was given to another group of male pups (Maternal-Mel-SHR). Controls received plain drinking water. Systolic blood pressure (SBP) was measured at 4, 6, 8, 12 and 16 weeks of age, after which the kidneys were collected for analysis of antioxidant enzyme profiles. SBP was significantly lower till the age of 8 weeks in Maternal-Mel-SHR and Mel-SHR than that in the controls, after which no significant difference was evident in SBP between the controls and Maternal-Mel-SHR. SBP in Mel-SHR was lower than that in controls and Maternal-Mel-SHR at 12 and 16 weeks of age. Renal glutathione peroxidase (GPx) and glutathione s-transferase (GST) activities, levels of total glutathione and relative GPx-1 protein were significantly higher in Mel-SHR. GPx protein was however significantly higher in Mel-SHR. No significant differences were evident between the three groups in the activities of superoxide dismutase, catalase and glutathione reductase. In conclusion, it appears that while antenatal and postpartum melatonin supplementation decreases the rate of rise in blood pressure in SHR offspring, it however does not alter the tendency of offspring of SHR to develop hypertension. [ABSTRACT FROM AUTHOR]

Glutathione peroxidase-1 (GPX-1) enzyme detoxifies peroxides by reacting with the GSH (reduced glutathione) responsible for the maintenance of the integrity of essential biomolecules. This study was conducted on 100 animals of two Indian draft breeds of cattle ( Bos indicus), Nimari, and Malvi. Genomic DNA was isolated from blood samples, and four fragments (80, 71, 78, and 442 bp) of the GPX-1 gene were amplified by polymerase chain reaction. PCR-SSCP analysis in 12% PAGE with silver staining revealed polymorphism in three of the fragments (80, 71, and 442 bp) in these two cattle breeds. Breed differences for the blood biochemical parameters (serum creatine kinase and lactic acid level) and overall draft ability were studied. The genetic polymorphism identified for the GPX-1 gene in this investigation would help in the identification of alleles related to draft capacity in these animals for future genetic improvement. [ABSTRACT FROM AUTHOR]

Keshan disease (KD) is a dilated cardiomyopathy closely related with a diet deficient in the mineral selenium. It is named for the northeastern Chinese county Keshan, where the disease prevalence is high because of selenium-deficient soil. KD is a gene-environment interaction disease. Here, we used stepwise multiple regression analysis to analyze the risk factors of the disease and the main clinical features in 71 KD patients and 290 controls. The variables analyzed included age, sex, family history of KD, blood selenium level, glutathione peroxidase-1 (GPx-1) activity, variance at codon198 in GPx- 1 gene, residence in an endemic area, abnormal electrocardiography (ECG) findings, and cardiothoracic (CT) ratio. The main risk factors found were low GPx-1 activity, family history of KD and living in an endemic area. The main clinical features were increased cardiac load on ECG and increased CT ratio and Tei index. Public health and clinical prevention efforts could focus on increasing GPx-1 activity to address KD. Is selenium deficiency really the certain cause of KD? This is not at all a settled question. And further study is promptly required to investigate the etiology of KD. [ABSTRACT FROM AUTHOR]

The complex biology of Parkinson's disease and the obscure mechanism of dopaminergic cell death in the course of the disease indicate that multiple intracellular pathways and numerous crucial elements contribute to the demise of these neurons. Therefore, multi-factorial approaches would more likely confer long-lasting survival and potentiate the biological function of dopamine neurons. We are proposing a multi-directional strategy to protect dopamine neurons against parkinsonian toxicity that involve transcription, anti-oxidant and neurotrophic factors. Specifically, Nurr1 an important DA transcription/ anti-inflammatory factor, glutathione peroxidase-1 an anti-oxidant enzyme (GPX-1) and glial cell line-derived neurotrophic factor (GDNF) a potent neurotrophic factor have all shown their capacity for dopaminergic neuroprotection. A model we are proposing is based on dopamine neuron-astrocyte-microglia co-culture that will supply all three factors in a tripartite fashion accelerating gene-to-gene and cell-to-cell cross-talks for synergy. While microglia will overexpress Nurr1, astrocytes will act as minipumps to secrete GDNF into the medium to act on GPX-1-overexpressing dopamine neurons growing within their proximity. The neurons will ultimately be exposed to the parkinsonian neurotoxin 6-OHDA and tested for their improved survival rate in vitro and in vivo, their integration capacity to neural network and their physiological function in the midbrain circuitry. [ABSTRACT FROM AUTHOR]

Abstract: Background: Keshan disease (KD) is a fatal dilated cardiomyopathy with unknown etiology. We studied the gene–environment interaction in the pathogenesis of KD by assessing the association of low blood selenium and polymorphisms in glutathione peroxidase-1 (GPx-1) gene. Methods: The concentration of blood selenium and the activity and polymorphisms of GPx-1 in 71KD patients and 290 controls were measured. The functions of rat neonatal cardiomyocytes resulting from overexpression of 2 variants of GPx-1 were studied. Results: Blood concentration of selenium and GPx-1 activity were lower in patients than in controls. Genetic analysis revealed a single nucleotide polymorphism (Pro198Leu) in GPx-1 gene associated with selenium deficiency as well as impaired GPx-1 activity. Gene–environment interaction analysis revealed a synergistic–multiplicative interaction between polymorphism of GPx-1 and selenium deficiency. Overexpression of the GPx-1 leucine-containing allele in cultured cardiomyocytes caused a 30% reduction in selenium-induced GPx-1 activity and increased serum starvation induced apoptosis as compared with that of the wild-type variant 198Pro. Conclusion: Selenium deficiency in carriers with the GPx-1 leucine-containing allele is associated with low GPx-1 enzyme activity, which may, in turn, increase the incidence of KD. Results from this unique disease may have broad implications for a gene–environment reaction in the etiology of other diseases. [Copyright &y& Elsevier]

Pollution with heavy metal salts is an important environmental problem today, having an adverse effect on public health. The endocrine system maintains homeostasis in the body. The antioxidant protection (GPX-1) of the pineal gland in mature rats was studied. Animals of the experimental group represented a model of microelementosis, achieved by adding a mixture of heavy metal salts for 90 days to drinking water: zinc (ZnSO4×7H2O) - 5 mg/l, copper (CuSO4×5H2O) - 1 mg/l, iron (FeSO4) - 10 mg/l, manganese (MnSO4×5H2O) - 0.1 mg/l, lead (Pb(NO3)2) - 0.1 mg/l, and chromium (K2Cr2O7) - 0.1 mg/l. Morphological, statistical and immunohistochemical (GPX-1) research methods were used. Long-term (90-days) intake of heavy metal salts mixture in the body of experimental animals brought about development of the general adaptation syndrome, the stage of chronic stress "subcompensation" in the pineal gland. Morphological rearrangements were of nonspecific polymorphic nature as severe hemodynamics disorder in the organ, impairment of vascular wall morphology, development of tissue hypoxia and oxidative stress, accompanied by processes of accelerated apoptosis in part of pinealocytes, by a significant decrease in glutathione peroxidase level in the organ and reactive astrogliosis as a response to the damaging agent's action. Along with the negative changes in the pineal gland, a compensatory-adaptive processes with signs of functional stress also occurred. A sufficiently high degree of glutathione peroxidase activity in 39% of pinealocytes located perivascularly, active adaptive glial reaction and activation of synthetic processes in some pinealocytes were also observed.

Background: Keratoconus (KC) is a degenerative eye disease which results from thinning of the cornea and causes vision distortion. Oxidative stress damage to KC corneas may be because of the failure of corneas to process reactive oxygen species which leads to corneal thinning and loss of vision. Genetic variants in antioxidant defense genes such as catalase (CAT) and glutathione peroxidase (GPX) can decrease antioxidant capacity or increase oxidative stress and alter the risk of KC in patients. We investigated and evaluated the effects of single nucleotide polymorphisms in CAT, GPX-1 on the risk of KC in an Iranian population sample., Methods: This case-control study was performed on 140 patients with KC and 150 healthy control subjects in a sample of Iranian population from Zahedan, southern Iran in 2015. Genotyping of CAT rs7943316 and GPX-1 rs1050450 polymorphisms was done using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method., Results: CAT rs7943316 A/T, AA genotype and A allele have a protective role against disease (OR =0.28, 95% CI =0.13-0.61, P =0.001 and OR = 0.50, 95% CI =0.35-0.72, P =0.0001, respectively) and decreased the risk of KC. Moreover, GPX-1 rs1050450 T allele increased the risk of KC in comparison with C allele (OR = 1.42, 95% CI = 1.01-2.03, P =0.03)., Conclusion: CAT rs7943316 A/T, AA genotype, and A allele decreased the risk of KC. Moreover, in GPX-1 rs1050450 C/T polymorphism, T allele was associated with an increased risk of KC in our population., Competing Interests: Conflict of interest The authors declare that there is no conflict of interests regarding the publication of this paper.

Hypoxia is a hallmark of various ischemic diseases such as ischemic heart disease, ischemic limb, ischemic stroke, and solid tumors. Gene therapies for these diseases have been developed with various therapeutic genes including growth factors, anti-apoptotic genes, and toxins. However, non-specific expression of these therapeutic genes may induce dangerous side effects in the normal tissues. To avoid the side effects, gene expression should be tightly regulated in an oxygen concentration dependent manner. The hypoxia inducible promoters and enhancers have been evaluated as a transcriptional regulation tool for hypoxia inducible gene therapy. The hypoxia inducible UTRs were also used in gene therapy for spinal cord injury as a translational regulation strategy. In addition to transcriptional and translational regulations, post-translational regulation strategies have been developed using the HIF-1α ODD domain. Hypoxia inducible transcriptional, translational, and post-translational regulations are useful for tissue specific gene therapy of ischemic diseases. In this review, hypoxia inducible gene expression systems are discussed and their applications are introduced., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Diabetes mellitus is known to increase the risk of neurodegeneration, and both diseases are reported to be linked to dysfunction of endoplasmic reticulum (ER). Astrocytes are important in the defense mechanism of central nervous system (CNS), with great ability of tolerating accumulation of toxic substances and sensitivity in Ca(2+) homeostasis which are two key functions of ER. Here, we investigated the modulation of the glucose-regulated protein 78 (GRP78) in streptozotocin (STZ)-induced diabetic mice and C6 cells cultured in high glucose condition. Our results showed that more reactive astrocytes were presented in the hippocampus of STZ-induced diabetic mice. Simultaneously, decrease of GRP78 expression was found in the astrocytes of diabetic mice hippocampus. In in vitro study, C6 cells were treated with high glucose to investigate the role of high glucose in GRP78 modulation in astrocytic cells. GRP78 as well as other chaperones like GRP94, calreticulin and calnexin, transcription levels were down-regulated after high glucose treatment. Also C6 cells challenged with 48h high glucose were activated, as indicated by increased level of glial fibrillary acidic protein (GFAP). Activated C6 cells simultaneously exhibited significant decrease of GRP78 level and was followed by reduced phosphorylation of Akt. Moreover, unfolded protein response was induced as an early event, which was marked by the induction of CHOP with high glucose treatment, followed by the reduction of GRP78 after 48h. Finally, the upsurge of ROS production was found in high glucose treated C6 cells and chelation of ROS could partially restore the GRP78 expression. Taken together, these data provide evidences that high glucose induced astrocytic activation in both in vivo and in vitro diabetic models, in which modulation of GRP78 would be an important event in this activation., (Copyright © 2013 National Cancer Institute, Cairo University. Published by Elsevier Ltd. All rights reserved.)

There is compelling experimental and clinical evidence suggesting a crucial role for inflammation in the initiation and also the progression of atherosclerosis. Numerous biomarkers involved at various levels of the inflammation cascade have been shown to be associated with adverse cardiovascular outcomes. Yet, to date, it is not clear whether inflammation simply accompanies the atherosclerotic process or represents a major driver. Among all blood biomarkers, C-reactive protein (CRP), the classical acute phase reactant that can be measured with high-sensitivity (hs) assays seems to be the most promising candidate. It has already found its way into the guidelines in primary prevention. Hs-CRP can also be used to identify a high-risk group for recurrent events in patients with manifest atherosclerosis. Several post hoc analyses of large-scale randomized clinical trials testing various statins have indicated that, besides low density lipoprotein (LDL) cholesterol, hs-CRP levels might also further aid in tailoring statin treatment. The large JUPITER trial has prospectively confirmed these findings in primary prevention in patients with elevated hs-CRP but normal LDL cholesterol levels. Still, statin therapy is not a specific anti-inflammatory regime acting on the inflammation cascade. Thus, to directly test the inflammation hypothesis, a novel, more proximally located cytokine-based approach is needed. Canakinumab, a fully human monoclonal antibody against interleukin-1β, might represent a promising compound in this regard and provide a proof of concept. If successful, this may become a novel strategy to treat high-risk patients with stable atherosclerotic disease to prevent recurrent events on top of standard medical care., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Therapeutic angiogenesis for peripheral artery disease (PAD), achieved by gene and cell therapy, has recently raised a great deal of hope for patients who cannot undergo standard revascularizing treatment. Although pre-clinical studies gave very promising data, still clinical trials of gene therapy have not provided satisfactory results. On the other hand, cell therapy approach, despite several limitations, demonstrated more beneficial effects but initial clinical studies must be constantly validated by larger randomized, multi-center, double-blinded, placebo-controlled trials. This review focuses on previous and recent gene and cell therapy studies for limb ischemia, including both experimental and clinical research, and summarizes some important papers published in this field. Moreover, it provides a short comment on combined gene and cell therapy approach on the example of heme oxygenase-1 overexpressing cells with therapeutic properties., (Copyright © 2013 Elsevier B.V. All rights reserved.)