Assessing the possible association between MTHFR (rs1801133) and GPx-1 (rs1050450) polymorphisms with the risk of type 2 diabetes, diabetic neuropathy, and diabetic retinopathy.

PURPOSE: Oxidative stress in chronic hyperglycemia could injure the tissues and onset of diabetes-related complications like retinopathy and neuropathy. This study investigates the association between methylenetetrahydrofolate reductase (MTHFR) and glutathione peroxidase (GPx) genetic variants with these complications. METHODS: In this case-control study, 400 individuals, including 100 healthy subjects and 300 patients with type 2 diabetes mellitus (T2DM) in three subgroups: with retinopathy(n = 100), with neuropathy(n = 100), and without complication (n = 100) from West Iran, were studied. MTHFR (rs1801133) and GPx-1 (rs1050450) variants were identified by the PCR-RFLP method. The plasma levels of GPx activity, glutathione, malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidative stress (TOS) were measured by chemical methods. RESULTS: Higher BMI, TOS and MDA levels were observed in patients with neuropathy compared to other patients and controls. Diabetic patients with neuropathy had lower levels of glutathione (7.8 ± 4.5; P < 0.001), GPx activity (39.5 ± 8.5; P < 0.001), and TAC (703.1 ± 129.1; P = 0.0001) in comparison with other groups. The patients without complication and retinopathic patients had higher plasma levels of glutathione (12.2 ± 2.4; p = 0.02) and TAC (793.4 ± 124.6; P < 0.001), respectively. MTHFR TT genotype significantly correlated with lower levels of TOS (3.5 ± 1.1; P < 0.001) and OSI (0.0050 ± 0.001; P < 0.001). Subjects with the GPx-1 TT genotype had higher levels of MDA (6.8 ± 2.5; P = 0.02) and lower levels of TOS (3.7 ± 1.6; P < 0.001), which is statistically significant. TT genotype of MTHFR was associated with 3.9 fold (95% CI 1.04-4.76; P = 0.0436) increased risk of neuropathy. Also, GPx-1 CT genotype increased the risk of retinopathy [OR = 2.7 (95% CI = 1.38-5.44; P = 0.0039)]. CONCLUSION: The MTHFR TT genotype increased the risk of neuropathy in diabetic patients significantly. The GPx-1 CT genotype is related to increased retinopathy risk among diabetic patients. Both MTHFR and Gpx-1 TT genotypes were associated with higher BMI levels.

Selenium nanoparticles ameliorate lumbar disc degeneration by restoring GPX1-mediated redox homeostasis and mitochondrial function of nucleus pulposus cells.

Intervertebral disc degeneration (IVDD) is a prevalent musculoskeletal disorder that involves the excessive accumulation of reactive oxygen species (ROS), resulting in mitochondrial dysfunction and matrix metabolism imbalance in nucleus pulposus cells (NPCs). Selenium, an indispensable trace element, plays a crucial role in maintaining mitochondrial redox homeostasis by being incorporated into antioxidant selenoproteins as selenocysteine. In this study, we employed a straightforward synthesis method to produce selenium nanoparticles (SeNPs) with consistent size and distribution, and evaluated their potential protective effects in ameliorating IVDD. In a simulated inflammatory environment induced by interleukin-1beta (IL-1ß) in vitro, SeNPs demonstrated a protective effect on the matrix synthesis capacity of NPCs through the up-regulation of aggrecan and type II collagen, while concurrently suppressing the expression of matrix degradation enzymes including MMP13 and ADAMTS5. Additionally, SeNPs preserved mitochondrial integrity and restored impaired mitochondrial energy metabolism by activating glutathione peroxidase1 (GPX1) to rebalance redox homeostasis. In a rat lumbar disc model induced by puncture, the local administration of SeNPs preserved the hydration of nucleus pulposus tissue, promoted matrix deposition, and effectively mitigated the progression of IVDD. Our results indicate that the enhancement of GPX1 by SeNPs may offer a promising therapeutic approach for IVDD by restoring mitochondrial function and redox homeostasis.

Association of MnSOD, CAT, and GPx1 Gene Polymorphism with Risk of Diabetic Nephropathy in South Indian Patients: A Case-Control Study.

Diabetic nephropathy (DN) is one of the common complications of type 2 diabetes mellitus (T2DM), and oxidative stress plays a key role in the pathogenesis of DN. Studies have demonstrated that antioxidants (MnSOD, CAT, and GPx1) may reduce the complications associated with T2DM. The purpose of the study is to correlate the role of antioxidant gene polymorphisms in the pathogenesis of DN among T2DM individuals in the South Indian population. It clarifies the importance of early manifestation and reliable genetic indicators modulating the oxidative stress mechanism in DN. The study participants were divided and grouped as Group 1: Control, Group 2: T2DM without DN, and Group 3: T2DM with DN (n = 100 in each group). The levels of plasma glucose, HbA1c, renal profile, SOD, CAT, GPx1, MDA, and TAS were assessed. MnSOD (rs4880), CAT (rs1049982), and GPx1 (rs1050450) polymorphisms were genotyped via Tetra-arms PCR. The genotypes of GPx1 depict a significant role in the progression of DN in T2DM patients (co-dominant [OR: 2.134; 95% CI (1.202-3.788), p < 0.01], dominant [OR: 2.015; 95% CI (1.117-3.634), p = 0.02], and recessive model [OR: 2.215; 95% CI (1.235-3.972), p = 0.008]); whereas rs4880 and rs1049982 polymorphisms are not associated with DN progression. As a result, GPx1 (rs1050450) polymorphism could be a diagnostic risk factor for developing DN in T2DM patients. Moreover, the genotypes of rs4880 and rs1049982 polymorphism show significant difference in the antioxidant parameters compared to the genotypes of rs1050450. In contradiction to earlier studies, the current study demonstrates that the genotypes of rs1050450 (GPx1) can be considered as an influential component for higher susceptibility and risk of developing DN in T2DM patients among the South Indian population.

Selenium Discrepancies in Fetal Bovine Serum: Impact on Cellular Selenoprotein Expression.

Selenium is an essential trace element in our diet, crucial for the composition of human selenoproteins, which include 25 genes such as glutathione peroxidases and thioredoxin reductases. The regulation of the selenoproteome primarily hinges on the bioavailability of selenium, either from dietary sources or cell culture media. This selenium-dependent control follows a specific hierarchy, with "housekeeping" selenoproteins maintaining constant expression while "stress-regulated" counterparts respond to selenium level fluctuations. This study investigates the variability in fetal bovine serum (FBS) selenium concentrations among commercial batches and its effects on the expression of specific stress-related cellular selenoproteins. Despite the limitations of our study, which exclusively used HEK293 cells and focused on a subset of selenoproteins, our findings highlight the substantial impact of serum selenium levels on selenoprotein expression, particularly for GPX1 and GPX4. The luciferase reporter assay emerged as a sensitive and precise method for evaluating selenium levels in cell culture environments. While not exhaustive, this analysis provides valuable insights into selenium-mediated selenoprotein regulation, emphasizing the importance of serum composition in cellular responses and offering guidance for researchers in the selenoprotein field.

Eldecalcitol inhibits the progression of oral cancer by suppressing the expression of GPx-1.

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.

Antioxidant Genetic Variants Modify Echocardiography Indices in Long COVID.

Although disturbance of redox homeostasis might be responsible for COVID-19 cardiac complications, this molecular mechanism has not been addressed yet. We have proposed modifying the effects of antioxidant proteins polymorphisms (superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GPX1), glutathione peroxidase 3 (GPX3) and nuclear factor erythroid 2-related factor 2, (Nrf2)) in individual susceptibility towards the development of cardiac manifestations of long COVID-19. The presence of subclinical cardiac dysfunction was assessed via echocardiography and cardiac magnetic resonance imaging in 174 convalescent COVID-19 patients. SOD2, GPX1, GPX3 and Nrf2 polymorphisms were determined via the appropriate PCR methods. No significant association of the investigated polymorphisms with the risk of arrhythmia development was found. However, the carriers of variant GPX1*T, GPX3*C or Nrf2*A alleles were more than twice less prone for dyspnea development in comparison with the carriers of the referent ones. These findings were even more potentiated in the carriers of any two variant alleles of these genes (OR = 0.273, and p = 0.016). The variant GPX alleles were significantly associated with left atrial and right ventricular echocardiographic parameters, specifically LAVI, RFAC and RV-EF (p = 0.025, p = 0.009, and p = 0.007, respectively). Based on the relation between the variant SOD2*T allele and higher levels of LV echocardiographic parameters, EDD, LVMI and GLS, as well as troponin T (p = 0.038), it can be proposed that recovered COVID-19 patients, who are the carriers of this genetic variant, might have subtle left ventricular systolic dysfunction. No significant association between the investigated polymorphisms and cardiac disfunction was observed when cardiac magnetic resonance imaging was performed. Our results on the association between antioxidant genetic variants and long COVID cardiological manifestations highlight the involvement of genetic propensity in both acute and long COVID clinical manifestations.

Polymorphisms of Antioxidant Enzymes SOD2 (rs4880) and GPX1 (rs1050450) Are Associated with Bladder Cancer Risk or Its Aggressiveness.

Background and Objectives: Oxidative stress induced by increased reactive oxygen species (ROS) production plays an important role in carcinogenesis. The entire urinary tract is continuously exposed to numerous potentially mutagenic environmental agents which generate ROS during their biotransformation. In first line defense against free radicals, antioxidant enzymes superoxide dismutase (SOD2) and glutathione peroxidase (GPX1) both have essential roles. Altered enzyme activity and decreased ability of neutralizing free oxygen radicals as a consequence of genetic polymorphisms in genes encoding these two enzymes are well described so far. This study aimed to investigate the association of GPX1 (rs1050450) and SOD2 (rs4880) genetic variants with the urothelial bladder cancer (UBC) risk independently and in combination with smoking. Furthermore, we aimed to determine whether the UBC stage and pathological grade were influenced by GPX1 and SOD2 polymorphisms. Material and Methods: The study population included 330 patients with UBC (mean age 65 ± 10.3 years) and 227 respective controls (mean age 63.4 ± 7.9 years). Single nucleotide polymorphism (SNP) of GPX1 (rs1050450) was analyzed using the PCR-RFLP, while SOD2 (rs4880) SNP was analyzed using the q-PCR method. Results: Our results showed that UBC risk was significantly increased among carriers of at least one variant SOD2 Val allele compared to the SOD2 Ala16Ala homozygotes (OR = 1.55, p = 0.03). Moreover, this risk was even more pronounced in smokers with at least one variant SOD2 Val allele, since they have even 7.5 fold higher UBC risk (OR = 7.5, p < 0.001). Considering GPX1 polymorphism, we have not found an association with UBC risk. However, GPX1 genotypes distribution differed significantly according to the tumor stage (p ˂ 0.049) and pathohistological grade (p ˂ 0.018). Conclusion: We found that SOD2 genetic polymorphism is associated with the risk of UBC development independently and in combination with cigarette smoking. Furthermore, we showed that GPX1 genetic polymorphism is associated with the aggressiveness of the disease.

MiR-185-5p suppresses acute myeloid leukemia by inhibiting GPX1.

Acute myeloid leukemia (AML) has been characterized by the swift development of abnormal cells in the bone marrow. This research aimed to examine the impacts of the miR-185-5p-GPX1 axis on AML progression and differentiation. Findings indicated that miR-185-5p and GPX1 levels were significantly reduced and elevated, respectively. The upregulation of miR-185-5p was observed to restrict the proliferation and invasion abilities of AML cells, and promote differentiate and apoptosis. Moreover, the overexpression of GPX1 was noticed to enhance the growth of AML cells. In conclusion, this research suggested that by targeting GPX1, miR-185-5p inhibited AML progression and downregulated AML cells' proliferation and invasion.

Genetic polymorphism impact superoxide dismutase and glutathione peroxidase activity in charcoal workers.

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.

A Response of the Pineal Gland in Sexually Mature Rats under Long-term Exposure to Heavy Metal Salts.

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.

MiR-646 regulates proliferation and migration of laryngeal carcinoma through the PI3K/AKT pathway via targeting GPX1.

Laryngeal cancer is a common type of head and neck malignancy. microRNA is implicated in the development and progression of various tumours. The present study aimed to explore the potential roles and mechanisms of miR-646 in laryngeal carcinoma cells. We detected the expression of miR-646 and observed that miR-646 was reduced in laryngeal cell lines. Subsequently, the proliferation, migration and invasion of TU212 and TU686 cells were evaluated using CCK-8 assays, cell proliferation ELISA BrdU and transwell assays after transfection with miR-646 mimic. Overexpression of miR-646 attenuated the proliferative and invasive abilities of TU212 and TU686 cells. Dual luciferase reporter assay confirmed that glutathione peroxidase 1 (GPX1) is a direct target of miR-646. Interestingly, restoration of GPX1 promoted cell proliferation and migration, and reversed the biological activities of miR-646 in cell proliferation and migration. It is worth noting that miR-646 overexpression blocked the activation of PI3K/AKT pathway, and this was partly abrogated by GPX1. 740Y-P, a PI3K agonist abolished the effects of miR-646 on cell proliferation and invasion. Taken together, miR-646 prohibited the proliferation and invasion of laryngeal carcinoma cells through the PI3K/AKT pathway via targeting GPX1.

VEGF-B is a potent antioxidant.

VEGF-B was discovered a long time ago. However, unlike VEGF-A, whose function has been extensively studied, the function of VEGF-B and the mechanisms involved still remain poorly understood. Notwithstanding, drugs that inhibit VEGF-B and other VEGF family members have been used to treat patients with neovascular diseases. It is therefore critical to have a better understanding of VEGF-B function and the underlying mechanisms. Here, using comprehensive methods and models, we have identified VEGF-B as a potent antioxidant. Loss of Vegf-b by gene deletion leads to retinal degeneration in mice, and treatment with VEGF-B rescues retinal cells from death in a retinitis pigmentosa model. Mechanistically, we demonstrate that VEGF-B up-regulates numerous key antioxidative genes, particularly, Gpx1 Loss of Gpx1 activity largely diminished the antioxidative effect of VEGF-B, demonstrating that Gpx1 is at least one of the critical downstream effectors of VEGF-B. In addition, we found that the antioxidant function of VEGF-B is mediated mainly by VEGFR1. Given that oxidative stress is a crucial factor in numerous human diseases, VEGF-B may have therapeutic value for the treatment of such diseases.

Comparative CpG methylation kinetic patterns of cis-regulatory regions of heat stress-related genes in Sahiwal and Frieswal cattle upon persistent heat stress.

The kinetic patterns of CpG methylation of the cis-regulatory region of heat stress-related genes on exposed to heat stress (at 42 °C) between the Sahiwal and Frieswal cattle was compared in the present study. Using an in vitro whole blood culture model, cells were continuously exposed to heat stress (at 42 °C) for 6 h. Methylation levels of five genes, viz., GPX1, HSP70, HSP90, c-FOS, and JUN were estimated by SyberGreen-based quantitative methylation-specific PCR (qMSP) assay. CpG methylation kinetics at different time points of heat stress (0.5, 1, 2, 4, 6 h) were analyzed using mixed ANOVA. The initial methylation level, estimated at 37 °C, of HSP70 was significantly high in the Sahiwal breed. A significant (p<0.001) time-dependent hypomethylation of an antioxidant gene (GPX1) CpG islands was detected at the acute phase of the stress. Heat shock protein gene (HSP70) showed a similar CpG methylation kinetics where the hypomethylation was prominent from 1 h and persisted up to 4 h. The heat stress responses of both Sahiwal and Frieswal cattle were identical as there was no distinctiveness in the methylation kinetics of CpG islands of studied genes. The acclimatization of Frieswal cattle-a breed developed in India over the years to the tropical climatic conditions, maybe one of the reasons for this similarity. Thus, the present study results could pave a path to understand the molecular mechanism of heat stress and adaptation of indigenous and crossbred cattle populations to the changing scenario in tropical climate conditions.

Human glutathione peroxidase codon 198 variant increases nasopharyngeal carcinoma risk and progression.

PURPOSE: Glutathione peroxidase 1 (GPx-1) is a selenium-dependent detoxifying enzyme involved in the protection of cells against oxidative damage. Some genetic association studies reported significant associations between GPx-1 Pro198Leu variant and carcinogenesis across different populations; however, the impact of this variant on nasopharyngeal carcinoma (NPC) has not been explored. Therefore, the present study was planned to evaluate the potential involvement of the GPx-1 Pro198Leu variant and plasma GPx activity in the risk of developing NPC in a Tunisian population. METHODS: The GPx-1 Pro198Leu genotype was determined in 327 NPC patients and 150 healthy controls by the RFLP-PCR analysis. The correlation between the GPx-1 variant and the clinicopathological parameters was examined. GPx activity was assessed in the plasma of 119 NPC patients and 58 healthy control subjects and according to GPx-1 genotypes and clinicopathological characteristics of NPC patients. RESULTS: A significant association was found between GPx-1 Pro198Leu variant and NPC risk in a Tunisian population. The allelic frequencies of Pro and Leu alleles were 32% versus 68% and 41% versus 59% in NPC cases and controls, respectively. Thus, the minor 198 Leu allele increased significantly in NPC patients and appeared as a potential risk factor for NPC occurrence (OR = 1.48, CI 95% = 1.14-1.91, p = 0.002). The plasma GPx activity was significantly higher in NPC patients than in controls (p = 0.03). According to the clinicopathological characteristics of NPC patients, GPx activity decreased significantly in patients with lymph node metastasis (p = 0.004). CONCLUSION: This is the first study showing a strong association between GPx-1 Pro198Leu genetic variant and NPC risk. GPx-1 Pro198Leu variant increased the development of regional lymph node metastasis. Plasma GPx activity was higher in NPC patients. Thus, GPx-1 gene could be considered as a determinant factor influencing NPC risk and progression.

MiR-29b-3p cooperates with miR-29c-3p to affect the malignant biological behaviors in T-cell acute lymphoblastic leukemia via TFAP2C/GPX1 axis.

Mounting evidence has illustrated the tumor regulatory roles of microRNAs (miRNAs) in T-cell acute lymphoblastic leukemia (T-ALL), a malignant carcinoma originated from T-cell precursors. However, the possible regulation mechanisms underlying miR-29b/29c-3p in T-ALL have not been interrogated yet. The aim of our study was to probe the association and possible molecular mechanism of miR-29b/29c-3p and Glutathione Peroxidase 1 (GPX1), a predicted highly expressed gene in acute myeloid leukemia (LAML) tissues on the cancer genome atlas (TCGA) website. In our paper, it was observed that GPX1 was relatively overexpressed in T-ALL cells, compared with normal T cells. Loss-of-function assays demonstrated that GPX1 knockdown inhibited the proliferation and activated the apoptosis in T-ALL cells. Then miR-29b/29c-3p was confirmed to regulate GPX1 mRNA and protein expression via decreasing Transcription Factor AP-2 Gamma (TFAP2C) expression. In summary, miR-29b-3p and miR-29c-3p targeted TFAP2C so as to repress GPX1 transcription, thereafter inhibiting GPXA expression. In the end, rescue experiments proved the whole regulation mechanism of miR-29b/29c-3p in T-ALL. Overall, the miR-29b/29c-3p -TFAP2C-GPX1 axis helped us to have a better understanding of T-ALL pathogenesis.

Glutathione Peroxidase-1 Knockout Facilitates Memory Impairment Induced by ß-Amyloid (1-42) in Mice via Inhibition of PKC ßII-Mediated ERK Signaling; Application with Glutathione Peroxidase-1 Gene-Encoded Adenovirus Vector.

A growing body evidence suggests that selenium (Se) deficiency is associated with an increased risk of developing Alzheimer's disease (AD). Se-dependent glutathione peroxidase-1 (GPx-1) of a major antioxidant enzyme, and the most abundant isoform of GPx in the brain. In the present study, we investigated whether GPx-1 is protective against memory impairments induced by beta-amyloid (Aß) (1-42) in mice. As the alteration of protein kinase C (PKC)-mediated ERK activation was recognized in the early stage of AD, we examined whether the GPx-1 gene modulates Aß (1-42)-induced changes in PKC and ERK levels. We observed that Aß (1-42) treatment (400 pmol, i.c.v.) significantly decreased PKC ßII expression in the hippocampus of mice. Aß (1-42)-induced neurotoxic changes [i.e., oxidative stress (i.e., reactive oxygen species, 4-hydroxy-2-noneal, and protein carbonyl), reduced PKC ßII and phospho-ERK expressions, and memory impairment under Y-maze and passive avoidance test] were more pronounced in GPx-1 knockout than in wild type mice. Importantly, exposure to a GPx-1 gene-encoded adenovirus vector (Adv-GPx-1) significantly increased GPx-1 mRNA and GPx activity in the hippocampus of GPx-1 knockout mice. Adv-GPx-1 exposure also significantly blocked the neurotoxic changes induced by Aß (1-42) in GPx-1 knockout mice. Treatment with ERK inhibitor U0126 did not significantly change Adv-GPx-1-mediated attenuation in PKC ßII expression. In contrast, treatment with PKC inhibitor chelerythrine (CHE) reversed Adv-GPx-1-mediated attenuation in ERK phosphorylation, suggesting that PKC ßII-mediated ERK signaling is important for Adv-GPx-1-mediated potentials against Aß (1-42) insult. Our results suggest that treatment with the antioxidant gene GPx-1 rescues Aß (1-42)-induced memory impairment via activating PKC ßII-mediated ERK signaling.

Genomics of Detoxification: How Genomics can be Used for Targeting Potential Intervention and Prevention Strategies Including Nutrition for Environmentally Acquired Illness.

Due to their genomic variants, some individuals are more highly affected by toxicants than others. Toxicant metabolizing and activating variants have been linked with a wide variety of health issues including an increased risk of miscarriages, birth defects, Alzheimer's, benzene toxicity, mercury toxicity and cancer. The study of genomics allows a clinician to identify pathways that are less effective and then gives the clinician the opportunity to counsel their patients about diet, supplements and lifestyle modifications that can improve the function of these pathways or compensate to some extent for their deficits. This article will review a few of these critical pathways relating to phase I and phase 2 detox such as GSTP1, GPX1, GSTT1 deletions, PON1 and some of the CYP 450 system as examples of how an individual's genomic vulnerabilities to toxicants can be addressed by upregulating or downregulating specific pathways via genomically targeted use of foods, supplements and lifestyle changes.

EDR Peptide: Possible Mechanism of Gene Expression and Protein Synthesis Regulation Involved in the Pathogenesis of Alzheimer's Disease.

The EDR peptide (Glu-Asp-Arg) has been previously established to possess neuroprotective properties. It activates gene expression and synthesis of proteins, involved in maintaining the neuronal functional activity, and reduces the intensity of their apoptosis in in vitro and in vivo studies. The EDR peptide interferes with the elimination of dendritic spines in neuronal cultures obtained from mice with Alzheimer's (AD) and Huntington's diseases. The tripeptide promotes the activation of the antioxidant enzyme synthesis in the culture of cerebellum neurons in rats. The EDR peptide normalizes behavioral responses in animal studies and improves memory issues in elderly patients. The purpose of this review is to analyze the molecular and genetics aspects of the EDR peptide effect on gene expression and synthesis of proteins involved in the pathogenesis of AD. The EDR peptide is assumed to enter cells and bind to histone proteins and/or ribonucleic acids. Thus, the EDR peptide can change the activity of the MAPK/ERK signaling pathway, the synthesis of proapoptotic proteins (caspase-3, p53), proteins of the antioxidant system (SOD2, GPX1), transcription factors PPARA, PPARG, serotonin, calmodulin. The abovementioned signaling pathway and proteins are the components of pathogenesis in AD. The EDR peptide can be AD.

[Association between GPX1 gene polymorphisms and noise-induced hearing loss].

Objective: To identify association between genetic polymorphism in the Glutathione peroxidase 1 gene (GPX1) and noise-induced hearing loss (NIHL) . Methods: A nested case control study was conducted based on a cohort of noise-exposed subjects. 392 cases were selected from the steel factory in Henan Province, 392 matched control subjects for each case were designated on the basis of the matched criterion including same gender, age (±5years) and duration of exposure to noise (±2years) . Two single nucleotide polymorphisms (SNPs) of GPX1 were genotyped by SNPscanTM multiplex SNP genotyping kit. Hardy-Weinberg equilibrium (HWE) tests were performed using Pearson's χ(2) for each SNP among control group, effects of genotypes of GPX1 on NIHL were analyzed by logistic regression. Results: All two SNPs were in HWE. After adjustment for covariates including smoking status, rs1987628 polymorphism was statistically significantly associated with the NIHL risk under codominant and Dominant inheritance models; In the subjects carrying rs1987628 GA genotype had a higher NIHL risk than those carrying the GG genotype, the adjusted OR value was 1.803 (95%CI 1.215-2.676, P=0.003) . And meanwhile, rs1987628 GA+AA genotype had a higher NIHL risk than those carrying the GG genotype, the adjusted OR value was 1.762 (95%CI 1.197-2.593, P=0.004) . Conclusion: It was suggested that genetic polymorphism in the GPX1 gene might be the genetic susceptible factor for NIHL.

Concomitant overexpression of triple antioxidant enzymes selectively increases circulating endothelial progenitor cells in mice with limb ischaemia.

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.