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Background: Oxidative damage has been implicated in multiple neurodegenerative diseases, including epilepsy. Selenium, in the form of selenoproteins is an integral part of the human antioxidant defense system. Though a relationship between the altered selenium levels and epilepsy has been reported, limited evidence is available about the expression pattern of selenoproteins in epileptic patients. Objective: This study aimed to determine the serum selenium levels in idiopathic epileptic and healthy individuals. Expression profiling of selenoproteins (GPx1, TRxR1 and SEPW1) both at mRNA and protein levels was also evaluated. Methods: Serum selenium levels of 30 patients with idiopathic generalized epilepsy and their age and gender matched 30 healthy controls were measured. Protein levels of Serum Glutathione Peroxidase 1 (GPx1), Thioredoxin Reductase 1 (TRxR1) and Selenoprotein W (SEPW1) were estimated using ELISA. mRNA expression of GPx1, TRxR1 and SEPW1 were determined using qRT-PCR. Results: The mean values for serum selenium levels in cases and controls were 37.6 ± 2.0 µmol/ml and 38.9 ± 2.7 µmol/ml, respectively. Selenium levels in cases were significantly lower as compared to controls (p = 0.031). No statistically significant differences were observed between the serum levels of selenoproteins GPx1, TRxR1 and SEPW1 in epileptic patients and the healthy group. GPx1 and TRxR1 expression was found to be down regulated (0.34 and 0.13 folds respectively) whereas SEPW 1 was found to be 0.04 folds up regulated in epileptic patients compared to the healthy subjects. Conclusion: Selenium deficiency observed in epileptic patients suggests the association between serum selenium levels and epilepsy. This study provides the information about the selenium status in Pakistani population and helps in understanding the role of selenium in the prevention of epilepsy. [ABSTRACT FROM AUTHOR]

Abstract Glutathione Peroxidase 1 (GPx1) gene has been reported for its role in cellular redox homeostasis, and the dysregulation of its expression is linked with the progression of diverse cancers. Non-synonymous single nucleotide polymorphism (nsSNPs) have been emerged as the crucial factors, playing their role in GPx1 overexpression. To understand the deleterious mutational effects on the structure and function of GPx1 enzyme, we delved deeper into the exploration of possibly damaging nsSNPs using in-silico based approaches. Eight widely utilized computational tools were employed to roughly shortlist the deleterious nsSNPs. Their damaging effects on structure and function of the genes were evaluated by using different bioinformatics tools. Subsequently, the three final proposed deleterious mutants including mutations rs373838463, rs2107818892, and rs763687242, were docked with their reported binder, TNF receptor-associated factor 2 (TRAF2). The lowest binding affinity and stability of the docked mutant complexes as compared to the wild type GPx1 were validated by molecular dynamic simulation. Finally, the comparison of RMSD, RMSF, RoG and hydrogen bond analyses between wild-type and mutant’s complexes validated the deleterious effects of proposed nsSNPs. This study successfully identified and verified the possibly damaging nsSNPs in GPx1 enzyme, which may be linked the progression of various types of cancer. Our findings underscore the value of in-silico approaches in mutational analysis and encourage further preclinical and clinical trials.

Abstract 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-1β) 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.

Abstract Background Microvascular complications of diabetes including retinopathy, nephropathy, and neuropathy are those long-term complications that affect small blood vessels. Diabetic nephropathy (DN) is characterized by persistent microalbuminuria. A meta-analysis of case–control studies aims to examine the relationship between MnSOD (rs4880) and GPx1 (rs1050450) and the risk of DN. Methods Various databases such as Web of Science, PubMed, Springer Link, Cochrane Library, Science Direct, Embase, and Google Scholar were utilized to extract relevant studies. The statistical software MedCalc version 22.009 was acquired to accomplish the meta-analysis of the included studies. Results A significant association was found between two SNPs (rs4880 and rs1050450) and DN in the homozygous recessive model [95% confidence interval (CI) 0.97–2.41, odds ratio (OR) TT vs CC = 1.53, P = 0.06] and heterozygous model [95% CI 0.92–1.97, OR CT vs CC = 1.35, P = 0.12], while there was no association with the other genetic models. A significant association between rs4880 and DN was perceived in the Asian population [95% CI 1.24–2.03, OR = 1.6, P

Sensitive skin (SS) is associated with discomfort, including burning, stinging, and itching. These symptoms are often exacerbated by environmental factors and personal care products. In this genome-wide association study (GWAS), we aimed to identify the genetic variants associated with SS in 1690 Korean female participants; 389 and 1301 participants exhibited sensitive and non-sensitive skin, respectively. Using a combination of self-reported questionnaires, patch tests, and sting tests, we selected 115 sensitive and 181 non-sensitive participants for genetic analysis. A GWAS was performed to identify the loci associated with SS. Although none of the single-nucleotide polymorphisms (SNPs) met the genome-wide significance threshold, we identified several SNPs with suggestive associations. SNP rs11689992 in the 2q11.3 region increased SS risk by approximately 3.67 times. SNP rs7614738 in the USP4 locus elevated SS risk by 2.34 times and was found to be an expression quantitative trait locus for GPX1, a gene involved in oxidative stress and inflammation. Additionally, SNPs rs12306124 in the RASSF8 locus and rs10483893 in the NRXN3 region were identified. These results suggest that the genetic variations affecting oxidative stress, cell growth regulation, and neurobiology potentially influence skin sensitivity, providing a basis for further investigation and the development of personalized approaches to manage sensitive skin. [ABSTRACT FROM AUTHOR]

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-1β) 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. [ABSTRACT FROM AUTHOR]

Human adenovirus (HAdV) can cause severe respiratory infections in immunocompromised patients, but its clinical treatment is seriously limited by side effects of drugs such as poor efficacy, low bioavailability and severe nephrotoxicity. Trace element selenium (Se) has been found will affect the disease progression of pneumonia, but its antivirus efficacy could be improved by speciation optimization. Therefore, herein we performed anti-HAdV effects of different Se speciation and found that lentinan (LNT)-decorated selenium nanoparticles (SeNPs) exhibited low cytotoxicity and excellent anti-HAdV antiviral activity. Furthermore, SeNPs@LNT reduced the HAdV infection-induced mitochondrial damage and excessive production of reactive oxygen species (ROS). It was also involved in the repair of host cell DNA damage and inhibition of viral DNA replication. SeNPs@LNT inhibited HAdV-induced apoptosis mainly by modulating the p53/Bcl-2 apoptosis signaling pathway. In vivo, SeNPs@LNT replenished Se by targeting the infected site through the circulatory system and was involved in the synthesis of Glutathione peroxidase 1 (GPx1). More importantly, GPx1 played an antioxidant and immunomodulatory role in alleviating HAdV-induced inflammatory cytokine storm and alleviating adenovirus pneumonia in Se-deficient mice. Collectively, this study provides a Se speciation of SeNPs@LNT with anti-HAdV activity, and demonstrate that SeNPs@LNT is a promising pharmaceutical candidate for the treatment of HAdV.

Reactive oxygen species (ROS) are a by-product of the activity of cytochrome P450 steroidogenic enzymes. Antioxidant enzymes protect against ROS damage. To identify if any particular antioxidant enzyme is used to protect against ROS produced by granulosa cells as follicles enlarge and produce oestradiol, we measured in the bovine granulosa cells the expression of two steroidogenic enzymes (CYP11A1, CYP19A1), important for progesterone and oestradiol production. We also measured the expression of the members (FDXR, FDX1, POR) of their electron transport chains (ETC). We measured antioxidant enzymes (GPXs 1–8, CAT, SODs 1 and 2, PRDXs 1–6, GSR, TXN, TXNRDs 1–3). Since selenium is an active component of GPXs, the selenium-uptake receptors (LRPs 2 and 8) were measured. Only the selenium-dependent GPX1 showed the same increase in expression as the steroidogenic enzymes did with increasing follicle size. GPX4 and PRDX2/6 decreased with follicle size, whereas SOD1/2, CAT, GSR, and TXNRD3 were lowest at the intermediate sizes. The other antioxidant enzymes were unchanged or expressed at low levels. The expression of the selenium-uptake receptor LRP8 also increased significantly with follicle size. Correlation analysis revealed statistically significant and strongly positive correlations of the steroidogenic enzymes and their ETCs with both GPX1 and LRP8. These results demonstrate a relationship between the expression of genes involved in steroidogenesis and selenium-containing antioxidant defence mechanisms. They suggest that during the late stages of folliculogenesis, granulosa cells are dependent on sufficient expression of GPX1 and the selenium transporter LRP8 to counteract increasing ROS levels caused by the production of steroid hormones.

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. [ABSTRACT FROM AUTHOR]

The significance of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving various aspects unexplored. Recent identification of Gpx1 as a palmitoylated protein has generated interest in exploring its potential involvement in novel pathological mechanisms related to angiogenesis. In this study, we demonstrate that Gpx1 undergoes palmitoylation at cysteine-76 and -113, with PPT1 playing a crucial role in modulating the depalmitoylation of Gpx1. Furthermore, we find that PPT1-regulated depalmitoylation negatively impacts Gpx1 protein stability. Interestingly, inhibiting Gpx1 palmitoylation, either through expression of a non-palmitoylated Gpx1 mutant or by expressing PPT1, significantly enhances neovascular angiogenesis. Conversely, in PPT1-deficient mice, angiogenesis is notably attenuated compared to wild-type mice in an Oxygen-Induced Retinopathy (OIR) model, which mimics pathological angiogenesis. Physiologically, under hypoxic conditions, Gpx1 palmitoylation levels are drastically reduced, suggesting that increasing Gpx1 palmitoylation may have beneficial effects. Indeed, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR disease model. Overall, our findings highlight the pivotal role of protein palmitoylation in angiogenesis and propose a novel mechanism whereby the PPT1-Gpx1 axis modulates angiogenesis, thereby providing a potential therapeutic strategy for targeting PPT1 to combat angiogenesis.

Background/Aim: Glutathione peroxidases (GPXs) are crucial antioxidant enzymes, counteracting reactive oxygen species (ROS). GPX overexpression promotes proliferation and invasion in cancer cells. Glutathione peroxidase-1 (GPX1), the most abundant isoform, contributes to invasion, migration, cisplatin resistance, and proliferation in various cancers. Nuclear factor-kappa B (NF-ĸB) participates in cell proliferation, apoptosis, and tumor progression. The inhibition of NF-ĸB expression reduces the malignancy of esophageal squamous cell carcinoma. This study aimed to explore the GPX1 and NF-ĸB signaling pathways and their correlation with gastric cancer cell proliferation and invasion. Materials and Methods: Cell culture, complementary DNA microarray analysis, western blotting, reverse transcription-polymerase chain reaction, zymography, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, GPX1 knock-down with short hairpin RNA (shRNA), standard two-chamber invasion assay, chromatin immunoprecipitation assay. Results: Hepatocyte growth factor (HGF) up-regulated GPX1 expression in gastric cancer cells. The NF-ĸB inhibitor, pyrrolidine dithiocarbamate down-regulated HGF-induced GPX1 protein levels. Furthermore, NF-ĸB and urokinase-type plasminogen activators were down-regulated in GPX1-shRNAtreated cells. Treatment with an Akt pathway inhibitor (LY294002) led to the down-regulation of GPX1 and NF-ĸB gastric cancer cells. GPX1 knockdown resulted in decreased HGF-mediated in vitro cell proliferation and invasion. The study identified the putative binding site of the GPX1 promoter containing the NF-ĸB binding site, confirmed through chromatin immunoprecipitation. Conclusion: HGF induced GPX1 expression through the NF-ĸB and Akt pathways, suggesting a central role in gastric cell proliferation and invasion. Hence, GPX1 emerges as a potential therapeutic target for gastric cancer. [ABSTRACT FROM AUTHOR]

The parenteral nutrition (PN) received by premature newborns is contaminated with peroxides that induce global DNA hypermethylation via oxidative stress. Exposure to peroxides could be an important factor in the induction of chronic diseases such as those observed in adults who were born preterm. As endogenous H2O2 is a major regulator of glucose–lipid metabolism, our hypothesis was that early exposure to PN induces permanent epigenetic changes in H2O2 metabolism. Three-day-old guinea pigs were fed orally (ON), PN or glutathione-enriched PN (PN+GSSG). GSSG promotes endogenous peroxide detoxification. After 4 days, half the animals were sacrificed, and the other half were fed ON until 16 weeks of age. The liver was harvested. DNA methylation and mRNA levels were determined for the SOD2, GPx1, GCLC, GSase, Nrf2 and Keap1 genes. PN induced GPx1 hypermethylation and decreased GPx1, GCLC and GSase mRNA. These findings were not observed in PN+GSSG. PN+GSSG induced Nrf2 hypomethylation and increased Nrf2 and SOD2 mRNA. These observations were independent of age. In conclusion, in neonatal guinea pigs, PN induces epigenetic changes, affecting the expression of H2O2 metabolism genes. These changes persist for at least 15 weeks after PN. This disruption may signify a permanent reduction in the capacity to detoxify peroxides. [ABSTRACT FROM AUTHOR]

Recent research on selenium-dependent glutathione peroxidase 2 (GPX2) tends to focus on possible roles in tumorigenesis. This is based on the idea that normally generated hydroperoxide species can damage DNA to produce mutations and react with protein sulfhydryl groups to perturb normal regulation of cancer-related pathways. GPX2 is one of many peroxidases available to control hydroperoxide levels. Altered GPX2 expression levels from normal to cancer or with cancer stages seems to be the main feature in bringing it to the attention of investigators. In this commentary, we examine this premise as a basis for cancer studies, largely by trying to place GPX2 within the larger context of antioxidant enzyme gene expression. We make use of public databases and illustrate their possible role in approaching this issue. Since use of such databases is new to us, we looked to sources in the literature to evaluate expression level data, finding general agreement with some discrepancies over the range of expression and relative expression levels among some samples. Using the database information, we critically evaluate methods used to study GPX2 in the current literature for a variety of cancers. Second, groups are now trying to compare enzymatic properties of GPX1 and GPX2 using proteins from bacterial cultures. We weigh in on these recent findings and discuss the impact on the relative GPX2 and GPX1 functions.

Purpose: Age-related macular degeneration (AMD) is a progressive disease resulting in loss of vision. One of the important factors in AMD disease is oxidative stress. Excessive accumulation of ROS and the inability of the antioxidant defense system to neutralize it can contribute to the development of lesions. One of the antioxidant enzymes is glutathione peroxidase. The aim of this study was to investigate the relation between genetic polymorphisms of GPX1 C594T and GPX4 C718T with the risk of AMD disease. Materials and Methods: In this case-control study, 122 AMD patients and 122 healthy controls group matched for gender and age. Genotyping of GPX1 and GPX4 were done by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Results: There was no significant relationship between allele and genotype frequency in the genetic polymorphisms of GPX1 C594T (rs1050450) and GPX4 C718T (rs713041) and susceptibility to AMD. The association between smoking and AMD was found in this study (OR = 2.165, CI = 1.145-4.092, P = 0.017). Also, there was a significant correlation between the number of patients who were working outside the room (OR = 2.067, CI = 1.168-3.659, P = 0.013). Conclusions: The current study suggested that the GPX1 C594T (rs1050450) and GPX4 C718T (rs713041) polymorphisms are not predisposing to AMD. [ABSTRACT FROM AUTHOR]

Recent research on selenium-dependent glutathione peroxidase 2 (GPX2) tends to focus on possible roles in tumorigenesis. This is based on the idea that normally generated hydroperoxide species can damage DNA to produce mutations and react with protein sulfhydryl groups to perturb normal regulation of cancer-related pathways. GPX2 is one of many peroxidases available to control hydroperoxide levels. Altered GPX2 expression levels from normal to cancer or with cancer stages seems to be the main feature in bringing it to the attention of investigators. In this commentary, we examine this premise as a basis for cancer studies, largely by trying to place GPX2 within the larger context of antioxidant enzyme gene expression. We make use of public databases and illustrate their possible role in approaching this issue. Since use of such databases is new to us, we looked to sources in the literature to evaluate expression level data, finding general agreement with some discrepancies over the range of expression and relative expression levels among some samples. Using the database information, we critically evaluate methods used to study GPX2 in the current literature for a variety of cancers. Second, groups are now trying to compare enzymatic properties of GPX1 and GPX2 using proteins from bacterial cultures. We weigh in on these recent findings and discuss the impact on the relative GPX2 and GPX1 functions. [ABSTRACT FROM AUTHOR]

Abstract Background Selenium is an essential trace element in the human body. In epidemiological and clinical studies, Se supplementation significantly reduced the incidence of lung cancer in individuals with low baseline Se levels. The significant action of selenium is based on the selenium‐containing protein as a mediator. Of note, the previous studies reported that the expression of selenium‐binding protein 1 (SELENBP1) was obviously decreased in many human cancer tissues including non‐small cell lung cancer (NSCLC). However, its roles in the origin and development of NSCLC are still unclear. Methods The expression of SELENBP1 was measured by qRT‐PCR, Western blotting and IHC in our collected clinical NSCLC tissues and cell lines. Next, the CCK‐8, colony formation, wound‐haeling, Millicell, Transwell, FCM assay, and in vivo xenograft model were performed to explore the function of SELENBP1 in NSCLC. The molecular mechanisms of SELENBP1 were investigated by Western blotting or IF assay. Results We further identified that the expression of SELENBP1 was significantly decreased in NSCLC tissues in TCGA database and 45 out of 59 collected clinical NSCLC tissues compared with adjacent nontumor tissues, as well as in four NSCLC cell lines compared with normal lung cells. Particularly, we unexpectedly discovered that SELENBP1 was obviously expressed in alveolar type 2 (AT‐II) cells for the first time. Then, a series of in vitro experiments uncovered that overexpression of SELENBP1 inhibited the proliferation, migration, and invasion of NSCLC cells, and induced cell apoptosis. Moreover, overexpression of SELENBP1 also inhibited growth and induced apoptosis of NSCLC cells in vivo. Mechanistically, we demonstrated that overexpression of SELENBP1 inhibited the malignant characteristics of NSCLC cells in part via inactivating the PI3K/AKT/mTOR signal pathway. Meanwhile, we found that overexpression of SELENBP1 inducing the apoptosis of NSCLC cells was associated with the activation of caspase‐3 signaling pathway under nonhigh level of oxidative stress, but overexpression of SELENBP1 facilitating the cell apoptosis might be related to its combining with GPX1 and colocalizing in the nucleus under high level of oxidative stress. Conclusions Our findings highlighted that SELENBP1 was an important tumor suppressor during the origin and development of NSCLC. It may help to discover novel biomarkers or drug therapy targets for NSCLC.

Background/Objective/Methods: Glutathione-S-transferase Mu1 (GSTM1) and glutathione peroxidase 1 (GPX1) are known antioxidant enzymes that help protect cells from the oxidative damage that occurs from smoking. This study explored the correlation between GSTM1 and GPX1 levels between a group of smokers with the GSTM1 and GPX1 genes in the Saudi population and a control group and investigated the genetic risk factors in the group of smokers. Results: The control and smokers' group (n = 50; aged 22.3 ± 3.1 years; BMI 24.6 ± 5.9 kg/m2) were genotyped using quantitative polymerase chain reaction (qPCR). In comparison with the control group, the smokers' group displayed a different genotype disruption of GSTM1 and GPX1. Carriers of the homozygous (TT) genotype of GSTM1 had more than a twofold (OR = 2.71, 95% CI = 0.10–70.79, P = 1.000) smoking risk than the carriers of the heterozygous (CT) genotype. Those with the GPX1 gene showed no risk in the control and smokers' groups. Smokers with the TT/GG combination (homozygous for GPX1 and normal for GPX1) were identified as high risk (OR = 2.58, 95% CI = 0.096–69.341). Conclusion: The main outcomes showed no significant association between genetic polymorphism of the GSTM1 and GPX1 genes and cigarette smoking in the Saudi Arabian population. However, the results showed a slight decrease in the number of GSTM1 and GPX1 gene modifications among smokers. [ABSTRACT FROM AUTHOR]

Background: Selenium is an essential trace element in the human body. In epidemiological and clinical studies, Se supplementation significantly reduced the incidence of lung cancer in individuals with low baseline Se levels. The significant action of selenium is based on the selenium‐containing protein as a mediator. Of note, the previous studies reported that the expression of selenium‐binding protein 1 (SELENBP1) was obviously decreased in many human cancer tissues including non‐small cell lung cancer (NSCLC). However, its roles in the origin and development of NSCLC are still unclear. Methods: The expression of SELENBP1 was measured by qRT‐PCR, Western blotting and IHC in our collected clinical NSCLC tissues and cell lines. Next, the CCK‐8, colony formation, wound‐haeling, Millicell, Transwell, FCM assay, and in vivo xenograft model were performed to explore the function of SELENBP1 in NSCLC. The molecular mechanisms of SELENBP1 were investigated by Western blotting or IF assay. Results: We further identified that the expression of SELENBP1 was significantly decreased in NSCLC tissues in TCGA database and 45 out of 59 collected clinical NSCLC tissues compared with adjacent nontumor tissues, as well as in four NSCLC cell lines compared with normal lung cells. Particularly, we unexpectedly discovered that SELENBP1 was obviously expressed in alveolar type 2 (AT‐II) cells for the first time. Then, a series of in vitro experiments uncovered that overexpression of SELENBP1 inhibited the proliferation, migration, and invasion of NSCLC cells, and induced cell apoptosis. Moreover, overexpression of SELENBP1 also inhibited growth and induced apoptosis of NSCLC cells in vivo. Mechanistically, we demonstrated that overexpression of SELENBP1 inhibited the malignant characteristics of NSCLC cells in part via inactivating the PI3K/AKT/mTOR signal pathway. Meanwhile, we found that overexpression of SELENBP1 inducing the apoptosis of NSCLC cells was associated with the activation of caspase‐3 signaling pathway under nonhigh level of oxidative stress, but overexpression of SELENBP1 facilitating the cell apoptosis might be related to its combining with GPX1 and colocalizing in the nucleus under high level of oxidative stress. Conclusions: Our findings highlighted that SELENBP1 was an important tumor suppressor during the origin and development of NSCLC. It may help to discover novel biomarkers or drug therapy targets for NSCLC. [ABSTRACT FROM AUTHOR]

Lasia spinosa leaf extract (LSML) has been studied as a functional food source for DNA damage protection and antioxidant gene expression in paracetamol (PCM)-induced liver injury. The DNA damage-protecting capacity of LSML was evaluated using pBR322 plasmid DNA. A toxic dose of PCM was administered to rats, followed by an intervention with LSML of 65–250 mg/kg for 22 days. In LSML-treated animals, a significant decrease in hepatic parameters, hepatocyte growth, and cell injury was noticed when compared to the hepatic control. The increase of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and decrease of malondialdehyde (MDA) were manifested. The serum total protein, ALP, ALT, AST, and bilirubin reverted to normal compared to the healthy and silymarin-treated groups. An elevated mRNA expression of SOD2, CAT, GPX1, PON1, and PFK1 was manifested in LSML-treated groups. The results demonstrate that LSML could be an antioxidant gene upregulating functional food sources to protect against liver injury.

Preventing islet β‐cells death is crucial for treating type 2 diabetes mellitus (T2DM). Currently, clinical drugs are being developed to improve the quality of T2DM care and self‐care, but drugs focused on reducing islets β‐cell death are lacking. Given that β‐cell death in T2DM is dominated ultimately by excessive reactive oxygen species (ROS), eliminating excessive ROS in β‐cells is a highly promising therapeutic strategy. Nevertheless, no antioxidants have been approved for T2DM therapy because most of them cannot meet the long‐term and stable elimination of ROS in β‐cells without eliciting toxic side‐effects. Here, it is proposed to restore the endogenous antioxidant capacity of β‐cells to efficiently prevent β‐cell death using selenium nanodots (SENDs), a prodrug of the antioxidant enzyme glutathione peroxidase 1 (GPX1). SENDs not only scavenge ROS effectively, but also "send" selenium precisely to β‐cells with ROS response to greatly enhance the antioxidant capacity of β‐cells by increasing GPX1 expression. Therefore, SENDs greatly rescue β‐cells by restoring mitophagy and alleviating endoplasmic reticulum stress (ERS), and demonstrate much stronger efficacy than the first‐line drug metformin for T2DM treatment. Overall, this strategy highlights the great clinical application prospects of SENDs, offering a paradigm for an antioxidant enzyme prodrug for T2DM treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The downregulation of glutathione peroxidase-1 (GPx1) plays a role in clasmatodendrosis (an autophagic astroglial death) in the hippocampus of chronic epilepsy rats. Furthermore, N-acetylcysteine (NAC, a GSH precursor) restores GPx1 expression in clasmatodendritic astrocytes and alleviates this autophagic astroglial death, independent of nuclear factor erythroid-2-related factor 2 (Nrf2) activity. However, the regulatory signal pathways of these phenomena have not been fully explored. In the present study, NAC attenuated clasmatodendrosis by alleviating GPx1 downregulation, casein kinase 2 (CK2)-mediated nuclear factor-κB (NF-κB) serine (S) 529 and AKT-mediated NF-κB S536 phosphorylations. 2-[4,5,6,7-Tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazole-1-yl]acetic acid (TMCB; a selective CK2 inhibitor) relieved clasmatodendritic degeneration and GPx1 downregulation concomitant with the decreased NF-κB S529 and AKT S473 phosphorylations. In contrast, AKT inhibition by 3-chloroacetyl-indole (3CAI) ameliorated clasmatodendrosis and NF-κB S536 phosphorylation, while it did not affect GPx1 downregulation and CK2 tyrosine (Y) 255 and NF-κB S529 phosphorylations. Therefore, these findings suggest that seizure-induced oxidative stress may diminish GPx1 expression by increasing CK2-mediated NF-κB S529 phosphorylation, which would subsequently enhance AKT-mediated NF-κB S536 phosphorylation leading to autophagic astroglial degeneration. [ABSTRACT FROM AUTHOR]

Objective:To investigate the association between obstructive sleep apnea syndrome (OSAS), glutathione peroxidase-1 (GPX1) Pro198Leu, and manganese superoxide dismutase (MnSOD) Ala16Val gene polymorphisms.Materials and Methods:The study included 81 patients with OSAS and 75 healthy controls from the Turkish population. Genotypes of the MnSOD rs4880 T/C (Ala16Val) and GPX1 rs1050450 T/C (Pro198Leu) variants were determined via single-nucleotide polymorphisms genotyping analysis, which is based on simple probe melting curve analysis.Results:The frequencies of the MnSOD rs4880 T/T, T/C, and C/C were 35.8%, 50.6%, and 13.5% in patients with OSAS and 34.6%, 49.3%, and 16% in the controls, respectively. No statistically significant difference was determined between patients and controls in terms of MnSOD rs4880 variant genotype and allele distribution (odds ratio: 1.07; 95% confidence interval: 0.68-1.69; p>0.05). The frequencies of the GPX1 rs1050450T/T, T/C, and C/C were 12.0%, 38.5%, and 49.4% in patients with OSAS and 13.1%, 42.1%, and 44.7% in the controls, respectively. No statistically significant difference was determined in the genotype and allele frequencies of the GPX1 rs1050450 variant between the patients and controls (p>0.05). Additionally, the haplotype was examined on the basis of combined genotypes for the two variants in patients with OSAS and controls, which revealed no statistically significant correlation.Conclusion:Our study indicates that two polymorphisms in these antioxidant enzymes were not associated with Turkish patients with OSAS. Further studies may reveal an association between these two polymorphisms with some clinical parameters in patients with OSAS.

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. [ABSTRACT FROM AUTHOR]

Over-accumulation of reactive oxygen species (ROS) causes mitochondrial dysfunction and impairs the osteogenic potential of bone marrow-derived mesenchymal stem cells (BMMSCs). Selenium (Se) protects BMMSCs from oxidative stress-induced damage; however, it is unknown whether Se supplementation can promote the repair of osteoporotic bone defects by rescuing the impaired osteogenic potential of osteoporotic BMMSCs (OP-BMMSCs). In vitro treatment with sodium selenite (Na2SeO3) successfully improved the osteogenic differentiation of OP-BMMSCs, as demonstrated by increased matrix mineralization and up-regulated osteogenic genes expression. More importantly, Na2SeO3 restored the impaired mitochondrial functions of OP-BMMSCs, significantly up-regulated glutathione peroxidase 1 (GPx1) expression and attenuated the intracellular ROS and mitochondrial superoxide. Silencing of Gpx1 completely abrogated the protective effects of Na2SeO3 on mitochondrial functions of OP-BMMSCs, suggesting the important role of GPx1 in protecting OP-BMMSCs from oxidative stress. We further fabricated Se-modified bone cement based on silk fibroin and calcium phosphate cement (SF/CPC). After 8 weeks of implantation, Se-modified bone cement significantly promoted bone defect repair, evidenced by the increased new bone tissue formation and enhanced GPx1 expression in ovariectomized rats. These findings revealed that Se supplementation rescued mitochondrial functions of OP-BMMSCs through activation of the GPx1-mediated antioxidant pathway, and more importantly, supplementation with Se in SF/CPC accelerated bone regeneration in ovariectomized rats, representing a novel strategy for treating osteoporotic bone fractures or defects. [ABSTRACT FROM AUTHOR]

Purpose: Cigarette smoke (CS) has been demonstrated to mediate oxidative stress (OS) and epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, thereby contributing to airway remodeling in chronic obstructive pulmonary disease (COPD). Studies have shown upregulation of Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, in the airway epithelium of smokers. Many studies indicate that UCHL1's regulation of EMT and OS has a complex role in various cell types, including respiratory epithelium. Thus, we aimed to investigate UCHL1's regulation of EMT, OS, and related mechanisms in cigarette smoke-exposed airway epithelium., Methods: Exposure to cigarette smoke (CS) or cigarette smoke extract (CSE) was employed to establish both animal and cellular models. Protein expression was analyzed using immunohistochemistry, immunofluorescence, and Western blotting. Lentiviral UCHL1 or GPX1-siRNA was used to modulate UCHL1 or GPX1 expression, respectively. Transwell assays were employed to evaluate cell migration and EMT-related alterations. Oxidative stress levels were assessed using specific assay kits., Results: This study validated that exposure to CS induces UCHL1 expression in bronchial epithelial cells both in vitro and in vivo, a phenomenon positively correlated with increased OS and EMT in the airway. Notably, UCHL1 overexpression counteracted CSE's impact on EMT markers, cell migration, and oxidative stress in BEAS-2B cells, while UCHL1 knockdown exacerbated these effects. Furthermore, in BEAS-2B cells treated with CSE, upregulation of UCHL1 was found to enhance the expression of glutathione peroxidase 1 (GPX1), an antioxidant enzyme. The effect of UCHL1 overexpression on EMT-related protein markers and cell migration was reversed upon GPX1 silencing via siRNA., Conclusions: These findings suggest that UCHL1-mediated regulation of GPX1 expression alleviates cigarette smoke-induced EMT-related protein markers change and cell migration in BEAS-2B cell., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical Approval: The animal study protocol was reviewed and approved by the Animal Ethics and Experimentation Committee of Yangzhou University (No. YXYLL-2018–80). The standards of practice in animal experiments were conducted according to the ARRIVE guidelines [52]. Consent for Publication: All authors have reviewed the manuscript and consent to its publication., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To explore the anti-cancer role of GABPA in the progression of gastric cancer (GC), and the underlying mechanism. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the expression pattern of GABPA in 45 pairs of GC and non-tumoral tissues. The relationship between GABPA expression and clinic pathological indicators of GC patients was analyzed. In AGS and SGC-7901 cells overexpressing GABPA, their migratory ability was determined by trans well and wound healing assay. The interaction between GABPA and its downstream target GPX1 was explored by dual-luciferase reporter assay, and their synergistical regulation on GC cell migration was finally elucidated. Results: GABPA was downregulated in GC tissues in comparison to normal ones. Low level of GABPA predicted high incidences of lymphatic and distant metastasis in GC. Overexpression of GABPA blocked AGS and SGC-7901 cells to migrate. GABPA could target GPX1 via the predicted binding site. GPX1 was upregulated in clinical samples of GC, and negatively correlated to GABPA level. The anticancer effect of GABPA on GC relied on the involvement of GPX1. Conclusions: GABPA is downregulated in GC samples, which can be utilized to predict GC metastasis. Serving as a tumor suppressor, GABPA blocks GC cells to migrate by targeting GPX1.

As oxidative stress is implicated in the pathogenesis of head and neck squamous cell cancer (HNSCC), the functions of antioxidant enzyme systems and DNA repair proteins are critical in the development of cancer. To investigate the role of genetic polymorphisms of the antioxidant superoxide dismutase 2 (SOD2) Val16Ala, glutathione peroxidase 1 (GPX1) Pro198Leu, and the DNA repair Xeroderma Pigmentosum Group D (XPD) Lys751Gln genes under exogenous risk factors, including smoking and alcohol consumption, in HNSCC carcinogenesis, we conducted a case-control study on 139 unrelated cases and 265 non-cancer controls. Polymorphisms were analyzed in additive, dominant and recessive genetic models, individually and in an interaction model. Carriers of the T allele of SOD2 were associated with an increased risk for HNSCC in males and smokers; similarly, the T allele of GPX1 was associated with elevated risk in the overall and smoker subgroup. A 12.47-fold increased risk was observed for the carriers of GPX1 TT, SOD2 CT and XPD CC genotypes for HNSCC. This is the first study presenting the potential roles of SOD2, GPX1 and XPD polymorphisms in interaction and under three genetic models in the development of HNSCC. The results suggest that these polymorphisms slightly modify the risk in HNSCC development individually but are significantly higher when they functioned and were evaluated together.

Aims: Deciphering the genetic relationships between major depressive disorder (MDD) and osteoarthritis (OA) may facilitate an understanding of their biological mechanisms, as well as inform more effective treatment regimens. We aim to investigate the mechanisms underlying relationships between MDD and OA in the context of common genetic variations. Methods: Linkage disequilibrium score regression was used to test the genetic correlation between MDD and OA. Polygenic analysis was performed to estimate shared genetic variations between the two diseases. Two-sample bidirectional Mendelian randomization analysis was used to investigate causal relationships between MDD and OA. Genomic loci shared between MDD and OA were identified using cross-trait meta-analysis. Fine-mapping of transcriptome-wide associations was used to prioritize putatively causal genes for the two diseases. Results: MDD has a significant genetic correlation with OA (rg = 0.29) and the two diseases share a considerable proportion of causal variants. Mendelian randomization analysis indicates that genetic liability to MDD has a causal effect on OA (bxy = 0.24) and genetic liability to OA conferred a causal effect on MDD (bxy = 0.20). Cross-trait meta-analyses identified 29 shared genomic loci between MDD and OA. Together with fine-mapping of transcriptome-wide association signals, our results suggest that Estrogen Receptor 1 (ESR1), SRY-Box Transcription Factor 5 (SOX5), and Glutathione Peroxidase 1 (GPX1) may have therapeutic implications for both MDD and OA. Conclusion: The study reveals substantial shared genetic liability between MDD and OA, which may confer risk for one another. Our findings provide a novel insight into phenotypic relationships between MDD and OA. Cite this article: Bone Joint Res 2022;11(1):12–22.

The synthesis of selenoproteins requires the co-translational recoding of an in-frame UGASec codon. Interactions between the Selenocysteine Insertion Sequence (SECIS) and the SECIS binding protein 2 (SBP2) in the 3′untranslated region (3′UTR) of selenoprotein mRNAs enable the recruitment of the selenocysteine insertion machinery. Several selenoprotein mRNAs undergo unusual cap hypermethylation and are not recognized by the translation initiation factor 4E (eIF4E) but nevertheless translated. The human eukaryotic translation initiation factor 3 (eIF3), composed of 13 subunits (a-m), can selectively recruit several cellular mRNAs and plays roles in specialized translation initiation. Here, we analyzed the ability of eIF3 to interact with selenoprotein mRNAs. By combining ribonucleoprotein immunoprecipitation (RNP IP) in vivo and in vitro with cross-linking experiments, we found interactions between eIF3 and a subgroup of selenoprotein mRNAs. We showed that eIF3 preferentially interacts with hypermethylated capped selenoprotein mRNAs rather than m7G-capped mRNAs. We identified direct contacts between GPx1 mRNA and eIF3 c, d, and e subunits and showed the existence of common interaction patterns for all hypermethylated capped selenoprotein mRNAs. Differential interactions of eIF3 with selenoprotein mRNAs may trigger specific translation pathways independent of eIF4E. eIF3 could represent a new player in the translation regulation and hierarchy of selenoprotein expression. [ABSTRACT FROM AUTHOR]

High levels of glucose (HG) induce reactive oxygen species-mediated oxidative stress in endothelial cells (ECs), which leads to endothelial dysfunction and tissue damage. However, the molecular mechanisms involved in HG-induced endothelial oxidative stress and damage remain elusive. Here we show that cellular ATP level-modulated p53 Thr55 phosphorylation plays a critical role in the process. Upon HG exposure, the elevated ATP levels induced the kinase activity of TAF1 (TBP-associated factor 1), which leads to p53 Thr55 phosphorylation. The phosphorylation dissociates p53 from the glutathione peroxidase 1 (GPX1) promoter and results in reduction of GPX1 expression. Inhibition of TAF1-mediated p53 Thr55 phosphorylation abolished those events, supporting the role of TAF1 in sensing cellular ATP elevation and in regulating GPX1 expression under the HG condition. Importantly, treating cells with HG increased intracellular H2O2 and cell apoptosis, as well as suppressed nitric oxide (NO) bioavailability and tube network formation. These effects were also remarkably reversed by inhibition of TAF1 and p53 Thr55 phosphorylation. We conclude that HG leads to endothelial dysfunction via TAF1-mediated p53 Thr55 phosphorylation and subsequent GPX1 inactivation. Our study thus revealed a novel mechanism by which HG induces endothelial oxidative stress and damage and possibly provided an avenue for targeted therapy for diabetes-associated cardiovascular diseases.

Endometrial cancer (EC) is a common gynecological cancer worldwide, often associated with a poor prognosis after recurrence or metastasis. Ovatodiolide (OVA) is a macrocyclic diterpenoid derived from Anisomeles indica that shows anticancer effects in various malignancies. This study aimed to evaluate the cytotoxic effects of OVA on EC cell proliferation and cancer stem cell (CSC) activity and explore its underlying molecular mechanisms. OVA treatment dose-dependently reduced the viability and colony formation of three EC cell lines (AN3CA, HEC-1A, and EMC6). It induced G2/M phase cell cycle arrest, associated with decreased cell division cycle 25C (CDC25C) expression and reduced activation of cyclin-dependent kinases 1 (CDK1) and 2 (CDK2). OVA also increased reactive oxygen species (ROS) production and DNA damage, activating the DNA damage-sensitive cell cycle checkpoint kinases 1 (CHK1) and 2 (CHK2) and upregulating the DNA damage marker γ-H2A.X variant histone (H2AX). It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated glutathione peroxidase 1 (GPX1), an antioxidant enzyme counteracting oxidative stress. Moreover, OVA reduced the self-renewal capacity of CSCs, reducing the expression of key stemness proteins Nanog homeobox (NANOG) and octamer-binding transcription factor 4 (OCT4). The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies. [Display omitted] • Ovatodiolide represses cell viability and proliferation of EC cells. • Ovatodiolide causes G2/M cell cycle arrest via DNA damage induction and CHK1/CHK2 pathway activation. • Ovatodiolide inhibits mTOR/NFκB signaling pathways. • Ovatodiolide raises intracellular ROS generation and represses GPX1 expression. • Ovatodiolide suppresses cancer stemness of EC cells via ROS generation. [ABSTRACT FROM AUTHOR]

We published the first paper to characterize GPX2 (aka GSHPx-GI) as a selenoenzyme with glutathione peroxidase activity in 1993. Among the four Se-GPX isozymes, GPX1-4, GPX1 and GPX2 are closely related in terms of structure, substrate specificities, and subcellular localization. What sets them apart are distinct patterns of gene regulation, tissue distribution and response to selenium. While we identified the digestive tract epithelium as the main site of GPX2 expression, later work has shown GPX2 is found more widely in epithelial tissues with concentration of expression in stem cell and proliferative compartments. GPX2 expression is regulated over a wide range of levels by many pathways, including NRF2, WNT, p53, RARE and this often results in attaching undue significance to GPX2 as GPX2 is only a part of a system of hydroperoxidase activities, including GPX1, peroxiredoxins and catalase. These other activities may play equal or greater roles, particularly in cell lines cultured without selenium supplementation and often with very low GPX2 levels. This could be assessed by examining levels of mRNA and protein among these various peroxidases at the outset of studies. As an example, it was found that GPX1 responds to the absence of GPX2 in mouse ileum and colon epithelium with higher expression. As such, both Gpx1 and Gpx2 had to be knocked out in mice to produce ileocolitis. However, we note that the actual role of GPX1 and GPX2 in relation to peroxiredoxin function is unclear. There may be an interdependence that requires only low amounts of GPX1 and/or GPX2 in a supporting role to maintain proper peroxiredoxin function. GPX2 levels may be prognostic for cancer progression in colon, breast, prostate and liver, however, there is no consistent trend for higher or lower levels to be favorable. [Display omitted] • GPX2 was discovered by investigators screening human liver cDNA libraries with GPX1 probes. • GPX2 was characterized as a cytoplasmic selenoprotein with GPX activity like GPX1 and high expression in gastrointestinal tract. A role for GPX2 in the crypt/gland regions of the mid-lower GI was indicated by work with GPX1-knockout mice, GPX2-knockout mice and a combination of the lines. • Generally independent regulation and compartmentalization define semi-independent roles for the GPX2 and GPX1 isoenzymes. There is likely interaction in other tissues. • Recent work has broadened the range of tissues with expression with suggestion of impact on tumororigenesis and metastasis. Much work is reported without adequate context for GPX2 as a component of an array of hydroperoxidases and performed under conditions where GPX2 protein levels may be miniscule due to cell line or inadequate selenium. • Possible dominance by GPX2 in basal cell compartments is indicated and represents a possible future direction for GPX2 research. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Medical Biochemistry is the property of Society of Medical Biochemists of Serbia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Both excessive production of reactive oxygen species (ROS) and impaired antioxidant function are found in patients with chronic kidney disease (CKD). Therefore, individual susceptibility towards CKD can be induced by functional variations of genes encoding antioxidant regulatory (nuclear factor erythroid 2 - related factor 2 (Nrf2)) and catalytic (superoxide dismutase (SOD2) and glutathione peroxidase (GPX1)) proteins. Several types of single nucleotide polymorphisms (SNPs) have been found within the genes encoding these proteins, with Nrf2 (-617C/A), SOD2 (Ala16Val) and GPX1 (Pro198Leu) conferring impaired catalytic activity. The most unexplored gene polymorphism in CKD susceptibility, progression and survival, with only two original studies published, is the Nrf2 (-617C/A) polymorphism. The results of these studies showed that there was no individual impact of this polymorphism on the susceptibility towards end stage renal disease (ESRD) development, oxidative phenotype and mortality. However, Nrf2 had a significant role in ESRD risk and survival, when combined with other antioxidant genes. The results regarding the impact of SOD2 (Ala16Val) and GPX1 (Pro198Leu) polymorphisms on either CKD or ESRD are still inconclusive. Namely, some studies showed that patients having variant SOD2 (Val) or GPX1 (Leu) allele were at increased risk of CKD development and progression, while other studies reported only weak or no association between these polymorphisms and CKD. Surprisingly, the only study that reported an association of GPX1 polymorphism with overall/cardiovascular survival in ESRD patients showed a significant impact of low activity GPX1 (Leu/Leu) genotype on better survival. In this review, we comprehensively and critically appraise the literature on these polymorphisms related to oxidative stress in CKD patients, in order to identify gaps and provide recommendations for further clinical research and translation. New developments in the field of antioxidant polymorphisms in CKD patients could lead to better stratification of CKD patients, based on a prognostic antioxidant gene panel, and provide a more personalised medicine approach for the need of antioxidant therapy in these patients.

Osmotic stress caused by drought and high salinity is a significant environmental threat that limits plant growth and agricultural yield. Redox regulation plays an important role in plant stress responses, but the mechanisms by which plants perceive and transduce redox signals are still underexplored. Here, we report a critical function for the thiol peroxidase GPX1 in osmotic stress response in rice, where it serves as a redox sensor and transducer. GPX1 is quickly oxidized upon exposure to osmotic stress and forms an intramolecular disulfide bond, which is required for the activation of bZIP68, a VRE-like basic leucine zipper (bZIP) transcription factor involved in the ABA-independent osmotic stress response pathway. The disulfide exchange between GPX1 and bZIP68 induces homo-tetramerization of bZIP68 and thus positively regulates osmotic stress response by regulating osmotic-responsive gene expression. Furthermore, we discovered that the nuclear translocation of GPX1 is regulated by its acetylation under osmotic stress. Taken together, our findings not only uncover the redox regulation of the GPX1-bZIP68 module during osmotic stress but also highlight the coordination of protein acetylation and redox signaling in plant osmotic stress responses. This work elucidates the mechanisms of plants perceive and transduce redox signals in response to osmotic stress. We show that the rice thiol peroxidase GPX1 serves as a redox sensor and transducer in osmotic stress response. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Turkish Sleep Medicine is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Xiaojun Shao1 *,* Ci Yan1 *,* Dongxue Sun,1 Chunfeng Fu,1 Chunsheng Tian,1 Li Duan,1 Gang Zhu1,2 1Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Central Laboratory, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gang ZhuDepartment of Psychiatry, Tthe First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of ChinaTel/ Fax +86-24-83282184Email gzhu@cmu.edu.cnObjective: The dopamine and oxidative stress hypotheses are leading theories of the pathoetiology of schizophrenia (SCZ). Glutathione Peroxidase 1 (GPx-1), a major antioxidant enzyme, and the most abundantly expressed member of the GPx family, plays an important role in metabolic dopamine changes, which are closely related to neurological and psychiatric disorders. The impact of GPx-1 polymorphisms has rarely been explored in the field of SCZ. Here, we explored the possible relationship between GPx-1 gene polymorphisms and SCZ in Chinese Han subjects by using the polymerase chain reaction-restriction fragment length polymorphism method.Methods: DNA from 786 patients (360 patients with schizophrenia and 426 healthy controls) was genotyped for the single-nucleotide polymorphisms rs1800668 C/T and rs1050450 C/T in GPx-1 using polymerase chain reaction-restriction fragment length polymorphism analysis. Analysis of the association between GPx-1 and SCZ was performed using SPSS 22.0, while Haploview 4.2 software and SHEsis software were used to perform linkage disequilibrium analysis and haplotype analysis.Results: The results indicated that the GPx-1 polymorphisms rs1050450 and rs1800668 were associated with SCZ. We found that the C-allele of rs1800668 C/T may be a protection factor against SCZ in general, but in particular, for males. Furthermore, the CT and TC (GPx-1 rs1800668 C/T and rs1050450 C/T) haplotypes may be susceptible to SCZ in the population. Finally, no significant differences in allelic or genotypic frequencies of rs1050450 were detected between cases and controls from whole or stratification analyses by gender.Conclusion: GPx-1 polymorphisms are related to SCZ in Chinese Han subjects. Our results suggested that GPx-1 may be a potential gene that influences SCZ.Keywords: case-control study, Chinese Han population, GPx1, polymorphism, schizophrenia

The downregulation of glutathione peroxidase-1 (GPx1) plays a role in clasmatodendrosis (an autophagic astroglial death) in the hippocampus of chronic epilepsy rats. Furthermore, N-acetylcysteine (NAC, a GSH precursor) restores GPx1 expression in clasmatodendritic astrocytes and alleviates this autophagic astroglial death, independent of nuclear factor erythroid-2-related factor 2 (Nrf2) activity. However, the regulatory signal pathways of these phenomena have not been fully explored. In the present study, NAC attenuated clasmatodendrosis by alleviating GPx1 downregulation, casein kinase 2 (CK2)-mediated nuclear factor-κB (NF-κB) serine (S) 529 and AKT-mediated NF-κB S536 phosphorylations. 2-[4,5,6,7-Tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazole-1-yl]acetic acid (TMCB; a selective CK2 inhibitor) relieved clasmatodendritic degeneration and GPx1 downregulation concomitant with the decreased NF-κB S529 and AKT S473 phosphorylations. In contrast, AKT inhibition by 3-chloroacetyl-indole (3CAI) ameliorated clasmatodendrosis and NF-κB S536 phosphorylation, while it did not affect GPx1 downregulation and CK2 tyrosine (Y) 255 and NF-κB S529 phosphorylations. Therefore, these findings suggest that seizure-induced oxidative stress may diminish GPx1 expression by increasing CK2-mediated NF-κB S529 phosphorylation, which would subsequently enhance AKT-mediated NF-κB S536 phosphorylation leading to autophagic astroglial degeneration.

Background: Breast cancer (BC) is the leading cause of cancer-related deaths among women worldwide. The application of advanced technology has promoted accurate diagnosis and treatment of cancer. Anhydroicaritin (AHI) is a flavonoid with therapeutic potential in BC treatment. The current study aimed to determine AHI’s mechanism in BC treatment via RNA sequencing, comprehensive bioinformatics analysis, and experimental verification.Methods: Network pharmacology and MTT (3-(4,5)-dimethylthiazolyl-3,5- diphenyltetrazolium bromide) experiments were conducted to first confirm AHI’s anti-BC effect. RNA sequencing was performed to identify the genes affected by AHI. Differential expression analysis, survival analysis, gene set enrichment analysis, and immune infiltration analysis were performed via bioinformatics analysis. Western blot analysis, reverse transcription–polymerase chain reaction (RT-PCR) experiment, molecular docking, and drug affinity responsive target stability (DARTS) experiments were also performed to confirm AHI’s direct effect on glutathione peroxidase 1 (GPX1) expression. Confocal immunofluorescence analysis was conducted to verify AHI’s effect on the occurrence and development of epithelial–mesenchymal transition (EMT). Finally, BC nude mouse xenografts were established, and AHI’s molecular mechanism on BC was explored.Results: Network pharmacology results demonstrated that AHI’s therapeutic targets on BC were related to the proliferation, invasion, and metastasis of BC cells. AHI significantly inhibited the proliferation of 4T1 and MDA-MB-231 BC cells in the MTT experiments. RNA sequencing results showed that AHI upregulated the GPX1 expression in the 4T1 and MDA-MB-231 BC cells. Next, bioinformatics analysis revealed that GPX1 is less expressed in BC than in normal breast tissues. Patients with high GPX1 expression levels tended to have prolonged overall survival and disease-free survival than patients with low GPX1 expression levels in BC. Western blot and RT-PCR experiments revealed that AHI increased the protein and mRNA levels of GPX1. Molecular docking and DARTS experiments confirmed the direct binding combination between AHI and GPX1. After the evaluation of the EMT scores of 1,078 patients with BC, we found a potential anti-BC role of GPX1 possibly via suppression of the malignant EMT. The confocal immunofluorescence analysis showed that AHI increased E-cadherin expression levels and reduced vimentin expression levels in BC cells. Animal experiments showed that AHI significantly inhibited tumor growth. AHI also inhibited EMT by enhancing GPX1 and caspase3 cleavage, hence inhibiting EMT markers (i.e., N-cadherin and vimentin) and Ki-67.Conclusion: GPX1 plays a critical role in BC, which may be a biomarker for the prognosis. In addition, AHI suppressed EMT by increasing GPX1 expression, which may serve as a potential therapy for BC treatment.

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.

Selenoproteins are translated via animal domain-specific elongation machineries that redefine dedicated UGA opal codons from termination of translation to selenocysteine (Sec) insertion, utilizing specific tRNA species and Sec-specific elongation factors. This has made recombinant production of mammalian selenoproteins in E. coli technically challenging but recently we developed a methodology that enables such production, using recoding of UAG for Sec in an RF1-deficient host strain. Here we used that approach for production of the human glutathione peroxidases 1, 2 and 4 (GPX1, GPX2 and GPX4), with all these three enzymes being important antioxidant selenoproteins. Among these, GPX4 is the sole embryonically essential enzyme, and is also known to be essential for spermatogenesis as well as protection from cell death through ferroptosis. Enzyme kinetics, ICP-MS and mass spectrometry analyses of the purified recombinant proteins were used to characterize selenoprotein characteristics and their Sec contents. This revealed a unique phenomenon of one-codon skipping, resulting in a lack of a single amino acid at the position corresponding to the selenocysteine (Sec) residue, in about 30% of the recombinant GPX isoenzyme products. We furthermore confirmed the previously described UAG suppression with Lys or Gln as well as a minor suppression with Tyr, together resulting in about 20% Sec contents in the full-length proteins. No additional frameshifts or translational errors were detected. We subsequently found that Sec-containing GPX4 could be further purified over a bromosulfophthalein-column, yielding purified recombinant GPX4 with close to complete Sec contents. This production method for homogenously purified GPX4 should help to further advance the studies of this important selenoprotein.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Metabolism serves mammalian feeding and active behavior, and is controlled by circadian clock. The molecular mechanism by which clock factors regulate metabolic homeostasis under oxidative stress is unclear. Here, we have characterized that the daily oxygen consumption rhythm was deregulated in Per1 deficient mice. Per1 deficiency impaired daily mitochondrial dynamics and deregulated cellular GPx-related ROS fluctuations in the peripheral organs. We identified that PER1 enhanced GPx activity through PER1/GPX1 interaction in cytoplasm, consequently improving the oxidative phosphorylation efficiency of mitochondria. Per1 expression was specifically elevated in the fasting peripheral organs for protecting mitochondrial from oxidation stress. These observations reveal that Per1-driven mitochondrial dynamics is a critical effector mechanism for the regulation of mitochondrial function in response to oxidation stress.

Selenium is a metalloid trace element essential for maintaining the optimal redox environment in cells and tissues. It is structurally incorporated into over 25 selenoproteins and enzymes. The glutathione peroxidase (GPx) family of enzymes has a critical role in human health because of its antioxidant function. The recommended daily allowance (RDA) for selenium intake in humans was established to maximize the activity of GPx in plasma. Suboptimal availability of selenium can limit the expression and activities of GPxs leading to a compromised redox environment. This can cause detrimental oxidative distress that could be prevented by increasing the availability of selenium. In cell culture studies, the medium is typically deficient in selenium; supplementation with selenium can increase selenoenzyme activities. However, the optimal level of supplementation in cell culture media has not been well characterized. We performed dose-response experiments for the activities of GPx1 and GPx4 vs. the level of selenium supplementation in cell culture medium. For this, we advanced an assay to determine the activities of both GPx1 and GPx4 efficiently in a single run. During the optimization process, we found that the observed activities of GPx1 and GPx4 depend greatly on the pH of the assay buffer; the observed activities increase with increasing pH, with pH 8 being optimal. Using the combination assay, we also found that the expression and activities for both GPx1 and GPx4 can be maximized in exponentially growing cells by supplementing cell culture media with ≈ 200 nM seleno-l-methionine, without concerns for toxicity. Optimizing the availability of selenium in cell culture to maximize the expression and activities GPx1 and GPx4 may allow for better translation of information from cell culture work to in vivo settings.