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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.

This study identified 13 endoplasmic reticulum stress (ERS)-related biomarkers associated with multiple sclerosis (MS) through integrated bioinformatics analysis (including weighted gene co-expression network analysis and machine learning algorithms) and single-cell sequencing, combined with validation in an experimental autoimmune encephalomyelitis (EAE) mouse model. Among them, GPX1, RCN1, and UBE2D3 exhibited high diagnostic value (AUC > 0.7, p < 0.05), and the diagnostic potential of GPX1 and RCN1 was confirmed in the animal model. The study found that memory B cells, plasma cells, neutrophils, and M1 macrophages were significantly increased in MS patients, while naive B cells and activated NK cells decreased. Consensus clustering based on key ERS-related genes divided MS patients into two subtypes. Single-cell sequencing showed that microglia and pericytes were the cell types with the highest expression of key ERS-related genes, and the APP-CD74 pathway was enhanced in the brain tissue of MS patients. Mendelian randomization analysis suggested that GPX1 plays a protective role in MS. These findings reveal the mechanisms of ERS-related biomarkers in MS and provide potential targets for diagnosis and treatment.

Introduction Ovarian cancer (OC) remains one of the most lethal gynecological malignancies, primarily due to challenges in early detection and the consequent poor prognosis. Genetic predisposition plays a critical role in OC development, with the Glutathione Peroxidase 1 (GPX1) gene receiving increasing attention. The GPX1 gene polymorphism rs1050450 has been implicated in various cancers, potentially through its impact on oxidative stress mechanisms. Objective This study aimed to investigate the association between the GPX1 (rs1050450) polymorphism and the risk of developing OC in a Turkish population. Methods A retrospective case-control study was conducted involving 90 women diagnosed with OC and 90 healthy controls. Genotyping of the GPX1 (rs1050450) polymorphism was performed using real-time PCR (RT-PCR). Statistical analyses were conducted using the SPSS software, with chi-square and t-tests applied where appropriate. Results The CC genotype of the GPX1 (rs1050450) polymorphism was significantly associated with a reduced risk of OC (P = 0.002; OR = 0.304; 95% CI = 0.161-0.577), whereas the TT genotype was linked to an increased risk, demonstrating a threefold elevation in susceptibility (P = 0.036; OR = 3.308; 95% CI = 1.024-10.682). Additionally, the T allele was associated with an approximately threefold increased risk of developing OC (P = 0.0002). Conclusion These findings suggest that the GPX1 (rs1050450) polymorphism may play a significant role in OC susceptibility, with the CC genotype offering potential protective effects and the TT genotype indicating increased risk. This genetic variant may serve as a useful marker for assessing OC risk; however, further studies involving larger and more diverse populations are needed to validate these results. Plain Language Summary Ovarian cancer (OC) is one of the deadliest gynecological cancers, largely due to its late diagnosis and poor prognosis. Several factors contribute to the development of OC, including genetic susceptibility. Glutathione Peroxidase 1 (GPX1) is an important antioxidant enzyme that protects cells from oxidative stress, which can damage DNA and contribute to cancer development. However, the role of GPX1 in ovarian cancer remains unclear, as it may either suppress or promote tumor growth depending on the context. A specific genetic variation in the GPX1 gene, known as rs1050450, has been linked to the risk of several types of cancer. In this study, we investigated whether this genetic variant is associated with an increased or decreased risk of ovarian cancer in Turkish women. Our findings suggest that women who carry the CC genotype of the GPX1 gene may have a lower risk of developing ovarian cancer, while those with the TT genotype may face a higher risk. Understanding the impact of genetic factors like GPX1 on ovarian cancer could help improve early diagnosis and guide personalized treatment strategies. However, additional research involving larger and more diverse populations is necessary to confirm these results and explore their clinical relevance.

Splicing factors are essential for nascent pre-mRNA processing and critical in cancer progression, suggesting that proteins with splicing functions represent potential molecular targets for cancer therapy. Here, we investigate the role of splicing factors in glioblastoma multiforme (GBM) progression and the possibility of targeting them for the treatment of the disease. The TCGA and CGGA public databases were used to screen for differentially expressed mRNA splicing factors. Immunohistochemistry and qRT-PCR were used to analyze the expression of non-POU domain-containing octamer-binding protein (NONO), a Drosophila behavior human splicing (DBHS) protein. Knockdown/overexpression of NONO with siRNA and lentiviral expression constructs was used to examine cell growth, apoptosis, and invasion in GBM cells. RNA sequencing was used to identify potential downstream molecular targets of NONO. RIP-PCR and RNA pulldown were used to determine the interaction between NONO and pre-mRNA. JC-1 staining and the seahorse assay were performed to assess redox homeostasis. Expression of NONO was increased in GBM samples and associated with poor survival in patients ( = 0.04). Knockdown of NONO suppressed GBM growth, and overexpression of NONO promoted GBM tumorigenesis and . RNA sequencing-based transcriptomic profiling confirmed that knockdown of NONO in U251 and P3 cells resulted in global intron retention of pre-mRNA and led to abnormal splicing of specific pre-mRNAs for and . NONO bound to a consensus motif in the intron of pre-mRNA in association with another DBHS protein family member, PSPC1. Knockdown of NONO impaired tumor growth, invasion, and redox homeostasis through aberrant splicing of . Finally, Auranofin, a small molecule inhibitor of NONO, suppressed GBM tumor growth in an orthotopic xenograft model in mice. We demonstrated that intron retention was a critical alternative RNA splicing event to occur in GBM progression, and that NONO was a key regulator of mRNA splicing in GBM. Targeting NONO represents a novel, potential therapeutic strategy for GBM treatment.

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.

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.

Selenium (Se) is an essential micronutrient that has several important functions in animal and human health. The biological functions of Se are carried out by selenoproteins (encoded by twenty-five genes in human and twenty-four in mice), which are reportedly present in all three domains of life. As a component of selenoproteins, Se has structural and enzymatic functions; in the latter context it is best recognized for its catalytic and antioxidant activities. In this review, we highlight the biological functions of Se and selenoproteins followed by an elaborated review of the relationship between Se and female reproductive function. Data pertaining to Se status and female fertility and reproduction are sparse, with most such studies focusing on the role of Se in pregnancy. Only recently has some light been shed on its potential role in ovarian physiology. The exact underlying molecular and biochemical mechanisms through which Se or selenoproteins modulate female reproduction are largely unknown; their role in human pregnancy and related complications is not yet sufficiently understood. Properly powered, randomized, controlled trials (intervention vs. control) in populations of relatively low Se status will be essential to clarify their role. In the meantime, studies elucidating the potential effect of Se supplementation and selenoproteins (i.e., GPX1, SELENOP, and SELENOS) in ovarian function and overall female reproductive efficiency would be of great value.

The sarcomagenic process initiates when mesenchymal stromal/stem cells (MSCs) or MSC-derived cells undergo tumoral transformation. Besides, sarcoma evolution is partly driven by the emergence of subpopulations of cancer stem cells (CSCs), which are strongly associated with more aggressive behaviors. Therefore, the characterization of CSC will contribute to the development of more effective therapies against sarcomas. Here, we compared the proteomes of adherent and CSC-enriched tumorsphere cultures in a tumor progression model of myxoid liposarcoma composed of three cell lines showing increasing aggressiveness after being serially transplanted in mice. We found that the expression of the antioxidant enzyme GPX1 increased constantly during the CSC-enrichment process in this model and other sarcoma lines. Depletion of GPX1 resulted in decreased proliferation and tumorsphere-forming potential and dramatically reduced tumor-formation ability . Conversely, GPX1 overexpression resulted in increased proliferation and tumorsphere formation. According to these findings, GPX1 expression in sarcoma patients was associated with aggressive phenotypes and worse prognosis. A proteomic analysis revealed that these effects were associated with the downregulation of interferon-mediated response, the IL6/JAK/STAT3 axis and the NFκB-mediated signaling in GPX1-silenced cells. Overall, these results suggest that GPX1 expression may serve as a functional marker of aggressive CSC subpopulations in sarcomas.

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.

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. Graphical Abstract