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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.

Numerous studies have demonstrated that the high expression of CXC motif chemokine ligand 16 (CXCL16) in cancer correlates with poor prognosis, as well as tumor cell proliferation, migration, and invasion. While CXCL16 can serve as a tumor biomarker, the underlying mechanism in modulating head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study, the aimed was to investigate the CXCL16 expression in HNSCC and to uncover the potential underlying mechanism. Hereby, we determined the high expression of CXCL16 in The Cancer Genome Atlas (TCGA) database, as well as in tissue samples from patients with HNSCC at our central hospital and from HNSCC cell lines. The results showed that CXCL16 knockdown inhibited the proliferation, migration, and invasion of HNSCC cells. Mechanistically, transcriptome sequencing revealed that CXCL16 may affect HNSCC cell growth by regulating the antioxidant pathway of glutathione peroxidase 1 (GPX1). The reactive oxygen species (ROS) levels were elevated in small interfering CXCL16 (si-CXCL16) cells, which may contribute to the inhibition of cell proliferation, migration, and invasion. Moreover, treatment of cells with the GPX1 inhibitor eldecalcitol (ED-71) revealed that HNSCC cell growth was significantly inhibited in the synergistic group of si-CXCL16 and GPX1 inhibitor compared to the si-CXCL16 group. In conclusion, CXCL16 contributed to the development of HNSCC cells by modulating the GPX1-mediated antioxidant pathway. Thus, targeting cellular CXCL16 expression seems to be a promising strategy for treating HNSCC.

Oxidative stress contributes to the propagation and exacerbation of inflammatory bowel disease (IBD) but the status of erythrocyte antioxidant defense remains unknown.MethodsErythrocyte activities of superoxide dismutase-1 (SOD1), catalase, and glutathione peroxidase-1 (GPx1) were determined in 174 IBD patients and 105 controls and referred to IBD activity, inflammation severity, nutritional status, systemic oxidative stress, anemia, and treatment.ResultsCatalase and GPx1 activities were decreased in active IBD, whereas SOD1 became upregulated by IBD-related oxidative stress. In Crohn's disease (CD) corticosteroids decreased SOD1 activity. SOD1 correlated indirectly with CD activity and erythrocyte sedimentation rate (ESR) and directly with transferrin. In ulcerative colitis (UC) anemia downregulated SOD1. Decreases in GPx activity corresponded with IBD activity, anemia, inflammation, and malnutrition. Oxidative stress in UC and corticosteroids in CD also downregulated GPx. Catalase activity was decreased by CD-related anemia, correlating directly with hemoglobin, and indirectly with CD activity, inflammatory and protein oxidative stress markers. When co-analyzed, anemia but not CD activity significantly contributed to catalase downregulation. In UC, catalase activity corresponded indirectly with UC endoscopic activity and inflammation and directly with hemoglobin. UC activity, anemia, and treatment with azathioprine negatively affected catalase. As indicators of active IBD, GPx1 showed a diagnostic accuracy of 73%, whereas catalase showed 63% as compared to 74% of C-reactive protein and ESR.ConclusionsErythrocyte antioxidant defense is impaired in active IBD. SOD1, GPx1, and CAT activities are differently affected by the disease type, activity, anemia, inflammation, oxidative stress, and treatment. As an active IBD indicator, GPx1 was comparable to C-reactive protein and ESR. Inflamm Bowel Dis 2010

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.

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.

This study investigated the direct roles of hydrogen peroxide (H2O2) in kidney aging using transgenic mice overexpressing glutathione peroxidase‐1 (GPX1 TG). We demonstrated that kidneys in old mice recapitulated kidneys in elderly humans and were characterized by glomerulosclerosis, tubular atrophy, interstitial fibrosis, and loss of cortical mass. Scavenging H2O2 by GPX1 TG significantly reduced mitochondrial and total cellular reactive oxygen species (ROS) and mitigated oxidative damage, thus improving these pathologies. The potential mechanisms by which ROS are increased in the aged kidney include a decreased abundance of an anti‐aging hormone, Klotho, in kidney tissue, and decreased expression of nuclear respiratory factor 2 (Nrf2), a master regulator of the stress response. Decreased Klotho or Nrf2 was not improved in the kidneys of old GPX1 TG mice, even though mitochondrial morphology was better preserved. Using laser capture microdissection followed by label‐free shotgun proteomics analysis, we show that the glomerular proteome in old mice was characterized by decreased abundance of cytoskeletal proteins (critical for maintaining normal glomerular function) and heat shock proteins, leading to increased accumulation of apolipoprotein E and inflammatory molecules. Targeted proteomic analysis of kidney tubules from old mice showed decreased abundance of fatty acid oxidation enzymes and antioxidant proteins, as well as increased abundance of glycolytic enzymes and molecular chaperones. GPX1 TG partially attenuated the remodeling of glomerular and tubule proteomes in aged kidneys. In summary, mitochondria from GPX1 TG mice are protected and kidney aging is ameliorated via its antioxidant activities, independent and downstream of Nrf2 or Klotho signaling. Glutathione Peroxidase‐1 overexpression reduces oxidative stress, preserves mitochondrial cristae structures, and improves kidney pathology and proteome gemodeling in the glomeruli and tubules of old mouse kidneys. These beneficial effects are downstream and independent of Klotho and Nrf2 signaling.

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.

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.

INTRODUCTION Blood biomarkers reflecting Alzheimer's disease (AD) pathophysiology can improve diagnosis and treatment. METHODS We applied top‐down proteomics to compare frontal lobe from 17 AD cases and 11 controls to blood platelets from a second independent study group of 124 AD patients, 61 with mild cognitive impairment (MCI), and 168 controls. Findings were immunologically validated. RESULTS Sixty AD‐associated proteoforms were identified in frontal lobe, with 26 identically represented in platelets. Validation in platelet samples confirmed elevated glutathione S‐transferase omega 1 (GSTO1) levels linked to single nucleotide polymorphism (SNP) rs4925 and increased superoxide dismutase 1 (SOD1) levels in AD. Bioinformatics revealed copper chaperone for superoxide dismutase (CCS) and glutathione peroxidase 1 (GPX1) as integral partners of these antioxidant enzymes. Both were detected to be reduced in frontal lobes and platelets in AD. SOD1 and CCS are already changed in MCI. DISCUSSION These four novel blood biomarkers, integrated with traditional AD biomarkers, may facilitate patient risk assessment and treatment, with SOD1 and CCS alterations in MCI offering early diagnostic potential. Highlights Platelets mirror several Alzheimer's disease (AD)–dependent neuronal changes, valuable for blood tests. As a start, 60 AD‐associated frontal lobe proteins were identified by top‐down proteomics. Fifty percent of these 60 AD‐affected brain proteins are represented identically in platelets. Among these, glutathione S‐transferase omega 1 (GSTO1), superoxide dismutase 1 (SOD1), copper chaperone for superoxide dismutase (CCS), and glutathione peroxidase 1 (GPX1) are identically AD related in brain and platelets. SOD1 and its crucial activating partner CCS are altered in the platelets of patients with mild cognitive impairment.