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Background: Renal ischemia-reperfusion (R-I/R) injury is the most prevalent cause of acute kidney injury, with high mortality and poor prognosis. However, the underlying pathological mechanisms are not yet fully understood. Therefore, this study aimed to investigate the role of N-myc downstream-regulated gene 2 ( Ndrg2 ) in R-I/R injury., Methods: We examined the expression of Ndrg2 in the kidney under normal physiological conditions and after R-I/R injury by immunofluorescence staining, real-time polymerase chain reaction, and western blotting. We then detected R-I/R injury in Ndrg2-deficient ( Ndrg2-/- ) mice and wild type ( Ndrg2+/+ ) littermates in vivo , and detected oxygen and glucose deprivation and reperfusion (OGD-R) injury in HK-2 cells. We further conducted transcriptomic sequencing to investigate the role of Ndrg2 in R-I/R injury and detected levels of oxidative stress and mitochondrial damage by dihydroethidium staining, biochemical assays, and western blot. Finally, we measured the levels of mitophagy in Ndrg2+/+ and Ndrg2-/- mice after R-I/R injury or HK-2 cells in OGD-R injury., Results: Ndrg2 was primarily expressed in renal proximal tubules and its expression was significantly decreased 24 h after R-I/R injury. Ndrg2-/- mice exhibited significantly attenuated R-I/R injury compared to Ndrg2+/+ mice. Transcriptomics profiling showed that Ndrg2 deficiency induced perturbations of multiple signaling pathways, downregulated inflammatory responses and oxidative stress, and increased autophagy following R-I/R injury. Further studies revealed that Ndrg2 deficiency reduced oxidative stress and mitochondrial damage. Notably, Ndrg2 deficiency significantly activated phosphatase and tensin homologue on chromosome ten-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. The downregulation of NDRG2 expression significantly increased cell viability after OGD-R injury, increased the expression of heme oxygenase-1, decreased the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, and increased the expression of the PINK1/Parkin pathway., Conclusion: Ndrg2 deficiency might become a therapy target for R-I/R injury by decreasing oxidative stress, maintaining mitochondrial homeostasis, and activating PINK1/Parkin-mediated mitophagy., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background: Coronary artery disease (CAD) significantly contributes to global fatalities. Recent studies have demonstrated the crucial roles of sortilin1 (SORT1) and sestrin1 (SESN1) in lipid metabolism, as well as their involvement in the development of CAD. The aberrant expression or activity of SORT1 can consequently lead to metabolic and vascular diseases. Sestrins, including SESN1, play a crucial role in helping cells survive by maintaining metabolic balance while also reducing oxidative stress (OS). OS contributes to the progression of atherosclerosis-related diseases, such as CAD. The study aimed to compare the gene expression of SORT1 and SESN1 in peripheral blood mononuclear cells (PBMCs), alongside serum OS markers, in CAD patients and controls., Materials: The case-control study included 49 CAD patients and 40 controls. The expression of the SORT1 and SESN1 genes was quantified using qRT-PCR, and the expression of the SORT1 protein was evaluated by western blotting. OS markers, including total oxidation status (TOS), total antioxidant capacity (TAC), and malondialdehyde (MDA), were measured using spectrophotometric and fluorometric methods., Results: SORT1 gene and protein expressions were similar between groups. CAD patients had a non-significant decrease in SESN1 gene expression. MDA levels were significantly higher in CAD patients, whereas TOS and TAC levels did not differ significantly., Conclusion: For atherosclerosis-related disorders like CAD, MDA shows potential as a non-invasive, easy-to-use, affordable, and stable biomarker. Further research is needed to elucidate the precise roles of SORT1 and SESN1 in CAD pathogenesis., (© 2024. The Author(s).)

Superoxide Dismutase 3 (SOD3) scavenges extracellular superoxide giving a hydrogen peroxide metabolite. Both Reactive Oxygen Species diffuse through aquaporins causing oxidative stress and biomolecular damage. SOD3 is differentially expressed in cancer and this research utilises Gene Expression Omnibus data series GSE2109 with 2,158 cancer samples. Genome-wide expression correlation analysis was conducted with SOD3 as the seed gene. Categorical SOD3 Pearson Correlation gene lists incrementing in correlation strength by 0.01 from ρ≥|0.34| to ρ≥|0.41| were extracted from the data. Positively and negatively SOD3 correlated genes were separated for each list and checked for significance against disease overlapping genes in the ClinVar and Orphanet databases via Enrichr. Disease causal genes were added to the relevant gene list and checked against Gene Ontology, Phenotype Ontology, and Elsevier Pathways via Enrichr before the significant ontologies containing causal and non-overlapping genes were reviewed with a literature search for possible disease and oxidative stress associations. 12 significant individually discriminated disorders were identified: Autosomal Dominant Cutis Laxa (p = 6.05x10-7), Renal Tubular Dysgenesis of Genetic Origin (p = 6.05x10-7), Lethal Arteriopathy Syndrome due to Fibulin-4 Deficiency (p = 6.54x10-9), EMILIN-1-related Connective Tissue Disease (p = 6.54x10-9), Holt-Oram Syndrome (p = 7.72x10-10), Multisystemic Smooth Muscle Dysfunction Syndrome (p = 9.95x10-15), Distal Hereditary Motor Neuropathy type 2 (p = 4.48x10-7), Congenital Glaucoma (p = 5.24x210-9), Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (p = 3.77x10-16), Classical-like Ehlers-Danlos Syndrome type 1 (p = 3.77x10-16), Retinoblastoma (p = 1.9x10-8), and Lynch Syndrome (p = 5.04x10-9). 35 novel (21 unique) genes across 12 disorders were identified: ADNP, AOC3, CDC42EP2, CHTOP, CNN1, DES, FOXF1, FXR1, HLTF, KCNMB1, MTF2, MYH11, PLN, PNPLA2, REST, SGCA, SORBS1, SYNPO2, TAGLN, WAPL, and ZMYM4. These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Stanworth, Zhang. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The liver is a complex organ with a highly organized structure in which tight junctions (TJs) play an important role in maintaining their function by regulating barrier properties and cellular polarity. Dysfunction of TJs is associated with liver diseases, including progressive familial intrahepatic cholestasis (PFIC). In this study, we investigated the molecular alterations in a liver-specific ZO-1 and ZO-2 double-knockout (DKO) mouse model, which exhibits features resembling those of PFIC4 patients with mutations in the ZO-2 gene. RNA-seq analysis revealed the upregulation of genes involved in the oxidative stress response, xenobiotic metabolism, and cholesterol metabolism in DKO livers. Conversely, the expression of genes regulated by HNF4α was lower in DKO livers than in the wild-type controls. Furthermore, age-associated analysis elucidated the timing and progression of these pathway changes as well as alterations in molecules related to TJs and apical polarity. Our research uncovered previously unknown implications of ZO-1 and ZO-2 in liver physiology and provides new insights into the molecular pathogenesis of PFIC4 and other tight junction-related liver diseases. These findings contribute to a better understanding of the complex mechanisms underlying liver function and dysfunction and may lead to the development of novel therapeutic strategies for liver diseases associated with tight junction impairment.Key words: tight junctions, ZO-1/ZO-2 knockout mouse, liver, transcriptome analysis, molecular pathological progression.

Ischemia/reperfusion (I/R) is a pathological process that occurs in numerous organs and is often associated with severe cellular damage and death. Ectodysplasin-A2 receptor (EDA2R) is a member of the TNF receptor family that has anti-inflammatory and antioxidant effects. However, to the best of our knowledge, its role in the progression of myocardial I/R injury remains unclear. The present study aimed to investigate the role of EDA2R during myocardial I/R injury and the molecular mechanisms involved. In vitro, dexmedetomidine (DEX) exhibited a protective effect on hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury and downregulated EDA2R expression. Subsequently, EDA2R silencing enhanced cell viability and reduced the apoptosis of cardiomyocytes. Furthermore, knockdown of EDA2R led to an elevated mitochondrial membrane potential (MMP), repressed the release of Cytochrome C and upregulated Bcl-2 expression. EDA2R knockdown also resulted in downregulated expression of Bax, and decreased activity of Caspase-3 and Caspase-9 in cardiomyocytes, reversing the effects of H/R on mitochondria-mediated apoptosis. In addition, knockdown of EDA2R suppressed H/R-induced oxidative stress. Mechanistically, EDA2R knockdown inactivated the NF-κB signaling pathway. Additionally, downregulation of EDA2R weakened myocardial I/R injury in mice, as reflected by improved left ventricular function and reduced infarct size, as well as suppressed apoptosis and oxidative stress. Additionally, EDA2R knockdown repressed the activation of NF-κB signal in vivo. Collectively, knockdown of EDA2R exerted anti-apoptotic and antioxidant effects against I/R injury in vivo and in vitro by suppressing the NF-κB signaling pathway.

Oxidative stress is encountered by fungi in almost all niches, resulting in fungal degeneration or even death. Fungal tolerance to oxidative stress has been extensively studied, but the current understanding of the mechanisms regulating oxidative stress tolerance in fungi remains limited. The entomopathogenic and endophytic fungus Metarhizium robertsii encounters oxidative stress when it infects insects and develops a symbiotic relationship with plants, and we found that host reactive oxygen species (ROSs) greatly limited fungal growth in both insects and plants. We identified a histone H3 deacetylase (HDAC3) that catalyzed the deacetylation of lysine 56 of histone H3. Deleting Hdac3 significantly reduced the tolerance of M. robertsii to oxidative stress from insects and plants, thereby decreasing fungal ability to colonize the insect hemocoel and plant roots. HDAC3 achieved this by regulating the expression of three genes in the ergosterol biosynthesis pathway, which includes the lanosterol synthase gene Las1 . The deletion of Hdac3 or Las1 reduced the ergosterol content and impaired cell membrane integrity. This resulted in an increase in ROS accumulation in fungal cells that were thus more sensitive to oxidative stress. We further showed that HDAC3 regulated the expression of the three ergosterol biosynthesis genes in an indirect manner. Our work significantly advances insights into the epigenetic regulation of oxidative stress tolerance and the interactions between M. robertsii and its plant and insect hosts.IMPORTANCEOxidative stress is a common challenge encountered by fungi that have evolved sophisticated mechanisms underlying tolerance to this stress. Although fungal tolerance to oxidative stress has been extensively investigated, the current understanding of the mechanisms for fungi to regulate oxidative stress tolerance remains limited. In the model entomopathogenic and plant symbiotic fungus Metarhizium robertsii , we found that the histone H3 deacetylase HDAC3 regulates the production of ergosterol, an essential cell membrane component. This maintains the cell membrane integrity to resist the oxidative stress derived from the insect and plant hosts for successful infection of insects and development of symbiotic associates with plants. Our work provides significant insights into the regulation of oxidative stress tolerance in M. robertsii and its interactions with insects and plants., Competing Interests: The authors declare no conflict of interest.

Oxidative stress (OS) is believed to be a significant factor in the decline of semen quality, with mitochondrial DNA copy number (mtDNAcn) serving as a sensitive biomarker for both semen quality and mitochondrial dysfunction resulting from oxidative stress. While glutathione S-transferases (GSTs) are commonly known as 'antioxidant' enzymes, there is ongoing debate regarding the relationship between GST genotypes and semen quality. In a study involving 568 male volunteers from the outpatient department of Puyang Reproductive Medicine Center, sperm mtDNAcn, semen quality, and GSTM1/GSTT1 genotypes were analyzed to investigate the potential link between GSTM1/GSTT1 gene variations and semen quality, as well as the impact of GSTs gene variations on the connection between sperm mtDNAcn and semen quality. Adjusting for variables such as age, BMI, smoking, and alcohol consumption, it was found that mtDNAcn was significantly correlated with decreased sperm concentration and total sperm count (b = - 0.109, - 0.128, respectively; P = 0.002, 0.001, respectively). GSTM1 was associated with progressive motility (OR 0.390, 95% CI 0.218, 0.697), Straight line velocity (VSL) (OR = 0.606, 95% CI 0.385, 0.953), and Straightness (STR) (OR 0.604, 95% CI 0.367, 0.994), while GSTT1 was linked to progressive motility (OR 0.554, 95% CI 0.324, 0.944) and Beat crossover frequency (OR 0.624, 95% CI 0.397, 0.982). The GSTT1 was found to moderate the relationship between mtDNAcn and sperm motility parameters linearity (LIN), STR, and Wobble (WOB), with additive interaction effects observed between GSTT1 and mtDNAcn on LIN, STR, and WOB (P for interaction = 0.008, 0.034, 0.010, respectively). Overall, this study suggests that GSTT1 and GSTM1 gene variations may play a role in sperm motility, with GSTT1 potentially influencing the impact of oxidative stress on sperm motility., (© 2024. The Author(s).)

Oxidative stress (OS) is strongly implicated in the pathophysiology of major depressive disorder (MDD) but the molecular mechanisms remain largely unknown. The purpose of this study is to identify genes related to both OS and MDD, and further to evaluate the utility of these genes as diagnostic markers and potential treatment targets. We searched datasets related to MDD from the Gene Expression Omnibus (GEO) database for differentially expressed genes (DEGs) also related to OS according to GeneCards. Bioinformatics analyses and machine learning algorithms were used to identify hub genes mediating OS-MDD interactions. A summary data-based Mendelian randomization (SMR) approach was employed to identify possible causal genes for MDD from blood tissue eQLT data. These investigations identified 32 genes mediating OS-MDD interactions, while SMR analysis identified KCNE1 (OR = 1.057, 95%CI = 1.013-1.102, P value = 0.010), MAPK3 (OR = 1.023, 95%CI = 1.004-1.043, P value = 0.020), and STIP1 (OR = 0.792, 95%CI = 0.641-0.979, P value = 0.031) as OS-related causal genes for MDD. These genes may thus serve as useful diagnostic markers and potential therapeutic targets., (© 2024. The Author(s).)

The objective of this study is to assess the influence of genetic polymorphisms in DGAT1 , LEP , and SCD1 on the oxidative stress biomarkers and bioactive protein levels in Hereford bulls. A total of sixty-eight bulls were analyzed at 22 months of age to assess growth metrics and carcass quality, with a focus on polymorphisms in these genes. The key markers of oxidative stress, including malondialdehyde (MDA), and the activities of antioxidant enzymes such as glutathione reductase (GluRed), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were measured, alongside bioactive compounds like taurine, carnosine, and anserine. The results show that the TT genotype of DGAT1 is linked to significantly higher MDA levels, reflecting increased lipid peroxidation, but is also associated with higher GluRed and GPx activities and elevated levels of taurine, carnosine, and anserine, suggesting an adaptive response to oxidative stress. The LEP gene analysis revealed that the CC genotype had the highest MDA levels but also exhibited increased GPx and SOD activities, with the CT genotype showing the highest SOD activity and the TT genotype the highest total antioxidant status (TAS). The SCD1 AA genotype displayed the highest activities of GluRed, GPx, and SOD, indicating a more effective antioxidant defence, while the VA genotype had the highest MDA levels and the VV genotype showed lower MDA levels, suggesting protective effects against oxidative damage. These findings highlight genotype specific variations in the oxidative stress markers and bioactive compound levels, providing insights into the genetic regulation of oxidative stress and antioxidant defences, which could inform breeding strategies for improving oxidative stress resistance in livestock and managing related conditions.

Adenosine-to-inosine (A-to-I) RNA editing plays an important role in the post-transcriptional regulation of eukaryotic cell physiology. However, our understanding of the occurrence, function and regulation of A-to-I editing in bacteria remains limited. Bacterial mRNA editing is catalysed by the deaminase TadA, which was originally described to modify a single tRNA in Escherichia coli. Intriguingly, several bacterial species appear to perform A-to-I editing on more than one tRNA. Here, we provide evidence that in the human pathogen Streptococcus pyogenes, tRNA editing has expanded to an additional tRNA substrate. Using RNA sequencing, we identified more than 27 editing sites in the transcriptome of S. pyogenes SF370 and demonstrate that the adaptation of S. pyogenes TadA to a second tRNA substrate has also diversified the sequence context and recoding scope of mRNA editing. Based on the observation that editing is dynamically regulated in response to several infection-relevant stimuli, such as oxidative stress, we further investigated the underlying determinants of editing dynamics and identified mRNA stability as a key modulator of A-to-I editing. Overall, our findings reveal the presence and diversification of A-to-I editing in S. pyogenes and provide novel insights into the plasticity of the editome and its regulation in bacteria., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Synthetic biology enables the reprogramming of cellular functions for various applications. However, challenges in scalability and predictability persist due to context-dependent performance and complex circuit-host interactions. This study introduces an iModulon-based engineering approach, utilizing machine learning-defined co-regulated gene groups (iModulons) as design parts containing essential genes for specific functions. This approach identifies the necessary components for genetic circuits across different contexts, enhancing genome engineering by improving target selection and predicting module behavior. We demonstrate several distinct uses of iModulons: (i) discovery of unknown iModulons to increase protein productivity, heat tolerance and fructose utilization; (ii) an iModulon boosting approach, which amplifies the activity of specific iModulons, improved cell growth under osmotic stress with minimal host regulation disruption; (iii) an iModulon rebalancing strategy, which adjusts the activity levels of iModulons to balance cellular functions, significantly increased oxidative stress tolerance while minimizing trade-offs and (iv) iModulon-based gene annotation enabled natural competence activation by predictably rewiring iModulons. Comparative experiments with traditional methods showed our approach offers advantages in efficiency and predictability of strain engineering. This study demonstrates the potential of iModulon-based strategies to systematically and predictably reprogram cellular functions, offering refined and adaptable control over complex regulatory networks., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

DNA damage induced by oxidative stress during cardiac hypertrophy activates the ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR) signaling, in turn aggravating the pathological cardiomyocyte growth. This study aims to identify the functional associations of long noncoding RNA (lncRNAs) with cardiac hypertrophy and DDR. The altered ventricular lncRNAs in the mice between sham and transverse aortic constriction (TAC) group were identified by microarray analysis, and a novel lncRNA AK144717 was found to gradually upregulate during the development of pathological cardiac hypertrophy induced by TAC surgery or angiotensin II (Ang II) stimulation. Silencing AK144717 had a similar anti-hypertrophic effect to that of ATM inhibitor KU55933 and also suppressed the activated ATM-DDR signaling induced by hypertrophic stimuli. The involvement of AK144717 in DDR and cardiac hypertrophy was closely related to its interaction with HMGB1, as silencing HMGB1 abolished the effects of AK144717 knockdown. The binding of AK144717 to HMGB1 prevented the interaction between HMGB1 and SIRT1, contributing to the increased acetylation and then cytosolic translocation of HMGB1. Overall, our study highlights the role of AK144717 in the hypertrophic response by interacting with HMGB1 and regulating DDR, hinting that AK144717 is a promising therapeutic target for pathological cardiac growth., (© 2024. The Author(s).)

LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2 -congenital muscular dystrophy (LAMA2-CMD). Various phenotypes have been linked to LAMA2-CMD; nevertheless, the precise mechanisms that malfunction during disease onset in utero remain unknown. We generated Lama2 -deficient C2C12 cells and found that Lama2 -deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W mouse model of LAMA2-CMD display impaired differentiation and fusion in vitro. We also showed that disease onset during fetal development is characterized by a significant down-regulation of gene expression in muscle fibers, causing pronounced effects on cytoskeletal organization, muscle differentiation, and altered DNA repair and oxidative stress responses. Together, our findings provide unique insights into the critical importance of the laminin-α2 chain for muscle differentiation and muscle cell homeostasis., (© 2024 Martins et al.)

Telomeres, repetitive sequences located at the extremities of chromosomes, play a pivotal role in sustaining chromosomal stability. Telomerase is a complex enzyme that can elongate telomeres by appending telomeric repeats to chromosome ends and acts as a critical factor in telomere dynamics. The gradual shortening of telomeres over time is a hallmark of cellular senescence and cellular death. Notably, telomere shortening appears to result from the complex interplay of two primary mechanisms: telomere shelterin complexes and telomerase activity. The intricate interplay of genetic, environmental, and lifestyle influences can perturb telomere replication, incite oxidative stress damage, and modulate telomerase activity, collectively resulting in shifts in telomere length. This age-related process of telomere shortening plays a considerable role in various chronic inflammatory and oxidative stress conditions, including cancer, cardiovascular disease, and rheumatic disease. Existing evidence has shown that abnormal telomere shortening or telomerase activity abnormalities are present in the pathophysiological processes of most rheumatic diseases, including different disease stages and cell types. The impact of telomere shortening on rheumatic diseases is multifaceted. This review summarizes the current understanding of the link between telomere length and rheumatic diseases in clinical patients and examines probable telomere shortening in peripheral blood mononuclear cells and histiocytes. Therefore, understanding the intricate interaction between telomere shortening and various rheumatic diseases will help in designing personalized treatment and control measures for rheumatic disease.

The identification of optimal candidate genes from large-scale blood transcriptomic data is crucial for developing targeted assays to monitor immune responses. Here, we introduce a novel, optimized large language model (LLM)-based approach for prioritizing candidate biomarkers from blood transcriptional modules. Focusing on module M14.51 from the BloodGen3 repertoire, we implemented a multi-step LLM-driven workflow. Initial high-throughput screening used GPT-4, Claude 3, and Claude 3.5 Sonnet to score and rank the module's constituent genes across six criteria. Top candidates then underwent high-resolution scoring using Consensus GPT, with concurrent manual fact-checking and, when needed, iterative refinement of the scores based on user feedback. Qualitative assessment of literature-based narratives and analysis of reference transcriptome data further refined the selection process. This novel multi-tiered approach consistently identified Glutathione Peroxidase 4 (GPX4) as the top candidate gene for module M14.51. GPX4's role in oxidative stress regulation, its potential as a future drug target, and its expression pattern across diverse cell types supported its selection. The incorporation of reference transcriptome data further validated GPX4 as the most suitable candidate for this module. This study presents an advanced LLM-driven workflow with a novel optimized scoring strategy for candidate gene prioritization, incorporating human-in-the-loop augmentation. The approach identified GPX4 as a key gene in the erythroid cell-associated module M14.51, suggesting its potential utility for biomarker discovery and targeted assay development. By combining AI-driven literature analysis with iterative human expert validation, this method leverages the strengths of both artificial and human intelligence, potentially contributing to the development of biologically relevant and clinically informative targeted assays. Further validation studies are needed to confirm the broader applicability of this human-augmented AI approach., (© 2024. The Author(s).)

Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood 1-3 . Here, to understand dysregulated haematopoiesis in Down syndrome, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human fetal liver and bone marrow samples from 3 fetuses with disomy and 15 fetuses with trisomy. We found that differences in gene expression in Down syndrome were dependent on both cell type and environment. Furthermore, we found multiple lines of evidence that haematopoietic stem cells (HSCs) in Down syndrome are 'primed' to differentiate. We subsequently established a Down syndrome-specific map linking non-coding elements to genes in disomic and trisomic HSCs using 10X multiome data. By integrating this map with genetic variants associated with blood cell counts, we discovered that trisomy restructured regulatory interactions to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Furthermore, as mutations in Down syndrome display a signature of oxidative stress 4,5 , we validated both increased mitochondrial mass and oxidative stress in Down syndrome, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Together, our single-cell, multi-omic resource provides a high-resolution molecular map of fetal haematopoiesis in Down syndrome and indicates significant regulatory restructuring giving rise to co-occurring haematological conditions., (© 2024. The Author(s).)

Stem cells are a unique class of cells that possess the ability to differentiate and self-renew, enabling them to repair and replenish tissues. To protect and maintain the potential of stem cells, the cells and the environment surrounding these cells (stem cell niche) are highly responsive and tightly regulated. However, various stresses can affect the stem cells and their niches. These stresses are both systemic and cellular and can arise from intrinsic or extrinsic factors which would have strong implications on overall aging and certain disease states. Therefore, understanding the breadth of drivers, namely epigenetic alterations, involved in cellular stress is important for the development of interventions aimed at maintaining healthy stem cells and tissue homeostasis. In this review, we summarize published findings of epigenetic responses to replicative, oxidative, mechanical, and inflammatory stress on various types of adult stem cells., (© 2024 Llewellyn et al.)

Background: Non-obstructive azoospermia (NOA) is a major contributor of male infertility. Herein, we used existing datasets to identify novel biomarkers for the diagnosis and prognosis of NOA, which could have great significance in the field of male infertility., Methods: NOA datasets were obtained from the Gene Expression Omnibus (GEO) database. CIBERSORT was utilized to analyze the distributions of 22 immune cell populations. Hub genes were identified by applying weighted gene co-expression network analysis (WGCNA), machine learning methods, and protein-protein interaction (PPI) network analysis. The expression of hub genes was verified in external datasets and was assessed by receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis (GSEA) was applied to explore the important functions and pathways of hub genes. The mRNA-microRNA (miRNA)-transcription factors (TFs) regulatory network and potential drugs were predicted based on hub genes. Single-cell RNA sequencing data from the testes of patients with NOA were applied for analyzing the distribution of hub genes in single-cell clusters. Furthermore, testis tissue samples were obtained from patients with NOA and obstructive azoospermia (OA) who underwent testicular biopsy. RT-PCR and Western blot were used to validate hub gene expression., Results: Two immune-related oxidative stress hub genes ( SHC1 and FGFR1 ) were identified. Both hub genes were highly expressed in NOA samples compared to control samples. ROC curve analysis showed a remarkable prediction ability (AUCs > 0.8). GSEA revealed that hub genes were predominantly enriched in toll-like receptor and Wnt signaling pathways. A total of 24 TFs, 82 miRNAs, and 111 potential drugs were predicted based on two hub genes. Single-cell RNA sequencing data in NOA patients indicated that SHC1 and FGFR1 were highly expressed in endothelial cells and Leydig cells, respectively. RT-PCR and Western blot results showed that mRNA and protein levels of both hub genes were significantly upregulated in NOA testis tissue samples, which agree with the findings from analysis of the microarray data., Conclusion: It appears that SHC1 and FGFR1 could be significant immune-related oxidative stress biomarkers for detecting and managing patients with NOA. Our findings provide a novel viewpoint for illustrating potential pathogenesis in men suffering from infertility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pan, Chen, Zhou, Xu, Li, Wang, Xu, Ren, Liu and Liu.)

Background: Imprinted genes play important functions in placentation and pregnancy; however, research on their roles in different placental diseases is limited. It is believed that epigenetic alterations, such as DNA methylation, of placental imprinting genes may contribute to the different pathological features of severe placental diseases, such as pre-eclampsia (PE) and placenta accreta spectrum disorders (PAS)., Results: In this study, we conducted a comparative analysis of the methylation and expression of placental imprinted genes between PE and PAS using bisulfite sequencing polymerase chain reaction (PCR) and quantitative PCR, respectively. Additionally, we assessed oxidative damage of placental DNA by determining 8-hydroxy-2'-deoxyguanosine levels and fetal growth by determining insulin-like growth factor 2 (IGF2) and cortisol levels in the umbilical cord blood using enzyme-linked immunosorbent assay. Our results indicated that methylation and expression of potassium voltage-gated channel subfamily Q member 1, GNAS complex locus, mesoderm specific transcript, and IGF2 were significantly altered in both PE and PAS placentas. Additionally, our results revealed that the maternal imprinted genes were significantly over-expressed in PE and significantly under-expressed in PAS compared with a normal pregnancy. Moreover, DNA oxidative damage was elevated and positively correlated with IGF2 DNA methylation in both PE and PAS placentas, and cortisol and IGF2 levels were significantly decreased in PE and PAS., Conclusions: This study suggested that DNA methylation and expression of imprinted genes are aberrant in both PE and PAS placentas and that PE and PAS have different methylation profiles, which may be linked to their unique pathogenesis., (© 2024. The Author(s).)

Background and Objectives : Polycystic ovary syndrome (PCOS) is a frequent and complex multidisciplinary disorder. Data regarding the role of genes involved in vitamin D metabolism in PCOS are as-yet elusive but suggest an association of VDR (vitamin D receptor) and vitamin D levels with metabolic, endocrine and cutaneous manifestations. The aim of this study was to evaluate the association between VDR gene polymorphisms and cutaneous manifestations, to find a correlation between hormonal parameters, oxidative stress and skin manifestations in women with PCOS, and to determine the impact of VDR gene polymorphisms on these parameters. Materials and Methods : This case-control study included 39 controls and 46 women with PCOS, matched by age and BMI distribution. Acne, hirsutism, seborrhea, androgenetic alopecia, oxidative stress and androgen hormones were recorded. VDR gene polymorphisms ApaI, FokI and TaqI were examined by polymerase chain reaction restriction fragment length polymorphism, and the androgen hormone (total testosterone, DHEAS), SHBG and malondialdehyde levels were assessed. Results : The most frequent skin manifestations in PCOS cases were acne followed by seborrhea, hirsutism and androgenic alopecia. The VDR-FokI polymorphism CC genotype had a significant protective role in the odds of acne (OR = 0.11, 95% CI: [0.02, 0.70], p = 0.015, p-corrected = 0.040) and seborrhea (OR = 0.15, 95% CI: [0.03, 0.75], p = 0.019, p-corrected = 0.039). The results demonstrated a significant protective effect of the C allele on the odds of acne and seborrhea in PCOS cases. Moreover, the dominant genotype of VDR-TaqI could have a protective role against oxidative stress (lower MDA levels) compared to patients carrying the TT genotype. Conclusions : In summary, this is the first study to demonstrate that the FokI CC genotype may have a protective role against both acne and seborrhea in women with PCOS, while the VDR-TaqI dominant genotype is associated with diminished oxidative stress in PCOS patients.

Myeloproliferative neoplasms (MPNs) are characterized by increased proliferation of myeloid lineages in the bone marrow. Calreticulin ( CALR ) 52 bp deletion and CALR 5 bp insertion have been identified in essential thrombocythemia (ET) and primary myelofibrosis (PMF). There is not much data on the crosstalk between mutated CALR and MPN-related signaling pathways, such as JAK/STAT, PI3K/Akt/mTOR, and Hedgehog. Calreticulin, a multifunctional protein, takes part in many cellular processes. Nevertheless, there is little data on how mutated CALR affects the oxidative stress response and oxidative stress-induced DNA damage, apoptosis, and cell cycle progression. We aimed to investigate the role of the CALR 52 bp deletion and 5 bp insertion in the pathogenesis of MPN, including signaling pathway activation and functional analysis in CALR -mutated cells. Our data indicate that the JAK/STAT and PI3K/Akt/mTOR pathways are activated in CALR -mutated cells, and this activation does not necessarily depend on the CALR and MPL interaction. Moreover, it was found that CALR mutations impair calreticulin function, leading to reduced responses to oxidative stress and DNA damage. It was revealed that the accumulation of G2/M- CALR -mutated cells indicates that oxidative stress-induced DNA damage is difficult to repair. Taken together, this study contributes to a deeper understanding of the specific molecular mechanisms underlying CALR -mutated MPNs.

This article delves into Alzheimer's disease (AD), a prevalent neurodegenerative condition primarily affecting the elderly. It is characterized by progressive memory and cognitive impairments, severely disrupting daily life. Recent research highlights the potential involvement of microRNAs in the pathogenesis of AD. MicroRNAs (MiRNAs), short non-coding RNAs comprising 20-24 nucleotides, significantly influence gene regulation by hindering translation or promoting degradation of target genes. This review explores the role of specific miRNAs in AD progression, focusing on their impact on β-amyloid (Aβ) peptide accumulation, intracellular aggregation of hyperphosphorylated tau proteins, mitochondrial dysfunction, neuroinflammation, oxidative stress, and the expression of the APOE4 gene. Our insights contribute to understanding AD's pathology, offering new avenues for identifying diagnostic markers and developing novel therapeutic targets., (© 2024. The Author(s).)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are chronic syndromes of unknown etiology, accompanied by numerous symptoms affecting neurological and physical conditions. Despite frequent revisions of the diagnostic criteria, clinical practice guidelines are often outdated, leading to underdiagnosis and ineffective treatment. Our aim was to identify microRNA (miRNA) biomarkers implicated in pathological mechanisms underlying these diseases. A comprehensive literature review using publicly accessible databases was conducted. Interesting miRNAs were extracted from relevant publications on ME/CFS and/or FM, and were then linked to pathophysiological processes possibly manifesting these chronic diseases. Dysregulated miRNAs in ME/CFS and FM may serve as promising biomarkers for these diseases. Key identified miRNAs, such as miR-29c, miR-99b, miR-128, miR-374b, and miR-766, were frequently mentioned for their roles in immune response, mitochondrial dysfunction, oxidative stress, and central sensitization, while miR-23a, miR-103, miR-152, and miR-320 were implicated in multiple crucial pathological processes for FM and/or ME/CFS. In summary, both ME/CFS and FM seem to share many dysregulated biological or molecular processes, which may contribute to their commonly shared symptoms. This miRNA-based approach offers new angles for discovering molecular markers urgently needed for early diagnosis or therapeutics to tackle the pathology of these medically unexplained chronic diseases.

Chronically elevated levels of glucose are deleterious to pancreatic β cells and contribute to β cell dysfunction, which is characterized by decreased insulin production and a loss of β cell identity. The Krüppel-like transcription factor, Glis3 has previously been shown to positively regulate insulin transcription and mutations within the Glis3 locus have been associated with the development of several pathologies including type 2 diabetes mellitus. In this report, we show that Glis3 is significantly downregulated at the transcriptional level in INS1 832/13 cells within hours of being subjected to high glucose concentrations and that diminished expression of Glis3 is at least partly attributable to increased oxidative stress. CRISPR/Cas9-mediated knockdown of Glis3 indicated that the transcription factor was required to maintain normal levels of both insulin and MafA expression and reduced Glis3 expression was concomitant with an upregulation of β cell disallowed genes. We provide evidence that Glis3 acts similarly to a pioneer factor at the insulin promoter where it permissively remodels the chromatin to allow access to a transcriptional regulatory complex including Pdx1 and MafA. Finally, evidence is presented that Glis3 can positively regulate MafA transcription through its pancreas-specific promoter and that MafA reciprocally regulates Glis3 expression. Collectively, these results suggest that decreased Glis3 expression in β cells exposed to chronic hyperglycemia may contribute significantly to reduced insulin transcription and a loss of β cell identity.

Patient-specific induced pluripotent stem cell-derived (iPSC-derived) cell lines allow for therapies to be tailored to individual patients, increasing therapeutic precision and efficiency. Bietti crystalline dystrophy (BCD) is a rare blinding disease estimated to affect about 67,000 individuals worldwide. Here, we used iPSC-derived retinal pigment epithelium (iRPE) cells from patients with BCD to evaluate adeno-associated virus-mediated (AAV-mediated) gene augmentation therapy strategies. We found that BCD iRPE cells were vulnerable to blue light-induced oxidative stress and that cellular phenotype can be quantified using 3 robust biomarkers: reactive oxygen species (ROS), 4-hydroxy 2-nonenal (4-HNE) levels, and cell death rate. Additionally, we demonstrated that AAV-mediated gene therapy can significantly reduce light-induced cell death in BCD iRPE cells. This is the first proof-of-concept study to our knowledge to show that AAV-CYP4V2 gene therapy can be used to treat light-induced RPE damage in BCD. Furthermore, we observed significant variability in cellular phenotypes among iRPE from patients with BCD of divergent mutations, which outlined genotype-phenotype correlations in BCD patient-specific cell disease models. Our results reveal that patient-specific iRPE cells retained personalized responses to AAV-mediated gene therapy. Therefore, this approach can advance BCD therapy and set a precedent for precision medicine in other diseases, emphasizing the necessity for personalization in healthcare to accommodate individual diversity.

Background: Intracranial aneurysm (IA) is a localized abnormal dilation of the cerebral vascular wall, the degeneration of which is closely related to high oxidative stress., Methods: Clinical information and RNA-seq data from five public datasets were downloaded from the Gene Expression Omnibus (GEO). Using the "GSVA" package, enrichment analysis was performed on the gene sets of the oxidative stress, reactive oxygen species (ROS), metabolism, and inflammatory pathways retrieved from the MsigDB and Kyoto encyclopedia of genes and genomes (KEGG) databases. Weighted gene co-expression network analysis (WGCNA) was conducted using the "WGCNA" package, followed by using the "limma" R package to select differentially expressed genes (DEGs). Key genes were determined by applying three machine learning algorithms (random forest, Lasso, and SVM-RFE). The expression levels of the key genes were verified by the quantitative real-time polymerase chain reaction (qRT-PCR) in IA. Finally, ESTIMATE and CIBERPSORT algorithms were used for immune infiltration analysis., Results: The enrichment score of the oxidative stress, ROS, metabolism, and inflammatory pathways was calculated, and we found that these pathways were significantly activated in IA samples with higher immune infiltration. The intersection between the blue module related to oxidative stress (610 genes identified by WGCNA) and 380 upregulated DEGs contained a total of 209 key genes, which were further processed by machine learning algorithms to obtain four crucial diagnostic markers (FLVCR2, SDSL, TBC1D2, and SLC31A1) for IA. These key genes are highly expressed in human brain vascular smooth muscle cells. The expressions of the four markers were significantly positively correlated with the abnormal activation phenotypes of oxidative stress, the ROS and glucometabolic pathways, and suppressive immune infiltration., Conclusion: This study employed WGCNA combined with three machine learning algorithms to identify four oxidative stress-related signature markers for IA, providing novel insights into the clinical management of IA patients., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background: Gastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood., Methods: To assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT-qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1's regulation of autophagy in GC., Results: Our findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo., Conclusion: PTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC., (© 2024. The Author(s).)

Cadmium, a common metal pollutant, has been demonstrated to induce type 2 diabetes by disrupting pancreatic β cells function. In this study, transcriptome microarray was utilized to identify differential gene expression in oxidative damage to pancreatic β cells following cadmium exposure. The results indicated that a series of mRNAs, LncRNAs, and miRNAs were altered. Of the differentially expressed miRNAs, miR-29a-3p exhibited the most pronounced alteration, with an 11.62-fold increase relative to the control group. Following this, the target gene of miR-29a-3p was identified as Col3a1 through three databases (miRDB, miRTarbase and Tarbase), which demonstrated a decrease across the transcriptome microarray. The upstream target gene of miR-29a-3p was identified as NONMMUT036805, with decreased expression observed in the microarray. Finally, the expression trend of NONMMUT036805/miR-29a-3p/Col3a1 was reversed following NAC pretreatment. This was accompanied by a reduction in oxidative damage indicators, MDA/ROS/GSH-Px appeared to be negatively affected to varying degrees. In conclusion, this study has demonstrated that multiple RNAs are altered during cadmium exposure-induced oxidative damage in pancreatic β cells. The NONMMUT036805/miR-29a-3p/Col3a1 axis has been shown to be involved in this process, which provides a foundation for the identification of potential targets for cadmium toxicity intervention., (© 2024. The Author(s).)

Background: Ulcerative colitis (UC) is a common chronic disease associated with inflammation and oxidative stress. This study aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and to explore oxidative stress-related genes underlying the pathogenesis of UC., Methods: The GSE75214, GSE48959, and GSE114603 datasets were downloaded from the Gene Expression Omnibus database. Following differentially expressed (DE) analysis, the regulatory relationships among these DERNAs were identified through miRDB, miRTarBase, and TargetScan; then, the lncRNA-miRNA-mRNA network was established. The Molecular Signatures Database (MSigDB) was used to search oxidative stress-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotation and enrichment analyses. Based on the drug gene interaction database DGIdb, drugs that interact with oxidative stress-associated genes were explored. A dextran sulfate sodium (DSS)-induced UC mouse model was used for experimental validation., Results: A total of 30 DE-lncRNAs, 3 DE-miRNAs, and 19 DE-mRNAs were used to construct a lncRNA-miRNA-mRNA network. By comparing these 19 DE-mRNAs with oxidative stress-related genes in MSigDB, three oxidative stress-related genes ( CAV1, SLC7A11 , and SLC7A5 ) were found in the 19 DEM sets, which were all negatively associated with miR-194. GO and KEGG analyses showed that CAV1, SLC7A11 , and SLC7A5 were associated with immune inflammation and steroid hormone synthesis. In animal experiments, the results showed that dexamethasone, a well-known glucocorticoid drug, could significantly decrease the expression of CAV1, SLC7A11 , and SLC7A5 as well as improve UC histology, restore antioxidant activities, inhibit inflammation, and decrease myeloperoxidase activity., Conclusion: SLC7A5 was identified as a representative gene associated with glucocorticoid therapy resistance and thus may be a new therapeutic target for the treatment of UC in the clinic., Competing Interests: The authors declare that they have no competing interests., (© 2024 Li et al.)

Background: Changes in the oxidative stress and lipid metabolism (OSLM) pathways play important roles in polycystic ovarian syndrome (PCOS) pathogenesis and development. Consequently, a systematic analysis of genes related to OSLM was conducted to identify molecular clusters and explore new biomarkers that are helpful for the diagnostic of PCOS., Methods: Gene expression and clinical data from 22 PCOS women and 14 normal women were obtained from the GEO database (GSE34526, GSE95728, and GSE106724). Consensus clustering identified OSLM-related molecular clusters, and WGCNA revealed co-expression patterns. The immune microenvironment was quantitatively assessed utilizing the CIBERSORT algorithm. Multiple machine learning models and connectivity map analyses were subsequently applied to explore potential biomarkers for PCOS, and nomograms were employed to develop a predictive multigene model of PCOS. Finally, the OSLM status of PCOS and the hub genes expression profiles were preliminarily verified using TUNEL, qRT‒PCR, western blot, and IHC assays in a PCOS mouse model., Results: 19 differential expression genes (DEGs) related to OSLM were identified. Based on 19 DEGs that were strongly influenced by OSLM, PCOS patients were stratified into two distinct clusters, designated Cluster 1 and Cluster 2. Distinct differences in the immune cell proportions existed in normal and two PCOS clusters. The random forest showed the best results, with the least cross-entropy and the utmost AUC (cross-entropy: 0.111 AUC: 0.960). Among the 19 OSLM-related genes, CXCR1, ACP5, CEACAM3, S1PR4, and TCF7 were identified by a Bayesian network and had a good fit with PCOS disease risk by the nomogram (AUC: 0.990 CI: 0.968-1.000). TUNEL assays revealed more severe DNA damage within the ovarian granule cells of PCOS mice than in those of normal mice (P < 0.001). The RNA and protein expression levels of the five hub genes were significantly elevated in PCOS mice, which was consistent with the results of the bioinformatics analyses., Conclusion: A novel predictive model was constructed for PCOS patients and five hub genes were identified as potential biomarkers to offer novel insights into clinical diagnostic strategies for PCOS., (© 2024. The Author(s).)

Background: The specific role of oxidative stress (OS) in vitiligo and alopecia areata (AA) remains unclear. The aim of this study was to analyze and identify the key markers of OS in vitiligo and AA by bioinformatics., Methods: We obtained vitiligo and AA datasets from gene expression omnibus (GEO) database. The difference-expressed genes of vitiligo and AA were identified by differential analysis, and the functions of difference-expressed genes were identified by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) enrichment analysis. Subsequently, Veen package was used to obtain the intersection genes of OS-related genes with vitiligo and AA. Finally, we used CIBERSORT to assess the infiltration of immune cells in vitiligo and AA., Results: Through enrichment analysis, we found that vitiligo and AA were mainly enriched in cell cycle and cell adhesion molecular channels. We identified KLB and EIF3C as key genes in OS regulation of vitiligo and AA, and found that KLB and EIF3C participate in disease progression by regulating T cells and neutrophils., Conclusions: According to our findings, KLB and EIF3C play a crucial role in the progression and development of vitiligo and AA, which have been identified as biomarkers and target for early diagnosis of patients., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Neurological diseases are expected to become the leading cause of death in the next decade. Although little is known about it, the interaction between oxidative stress and inflammation is harmful to the nervous system. To find an advanced tool for neural genetics, mouse haploid neural stem cells (haNSCs) from the somite of chimeric mouse embryos at E8.5 is established. The haNSCs present a haploid neural progenitor identity for long-term culture, promising to robustly differentiate into neural subtypes and being able to form cerebral organoids efficiently. Thereafter, haNSC mutants via a high-throughput approach and screened targets of oxidative stress is generated using the specific mutant library. Deletion of Nfkbia (the top hit among the insertion mutants) reduces damage from reactive oxygen species (ROS) in NSCs exposed to H 2 O 2 . Transcriptome analysis revealed that Atp2b4 is upregulated significantly in Nfkbia-null NSCs and is probably responsible for the observed resistance. Additionally, overexpression of Atp2b4 itself can increase the survival of NSCs in the presence of H 2 O 2 , suggesting that Atp2b4 is closely involved in this resistance. Herein, a powerful haploid system is presented to study functional genetics in neural lineages, shedding light on the screening of critical genes and drugs for neurological diseases., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Oxidative stress has been identified as a major factor in the development and progression of pain and psychiatric disorders, but the underlying biomarkers and molecular signaling pathways remain unclear. This study aims to identify oxidative stress-related biomarkers and signaling pathways in pain-depression comorbidity. Integrated bioinformatics analyses were applied to identify key genes by comparing pain-depression comorbidity-related genes and oxidative stress-related genes. A total of 580 differentially expressed genes and 35 differentially expressed oxidative stress-related genes (DEOSGs) were identified. By using a weighted gene co-expression network analysis and a protein-protein interaction network, 43 key genes and 5 hub genes were screened out, respectively. DEOSGs were enriched in biological processes and signaling pathways related to oxidative stress and inflammation. The five hub genes, RNF24, MGAM, FOS, and TKT, were deemed potential diagnostic and prognostic markers for patients with pain-depression comorbidity. These genes may serve as valuable targets for further research and may aid in the development of early diagnosis, prevention strategies, and pharmacotherapy tools for this particular patient population.

Exposure to heavy metals and lifestyle factors like smoking contribute to the production of free oxygen radicals. This fact, combined with a lowered total antioxidant status, can induce even more damage in the development of ankylosing spondylitis (AS). Despite the fact that some researchers are looking for more genetic factors underlying AS, most studies focus on polymorphisms within the genes encoding the human leukocyte antigen (HLA) system. The biggest challenge is finding the effective treatment of the disease. Genetic factors and the influence of oxidative stress, mineral metabolism disorders, microbiota, and tobacco smoking seem to be of great importance for the development of AS. The data contained in this review constitute valuable information and encourage the initiation and development of research in this area, showing connections between inflammatory disorders leading to the pathogenesis of AS and selected environmental and genetic factors.

Salinity tolerance was studied in chickpea accessions from a germplasm collection and in cultivars from Kazakhstan. After NaCl treatment, significant differences were found between genotypes, which could be arranged into three groups. Those that performed poorest were found in group 1, comprising five ICC accessions with the lowest chlorophyll content, the highest leaf necrosis (LN), Na + accumulation, malondialdehyde (MDA) content, and a low glutathione ratio GSH/GSSG. Two cultivars, Privo-1 and Tassay, representing group 2, were moderate in these traits, while the best performance was for group 3, containing two other cultivars, Krasnokutsky-123 and Looch, which were found to have mostly green plants and an exact opposite pattern of traits. Marker-trait association (MTA) between 6K DArT markers and four traits (LN, Na + , MDA, and GSH/GSSG) revealed the presence of four possible candidate genes in the chickpea genome that may be associated with the three groups. One gene, ATP-binding cassette, CaABCC6 , was selected, and three haplotypes, A, D1, and D2, were identified in plants from the three groups. Two of the most salt-tolerant cultivars from group 3 were found to have haplotype D2 with a novel identified SNP. RT-qPCR analysis confirmed that this gene was strongly expressed after NaCl treatment in the parental- and breeding-line plants of haplotype D2. Mass spectrometry of seed proteins showed a higher accumulation of glutathione reductase and S-transferase, but not peroxidase, in the D2 haplotype. In conclusion, the CaABCC6 gene was hypothesized to be associated with a better response to oxidative stress via glutathione metabolism, while other candidate genes are likely involved in the control of chlorophyll content and Na + accumulation.

Deoxynivalenol (DON) is a prevalent toxin causing severe liver damage through hepatocellular oxidative stress. However, the underlying mechanisms and effective therapeutic approaches remain unknown. Here, the unique role of the xenobiotic metabolism factor pregnane X receptor (PXR) in mediating DON-induced hepatocellular oxidative stress is investigated. Treatment with the PXR agonist 3-indole-propionic acid (IPA) alleviates DON-induced oxidative stress and liver injury both in vitro and in vivo. Mechanistically, it is discovered for the first time that PXR agonist IPA directly transactivates the m 6 A demethylase FTO expression, leading to site-specific demethylation and decreased abundance of YTHDC1-bound Malat1 lncRNA at single-nucleotide resolution. The diminished m 6 A modification of Malat1 lncRNA reduces its stability and augments antioxidant pathways governed by NRF2, consequently mitigating DON-induced liver injury. Furthermore, Malat1 knockout mice exhibit decreased DON-induced liver injury, emphasizing the role of Malat1 lncRNA in oxidative stress. Collectively, the findings establish that PXR-mediated m 6 A-dependent Malat1 lncRNA expression determines hepatocyte oxidative stress via m 6 A demethylase FTO, providing valuable insights into the potential mechanisms underlying DON-induced liver injury and offers potential therapeutic strategies for its treatment., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Preterm born (PTB) infants are at risk for injuries related to oxidative stress. We investigated the association between antioxidant and neurodevelopmental gene polymorphisms and oxidative stress parameters in PTB male young adults and their term-born counterparts at rest and during exercise. Healthy young PTB (N = 22) and full-term (N = 15) males underwent graded exercise tests in normobaric normoxic (F i O 2  = 0.21) and hypoxic (F i O 2  = 0.13) conditions. CAT rs1001179 was associated with decrease in nitrites in the whole group and in PTB individuals (P = 0.017 and P = 0.043, respectively). GPX1 rs1050450 was associated with decrease in ferric reducing antioxidant power in the whole group and in full-term individuals (P = 0.017 and P = 0.021, respectively). HIF1A rs11549465 was associated with decrease in nitrotyrosine and increase in malondialdehyde (P = 0.022 and P = 0.018, respectively). NOTCH4 rs367398 was associated with increase in advanced oxidation protein products and nitrites (P = 0.002 and P = 0.004, respectively) in hypoxia. In normoxia, NOTCH4 rs367398 was associated with increase in malondialdehyde in the whole group (P = 0.043). BDNF rs6265 was associated with decreased nitrites/nitrates in the whole group and in PTB individuals (P = 0.009 and P = 0.043, respectively). Polymorphisms in investigated genes and PTB might influence oxidative stress response after exercise in normoxic or hypoxic conditions far beyond the neonatal period in young male adults., (© 2024. The Author(s).)

Alterations in mitochondrial function have been linked to a variety of cellular and organismal stress responses including apoptosis, aging, neurodegeneration and tumorigenesis. However, adaptation to mitochondrial dysfunction can occur through the activation of survival pathways, whose mechanisms are still poorly understood. The yeast Saccharomyces cerevisiae is an invaluable model organism for studying how mitochondrial dysfunction can affect stress response and adaptation processes. In this study, we analyzed and compared in the absence and in the presence of osmostress wild-type cells with two models of cells lacking mitochondrial DNA: ethidium bromide-treated cells (ρ 0 ) and cells lacking the mitochondrial pyrimidine nucleotide transporter RIM2 (Δ RIM2 ). Our results revealed that the lack of mitochondrial DNA provides an advantage in the kinetics of stress response. Additionally, wild-type cells exhibited higher osmosensitivity in the presence of respiratory metabolism. Mitochondrial mutants showed increased glycerol levels, required in the short-term response of yeast osmoadaptation, and prolonged oxidative stress. The involvement of the mitochondrial retrograde signaling in osmoadaptation has been previously demonstrated. The expression of CIT2 , encoding the peroxisomal isoform of citrate synthase and whose up-regulation is prototypical of RTG pathway activation, appeared to be increased in the mutants. Interestingly, selected TCA cycle genes, CIT1 and ACO1 , whose expression depends on RTG signaling upon stress, showed a different regulation in ρ 0 and Δ RIM2 cells. These data suggest that osmoadaptation can occur through different mechanisms in the presence of mitochondrial defects and will allow us to gain insight into the relationships among metabolism, mitochondria-mediated stress response, and cell adaptation., Competing Interests: The authors declare no conflicts of interest.

Background: Preeclampsia is one of the three leading causes of worldwide maternal mortality. Oxidative stress-mediated endothelial damage is expected to be an ultimate common mechanism in the pathophysiology of preeclampsia. The role of bioamines is also well-established in the induction of preeclampsia. This project is aimed to understand the factors which may affect the induction, progression, and aggravation of preeclampsia and oxidative stress during pregnancy. This study will explore the methylation pattern of the Catechol-O-methyltransferase gene to determine its role in the pathogenesis of preeclampsia, association of Val158Met polymorphism with a wide range of oxidative stress biomarkers, major antioxidants vitamins, and blood pressure regulating amines in preeclamptic Pakistani women., Methods and Analysis: In this prospective case-control study, 85 preeclamptic and 85 normotensive pregnant women will be recruited in their third trimesters. DNA will be extracted from peripheral blood and Val158Met polymorphism in the Catechol-O-methyltransferase gene will be examined on PCR amplified product digested with Hin1II (NlaIII) restriction enzyme, further validated by Sanger sequencing. Methylation-sensitive PCR will also be performed. Oxidative stress biomarkers, antioxidant vitamins, bioamines, and catechol-O-methyltransferase levels will be measured by ELISA. The data will be used to correlate maternal and fetal outcomes in both groups., Discussion: This study will help to identify and understand the multifactorial path and cause-effect relationship of gene polymorphism, oxidative stress biomarkers, major antioxidants vitamins, and blood pressure regulating amines in the pathogenesis and aggravation of preeclampsia in the Pakistani population. The outcome of this project will be particularly helpful in reducing the incidence of preeclampsia and further improving its management., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yousuf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Oxidative stress represents a critical facet of the array of abiotic stresses affecting crop growth and yield. In this paper, we investigated the potential differences in the functions of two highly homologous Arabidopsis DSS1 proteins in terms of maintaining genome integrity and response to oxidative stress. In the context of homologous recombination (HR), it was shown that overexpressing AtDSS1(I) using a functional complementation test increases the resistance of the Δ dss1 mutant of Ustilago maydis to genotoxic agents. This indicates its conserved role in DNA repair via HR. To investigate the global transcriptome changes occurring in dss1 plant mutant lines, gene expression analysis was conducted using Illumina RNA sequencing technology. Individual RNA libraries were constructed from three total RNA samples isolated from dss1(I) , dss1(V) , and wild-type (WT) plants under hydrogen peroxide-induced stress. RNA-Seq data analysis and real-time PCR identification revealed major changes in gene expression between mutant lines and WT, while the dss1(I) and dss1(V) mutant lines exhibited analogous transcription profiles. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed significantly enriched metabolic pathways. Notably, genes associated with HR were upregulated in dss1 mutants compared to the WT. Otherwise, genes of the metabolic pathway responsible for the synthesis of secondary metabolites were downregulated in both dss1 mutant lines. These findings highlight the importance of understanding the molecular mechanisms of plant responses to oxidative stress.

Purpose: Severe community-acquired pneumonia (SCAP) is a common respiratory system disease with rapid development and high mortality. Exploring effective biomarkers for early detection and development prediction of SCAP is of urgent need. The function of miR-486-5p in SCAP diagnosis and prognosis was evaluated to identify a promising biomarker for SCAP., Patients and Methods: The serum miR-486-5p in 83 patients with SCAP, 52 healthy individuals, and 68 patients with mild CAP (MCAP) patients were analyzed by PCR. ROC analysis estimated miR-486-5p in screening SCAP, and the Kaplan-Meier and Cox regression analyses evaluated the predictive value of miR-486-5p. The risk factors for MCAP patients developing SCAP were assessed by logistic analysis. The alveolar epithelial cell was treated with Klebsiella pneumonia to mimic the occurrence of SCAP. The targeting mechanism underlying miR-486-5p was evaluated by luciferase reporter assay., Results: Upregulated serum miR-486-5p screened SCAP from healthy individuals and MCAP patients with high sensitivity and specificity. Increasing serum miR-486-5p predicted the poor outcomes of SCAP and served as a risk factor for MCAP developing into SCAP. K. pneumonia induced suppressed proliferation, significant inflammation and oxidative stress in alveolar epithelial cells, and silencing miR-486-5p attenuated it. miR-486-5p negatively regulated FOXO1, and the knockdown of FOXO1 reversed the effect of miR-486-5p in K. pneumonia-treated alveolar epithelial cells., Conclusion: miR-486-5p acted as a biomarker for the screening and monitoring of SCAP and predicting the malignancy of MCAP. Silencing miR-486-5p alleviated inflammation and oxidative stress induced by K. pneumonia via negatively modulating FOXO1., (© 2024. The Author(s).)

Fructosamine-3-kinases (FN3Ks) are a conserved family of repair enzymes that phosphorylate reactive sugars attached to lysine residues in peptides and proteins. Although FN3Ks are present across the Tree of Life and share detectable sequence similarity to eukaryotic protein kinases, the biological processes regulated by these kinases are largely unknown. To address this knowledge gap, we leveraged the FN3K CRISPR Knock-Out (KO) HepG2 cell line alongside an integrative multi-omics study combining transcriptomics, metabolomics, and interactomics to place these enzymes in a pathway context. The integrative analyses revealed the enrichment of pathways related to oxidative stress response, lipid biosynthesis (cholesterol and fatty acids), and carbon and co-factor metabolism. Moreover, enrichment of nicotinamide adenine dinucleotide (NAD) binding proteins and localization of human FN3K (HsFN3K) to mitochondria suggests potential links between FN3K and NAD-mediated energy metabolism and redox balance. We report specific binding of HsFN3K to NAD compounds in a metal and concentration-dependent manner and provide insight into their binding mode using modeling and experimental site-directed mutagenesis. Our studies provide a framework for targeting these understudied kinases in diabetic complications and metabolic disorders where redox balance and NAD-dependent metabolic processes are altered., (© 2024. The Author(s).)

The alterations in DNA methylation and transcriptome in trophoblast cells under conditions of low oxygen and oxidative stress have major implications for pregnancy-related disorders. However, the exact mechanism is still not fully understood. In this study, we established models of hypoxia (H group) and oxidative stress (HR group) using HTR-8/SVneo trophoblast cells and performed combined analysis of genome-wide DNA methylation changes using reduced representation bisulphite sequencing and transcriptome expression changes using RNA sequencing. Our findings revealed that the H group exhibited a higher number of differentially methylated genes and differentially expressed genes than the HR group. In the H group, only 0.90% of all differentially expressed genes displayed simultaneous changes in DNA methylation and transcriptome expression. After the threshold was expanded, this number increased to 6.29% in the HR group. Notably, both the H group and HR group exhibited concurrent alterations in DNA methylation and transcriptome expression within Axon guidance and MAPK signalling pathway. Among the top 25 differentially methylated KEGG pathways in the promoter region, 11 pathways were commonly enriched in H group and HR group, accounting for 44.00%. Among the top 25 KEGG pathways in transcriptome with significant differences between the H group and HR group, 10 pathways were consistent, accounting for 40.00%. By integrating our previous data on DNA methylation from preeclamptic placental tissues, we identified that the ANKRD37 and PFKFB3 genes may contribute to the pathogenesis of preeclampsia through DNA methylation-mediated transcriptome expression under hypoxic conditions., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein-coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO 2 peak, 400-m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO 2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Microtia is reported to be one of the most common congenital craniofacial malformations. Due to the complex etiology and the ethical barrier of embryonic study, the precise mechanisms of microtia remain unclear. Here we report a rare case of microtia with costal chondrodysplasia based on bioinformatics analysis and further verifications on other sporadic microtia patients., Results: One hundred fourteen deleterious insert and deletion (InDel) and 646 deleterious SNPs were screened out by WES, candidate genes were ranked in descending order according to their relative impact with microtia. Label-free proteomic analysis showed that proteins significantly different between the groups were related with oxidative stress and energy metabolism. By real-time PCR and immunohistochemistry, we further verified the candidate genes between other sporadic microtia and normal ear chondrocytes, which showed threonine aspartase, cadherin-13, aldolase B and adiponectin were significantly upregulated in mRNA levels but were significantly lower in protein levels. ROS detection and mitochondrial membrane potential (∆ Ψ m) detection proved that oxidative stress exists in microtia chondrocytes., Conclusions: Our results not only spot new candidate genes by WES and label-free proteomics, but also speculate for the first time that metabolism and oxidative stress may disturb cartilage development and this might become therapeutic targets and potential biomarkers with clinical usefulness in the future., (© 2024. The Author(s).)

Previous evidence suggests elevated levels of oxidatively-induced DNA damage, particularly 8-hydroxy-2'-deoxyguanosine (8-OH-dG), and abnormalities in the repair of 8-OH-dG by the base excision repair (BER) in bipolar disorder (BD). However, the genetic disposition of these abnormalities remains unknown. In this study, we aimed to investigate the levels of oxidatively-induced DNA damage and BER mechanisms in individuals with BD and their siblings, as compared to healthy controls (HCs). 46 individuals with BD, 41 siblings of individuals with BD, and 51 HCs were included in the study. Liquid chromatography-tandem mass spectrometry was employed to evaluate the levels of 8-OH-dG in urine, which were then normalized based on urine creatinine levels. The real-time-polymerase chain reaction was used to measure the expression levels of 8-oxoguanine DNA glycosylase 1 (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), poly ADP-ribose polymerase 1 (PARP1), and DNA polymerase beta (POLβ). The levels of 8-OH-dG were found to be elevated in both individuals with BD and their siblings when compared to the HCs. The OGG1 and APE1 expressions were downregulated, while POLβ expressions were upregulated in both the patient and sibling groups compared to the HCs. Age, smoking status, and the number of depressive episodes had an impact on APE1 expression levels in the patient group while body mass index, smoking status, and past psychiatric history had an impact on 8-OH-dG levels in siblings. Both individuals with BD and unaffected siblings presented similar abnormalities regarding oxidatively-induced DNA damage and BER, suggesting a link between abnormalities in DNA damage/BER mechanisms and familial susceptibility to BD. Our findings suggest that targeting the oxidatively-induced DNA damage and BER pathway could offer promising therapeutic strategies for reducing the risk of age-related diseases and comorbidities in individuals with a genetic predisposition to BD., (© 2024. The Author(s).)

The detrimental effects of ultraviolet C (UVC) radiation on living organisms, with a specific focus on the fruit fly Drosophila melanogaster, were examined. This study investigated the impact of heightened UVC radiation exposure on D. melanogaster by assessing mortality and fertility rates, studying phenotypic mutations, and investigating the associated molecular mechanisms. The findings of this study revealed that UVC radiation increases mortality rates and decreases fertility rates in D. melanogaster. Additionally, phenotypic wing mutations were observed in the exposed flies. Furthermore, the study demonstrated that UVC radiation downregulates the expression of antioxidant genes, including superoxide dismutase (SOD), manganese-dependent superoxide dismutase (Mn-SOD), zinc-dependent superoxide dismutase (Cu-Zn-SOD), and the G protein-coupled receptor methuselah (MTH) gene. These results suggest that UVC radiation exerts a destructive effect on D. melanogaster by inducing oxidative stress, which is marked by the overexpression of harmful oxidative processes and a simultaneous reduction in antioxidant gene expression. In conclusion, this study underscores the critical importance of comprehending the deleterious effects of UVC radiation, not only to safeguard human health on Earth, but also to address the potential risks associated with space missions, such as the ongoing Emirate astronaut program., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lotfy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Therapy resistance in gastric cancer poses ongoing challenges, necessitating the identification of ferroptosis-related genes linked to overall survival for potential therapeutic insights. The purpose of the study was to identify ferroptosis-related genes contributing to therapy resistance in gastric cancer and explore their associations with overall survival. Differentially expressed ferroptosis-related genes were identified in therapy-resistant versus therapy-responsive gastric cancer patients. Hub genes were selected from these genes. Enrichment analysis focused on oxidative stress and ROS metabolism. Validation was conducted in a TCGA stomach adenocarcinoma dataset. A hub gene-based risk model (DUSP1/TNF/NOX4/LONP1) was constructed and assessed for overall survival prediction. Associations with the tumor immune microenvironment were examined using the ESTIMATE algorithm and correlation analysis. Ten hub genes were identified, enriched in oxidative stress and ROS metabolism. Validation confirmed their aberrant expressions in the TCGA dataset. The hub gene-based risk model effectively predicted overall survival. High G6PD/TNF expression and low NOX4/SREBF1/MAPK3/DUSP1/KRAS/SIRT3/LONP1 expression correlated with stromal and immune scores. KRAS/TNF/MAPK3 expression positively correlated with immune-related SREBF1/NOX4 expression. DUSP1/NOX4/SREBF1/TNF/KRAS expression was associated with immune cell infiltration. The hub gene-based risk model (DUSP1/TNF/NOX4/LONP1) shows promise as an overall survival predictor in gastric cancer. Ferroptosis-related hub genes represent potential therapeutic targets for overcoming therapy resistance in gastric cancer treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The aim of this study was to investigate the DNA methylation profile in genes encoding catalase (CAT) and superoxide dismutase (SOD3) enzymes, which are involved in oxidative stress mechanisms, and in genes encoding pro-inflammatory cytokines interleukin-6 (IL6) and tumor necrosis factor-alpha (TNF-α) in the oral mucosa of oncopediatric patients treated with methotrexate (MTX®). This was a cross-sectional observational study and the population comprised healthy dental patients (n = 21) and those with hematological malignancies (n = 64) aged between 5 and 19 years. Oral conditions were evaluated using the Oral Assessment Guide and participants were divided into 4 groups: 1- healthy individuals; 2- oncopediatric patients without mucositis; 3- oncopediatric patients with mucositis; 4- oncopediatric patients who had recovered from mucositis. Methylation of DNA from oral mucosal cells was evaluated using the Methylation-Specific PCR technique (MSP). For CAT, the partially methylated profile was the most frequent and for SOD3 and IL6, the hypermethylated profile was the most frequent, with no differences between groups. For TNF-α, the hypomethylated profile was more frequent in the group of patients who had recovered from mucositis. It was concluded that the methylation profiles of CAT, SOD3, and IL6 are common profiles for oral cells of children and adolescents and have no association with oral mucositis or exposure to chemotherapy with MTX®. Hypomethylation of TNF-α is associated with oral mucosal recovery in oncopediatric patients who developed oral mucositis during chemotherapy.

Background: Sepsis-induced myopathy (SIM) a complication of sepsis that results in prolonged mechanical ventilation, long-term functional disability, and increased patient mortality. This study was performed to identify potential key oxidative stress-related genes (OS-genes) as biomarkers for the diagnosis of SIM using bioinformatics., Methods: The GSE13205 was obtained from the Gene Expression Omnibus (GEO) database, including 13 SIM samples and 8 healthy samples, and the differentially expressed genes (DEGs) were identified by limma package in R language. Simultaneously, we searched for the genes related to oxidative stress in the Gene Ontology (GO) database. The intersection of the genes selected from the GO database and the genes from the GSE13205 was considered as OS-genes of SIM, where the differential genes were regarded as OS-DEGs. OS-DEGs were analyzed using GO enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction (PPI) networks. Hub genes in OS-DEGs were selected based on degree, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed., Results: A total of 1089 DEGs were screened from the GSE13205, and 453 OS-genes were identified from the GO database. The overlapping DEGs and OS-genes constituted 25 OS-DEGs, including 15 significantly upregulated and 10 significantly downregulated genes. The top 10 hub genes, including CD36, GPX3, NQO1, GSR, TP53, IDH1, BCL2, HMOX1, JAK2, and FOXO1, were screened. Furthermore, 5 diagnostic genes were identified: CD36, GPX3, NQO1, GSR, and TP53. The ROC analysis showed that the respective area under the curves (AUCs) of CD36, GPX3, NQO1, GSR, and TP53 were 0.990, 0.981, 0.971, 0.971, and 0.971, which meant these genes had very high diagnostic values of SIM. Finally, based on these 5 diagnostic genes, we found that miR-124-3p and miR-16-5p may be potential targets for the treatment of SIM., Conclusions: The results of this study suggest that OS-genes might play an important role in SIM. CD36, GPX3, NQO1, GSR, and TP53 have potential as specific biomarkers for the diagnosis of SIM., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)