Frontiers in bioscience (Landmark edition)最新文献

{"title":"XLOC_015548 Mitigates Skeletal Muscle Atrophy via the Gadd45g/MEK/ERK Pathway and Redox Regulation.","authors":"Tiantian Qi, Haotian Qin, Fei Yu, Zimeng Zhou, Yingqi Chen, Peng Liu, Hui Zeng, Jian Weng","doi":"10.31083/FBL36233","DOIUrl":"https://doi.org/10.31083/FBL36233","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle atrophy is a common musculoskeletal disorder that significantly reduces patient quality of life. Long non-coding RNA (lncRNA) XLOC_015548 has been identified as a pivotal regulator of C2C12 myoblast proliferation and differentiation. However, its role in mitigating denervation-induced muscle atrophy and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>We employed lentiviral-mediated stable expression of XLOC_015548 in C2C12 myoblasts and skeletal muscle-specific XLOC_015548-edited mouse models to investigate the function of this lncRNA. Muscle atrophy models were established <i>in vitro</i> by glucocorticoid-induced atrophy with dexamethasone (DEX) and <i>in vivo</i> by sciatic nerve transection-induced denervation. The MEK inhibitor U0126 was used to assess the role of the growth arrest and DNA damage-inducible 45 gamma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Gadd45g/MEK/ERK) signaling pathway.</p><p><strong>Results: </strong>Overexpression of XLOC_015548 significantly activated the MEK/ERK signaling pathway (<i>p</i> < 0.05) by downregulating Gadd45g expression (<i>p</i> < 0.05) and promoting its cytoplasmic localization, thereby enhancing cell proliferation and myotube formation. Furthermore, XLOC_015548 reduced the level of reactive oxygen species (ROS) (<i>p</i> < 0.01), stabilized the mitochondrial membrane potential, and alleviated DEX-induced oxidative stress. These protective effects were partially reversed by U0126, confirming the involvement of the MEK/ERK pathway. Skeletal muscle-specific overexpression of XLOC_015548 <i>in vivo</i> significantly reduced denervation-induced muscle atrophy (<i>q</i> < 0.05) and increased the muscle fiber cross-sectional area.</p><p><strong>Conclusion: </strong>XLOC_015548 plays a critical role in promoting myogenic differentiation and protecting against muscle atrophy by regulating Gadd45g expression, activating the MEK/ERK signaling pathway, and reducing oxidative stress. These findings underscore the therapeutic potential of XLOC_015548 in skeletal muscle atrophy, and provide a foundation for lncRNA-based treatment strategies.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"36233"},"PeriodicalIF":3.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Signature Composed of Hypoxia, Glycolysis, Lactylation Related Genes to Predict Prognosis and Immunotherapy in Hepatocellular Carcinoma.","authors":"Feng Yi, Shichao Long, Yuanbing Yao, Kai Fu","doi":"10.31083/FBL33422","DOIUrl":"https://doi.org/10.31083/FBL33422","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The hypoxic microenvironment in HCC enhances glycolysis and co-directed lactate accumulation, which leads to increased lactylation. However, the exact biological pattern remains to be elucidated. Therefore, we sought to identify hypoxia-glycolysis-lactylation (HGL) prognosis-related signatures and validate this <i>in vitro</i>.</p><p><strong>Methods: </strong>Transcriptomic data of patients with HCC were collected from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. Differentially expressed HGL genes between HCC and normal tissues were obtained by DEseq2. The consensus clustering algorithm was employed to stratify patients into two distinct clusters. Subsequently, the single sample Gene Set Enrichment Analysis (ssGSEA), Tumor Immune Estimation Resource (TIMER) and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were utilized to assess immune infiltration and immune evasion. Least Absolute Shrinkage and Selection Operator (LASSO) and COX regression analysis were used to identify an HGL prognosis-related signature. Based on spatial transcriptome and histological data, we analyzed the expression of these genes in HCC and explored the function of Homer Scaffold Protein 1 (HOMER1) in HCC cells.</p><p><strong>Results: </strong>We identified 72 differentially expressed HGL genes and two HGL clusters. Cluster2, with better survival (<i>p</i> < 0.001), was significantly enriched in metabolic-related pathways. The HGL prognosis-related signature exhibited great predictive efficacy for patients in TCGA, ICGC, and GSE148355 databases (3-year area under the curve (AUC) = 0.822, 0.738, and 0.707, respectively). The elevated expression of HOMER1 in HCC was revealed by the combination of spatial transcriptome and histological data. Knocking down HOMER1 significantly inhibited the malignant progression of HCC cells.</p><p><strong>Conclusions: </strong>We identified a signature with great predictive efficacy and discovered a gene, HOMER1, that influences the malignant progression of HCC with the potential to become a novel therapeutic target.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"33422"},"PeriodicalIF":3.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Flow of Life: Convergent Approaches to Understanding Musculoskeletal Health from Molecular- to Meso-Length Scales.","authors":"Melissa Louise Knothe Tate","doi":"10.31083/FBL25231","DOIUrl":"https://doi.org/10.31083/FBL25231","url":null,"abstract":"<p><p>In the current perspective and review article, we address the human body as a living ecosystem with collecting watersheds and draining hydrosheds; we integrate our discoveries over the past quarter of a century and pose the critical open research questions to be addressed going forward, with the aim to improve cell, tissue, organ and organismal health. First, we address the flow of fluid through the tissues of the musculoskeletal system, after which we describe the interactions of the fluid, at multiple lengths and time scales, with the molecular to macroscopic non-fluid tissue components, discussing bone and tissues in the context of \"living\" chromatography and/or electrophoresis columns. Thereafter, we discuss the implications of functional barrier integrity, and the effects of cytokines on active barrier function and molecular transport between organ systems, tissue compartments, and within tissues. In addition, we address the fluid and its flow and the multi-physics implications thereof for the living inhabitants of tissues, i.e., the cells. Finally, we describe the implications of the solid and fluid components and the cellular inhabitants on ecosystem health, where the tissues and organs comprise the organism form interacting ecosystems throughout life and in the context of health and disease. By taking convergent approaches to understanding musculoskeletal, human and environmental health (which themselves are interdependent), we hope to pave new paths of innovation and discovery, to improve the lives of our worlds' inhabitants, from the worlds of our bone and joints and bodies to the interacting ecosystems of our Earth to unknown worlds beyond our current understanding.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"25231"},"PeriodicalIF":3.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-Highly Expressed <i>SLC17A9</i> and <i>KCNH1</i> as Potential Prognostic Biomarkers and Therapeutic Targets in Clear Cell Renal Cell Carcinoma.","authors":"Zongpan Ke, Zhiwang Tang, Deyun Shen, Yixun Liu, Yawei Shu, Xiangyu Mu, Zexuan Li, Ping Xiang, Bing Zhong, Xuechun Hu, Ruoyun Tan, Jun Xiao","doi":"10.31083/FBL38061","DOIUrl":"https://doi.org/10.31083/FBL38061","url":null,"abstract":"<p><strong>Background: </strong>The vesicular nucleotide transporter Solute Carrier Family 17 Member 9 (SLC17A9) has recently been recognized as a significant modulator of oncogenic pathways, with its elevated expression levels being closely linked to the aggressiveness of clear cell renal cell carcinoma (ccRCC). A comprehensive understanding of the role of SLC17A9 and its associated protein markers presents substantial potential for the advancement of targeted therapeutic interventions.</p><p><strong>Methods: </strong>Our study commenced with a comprehensive bioinformatics analysis to identify differentially expressed genes potentially associated with ccRCC. Leveraging The Cancer Genome Atlas (TCGA) database, we predicted the clinical relevance of these cancer-associated genes and validated their expression profiles through multiple experimental methodologies. Functional assays were conducted to assess the impact of these genes on renal cancer cell lines. Additionally, we generated cell lines overexpressing oncogenes and identified downstream targets through RNA sequencing, followed by mechanistic exploration of their interactions. Finally, bioinformatics tools were subsequently employed to assess the diagnostic and prognostic significance of these genes in patients with ccRCC.</p><p><strong>Results: </strong>The bioinformatics analysis revealed SLC17A9 as a highly expressed oncogene in ccRCC, serving as a robust prognostic marker. Experimental validation demonstrated that SLC17A9 promotes ccRCC cell growth, proliferation, and migration. Lentivirus-based experiments revealed Potassium Voltage-Gated Channel Subfamily H Member 1 (KCNH1) as a downstream target regulated by SLC17A9 (<i>p</i> < 0.05). Database analysis further confirmed KCNH1's oncogenic role in ccRCC, with significant implications for patient survival. Notably, SLC17A9 and KCNH1 collaboratively drive the initiation and progression of renal cancer. Elevated expression of SLC17A9 and KCNH1 correlates with poorer prognosis (<i>p</i> < 0.001), whereas lower expression levels are associated with favorable outcomes in ccRCC patients. These findings highlight SLC17A9 and KCNH1 as critical biomarkers and potential therapeutic targets in ccRCC.</p><p><strong>Conclusion: </strong>SLC17A9 and KCNH1 serve as critical prognostic biomarkers in ccRCC, with SLC17A9 driving tumor progression through KCNH1 regulation. Their upregulated expression predicts poor clinical outcomes, while reduced levels correlate with improved survival, highlighting their dual role as therapeutic targets.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"38061"},"PeriodicalIF":3.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategies for <i>in Silico</i> Drug Discovery to Modulate Macromolecular Interactions Altered by Mutations.","authors":"Pitambar Poudel, Maria A Miteva, Emil Alexov","doi":"10.31083/FBL26339","DOIUrl":"https://doi.org/10.31083/FBL26339","url":null,"abstract":"<p><p>Most human diseases have genetic components, frequently single nucleotide variants (SNVs), which alter the wild type characteristics of macromolecules and their interactions. A straightforward approach for correcting such SNVs-related alterations is to seek small molecules, potential drugs, that can eliminate disease-causing effects. Certain disorders are caused by altered protein-protein interactions, for example, Snyder-Robinson syndrome, the therapy for which focuses on the development of small molecules that restore the wild type homodimerization of spermine synthase. Other disorders originate from altered protein-nucleic acid interactions, as in the case of cancer; in these cases, the elimination of disease-causing effects requires small molecules that eliminate the effect of mutation and restore wild type p53-DNA affinity. Overall, especially for complex diseases, pathogenic mutations frequently alter macromolecular interactions. This effect can be direct, i.e., the alteration of wild type affinity and specificity, or indirect via alterations in the concentration of the binding partners. Here, we outline progress made in methods and strategies to computationally identify small molecules capable of altering macromolecular interactions in a desired manner, reducing or increasing the binding affinity, and eliminating the disease-causing effect. When applicable, we provide examples of the outlined general strategy. Successful cases are presented at the end of the work.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"26339"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-Species Multi-Omics Analysis Reveals Myeloid-Driven Endothelial Oxidative Stress in Ischemic Stroke.","authors":"Ziqi Cheng, Hua Zhu, Shi Feng, Yonggang Zhang, Xiaoxing Xiong","doi":"10.31083/FBL37429","DOIUrl":"https://doi.org/10.31083/FBL37429","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke is a leading cause of mortality and disability worldwide, yet the interplay between peripheral and central immune responses is still only partially understood. Emerging evidence suggests that myeloid cells, when activated in the periphery, infiltrate the ischemic brain and contribute to the disruption of the blood-brain barrier (BBB) through both inflammatory and metabolic mechanisms.</p><p><strong>Methods: </strong>In this study, we integrated bulk RNA-sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and flow cytometry data from human and mouse models of ischemic stroke. Mouse stroke models were induced by transient middle cerebral artery occlusion (tMCAO), and brain tissues were later collected at specified time points for analysis. We examined time-dependent transcriptional changes in the peripheral blood, delineated cell-type-specific responses by single-cell profiling, and validated myeloid infiltration into the ischemic brain. We also investigated endothelial metabolic reprogramming and oxidative stress by combining scMetabolism analyses (a computational R package for inferring metabolic pathway activity at the single-cell level) with <i>in vitro</i> oxygen-glucose deprivation/reperfusion (OGD/R) experiments.</p><p><strong>Results: </strong>Cross-species bulk RNA-seq revealed a modest early immune shift at 3 h post-stroke, escalating significantly by 24 h, with robust myeloid-centric gene signatures conserved in humans and mice. Single-cell analyses confirmed a pronounced expansion of neutrophils, monocytes, and megakaryocytes in peripheral blood, coupled with a decrease in T and B lymphocytes. Spatial transcriptomics and flow cytometry demonstrated substantial infiltration of CD11b⁺ myeloid cells into the infarct core, which showed extensive interaction with endothelial cells. Endothelial scRNA-seq data showed reductions in the oxidative phosphorylation, glutathione, and nicotinate metabolic pathways, together with elevated pentose phosphate pathway activity, suggestive of oxidative stress and compromised antioxidant capacity. Functional scoring further indicated diminished endothelial inflammation/repair potential, while <i>in vitro</i> OGD/R experiments revealed morphological disruption, CD31 downregulation, and increased 4-hydroxynonenal (4-HNE), underscoring the importance of endothelial oxidative damage in BBB breakdown.</p><p><strong>Conclusions: </strong>These multi-omics findings highlight the existence of a coordinated peripheral-central immune axis in ischemic stroke, wherein myeloid cell recruitment and endothelial metabolic vulnerability jointly exacerbate inflammation and oxidative stress. The targeting of endothelial oxidative injury and myeloid-endothelial crosstalk may represent a promising strategy to mitigate secondary brain injury in ischemic stroke.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"37429"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Potential and Challenges of Human Pluripotent Stem Cells in the Treatment of Diabetic Nephropathy.","authors":"Wanyue Xu, Fangyu Yi, Haiyang Liao, Caifeng Zhu, Xiaodi Zou, Yanzhao Dong, Weijie Zhou, Zexing Sun, Jiazhen Yin","doi":"10.31083/FBL28283","DOIUrl":"https://doi.org/10.31083/FBL28283","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is a prevalent complication of diabetes, with current treatment options offering limited effectiveness, particularly in advanced stages. Human pluripotent stem cells (hPSCs), particularly induced PSCs (iPSCs), show promising potential in the treatment of DN due to their pluripotency, capacity for differentiation into kidney-specific cells, and suitability for personalized therapies. iPSC-based personalized approaches can effectively mitigate immune rejection, a common challenge with allogeneic transplants, thus enhancing therapeutic outcomes. Clustered regularly interspaced short palindromic repeats (CRISPR) gene editing further enhances the potential of hPSCs by enabling the precise correction of disease-associated genetic defects, increasing both the safety and efficacy of therapeutic cells. In addition to direct treatment, hPSCs have proven valuable in disease modeling and drug screening, particularly for identifying and validating disease-specific targets. Kidney organoids derived from hPSCs replicate key features of DN pathology, making them useful platforms for validating therapeutic targets and assessing drug efficacy. Comparatively, both hPSCs and mesenchymal SCs (MSCs) have shown promise in improving renal function in preclinical models, with hPSCs offering broader differentiation capacity. Integration with tissue engineering technologies, such as three-dimensional bioprinting and bioengineered scaffolds, expands the regenerative potential of hPSCs by supporting the formation of functional renal structures and enhancing <i>in vivo</i> integration and regenerative capacity. Despite current challenges, such as tumorigenicity, genomic instability, and limited direct research, advances in gene editing, differentiation protocols, and tissue engineering promise to address these barriers. Continued optimization of these approaches will likely lead to successful clinical applications of hPSCs, potentially revolutionizing treatment options for DN.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"28283"},"PeriodicalIF":3.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of <i>PAK1IP1</i> can Induce Pyroptosis to Inhibit the Progression of Hepatocellular Carcinoma.","authors":"Xiaoliang Lu, Jie Chen, Zefa Lu, Hong Zang","doi":"10.31083/FBL26654","DOIUrl":"https://doi.org/10.31083/FBL26654","url":null,"abstract":"<p><strong>Aim: </strong>To identify potential prognostic biomarkers and uncover new mechanisms underlying hepatocellular carcinoma (HCC).</p><p><strong>Background: </strong>HCC is a prevalent and fatal malignancy originating from hepatic cells, with a consistently rising incidence in recent decades.</p><p><strong>Objective: </strong>To identify potential prognostic biomarkers, specifically focusing on the role of PAK1-interacting protein 1 (PAK1IP1), and to uncover novel mechanistic insights in HCC.</p><p><strong>Methods: </strong>HCC-related datasets (GSE45267 and GSE49515) and data from The Cancer Genome Atlas (TCGA) were retrieved for the analysis of differentially expressed genes (DEGs). The common DEGs were subsequently subjected to weighted gene co-expression network analysis (WGCNA), protein-protein interaction network (PPI), risk model, expression, survival, and prognostic nomogram to determine key genes associated with HCC. Further, the key gene was analyzed using clinical feature analysis, immunoassay, and cell experiments to investigate its exact role in HCC.</p><p><strong>Results: </strong>Based on the above comprehensive analysis, we targeted the key gene <i>PAK1IP1</i> with a good prognostic value in HCC. <i>PAK1IP1</i> showed a remarkably higher increase in tumor samples than in normal samples, which might be related to immune cell infiltration in liver cancer. It was up-regulated in HCC cells, and its knockdown could suppress HCC proliferation and migration. Besides, enzyme-linked immunosorbent assay (ELISA) showed that <i>PAK1IP1</i> could regulate lipopolysaccharide (LPS)-induced pyroptosis of HCC cells. Knocking down <i>PAK1IP1</i> could lead to increased expression of caspase 3 (CASP-3), gasdermin E (GSDME)-N, cleaved caspase-1, and gasdermin-D (GSDMD)-N in HCC cells, inducing pyroptosis, thereby inhibiting the development of HCC.</p><p><strong>Conclusion: </strong>To summarize, <i>PAK1IP1</i> was identified as a promising prognostic biomarker, and the knockdown of <i>PAK1IP1</i> can induce pyroptosis to suppress HCC development, which sheds new light on HCC tumorigenesis.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"26654"},"PeriodicalIF":3.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the Role of Oxidative Stress in Male Infertility: Insights from Reactive Oxygen Species to Antioxidant Therapeutics.","authors":"Ye Zhou, Hengyan Zhang, Heguo Yan, Pingxing Han, Jing Zhang, Yangwen Liu","doi":"10.31083/FBL27046","DOIUrl":"https://doi.org/10.31083/FBL27046","url":null,"abstract":"<p><p>Male infertility represents a major health concern, accounting for approximately 50% of all infertility cases in couples. This condition arises from multiple etiologies, with oxidative stress gaining increasing attention in recent studies. During the final stages of sperm maturation, the majority of the cytoplasm is discarded, leaving sperm with a diminished antioxidant defense system, which makes them highly susceptible to the detrimental effects of reactive oxygen species (ROS). ROS can be generated from both intrinsic and extrinsic sources. Intrinsically, ROS are primarily produced by mitochondrial activity, while extrinsic factors include alcohol consumption, smoking, circadian rhythm disruption, gut microbiota imbalance, and leukocyte infiltration. Excessive ROS production leads to DNA damage, apoptosis, and epigenetic modifications in sperm, ultimately impairing sperm motility and contributing to infertility. This review provides a comprehensive examination of ROS sources and examines the mechanisms by which ROS induce sperm damage. Furthermore, it explores the therapeutic potential of antioxidants in mitigating oxidative stress and improving sperm quality.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"27046"},"PeriodicalIF":3.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early and Late Responses of Cultured Human Mesenchymal Stem Cells (MSCs) to Cell-free DNA (cfDNA) in Patients With Acute Myocardial Infarction.","authors":"Elena M Malinovskaya, Natalia N Veiko, Elisaveta S Ershova, Larisa V Kameneva, Marina S Konkova, Svetlana V Kostyuk","doi":"10.31083/FBL28255","DOIUrl":"https://doi.org/10.31083/FBL28255","url":null,"abstract":"<p><strong>Background: </strong>Acute myocardial infarction (AMI) is accompanied by damage to heart tissues and some cell death. Stem cells are localized in the affected area and contribute to tissue repair. Studies have previously shown that the concentration of cell-free DNA (cfDNA) in the blood (ami-cfDNA) increases significantly in patients with AMI, and GC-rich and oxidized DNA fragments accumulate in the composition of ami-cfDNA. As a result, ami-cfDNA exhibits biological activity in vitro against various types of differentiated human cells. Potentially, ami-cfDNA can influence the functional activity and direction of stem cell differentiation. To verify this assumption, we investigated the effect of ami-cfDNA fragments isolated from the blood of patients with AMI on human adipose tissue mesenchymal stem cells (MSCs) <i>in vitro</i>.</p><p><strong>Materials and methods: </strong>The MSC line was used and characterized by stem cell surface markers. Ami-cfDNA and control (hc-cfDNA) samples were isolated from the blood plasma of seven AMI patients and ten healthy donors. The early (0.5-3 hours) and late (1-3 weeks) responses of MSCs to cfDNA action were analyzed. The level of reactive oxygen species, the expression level of numerous genes (<i>NOX4</i>, <i>NRF2</i>, <i>BRCA1</i>, <i>BCL2</i>, <i>BAX</i>, <i>MYOD1</i>, <i>MYOG</i>, <i>MYF5</i>, <i>MRF4</i>, <i>RUNX2</i>, <i>SPP1</i>, <i>OCN</i>, <i>LPL</i>, <i>AP2</i>), the level of double-stranded DNA breaks in nuclei, and changes in the spatial organization of the chromatin in the nucleus were determined using the quantitative (real-time) polymerase chain reaction (qPCR), flow cytometry, fluorescence microscopy, fluorescent <i>in situ</i> hybridization (FISH) assays.</p><p><strong>Results: </strong>Introducing ami-cfDNA fragments into the cell culture medium stimulates rapid and transient induction of oxidative stress in MSCs (early response). Oxidative stress stimulates the spatial reorganization of chromatin to develop an adaptive response (AR). The adaptive response includes an antioxidant and anti-apoptotic response and activation of repair genes. The ami-cfDNA fragments, unlike hc-cfDNA, stimulate the myogenic differentiation of MSCs under prolonged exposure (late response).</p><p><strong>Conclusions: </strong>The ami-cfDNA increases the survival of MSCs in the model system by inducing a pronounced adaptive cellular response. Prolonged exposure to ami-cfDNA provokes myogenic differentiation of MSCs. Under acute stress conditions caused by AMI in the body, ami-cfDNA may positively affect the restoration of damaged heart muscle.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 4","pages":"28255"},"PeriodicalIF":3.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}