Antioxidants & redox signaling最新文献

Background: Osteoarthritis (OA), characterized by articular cartilage degeneration, is exacerbated by diabetes mellitus (DM), an independent risk factor whose molecular mechanisms remain incompletely understood. This study investigates novel regulators and pathways underlying DM-associated OA pathogenesis.

Methods: We used bioinformatic analysis of transcriptomic data from OA and diabetic OA (DM-OA) cohorts to identify differentially expressed genes. We constructed functional enrichment and protein-protein interaction (PPI) networks. In vivo, we modeled diabetic OA in mice via high-fat diet/streptozotocin induction combined with destabilization of the medial meniscus surgery. In vitro, we exposed chondrocytes to high glucose to mimic diabetic conditions. We genetically modulated leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) through chondrocyte-specific knockout (KO) in LGR6-deficient mice and overexpression (OE) via intra-articular delivery of adeno-associated virus serotype 9. We validated key molecular changes using quantitative reverse transcription polymerase chain reaction, Western blotting, immunohistochemistry, and ferroptosis-associated assays (reactive oxygen species, glutathione, malondialdehyde [MDA], and mitochondrial morphology).

Results: LGR6 expression was significantly downregulated in DM-OA cartilage. PPI analysis highlighted interactions between LGR6, collagen type II (COL2A1), and matrix metalloproteinase (MMP)13. LGR6 KO exacerbated OA severity, cartilage degradation, and inflammatory markers (MMP3, MMP13, and nitric oxide synthase-2) while reducing extracellular matrix (ECM) components (COL2A1 and SRY-box transcription factor 9). Conversely, LGR6 OE attenuated cartilage damage, suppressed catabolic factors, and restored ECM synthesis. Mechanistically, LGR6 deficiency intensified ferroptosis, evidenced by elevated lipid peroxidation (MDA), mitochondrial cristae disruption, and dysregulation of glutathione peroxidase 4/prostaglandin-endoperoxide synthase 2. LGR6 activation reversed these effects, restoring redox homeostasis and mitochondrial integrity.

Innovation: This study identifies LGR6 as a pivotal inhibitor of chondrocyte ferroptosis in DM-OA, revealing a previously unexplored link between hyperglycemia, mitochondrial dysfunction, and iron-dependent cell death.

Conclusion: LGR6 safeguards cartilage by suppressing ferroptosis and maintaining mitochondrial biogenesis in diabetic conditions. Targeting the LGR6 pathway offers a promising therapeutic strategy for DM-associated OA. Antioxid. Redox Signal. 00, 000-000.

Aims: Hydrogen sulfide (H₂S) is a signaling molecule implicated in diverse physiological processes, yet its role in sperm function remains poorly understood. This study characterizes protein persulfidation, a post-translational modification mediated by H₂S in boar spermatozoa, tracks its distribution during sperm maturation, and assesses whether H₂S influences sperm motility during capacitation.

Methods: Persulfidation was localized using fluorescent labeling and confirmed by Western blotting across epididymal and post-ejaculatory stages. LC-MS/MS identified persulfidated proteins, which were subsequently assigned to their biological roles. In functional assays, the H₂S biosynthesis inhibitor aminooxyacetic acid (AOAA) was applied at graded concentrations during sperm capacitation. These assays included computer-assisted sperm analysis (CASA) with k-means clustering, electrochemical measurement of H₂S, and flow cytometry to assess mitochondrial membrane potential.

Results: Persulfidation was consistently detected in spermatozoa, predominantly in the midpiece, and persisted throughout maturation. Proteomic analysis revealed 36 persulfidated proteins, including regulators of motility, energy metabolism, and antioxidant defense. AOAA exposure induced time- and dose-dependent changes: early inhibition of H₂S synthesis reduced motility, whereas later recovery of H₂S levels correlated with better preservation of motility. Cluster analysis uncovered shifts in motile subpopulations, notably prolonged maintenance of hyperactivated-like sperm under AOAA treatment.

Conclusion: This study provides the first comprehensive evidence that persulfidation is a functionally relevant modification in boar spermatozoa. H₂S appears to modulate motility during capacitation, either through persulfidation of proteins or via ion channels and other signaling pathways. These findings highlight H₂S signaling as a novel regulatory axis in male reproduction and suggest new avenues for fertility research. Antioxid. Redox Signal. 00, 000-000.

Aims: Mitochondrial dysfunction is recognized as a central pathological mechanism in subarachnoid hemorrhage (SAH). This study aimed to investigate whether mitophagy serves as a key mechanism by which hydrogen (H₂) exerts its antioxidative effects following SAH. Results: Using in vivo (mouse SAH model) and in vitro (HT22 cell SAH model) approaches, we demonstrated that H₂ inhalation significantly improved neurological function and alleviated oxidative stress and apoptosis. Mechanistically, H₂ maintained mitochondrial membrane potential and functional integrity by enhancing phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. RNA sequencing and functional assays identified nuclear factor erythroid 2-related factor 2 (NRF2) as the key upstream target. H₂ promoted NRF2 nuclear translocation and activated the antioxidant pathway. Dual-luciferase reporter assays further confirmed that NRF2 directly binds to and activates the PINK1 promoter. Pharmacological inhibition of NRF2 (ML385) or mitophagy (Mdivi-1) abolished the protective effects of H₂, confirming that the NRF2-PINK1/Parkin axis is central to the effect of H₂. Innovation: The present study clearly establishes the NRF2-PINK1/Parkin axis as a key mechanism underlying the neuroprotective effect of H₂ in SAH. This study connects mitochondrial quality control with endogenous antioxidant systems, suggesting H₂ administration as a potential mitochondrion-targeted clinical intervention. Conclusion: The NRF2-PINK1/Parkin axis is a novel and key mechanism underlying the neuroprotective effect of H₂ in SAH. This finding advances our understanding beyond general antioxidant theories by demonstrating a specific, multistep molecular cascade. H₂ administration is a potential mitochondrion-targeted intervention with strong implications for clinical translation in SAH patients. Antioxid. Redox Signal. 00, 000-000.

Background: Metabolic-associated fatty liver disease (MASLD) is a leading cause of chronic liver injury worldwide, characterized by hepatic lipid accumulation, oxidative stress, inflammation, and mitochondrial dysfunction. Despite its prevalence, no approved pharmacological treatments currently exist. Atraric acid (AA), a natural compound with antioxidant and anti-inflammatory properties, has not been previously investigated in MASLD. Objective: This study aimed to evaluate the therapeutic potential of AA and elucidate its underlying mechanisms in MASLD. Methods: MASLD was modeled in mice using a high-fat diet and in alpha mouse liver 12 hepatocytes using oleic acid/palmitic acid. AA's effects on liver injury, mitochondrial function, and inflammatory signaling were assessed through biochemical assays, histology, transcriptomic analysis, and mechanistic studies involving adenosine 5'-monophosphate-activated protein kinase (AMPK) inhibition and liver-specific AMPK knockout models. Results: AA significantly improved hepatic steatosis, reduced serum alanine transaminase and aspartate aminotransferase levels, and alleviated inflammation in MASLD mice. In vitro, AA restored mitochondrial membrane potential, enhanced adenosine triphosphate production, and suppressed reactive oxygen species accumulation and NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome activation. Mechanistically, AA directly interacted with AMPK, promoted its phosphorylation, and upregulated peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α), thereby improving mitochondrial biogenesis and redox balance. These protective effects were abolished by AMPKα inhibition or knockout, confirming AMPK as a key mediator. Additionally, AA modulated related pathways, including SIRT1 and mTOR, suggesting broader metabolic benefits. Conclusion: AA mitigates MASLD by activating the AMPK-PGC-1α axis, restoring mitochondrial function, and reducing ROS-driven inflammation. These findings highlight AA as a promising candidate for MASLD therapy and warrant further clinical investigation. Antioxid. Redox Signal. 00, 000-000.

Aims: Group 2 innate lymphoid cells (ILC2s) play key roles in allergic asthma development. We have previously discovered that CD5 antigen-like protein (CD5L) can inhibit allergic airway inflammation. In this study, we investigate the effect of CD5L on ILC2s and the underlying mechanism. Results: Our findings demonstrated that CD5L suppresses allergic airway inflammation by inhibiting ILC2s. CD5L inhibited NF-κB, MAPK, and PI3K-AKT pathways in ILC2s, thus reducing interleukin (IL)-5 and IL-13 production. CD5L increased the level of lysophosphatidylcholine (lysoPC) in ILC2s through the transforming growth factor beta (TGF-β) signaling pathway. The elevated lysoPC further induced reactive oxygen species (ROS) production in ILC2s, and the increased ROS fed back to increase the level of lysoPC. The accumulated ROS induced ILC2 apoptosis. The scavenger receptor CD36 mediated the inhibitory effect of CD5L on ILC2s and allergic airway inflammation. Finally, CD5L was shown to be potential therapeutic for allergic asthma. Innovation: This study is the first to demonstrate that CD5L suppresses allergic airway inflammation by inhibiting ILC2 responses. It is the initial discovery that CD5L promotes ILC2 apoptosis, whereas CD5L was previously recognized as an apoptosis inhibitor. The regulation of TGF-β signaling pathway on lysoPC is demonstrated for the first time. Conclusion: This study demonstrated that CD5L inhibits ILC2 activation and induces ILC2 apoptosis, thereby suppressing allergic airway inflammation. CD5L can serve as a novel therapeutic strategy for allergic asthma. Antioxid. Redox Signal. 00, 000-000.

The exponential growth of biomedical literature has rendered traditional search methods inadequate. Artificial intelligence (AI) tools have emerged and are developing as transformative solutions for literature search and knowledge mining. This first article of a series, intended to address different components of biomedical research, provides a comprehensive analysis of recent advancements, practical applications, and challenges in deploying AI for biomedical research. The objective of this work is to synthesize the evolution, capabilities, and limitations of AI-driven tools for literature discovery, summarization, and evidence synthesis, offering actionable insights for researchers across disciplines. AI tools have progressed from keyword-based retrieval to semantic and multimodal approaches. Platforms such as Elicit, BioGPT, and PubTator 3.0 enable rapid extraction of gene-disease associations and evidence-based insights, while ResearchRabbit and Connected Papers visualize citation networks. Systematic review tools like Rayyan and Covidence reduce screening time by up to 50%. Variability in output quality, risk of hallucination, and lack of algorithmic transparency pose challenges. Open-source solutions (e.g., BioGPT, DeepChem) and explainability-focused tools (e.g., Scite.ai) offer promising pathways to mitigate these concerns. AI-driven literature workflows can accelerate hypothesis generation, systematic reviews, and translational research. However, close human expert oversight remains indispensable to ensure rigor and interpretive accuracy. These technologies are not a passing trend; they are forging the contours of tomorrow's research landscape. The peril lies as much in reckless adoption as in willful oblivion. This editorial serves as a general roadmap for integrating trustworthy AI tools into biomedical research, fostering high-impact innovation. Antioxid. Redox Signal. 00, 000-000.

Neuroinflammation contributes to the onset and progression of a variety of central nervous system (CNS) diseases, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, intracerebral hemorrhage, and neurodevelopmental disorders related diseases. Microglia are essential for the neurodevelopment of a healthy brain and the integrity of the blood-brain barrier. Activation of microglia is the brain's defense mechanism against damaged tissues and harmful pathogens. However, their activation can trigger neuroinflammation, which can exacerbate or induce damage to the CNS. Cytokines are small proteins that can act in either an autocrine or paracrine manner. Cytokines are highly expressed in microglia and are potential mediators of neuroinflammation. We review the recent research progress on the role of cytokines such as interleukin-1 (IL-1β), tumor necrosis factor-α , IL-6, IL-4, and transforming growth factor-β in regulating neuroinflammation in various CNS diseases. Understanding how these cytokines affect microglia-mediated neuroinflammation will provide important therapeutic insights for preventing and managing CNS dysfunction, with potential clinical relevance for developing targeted anti-inflammatory therapies and biomarker-based diagnostic strategies. Antioxid. Redox Signal. 00, 000-000.

Significance: Endothelial cells (ECs) are specialized cells lining the interior surface of blood vessels, playing a crucial role in vascular biology. They exhibit remarkable versatility, adapting to various tissue requirements. Their ability to respond to physiological and pathological stimuli ensures proper tissue function and homeostasis. Recent Advances: Hypoxia is when the oxygen level in a given organ, tissue, or cell type drops below the physiological level and is insufficient to maintain adequate homeostasis. ECs respond to hypoxia by activating various mechanisms. Hypoxia-induced changes in ECs can promote survival in low-oxygen environments by altering cellular metabolism and inducing neoangiogenesis. However, hypoxia-induced EC responses can also be detrimental, leading to increased production of reactive oxygen species, heightened inflammation, changes in vascular tone, increased permeability of the endothelial barrier, and a higher risk of coagulation. Critical Issues: Hypoxia-induced EC responses contribute to the pathogenesis of various diseases, including metabolic diseases (e.g., diabetes, chronic kidney disease), infectious diseases, chronic inflammation, neoplastic diseases, cardiovascular diseases (e.g., atherosclerosis, myocardial infarction, and stroke) lung diseases (e.g., chronic obstructive pulmonary disease and pulmonary hypertension), eye diseases (age-related macular degeneration and retinopathy), and neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease). Future Directions: Detailed, disease-specific investigations are essential to delineate how endothelial hypoxia responses contribute to various pathologies. Understanding these mechanisms could reveal whether targeting endothelial hypoxia holds therapeutic potential. Antioxid. Redox Signal. 43, 849-868.

Aims: This study explores the role of oxidative stress and the CEBPB/HMGB1/VCAM1 signaling axis in sepsis-exacerbated coronary artery disease (CAD). Methods: A sepsis-exacerbated CAD model was established in male ApoE^-/- mice using cecal ligation and puncture (CLP) surgery followed by a high-fat diet (HFD) to induce coronary atherosclerosis. Lentiviral-mediated overexpression and knockdown of CEBPB and VCAM1 were performed via tail vein injection. In vitro experiments employed THP-1-derived macrophages and human aortic endothelial cells (HAECs). Key methodologies included single-cell RNA sequencing, bulk transcriptomics, chromatin immunoprecipitation, dual-luciferase reporter assays, enzyme-linked immunosorbent assay, reactive oxygen species (ROS) detection, and flow cytometry to elucidate the molecular mechanisms of the CEBPB/HMGB1/VCAM1 axis. Results: CEBPB was upregulated in macrophages under septic conditions, promoting HMGB1 transcription and triggering pyroptosis and ROS overproduction. Released HMGB1 enhanced macrophage-endothelial adhesion and upregulated VCAM1 expression in endothelial cells (ECs) via the NF-κB pathway, contributing to endothelial dysfunction. These effects were validated in vivo using the CLP + HFD mouse model, where CEBPB knockdown or VCAM1 overexpression modulated inflammatory and vascular markers. In vitro, functional damage to ECs was observed upon co-culture with activated macrophages, but this was alleviated by targeting HMGB1 or VCAM1. Innovation: The CEBPB/HMGB1/VCAM1 axis links systemic inflammation to oxidative vascular damage in sepsis, offering a therapeutic target for CAD complications. Conclusion: The findings provide novel insights into the interplay of oxidative stress and inflammatory signaling in sepsis-exacerbated CAD, suggesting actionable strategies to prevent cardiovascular complications. Antioxid. Redox Signal. 43, 886-912.

Aims: Obesity remains a major global health issue, with the increasing focus on the incretin hormone glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) for therapeutic strategies. D-allulose is predicted to modulate GLP-1R via mechanisms linked to endoplasmic reticulum stress and reactive oxygen species (ROS) pathways, positively influencing GLP-1R stability and functionality. This study investigates the potential of D-allulose as a therapeutic and preventive agent against obesity. It focuses on the impact of D-allulose on adipocyte differentiation and obesity in high-fat diet (HFD)-administered and GLP-1R knockout (KO) mice over 12 weeks. Results: D-allulose effectively regulated adipocyte differentiation by inhibiting the NADP⁺/NADPH-ROS-inositol-requiring enzyme 1α (IRE1α)-regulated IRE1-dependent decay (RIDD) axis, resulting in controlled decay of GLP-1R, a newly identified RIDD target. Furthermore, in vivo studies revealed that D-allulose administration significantly regulated body weight and other obesity parameters in HFD-fed mice. However, these effects were not observed in GLP-1R KO mice, suggesting that the antiobesity effects of D-allulose rely on the presence of GLP-1R. Innovation and Conclusion: This study highlights the efficacy of D-allulose in controlling obesity through mechanisms dependent on GLP-1R, suggesting its potential as an effective treatment for obesity with normal GLP-1R function. Antioxid. Redox Signal. 43, 819-832.