Antioxidants & redox signaling最新文献

Background: The aim of this study was to construct a machine learning (ML) model to predict the effect of dietary antioxidants on cardiovascular-arthritis comorbidity.

Methods: In this study, 44 dietary antioxidants were selected based on the National Health and Nutrition Examination Survey data from 2007 to 2010 and from 2017 to 2018, and demographic covariates such as gender and age were included for analysis. In addition, 10 mainstream ML models were investigated for the evaluation, and a comprehensive evaluation system of the multi-indicator empowerment algorithms was constructed to comprehensively measure the model performance. To further enhance the model interpretability, SHapley Additive exPlanations (SHAP) values and Local Interpretable Model-agnostic Explanation (LIME) methods were introduced to deeply analyze the prediction mechanism.

Results: A total of 8046 participants were included in this study, of whom 380 had cardiovascular disease and arthritis comorbidities. After multiple covariates were eliminated, 34 indicators of nutritional antioxidant intake and 11 demographic baseline characteristics were selected as key predictors. The multicriteria-based assessment system demonstrated excellent performance of the logistic regression machine model. It performed optimally on the validation set with an area under the receiver operating characteristic curve of 0.871. Notably, the study of SHAP and LIME algorithms revealed the opposite biological effects of total and single flavonoid intake as well as the heterogeneity of dietary antioxidants in different age-sex characterized populations.

Conclusion: This study suggests that future strategies should consider antioxidant types and individual traits, promoting diverse natural foods over single supplements to advance precision nutrition. Antioxid. Redox Signal. 44, 251-270.

Aims: Radiation therapy is a crucial treatment modality for head and neck squamous cell carcinomas (HNSCCs). However, acquired radiation resistance due to various mechanisms poses a major clinical challenge for therapeutic strategies. Intriguingly, reactive oxygen species (ROS) are versatile signaling molecules that promote various cellular functions at low concentrations but induce cell death at above-critical threshold levels.

Results: Here, we found that radioresistant (RR) cancer cells exhibited reduced ROS levels and activation of the mesenchymal-epithelial transition factor/signal transducer and activator of transcription 3 (c-MET/STAT3) pathway. To target common vulnerabilities in RR cancers, we applied ROS enhancement therapy using nonthermal plasma-activated media (NTPAM), a novel approach that effectively inhibits the viability of RR cancer cells and is associated with inactivation of the c-MET/STAT3 pathway. Mechanistically, the downregulation of total c-MET is related to ROS-mediated lysosomal degradation. In addition, NTPAM suppressed tumor growth in a mouse model of RR cancer, concurrently reducing the levels of both the total and activated forms of c-MET and decreasing STAT3 phosphorylation.Innovations and Conclusions:These findings suggest that ROS enhancement therapy can overcome radiation resistance, thereby offering a compelling rationale for considering NTPAM as a stand-alone or complementary therapeutic approach for treating patients with HNSCCs. Antioxid. Redox Signal. 44, 182-196.

Aims: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular event characterized by early brain injury (EBI) within 72 h that is driven by oxidative stress, mitochondrial dysfunction, and metabolic collapse. The retinoic acid receptor-related orphan receptor alpha (RORα) is a nuclear receptor implicated in metabolic and inflammatory regulation, but it has not been studied in SAH. We aimed to determine whether RORα confers neuroprotection after SAH and to elucidate its underlying mechanisms.

Methods and results: We used mouse SAH models and primary cortical neurons to assess the RORα expression, functional outcomes, and metabolic changes. The RORα expression was markedly reduced post-SAH. Genetic knockdown or deficiency (staggerer mice) exacerbated neuronal apoptosis, neuroinflammation, and behavioral deficits. Conversely, pharmacological activation with SR1078 significantly improved neurological scores, preserved neuronal morphology, and reduced oxidative stress. RORα overexpression or SR1078 treatment enhanced neuronal viability in vitro under hemoglobin-induced stress. Transcriptomic and epigenomic profiling revealed that RORα directly regulated glucose-6-phosphate dehydrogenase and α subunit of peroxisome proliferator activated receptor-γ coactivator-1. This promoted pentose phosphate pathway flux and mitochondrial biogenesis. A metabolic flux analysis confirmed increased nicotinamide adenine dinucleotide phosphate hydrogen and glutathione synthesis, reduced reactive oxygen species accumulation, and an improved oxygen consumption rate and spare respiratory capacity. All of these results indicated a shift toward oxidative phosphorylation and enhanced bioenergetics.

Innovation and conclusion: We are the first to demonstrate that RORα activation reprogrammed neuronal glucose metabolism and strengthened antioxidant defenses to mitigate SAH-induced EBI. The targeting of RORα could represent a promising therapeutic strategy for stroke-related metabolic failure and oxidative stress. Future work should explore the translational potential in clinical settings. Antioxid. Redox Signal. 44, 275-291.

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. 44, 332-356.

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. 44, 357-372.

Aims: Mitochondrial homeostasis is essential for maintaining central nervous system function. Both inflammation and oxidative stress induced by chronic intermittent hypoxia (CIH) can result in neuronal mitochondrial injury in obstructive sleep apnea syndrome (OSAS)-related cognitive dysfunction. Recent evidence implicates neuronal impairment caused by abnormal activation of microglia as a key contributor to CIH-induced cognitive dysfunction. However, the mechanism between microglia and neuronal injury remains elusive. This study seeks to elucidate the underlying mechanism of microglia-mediated neuronal injury in CIH-induced cognitive dysfunction.

Results: Both the levels of pro-inflammatory factors and reactive oxygen species (ROS) were elevated; neuronal mitochondrial and cytomembrane injury and neuronal pyroptosis also occurred in CIH models in vitro and in vivo. Microglial cells RNA sequencing data revealed that CIH upregulated the nucleotide-binding and oligomerization domain-like receptor pathway, and in vitro experiments confirmed that the thioredoxin-interacting protein (TXNIP)/nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3)/gasdermin D (GSDMD) pathway modulated inflammation and oxidative stress in BV-2 cells and regulated neuronal mitochondrial and cytomembrane injury and pyroptosis. Co-immunoprecipitation results verified that TXNIP bound directly to NLRP3 in BV-2 cells. Furthermore, GSDMD-derived inhibitor (Ac-FLTD-CMK) abolished the elevation in inflammation and oxidative stress markers induced by TXNIP overexpression after CIH exposure. In addition, it alleviated HT-22 cells' mitochondrial and cytomembrane injury and suppressed the activation of TXNIP/NLRP3/GSDMD pathway in BV-2 cells induced by CIH after the application of mitochondrial antioxidant Mito-TEMPO to BV-2 cells, thereby mitigating microglia-mediated neuronal pyroptosis. These findings were corroborated by in vivo experiments.

Innovation and conclusion: These results reveal that microglial TXNIP/NLRP3/GSDMD pathway activation is a key mechanism linking CIH to neuronal injury in OSAS-related cognitive dysfunction. Inhibition of TXNIP/NLRP3/GSDMD pathway and antioxidant therapy could protect against CIH-induced cognitive dysfunction by ameliorating the damaging effects of cytokines of inflammation and oxidative stress from microglia, while preventing neuronal mitochondrial and cytomembrane injury and pyroptosis. This work identifies a promising target for pharmacological intervention in OSAS-related cognitive dysfunction. Antioxid. Redox Signal. 44, 373-392.

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. 44, 393-409.

Significance: The high level of metabolism in the central nervous system (CNS) induces the production of large amounts of free radicals following stroke, thereby resulting in oxidative stress. The brain is particularly vulnerable to oxidative stress-induced damage due to its high oxygen consumption. Astrocytes, as key regulators of CNS homeostasis, play a critical role in modulating oxidative stress and maintaining CNS function.

Recent advances: Accumulating evidence has shown that astrocytes undergo polarization into two distinct states: A1 (neurotoxic and pro-inflammatory) and A2 (neuroprotective and anti-inflammatory) phenotypes following ischemic stroke, which, respectively, exhibit harmful and beneficial roles in oxidative stress-induced brain injury. In addition, metabolic crosstalk between astrocytes and neurons during the acute phase of ischemic stroke, involving lactate, amino acids, healthy mitochondria, and fatty acids, is crucial in maintaining neuronal morphology and function.

Critical issues: A2 astrocytes possess significant antioxidative capabilities by expressing high levels of antioxidative stress genes. Notably, the polarization of astrocytes toward the A2 subtype appears to enhance their beneficial and supportive role in metabolic crosstalk with neurons. A deeper understanding of astrocytic roles, particularly those of A2 astrocytes, in redox regulation and astrocyte-neuron metabolic crosstalk may provide novel therapeutic strategies for ischemic stroke. Therefore, in this review, we mainly discuss the roles of astrocytes, particularly A2 astrocytic polarization, in redox regulation and metabolic crosstalk with neurons following ischemic stroke.

Future direction: Elucidating the molecular mechanisms underlying astrocytic polarization toward the A2 subtype during the pathological process of ischemic stroke represents a promising avenue for future research. Antioxid. Redox Signal. 44, 410-435.

Aims: Cataracts are the leading cause of blindness worldwide, and the mechanism underlying cataract formation is linked to the oxidative damage and the apoptosis of lens epithelial cells. Retinoic acid Receptor-related orphan receptor α (RORα), a transcription factor, prevents oxidative stress and cell apoptosis. RORα is decreased in the lens from patients with cataract, but it remains unclear whether decreases in RORα are attributed to cataract formation.

Results: Here, rat models of selenite-induced cataracts were used for in vivo experiments. In vitro, human lens epithelial cells (SRA01-04) were treated with selenite. RORα was downregulated in the lens from rat models of selenite-induced cataracts. The RORα agonist SR1078 significantly mitigated the degree of lens opacity. SR1078 reduced oxidative stress, cell apoptosis, and mitochondrial dysfunction and promoted the peroxisome proliferative activated receptor gamma coactivator (PGC-1α) and the nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 pathways in the lens from rat models of selenite-induced cataracts and lens epithelial cells upon selenite stimulation. RORα overexpression showed a similar protective effect on lens epithelial cells in vitro. Nerve growth factor (NGF) expression was up-regulated by RORα overexpression. Although RORα overexpression prevented selenite-induced damage to lens epithelial cells, the damage recurred following NGF knockdown.

Conclusion: RORα protects against selenite-induced oxidative stress and cellular apoptosis. In the context of cataractogenesis, NGF is newly identified as a transcriptional target of RORα, and its reduction is related to mitochondrial dysfunction in lens epithelial cells. Our study highlights the translational potential of RORα activation as a nonsurgical cataract intervention. 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.