Antioxidants & redox signaling最新文献

Aims: α-Tocopherol is a potent natural antioxidant with a variety of biological functions and is widely used in clinical practice. However, the effect and mechanism of α-tocopherol on liver fibrosis remain unknown. The core of liver fibrosis is the activation of hepatic stellate cell (HSC). Inhibiting HSC activation may be the underlying mechanism by which α-tocopherol alleviates liver fibrosis. Results: Our study revealed that α-tocopherol improved liver injury and fibrosis in both CCl₄ and bile duct ligation induced liver fibrosis model mice. α-Tocopherol inhibited HSC activation by promoting nuclear erythroid 2-related factor 2 (Nrf2) translocation into the nucleus. α-Tocopherol directly promoted Nrf2 nuclear translocation by reducing its degradation, additionally, α-tocopherol suppressed autophagy by inhibiting endoplasmic reticulum stress, resulting in increased SQSTM1 competition to bind KEAP1 and indirectly promoting Nrf2 translocation into the nucleus. The increased Nrf2 nuclear translocation upregulated the expression of antioxidant genes, thereby reducing ROS and subsequently inhibiting HSC activation. Moreover, the antifibrotic and hepatoprotective effects of α-tocopherol were verified by the addition of the Nrf2 activator-curcumin, the autophagy inhibitor-3-methyladenine and the endoplasmic reticulum stress inhibitor-sodium 4-phenylbutyrate. Innovation and Conclusion: Our study is the first to identify the mechanism by which α-tocopherol alleviates liver fibrosis. Broadly speaking, this study demonstrated that α-tocopherol promotes Nrf2 nuclear translocation by reducing Nrf2 degradation and inhibiting endoplasmic reticulum stress, which then inhibits HSC activation and ultimately ameliorates liver injury and fibrosis. Therefore, α-tocopherol may become a novel therapeutic strategy for liver fibrosis. Antioxid. Redox Signal. 43, 833-848.

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. 00, 000-000.

Aims: Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis. The relationship between SIC and protein acetylation, particularly the balance between acetylation and deacetylation in cardiomyocyte subcellular structures, as well as how nuclear-mitochondrial coordination maintains standard antioxidant stress capacity, remains unclear. This study focused on exploring the nuclear-mitochondrial regulatory mechanisms formed by the interplay of Sirtuin 3 (SIRT3) and Forkhead box O3a (FOXO3a). Results: In vivo, SIC markers increased significantly in wild-type CLP (Cecal Ligation and Puncture) mice at 72 h (CLP72h) but were partially reversed in CLP72h+oeSIRT3 mice. CLP72h mice exhibited significantly reduced mitochondrial area, aspect ratio, and mtDNA copy number. Echocardiography revealed significantly impaired cardiac function. Western blotting showed significantly decreased nuclear and mitochondrial long-form SIRT3, nuclear long-form and mitochondrial short-form FOXO3a, and mitochondrial superoxide dismutase 2 (SOD2), with significantly increased acetylation in CLP72h mice. In vitro, oeSIRT3 preserved nuclear FOXO3a localization and mitochondrial membrane potential, with CLP72h+oeSIRT3 mice showing significantly reduced oxidative stress. The long form of SIRT3 plays a crucial deacetylation role in SIC and influences SOD2 partially through FOXO3a. Innovation: This study explored the roles of different SIRT3 and FOXO3a isoforms in combating oxidative stress in SIC through dynamic nucleus-mitochondrial regulation. Conclusion: This study underscores the critical role of the SIRT3-FOXO3a axis in enhancing mitochondrial antioxidant capacity through a nuclear-mitochondrial network during SIC, offering new insights into molecular mechanisms and potential therapeutic strategies for SIC. Antioxid. Redox Signal. 43, 805-818.

Aims: To investigate if nimodipine alleviates traumatic brain injury (TBI)-induced neuronal apoptosis and neurological deficits by inhibiting extracellular histone-mediated Ca²⁺ influx, mitochondrial damage, and Caspase pathway activation. Results: In vitro, nimodipine significantly reduced histone-induced Ca²⁺ influx in cortical neurons, reversed by Ca²⁺ activator A23187. It restored neuronal proliferation (↑3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, ↑Ki67+ cells), reduced apoptosis (↓Annexin V/propidium iodide), improved mitochondrial function (↑ΔΨm/adenosine triphosphate, ↓reactive oxygen species/malondialdehyde, ↑Glutathione Peroxidase), and modulated apoptosis markers (↓Bax, ↑Bcl-2). These effects were blocked by A23187 or Caspase activator AD-2646, which increased Cleaved Caspase-3/9 and PARP1. Molecular docking confirmed nimodipine-histone binding. Transcriptomics revealed nimodipine reversed histone-induced dysregulation of Ca²⁺ signaling, mitochondrial apoptosis, and oxidative stress pathways, with Caspase-3 as a key protein-protein interaction node. In vivo, nimodipine improved spatial memory (Morris maze), neurological function (↓modified neurological severity score), and motor coordination (↑rotarod) in TBI mice. It reduced brain lesions (2,3,5-triphenyltetrazolium chloride), neuronal loss (hematoxylin and eosin/Nissl), Ca²⁺ accumulation, and proapoptotic protein expression and restored ΔΨm. Histone coadministration attenuated these benefits. Innovation: First demonstration that nimodipine directly targets extracellular histone-induced Ca²⁺ influx-a key TBI pathology mechanism-preserving mitochondrial integrity and inhibiting the Caspase cascade, extending beyond its known vasodilatory effects. Conclusion: Nimodipine mitigates post-TBI neuronal apoptosis and dysfunction by blocking extracellular histone-driven Ca²⁺ overload, preventing mitochondrial damage, and suppressing Caspase activation, significantly improving functional recovery. Antioxid. Redox Signal. 43, 869-885.

Aims: Plasma-activated liquid (PAL), an indirect application form of cold-atmospheric plasma (CAP)-an ionized gas generating reactive oxygen and nitrogen species, has been proposed as an innovative therapeutic approach for various cancer types. Despite accumulating evidence suggesting that PAL induces cell death through multiple mechanisms, the involvement of ferroptosis, a form of cell death driven by iron and lipid peroxidation, in osteosarcoma (OS) remains predominantly unknown. Results: CAP was used to activate the liquid for various durations, resulting in different doses of PAL. The antitumor efficacy of PAL was directly correlated with both the dosage and duration of treatment and was achieved by increasing the level of intracellular reactive oxygen species. Through screening three effective PAL doses, we discovered that PAL significantly influenced the migration and invasion capabilities of OS cells. Proteomic sequencing revealed increases in several ferroptosis-related antioxidant proteins in the PAL-treated group. Subsequent findings revealed that PAL modulated nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream ferroptosis-related genes, predominantly resulting in the induction of ferroptosis by depleting glutathione peroxidase 4 (GPX4) in human OS cells. Finally, utilizing an OS xenograft model, we found that PAL effectively suppressed tumor growth in vivo via ferroptosis. Innovation: Our study highlights the importance of the NRF2/GPX4 axis as a pivotal pathway in PAL-induced ferroptosis. In vivo experiments provided compelling evidence supporting the potential of PAL as a potent therapeutic strategy for OS treatment. Conclusion: High-dose PAL-induced sustained oxidative stress by simultaneously targeting NRF2 inactivation and GPX4 degradation, establishing redox imbalance as a critical ferroptotic checkpoint in OS therapy. Antioxid. Redox Signal. 00, 000-000.

Aims: Polystyrene microplastics (PS-MPs) are emerging environmental pollutants, but their impact on lung cancer treatment remains unclear. This study investigates how PS-MPs affect radiotherapy efficacy in lung cancer, focusing on their role in ferroptosis regulation and NF-κB pathway activation. Results: PS-MPs were rapidly internalized by lung cancer cells and remained detectable across multiple passages. Exposure to PS-MPs promoted lung cancer cell proliferation, increased mitochondrial length, and elevated Ki67 and c-Myc expression. Following ionizing radiation, PS-MPs significantly attenuated radiation-induced ferroptosis, as evidenced by reduced mitochondrial damage, lipid peroxidation, and glutathione depletion. Transcriptomic analysis revealed that PS-MPs activated the NF-κB pathway, leading to increased phosphorylation of IKKβ, IκBα degradation, and enhanced nuclear translocation of NF-κB. In vivo, PS-MPs accumulated in lung tumor-bearing mice, reducing radiotherapy efficacy by increasing tumor volume and weight while decreasing survival rates. Knockdown of NF-κB restored ferroptosis sensitivity and mitigated PS-MPs-induced radioresistance, confirming the NF-κB-dependent inhibition of ferroptosis. Innovation and Conclusion: This study provides the first evidence that PS-MPs impair radiotherapy efficacy in lung cancer by suppressing ferroptosis via NF-κB activation. Unlike previous research focusing on microplastic toxicity in normal tissues, our findings highlight their oncological impact and potential role as an environmental factor influencing cancer therapy resistance. These results emphasize the need for further investigation into microplastics as emerging disruptors of redox homeostasis in oncology and their broader implications for environmental and cancer research. Antioxid. Redox Signal. 00, 000-000.

Aims: Cathodal transcranial direct current stimulation (C-tDCS), a noninvasive physical therapy, has potential neuroprotective effects in acute ischemic stroke. However, the rational timing of its application and the underlying mechanisms remain inadequately understood. This study aims to investigate its neuroprotective effects and the involved mechanisms. Results: Our in vivo results indicated that C-tDCS applied during the reperfusion phase but not during the ischemic phase significantly improved neurological outcomes, reduced infarct volume, and mitigated histopathological damage in middle cerebral artery occlusion/reperfusion rats. C-tDCS during the reperfusion phase suppressed ferroptosis, activated nuclear factor erythroid 2-related factor 2 (Nrf2), and inhibited mitophagy. In vitro, the ferroptosis inducer RSL3 negated the protective effects of cathodal direct current stimulation on HT22 neuronal cells subjected to oxygen-glucose deprivation/reoxygenation injury. Furthermore, the Nrf2 inhibitor ML385 and the mitophagy activator FCCP reversed the inhibitory effects of C-tDCS on ferroptosis, with FCCP also affecting Nrf2 activation by C-tDCS. Innovation and Conclusions: These results demonstrate that C-tDCS during reperfusion attenuates cerebral ischemia-reperfusion injury by coordinating mitophagy inhibition and Nrf2 activation to counteract ferroptosis, which provides new evidence for its potential translational clinical applications. Antioxid. Redox Signal. 43, 693-708.

Aims: This study aimed to investigate the potential molecular mechanisms of Akkermansia muciniphila (Akk) in the treatment of abdominal aortic aneurysm (AAA) through the use of 16S rRNA sequencing and transcriptome sequencing technologies. Results: 16S rRNA sequencing analysis revealed distinct microbial composition in Sham, AAA, and Akk-treated AAA groups, highlighting the key role of Akk. Akk treatment prevented AAA development, reduced extracellular matrix degradation, and suppressed neutrophil extracellular trap (NET) formation. High mobility group box 1 (HMGB1) promoted AAA formation, antagonizing Akk's effects on NETs. Cell studies showed NET-induced ferroptosis in vascular smooth muscle cells (VSMCs), blocked by ferroptosis inhibitor ferrostatin-1, with HMGB1 overexpression enhancing ferroptosis and AMP-activated protein kinase (AMPK) inhibition reversing it. Akk activated AMPK to inhibit ferroptosis, consistent with in vivo results. Innovation: This study combines molecular analyses, cellular experiments, and animal studies to uncover Akk's mechanisms in AAA treatment. Identification of pathways influencing VSMCs' response to NETs and ferroptosis is a significant advancement in vascular biology. Conclusion: Akk mitigates HMGB1-mediated NET formation, activates AMPK to reduce VSMC ferroptosis, and inhibits AAA progression. These findings offer insights into AAA pathogenesis and propose Akk as a potential therapeutic agent for this condition. Antioxid. Redox Signal. 43, 782-804.

Significance: Sequestosome 1 (SQSTM1/p62, hereafter referred to as p62) is a multifunctional ubiquitin-binding autophagy receptor that acts as a critical bridge between the kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) pathway and selective autophagy through diverse post-translational modifications (PTMs) and their reverse processes. Recent Advances: As a selective autophagy receptor, p62 facilitates the degradation of ubiquitinated substrates while functioning as a signaling hub to orchestrate cellular responses to oxidative stress. Given its central role in multiple signaling pathways, p62 is subject to tight and intricate regulation. Beyond transcriptional control, p62 activity is finely modulated by diverse PTMs and their reverse processes, including phosphorylation, dephosphorylation, ubiquitination, deubiquitination, acetylation, deacetylation, S-Acylation, and deacylation, which collectively fine-tune its roles in selective autophagy and the KEAP1-NRF2 pathway. Mounting evidence underscores that the PTMs and their reverse processes of p62 are implicated in diverse pathologies through both direct and indirect mechanisms, spanning multiple cancer subtypes, neurodegenerative disorders, inflammatory conditions, non-alcoholic fatty liver disease (NAFLD), and metal-induced toxicity, as well as infectious diseases. Critical Issues: This review synthesizes current knowledge on the PTMs and their reverse processes of p62, its functional implications, its disease-associated mechanisms, and molecular regulators, aiming to provide novel insights for targeting the PTMs and their reverse processes of p62 in therapeutic strategies. Future Directions: Targeting p62 PTMs and their reverse processes may be a promising strategy to ameliorate various diseases, including cancer, neurodegenerative disorders, inflammatory conditions, NAFLD, metal-induced toxicity, and infectious diseases. Antioxid. Redox Signal. 43, 745-764.

Aims: Hepatic ischemia/reperfusion (I/R) injury induces liver damage and secondary neuronal injury, particularly in D1-medium spiny neurons (D1-MSNs). This study investigates whether remifentanil exerts neuroprotective effect by regulating oxidative stress and inflammation via fibroblast growth factor 18 (FGF18) upregulation. Results: Remifentanil markedly attenuated liver and striatal injury in a murine I/R model, as indicated by decreased serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, along with reduced inflammatory cytokines interleukin 1 beta and interleukin 18. Oxidative stress was mitigated through enhanced activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and reduced reactive oxygen species levels, confirmed by lower dihydroethidium and mitochondrial superoxide indicator red fluorescence. Neuronal injury was alleviated, demonstrated by improved D1-MSN morphology, reduced apoptosis, increased expression of D1-dopamine receptor and Substance P, and fewer c-Fos-positive cells. Transcriptomic and machine learning analyses identified FGF18 as a key mediator of remifentanil's neuroprotective effects. Functional studies further confirmed that FGF18 overexpression reduced neuronal damage, whereas its knockdown abolished the protective effects of remifentanil, highlighting its pivotal role. Innovation: This study is the first to demonstrate that remifentanil exerts neuroprotective effects in hepatic I/R injury by upregulating FGF18, providing new insights into its combined hepatoprotective and neuroprotective mechanisms. Conclusion: Remifentanil mitigates hepatic I/R-induced injury to D1-MSNs by upregulating FGF18, thereby reducing oxidative stress and inflammation while preserving neuronal structure and function. These findings identify FGF18 as a potential therapeutic target for liver I/R-related neurological damage. Antioxid. Redox Signal. 43, 709-726.