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: Hypothyroidism frequently causes myocardial injury, but the role of thyroid hormone receptor alpha (THRA) remains unclear. This study investigated the function and mechanism of THRA in hypothyroidism-associated cardiac damage. Methods: A propylthiouracil (PTU)-induced hypothyroid mouse model was utilized, incorporating wild-type and THRA-knockout (KO) groups with or without thyroxine (T4) treatment. Systemic parameters, cardiac injury, histopathology, and molecular pathways were analyzed using enzyme-linked immunosorbent assay, immunohistochemistry, Western blot, quantitative polymerase chain reaction, RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays. Results: PTU-induced hypothyroidism significantly reduced body weight, impaired cardiac function, and dysregulated thyroid hormones. THRA KO exacerbated these effects and completely abolished the therapeutic response to T4. Crucially, group KO-M markedly elevated markers of ferroptosis, including iron overload, malondialdehyde, and reactive oxygen species, while suppressing the reduced-to-oxidized glutathione ratio (GSH/GSSG) and key antiferroptotic proteins like glutathione peroxidase 4 (GPX4), compared with group M. Mechanistically, we identified GATA binding protein 4 (GATA4) as an upstream transcriptional activator of THRA. Furthermore, THRA itself directly bound to the GPX4 promoter and transactivated its expression. This GATA4-THRA-GPX4 axis was essential for cardioprotection, alongside modulation of the phosphoinositide 3-kinase/protein kinase B signaling pathway. Conclusion: This study defines the GATA4-THRA-GPX4 transcriptional axis as a crucial mechanism that protects the heart from hypothyroidism-driven ferroptosis, uncovering a previously unrecognized transcriptional axis that is crucial for cardioprotection during hypothyroidism. Antioxid. Redox Signal. 00, 000-000.

Aims: This study aims to evaluate the protective effects of dexmedetomidine-loaded polypeptide nanomicrospheres (PNM@Dex) in a mouse model of intestinal ischemia/reperfusion (I/R) injury and investigate the underlying molecular mechanisms, focusing on autophagy activation in enteric neurons. Results: PNM@Dex, synthesized via solid-phase peptide synthesis and coprecipitation, exhibited uniform spherical morphology (∼150 nm) and high drug encapsulation efficiency. In vitro studies demonstrated that PNM@Dex promoted autophagy in enteric neurons, attenuated oxidative stress and apoptosis, and improved cell viability. In vivo administration significantly mitigated intestinal injury, suppressed inflammatory cytokine production, and increased the expression of autophagy-related proteins. Autophagy inhibition assays confirmed the essential role of autophagy in mediating the protective effects of PNM@Dex. Innovation: This study represents the first successful incorporation of dexmedetomidine into polypeptide nanomicrospheres for targeted delivery to enteric neurons. The nanoplatform achieved sustained release, enhanced autophagy, and exerted strong anti-inflammatory and antioxidant effects, offering a novel therapeutic approach for intestinal I/R injury and potential protection in intestinal transplantation. Conclusion: PNM@Dex effectively alleviated intestinal I/R-induced damage through autophagy induction, oxidative stress reduction, and inflammation modulation, underscoring its promise as a therapeutic strategy for intestinal protection and transplantation. Antioxid. Redox Signal. 00, 000-000.

Aims: Ferroptosis has been implicated in the pathogenesis of lupus nephritis (LN), yet its precise role and mechanisms remain unclear. This study aimed to clarify the role of ferroptosis in LN progression and its underlying mechanisms. Methods: Transmission electron microscopy (TEM) was used to assess mitochondrial morphology in renal tissues from LN patients and MRL/lpr mice. Multidimensional mass spectrometry-based shotgun lipidomics was applied to analyze lipid alterations in renal cortex, medulla, and isolated renal tubules. Immunoblotting and reverse transcription quantitative PCR were performed to evaluate ferroptosis-related proteins and their messenger RNAs (mRNAs). Primary renal tubular epithelial cells (RTECs) from the distinct renal regions (cortex/medulla) were isolated and exposed to oxidative stress in vitro. Ferroptosis inducer erastin and inhibitor ferrostatin-1 (Fer-1) were used in vivo to determine causal effects. Results: TEM revealed typical ferroptotic mitochondrial changes in renal tissues from both LN patients and lupus-prone mice. In MRL/lpr mice, ferroptosis occurred as early as the pre-LN stage (8 weeks) and worsened by 14 weeks, with cortical tubules showing more severe damage than medullary tubules. Lipidomics demonstrated significant increases in lysophospholipids (e.g., 22:4 lysophosphatidylethanolamine, p < 0.001; 20:4 lysophosphatidylcholine, p < 0.01) and HNE species (p < 0.05), along with reductions in plasmalogens (e.g., 18:1-20:4 plasmenylcholine, p < 0.001). Mechanistically, ferroptosis was driven by downregulation of glutathione peroxidase 4 (p < 0.001) and solute carrier family 7 member 11 (p < 0.01) and upregulation of Acyl-CoA synthetase long chain family member 4 (p < 0.05), consistent with mRNA changes. Functionally, cortical RTECs cultured in vitro exhibited higher lipid reactive oxygen species (p < 0.001) and ferrous ion (Fe²⁺) accumulation (p < 0.01). In vivo, erastin accelerated LN progression, whereas Fer-1 significantly reduced proteinuria, renal pathology, and inflammatory cytokines. Innovation and Conclusion: The study provided direct evidence of ferroptosis markers in renal tissues of LN patients. RTECs exhibited the intrinsic abnormalities that trigger ferroptosis, greatly contributing to the progression of LN. Our findings highlighted the critical role of region-specific tubular ferroptosis in driving renal pathology. Early intervention targeting ferroptosis of RTECs in the renal cortex might be an effective strategy for treating LN. Antioxid. Redox Signal. 00, 000-000.

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: Endogenous hydrogen sulfide (H₂S) is involved in the occurrence and development of breast cancer, while its underlying mechanism is not yet clear. Here, we aimed to focus on the molecular mechanism of endogenous H₂S promoting the proliferation and metastasis of breast cancer. Results: In this study, four major findings were revealed: (1) Inhibition of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) increased the content of glucose in the supernatant of breast cancer cell and decreased the production of intracellular lactic acid and adenosine triphosphate. (2) Phosphoglycerate kinase 1 (PGK1) was persulfidated at Cys108 and Cys316, and its persulfidation level in breast cancer tissue was significantly higher than that in paracancerous tissue. (3) Blocking the persulfidation of PGK1 inhibited glycolysis and malignant biological behaviors of breast cancer cell. (4) The CSE inhibitor reduced the persulfidation of PGK1 and inhibited the growth and metastasis of xenograft tumors, whereas sodium hydrosulfide reversed the effect of CSE inhibitor. Preface PGK1 is not the only potential target for persulfidation. Innovation and Conclusion: This study revealed a novel mechanism involved in the upregulation of endogenous H₂S in breast cancer. Endogenous H₂S regulates glycolysis of breast cancer cells by mediating PGK1 persulfidation modification at Cys108 and Cys316, thereby promoting tumor proliferation and metastasis. This study offers a potential therapeutic strategy through targeting the upregulated endogenous H₂S and persulfidation of PGK1. Antioxid. Redox Signal. 00, 000-000.

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. 00, 000-000.