Redox Report最新文献

Objective: To evaluate the efficacy and underlying molecular mechanisms of artesunate (ART) in experimental autoimmune uveitis (EAU).

Methods: An EAU mouse model was established and treated with ART via oral gavage. Disease severity was assessed by clinical scoring and retinal histology. SPR analysis examined ART binding to LCN2 and STAT3. Immunofluorescence co-staining was conducted to evaluate the expression and co-localization of LCN2 with microglia in retinal tissues. Western blot analysis was performed to measure protein levels of STAT3, LCN2, SLC7A11, FTH1, GPX4, IL-6, IL-1β, IL17A and TNF-α. In vitro, BV2 microglial cells were used, and LCN2 was knocked down with siRNA. Inflammatory cytokine concentrations in retina and BV2 cell culture supernatants were assessed through ELISA.

Results: ART treatment significantly improved clinical and histopathological scores in EAU mice and exhibited moderate binding affinity for LCN2 and STAT3. It suppressed microglial activation and downregulated the expression of LCN2 and STAT3, along with the release of IL-6, IL-1β, IL17A and TNF-α. In BV2 microglial cells, ART decreased LCN2 expression and attenuated proinflammatory cytokine secretion.

Conclusions: Artesunate attenuates EAU by inhibiting the LCN2-STAT3 axis and suppressing the activation of microglial and Th17 cells.

Background: Selenium nanoparticles (SeNPs) and selenoneine (SeN) are prospective nutritional supplements and therapeutic agents postulated to counteract Se deficiency and alleviate oxidative stress induced by various pathological conditions.

Methods: X-ray fluorescence microscopy (XFM) and high energy resolution fluorescence detected X-ray absorption spectroscopy (HERFD-XAS) investigated Se distribution and speciation in mice fed supranutritional doses of SeNPs (10 mg Se/kg in feed) and SeN (5 mg Se/kg in feed).

Results: Mice fed control and SeNP diets showed equivalent Se distributions in the liver and testes, however, Se concentrations were elevated in the renal tubules of mice supplemented with SeNPs. Negligible differences in the composition of selenospecies were detected in tissues from mice fed SeNPs and control diets. Mice supplemented with SeN exhibited significant elevations in Se across all analysed tissues. Se Kα₁ HERFD-XAS data revealed reduced SeN as the predominant selenospecies in tissues and blood from mice fed the SeN diet. Characterisation of the SeN-enriched feed showed that SeN was initially present in both the oxidised dimer and reduced monomer forms.

Conclusion: These results support the hypothesised in vivo reduction of SeN and subsequent bioaccumulation in the blood and various tissues. The present findings highlight marked differences in the bioavailability and utilisation of these purported therapeutic selenocompounds.

Background: Mesenchymal stem cells (MSCs) are a potential therapy for acute respiratory distress syndrome (ARDS), but their mechanisms in repairing mitochondrial damage in ARDS endothelial cells remain unclear.

Methods: We first examined MSCs' mitochondrial transfer ability and mechanisms to mouse pulmonary microvascular endothelial cells (MPMECs) in ARDS. Then, we investigated how MSC-mediated mitochondrial transfer affects the repair of endothelial damage. Finally, we elucidated the mechanisms by which MSC-mediated mitochondrial transfer promotes vascular regeneration.

Results: Compared to mitochondrial-damaged MSCs, normal MSCs showed a significantly higher mitochondrial transfer rate to MPMECs, with increases of 41.68% in vitro (P < 0.0001) and 10.50% in vivo (P = 0.0005). Furthermore, MSC-mediated mitochondrial transfer significantly reduced reactive oxygen species (P < 0.05) and promoted proliferation (P < 0.0001) in MPMECs. Finally, MSC-mediated mitochondrial transfer significantly increased the activity of the tricarboxylic acid (TCA) cycle (MD of CS mRNA: 23.76, P = 0.032), and further enhanced fatty acid synthesis (MD of FAS mRNA: 6.67, P = 0.0001), leading to a 6.7-fold increase in vascular endothelial growth factor release from MPMECs and promoted vascular regeneration in ARDS.

Conclusion: MSC-mediated mitochondrial transfer to MPMECs activates the TCA cycle and fatty acid synthesis, promoting endothelial proliferation and pro-angiogenic factor release, thereby enhancing vascular regeneration in ARDS.

Background: Pulmonary metastases in osteosarcoma (OS) are associated with a poor prognosis. Rotenone has shown anti-cancer activity. However, its effects on metastasis and the underlying mechanisms remain unknown. This study investigated the potential use of Rotenone for OS treatment.

Methods: The effect of Rotenone and ROS/Ca²⁺/AMPK/ZO-2 pathway on metastasis and EMT was evaluated by Western blot, Transwell and Wound healing. Flow cytometer was employed to measure the intracellular Ros and Ca²⁺ levels. The subcellular location of ZO-2 was detected by IF, interaction between AMPK and ZO-2 were examined by Co-IP. Then, subcutaneous tumor and metastasis models were used to evaluate the function of Rotenone in OS metastasis.

Results: Rotenone-induced ROS led to increased intracellular Ca²⁺, which promoted the EMT of OS cells through activation of AMPK and ZO-2 nuclear translocation. Inhibition of ROS production decreased intracellular Ca²⁺, restraining AMPK activity. Knock-down of ZO-2 significantly suppressed the anti-metastasis effects of Rotenone in OS cells. Moreover, Rotenone elevated p-AMPK and ZO-2 expression but inhibited EMT and lung metastasis in vivo.Conclusion These results provide evidence supporting an anti-metastatic effect of Rotenone. These findings support the use of Rotenone in the prevention of OS metastasis.

Background: Sepsis-induced cardiomyopathy (SIC) involves ferroptosis, an iron-dependent cell death. Hypoxia-inducible factor-1α (HIF-1α) regulates autophagy and apoptosis, but its role in ferroptosis remains unclear. This study investigates the interaction between the HIF1A/BNIP3 signaling pathway and the ferroptosis axis, SLC7A11/GPX4, in septic myocardial injury.

Methods: A rat model of septic myocardial injury was created via cecal ligation and puncture (CLP), with an in vitro model using lipopolysaccharide (LPS)-treated H9c2 cardiomyocytes. Groups: sham, CLP, CLP + solvent, CLP + HIF1A inhibitor (LW6), CLP + ferroptosis inhibitor (Fer-1), and CLP + LW6 + Fer-1. Cardiac function, histopathological changes, and biomarkers (myocardial injury/inflammation/ferroptosis) were measured. In vitro, H9c2 cells were treated with LPS, LW6, or fenbendazole (FZ) and transfected with BNIP3 shRNA. Various assays were used to evaluate cell viability, ROS levels, and protein interactions.

Results: (1) HIF1A/BNIP3 activation aggravated septic myocardial injury and ferroptosis; inhibition reversed this. (2) BNIP3 knockdown alleviated LPS-induced injury and ferroptosis in H9c2 cells. (3) BNIP3 and BECN1 competed for BCL-2 binding, modulating ferroptosis-related signaling.

Conclusion: BCL-2 links the HIF1A/BNIP3 and BECN1/SLC7A11/GPX4 pathways, offering insights into septic myocardial injury mechanisms and potential therapeutic targets.

Objective: To investigate the protective effects of varespladib against Naja atra-induced acute liver injury (ALI) and to elucidate the toxic mechanism of snake venom phospholipase A₂ (SVPLA₂)-induced hepatic oxidative stress, with a particular focus on the role of Nrf2 signaling and its downstream pathways.Methods: A combination of in vivo and in vitro models of N. atra envenomation was employed to assess liver injury, oxidative stress, and mitochondrial dysfunction. The interaction between SVPLA₂ and Nrf2 was analyzed, and the effects of varespladib treatment on these processes were evaluated using histological analysis, biochemical assays, and molecular techniques targeting oxidative stress, ferroptosis, mitophagy, and apoptosis.Results: Varespladib significantly alleviated N. atra-induced ALI. SVPLA₂ was found to directly bind to Nrf2, leading to severe oxidative stress. This oxidative stress initiated a cascade involving Nrf2-mediated ferroptosis, mitochondrial dysfunction, excessive mitophagy, and mitochondria-dependent apoptosis. Treatment with varespladib effectively reversed these pathological events by inhibiting SVPLA₂ activity.Conclusion: Varespladib shows strong therapeutic potential for N. atra envenomation by targeting SVPLA₂. Nrf2 was identified as a direct toxic target of SVPLA₂, and Nrf2-mediated ferroptosis and mitochondrial dysfunction were key mechanisms underlying SVPLA₂-induced hepatic injury.

Current treatment options for head and neck squamous cell carcinoma (HNSCC) are limited. Aspartate aminotransaminase (GOT1) plays an important role in cancer development but its role in HNSCC remains unknown. We combined proteomics and metabolomics to identify high GOT1expression in human cancer tissues. The effects of GOT1 knockdown on cancer cell proliferation were confirmed using CCK8, wound healing assays, colony formation assays, and EdU assays. The anti-apoptotic ability of cancer cells was evaluated using TUNEL assay and flow cytometry. GOT1 knockdown caused mitochondrial dysfunction and was characterized by reduced mitochondrial membrane potential and altered expression of mitochondrial electron transport chain complexes and key transcription factors, as measured by JC-1 and qRT-PCR. Given that mitochondria are the primary source of reactive oxygen species (ROS), we assessed cellular ROS and mitochondrial superoxide levels by flow cytometry and found a significant increase. GOT1 knockdown increased the sensitivity of cells to cisplatin and decreased the volume of tumors in vivo. In summary, GOT1 knockdown inhibited proliferation and promoted apoptosis via ROS overproduction from mitochondrial dysfunction, thereby increasing cisplatin sensitivity. RNA-seq further identified aldehyde dehydrogenase 3A1 (ALDH3A1) as potentially downstream target of GOT1. These findings suggest that GOT1 knockdown may improve clinical outcomes in HNSCC.

Objective: Epilepsy is a chronic neurological condition characterized by recurrent seizures, often linked to neuroinflammation and oxidative stress that exacerbate neuronal injury. Neuropilin-2 (NRP2) and Nuclear Factor-Kappa B (NF-κB) are key mediators in these pathways. This study evaluated the neuroprotective effects of emodin, a bioactive anthraquinone with antioxidant and anti-inflammatory properties, in a pentylenetetrazole (PTZ)-induced mouse model of epilepsy.

Methods: Seizure severity, anxiety-like behavior (Elevated Plus Maze), and cognitive function (Morris Water Maze) were assessed. Oxidative stress markers including glutathione (GSH), catalase, lipid peroxidation (LPO), and glutathione-S-transferase (GST) were measured. Expression of NRP2, NF-κB, and proinflammatory cytokines (TNF-α, IL-6) was quantified. Docking studies examined emodin's binding affinity to NRP2 and NF-κB.

Results: Emodin (200 mg/kg) significantly reduced seizure frequency and severity, improved anxiety-like behavior, and enhanced cognition. Biochemical analysis showed restored oxidative balance, with increased GSH and catalase activity and reduced LPO and GST dysfunction. Molecular studies revealed downregulation of NRP2, NF-κB, and cytokines. Docking confirmed strong binding affinity to NRP2 and NF-κB.

Conclusion: Emodin alleviates oxidative stress and neuroinflammation by modulating NRP2 and NF-κB pathways, suggesting therapeutic potential in epilepsy.

Objectives: Bone remodeling imbalance contributes to osteoporosis. Though current medications enhance osteoblast involvement in bone formation, the underlying pathways remain unclear. This study was aimed to explore the pathways involved in bone formation by osteoblasts, we investigate the protective role of glycolysis and N6-methyladenosine methylation (m6A) against oxidative stress-induced impairment of osteogenesis in MC3T3-E1 cells.

Methods: We utilized a concentration of 200 μM hydrogen peroxide (H₂O₂) to establish an oxidative damage model of MC3T3-E1 cells. Subsequently, we examined the alterations in the m6A methyltransferases (METTL3, METTL14), glucose transporter proteins (GLUT1, GLUT3) and validated m6A methyltransferase overexpression in vitro and in an osteoporosis model. The osteoblast differentiation and osteogenesis-related molecules and serum bone resorption markers were measured by biochemical analysis, Alizarin Red S staining, Western blot and ELISA.

Results: H₂O₂ treatment inhibited glycolysis and osteoblast differentiation in MC3T3-E1 cells. However, when METTL14 was overexpressed, these changes induced by H₂O₂ could be mitigated. Our findings indicate that METTL14 promotes GLUT3 expression via YTHDF1, leading to the modulation of various parameters in the H₂O₂-induced model. Similar positive effects of METTL14 on osteogenesis were observed in an ovariectomized mouse osteoporosis model.

Discussion: METTL14 could serve as a potential therapeutic approach for enhancing osteoporosis treatment.

Background: Tropoelastin (TE), the soluble precursor of elastin, is critical for the elasticity of arteries, lungs, and skin. Oxidative damage to TE has been implicated in vascular diseases, but the isoform-specific effects remain poorly understood. Hypochlorous acid (HOCl), generated by the enzyme myeloperoxidase (MPO) targets extracellular matrix proteins during inflammatory processes. However, the differential susceptibility and functional consequences in specific TE isoforms are unknown.

Methods: We investigated the effects of HOCl and MPO-derived oxidants on two human TE isoforms, TE2 and TE6. Oxidative modifications were analyzed using high-resolution LC-MS/MS, with site-specific identification of chlorinated tyrosines and oxidized cysteine residues. Functional consequences were assessed using turbidity-based coacervation assays.

Results: TE2 exhibited chlorination at multiple tyrosine residues, particularly 3,5-dichlorotyrosine, while showing minimal cysteine oxidation. In contrast, TE6 was more oxidised at its single disulfide bond, resulting in irreversible sulfonic acid formation. These isoform-specific patterns translated into functional differences: TE2 demonstrated enhanced coacervation , whereas TE6 showed reduced assembly capacity, consistent with structural destabilization.

Conclusion: HOCl and MPO-derived oxidants induce distinct modifications in tropoelastin isoforms, resulting in divergent effects on protein self-assembly. These findings highlight the importance of isoform context in extracellular matrix remodeling under oxidative stress and may have implications for vascular pathologies.