Redox Report最新文献

Background: Interleukin-6 (IL-6) is a pleiotropic cytokine that participates in multiple metabolic disorders. IL-6 is well recognized to induce hepcidin expression and decreased serum iron through the JAK2/STAT3 pathway under inflammatory conditions. Targeted inhibition of IL-6 represents a potential therapeutic regimen for multiple diseases. The current study aimed to explore the physiological concentration of IL-6 in sustaining systemic iron homeostasis.

Methods: IL-6-knockout mice (IL-6-/-) were established in the current study. Western blot measured the expression of key iron-related proteins in liver, kidney, spleen and duodenum, as well as hepatic hepcidin mRNA expression. Serum iron and hematologic parameters were detected. ELISA and Masson's trichrome staining were performed to detect renal TGF-β1 expression and collagen deposition. Furthermore, bone marrow-derived and peritoneal macrophages were prepared to identify the iron recycling.

Results: Serum iron and tissue iron content were markedly elevated in IL-6-/- mice. Mechanistically, decreased renal erythropoietin (EPO) synthesis contributed to iron utilization, macrophage-mediated recycling of iron was markedly reduced, thereby resulting in systemic iron accumulation. However, IL-6-/- mice displayed increased Hepcidin expression via p-ERK activation and a significant reduction in duodenal iron uptake.

Conclusion: This study highlighted the critical role of IL-6 in iron homeostasis both in physiological and pathological situations.

Alzheimer's disease and Parkinson's disease are the two most prevalent neurodegenerative disorders worldwide, both characterized by progressive neuronal loss. Despite distinct pathophysiological features, they share cellular dysfunctions such as abnormal protein aggregation, oxidative stress, and neuroinflammation, research into which might be beneficial for developing novel therapeutic strategies that could tackle both conditions. This review highlights the emerging role of the gasotransmitters nitric oxide, carbon monoxide and hydrogen sulfide as modulators of adult neurogenesis and neuroprotection in Alzheimer's disease and Parkinson's disease. We have gathered recent evidence demonstrating that these endogenous gases exert anti-inflammatory, antioxidant, and anti-apoptotic effects, and, critically, promote neurogenesis - suggesting a dual neuroprotective and neuroregenerative therapeutic potential. The unique physicochemical features of these gasotransmitters, including their ability to cross the blood-brain barrier and diffuse rapidly throughout the neural tissue, further support their suitability as candidates for innovative neuroregenerative treatments. While clinical translation remains challenging, harnessing the neurogenic and neuroprotective actions of these gasotransmitters may offer transformative avenues for addressing the increasing burden of Alzheimer's disease and Parkinson's disease.

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.

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.

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: 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.

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.

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.

The primary treatment for hepatocellular carcinoma (HCC) involves surgical removal of the primary tumor, but this creates a favorable environment for the proliferation and spread of residual and circulating cancer cells. The development of remimazolam-based balanced anesthesia is crucial for future antitumor applications. It is important to understand the mechanisms of cytotoxicity for HCC in detail.

We performed cell viability analysis, western blotting analysis, reverse transcription-polymerase chain reaction analysis, and flow cytometry analysis in two HCC cell lines, HepG2 and Hep3B cells.

Our data demonstrated that remimazolam induced cytotoxicity by suppressing cell proliferation, inhibiting G1 phase progression, and affecting mitochondrial reactive oxygen species (ROS) levels, leading to apoptosis, DNA damage, cytosolic ROS elevation, lipid peroxidation, autophagy, mitochondrial depolarization, and endoplasmic reticulum stress. Inhibitors of apoptosis, autophagic cell death, and ferroptosis and a ROS scavenger failed to rescue cell death caused by remimazolam besylate. Our combination index revealed that remimazolam besylate has the potential to act as a sensitizer for targeted tyrosine kinase inhibitor therapy for HCC.

Our findings open up new possibilities for combinatory HCC therapy using remimazolam, leveraging its dual functional roles in surgery and drug therapy for liver cancers.