Redox Report最新文献

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.

Oxidative stress (OS) plays a key role in the pathophysiology of COVID-19 and may be associated with sequelae after severe SARS-CoV-2 infection. This study evaluated OS and inflammation biomarkers in blood from individuals with post-acute sequelae of COVID-19 (PASC). 64 male and female participants were distributed into three groups: healthy individuals (n = 20), acute COVID-19 patients (symptoms for <3 weeks, n = 15), and PASC patients (symptoms for >12 weeks, n = 29). Analyses included inflammatory cytokines, myeloperoxidase (MPO) activity, and OS markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), gamma-glutamyl transferase (GGT), reduced glutathione (GSH), uric acid (UA), thiobarbituric acid reactive substances (TBARS), and protein carbonyls (PC). Individuals with PASC showed increased IL-6 and IL-8. Both COVID-19 groups exhibited decreased SOD and CAT. GST decreased only in the acute group. Elevated GGT and GSH were found in the PASC group. High UA levels were observed in PASC individuals. There were no changes in TBARS values ⁣⁣in the PASC group. However, PC concentrations were elevated only in this group. Correlations were identified between inflammatory markers and OS parameters. These findings suggest that individuals with PASC pronounced OS, which potentially exacerbates disease complications. Monitoring OS biomarkers could aid in patient prognosis and management.

Background: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a major global health threat due to prolonged treatment and drug-resistant strains. Host-directed therapy (HDT), which modulates host-pathogen interactions, offers potential to shorten treatment and limit resistance. This study investigates the effects of Scutellarin (SCU), a flavonoid from Scutellaria baicalensis, on Mtb-infected macrophages within the HDT framework.

Methods: Anti-pyroptotic and anti-inflammatory effects of SCU were assessed in Mtb-infected THP-1 and J774A.1 macrophages, and in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. Mitochondrial function was evaluated by oxygen consumption rate(OCR), membrane potential, and superoxide levels; glycolytic activity was measured by proton efflux rate (GlycoPER). Expression of inflammasome-related markers was analyzed by Western blot, qPCR, ELISA, immunofluorescence, and flow cytometry. The role of hypoxia-inducible factor 1-alpha (HIF-1α) was examined via siRNA knockdown.

Results: SCU inhibited NLRP3 inflammasome activation, reduced IL-1β and IL-18 secretion, and attenuating pyroptosis. It restored mitochondrial integrity by regulating p-DRP1, MFN2, and Cytochrome C expression, and suppressed HIF-1α-mediated glycolytic reprogramming. Silencing of HIF-1α confirmed its role in SCU's mechanism. In vivo, SCU reduced pulmonary inflammation and cytokine release in LPS-induced ALI.

Conclusion: SCU alleviates Mtb-induced pyroptosis and inflammation in macrophages by inhibiting the HIF-1α-mediated Warburg effect.

Objectives: Recent studies have highlighted the strong association between kidney disease and ferroptosis. However, the role of ferroptosis in diabetic nephropathy (DN) remains unclear. This study aimed to determine the role of ACSF2 in renal tubule injury in DN and its underlying mechanisms.

Methods: We established diabetic kidney disease models both in vivo, using db/db mice, and in vitro, using high glucose induced HK-2 cells.

Results: A significant upregulation of ACSF2 was observed in the renal tubules of patients with DN and db/db mice. ACSF2 expression correlated with renal tubule injury and renal function, indicating its potential as an independent biomarker in patients with DN. Silencing ACSF2 alleviated high glucose-induced renal tubular epithelial cell injury by reducing oxidative stress-induced ferroptosis in vivo and in vitro. Mechanistically, liquid chromatography-tandem mass spectrometry and co-immunoprecipitation demonstrated that ACSF2 specifically binds to PGK1. ACSF2 affected Keap1 dimerization by regulating PGK1 phosphorylation at serine 203, which subsequently affects the levels of NRF2. Moreover, PGK1 stabilizes ACSF2 via deubiquitination, establishing a positive feedback loop. The results provide evidence that the interaction between ACSF2 and PGK1 promotes DN progression by regulating oxidative stress-induced ferroptosis.

Discussion: ACSF2 participates in crosstalk between oxidative stress and ferroptosis. This could be a potential therapeutic target for DN.

The death of human nucleus pulposus derived stem cells (NPSCs) is a key factor affecting the endogenous repair capability and degeneration of intervertebral discs (IVD). ASIC1a is thought to be closely associated with cells destiny in IVD degeneration (IVDD). However, its physiological and pathological roles in human NPSCs are unclear. In this study, we found that the content of ASIC1a increased with IVDD in both rats and human discs. In acidosis-treated NPSCs, the expression level of ASIC1a increased, accompanied by inhibition of cells viability and activation of mitochondrial apoptotic pathway. Additionally, ASIC1a overexpression activated the mitochondrial apoptotic pathway and increased the level of cellular and mitochondrial ROS in human NPSCs. Moreover, we demonstrated that the dysfunction of SIRT3-regulated mitochondrial redox homeostasis was involved in ASIC1a overexpression-induced apoptosis in human NPSCs. The in vivo experiments also demonstrated that the ASIC1a/SIRT3 pathway was involved in IVDD. Overall, these findings showed that ASIC1a disrupted mitochondrial function and aggravated mitochondrial oxidative stress by inhibiting the expression of SIRT3, which activated human NPSC apoptosis and aggravated IVDD. These findings provide new insights for the development of innovative treatment strategies for IVDD.HighlightsAcidosis inhibited human NPSCs activity and promoted apoptosis via mitochondria.ASIC1a promoted acidosis-induced apoptosis of human NPSCs.ASIC1a inhibited SIRT3 expression, aggravating mitochondrial oxidative stress.ASIC1a promoted IVDD via mitochondrial oxidative stress and apoptosis.

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.

Background: The most prevalent endocrine disorder affecting women is PCOS. Programmed death of ovarian cells has yet to be elucidated. Ferroptosis is a kind of iron-dependent necrosis featured by significantly Fe⁺²-dependent lipid peroxidation. The ongoing study aimed to reinforce fertility by combining therapy with AgNPs and (Zileuton) in PCOS rats' model.

Methods: The study included 75 adult female rats divided into 5 groups; control, PCOS, PCOS treated with AgNPs, PCOS treated with Zileuton, and PCOS group treated with AgNPs and Zileuton. The study investigated the anti-ferroptotic, anti-inflammatory, antioxidant, antiapoptotic, histopathological and immunohistochemical examinations of COX-2 and VEGF.

Results: The combination of AgNPs and Zileuton showed significant reduction of inflammatory mediators (IL-6, TNF-α, NFk-B) compared with diseased group (P-value < 0.05), regression of ferroptosis marks (Panx1 and TLR4 expression, Fe⁺² levels) compared with diseased group (P-value < 0.05), depression of apoptotic marker caspase 3 level compared with diseased animals (P-value < 0.05), depression of MDA level, elevation of HO-1, GPx4 activity, and reduction of Cox2 and VEGF as compared with the diseased, AgNPs or zileuton-treated groups (P-value < 0.05).

Conclusion: The study showed that the combination of AgNPs and zileuton guards against, inflammation, apoptosis, and ferroptosis in PCO.

Background: Long non-coding RNAs (lncRNAs) are increasingly recognized in keloid pathogenesis. This study investigates the role and mechanisms of HOXA11-AS in keloid formation.

Methods: Expression levels of HOXA11-AS and related proteins were measured in keloid tissues and fibroblasts using qRT-PCR, Western blot, and ELISA. Functional assays assessed cell proliferation, migration, fibrosis, and oxidative stress. RIP, ChIP, Co-IP, FISH, and luciferase assays were used to explore interactions among HOXA11-AS, YY1, Nrf2, EZH2, and DNMT1. An in vivo mouse xenograft model validated the findings.

Results: HOXA11-AS was upregulated in keloids. Silencing HOXA11-AS reduced fibroblast proliferation, migration, fibrosis, and oxidative stress. Its overexpression had the opposite effect, which was reversed by Nrf2 pathway inhibition. HOXA11-AS promoted the methylation of the Nrf2 promoter via DNMT1 recruitment, mediated by EZH2. YY1 enhanced HOXA11-AS transcription by binding to its promoter. The YY1/HOXA11-AS axis was confirmed in vivo.

Conclusion: YY1-induced HOXA11-AS drives keloid formation by promoting oxidative stress and inflammation through epigenetic suppression of Nrf2 signaling.