Redox Report最新文献

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.

Objective: Chronic liver diseases (CLDs) are prevalent globally. The purpose of the current study was to elucidate the regulatory mechanisms underlying the pathophysiological processes in CLDs.

Methods and results: Using the GEO database, we identified cysteine and methionine metabolism as a commonly enriched pathway in some CLDs. We then confirmed that hepatic cystathionine γ-lyase (Cth), a key enzyme in this pathway, was significantly downregulated in some CLDs in humans and rodent models. Cth-deficient mice exhibited hepatic necroptosis, inflammation and mitochondrial impairment. Omics revealed methionine cycle dysregulation and reduced betaine, a methionine cycle metabolite. Betaine supplementation rewired the methionine cycle, and alleviated necroptosis, inflammation and mitochondrial impairment. Dysregulation of fatty acid β-oxidation, glycolysis and lipid biosynthesis caused by Cth deficiency was improved by betaine. Cth deficiency decreased Pparα, Nrf2, Pgc-1α, and Srebf2 (the transcription factors linked to mitochondria function and metabolism) expression while increasing Irf8 and Irf9, changes reversed by betaine. Histone methylation (H3K9me3, H3K27me3, H3K79me3) decreased, and acetylation (H3K27ac) increased with Cth deficiency, which betaine corrected. Irf8 and Irf9 and Ppara and Ppargc1a expression were regulated by H3K27me3 and H3K79me3 in hepatocytes, respectively.

Discussion: Our study indicates that CTH is the key factor for maintaining hepatocyte function and survival through homeostasis of the methionine cycle and immediately highlights a new potential target of hepatic protection therapy for some CLDs.

Background: Sensory neurons relay the pain signals to the brain via the nociceptive system. Notably, reactive oxygen species (ROS) serve as signaling molecules in the somatosensory system; however, their contribution to sensing noxious stimuli remains poorly understood.

Methods: Herein, the role of protein kinase G (PKG)1α, which is highly expressed in sensory neurons and serves as a ROS target, was investigated in sensory neurons in the processing of acute nociceptive pain. Cys42Ser PKG1α-knock-in (PKG1α-KI) mice, devoid of redox-dependent PKG1α activation, were subjected to behavioral testing, ROS detection assays, gene expression experiments, and imaging analyses.

Results: Interestingly, PKG1α-KI mice showed reduced behavioral responses to noxious heat and the transient receptor potential cation channel subfamily V member 1 (TRPV1) agonist capsaicin. Moreover, capsaicin-induced sensory neuron stimulation upregulated ROS production and redox-dependent PKG1α activation. Calcium imaging results and patch-clamp recordings revealed that capsaicin-induced calcium flux and neuronal excitability was reduced in sensory neurons of PKG1α-KI mice.

Conclusion: Altogether, the findings of this study show the effects of redox-dependent PKG1α activation on capsaicin/TRPV1-mediated signaling in sensory neurons during acute nociceptive pain.

Objectives: Many countries in the world are entering society with an aging population. The kidney is one of the most sensitive organs in the body to aging. Kidney function gradually declines with aging. Renal aging is one of the main triggers of CDK. Therefore, many researchers in the field are looking for natural, green and healthy anti-renal-aging bioactive molecules.

Methods and results: Western-blot, ELISA and indirect immunofluorescence were performed to evaluate the biological activity of fucoxanthin against renal aging in vitro and in vivo models. First, in the in vitro model, we evaluated the effect of fucoxanthin on renal cell senescence. We found that fucoxanthin could alleviate the kidney cell senescence caused by H₂O₂ by detecting a series of senescence markers. In the in vivo model, the experimental results showed that fucoxanthin could alleviate the aging of the kidney by Sa-β-gal staining and detection of aging-related marker molecules. Furthermore, we also found that fucoxanthin could alleviate kidney fibrosis.

Conclusions: In this study, our results showed that fucoxanthin was able to alleviate renal aging in vivo and in vitro models, suggesting that fucoxanthin could be a functional food to treat and relieve kidney aging.

Objectives: Doxorubicin (DOX) induces dose-dependent cardiotoxicity, primarily through oxidative stress and metabolic dysregulation. Although NAD⁺ deficiency has been implicated in cardiovascular pathology, its role in DOX-induced cardiotoxicity (DIC) remains poorly understood. This study investigated NAD⁺ metabolism dysregulation as a redox-sensitive mechanism in DIC pathogenesis.

Methods: Human cardiomyocytes (AC16), mouse atrial myocytes (HL-1), and C57BL/6 mice were used to establish the DIC model. The role and mechanism of NAD⁺ in DIC were investigated using a range of methods.

Results: Using integrated in vitro and in vivo models, we demonstrated that DOX induces myocardial oxidative damage accompanied by NAD⁺ depletion. Exogenous NAD⁺ supplementation mitigated the DOX-induced cardiomyocyte death and redox imbalance. Mechanistically, pharmacological CD38 inhibition with 78C or genetic silencing failed to restore the NAD⁺ pool, whereas nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) overexpression, combined with nicotinamide mononucleotide (NMN) administration, effectively rescued NAD⁺ levels and attenuated oxidative stress. Computational and functional analyses identified FOXO1 as a transcriptional repressor of NMNAT3 following DOX exposure.

Conclusion: This study establishes the dysregulation of the FOXO1-NMNAT3 axis as a key mechanism underlying NAD⁺ depletion in DIC. Targeting this axis through NAD⁺ replenishment, particularly by activating NMNAT3, offers a novel redox-based therapeutic strategy against DIC.