Free Radical Research最新文献

Wilson's disease (WD) is an autosomal recessive disorder associated with impaired copper metabolism that results in hepatic manifestations. However, as a rare disease, the underlying pathogenic mechanism and drug development have lagged behind. Studies have reported that copper accumulation is associated with potential increases in iron levels, which can lead to further exacerbation of oxidative damage and has been observed in WD patients. Therefore, removing excess copper from the body and enhancing antioxidant capacity are crucial in treatment. Melatonin (MLT) is an endogenous hormone with anti-oxidative stress, anti-inflammatory, and anti-ferroptosis properties, and can chelate transition metals. Thus, the study aimed to investigated the relationship between WD and ferroptosis, and the therapeutic efficacy and mechanism of MLT using copper-laden rats and HepG2 cell models. Our results suggested that copper overload significantly increased oxidative stress and altering ferroptosis-related metabolites of the liver in copper-laden rats. In vivo and in vitro experiments showed that copper overload disrupts the ceruloplasmin-ferroportin (Cp-Fpn) iron transport system, leading to increased iron levels and promoting ferroptosis, as indicated by the decreased levels of ferroptosis-related proteins GPX4, with these findings further supported by RSL3 and Ferrostatin-1. Further, we found that MLT could improve liver function, iron levels and enhance its antioxidant capacity. In addition, MLT was also able to inhibit ferroptosis by activating the Nrf2/SLC7A11/GPX4 pathway. The effect is more effective than penicillamine, the current therapeutic drugs.Key Policy HighlightsCopper overload induces hepatic ferroptosis in Wilson's disease via iron accumulation, glutathione depletion, and lipid peroxidation.Reduced ceruloplasmin disrupts the ferroportin-mediated iron efflux system, aggravating ferroptosis.Melatonin alleviates liver injury and copper accumulation by inhibiting ferroptosis via activation of the Nrf2/SCL7A11/Gpx4 pathway.

Small dihydroxy- and trihydroxybenzenes are polyphenolic compounds found in plant-based materials and formed by the human gut microbiota from other dietary phenolics. This study aimed to explore how 5 structurally related hydroxybenzenes interact with the biologically relevant metals iron and copper under various (patho)physiological pH conditions, focusing on their chelating and reducing abilities, influence on the metal-driven Fenton reactions, and their role in copper-induced hemolysis. Only compounds with hydroxyl groups in an ortho-position, specifically pyrogallol and 4-methylcatechol, were able to strongly chelate Fe²⁺ at neutral pH and exhibited the largest capacity to reduce Fe³⁺ and Cu²⁺. However, the ability to chelate metals did not translate into inhibition of the Fenton reaction. Only 2,4-dihydroxyacetophenone and resorcinol, compounds with hydroxyl groups in a meta-position that lack chelating capability, were effective in suppressing hydroxyl radical formation triggered by the Fe²⁺-driven Fenton reaction. Interestingly, pyrogallol, despite its strong pro-oxidant properties, was the only compound that protected human erythrocytes from Cu-induced lysis. In conclusion, solely pyrogallol seems to have a protective effect against copper-induced toxicity under biologically relevant conditions.

Our study focused on the spatiotemporal analysis of reactive oxygen species (ROS), a key factor in hepatic ischemia-reperfusion injury, using a rat model to evaluate potential clinical applications. By inducing partial hepatic ischemia-reperfusion in rats through ligation of left portal vein and hepatic artery (one hour ischemia followed by reperfusion), we explored ROS generation using an imaging probe, 1-acetoxy-3-carbamoyl-2,2,5,5-tetramethylpyrroline (ACP), which reacts with ROS to produce a detectable T1-enhanced magnet resonance imaging (MRI) signal. In the rat model, the region of the left liver ischemia-reperfusion showed extremely mild liver injury one hour after reperfusion. After 12 h of reperfusion, extensive hepatocellular necrosis was observed, mainly in the hepatic interlobular region. One hour after reperfusion, the ACP-derived MRI signal increased in the region of left lobe ischemia-reperfusion was significantly higher than that in the non-ischemia-reperfusion region of the same rat right lobe. Administration of edaravone targeting the period of excessive ROS production at 1 h after reperfusion significantly suppressed hepatic injury 12 h after ischemia-reperfusion. Given MRI's crucial role in clinical diagnostics and its adaptability, our research suggests a promising strategy for early intervention in organ damage by monitoring and modulating ROS levels, potentially revolutionizing patient care.

Mitochondrial function and redox regulatory processes are crucial aspects of cellular metabolism and energy production. Cancers, including gliomas, largely exhibit altered mitochondrial function, which can lead to changes in cellular signaling pathways and redox homeostasis. Aberrant redox signaling can promote glioma progression by influencing cell proliferation, metastasis, and therapeutic response. Several cancer-associated driver mutations - genetic alterations that confer survival and growth advantage to cancer cells, are associated with gliomas and affect mitochondrial function and redox states. Here is an overview of the crucial intersection between mitochondrial function and driver genes in glioma, highlighting some of the recent advances that augment our understanding of this intersection.

Stomach adenocarcinoma (STAD) is a highly prevalent and lethal malignancy worldwide, with its occurrence and progression regulated by multiple factors. In recent years, selenoprotein glutathione peroxidase 3 (GPX3) has gained significant attention due to its antioxidant properties and role in cellular oxidative stress regulation across various cancers. Our study delved into the expression of GPX3 in STAD and investigated its impact on tumor cell growth, providing insights into its potential anti-tumor mechanisms. The expression levels of GPX3 were analyzed in STAD tissues sourced from the TCGA database and contrasted with the levels found in normal gastric tissues. The expression levels of GPX3 were contrasted between STAD tissues and normal gastric tissues, and their correlation with patient prognosis was assessed by survival analysis. Additionally, we validated GPX3 expression changes and its effects on tumor cell growth using quantitative PCR (qPCR) and CCK-8 proliferation assays in STAD cell lines (MNK-45, MGC-803, N87, and HGC-27). Our findings suggest that GPX3 expression is significantly downregulated in STAD tissues compared to normal gastric tissues. Survival analysis further reveals that patients with high GPX3 expression exhibit better long-term survival rates, suggesting a potential tumor-suppressive function. In vitro experiments confirmed effective knockdown or overexpression of GPX3 in STAD cell lines. CCK-8 proliferation assays demonstrated that GPX3 overexpression significantly inhibited tumor cell proliferation, whereas GPX3 knockdown promoted cell growth. This study provides new experimental evidence supporting GPX3 as a potential therapeutic target for STAD and offers a theoretical foundation for future molecular-targeted therapies for STAD.

Amino acid metabolism plays a crucial role in tumor biology. The sodium-independent cystine/glutamate exchange system, known as system X_c^-, is significantly activated in cancer cells and plays a role in tumor progression. Copper (Cu), an essential micronutrient, plays a crucial role in physiological processes; however, its accumulation in tumors has been associated with tumor progression. Nonetheless, the relationship between system X_c^--mediated amino acid metabolism and Cu remains inadequately understood. In this study, CuCl₂ treatment resulted in the significant induction of SLC7A11, a light chain subunit of system X_c^-, and glutamate receptor mGluR1 expression in human triple-negative MDA-MB-231 cells. Conversely, FeCl₂ treatment induced the expression of SLC7A11 but not mGluR1, indicating that Cu specifically activated SLC7A11-mediated amino acid metabolism. The investigation focused on the role of Nrf2, a redox-sensitive transcription factor, in the induction of SLC7A11 under conditions of oxidative stress induced by CuCl₂ treatment. Upon treatment with CuCl₂, the nuclear translocation of Nrf2 was observed, and knockdown of Nrf2 significantly suppressed the induction of SLC7A11. Given that the Cu chaperone, antioxidant-1 (Atox1), functions as a Cu-dependent transcription factor, the role of Atox1 in the expression of SLC7A11 was further investigated. Like the effects of Nrf2 knockdown, Atox1 was found to play a pivotal role in the Cu-mediated induction of SLC7A11. Our findings indicate that intratumoral Cu influences the expression of SLC7A11 and may play a role in tumor progression.

Dihydroethidium (DHE) is widely used for superoxide detection, yet reported excitation and emission values vary across studies. To address this, we employed full-spectrum scanning to compare DHE fluorescence between a xanthine oxidase (XO)-based cell-free system and a rotenone-treated cellular model, and to assess factors contributing to spectral shifts. In the XO system, the excitation peak was ∼480 nm, whereas in cells it shifted to ∼520 nm. Riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) accounted for this shift, while calcium and bicarbonate ions modulated both peak position and fluorescence intensity. Riboflavin depletion reduced intracellular flavin levels but did not restore the peak to 480 nm, indicating additional roles for FMN and FAD. Among scavengers, only tiron directly inhibited DHE fluorescence in the cell-free system, with enhanced activity in the presence of Ca²⁺ and Mg²⁺. In contrast, responses in cells varied by type and rotenone concentration, suggesting indirect modulation through endogenous antioxidant defenses. Addition of FMN, FAD, or cell lysates to the cell-free system attenuated scavenger efficacy, supporting intracellular interference. These findings demonstrate that riboflavin metabolism and ionic microenvironments critically shape DHE spectral behavior. Accurate interpretation of DHE-based superoxide detection therefore requires prior spectral evaluation to distinguish genuine superoxide signals from cofactor- or ion-dependent effects.

Betulinic acid (BA) is a pentacyclic triterpenoid with broad pharmacological potential and widely recognized for its neuroprotective effects. This study investigated the potential protective effects of this compound on in vitro differentiated human neuroblastoma SH-SY5Y cells against LPS and FeSO₄-induced ferroptosis, apoptosis, neuroinflammation, and dopaminergic cell death, and explored the underlying mechanisms. Differentiated human neuroblastoma SH-SY5Y cells were exposed to LPS and FeSO₄, and the cellular viability was evaluated using the MTT assay. Flow cytometry was performed to assess apoptotic cell death. Additionally, the expression levels of key markers associated with ferroptosis, apoptosis, and other relevant signaling proteins were analyzed through western blotting and Immunocytochemical staining techniques. However, co-exposure with LPS and FeSO₄ resulted in a dose-dependent reduction in cell viability, which was significantly reversed by pretreatment with BA (0.3-30μM). Exposure to LPS and FeSO₄ increased the DMT1, Bax, caspase-3, and alpha-synuclein, and decreased the GPX4, FTH1, SLC7A11, Nrf2, Keap1, HO-1, PARK7, Bcl-2, NeuN, and TH levels, resulting in cell ferroptosis, apoptosis, and dopaminergic cell death. Furthermore, LPS and FeSO₄ significantly increased the expression of IL-6, TNF-α, and phosphorylation of p38, pMAPK, and pNFkB in the cells. Pretreatment with BA markedly suppressed LPS and FeSO₄-induced upregulation of pro-inflammatory cytokines, ferroptosis, apoptosis, and dopaminergic cell death markers. These findings suggest that BA exerts neuroprotection by modulating the GPX4/Nrf2/Keap-1/HO-1 antioxidant defense and p38MAPK/NF-κB inflammatory signaling pathways, highlighting its potential as a therapeutic agent for oxidative stress-related neurodegenerative conditions, such as Parkinson's disease (PD).

Hypoxia-inducible factor (HIF) signaling plays a critical role in immune cell function. Pseudohypoxia is characterized as iron-mediated stabilization of HIF-1α under normoxic conditions, which can be induced by iron chelators. This study explored whether iron chelators exert antitumor effects by enhancing tumor immune responses and elucidating the underlying mechanisms. The iron chelators Super-polyphenol 10 (SP10) and Deferoxamine (DFO) were used to create iron-deficient and pseudohypoxia conditions. Pseudohypoxia induced by iron chelators stimulates IL-2 secretion from T cells and from both human and murine nonsmall cell lung cancer (NSCLC) cell lines (A549, PC-3, and LLC). Administration of SP10 reduced tumor growth when LLC tumors were implanted in C57BL/6 mice; however, this was not observed in immunodeficient RAG1-deficient C57BL/6 mice. SP10 itself did not directly inhibit LLC cells proliferation in vitro, suggesting an activation of the tumor immune response. SP10 synergistically enhanced the efficacy of PD-1 antibody therapy in lung cancer by increasing the number of tumor-infiltrating lymphocytes (TILs). In conclusion, iron chelation-induced pseudohypoxia activates tumor immune responses by directly upregulating HIF-1α, augmenting T cell function, and inducing IL-2 secretion from T cells, and cancer cells, thereby amplifying the immune efficacy of the PD-1 antibody in lung cancer treatment.

MicroRNAs (miRNAs) (miRs) are a small class of endogenous non-coding RNA molecules that play a key role in various physiological and pathological processes. Likewise, oxidative stress can cause damage to many parts of the body and can contribute to disease development. Hence, this review aims to address the crosstalk between reactive oxygen species (ROS) and miRNAs in respiratory diseases. This review begins with an overview of the sources and regulation of free radicals, oxidative stress-mediated lung pathologies, and miRNAs biogenesis. Indeed, growing evidence suggests that miRNAs can modify cellular redox status in both nonmalignant and malignant respiratory diseases. We also discussed ROS-responsive miRNAs that have implications in disease development. Mechanistic pathways by which the complex interplay between miRNAs and ROS occurs have been discussed. Thus, targeting miRNAs may provide potential new strategies to specifically overcome oxidative stress-mediated development of many lung diseases.