Free Radical Research最新文献

Avenanthramides (AVAs), unique polyphenols in oats, have received much attention due to their biologically beneficial properties. Herein, density functional theory (DFT) calculations and molecular docking were performed to elucidate the structure-antioxidant capacity relationship and underlying mechanism of A-type AVAs under physiological conditions. Further, the interaction effects between AVAs and Kelch-like ECH-associated protein 1 (Keap1) for activating the Nrf2-ARE (nuclear factor-E2-related factor 2-antioxidant response element) signaling pathway were explored. The results showed that the representative A-type AVA 2 c_d displayed excellent HOO^• scavenging capacity in water at physiological pH with an overall rate constant (k_overall = 2.97 × 10⁷ M^-1 s^-1) higher than that of reference antioxidants Trolox and BHT, while moderate capacity in lipid-like media. Formal hydrogen atom transfer (fHAT) mechanism is more favored in lipid media, whereas in aqueous solution at physiological pH, the hydrogen transfer from dianion species plays a dominant role (99.4%) in the overall reactivity. The results also highlighted the effects of central double bond, hydroxyl, carboxyl and solvents in antiradical processes. Molecular docking and DFT calculations showed that 2c and 2 c_d can bind strongly to Keap1 through hydrogen bonding and cysteine residues based covalent binding, which disrupts the Keap1-Nrf2 interaction. Collectively, 2c and 2 c_d are promising candidates as multifunctional antioxidant with radical trapping and Nrf2 activation effects.

Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer. Ferroptosis is a novel therapeutic target against treatment resistance in NSCLC. However, its regulation by m6A RNA modification remains incompletely elucidated. m6A RNA modification mediates mRNA stability, translation, and splicing to target transcripts. Methyltransferase like 7B (METTL7B) has been implicated in tumor progression, but its role in NSCLC ferroptosis via m6A modification have not been reported. We aimed to investigate the mechanism of METTL7B-medaited m6A modification in NSCLC cell ferroptosis. NSCLC cells (SK-MES-1/PC9/H1975/A549) and normal cells (BEAS-2B) were cultured. The expression of METTL7B, long non-coding RNA 02159 (LINC02159), and aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) was determined. After METTL7B knockdown, cell viability was measured by MTT assay; ferroptosis-related factors were analyzed. m6A quantification was performed. m6A enrichment on LINC02159 was analyzed. The interaction between LINC02159 and KAT2A was verified. KAT2A and H3K27ac enrichment on the ARNTL2 promoter was detected. The roles of LINC02159 and ARNTL2 were validated. METTL7B, LINC02159, and ARNTL2 were upregulated in NSCLC cells compared to BEAS-2B cells. METTL7B knockdown increased iron ions, reactive oxygen species, and malondialdehyde levels and decreased cell viability, superoxide dismutase, and glutathione levels. METTL7B potentially upregulate LINC02159 expression through m6A modification. LINC02159 may recruit KAT2A to enhance H3K27ac enrichment on the ARNTL2 promoter, thereby promoting ARNTL2 expression. Overexpression of LINC02159 or ARNTL2 partially reversed the pro-ferroptotic effects of METTL7B knockdown on NSCLC cells. In conclusion, METTL7B inhibits ferroptosis in NSCLC cells via the LINC02159/KAT2A/ARNTL2 axis in an m6A-dependent manner.

Oxidative stress within the follicular microenvironment plays a critical role in oocyte quality and reproductive outcomes. This prospective study examines the association between follicular fluid redox status, maternal age, ovarian reserve, and clinical outcomes in women undergoing in vitro fertilization. Follicular fluid samples were obtained from women undergoing fresh embryo transfer cycles and analyzed for oxidative damage markers (malondialdehyde, nitric oxide, ischemia-modified albumin, sialic acid) and antioxidant parameters (superoxide dismutase, catalase, glutathione, and thiol-disulfide homeostasis). Participants were stratified according to maternal age (≤35 vs. >35 years), serum estradiol levels on the day of human chorionic gonadotropin trigger (≤90th vs. >90th percentile), and clinical pregnancy outcome. Anti-Müllerian hormone and follicle-stimulating hormone levels were recorded as indicators of ovarian reserve. Women aged >35 years exhibited significantly higher malondialdehyde and sialic acid levels, accompanied by reduced antioxidant enzyme activities. Cycles resulting in clinical pregnancy showed lower oxidative stress and higher antioxidant capacity compared with non-pregnant cycles. Malondialdehyde levels correlated positively with age and follicle-stimulating hormone, while antioxidant parameters correlated positively with anti-Müllerian hormone and pregnancy outcome. Receiver operating characteristic analysis demonstrated moderate discriminative ability of malondialdehyde, superoxide dismutase, catalase, and glutathione for clinical pregnancy. These findings indicate that age-related redox imbalance in follicular fluid is associated with diminished ovarian reserve and reduced in vitro fertilization success. Assessment of follicular fluid oxidative stress parameters may provide clinically relevant insights into female reproductive potential.

Ulcerative colitis (UC), a major form of inflammatory bowel disease (IBD), is characterized by chronic inflammation and ulceration of the colonic mucosa. Its etiology is multifactorial, involving genetic, environmental, and immune factors. Recent evidence highlights the crucial role of ferroptosis, an iron-dependent regulated cell death pathway, in UC pathogenesis. Ferroptosis is marked by excessive accumulation of lipid peroxides, reactive oxygen species, and iron overload, all contributing to epithelial injury. The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model closely mimics human UC and demonstrates elevated free iron, increased malondialdehyde levels, and decreased glutathione peroxidase 4 expression hallmarks of ferroptotic damage. These molecular disturbances lead to oxidative stress, epithelial barrier dysfunction, and sustained inflammation. Importantly, ferroptosis inhibition shows therapeutic potential. Small-molecule inhibitors such as Ferrostatin-1 and Liproxstatin-1 effectively reduce mucosal damage and restore antioxidant balance, while iron chelators like deferoxamine alleviate iron overload and ROS generation. Moreover, natural compounds including curcumin, resveratrol, epigallocatechin-3-gallate, baicalein, and quercetin demonstrate anti-ferroptotic activity by modulating the nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 pathway, enhancing glutathione peroxidase 4 function, and maintaining iron homeostasis. Collectively, these findings establish ferroptosis as a pivotal mechanism in TNBS-induced UC, linking oxidative stress and iron dysregulation to mucosal injury. Targeting ferroptosis offers a promising therapeutic avenue for UC management, though further clinical and translational studies are needed to validate its efficacy and safety.

Cigarette smoke (CS) is a complex mixture of numerous chemicals, including p-benzosemiquinone (pBSQ), which oxidizes to p-benzoquinone (pBQ) in the lungs of smokers and enters circulation. Despite its high reactivity, the direct impact of pBQ on human red blood cells (RBC) remains underexplored. Herein, we investigated the molecular insights into how pBQ compromises human RBC physiology and its role in mediating CS-associated pathologies by integrating redox biochemistry, membrane integrity, and omics-based approaches. Our findings reveal that pBQ disrupted redox homeostasis, evidenced by glutathione depletion, elevated reactive oxygen species, lipid peroxidation, and reduced antioxidant enzyme activity. pBQ also triggered methemoglobin formation, hemoglobin aggregation, and reduced oxygen-binding capacity. Biophysical analysis of RBCs revealed reduced membrane fluidity, alterations in membrane proteins and lipids, disrupted zeta potential, and sedimentation dynamics, suggesting altered deformability, an indication of impaired microvascular transit. Untargeted metabolomics and lipidomics profiling revealed metabolic reprogramming and remodelling of the membrane lipids. Depletion of polyunsaturated fatty acids alongside accumulation of saturated species in the membrane points towards membrane stiffening. Pathway analysis highlighted perturbations in fatty acid biosynthesis and redox homeostasis. Disease enrichment analysis linked these changes to hypertension and other pathologies that are previously linked to redox imbalance and CS exposure. Notably, NAC co-treatment mitigated these effects, preserving RBC integrity and redox homeostasis. These findings underscore that pBQ is a critical mediator of CS-induced RBC dysfunction and establish a mechanistic link to its contribution to smoking-associated complications.

Spermidine (SPD) is a naturally-occurring polyamine with a range of unique properties including anti-inflammatory, antioxidant, and cardioprotective effects. Ferroptosis, a form of cell death that is regulated by reactive oxygen species (ROS), plays a pivotal role in sepsis-induced cardiomyopathy. However, the interplay among spermidine levels, septic myocardial injury, and ferroptosis is unclear. This study aimed to investigate the effect of spermidine on ferroptosis and the underlying mechanisms of lipopolysaccharide (LPS)-induced acute myocardial damage during sepsis. A septic myocardial injury model was established using LPS treatment of H9c2 cells and C57BL/6 mice. Spermidine mitigated LPS-induced myocardial injury, decreased inflammatory responses and oxidative stress, and inhibited cardiomyocyte ferroptosis in both cellular and animal models. Spermidine reduced intracellular iron and malondialdehyde levels, while elevating glutathione levels and the expression of cardiac ferroptosis-related proteins. SPD was found to suppress lipid peroxidation and ferroptosis by activating the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Silencing Nrf2 ceased the inhibitory effect of SPD on ferroptosis in H9c2 cells. Spermidine exerted a protective effect against LPS-induced acute myocardial injury and may ameliorate LPS-induced septic myocardial ferroptosis via the Nrf2 pathway.

Non-thermal plasma (NTP) has been reported to exhibit various biological effects, including hemostatic, anticancer, and wound-healing properties. However, the effects of NTP on allergic responses in mast cells and basophils have not been sufficiently investigated. In this study, we examined the effects of NTP on immunoglobulin E (IgE)-mediated degranulation and cytokine expression in the basophilic cell line RBL-2H3. To induce degranulation and cytokine expression as part of allergic reactions, we treated the cells with 2,4-dinitrophenylated bovine serum albumin (BSA) after sensitization or with the Ca²⁺ ionophore A23187. Cells were also treated with NTP-activated acetated Ringer's solution (PAA). Degranulation was measured by quantifying the β-hexosaminidase (β-hex) activity. PAA treatment inhibited both antigen stimulation- and A23187-induced degranulation in RBL-2H3 cells, and suppressed antigen-induced mRNA expression of cytokines, including IL-4, IL-6, and TNF-α. Antigen stimulation caused disintegration of the F-actin cytoskeleton, and PAA treatment suppressed these morphological changes. Cotreatment with PAA and catalase blocked the inhibitory effects of PAA on antigen stimulation-induced degranulation. PAA also inhibited A23187-induced extracellular signal-regulated kinase (ERK) phosphorylation and antigen stimulation- or store-operated Ca²⁺ entry inducer thapsigargin-induced cellular Ca²⁺ influx. These results indicate that PAA effectively inhibits immunological responses in allergic cells - such as degranulation and cytokine expression - by suppressing ERK phosphorylation and Ca²⁺ influx. These findings suggest that PAA may be an effective therapeutic option for treating patients with allergic diseases.

Hydrogen peroxide and peroxynitrite play important roles as signaling molecules to maintain the biological functions; however, excess levels of these oxidants are associated with various diseases. Despite their important roles in vivo, effective methods to measure these oxidants in the body with high sensitivity have not yet been established. Therefore, in this study, we aimed to design a radioiodinated boronic acid probe for the in vivo detection of hydrogen peroxide and peroxynitrite. The probe contained boronic acid, a well-known substructure that reacts with hydrogen peroxide and peroxynitrite, at positions 3 and 6 of the xanthene moiety and radioiodine at the phthalide moiety of fluorescein. I-125 labeling was successful, resulting in a radiochemical yield of 60% and radiochemical purity of >95%. In vitro selectivity studies demonstrated that the probe showed significant responses to both hydrogen peroxide and peroxynitrite while exhibiting minimal reactivity toward other reactive oxygen species including superoxide, nitric oxide, and peroxy radicals. In biodistribution studies using lipopolysaccharide (LPS)-treated mice generating reactive oxidants, the boronic acid probe was significantly accumulated in various organs damaged by LPS. However, this phenomenon was inhibited by administration of the antioxidant, N-acetylcysteine, to LPS-treated mice. These results highlight the potential of the developed radioiodinated boronic acid probe to detect hydrogen peroxide and peroxynitrite in living organisms, suggesting it as a candidate for the in vivo detection and functional evaluation of these oxidants in various diseases.

With lung cancer rates climbing steadily, the development of effective prevention strategies has become more crucial than ever. Our previous research has revealed that ginger oil possesses potential lung cancer preventive activity, demonstrating inhibitory effects against tobacco carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer in A/J mice. 6-Gingerol, a bioactive compound from ginger (Zingiber officinale Rosc.), exhibits multiple pharmacological activities. However, the preventive efficacy of 6-Gingerol against tobacco carcinogen-induced lung cancer remains unclear. This study investigated the chemopreventive effects of 6-Gingerol on NNK-induced lung tumorigenesis in A/J mice and Beas-2b cells. Results indicated that 6-Gingerol significantly reduced lung tumor count and improved tissue structure compared to NNK alone. In vitro, 6-Gingerol protected Beas-2b cells from NNK-induced damage. Mechanistically, 6-Gingerol activated the Nrf2 pathway, enhancing antioxidant enzyme expression and reducing oxidative stress. Additionally, 6-Gingerol exhibited anti-inflammatory effects by inhibiting the NNK-activated TLR4/NF-κB pathway. In conclusion, 6-Gingerol shows significant chemopreventive effects against NNK-induced lung cancer via activating Nrf2 and suppressing TLR4/NF-κB, underscoring its potential as a preventive agent functional food in lung cancer development.

This study provides a comprehensive assessment of the antioxidant potential of Asphodelus tenuifolius Cav. From El-Oued region of southeastern Algeria, through a combined spectrophotometric, electrochemical, and chromatographic approach. A hydroethanolic crude extract was fractionated using solvents of increasing polarity (chloroform, ethyl acetate, and n-butanol). HPLC profiling identified and quantified nine major phenolic compounds, with quercetin dominating the chloroform fraction at exceptionally high levels alongside significant amounts of chlorogenic acid and naringin. Antioxidant capacity was evaluated using complementary assays. The chloroform fraction exhibited the highest total phenolic content and flavonoid content, correlating with its potent radical scavenging activity in the DPPH assay. In contrast, electrochemical analysis revealed that the ethyl acetate fraction was most effective against the superoxide anion (O₂•^-), with the lowest IC₅₀ value. Thermodynamic parameters further confirmed spontaneous and energetically favorable interactions between extract constituents and O₂•^- radicals, underscoring the mechanistic plausibility of the observed effects. To the best of our knowledge, this work delivers the first integrated electrochemical and chromatographic evidence of the antioxidant potential of A. tenuifolius extracts. By establishing clear correlations between phytochemical composition and functional outcomes, the study positions this species as a promising source of high-value bioactive compounds for several applications.