Free Radical Research最新文献

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.

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 remodeling of the membrane lipids. Depletion of polyunsaturated fatty acids alongside accumulation of saturated species in the membrane points toward 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.

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.

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.

Breast cancer (BC) is among the most prevalent malignant tumors affecting women, with a persistently high mortality rate. Reactive oxygen species (ROS) significantly contribute to BC progression by damaging cellular components and activating oncogenic signaling pathways. Peroxiredoxins (Prdxs), a crucial class of antioxidant enzymes, regulate cellular redox homeostasis and play dual roles in cancer development and progression. Substantial progress has been achieved in studying Prdxs in cancers such as cervical cancer, squamous cell carcinoma, and lung cancer; however, a comprehensive understanding of roles for Prdxs in BC remains lacking. This paper reviews the differential expression and functional characteristics of Prdxs across various molecular subtypes of BC, with a particular focus on triple-negative BC. Moreover, aberrant Prdxs expression is strongly associated with poor prognosis, chemoresistance, and increased invasiveness in BC patients. Given the pivotal roles of Prdxs in BC, investigating therapeutic strategies targeting Prdxs and related ROS levels is imperative. Additionally, combining such approaches with immunotherapy highlights the potential implication of Prdxs in precision cancer therapy.

Nano-theranostics using biodegradable polymers are effective for the diagnosis and treatment of intractable cancers; however, there is a need for technology that controls bioavailability and biodegradability without compromising biocompatibility. In this study, peptide nanoparticles (NPs) with controlled particle size and biodegradability were prepared by ionizing radiation and loaded with imaging agents and anticancer drugs to develop novel nano-theranostics for pancreatic cancer diagnosis and treatment. Peptides composed of histidine, glycine, glutamic acid, and an arginine-glycine-aspartic acid motif were synthesized by the solid-phase synthesis method. Their aqueous solutions were irradiated with γ-rays to produce NPs with a particle size of less than 50 nm, enabling penetration of the pancreatic cancer stroma. The radiation crosslinking of peptides, with or without the arginine-glycine-aspartic acid motif, in water was investigated by pulse radiolysis. Peptide NPs loaded with fluorescent labeling or magnetic resonance imaging (MRI) agents were efficiently taken up by pancreatic cancer cells. Cisplatin-loaded peptide NPs produced by higher-dose irradiation suppress drug-release rates owing to their lower biodegradability. In conclusion, peptide NPs with controllable particle size and biodegradability were produced by ionizing radiation and loaded with fluorescent labeling agents, MRI agents, and anticancer drugs to develop a new nano-theranostics drug for pancreatic cancer diagnosis and treatment.

Introduction: Oxidative stress is implicated in various diseases, and the NADPH oxidase enzyme complex (NOX) is a significant source of reactive oxygen species (ROS). Research linking genetic polymorphisms to enzyme activity has produced conflicting results. Methods: We aimed to establish a robust protocol to assess NOX activity in vitro under highly standardized conditions and correlate these measurements with genetic polymorphisms catalogued by the 1000 Human Genome Project and the HapMap Project. Lymphoblastoid cell lines (LCLs) served as a model system with samples from healthy participants from three Caucasian populations. NOX activity stimulated by phorbol 12-myristate 13-acetate was measured using chemiluminescence in 290 LCLs (198 in a training and 92 in a test set) through a series of multiply repeated measurements per LCL comprising in total over 1,500 NOX activity assessments. The association between NOX activity and single nucleotide polymorphisms (SNPs) in the NOX subunit genes CYBA, CYBB, NCF1, NCF2, and NCF4 was subsequently examined. Results: Out of 651 valid polymorphic markers, 308 had a minor allele frequency of ≥ 5%, and 15 SNPs showed a statistically significant correlation with NOX activity in the training set. However, these 15 associations were not confirmed in the test set (all p ≥ 0.1). Additional analyses treating all 290 LCLs as a single cohort yielded three associations at p < 0.01, i.e. CYBA rs1017828, NCF1 rs191081238, and NCF4 rs4821544. However, statistical significance could not be called for any of these genetic markers upon adjustment for multiple testing, regardless whether a co-dominant, dominant or recessive allelic effect was assumed. Conclusion: Our results do not support a reproducible impact of common genetic diversity in NOX subunits on the enzyme activity in LCLs of subjects of Caucasian origin. This study represents the largest evaluation concerning relationships between NOX genetic variants and enzyme activity to date.

Despite the potential of drug-radiotherapy combinations, a limited number of oncology drugs are approved by FDA for use along with radiotherapy. Currently, there is no agent available in the clinic that can exhibit dual radiomodifying behavior. Despite availability of sophisticated, high-precision techniques in radiotherapy for accurate targeting of tumors, normal tissue toxicity impedes its use in curative settings. Combining radiotherapy with an agent that can protect normal tissue and augment tumor killing can improve therapy outcomes. Other than combining drugs for therapeutic radiation exposure, there is a pressing need of identifying agents for management of unwanted effects of accidental radiation exposure. There is a serious deficit in the repertoire of currently available safe and effective radiation countermeasures. Baicalein, a bioactive component from the roots of traditional Chinese medicinal herb Scutellaria baicalensis has been shown to protect against acute as well as chronic effects of radiation exposure including normal tissue injury to lungs, gut, hematopoietic system, intestine, endothelial and neuronal cells by us and other labs worldwide. Further, administration of baicalein alone or in combination with other agents prevents radiation-induced mortality in mice. Additionally, numerous studies have reported radiosensitizing potential of baicalein in lung, breast, esophageal, cervical and prostate cancer. Moreover, safety, tolerability, and pharmacokinetics of baicalein is well established in healthy human subjects. Here we provide a succinct overview of the distinctive radiomodifying potential of baicalein, safety, pharmacology underscoring its utility as a prospective radiomodifier in clinical settings.

DNA damage arises not only from the direct action of ionizing radiation but also from indirect action mediated by highly reactive hydroxyl radicals (^•OH). This study aimed to determine whether the protective or sensitizing effects of amino acids against X-ray-induced DNA damage are associated with the side-chain characteristics of these amino acids. Seven amino acids with distinct side-chain properties were investigated. The rate constants for their reactions with ^•OH were determined by electron pulse radiolysis. Highly purified, scavenger-free plasmid DNA (pUC18) was irradiated with X-rays in the presence of each amino acid, whose concentrations were adjusted to scavenge ∼14% of ^•OH. DNA strand breaks (SSBs and DSBs) were quantified by agarose gel electrophoresis. At the same time, oxidative base lesions and apurinic/apyrimidinic (AP) sites were detected as enzyme-sensitive sites (ESSs) using formamidopyrimidine-DNA glycosylase (Fpg), endonuclease III (Nth), and endonuclease IV (Nfo). Despite equivalent ^•OH scavenging capacities, the extent and spectrum of DNA damage varied markedly among the amino acids. Aspartic acid (Asp) and phenylalanine (Phe) exhibited the strongest overall protection, while glycine (Gly) showed the weakest protection, even with partial sensitization. Amino acids with highly hydrophilic or hydrophobic side chains tended to exhibit more substantial protective effects, although a clear correlation was not always observed for molecular weight or isoelectric point. Side-chain properties and potential chemical repair mechanisms are likely to contribute to the modulation of DNA damage. This work provides new mechanistic insights into amino acid-mediated DNA radioprotection, suggesting promising directions for molecular-level studies of amino-acid-DNA interactions.

Parkinson's disease (PD) is one of the most widespread neurodegenerative diseases that affect the central nervous system (CNS) in elderly individuals. As of right now, there is no recognized cure for this illness. Bioactive phytochemicals are a natural alternative that can help older persons postpone age-related cognitive diseases. This study attempts to establish whether nicotine, may diminish Parkinsonism in a model of Caenorhabditis elegans disease. This study analyzes the antioxidant and restorative mitochondrial dysfunction potential of nicotine and its related neuroprotective benefits by utilizing models of Caenorhabditis worm strains that are different from the wild type. We examined the effects of nicotine on oxidative stress tolerance and associated regulatory pathways using a model of Caenorhabditis worms. Our results showed that wild-type C. elegans treated with nicotine had higher survival rates during oxidative stress caused by Juglone than those treated with the control. Nicotine decreased intracellular reactive oxygen species levels in C. elegans. In addition, nicotine increased levels of SOD, CAT, and MDA as well as the expression of genes related to stress response, including gst-4, hsf-6, and hsf-1, and mitochondrial function genes, including mev-1, isp-1, and cox-4. Finally, our molecular analysis indicates that the anti-oxidative effects of nicotine are mediated via skin-1 modulation. After Paraquat was administered, nicotine therapy also resulted in higher levels of ATP and MMP. Our research clarifies the various mechanisms of action and communication pathways that underlie nicotine's antioxidant activity in vivo, offering a solid pharmacological foundation for its potential therapeutic use in neurodegeneration.