Free Radical Research最新文献

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.

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.

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.

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.

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.

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.

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.

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.

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.