Search Results (149)

Asthma is a heterogeneous chronic airway disease in which oxidative stress (OS) plays a central mechanistic role beyond classical immune-mediated inflammation. Reactive oxygen and nitrogen species (ROS/RNS), generated by recruited inflammatory cells and activated airway structural cells, drive epithelial injury, mucus hypersecretion, airway remodeling, and modulate key transcription factors including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. This review synthesizes current evidence on the multilevel redox-based determinants of asthma severity, spanning from genetic polymorphisms to circulating biomarkers. We examine serum antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxiredoxins (PRDXs), and the thioredoxin (Trx) system as dynamic indicators of systemic redox status and disease severity, alongside oxidative enzymes including NADPH oxidases and dual oxidases (NOX/DUOX), xanthine oxidase (XO), and myeloperoxidase (MPO) that serve as upstream sources of airway oxidant burden. Functional genetic polymorphisms in antioxidant genes (SOD2, CAT, glutathione S-transferase mu 1/glutathione S-transferase theta 1 (GSTM1/GSTT1), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/KEAP1)) and oxidative enzyme genes including nitric oxide synthase 1/2/3 (NOS1/2/3), MPO, cytochrome b-245 alpha chain (CYBA), and xanthine dehydrogenase (XDH) are reviewed as modulators of individual redox capacity and asthma susceptibility, with particular attention to gene–environment interactions. We further discuss oxidative damage biomarkers, including malondialdehyde (MDA), 8-isoprostanes, 4-hydroxynonenal, 8-oxo-7, 8-dihydro-2′-deoxyguanosine, protein carbonyls, 3-nitrotyrosine, and advanced oxidation protein products as indicators of lipid, DNA, and protein oxidation that correlate with disease activity and control. The roles of micronutrient cofactors in modulating antioxidant enzyme function and their potential as contextual biomarkers are also addressed. Additionally, emerging evidence on microRNAs (miRNAs) linked to OS biology in asthma is presented. Finally, we critically evaluate the challenges limiting clinical translation, including biomarker non-specificity, analytical variability, gene–environment complexity, and the absence of standardized reference ranges. This integrated framework supports the development of multilevel redox prognostic panels combining genetic, enzymatic, and oxidative damage readouts for improved asthma phenotyping, severity stratification, and personalized therapeutic approaches. Full article

Microplastic exposure is an emerging environmental risk factor for cardiovascular health; however, whether cardiovascular alterations can be detected after exposure cessation remains unclear. This study investigated subclinical cardiovascular alterations following repeated oral exposure to polystyrene microplastics (PSMPs), with particular emphasis on redox imbalance and mitochondrial function in delayed cardiovascular alterations. Male Sprague-Dawley rats were administered 0.5 μm PSMPs via oral gavage at varying dosages of 5 or 20 mg/kg every 5 days for 70 days, followed by a 35-day exposure-free period. Repeated exposure to PSMPs did not affect body or organ weights but altered cardiac serum biochemical markers. Cardiac tissue exhibited elevated NADPH oxidase 4 (NOX4) expression and decreased superoxide dismutase 1 (SOD1), SOD2, and catalase (CAT) activities, whereas malondialdehyde (MDA) levels remained unchanged, indicating a state of chronic, low-level oxidative stress. Mitochondrial respiratory chain activities, including nicotinamide adenine dinucleotide cytochrome c reductase (NCCR) and succinate cytochrome c reductase (SCCR), were significantly reduced. Ultrastructural analysis revealed mitochondrial swelling and cristae disruption. In parallel, mitochondrial biogenesis-related proteins, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM), were downregulated, while mitophagy markers, including PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (Parkin), microtubule-associated protein 1 light chain 3 (LC3), and sequestosome 1 (p62), were upregulated. Notably, most significant alterations were primarily observed in the high-dose group. Furthermore, the aorta showed increased oxidative stress markers without overt structural remodeling. These findings suggest that repeated exposure to PSMP is associated with subclinical cardiac redox–mitochondrial dysregulation, potentially involving redox imbalance, impaired mitochondrial respiratory chain activity, reduced mitochondrial biogenesis, and altered mitochondrial quality-control markers. Full article

Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated “redox-dead” DRP1-C631A knock-in mutant (Drp1^C/A) BM exhibited markedly reduced limb perfusion recovery and CD31⁺ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G⁺ neutrophil accumulation, pro-inflammatory F4/80⁺CD80⁺ M1-like macrophages and reduced anti-inflammatory F4/80⁺CD206⁺ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1^C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD. Full article

The exact mechanisms of skin involvement in type 1 diabetes (DM1) remain poorly understood. This study aimed to evaluate the relationship between antioxidants, oxidative stress, protein glycation, and glycoxidation, as well as matrix metalloproteinase (MMP) activity, in the skin of rats with DM1, while investigating whether insulin administration improves skin homeostasis. Male Wistar rats were assigned to three groups: control, diabetes, and diabetes treated with insulin. Significantly higher expression of GSH (gluthatione) and GSH-Px (glutathione peroxidase), elevated levels of AGE (Advanced Glycation End products), DT (dityrosine), KN (kynurenine), NFKN (N-formylkynurenine) and ONOO- (peroxynitrite), as well as increased activity of GLU (β-D-glucuronidase), NADPH oxidase (NOX) and MMP-1, -2, -3, -7, -9, -11 and -13 were observed in the skin of rats with DM1. Insulin treatment normalizes the skin’s antioxidant barrier and eliminates oxidative stress. It also reduces the intensity of protein glycation and glycoxidation, though not to the levels observed in the control group. Summarizing, in diabetic skin there is a complex interaction between the thiol antioxidant barrier, oxidative damage, protein glycation and glycoxidation as well as MMP expression. Insulin restores physiological balance in skin cells; however, glycation and ECM remodeling are still more pronounced than in healthy skin. Full article

Prostate adenocarcinoma (PRAD) poses a significant challenge due to therapy resistance and an immunosuppressive tumor microenvironment (TME). Ferroptosis has emerged as a therapeutic vulnerability, yet its immunomodulatory role in PRAD remains elusive. Here, we employed a multi-omics approach—integrating bulk RNA-seq (498 tumors), single-cell RNA-seq (68,322 cells), and spatial transcriptomics (19,483 spots)—to decode the ferroptosis-immune landscape. We derived a robust 16-gene ferroptosis signature that predicted biochemical recurrence (C-index = 0.76) and validated it in two independent cohorts. Crucially, high-risk tumors exhibited a “cold” immunosuppressive TME enriched in regulatory T cells and M2 macrophages, alongside elevated immune checkpoints (HAVCR2, CTLA4, PDCD1). Single-cell and virtual knockout analyses revealed that cancer epithelial cells evade ferroptosis via NFE2L2-associated antioxidant defenses, which strongly correlates with immune exclusion. Spatial transcriptomics further demonstrated spatially organized vulnerabilities, with ferroptosis-resistant tumor cores and immune-infiltrated invasive margins. To identify therapeutic interventions, we utilized drug response modeling and molecular docking, prioritizing RSL3, Atovaquone (targeting NOX4 (NADPH oxidase 4)/DHODH), and Sorafenib (targeting TrxR1 (thioredoxin reductase 1, encoded by TXNRD1)) as potent agents with potential ferroptosis-modulatory activity. Collectively, our findings demonstrate that NFE2L2-associated ferroptosis resistance shapes immune evasion in PRAD. Targeting ferroptosis regulators provides a compelling therapeutic rationale to remodel the TME and synergize with immune checkpoint blockade. Full article

Gelatin hydrolysate (GH), a bioactive compound derived from collagen, has demonstrated potential therapeutic benefits in various medical conditions. However, its effects on chronic cerebral hypoperfusion-induced vascular dementia remain underexplored. This study aimed to investigate the anti-oxidative stress effects of GH in alleviating brain damage and cognitive impairment in CCH-induced rats. Male Wistar rats underwent bilateral common carotid artery occlusion to induce CCH and were randomly divided into five groups: (1) sham, (2) 2-vessel occlusion (2VO), (3) 2VO + 250 mg/kg GH, (4) 2VO + 500 mg/kg GH, and (5) 2VO + piracetam. Treatments were administered for 35 days of post-operation. GH treatment significantly mitigated oxidative stress, as evidenced by reduced levels of reactive oxygen species (ROS), nitric oxide (NO), and the expression of 4-hydroxynonenal (4-HNE) and NADPH oxidase 4 (NOX4). Furthermore, GH exhibited antioxidant activity by upregulating superoxide dismutase (SOD) levels via nuclear factor E2-related factor 2 (Nrf-2) activation. This, in turn, reduced neuronal apoptosis by decreasing Bax and cleaved-caspase 3 levels and increasing Bcl-2 expression. Additionally, GH treatment ameliorated Tau protein hyperphosphorylation and improved synaptic function. Overall, GH exerted neuroprotective effects against oxidative stress-related neuronal damage and enhanced neuroplasticity, learning, and memory in rats with CCH-induced cognitive impairment. Full article

(1) Background: Babassu (Attalea speciosa) mesocarp is a functional food rich in nutrients and phenolic compounds, offering antioxidant and metabolic benefits. However, its effects on lipid peroxidation and pro-oxidant enzymes remain poorly explored. (2) Methods: The antioxidant potential of a hydroalcoholic extract of babassu mesocarp (HEB) was assessed using DPPH radical scavenging and lipid peroxidation inhibition, measured by the TBARS assay. Cytotoxicity was assessed by the MTT assay. Molecular docking was conducted to investigate interactions between HEB-derived compounds and NADPH oxidase and xanthine oxidase. (3) Results: HEB showed dose-dependent antioxidant activity (IC₅₀ = 4.734 µg/mL) and effectively inhibited lipid peroxidation (IC₅₀ = 51.35 µg/mL), with no cytotoxic effects. In silico analyses suggested potential inhibition of pro-oxidant enzymes. (4) Conclusions: HEB exhibits a strong ability to inhibit lipid peroxidation and theoretical enzyme-inhibitory potential, supporting its use in functional foods and nutraceuticals. Full article

Traffic-related air pollution (TRAP) is known to contribute to oxidative stress in the central nervous system (CNS) and has been linked to increased risk of Alzheimer’s disease (AD). Alterations in the renin–angiotensin system (RAS), specifically increased angiotensin II (Ang II) signaling via the angiotensin II type 1 (AT₁) receptor, are implicated in increased oxidative stress in the CNS via activation of NADPH oxidase (NOX). As exposure to TRAP may further elevate AD risk, we investigated whether exposure to inhaled mixed gasoline and diesel vehicle emissions (MVE) promotes RAS-dependent expression of factors that contribute to AD pathophysiology in an apolipoprotein E-deficient (ApoE^−/−) mouse model. Male ApoE^−/− mice (6–8 weeks old) on a high-fat diet were treated with either an ACE inhibitor (captopril, 4 mg/kg/day) or water and exposed to filtered air (FA) or MVE (200 µg PM/m³) for 30 days. MVE exposure elevated plasma Ang II, inflammation, and oxidative stress in the hippocampus, associated with increased levels of Aph-1 homolog B (APH1B), a gamma-secretase subunit, and beta-secretase 1 (BACE1), involved in Aβ production. Each of these endpoints was normalized with ACEi treatment. These findings indicate that TRAP exposure in ApoE^−/− mice drives a RAS- and NOX-dependent oxidative and inflammatory response and shifts Aβ processing towards an amyloidogenic profile before overt Aβ deposition, suggesting a potential therapeutic approach for air pollution-induced AD risk. Full article

Nanoplastics are persistent environmental pollutants with potential risks to human health. Due to their small size, nanoplastics are internalized by macrophages, potentially altering their function. In this study we found that, in macrophages, 50 nm polystyrene nanoplastics were predominantly present in endosomes, lysosomes, and in the endoplasmic reticulum. Internalization of polystyrene nanoplastics increased the bactericidal activity of macrophages, which was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium. Consistently, measurements of cellular and mitochondrial reactive oxygen species by flow cytometry revealed that polystyrene nanoplastics induced reactive oxygen species production in macrophages. In contrast, internalization of polystyrene nanoplastics reduced the levels of nitric oxide released by macrophages in response to E. coli. Internalization of polystyrene nanoplastics followed by the addition of E. coli induced high expression levels of the aconitate decarboxylase 1 gene. In the absence of this gene, killing of E. coli by macrophages exposed to polystyrene nanoplastics was significantly attenuated with respect to control macrophages, indicating a role for the mitochondrial metabolite itaconate in the increased bactericidal activity of macrophages exposed to polystyrene nanoplastics. Collectively, our results indicate that exposure of macrophages to polystyrene nanoplastics increases their bactericidal activity through the production of reactive oxygen species and of itaconate. Full article

Oxidative stress is a key driver of chronic inflammatory diseases. Anodendron affine is a native Formosan plant species in Taiwan that remains largely underexplored phytochemically and bioactivity. To reveal the bioactive constituents and assess its potential as a source of anti-inflammatory antioxidants, we performed bioactivity-guided fractionation and evaluated the inhibition of superoxide anion (O₂^•−) generation in formyl-L-methionyl-L-leucyl-L-phenylalanine-stimulated human neutrophils. Molecular docking simulations were employed to model interactions with Formyl peptide receptor 1 (FPR1) and the Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, including neutrophil cytosol factor 1 (p47phox) and NADPH oxidase 2 (NOX2), to propose a theoretical mechanism of action. Phytochemical investigation led to the isolation of two new compounds, methyl 4,5-O-diferuloyl-3-methoxyquinate (1) and 16-pregnen-3,12,20-trione (2), together with four known compounds. Notably, 4-hydroxy-3-prenylbenzoic acid (5) exhibited potent inhibitory activity (IC₅₀ = 17.65 ± 0.97 μM), surpassing the activity of the positive control, ibuprofen (IC₅₀ = 27.85 ± 3.56 μM). Docking studies suggested that anodendrosin H (4) and 4-hydroxy-3-prenylbenzoic acid (5) exhibit high predicted binding affinity to p47phox and NOX2. Based on these results, compounds 1, 4, and 5 from A. affine were identified as potential lead candidates for the development of novel anti-inflammatory therapeutics. Full article

Candida albicans is a pathogenic fungus that expresses a fungal NADPH oxidase known as C. albicans Cfl11, which produces reactive oxygen species (ROS). Secretion of these ROS triggers caspase 3–mediated cell death in hepatocytes, which was attenuated in a mutant with a disrupted CaCFL11 gene (designated Cacfl11Δ mutant). Here, we compared the effects of the C. albicans wild-type strain and the Cacfl11Δ mutant. Our findings revealed that C. albicans reduces the viability of HaCaT keratinocytes in a contact-independent manner. Furthermore, exposure to C. albicans increased intracellular ROS production and caspase 3 activity in HaCaT keratinocytes. These changes were attenuated when HaCaT keratinocytes were exposed to the Cacfl11Δ mutant or when HaCaT keratinocytes were treated with the known antioxidant N-acetylcysteine. Furthermore, wild-type C. albicans, but not the Cacfl11Δ mutant, disrupted transepithelial electrical resistance and modulated the downregulation of the tight-junction genes occludin and junction adhesion molecule 1 in HaCaT keratinocytes. Collectively, these results show that fungal ROS secretion via CaCFL11 is a potent virulence factor in mediating keratinocyte viability and barrier function. Full article

Neuroinflammation and oxidative stress are key drivers of various ocular diseases. Experimental hypoxia, modeled using cobalt chloride (CoCl₂), induces hypoxia-inducible factor 1-alpha (HIF-1α) stabilization, mitochondrial dysfunction, and excessive reactive oxygen species (ROS) production, primarily via the NADPH oxidase 2 (Nox2)–voltage-gated proton channel Hv1 axis. Although Botulinum neurotoxin type A (BoNT/A) is classically recognized for SNAP-25 cleavage, recent studies suggest broader anti-inflammatory and neuroprotective effects. We evaluated BoNT/A in R28 retinal precursor cells and ex vivo retinal explants subjected to CoCl₂-induced hypoxic stress. BoNT/A pretreatment attenuated CoCl₂-induced upregulation of HIF-1α, Hv1, Nox2, NOD-like receptor protein 3 (NLRP3), COX2, and nuclear factor kappa B (NF-κB), while enhancing protective mediators including suppressor of cytokine signaling 3 (SOCS3), Growth Associated Protein 43 (Gap43), and Syntaxin12. Brn3a expression and retinal architecture were preserved, apoptotic cell death reduced, and glial activation suppressed. Moreover, BoNT/A decreased mitochondrial ROS accumulation, restored voltage-dependent anion channel 1 (VDAC1) distribution, and partially stabilized intracellular pH. These findings indicate that BoNT/A mitigates oxidative stress and inflammation in hypoxia-driven retinal injury, at least in part, via modulation of the Nox2–Hv1–ROS axis, and support its potential as a therapeutic candidate for ocular disorders associated with hypoxia and neuroinflammation. Full article

In recent decades, chemotherapy has significantly improved cancer survival, yet its adverse effects on non-cancerous tissues raise increasing concerns. In this context, growing attention has been focused on natural compounds that may be useful in mitigating the undesirable effects of chemotherapeutic agents. Here, we aimed to demonstrate that Cytosporone B (CsnB) is a potent agent for counteracting the cardiovascular effects induced by Imatinib. To this end, 12-week-old male Wistar rats were studied; they were divided into three groups as follows: (1) control, (2) Imatinib-treated (Imatinib: 60 mg/kg/day, per os), (3) Imatinib + CsnB-treated (CsnB: 5 mg/kg/day, i.p.). After the two-week-long experimental period, rats were euthanized. Their hearts were used for the following biochemical measurements: NADPH oxidase (NOX4), high mobility group box 1 (HMGB1), peptidylarginine deiminase 4 (PAD4), inducible nitric oxide synthase (iNOS) expression, tumor necrosis factor-alpha (TNF-α) level, and myeloperoxidase (MPO) activity. Imatinib caused a marked upregulation of key inflammatory and oxidative markers, including HMGB1, TNF-α, MPO, iNOS, PAD4, and NOX4 in cardiac tissue; however, CsnB treatment mitigated these elevations, implying its role in opposing Imatinib-induced inflammatory and oxidative processes in the heart. Our findings suggest that CsnB holds promise as a cardioprotective agent capable of modulating Imatinib-induced adverse cardiac effects. Full article

The relationship between periodontitis and cardiovascular diseases (CVDs) extends beyond epidemiological associations, as demonstrated by meta-analyses showing a significantly increased risk for coronary heart disease development. At the core of this association lies systemic inflammation, where periodontal pathogens initiate cascades of pro-inflammatory cytokines. This inflammatory response manifests through substantial elevations in interleukin-1 beta (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in periodontitis patients. Oxidative stress plays a crucial role, with Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase 2 (NOX2) activation leading to markedly increased superoxide production compared to healthy controls. The peroxynitrite formed via NO–superoxide interaction accumulates in affected vascular tissues, substantially reducing nitric oxide (NO) bioavailability. Molecular mimicry mechanisms are evidenced by P. gingivalis heat shock protein sharing significant sequence homology with human HSP60, triggering autoimmune responses that affect cardiovascular tissues. Epigenetic modifications show specific alterations, with Nrf2 target gene expression substantially downregulated in chronic periodontal inflammation, particularly affecting heme oxygenase-1 (HO-1) and NAD(P)H:Quinone Oxidoreductase 1 (NQO1) expression. These molecular pathways create a complex network of interactions that fundamentally link periodontal and cardiovascular pathologies. Full article

Inorganic arsenic [As(III) and As(V)] is a pervasive environmental contaminant in groundwater systems, early-life exposure to which is associated with an impaired cognitive ability and an increased risk of neurobehavioral disorders. Although the effect of As(III) on the neurons is well studied, the involvement of the microglia remains unclear. In this study, the effects of sodium arsenite (NaAsO₂) on microglial activation and the underlying NLRP3 inflammasome mechanism were determined. Pregnant rats were gavaged with NaAsO₂ (0, 1, 4, and 10 mg/kg body weight), which dissociates in aqueous solutions into bioactive arsenite species [As(OH)₃], from gestational day 1 (GD1) to postnatal day 21 (PND21). The results showed that As(III) induces learning and memory impairments and microglial activation in the hippocampus of offspring rats (PND21). Increased expression of NLRP3, the activation of caspase-1, and the production of interleukin-1β were observed in both the hippocampus of As(III)-exposed offspring rats and As(III)-exposed microglial BV2 cells under culture conditions. Interestingly, blocking the NLRP3 inflammasome using MCC950 mitigated its activation. Furthermore, inhibition of NADPH oxidase 2 (NOX2) using apocynin or specific siRNA significantly reduced As(III)-induced microglial NLRP3 inflammasome activation. In addition, inactivation of the microglial NLRP3 inflammasome or NOX2 markedly rescued As(III)-induced neurotoxicity in the hippocampal HT22 cells. Taken together, this study reveals that NOX2/NLRP3-inflammasome-dependent microglial activation promotes As(III)-induced learning and memory impairments in developmental rats. Full article