Antioxidants

30 pages, 6348 KB

Open AccessReview

Macrophage Immune-Redox Modulation by Phenylethanoid- and Flavonoid-Rich Botanical Extracts: NF-κB/iNOS–Nrf2 Crosstalk and the Proposed Role of Buddleja globosa

by Yilka Mena-Linares, Humberto Vélez-Slimani and Luis A. Salazar

Antioxidants 2026, 15(9), 1158; https://doi.org/10.3390/antiox15091158 (registering DOI) - 11 Sep 2026

Abstract

Macrophage activation depends on the balance between pro-inflammatory signaling and cytoprotective antioxidant responses. Persistent nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) activity, together with insufficient nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, promotes oxidative and nitrosative stress and [...] Read more.

Macrophage activation depends on the balance between pro-inflammatory signaling and cytoprotective antioxidant responses. Persistent nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) activity, together with insufficient nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, promotes oxidative and nitrosative stress and contributes to chronic inflammation. Phenylethanoid- and flavonoid-rich botanical extracts may modulate this immune-redox network, but the available evidence is dispersed across plant species, extraction procedures, isolated compounds, and experimental models. This review examines the phytochemical composition and biological effects of these preparations, with particular emphasis on Buddleja globosa Hope. Evidence concerning verbascoside, luteolin, apigenin, quercetin derivatives, and other constituents is integrated with findings related to toll-like receptor 4/NF-κB signaling, iNOS-derived nitric oxide, inflammatory cytokines, reactive oxygen species, and Keap1–Nrf2-dependent cytoprotective responses. Direct evidence obtained with B. globosa extracts is distinguished from mechanistic findings generated using isolated constituents or related botanical preparations. Current studies support antioxidant and inflammation-modulating activities, but interpretation is limited by phytochemical variability, inconsistent dosing, incomplete cytotoxicity assessment, and limited use of macrophage-specific models. Future work should prioritize chemically standardized extracts, direct extract–constituent comparisons, pathway-specific validation, and formulation strategies that improve stability, reproducibility, and biological performance. Full article

(This article belongs to the Topic Natural Bioactive Compounds as a Promising Approach to Mitigating Oxidative Stress—Second Edition)

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17 pages, 480 KB

Open AccessArticle

Leakage-Aware Machine Learning and Deep Learning Benchmarking of Food Antioxidant Capacity Prediction on the Antioxidant Food Table

by Erkan Caner Ozkat

Antioxidants 2026, 15(9), 1157; https://doi.org/10.3390/antiox15091157 (registering DOI) - 11 Sep 2026

Abstract

The Antioxidant Food Table is the largest open collection of measured food antioxidant capacity. It covers 3139 products assayed by the ferric reducing ability of plasma (FRAP) method. The table has served mainly as a dietary lookup source and has never been machine-readable [...] Read more.

The Antioxidant Food Table is the largest open collection of measured food antioxidant capacity. It covers 3139 products assayed by the ferric reducing ability of plasma (FRAP) method. The table has served mainly as a dietary lookup source and has never been machine-readable or benchmarked. Here it was extracted into a validated open dataset (3135 records, 99.9%). A leakage-aware benchmark of antioxidant capacity prediction from product description and category was then constructed. Eighteen predictors, from naïve baselines to deep networks and fusions, were evaluated under two partitioning regimes with the same five seeds and permutation controls. Since 39.4% of records share a product name, the conventional random split rewards memorization. A learning-free duplicate lookup explained 45% of the apparent k-nearest-neighbor advantage over the category median. In grouped evaluation, ridge regression on term frequency–inverse document frequency (TF–IDF) features (

R^{2} = 0.674

) outperformed both deep networks. Pretrained word vectors did not close this gap. An equal-weight fusion of all eight models performed best (

R^{2} = 0.684

) with 2.6-fold lower variability. Protocol and representation, rather than architecture, dominated the outcome on this benchmark. The dataset, code, and predictions are released openly. Full article

(This article belongs to the Special Issue Artificial Intelligence and Other Bioinformatic Modern Technologies Approaches to the Study of Antioxidant Capacity in Food Production)

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13 pages, 1501 KB

Open AccessArticle

Differential Associations of Lipopolysaccharide, Soluble NOX2-Derived Peptide, and Hydrogen Peroxide with Adiposity and Muscularity in Adults on Maintenance Hemodialysis

by Giovanni Imbimbo, Federica Foti, Thomas Ammann, Maria Grazia Chiappini, Vittoria Cammisotto, Valentina Castellani, Pasquale Pignatelli and Alessio Molfino

Antioxidants 2026, 15(9), 1156; https://doi.org/10.3390/antiox15091156 (registering DOI) - 11 Sep 2026

Abstract

Background: Endotoxemia and oxidative stress may contribute to adverse body-composition changes in patients receiving maintenance hemodialysis, but their relationships with adiposity and muscularity remain incompletely defined. We investigated whether the concentrations of circulating lipopolysaccharide (LPS), soluble NOX2-derived peptide (sNox2-dp), and hydrogen peroxide (H [...] Read more.

Background: Endotoxemia and oxidative stress may contribute to adverse body-composition changes in patients receiving maintenance hemodialysis, but their relationships with adiposity and muscularity remain incompletely defined. We investigated whether the concentrations of circulating lipopolysaccharide (LPS), soluble NOX2-derived peptide (sNox2-dp), and hydrogen peroxide (H₂O₂) showed differential associations with bioimpedance-derived body-composition compartments and explored their relationships with normalized protein catabolic rate (nPCR), a surrogate of protein intake. Methods: In this observational, cross-sectional study, adult patients receiving maintenance hemodialysis were enrolled at a single center. Serum LPS and sNox2-dp and H₂O₂ concentrations were measured before dialysis. Body composition was assessed by bioimpedance analysis; fat mass (FM) was used as an index of adiposity, whereas intracellular water indexed to height squared (ICW/h²) was used as a proxy of muscularity. Associations were examined using Spearman correlation and multivariable linear regression adjusted for age, sex, and nPCR. Results: A total of 58 participants were included with a median age of 73 years; 64% were male and mean body mass index was 24.6 ± 4.2 kg/m². LPS correlated with sNox2-dp (rho = 0.420, p = 0.001), whereas sNox2-dp correlated with H₂O₂ (rho = 0.352, p = 0.007); the LPS–H₂O₂ association was borderline (rho = 0.259, p = 0.050). sNox2-dp correlated positively with fat-free mass, total body water, ICW, and ICW/h², whereas LPS correlated with FM (rho = 0.305, p = 0.023). Participants with nPCR > 0.89 g/kg/day had higher LPS concentrations than those with lower nPCR (p = 0.015), and nPCR correlated with ICW/h² (rho = 0.36, p = 0.007). In multivariable analysis, LPS remained independently associated with FM (β = 0.210, p = 0.046). nPCR was positively associated with ICW/h² at the threshold of statistical significance (β = 1.393, p = 0.050), whereas sNox2-dp showed a nonsignificant positive trend (p = 0.060). Conclusions: In maintenance hemodialysis, endotoxemia and NOX2 activation showed differential associations with body composition: LPS with adiposity and sNox2-dp with muscularity. Higher nPCR was associated with both greater muscularity and higher LPS concentrations, suggesting a complex relationship between protein intake, the gut–oxidative-stress axis, and body composition. Full article

(This article belongs to the Special Issue Antioxidants in Chronic and End-Stage Kidney Disease: Defining Biological and Clinical Plausibility)

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16 pages, 598 KB

Open AccessArticle

Mitochondrial DNA Haplogroups Influence Oxidative Stress Profiles and Susceptibility to Metabolic Syndrome in an Asian Population

by Shao-Wen Weng, Yu-Han Lin, Shih-Hsuan Chen, Tsu-Kung Lin, Pei-Wen Wang and Chia-Wei Liou

Antioxidants 2026, 15(9), 1155; https://doi.org/10.3390/antiox15091155 (registering DOI) - 11 Sep 2026

Abstract

Mitochondrial DNA (mtDNA) haplogroups influence mitochondrial function and reactive oxygen species (ROS) production, potentially modulating susceptibility to metabolic disorders. This study investigated the associations between mtDNA haplogroups, systemic oxidative stress, and metabolic syndrome in 2486 Taiwanese individuals. Serum thiobarbituric acid-reactive substances (TBARS) and [...] Read more.

Mitochondrial DNA (mtDNA) haplogroups influence mitochondrial function and reactive oxygen species (ROS) production, potentially modulating susceptibility to metabolic disorders. This study investigated the associations between mtDNA haplogroups, systemic oxidative stress, and metabolic syndrome in 2486 Taiwanese individuals. Serum thiobarbituric acid-reactive substances (TBARS) and free thiols were measured as markers of oxidative and antioxidative status, respectively, while mtDNA haplogroups were determined using multiplex PCR and Luminex genotyping. Macrohaplogroups N (51%) and M (49%) were predominant, with haplogroups B, F, D, and M7 most frequently observed. Although the overall haplogroup distribution is genetically similar to populations in Southern China, the distribution among the Taiwanese population shows distinct differences. Haplogroup B was significantly associated with higher TBARS levels, lower thiol concentrations, and an increased prevalence of diabetes and metabolic syndrome (OR 1.34, p = 0.004). Individuals with metabolic syndrome exhibited higher oxidative stress and lower antioxidative biomarker levels than those without the syndrome, while a progressive imbalance in oxidative–antioxidative status was observed with increasing numbers of metabolic syndrome components. These findings suggest that mtDNA haplogroups, particularly haplogroup B, may contribute to metabolic syndrome susceptibility through modulation of systemic oxidative stress. Full article

(This article belongs to the Special Issue Advances in Oxidative Stress, Mitochondrial Dysfunction and Antioxidant Therapies in Endocrine and Metabolic Disorders)

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49 pages, 2829 KB

Open AccessReview

CYP2D6 as an Emerging Endogenous Oxidative Stress Modulator in Cardiovascular Disease: Genetic, Pharmacological, and Redox Perspectives

by Cheng-Wu Yang, Wen-Hua Chen and Tzong-Shyuan Lee

Antioxidants 2026, 15(9), 1154; https://doi.org/10.3390/antiox15091154 - 10 Sep 2026

Abstract

Oxidative stress is a central and well-established driver of cardiovascular disease, contributing to mitochondrial dysfunction, endothelial injury, inflammatory activation, and progressive myocardial and vascular remodeling. Although the major endogenous sources of cardiovascular reactive oxygen species (ROS), including NADPH oxidases, mitochondrial electron transport chain [...] Read more.

Oxidative stress is a central and well-established driver of cardiovascular disease, contributing to mitochondrial dysfunction, endothelial injury, inflammatory activation, and progressive myocardial and vascular remodeling. Although the major endogenous sources of cardiovascular reactive oxygen species (ROS), including NADPH oxidases, mitochondrial electron transport chain leakage, and uncoupled nitric oxide synthase, are well characterized, an additional and underappreciated contributor has recently emerged: cytochrome P450 2D6 (CYP2D6), an enzyme classically regarded as a hepatic drug-metabolizing protein. Accumulating evidence indicates that CYP2D6 is expressed extrahepatically in cardiac, vascular, and neural tissue, where uncoupled catalytic cycling is proposed to generate ROS independently of its canonical xenobiotic-metabolizing role, although direct experimental evidence for this pathway in human cardiac and vascular tissue remains limited. CYP2D6-derived oxidative processes may interact with mitochondrial respiratory function, endothelial nitric oxide bioavailability, and redox-sensitive inflammatory pathways, potentially contributing to cardiovascular vulnerability under specific genetic or pathological conditions. Critically, the magnitude of this oxidative contribution is not fixed: it is dynamically shaped by inherited CYP2D6 genetic variation, with poor and ultra-rapid metabolizer phenotypes exhibiting divergent oxidative burden and pharmacokinetic vulnerability, and is further amplified by polypharmacy, multimorbidity, and inflammation-driven phenoconversion, whereby clinically expressed CYP2D6 activity diverges from inherited genotype in ways that intensify redox imbalance. These dynamics are particularly relevant in East Asian populations, where the decreased-function CYP2D6*10 allele is highly prevalent. In this narrative, hypothesis-generating review, we integrate evidence from pharmacogenomics, redox biology, and cardiovascular pharmacology to propose a conceptual framework that reframes CYP2D6 as a genetically and pharmacologically tunable node within cardiovascular redox biology. We further examine emerging redox biomarkers, multi-omics platforms, and AI-assisted modeling as translational strategies for capturing this dynamic oxidative risk in real time. This framework supports a shift from static genotype-guided prescribing toward oxidative-risk-informed, adaptive cardiovascular precision medicine. Importantly, our focus on CYP2D6 should not be interpreted as evidence that it is a major cardiovascular CYP isozyme or an established driver of cardiovascular pathology. Rather, CYP2D6 is examined here as a deliberately hypothesis-generating candidate whose unusually strong pharmacogenetic variability, clinically important cardiovascular drug substrates, dynamic susceptibility to phenoconversion, extrahepatic expression, and mechanistically plausible links to endogenous substrate metabolism and CYP-associated ROS generation provide a convergent rationale for focused investigation. The mechanistic framework proposed in this review has not yet been experimentally and prospectively validated and should not be applied directly to clinical decision-making without supporting clinical data. Full article

(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)

23 pages, 1453 KB

Open AccessArticle

Valorization of Sardinian Grapevine Leaves as a Sustainable Source of Flavonols with Anticancer Potential

by Ylenia Spissu, Maria Lauda Tomasi, Carla Cossu, Andrea Floris, Emanuela Azara, Gavina Rita Serra, Irene Marchesi, Francesco Paolo Fiorentino, Gaia Rocchitta, Riccarda Zappino and Antonio Barberis

Antioxidants 2026, 15(9), 1153; https://doi.org/10.3390/antiox15091153 - 10 Sep 2026

Abstract

Grapevine (Vitis vinifera L.) leaves are an abundant agricultural by-product and an underexploited source of bioactive polyphenols. This study characterized hydroalcoholic leaf extracts from autochthonous Sardinian cultivars and evaluated their effects in RKO human colorectal carcinoma cells. LC–HRMS revealed flavonol-rich profiles dominated [...] Read more.

Grapevine (Vitis vinifera L.) leaves are an abundant agricultural by-product and an underexploited source of bioactive polyphenols. This study characterized hydroalcoholic leaf extracts from autochthonous Sardinian cultivars and evaluated their effects in RKO human colorectal carcinoma cells. LC–HRMS revealed flavonol-rich profiles dominated by glycosylated derivatives of quercetin, kaempferol, and isorhamnetin, with marked cultivar-dependent differences and higher total flavonol abundance in Cannonau and Nieddera. Cyclic voltammetry showed distinct redox reactivity among extracts, with Vermentino and Martellada Bianca displaying the strongest electrochemical responses, consistent with their modulation of intracellular reactive oxygen species. In RKO cells, the extracts reduced metabolic activity in a dose-dependent manner, with IC50 values ranging from 100.3 to 251.8 µg/mL. At the molecular level, treatments modulated c-myb expression and shifted the bax/bcl2 balance toward a pro-apoptotic profile. These effects were supported by DAPI staining, showing chromatin condensation and nuclear fragmentation, and by moderate activation of caspase-3/7. Overall, Sardinian grapevine leaf extracts showed cultivar-specific phenolic composition, redox activity, and pro-apoptotic effects in an in vitro colorectal cancer model, supporting their potential valorization as sustainable sources of bioactive compounds. Further studies addressing bioavailability, metabolism, and in vivo effects are required to assess their physiological relevance and translational potential. Full article

(This article belongs to the Special Issue The Role of Natural Antioxidants in Fruits and Vegetables in Human Health)

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27 pages, 1062 KB

Open AccessReview

Oxidative Stress in Vascular Aging: Therapeutic Potential of the Antioxidant Paradox. A State-of-the-Art Review

by Aleyma Veliz Perez, Mihaela Badea and Sehrish Bilal

Antioxidants 2026, 15(9), 1152; https://doi.org/10.3390/antiox15091152 - 10 Sep 2026

Abstract

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with aging as one of its main risk factors. Cellular senescence and oxidative stress form a bidirectional vicious cycle that drives vascular aging, endothelial dysfunction, and atherosclerotic progression. This state-of-the-art review synthesizes current [...] Read more.

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with aging as one of its main risk factors. Cellular senescence and oxidative stress form a bidirectional vicious cycle that drives vascular aging, endothelial dysfunction, and atherosclerotic progression. This state-of-the-art review synthesizes current evidence on the interplay between oxidative stress and senescence in cardiovascular aging and critically assesses whether antioxidant strategies can benefit vascular health. A targeted literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus (2016–2026). While endogenous antioxidant defenses decline with age, exogenous antioxidants, including resveratrol, vitamins C and E, omega-3 fatty acids, carotenoids, and coenzyme Q10,demonstrate promising preclinical effects, yet large-scale clinical trials have yielded inconsistent results. The VITAL and STRENGTH trials failed to demonstrate significant cardiovascular benefit with omega-3 supplementation, and elevated serum β-carotene was found paradoxically associated with increased cardiovascular mortality. Emerging mitochondria-targeted antioxidants (MitoQ, MitoTEMPO) show preclinical promise but require further clinical validation. Current evidence does not support antioxidant supplementation for cardiovascular prevention. Lifestyle interventions, particularly antioxidant-rich dietary patterns such as the Mediterranean diet, remain the safest strategy. Future research should develop personalized approaches guided by oxidative stress biomarkers and long-term trials. Full article

(This article belongs to the Special Issue Women’s Special Issue Series: Antioxidants in Human Health—2nd Edition)

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31 pages, 23107 KB

Open AccessArticle

Fungal-Derived Decahydrofluorene Alkaloids Promote Mitochondrial Resilience and Neuroprotection in Cellular and Animal Models of Parkinson’s Disease

by Alberto Vázquez-Jiménez, Margarita M. Marques, José M. Sánchez, Jesús Agulla, Rebeca Lapresa, Mónica Trigal-Martínez, Rosalía Fernández-Alonso, Gracia Merino, Antonio Fernández, Antonella Consiglio, Juan P. Bolaños, Ángeles Almeida, María C. Marín and Lorena López-Ferreras

Antioxidants 2026, 15(9), 1151; https://doi.org/10.3390/antiox15091151 - 10 Sep 2026

Abstract

Parkinson’s disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 [...] Read more.

Parkinson’s disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 exhibited a favorable safety profile and protected SHSY5Y against 6-hydroxydopamine- (6-OHDA), rotenone-, and 1-Methyl-4-phenylpyridinium-iodide (MPP⁺)-induced neurotoxicity by preserving mitochondrial membrane potential and network integrity. Transcriptomic analyses revealed selective restoration of gene-expression programs associated with oxidative phosphorylation, mitochondrial bioenergetics, and stress adaptation disrupted by MPP⁺. CL0179 also enhanced SIRT1 activity under MPP⁺ stress, whereas pharmacological SIRT1 inhibition partially attenuated protection of mitochondrial membrane potential and cell viability. In LRRK2-G2019S astrocytes, CL0179 reduced ROS and α-synuclein accumulation and restored mitochondrial organization, while in human dopaminergic neurons, it attenuated toxin-induced mitochondrial depolarization and preserved neuronal architecture. To overcome the low production of CL0179, we generated the structurally related analogue CL0670. Both compounds crossed the blood–brain barrier and protected mouse primary cortical neurons, while CL0670 improved motor deficits in a 6-OHDA mouse model. Collectively, these compounds promote mitochondrial resilience and stress-adaptive neuroprotection, supporting their potential for PD and related neurodegenerative disorders. Full article

(This article belongs to the Special Issue Targeting Mitochondrial Dysfunction and Oxidative Stress for Neuroprotection)

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19 pages, 1876 KB

Open AccessArticle

Urinary Extracellular Vesicle-Derived miRNAs Reveal a Coordinated Stress-Response Network Linked to Advanced Glycation End-Products in Children and Adolescents

by Fabio Lauria, Paola Russo, Alfonso Siani, Ivana Sirangelo, Ilenia D’Orsi, Pasquale Marena, Antje Hebestreit, Ronja Foraita and Giuseppe Iacomino

Antioxidants 2026, 15(9), 1150; https://doi.org/10.3390/antiox15091150 - 10 Sep 2026

Abstract

The widespread consumption of ultra-processed foods increases exposure to advanced glycation end-products (AGEs), key mediators of oxidative stress and chronic low-grade inflammation. Although AGEs contribute to adult metabolic dysfunction, their early molecular correlates in pediatric populations remain insufficiently defined. Extracellular vesicle (EV)-associated miRNAs [...] Read more.

The widespread consumption of ultra-processed foods increases exposure to advanced glycation end-products (AGEs), key mediators of oxidative stress and chronic low-grade inflammation. Although AGEs contribute to adult metabolic dysfunction, their early molecular correlates in pediatric populations remain insufficiently defined. Extracellular vesicle (EV)-associated miRNAs represent stable, non-invasive indicators of systemic stress responses. This study evaluated the association between urinary AGEs and urinary EV-associated miRNAs in 94 Italian children and adolescents from the I.Family cohort. Fluorescent AGEs were quantified via spectrofluorimetry, and EV-enriched urinary miRNAs were profiled using next-generation sequencing. Differential expression and multivariable generalised linear models (adjusted for age, sex, BMI z-score, and hs-CRP) were performed. Differential expression analysis revealed a significant upregulation of hsa-miR-4516 in participants with high versus low urinary AGE levels (fold change = 2.31; FDR = 0.024). In multivariable continuous models, hsa-miR-4516 remained the primary AGE-associated miRNA, though the association attenuated following adjustment for BMI z-score and hs-CRP. Functional enrichment and network analyses highlighted pathways governing oxidative stress responses, proteostasis, and cellular survival. Overall, urinary EV-associated miRNAs may reflect coordinated biological responses to dietary AGE burden rather than serving as direct exposure biomarkers, offering integrated, non-invasive insights into early metabolic and inflammatory adaptations in children. Full article

(This article belongs to the Special Issue Glycation, Dicarbonyl Stress, and Redox Homeostasis: From Human Disease to Microbial and Plant Systems)

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13 pages, 1125 KB

Open AccessArticle

Phytochemical Investigation of Crataegus almaatensis Leaves: Isolation, Structural Characterization, and Antioxidant Activity of Flavonoids, Flavolignans, and Phenolic Glycosides

by Zhanar Nabiyeva, Akerke Kulaipbekova, Asylbek Kozybayev, Handi Yang, Fuhang Song, Abdyssemat Samadun, Elmira Assembayeva and Nasi Ai

Antioxidants 2026, 15(9), 1149; https://doi.org/10.3390/antiox15091149 - 10 Sep 2026

Abstract

A systematic phytochemical investigation of the leaves of Crataegus almaatensis Pojark., an endemic hawthorn species native to the mountainous regions of Kazakhstan, was carried out. Multi-step chromatographic fractionation, comprising ultrasound-assisted methanol extraction, sequential liquid–liquid partitioning, silica gel column chromatography, and preparative HPLC, afforded [...] Read more.

A systematic phytochemical investigation of the leaves of Crataegus almaatensis Pojark., an endemic hawthorn species native to the mountainous regions of Kazakhstan, was carried out. Multi-step chromatographic fractionation, comprising ultrasound-assisted methanol extraction, sequential liquid–liquid partitioning, silica gel column chromatography, and preparative HPLC, afforded five phenolic compounds as individual, spectroscopically homogeneous constituents from the ethyl acetate fraction. The structures of all isolated compounds were elucidated by comprehensive analysis of high-resolution mass spectrometry (HR-ESI-QTOF-MS) data and one- and two-dimensional NMR spectroscopy (¹H, ¹³C, HSQC, HMBC) in DMSO-d₆. The following compounds were identified: (−)-epicatechin, cinchonain Ia, a methoxy- and hydroxy-substituted diaryl ether β-D-glucopyranoside, kakispyrol, and a dimethoxy-substituted diaryl ether β-D-glucopyranoside. The isolated compounds belong to three chemical classes: flavanols, flavolignans, and diaryl ether-type phenolic glycosides. Evaluation of ABTS and DPPH radical-scavenging activity revealed compound-specific antioxidant profiles, with compound 5 (cinchonain Ia) showing activity comparable to the ascorbic acid standard. This study provides, for the first time, a detailed structural characterization of individual phenolic metabolites from C. almaatensis leaves and makes a significant contribution to understanding the chemical diversity of this endemic species. Full article

(This article belongs to the Special Issue Phytochemical Analysis and Evaluation of Antioxidant Properties in Medicinal Plants)

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15 pages, 4682 KB

Open AccessArticle

Evolutionary Conservation of the Copper-Dependent Thiol Oxidase Activity of Selenium-Binding Proteins

by Hanna Schlemminger, Swantje Melina Lockowandt, Alina Löser, Anna Patricia Kipp, Lars-Oliver Klotz and Holger Steinbrenner

Antioxidants 2026, 15(9), 1148; https://doi.org/10.3390/antiox15091148 - 10 Sep 2026

Abstract

Human selenium-binding protein 1 (SELENBP1) is a methanethiol oxidase (MTO), converting methanethiol (MT) to hydrogen sulfide (H₂S), hydrogen peroxide (H₂O₂) and formaldehyde (HCHO). SELENBP1 has orthologs in all domains of life. RdMTO, an orthologous enzyme recently identified [...] Read more.

Human selenium-binding protein 1 (SELENBP1) is a methanethiol oxidase (MTO), converting methanethiol (MT) to hydrogen sulfide (H₂S), hydrogen peroxide (H₂O₂) and formaldehyde (HCHO). SELENBP1 has orthologs in all domains of life. RdMTO, an orthologous enzyme recently identified in the marine bacterium Roseobacter denitrificans, was postulated to require the cysteine residue closest to its C-terminus, Cys448, for MT binding and to oxidize MT to sulfane sulfur (S⁰) rather than to H₂S. SELENBP1 and RdMTO exhibit ~53% sequence identity, with Cys448 (numbered Cys466 in SELENBP1) and amino acids required for copper binding being conserved. Therefore, we here compared the MTO activity of recombinant SELENBP1 and RdMTO. We found that SELENBP1, like RdMTO, converts MT as well as structurally related alkyl thiols to form H₂S, H₂O₂ and, in the case of MT, HCHO in a strictly copper-dependent manner. MTO activity of both proteins was lowered but not abrogated upon mutation of their respective C-terminal cysteine residue. Thus, the catalytic mechanism of selenium-binding proteins that act as copper-dependent MTOs appears to be evolutionarily conserved from bacteria to humans. Presumably, this enzyme is an early evolutionary invention of prokaryotes, in order to cope with toxic thiols in their environment. Full article

(This article belongs to the Section ROS, RNS and RSS)

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19 pages, 2412 KB

Open AccessArticle

Cunermuspir, a Copper(I)–Niacin Complex, Modulates Mitochondrial Respiration and Cellular Oxidant Handling in Fibroblasts from Children with Autism Spectrum Disorder

by Sophie Wallace, Spencer Lawes, Adrienne C. Scheck and Richard E. Frye

Antioxidants 2026, 15(9), 1147; https://doi.org/10.3390/antiox15091147 - 10 Sep 2026

Abstract

Copper is a redox-active transition metal that is essential for the assembly and catalytic function of cytochrome c oxidase (Complex IV), the terminal enzyme of the mitochondrial electron transport chain and a principal site of physiological oxygen reduction. Elevated Complex IV activity and [...] Read more.

Copper is a redox-active transition metal that is essential for the assembly and catalytic function of cytochrome c oxidase (Complex IV), the terminal enzyme of the mitochondrial electron transport chain and a principal site of physiological oxygen reduction. Elevated Complex IV activity and respiratory chain uncoupling are among the most consistently replicated biological findings in autism spectrum disorder (ASD), yet the interaction between mitochondrial copper delivery, respiration, and cellular oxidant handling in ASD has not been systematically defined. We treated dermal fibroblasts from 9 children with ASD and 10 typically developing controls with the copper(I)–niacin complex Cunermuspir (0, 50, or 100 µM for 1 or 24 h exposure) and challenged them with graded concentrations (0–5.0 µM) of the redox-cycling agent 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). Mitochondrial respiration was profiled by Seahorse XF respirometry (2133 observations across 28 experiments), and cellular reactive oxygen species (CellROX™ Green) and mitochondrial mass/polarization (MitoTracker™ Deep Red) were quantified by fluorescence imaging. ASD fibroblasts displayed a hypermetabolic, uncoupled respiratory phenotype (~73% higher baseline respiration; ~109% higher proton leak; reduced coupling efficiency). Linear mixed models with polynomial dose terms revealed significant ASD × Cunermuspir complex interactions (ASD × Cunermuspir and/or their higher-order interactions with DMNQ and treatment) for four respiratory parameters. ASD cells exhibited lower steady-state oxidation-dependent CellROX™ Green fluorescence than controls despite greater respiratory uncoupling, as well as lower steady-state MitoTracker™ Deep Red fluorescence; Cunermuspir reshaped the MitoTracker™ DMNQ dose–response in an ASD-selective manner. These findings identify the Cunermuspir-associated modulation of the ASD mitochondrial and oxidant handling phenotype and motivate further mechanistic and translational evaluation. Full article

(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)

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30 pages, 10406 KB

Open AccessArticle

The Proteasome Safeguards Red Blood Cell Integrity During Storage and After Transfusion

by Sandy Peltier, Théo Michel, Fanny Mialane, Mickaël Marin, Michaël Dussiot, Céline Rodriguez, Monika Dzieciatkowska, Marie Tamagne, Camille Roussel, Stéphanie Vicca, Olivier Hermine, Pierre A. Buffet, Benoit Vingert, Steven L. Spitalnik, Angelo D’Alessandro, Michel Prudent and Pascal Amireault

Antioxidants 2026, 15(9), 1146; https://doi.org/10.3390/antiox15091146 - 9 Sep 2026

Abstract

Pre-transfusion storage of red blood cells (RBCs) induces aging in vitro driven by metabolic and oxidative stress, limiting transfusion efficacy. Unlike nucleated cells where multiple hallmarks characterize aging, proteostasis is expected to play a main role in anucleate RBCs, including proteasomal protein degradation. [...] Read more.

Pre-transfusion storage of red blood cells (RBCs) induces aging in vitro driven by metabolic and oxidative stress, limiting transfusion efficacy. Unlike nucleated cells where multiple hallmarks characterize aging, proteostasis is expected to play a main role in anucleate RBCs, including proteasomal protein degradation. Although proteasomal activity declines during aging in vitro, its role in generating downstream alterations and post-transfusion clearance remains unclear. We hypothesized that proteasome inhibition accelerates RBC aging in vitro, particularly following re-exposure to physiological conditions. We evaluated the impact of proteasome inhibition (i.e., epoxomicin) on RBC quality during storage and physiological restoration in vitro. Additionally, young and old RBC subpopulations were compared. Proteasome inhibition during storage depleted ATP and altered RBC morphology without immediate oxidative damage. Physiological restoration of proteasome-inhibited RBCs caused accelerated ATP depletion, massive protein aggregation, reduced deformability, hemolysis, and phosphatidylserine exposure, particularly in long-stored RBCs. Strikingly, RBCs aged in vivo also exhibited low proteasomal activity and behaved similarly to stored RBCs following physiological restoration. In conclusion, proteasomal dysfunction is a key hallmark of RBC aging and senescence, driving molecular and cellular modifications that mark RBCs for clearance in vivo. Therefore, enhancing proteasomal function could improve RBC storage quality and transfusion efficacy. Full article

(This article belongs to the Special Issue Oxidative Stress in Cell Senescence)

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37 pages, 5946 KB

Open AccessArticle

Biopriming with Schizophyllum commune Polysaccharides Modulates Antioxidant and Biochemical Responses in Pisum sativum L. Seedlings

by Jovana Mišković, Milena Rašeta, Gordana Gojgić-Cvijović, Marko Radenković, Nenad Krsmanović, Nemanja Živanović, Gordana Ćirić-Marjanović, Maja Milojević-Rakić, Gordana Tamindžić and Maja Karaman

Antioxidants 2026, 15(9), 1145; https://doi.org/10.3390/antiox15091145 - 9 Sep 2026

Abstract

This study investigated the biostimulant potential of endo- and exo-polysaccharides (PSHs) obtained from two Schizophyllum commune strains originating from Italy (ITA) and Serbia (SRB), with a primary focus on their ability to modulate the antioxidant defense and biochemical responses of Pisum sativum L. [...] Read more.

This study investigated the biostimulant potential of endo- and exo-polysaccharides (PSHs) obtained from two Schizophyllum commune strains originating from Italy (ITA) and Serbia (SRB), with a primary focus on their ability to modulate the antioxidant defense and biochemical responses of Pisum sativum L. seedlings under optimal and drought conditions. The PSH fractions were structurally characterized by complementary spectroscopic and microscopic approaches, revealing strain- and drying-dependent differences in their structural features. The characterized PSHs were subsequently applied as seed biopriming agents, and pea seedlings were grown under two conditions: optimal growth and drought stress. Their effects were evaluated by analyzing enzymatic and non-enzymatic antioxidant responses, together with selected physiological and biochemical traits. Among the tested treatments, exo-PSHs differentially modulated antioxidant enzymes, with SRB primarily enhancing peroxidase and glutathione peroxidase and ITA increasing ascorbate peroxidase and catalase activity. SRB PSHs, particularly exo-PSH, showed the most pronounced effects on antioxidant-related responses, enhancing ABTS scavenging activity and altering DPPH capacity by approximately 35% compared with the control. In addition, endo-PSH from the ITA strain increased chlorophyll content by 26.12% and proline levels by 1.5-fold, indicating a distinct strain-dependent effect on plant physiological responses, particularly under stress conditions. LC–MS/MS profiling of plant MeOH extracts revealed a diverse range of secondary metabolites, including phenolic compounds, e.g., liquiritigenin, ferulic, and protocatechuic acids, which may contribute to the observed antioxidant responses. Multivariate analysis further supported clear biochemical differentiation among PSH treatments and growth conditions, confirming that the responses were dependent on both PSH origin and environmental conditions. Overall, these findings demonstrate that structurally distinct S. commune PSHs can differentially modulate antioxidant defense and key biochemical traits in pea seedlings, supporting their potential as sustainable fungus-derived biostimulants for enhancing plant resilience under both optimal and drought conditions. Full article

(This article belongs to the Special Issue Antioxidant and Anti-Inflammatory Properties of Mushrooms: From Structure to Functionality)

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65 pages, 5806 KB

Open AccessReview

Allium ursinum L. as a Source of Natural Antioxidants: Phytochemical Diversity, Biological Effects, and Functional Food Applications

by Cristina Adriana Rosan, George Alin Opris, Alexandra Cristina Tocai (Moțoc), Daniela Gitea, Ruben Budău, Manuel Alexandru Gitea and Simona Ioana Vicas

Antioxidants 2026, 15(9), 1144; https://doi.org/10.3390/antiox15091144 - 9 Sep 2026

Abstract

Allium ursinum L. (wild garlic) is a promising source of bioactive compounds for functional foods, nutraceuticals, and clean-label products. This review integrates current evidence on its phytochemical composition, biological activities, and food applications. The species contains sulfur compounds, polyphenols, vitamins, minerals, and pigments, [...] Read more.

Allium ursinum L. (wild garlic) is a promising source of bioactive compounds for functional foods, nutraceuticals, and clean-label products. This review integrates current evidence on its phytochemical composition, biological activities, and food applications. The species contains sulfur compounds, polyphenols, vitamins, minerals, and pigments, whose levels vary with plant organ, developmental stage, environmental conditions, and processing. These constituents are associated mainly with antioxidant, antimicrobial, cardioprotective, and cytoprotective effects; however, evidence is derived predominantly from in vitro and animal studies, with limited clinical validation. In food systems, A. ursinum may enhance nutritional value, oxidative stability, sensory properties, and shelf life. Extraction, encapsulation, and stabilization technologies may support its use as a natural alternative to synthetic additives. Nevertheless, compositional variability, processing stability, bioavailability, authenticity, quality control, and raw-material supply remain major barriers to standardization and industrial application. Further research should combine phytochemical characterization with technological, safety, clinical, and sustainability assessments to enable reliable use of A. ursinum in food and nutraceutical products. Full article

(This article belongs to the Special Issue Antioxidant Components of Food and Medicine Homology and Exploring Their Applications)

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35 pages, 2744 KB

Open AccessReview

Phytochemicals and Irisin as Multi-Target Regulators of Adipose Tissue Browning and Metabolic Reprogramming: Synergies with GLP-1 Pathways

by Nuriye Nuray Ulusu

Antioxidants 2026, 15(9), 1143; https://doi.org/10.3390/antiox15091143 - 9 Sep 2026

Abstract

Background: Obesity is a multifaceted metabolic disorder characterized by systemic disturbances, particularly impaired energy homeostasis, chronic low-grade inflammation, and mitochondrial dysfunction across the brain, gut, adipose tissue, and liver axes. Objectives: This review aims to examine the metabolic properties and molecular mechanisms of [...] Read more.

Background: Obesity is a multifaceted metabolic disorder characterized by systemic disturbances, particularly impaired energy homeostasis, chronic low-grade inflammation, and mitochondrial dysfunction across the brain, gut, adipose tissue, and liver axes. Objectives: This review aims to examine the metabolic properties and molecular mechanisms of six key phytochemicals (berberine, resveratrol, catechins, capsaicin, thymoquinone, and phycocyanin) and the exercise-induced myokine irisin, and their roles in mitochondrial signaling and metabolic reprogramming. Sources of Evidence: A comprehensive literature search was conducted across major electronic databases, including PubMed, Web of Science, and Scopus, to identify relevant mechanistic, in vivo, and in vitro studies. Results: Both the selected phytochemicals and irisin act as multi-target regulators that modulate key signaling pathways, including AMPK, PI3K/Akt/mTOR, SIRT1, Nrf2, and PPARγ. These phytochemicals and irisin can drive cell- and tissue-specific metabolic reprogramming, promoting the browning of white adipocytes, suppressing de novo lipogenesis in hepatocytes, and enhancing fatty acid oxidation in skeletal myocytes. This synergistic metabolic reprogramming enhances thermogenesis and increases energy expenditure. Conclusions: Co-targeting redox signaling and metabolic pathways via phytochemicals and irisin offers a powerful strategy against obesity. This integrative framework restores multi-organ homeostasis, laying the groundwork for targeted metabolic therapies. Full article

(This article belongs to the Special Issue Mitochondrial and Redox Signaling in Exercise, Aging, and Metabolic Health)

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18 pages, 705 KB

Open AccessArticle

Serum Redox Biomarkers in Canine Mast Cell Tumors: Exploratory Associations with Proliferative Activity and Clinicopathological Features

by Argyrios Ginoudis, Dimitra Pardali, Mathios E. Mylonakis, Serafeim Chaintoutis, Dimitris Galiatsatos, Angelos-Lauris Thomas and Zoe Polizopoulou

Antioxidants 2026, 15(9), 1142; https://doi.org/10.3390/antiox15091142 - 9 Sep 2026

Abstract

Canine mast cell tumors (MCTs) exhibit heterogeneous biological behavior and provide a clinically relevant setting in which relationships between tumor phenotype and systemic redox homeostasis can be investigated. This exploratory prospective cohort study evaluated complementary circulating redox-related biomarkers representing hydroperoxide-derived oxidant products, antioxidant [...] Read more.

Canine mast cell tumors (MCTs) exhibit heterogeneous biological behavior and provide a clinically relevant setting in which relationships between tumor phenotype and systemic redox homeostasis can be investigated. This exploratory prospective cohort study evaluated complementary circulating redox-related biomarkers representing hydroperoxide-derived oxidant products, antioxidant capacity, lipid peroxidation-related products, and oxidative DNA damage, and examined their associations with clinicopathological features of canine MCTs. Sixty-seven dogs with cytologically and histologically confirmed cutaneous or subcutaneous MCTs were included. Clinical staging was performed using cytological evaluation of lymph nodes, liver and spleen, and excised tumors were classified according to the Patnaik and Kiupel systems. Proliferative activity was assessed using Ki-67, and surgically excised lymph nodes were classified according to the Weishaar HN system. Serum reactive oxygen metabolites (d-ROMs), malondialdehyde (MDA), 8-hydroxy-2′-deoxyguanosine (8-OHdG) and antioxidant capacity using the OXY-adsorbent test were measured before therapeutic intervention. In the unadjusted analysis, serum MDA concentrations were higher in dogs with Ki-67 >23 than in dogs with Ki-67 ≤23 (median 10.8 vs. 7.0 μmol/L; raw p = 0.0254); however, this comparison did not remain statistically significant after Bonferroni correction for the 12 formal inferential biomarker × clinicopathological comparisons (adjusted p = 0.3052). The estimated Hodges–Lehmann location shift was +3.00 μmol/L (unadjusted bootstrap 95% CI, 0.58–6.00). No evaluated biomarker–clinicopathological association remained statistically significant after multiplicity adjustment. The observed MDA–Ki-67 pattern should therefore be regarded as exploratory and hypothesis-generating rather than as evidence of established prognostic or clinical utility. Long-term data on recurrence, progression, and survival were not available; therefore, prognostic utility could not be evaluated. Larger prospective studies incorporating longitudinal outcomes are warranted. Full article

(This article belongs to the Special Issue Oxidative Stress and Biomarkers in Veterinary Medicine)

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29 pages, 2336 KB

Open AccessArticle

Oxidative Stress and Inflammatory Cytokines as Drivers of Cardiac Remodeling in COPD Patients

by Elena-Andreea Moaleș, Lucia Corina Dima-Cozma, Cristina Andreea Adam, Doina-Clementina Cojocaru, Cristina Gena Dascălu, Andreea Iațentiuc, Iustin Mihai Iațentiuc, Tatiana Drâmbă, Maura Gabriela Felea, Robert Negru, Ioana Mădălina Zota, Romică Sebastian Cozma, Maria Magdalena Leon and Florin Mitu

Antioxidants 2026, 15(9), 1141; https://doi.org/10.3390/antiox15091141 - 9 Sep 2026

Abstract

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a systemic disease characterized by chronic inflammation and oxidative stress, with frequent cardiovascular involvement. This study investigated the associations between oxidative stress-related inflammatory markers and structural and electrical cardiac abnormalities in patients with COPD [...] Read more.

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a systemic disease characterized by chronic inflammation and oxidative stress, with frequent cardiovascular involvement. This study investigated the associations between oxidative stress-related inflammatory markers and structural and electrical cardiac abnormalities in patients with COPD using a comprehensive multimodal cardiopulmonary assessment. A total of 100 clinically stable patients with COPD underwent inflammatory biomarker evaluation (IL-6, IL-8, IL-1β, and TNF-α), transthoracic echocardiography and 24 h Holter ECG monitoring. Advanced COPD was associated with significant differences in several structural cardiac parameters, including left atrial volume (p = 0.016), left atrial height (p = 0.027), and selected left ventricular parameters, while left ventricular ejection fraction remained preserved. Electrical abnormalities were significantly associated with systemic inflammatory markers. SII showed the highest discriminatory performance for sinus rhythm abnormalities (AUC = 0.736), whereas IL-6 showed the highest discriminatory performance for ventricular premature complexes (AUC = 0.732). Ventricular ectopic activity was also associated with significantly higher SII, SIRI, MLR, NLR, and PLR. Systemic inflammatory markers were associated with structural and electrical cardiac abnormalities in COPD, suggesting that they may provide complementary information regarding cardiovascular involvement. However, given the cross-sectional design and moderate discriminatory performance of these biomarkers, the findings should be considered exploratory and do not establish causal relationships. Prospective studies are needed to determine their potential role in cardiovascular risk stratification. Full article

(This article belongs to the Special Issue Oxidative Stress in Lung Diseases)

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27 pages, 1987 KB

Open AccessReview

From Retina to Vasculature: Oxidative Stress as a Common Mechanistic Link Between Age-Related Macular Degeneration and Cardiovascular Disease

by Jan Krekora, Jarosław Drożdż, Janusz Blasiak and Kai Kaarniranta

Antioxidants 2026, 15(9), 1140; https://doi.org/10.3390/antiox15091140 - 9 Sep 2026

Abstract

Increasing epidemiological and experimental evidence suggests that age-related macular degeneration (AMD) and cardiovascular disease (CVD) share multiple pathogenic mechanisms. Among these, oxidative stress has emerged as one of the most plausible links connecting retinal degeneration and cardiovascular pathology. Excessive production of reactive oxygen [...] Read more.

Increasing epidemiological and experimental evidence suggests that age-related macular degeneration (AMD) and cardiovascular disease (CVD) share multiple pathogenic mechanisms. Among these, oxidative stress has emerged as one of the most plausible links connecting retinal degeneration and cardiovascular pathology. Excessive production of reactive oxygen and nitrogen species, combined with declining antioxidant defenses, contributes to lipid peroxidation, mitochondrial dysfunction, chronic inflammation, complement activation, cellular senescence, and impaired cellular stress responses in both the retina and the vascular system. Notably, drusen (AMD) and atherosclerotic plaques (CVD) share several molecular constituents. Therefore, AMD and CVD may represent tissue-specific manifestations of broader age-related disturbances in redox homeostasis and inflammatory regulation. Nevertheless, the coexistence of AMD and CVD is incomplete, suggesting that genetic susceptibility, tissue-specific responses to oxidative stress, biological aging, and mechanisms of cellular resilience influence disease expression. In this review, we summarize current evidence linking AMD and CVD, examine oxidative stress-driven molecular pathways common to both disorders, discuss emerging biomarkers and therapeutic targets, and highlight important unresolved questions regarding disease heterogeneity and causal relationships. A better understanding of the shared mechanisms underlying AMD and CVD may facilitate the development of integrated preventive strategies, improved risk stratification, and more personalized therapeutic approaches for age-related diseases. Full article

(This article belongs to the Special Issue Oxidative Stress and Redox Signalling Across Ocular Diseases: Mechanisms, Tissue-Specific Pathology, and Therapeutic Targets)

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