Antioxidants

18 pages, 2848 KB

Open AccessArticle

Urate as a CO₃^•− Scavenger and Regulator of SOD-1 and OGG1 Enzymes: Insights from DFT, Molecular Docking, and Molecular Dynamics

by Ana Amić, Žiko Milanović and Denisa Mastiľák Cagardová

Antioxidants 2026, 15(6), 761; https://doi.org/10.3390/antiox15060761 (registering DOI) - 16 Jun 2026

Abstract

The potency of urate, an abundant human plasma antioxidant, in preventing oxidative damage caused by the carbonate radical anion CO₃^•−, was studied using quantum chemical calculations. The influence of microhydration of CO₃^•−/CO₃²⁻ and urate⁻ [...] Read more.

The potency of urate, an abundant human plasma antioxidant, in preventing oxidative damage caused by the carbonate radical anion CO₃^•−, was studied using quantum chemical calculations. The influence of microhydration of CO₃^•−/CO₃²⁻ and urate⁻/urate^• couples on the thermodynamic and kinetics of the one-electron oxidation process was investigated. Depending on the degree of microhydration, the estimated rate constant for one-electron transfer is in the range of 2.0–7.3 × 10⁹ M⁻¹ s⁻¹, in good agreement with the experimental value of 1.3 × 10⁹ M⁻¹ s⁻¹. Modeling using vertical detachment energy and electron affinity, the driving forces of single electron transfer revealed urate(H₂O)₆⁻ and CO₃(H₂O)₉^•− clusters as the most likely existing species in water. Molecular docking revealed a favorable interaction of urate with the catalytic pocket of SOD1. Urate binds more strongly to the anionic active center of SOD1 than the reference inhibitor LSC-1, indicating its potency to prevent HCO₃⁻-supported CO₃^•− formation. In contrast, the known OGG1 inhibitor TH13264 shows substantially stronger binding than urate, indicating urate’s weaker affinity toward the DNA repair enzyme catalytic pocket. The molecular dynamics data indicate that urate binding does not destabilize either SOD1 or OGG1. In light of increasing evidence that the major source of oxidative stress could be CO₃^•−, rather than the commonly assumed hydroxyl radical HO^•, the obtained results indicate the inherent ability of plasma to combat oxidative stress induced by this selective, milder oxidant. Such an ability with respect to the non-selective, highly reactive HO^• does not exist in vivo. Full article

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

► Show Figures

Figure 1

17 pages, 268 KB

Open AccessArticle

Assessment of the Impact of Cold Atmospheric Plasma Application on Wound Healing in Streptozotocin-Induced Diabetic Rats

by Emine Ersozlu, Emine Iyigun and Muhammed Kamil Turan

Antioxidants 2026, 15(6), 760; https://doi.org/10.3390/antiox15060760 (registering DOI) - 16 Jun 2026

Abstract

Diabetic wounds remain a major clinical challenge due to impaired healing associated with persistent inflammation, oxidative stress, and microvascular dysfunction. Plasma-based therapies have emerged as promising approaches for promoting tissue repair; however, comparative evidence regarding different plasma modalities remains limited. In this study, [...] Read more.

Diabetic wounds remain a major clinical challenge due to impaired healing associated with persistent inflammation, oxidative stress, and microvascular dysfunction. Plasma-based therapies have emerged as promising approaches for promoting tissue repair; however, comparative evidence regarding different plasma modalities remains limited. In this study, we evaluated and compared the effects of atmospheric pressure cold plasma (APCP) and plasma-activated water (PAW) on wound healing in a streptozotocin-induced diabetic rat model. Forty Wistar albino rats were randomly assigned to five groups: isotonic wet dressing, hydrocolloid dressing, APCP treatment, PAW application, and a non-diabetic control group. Wound healing was assessed using macroscopic evaluation, histopathological analysis, and biochemical measurements of systemic oxidative status. PAW treatment significantly accelerated wound closure during the early healing phase compared with conventional dressing methods (p < 0.05). Histological findings demonstrated enhanced re-epithelialization, increased collagen deposition, and improved follicular regeneration in the PAW group. Although total oxidant status (TOS) did not differ significantly among groups (p = 0.996), total antioxidant status (TAS) was significantly increased following PAW treatment (p < 0.05), indicating a more favorable systemic antioxidant profile. These findings suggest an association between improved wound healing and a more favorable systemic antioxidant profile following PAW treatment. However, because local wound-level redox parameters and molecular markers were not assessed, the contribution of redox-related mechanisms remains to be clarified. Moreover, PAW demonstrated superior therapeutic efficacy compared with direct plasma application, highlighting its potential as a non-invasive approach for diabetic wound management. Full article

(This article belongs to the Special Issue Reactive Oxygen Species (ROS): Key Components in Infection Control, Wound Healing, and Cancer Therapy)

47 pages, 3030 KB

Open AccessReview

Beyond KEAP1: The Context-Specific NRF2 Partner Code in Disease and Therapy

by Seung-Jin Kwag, Jin-Kwon Lee, Seung-Jun Lee, Jeongyun Hwang and Young-Sool Hah

Antioxidants 2026, 15(6), 759; https://doi.org/10.3390/antiox15060759 (registering DOI) - 16 Jun 2026

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited [...] Read more.

Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited by coactivator assembly despite unchanged NRF2 abundance; and NRF2 activation can be beneficial or harmful depending on disease context, as illustrated by lung cancer models in which NRF2 paradoxically promotes metastasis through BTB and CNC homology 1 (BACH1) stabilization. We synthesize these observations into an NRF2 partner-code framework in which NRF2 acts as a context-dependent transcriptional platform assembled through four partly independent modules: a degradation module (KEAP1; β-transducin repeat-containing protein, β-TrCP; HMG-CoA reductase degradation protein 1/synoviolin 1, Hrd1/SYVN1; WD repeat-containing protein 23/DDB1- and CUL4-associated factor 11, WDR23/DCAF11); a cytoplasmic scaffold module (p62/sequestosome 1, p62/SQSTM1; IQ motif-containing GTPase-activating protein 1, IQGAP1; type I phosphatidylinositol 4-phosphate 5-kinase γ/heat shock protein 27, PIPKIγ–HSP27; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1; peptidyl-prolyl isomerase A/cyclophilin A, PPIA); a nuclear coactivator module at Neh4/5 (CREB-binding protein/p300, CBP/p300; receptor-associated coactivator 3/steroid receptor coactivator 3, RAC3/SRC-3; protein arginine methyltransferase 1/coactivator-associated arginine methyltransferase 1, PRMT1/CARM1; Mediator complex subunit 16, MED16); and a DNA/chromatin module at Neh1 (small musculoaponeurotic fibrosarcoma [Maf] proteins, BACH1, and chromodomain helicase DNA-binding protein 6, CHD6). Mapping 22 partners onto the Neh-domain architecture identifies approximately 25 pharmacologically addressable interfaces, stratified into four translational tiers. The framework reframes NRF2 pharmacology around one principle: the most actionable target is often a partner rather than NRF2 itself, with disease context dictating the direction of modulation. We close with five testable hypotheses and a partner-code decision matrix linking disease, biomarker, and candidate target. Full article

(This article belongs to the Section Antioxidant Enzyme Systems)

► Show Figures

Figure 1

23 pages, 3226 KB

Open AccessArticle

Physalis angulata Leaf Extract Attenuates H₂O₂-Induced Neurotoxicity in Zebrafish Through Metabolomic Evidence of Antioxidant Pathway Restoration

by Fanny Anabel Sulistio, Richard Johari James, Salfarina Ramli, Callista Andinie Mulyadi, Hasseri Halim, Michael Vin, Fadlina Chany Saputri, Indri Yuliani Hamdani, Syariful Mubarok, Aliyya Hanaa Naila, Amorisa Savitri and Donna Maretta Ariestanti

Antioxidants 2026, 15(6), 758; https://doi.org/10.3390/antiox15060758 (registering DOI) - 16 Jun 2026

Abstract

Neurological disorders affect billions of people worldwide, with oxidative stress and its associated cellular mechanisms recognized as key pathological drivers of neuronal damage. Despite this, natural agents capable of targeting these mechanisms remain underexplored. Physalis angulata L. (PA) contains physalins and withanolides known [...] Read more.

Neurological disorders affect billions of people worldwide, with oxidative stress and its associated cellular mechanisms recognized as key pathological drivers of neuronal damage. Despite this, natural agents capable of targeting these mechanisms remain underexplored. Physalis angulata L. (PA) contains physalins and withanolides known for their neuroprotective properties, though its in vivo neuroprotective mechanism remains poorly characterized. This study evaluated the preventive neuroprotective effects of PA leaf extract using an integrated developmental, behavioral, and metabolomic approach in a H₂O₂-induced zebrafish (Danio rerio) model. PA extract demonstrated moderate-to-strong antioxidant capacity (ABTS IC₅₀ = 66.66 ppm; DPPH IC₅₀ = 114.91 ppm). Treatment with 50 ppm PA extract provided optimal neuroprotection, significantly restoring body length, yolk sac utilization, and heart rate, while markedly improving locomotor activity and reducing anxiety-like thigmotaxis behavior. Notably, PA extract demonstrated superior efficacy compared to N-acetylcysteine (NAC) across multiple developmental and behavioral endpoints. Metabolomic profiling of zebrafish embryo homogenates provided direct in vivo biochemical evidence of antioxidant pathway modulation, demonstrating that PA extract mitigated metabolic disruption by restoring amino acid metabolism (glycine, serine, and threonine), glutathione synthesis, glycerophospholipid homeostasis, and one-carbon pool metabolism. These findings demonstrate that P. angulata exerts multi-target neuroprotection by restoring antioxidant pathways and promoting metabolic homeostasis, supporting its potential as a natural therapeutic candidate for oxidative stress-related neurological conditions. Full article

(This article belongs to the Section Natural and Synthetic Antioxidants)

► Show Figures

Figure 1

23 pages, 1231 KB

Open AccessReview

Iron Compartmentalisation and Vascular Endothelial Cell Dysfunction

by Theo Issitt, George W. Kagugbe, Quezia K. Toe, S. John Wort and Gregory J. Quinlan

Antioxidants 2026, 15(6), 757; https://doi.org/10.3390/antiox15060757 (registering DOI) - 15 Jun 2026

Abstract

Iron is essential for life, but its safe use by the body depends on it being kept within tightly controlled compartments. When this compartmentalisation is disrupted—through haemolysis, saturation of scavenger proteins, or dysregulation of the hepcidin–ferroportin axis—damaging iron species accumulate in the circulation [...] Read more.

Iron is essential for life, but its safe use by the body depends on it being kept within tightly controlled compartments. When this compartmentalisation is disrupted—through haemolysis, saturation of scavenger proteins, or dysregulation of the hepcidin–ferroportin axis—damaging iron species accumulate in the circulation and within vascular cells, with potentially serious consequences for endothelial function. This review explores the mechanisms by which iron dysregulation compromises vascular endothelial cell biology across a range of disease states, including haemolytic anaemias, atherosclerosis, cerebrovascular disease, extracorporeal circulatory support, and iatrogenic iron loading. Common pathological themes emerge: depletion of nitric oxide bioavailability, oxidative stress, endothelial activation, and in chronic settings, vascular remodelling. The review subsequently focuses in depth on the pulmonary vasculature, where dysregulated iron compartmentalisation has emerged as a key contributor to the pathogenesis of pulmonary hypertension. Here, iron-driven mitochondrial dysfunction, smooth muscle cell proliferation, and iron-dependent lipid peroxidation via ferroptosis are discussed as mechanistic drivers of pulmonary vascular remodelling. The therapeutic implications of targeting iron handling in pulmonary hypertension are considered, including modulation of the hepcidin–ferroportin axis. Together, the evidence presented highlights disordered iron compartmentalisation as a unifying pathological thread across vascular disease and a compelling target for intervention. Full article

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

► Show Figures

Figure 1

37 pages, 2486 KB

Open AccessArticle

Bioactive Profile, Antioxidant, and Antimicrobial Activity of Sweet and Hot Peppers at Different Stages of Ripeness

by Elena Coyago-Cruz, Gabriela Méndez, Santiago Buyancela, Fátima Rodríguez-Muñoz and Jorge Heredia-Moya

Antioxidants 2026, 15(6), 756; https://doi.org/10.3390/antiox15060756 (registering DOI) - 15 Jun 2026

Abstract

The genus Capsicum is widely used worldwide for its culinary value and functional potential. The objective of this study was to evaluate the bioactive compounds, antioxidant and antimicrobial activity of sweet and hot pepper at different stages of ripeness. Six varieties of peppers [...] Read more.

The genus Capsicum is widely used worldwide for its culinary value and functional potential. The objective of this study was to evaluate the bioactive compounds, antioxidant and antimicrobial activity of sweet and hot pepper at different stages of ripeness. Six varieties of peppers at five stages of ripeness were analysed. Mineral parameters (Ca, Fe, Na, K, Mg) were determined by atomic absorption spectrophotometry, while bioactive compounds (vitamin C, organic acids, carotenoids, and phenols) were analysed by liquid chromatography. Antioxidant activity was evaluated using ABTS and DPPH assays, and antimicrobial activity was assessed by minimum inhibitory concentration against bacteria and yeasts. Multivariate analyses (PCA and heatmap) were carried out at a significance level of p < 0.05. The results showed that genotype was the main determinant of variability, surpassing the effect of ripeness. Potassium was the predominant mineral (3431.5 mg/100 g DW) in Malagueta chilli M5. Variety-specific peaks were identified, notably vitamin C in Habanero chilli (M3) (10,319.5 mg/100 g DW), capsaicin in Malagueta chilli (M5) (1949.8 mg/100 g DW), and carotenoids in Orange medium peppers (M5) (9495.8 mg/100 g DW). Antioxidant activity was higher in hot varieties (41.3 mmol ET/100 g DW in Habanero chilli (M2) by DPPH), while antimicrobial activity varied against Escherichia coli (2.6 mg/mL in Yellow medium peppers (M4)), Staphylococcus aureus (5.2 mg/mL in Orange medium pepper), and Streptococcus mutans (2.0 mg/mL in Jalapeño chilli), with low MIC values. Multivariate analyses confirmed that chemical and biological variability is primarily structured by genotype. Full article

(This article belongs to the Special Issue Plant Materials and Their Antioxidant Potential, 3rd Edition)

17 pages, 2564 KB

Open AccessArticle

Allomyrinasin, an Edible Insect-Derived Peptide, Ameliorates High-Fat Diet-Induced Hepatic Oxidative Stress and Metabolic Dysfunction

by Kyong Kim, Chae-Heon Lee, Chae-Eun Kim, Eun-Young Park, Jae-Sam Hwang and Yoon Sin Oh

Antioxidants 2026, 15(6), 755; https://doi.org/10.3390/antiox15060755 (registering DOI) - 15 Jun 2026

Abstract

Allomyrinasin is an antimicrobial peptide derived from the larvae of the edible insect Allomyrina dichotoma and has been reported to exert anti-inflammatory activity, although its role in metabolic regulation remains unclear. This study aimed to investigate the metabolic and hepatoprotective effects of allomyrinasin [...] Read more.

Allomyrinasin is an antimicrobial peptide derived from the larvae of the edible insect Allomyrina dichotoma and has been reported to exert anti-inflammatory activity, although its role in metabolic regulation remains unclear. This study aimed to investigate the metabolic and hepatoprotective effects of allomyrinasin in a high-fat diet (HFD)–induced obese mouse model. Male C57BL/6J mice were fed an HFD for 6 weeks to induce body weight gain and hyperglycemia, followed by 10 weeks of oral administration of allomyrinasin (0.1 mg/kg/day) under continued HFD conditions, with metformin used as a positive control. Metabolic parameters related to glucose homeostasis, insulin sensitivity, lipid metabolism, hepatic injury, oxidative stress, inflammation, and fibrotic responses were evaluated. Allomyrinasin significantly attenuated HFD-associated body weight gain and improved glucose tolerance and insulin sensitivity. These effects were accompanied by favorable modulation of serum lipid profiles and suppression of hepatic lipogenic signaling, including reduced expression of key regulators of de novo lipogenesis. In parallel, allomyrinasin mitigated hepatic inflammatory, fibrotic, and oxidative stress-related alterations, as reflected by improvements in biochemical markers and molecular analyses. Collectively, these findings indicate that allomyrinasin contributes to the improvement of metabolic regulation and hepatic homeostasis in HFD-fed mice. Our results support allomyrinasin as a promising food-applicable bioactive peptide and potential functional ingredient for the prevention or management of obesity-related metabolic disorders. Full article

(This article belongs to the Section Natural and Synthetic Antioxidants)

► Show Figures

Figure 1

32 pages, 26574 KB

Open AccessArticle

Cannabigerol and Cannabichromene Induce Lung Cancer Cell Death and Apoptosis—Contribution of PPARα to Cannabigerol Effects

by Theresa Spengler, Felix Wittig, Marcus Frank and Burkhard Hinz

Antioxidants 2026, 15(6), 754; https://doi.org/10.3390/antiox15060754 (registering DOI) - 15 Jun 2026

Abstract

Cannabinoids are potential anticancer agents for the add-on treatment of malignant tumors. Here, the effects of the previously less-explored non-psychoactive phytocannabinoids cannabigerol (CBG) and cannabichromene (CBC) on survival, apoptosis, and mitochondrial function were assessed in A549 and H460 lung cancer cells. CBG and [...] Read more.

Cannabinoids are potential anticancer agents for the add-on treatment of malignant tumors. Here, the effects of the previously less-explored non-psychoactive phytocannabinoids cannabigerol (CBG) and cannabichromene (CBC) on survival, apoptosis, and mitochondrial function were assessed in A549 and H460 lung cancer cells. CBG and CBC triggered concentration-dependent cell death, autophagy, and mitochondrial apoptosis in both cell lines, with apoptosis indicated by Annexin V staining, activation of caspase-8, -9, and -3/7, loss of mitochondrial membrane potential, and elevated cytosolic levels of mitochondrial cytochrome c. CBG also upregulated ATF4, a stress-responsive transcription factor involved in autophagy and apoptotic signaling, and enhanced PARP cleavage. Both cannabinoids increased mitochondrial superoxide formation and reduced the mitochondrial oxygen consumption rate, with CBG additionally decreasing NDUFB8, a subunit of respiratory chain complex I. Pharmacological receptor modulation showed that CBG- and CBC-induced cell death occurred independently of CB₁, CB₂, TRPV1, TRPM8, and PPARγ, whereas CBG-mediated cell death relied on PPARα, which also contributed to its apoptotic effects. In summary, CBG and CBC induce apoptosis and cell death in A549 and H460 cells, with PPARα mediating the effects of CBG, highlighting its potential as a therapeutic target. Full article

(This article belongs to the Section Antioxidant Enzyme Systems)

► Show Figures

Figure 1

25 pages, 3972 KB

Open AccessArticle

Ultrasound-Treated Sweet Potato Peel Enhances Nutritional Quality and Antioxidant Potential of Gluten-Free Brownies: A Metabolomics and Cell-Based Approach

by Pablo Ayuso, Rocío Peñalver, Jhazmin Quizhpe, Pascual García-Pérez and Gema Nieto

Antioxidants 2026, 15(6), 753; https://doi.org/10.3390/antiox15060753 (registering DOI) - 15 Jun 2026

Abstract

Agri-food by-products such as sweet potato peel (SP) represent a sustainable and valuable source of bioactive compounds for improving gluten-free (GF) foods. This study evaluated the nutritional and functional impact of incorporating SP at 8% and 16%, either untreated or ultrasound-assisted extraction (UAE)-treated, [...] Read more.

Agri-food by-products such as sweet potato peel (SP) represent a sustainable and valuable source of bioactive compounds for improving gluten-free (GF) foods. This study evaluated the nutritional and functional impact of incorporating SP at 8% and 16%, either untreated or ultrasound-assisted extraction (UAE)-treated, into GF brownies. An untargeted metabolomics approach combined with chemometrics was applied to characterize phytochemical modulation after in vitro digestion of the brownies, while antioxidant and anti-inflammatory effects were assessed using RAW264.7 macrophages. SP incorporation increased the dietary fiber (reaching a content of 7.86%) and glycosylated flavonoid content in reformulated brownies, leading to a reduction of inflammatory markers in the cellular model. Sensory evaluation showed that SP addition did not significantly affect texture-related attributes or extract-related perception. In contrast, UAE acted as an efficient extraction strategy, enhancing terpenoid-like compounds and total phenolic content (TPC), reaching values of 401.97 mg GAE 100 g⁻¹ after 16% incorporation. Overall, combining SP valorization with UAE represents a promising strategy to develop nutritionally enhanced GF products, providing a foodomics-based framework for next-generation functional bakery products. Full article

(This article belongs to the Special Issue The Role of Antioxidants in Food Safety and Quality)

► Show Figures

Figure 1

15 pages, 3120 KB

Open AccessArticle

Quorum Sensing Regulator CinR Directly Activates the Catalase–Peroxidase Gene katG to Alleviate Oxidative Stress and Promote Symbiotic Nitrogen Fixation in Rhizobium etli CFN42

by Xuelian Chen, Tianyi Wu, Zhi Zheng, Chuling Gan, Jian Lin, Siqing Yin, Zi Li, Hongjian Liu, Yajun Cao, Zhi Huang, Hui Wang, Guoxi Zhang and Zengtao Zhong

Antioxidants 2026, 15(6), 752; https://doi.org/10.3390/antiox15060752 (registering DOI) - 15 Jun 2026

Abstract

Many rhizobia use quorum sensing (QS) systems to detect their population density and modify their symbiotic behavior with the legume host. There are three LuxRI-type QS systems in Rhizobium etli CFN42, and CinR plays a key role in symbiotic performance. However, the details [...] Read more.

Many rhizobia use quorum sensing (QS) systems to detect their population density and modify their symbiotic behavior with the legume host. There are three LuxRI-type QS systems in Rhizobium etli CFN42, and CinR plays a key role in symbiotic performance. However, the details of how CinR regulates the symbiotic process remain unknown. In this study, we employed the RNA-Seq method to screen differentially expressed genes between the wild-type strain and the ΔcinR mutant of R. etli CFN42. We found that most of the genes related to reactive oxygen species (ROS) were expressed at lower levels in the ΔcinR mutant than in CFN42. We also found that the ΔcinR mutant was more sensitive to H₂O₂ than to CFN42. We then showed that CinR positively regulated katG expression and possessed an affinity to bind the katG promoter in the absence of the AHL ligand. The addition of AHLs promoted CinR binding to the katG promoter and enhanced katG expression. Accumulation of H₂O₂ and O₂^•− was observed in root nodules formed by the ΔcinR mutant. Crucially, katG overexpression rescued the H₂O₂-sensitive phenotype in vitro and partially restored defective symbiotic performance in nodules formed by the ΔcinR mutant on the common bean. These results suggest that CinR globally regulates ROS scavenging gene expression in order to balance oxidative stress within root nodules, promoting nitrogenase activity of R. etli CFN42. Full article

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

► Show Figures

Figure 1

25 pages, 1866 KB

Open AccessReview

Oxidative Stress in Glaucoma: From Pathogenic Mechanisms to Emerging Antioxidant Therapies

by Akiko Hanyuda, Satoru Tsuda, Naoki Takahashi, Masataka Sato, Kota Sato, Noriko Himori and Toru Nakazawa

Antioxidants 2026, 15(6), 751; https://doi.org/10.3390/antiox15060751 (registering DOI) - 14 Jun 2026

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. While elevated intraocular pressure (IOP) remains the primary modifiable risk factor, a certain proportion of patients continue to deteriorate despite [...] Read more.

Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. While elevated intraocular pressure (IOP) remains the primary modifiable risk factor, a certain proportion of patients continue to deteriorate despite adequate IOP control, pointing to IOP-independent mechanisms of neurodegeneration. Oxidative stress—defined as an imbalance between the production of reactive oxygen species and the capacity of endogenous antioxidant defenses—has emerged as a central, multi-tiered contributor to glaucoma pathogenesis. In the anterior segment, chronic oxidative damage to the trabecular meshwork impairs aqueous humor outflow and drives IOP elevation. In addition, oxidative stress may impair ocular biomechanical integrity, including corneal hysteresis and lamina cribrosa, resulting in heightened susceptibility to IOP fluctuations. In the posterior segment, oxidative stress directly contributes to mitochondrial damage and vascular endothelial injury, leading to RGC apoptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway coordinates the principal endogenous antioxidant response, while nicotinamide adenine dinucleotide (NAD⁺) depletion links redox imbalance to metabolic vulnerability of RGCs. This narrative review synthesizes evidence published up to March 2026 on the molecular mechanisms of oxidative stress in glaucoma, the role of biomarkers in aqueous humor and systemic circulation, and the translational landscape of antioxidant-based neuroprotection—including nicotinamide, coenzyme Q10, alpha-lipoic acid, and Nrf2-activating compounds. We highlight gaps between preclinical promise and clinical evidence, and outline priorities for future randomized controlled trials. Full article

(This article belongs to the Special Issue Role of Oxidative Stress in Eye Diseases)

► Show Figures

Figure 1

26 pages, 1876 KB

Open AccessArticle

Phenolic Profile and Antioxidant Potential of Selected European Astragalus Species: Comparative UHPLC–DAD–ESI/TOF–MS and In Vitro Study

by Jakub Gębalski, Milena Gębalska, Ewa Kiełkowska, Piotr Sit, Iga Hołyńska-Iwan, Magdalena Wójciak and Daniel Załuski

Antioxidants 2026, 15(6), 750; https://doi.org/10.3390/antiox15060750 (registering DOI) - 13 Jun 2026

Abstract

Plants of the genus Astragalus are recognized as rich sources of bioactive compounds with antioxidant and therapeutic potential; however, European species remain less explored than the well-known Astragalus membranaceus (Fisch.) Bunge. The aim of this study was to compare the phytochemical composition and [...] Read more.

Plants of the genus Astragalus are recognized as rich sources of bioactive compounds with antioxidant and therapeutic potential; however, European species remain less explored than the well-known Astragalus membranaceus (Fisch.) Bunge. The aim of this study was to compare the phytochemical composition and in vitro biological activity of selected Astragalus species occurring in Poland (A. cicer L., A. glycyphyllos L., A. membranaceus). Phenolic compounds in methanolic extracts obtained from the roots and aerial parts were analyzed using spectrophotometric methods and UHPLC–DAD–ESI/TOF–MS. Antioxidant activity was evaluated using DPPH, ABTS, FRAP, CUPRAC, metal chelation, superoxide radical scavenging, and lipid peroxidation (TBARS) assays. Additionally, enzyme inhibition toward α-amylase, lipase, hyaluronidase, tyrosinase, and butyrylcholinesterase was assessed. The root of A. membranaceus exhibited the highest total phenolic content (199.84 ± 3.64 mg GAE/g extract) and the strongest antioxidant activity (DPPH IC₅₀ = 36.53 ± 1.22 µg/mL; ABTS IC₅₀ = 26.31 ± 0.03 µg/mL), as well as the most pronounced α-amylase inhibition (IC₅₀ = 17.78 ± 1.16 µg/mL). It also demonstrated moderate protective effects against AAPH-induced lipid peroxidation. The herb of A. cicer showed moderate radical scavenging capacity and the most effective inhibition of lipid peroxidation at higher concentrations. Extracts of A. glycyphyllos displayed weaker radical scavenging but notable metal-chelating properties. Selected extracts also exhibited moderate inhibitory activity against tyrosinase and butyrylcholinesterase. A. membranaceus remains the most potent source of phenolic compounds and antioxidant activity; European species such as A. cicer and A. glycyphyllos represent promising, locally available alternatives and may be used in phytotherapy and functional products. Full article

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

► Show Figures

Graphical abstract

26 pages, 8571 KB

Open AccessFeature PaperArticle

Phenazine Methosulfate Rewires Mitochondrial Redox Circuits to Restore Membrane Potential and ATP Synthesis Under ETC Blockade in Glioblastoma Cells

by Andrius Kleinauskas, Marianna Canonaco, Tine Therese Henriksen Raabe, Elin Ryan, Petras Juzenas, Beata Grallert, Aspasia Valiraki, Athanasios Papakyriakou and Theodossis A. Theodossiou

Antioxidants 2026, 15(6), 749; https://doi.org/10.3390/antiox15060749 (registering DOI) - 13 Jun 2026

Abstract

Mitochondrial electron transport chain (ETC) dysfunction is a major driver of bioenergetic failure, redox imbalance, and drug toxicity, yet strategies to restore oxidative phosphorylation under ETC blockade remain limited. Redox-active small molecules could, in principle, shuttle electrons from NADH to distal ETC components [...] Read more.

Mitochondrial electron transport chain (ETC) dysfunction is a major driver of bioenergetic failure, redox imbalance, and drug toxicity, yet strategies to restore oxidative phosphorylation under ETC blockade remain limited. Redox-active small molecules could, in principle, shuttle electrons from NADH to distal ETC components and oxygen, thereby modulating both respiration and reactive oxygen species (ROS) formation. Here, we show that the enzyme-independent redox cycler phenazine methosulfate (PMS) rewires mitochondrial redox circuits and restores respiration in human glioblastoma cells and cell-free systems under ETC inhibition. At subtoxic concentrations, PMS acutely increased oxygen consumption and mitochondrial superoxide generation via NADH–PMS–O₂ redox cycling, while restoring mitochondrial membrane potential and ATP synthesis under ETC blockade, and shifting metabolism away from glycolytic lactate production. This profile is consistent with a protective redox-bypass role, distinct from the pro-apoptotic effects reported following high-dose, prolonged PMS exposure. The PMS-driven restoration of electron flow, mitochondrial membrane potential, and respiratory ATP synthesis under inhibition of Complex I (rotenone), III (antimycin A and myxothiazol), and/or IV (cyanide) is consistent with direct cytochrome c reduction, as demonstrated herein, and engagement of multiple ETC redox centers, including coenzyme Q₁₀. In metformin-treated cells, PMS reversed suppression of respiration and lactate accumulation, outperforming existing redox-bypass strategies. These findings identify PMS-driven redox cycling as a previously unrecognized chemical redox-bypass mechanism that both regenerates mitochondrial bioenergetics and reshapes ROS production, suggesting a potential approach to counteract drug- and toxin-induced mitochondrial dysfunction and to exploit redox vulnerabilities in cancer. Full article

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

► Show Figures

Figure 1

13 pages, 1758 KB

Open AccessArticle

Mechanistic Insights into Starch-Polyphenol Complexation: Role of Structural Differences in Galloyl-Based Polyphenols

by Liang Wang, Leyi Li, Seda Arioglu-Tuncil, Ting He and Kai Wang

Antioxidants 2026, 15(6), 748; https://doi.org/10.3390/antiox15060748 (registering DOI) - 13 Jun 2026

Abstract

Fruit and vegetable processing by-products, such as peels and pomace, are rich in antioxidant polyphenols and represent promising sources of functional ingredients, but how their galloyl-based polyphenols interact with starch remains insufficiently understood. In this study, corilagin with three non-free galloyl moieties and [...] Read more.

Fruit and vegetable processing by-products, such as peels and pomace, are rich in antioxidant polyphenols and represent promising sources of functional ingredients, but how their galloyl-based polyphenols interact with starch remains insufficiently understood. In this study, corilagin with three non-free galloyl moieties and 1,2,3,4,6-O-pentagalloyl glucose with five free galloyl moieties were used as model polyphenols to clarify how galloyl moiety number and accessibility modulate their complexation with high-amylose maize starch (HAMS). Size-exclusion chromatography showed that both polyphenols preferentially complexed with amylose, while FTIR confirmed that complex formation occurred mainly through non-covalent interactions. The two polyphenols induced distinct changes in HAMS structure. Corilagin disrupted short-range order and produced no detectable crystalline structure, whereas 1,2,3,4,6-O-pentagalloyl glucose enhanced molecular order and induced V-type crystallization. Isothermal titration calorimetry revealed more binding sites but weaker affinity for corilagin, with thermodynamic signatures indicating hydrogen bonding and van der Waals interactions. By contrast, 1,2,3,4,6-O-pentagalloyl glucose showed stronger affinity and hydrophobic interaction-dominated binding. Molecular dynamics simulations further confirmed that 1,2,3,4,6-O-pentagalloyl glucose formed a more stable association with the amylose helix than corilagin. These results indicate that galloyl moiety characteristics markedly influence starch–polyphenol interaction mechanisms, providing guidance for the utilization of polyphenol-rich agro-processing by-products in functional starch-based foods. Full article

(This article belongs to the Special Issue Antioxidant Properties and Applications of Food By-Products—2nd Edition)

► Show Figures

Figure 1

40 pages, 1337 KB

Open AccessReview

Scorpion Venom Peptides: From Structural Scaffolds to Therapeutic Applications—A Focus on Antioxidant Mechanisms and Translational Perspectives

by Man Wang, Haoqi Li, Sheng Li, Yanjie Guo, Yijin Xu, Jie Zhao and Lili Chen

Antioxidants 2026, 15(6), 747; https://doi.org/10.3390/antiox15060747 (registering DOI) - 12 Jun 2026

Abstract

Scorpion venom peptides, with their stable disulfide backbone, compact structural framework, and highly selective regulation of ion channels, have long been regarded as important molecular probes in neuropharmacology. However, recent studies have revealed their potential for regulating oxidative stress, inflammation, and neuroprotection, making [...] Read more.

Scorpion venom peptides, with their stable disulfide backbone, compact structural framework, and highly selective regulation of ion channels, have long been regarded as important molecular probes in neuropharmacology. However, recent studies have revealed their potential for regulating oxidative stress, inflammation, and neuroprotection, making them a new research frontier. In this article, we focus on scorpion venom peptides as drugs, constructing an integrated knowledge framework from structural classification to clinical translation. First, scorpion venom peptides are systematically classified based on cysteine arrangement patterns and three-dimensional folding topology, and their structure–activity relationships are summarized. Based on this, the molecular mechanisms by which scorpion venom peptides regulate ion channels are systematically analyzed. We review the emerging pharmacological activities of scorpion venom peptides. Of particular note, the representative molecule SVHRSP has shown multi-target synergistic antioxidant and neuroprotective activity in models of Parkinson’s disease. We also systematically evaluate the application of engineering strategies, including cyclisation modification, nanodelivery, recombinant expression, and AI-assisted optimization, to overcome the translational bottlenecks in the development of scorpion venom peptides. However, it should be noted that most SVHRSP-related findings have been reported by a single research group; independent replication, pharmacokinetic characterization, and human efficacy data are still lacking. Its IND approval permits clinical investigation but does not yet constitute proven therapeutic benefit in patients. By integrating molecular structure, redox regulation mechanisms, and translational medicine perspectives, this review aims at providing a theoretical basis and practical pathways for scorpion venom peptides as precision therapeutic molecules for oxidative stress-related diseases. Full article

(This article belongs to the Special Issue Antioxidant Peptides)

35 pages, 6134 KB

Open AccessReview

Redox Network Failure in Chronic Kidney Disease: Hydrogen Sulfide Deficiency, Reactive Sulfur Species Dysregulation and the Uremic Toxin–AhR–Mitochondrial Axis

by Kuo-Cheng Lu, Chia-Chao Wu, Te-Chao Fang, Yi-Chou Hou, Cai-Mei Zheng and Chien-Lin Lu

Antioxidants 2026, 15(6), 746; https://doi.org/10.3390/antiox15060746 (registering DOI) - 12 Jun 2026

Abstract

Chronic kidney disease (CKD) affects approximately 700 million people worldwide and is a major contributor to end-stage renal disease (ESRD), cardiovascular morbidity, and premature mortality. Although oxidative stress has long been considered central to CKD progression, conventional antioxidant strategies have not consistently improved [...] Read more.

Chronic kidney disease (CKD) affects approximately 700 million people worldwide and is a major contributor to end-stage renal disease (ESRD), cardiovascular morbidity, and premature mortality. Although oxidative stress has long been considered central to CKD progression, conventional antioxidant strategies have not consistently improved clinical outcomes, suggesting that excess reactive oxygen species (ROS) alone cannot fully account for the underlying disease pathophysiology. Emerging evidence supports a broader paradigm of redox network failure, characterized by the disruption of coordinated signaling among ROS, nitric oxide (NO), and reactive sulfur species (RSS). Within this framework, hydrogen sulfide (H₂S), a major endogenous RSS, functions as a key regulator of renal redox homeostasis. CKD is consistently associated with systemic and renal H₂S deficiency, accompanied by downregulation of cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), as well as impaired transsulfuration and disrupted mitochondrial sulfide oxidation. Importantly, this deficiency cannot be explained solely by reduced renal function but instead reflects active suppression of H₂S biosynthesis. Uremic toxins, particularly indoxyl sulfate (IS), contribute to this process through activation of the aryl hydrocarbon receptor (AhR), which inhibits specificity protein 1 (Sp1)-dependent transcription of H₂S-producing enzymes. This IS–AhR–Sp1 axis provides a mechanistic link between toxin accumulation and disruption of the sulfur arm of the redox network, amplifying oxidative stress, endothelial dysfunction, mitochondrial impairment, ferroptotic vulnerability, and fibrotic remodeling. Beyond H₂S itself, downstream RSS, including persulfides, polysulfides, and thiosulfate, may represent the principal bioactive mediators of sulfur-dependent redox signaling, and their coordinated depletion in CKD may impair redox buffering capacity beyond what H₂S measurement alone reflects. This review integrates current evidence to propose a conceptual model in which CKD progression involves failure of coordinated redox signaling—characterized by feed-forward network collapse and threshold-dependent transition to a self-sustaining high-ROS state—with H₂S deficiency representing one mechanistically supported component of this broader network disruption. This framework highlights the therapeutic potential of targeting redox network restoration rather than isolated oxidative pathways in CKD. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) and Hydrogen Sulfide (H₂S) in Biology, Illness, and Therapies—3rd Edition)

► Show Figures

Figure 1

27 pages, 7756 KB

Open AccessReview

Antioxidant Nanotherapies for Intervertebral Disk Degeneration: Progress and Prospects

by Yingzi Zhou, Yihang Fan, Yuxuan Hu and Huihui Wang

Antioxidants 2026, 15(6), 745; https://doi.org/10.3390/antiox15060745 (registering DOI) - 11 Jun 2026

Abstract

Intervertebral disk degeneration (IVDD) is widely recognized as a major contributor to discogenic low back pain (LBP), imposing a substantial burden on global public health and socioeconomic systems. Growing evidence confirms that disrupted redox homeostasis, excessive reactive oxygen species (ROS) accumulation, and oxidative [...] Read more.

Intervertebral disk degeneration (IVDD) is widely recognized as a major contributor to discogenic low back pain (LBP), imposing a substantial burden on global public health and socioeconomic systems. Growing evidence confirms that disrupted redox homeostasis, excessive reactive oxygen species (ROS) accumulation, and oxidative stress act as major convergent mechanisms that propagate inflammatory cascades, nucleus pulposus cell dysfunction, and extracellular matrix degradation. Although conventional conservative therapies and surgical interventions are clinically effective in relieving macrostructural compression, they remain limited in resolving localized molecular dysregulation. In recent years, nanotechnology has emerged as a promising strategy for overcoming the limitations of traditional therapy for IVDD. This review provides an analysis of four categories of antioxidant nanotherapies for IVDD, including inorganic functional nanozymes, bioactive nanomaterials, stimuli-responsive nanosystems, and nanocomposite scaffolds. We elaborate on their mechanisms in scavenging excessive ROS, restoring redox equilibrium, protecting mitochondrial function, and ameliorating oxidative stress-induced degeneration. Integrating structural biomimicry with microenvironmental responsiveness enables the engineering of composite nanosystems with multi-pathway ROS-scavenging capabilities. Therefore, these platforms emerge as promising therapeutic strategies for arresting IVDD progression. Finally, we discuss the key obstacles to clinical translation. Overall, this review provides insights into the development of redox-targeted therapies. Full article

(This article belongs to the Section Natural and Synthetic Antioxidants)

► Show Figures

Figure 1

22 pages, 755 KB

Open AccessArticle

Green Extraction of Phenolic Compounds from Blueberry (Vaccinium corymbosum L.) By-Products Using Natural Deep Eutectic Solvents for Cosmetic Applications

by Yassine Jaouhari, Giuseppe Morreale, Lorella Giovannelli, Elia Bari, Hélder Oliveira, Nuno Mateus, Alessandro Candiani, Beatriz Gullón, Matteo Bordiga, Jean Daniel Coïsson and Pedro Ferreira-Santos

Antioxidants 2026, 15(6), 744; https://doi.org/10.3390/antiox15060744 (registering DOI) - 11 Jun 2026

Abstract

The valorization of agri-food by-products generated during juice extraction represents a key strategy within circular economy frameworks, as it reduces the environmental impact of waste disposal while creating added value and improving the food supply chain. In this work, five betaine-based natural deep [...] Read more.

The valorization of agri-food by-products generated during juice extraction represents a key strategy within circular economy frameworks, as it reduces the environmental impact of waste disposal while creating added value and improving the food supply chain. In this work, five betaine-based natural deep eutectic solvents (NaDES) differing in their hydrogen-bond donors, namely citric acid, lactic acid, acetic acid, glycerol, and ethylene glycol, were used for the green extraction of blueberry pomace, a largely underutilized by-product that is nevertheless rich in bioactive compounds. The extracts were characterized by liquid chromatography coupled with diode-array and tandem mass spectrometric detection, allowing targeted profiling of anthocyanins and non-anthocyanin phenolics, including phenolic acids, flavonoids, and phenolic aldehydes. The extraction performance of NaDES was benchmarked against conventional solvents (water and ethanol) to evaluate differences in selectivity and efficiency toward distinct phenolic classes. Antioxidant capacity was determined using DPPH and ABTS radical scavenging assays. Among the NaDES systems, the betaine–citric acid NaDES extract exhibited notable phenolic recovery together with marked radical scavenging activity. After evaluating its inhibitory activity against elastase and tyrosinase, enzymes involved in the skin aging process, the selected NaDES extract was incorporated into a natural-based antiaging cosmetic formulation, and its main physicochemical properties were assessed to verify suitability for topical application. This study demonstrated that the use of NaDES represents an environmentally friendly and sustainable approach to transform blueberry by-products into high-value, safe, and ready-to-use cosmetic functional ingredients without the need for solvent removal. Full article

(This article belongs to the Special Issue Antioxidants from Food and Food Wastes for Nutraceutical, Pharmaceutical and Cosmetic Fields, 2nd Edition)

► Show Figures

Figure 1

20 pages, 3039 KB

Open AccessArticle

Skimmianine Pretreatment Attenuates Cerebellar Neuroinflammation and Myelin Injury Following Experimental Cerebral Ischemia–Reperfusion

by Fırat Aşır, Ebru Gökalp Özkorkmaz, Murat Yalçın, Fırat Şahin and Tuğcan Korak

Antioxidants 2026, 15(6), 743; https://doi.org/10.3390/antiox15060743 (registering DOI) - 11 Jun 2026

Abstract

Objective: Cerebral ischemia/reperfusion (I/R) injury triggers oxidative stress, neuroinflammation, neuronal degeneration, and white matter damage not only in directly affected cerebral regions but also in remote brain areas such as the cerebellum. Skimmianine, a naturally occurring furoquinoline alkaloid, has been reported to possess [...] Read more.

Objective: Cerebral ischemia/reperfusion (I/R) injury triggers oxidative stress, neuroinflammation, neuronal degeneration, and white matter damage not only in directly affected cerebral regions but also in remote brain areas such as the cerebellum. Skimmianine, a naturally occurring furoquinoline alkaloid, has been reported to possess antioxidant and anti-inflammatory properties. This study investigated the protective effects of skimmianine pretreatment against secondary cerebellar injury following experimental cerebral I/R. Materials and Methods: Thirty-two female Wistar rats were randomly assigned to sham, Skimmianine, I/R, and I/R + Skimmianine groups (n = 8/group). Cerebral I/R was induced by transient middle cerebral artery occlusion for 60 min followed by 23 h reperfusion. Skimmianine (40 mg/kg/day, intraperitoneally) was administered for 14 days before ischemia induction. Oxidative stress markers, neuroinflammatory mediators, histopathological alterations, behavioral outcomes, and ultrastructural changes were evaluated. In addition, network pharmacology and molecular docking analyses were performed to explore potential molecular mechanisms. Results: Cerebral I/R significantly decreased TAS levels compared with sham (0.89 ± 0.15 vs. 1.52 ± 0.18 mmol Trolox Eq/L) and increased TOS (15.60 ± 3.03 vs. 6.80 ± 1.41 µmol H₂O₂ Eq/L), OSI (17.48 ± 0.50 vs. 4.43 ± 0.47), TNF-α (68.4 ± 10.2 vs. 18.6 ± 4.4 pg/mL), Iba1 (41.3 ± 9.7 vs. 11.7 ± 1.6 pg/mL), and GFAP levels (334.5 ± 12.5 vs. 87.7 ± 9.5 ng/mL; all p < 0.001). I/R also impaired motor performance, as shown by increased beam crossing time (11.7 ± 2.2 vs. 4.8 ± 0.7 s) and grid foot fault rate (18.6 ± 4.0% vs. 3.4 ± 1.1%). Skimmianine pretreatment significantly improved these alterations, increasing TAS to 1.29 ± 0.20 mmol Trolox Eq/L and reducing TOS, OSI, TNF-α, Iba1, and GFAP levels to 9.20 ± 2.04, 7.07 ± 0.47, 34.9 ± 7.4, 24.2 ± 6.9, and 237.0 ± 7.9, respectively, compared with the untreated I/R group. Histopathological scores for Purkinje cell loss, edema, vascular congestion, and TNF-α expression were also significantly reduced by skimmianine. Quantitative TEM analysis showed that I/R reduced myelin thickness (0.29 ± 0.05 vs. 0.53 ± 0.07 µm), increased G-ratio values (0.75 ± 0.05 vs. 0.63 ± 0.04), and increased vacuolized fibers (24.70 ± 4.20% vs. 3.20 ± 1.10%), whereas skimmianine partially restored myelin thickness (0.42 ± 0.07 µm), reduced the G-ratio (0.68 ± 0.05), and decreased vacuolized fibers (11.20 ± 2.80%; p < 0.05 vs. I/R). Molecular docking demonstrated favorable binding between skimmianine and TNF-α, with a predicted binding energy of −6.953 kcal/mol. Conclusions: These findings indicate that skimmianine exerts neuroprotective effects against secondary cerebellar injury following cerebral I/R through coordinated modulation of oxidative stress, systemic neuroinflammatory responses, astroglial injury-associated pathways, and inflammation-related mechanisms. Full article

(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection)

► Show Figures

Figure 1

Journal Description

Antioxidants

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI