Antioxidants

25 pages, 1520 KB

Open AccessArticle

Design and Synthesis of Caffeine-Based Derivatives with Antioxidant and Neuroprotective Activity: In Vitro Evaluation and SwissADME Profiling

by Denitsa Stefanova, Alime Garip, Virginia Tzankova, Stefan Kostov, Emilio Mateev, Alexander Zlatkov and Yavor Mitkov

Antioxidants 2026, 15(2), 217; https://doi.org/10.3390/antiox15020217 - 6 Feb 2026

Abstract

Oxidative stress and excitotoxicity are key contributors to neuronal damage in various neurodegenerative diseases. Caffeine, a widely used neuroactive compound with moderate antioxidant properties, may benefit from structural modifications to enhance its neuroprotective potential. In this study, a series of novel caffeine derivatives [...] Read more.

Oxidative stress and excitotoxicity are key contributors to neuronal damage in various neurodegenerative diseases. Caffeine, a widely used neuroactive compound with moderate antioxidant properties, may benefit from structural modifications to enhance its neuroprotective potential. In this study, a series of novel caffeine derivatives was synthesized and evaluated for antioxidant and potential neuroprotective relevance using in vitro models of oxidative stress and glutamate-induced excitotoxicity in SH-SY5Y human neuroblastoma cells. Antioxidant capacity was assessed using ABTS•⁺ radical cation decolorization and DPPH radical scavenging assays. Most derivatives exhibited strong free radical scavenging activity, surpassing both caffeine and the reference antioxidant Trolox at low concentrations (5 µM). Notably, compounds AL-7, AL-8, AL-9, and AL-10 demonstrated particularly high activity. Cytotoxicity evaluation using the MTT assay revealed low toxicity for all compounds, with calculated IC₅₀ values above 500 µM. Intracellular reactive oxygen species (ROS) levels measured by the DCFH-DA assay showed that several derivatives, especially AL-4, significantly reduced H₂O₂-induced oxidative stress. In neuroprotection assays, compounds AL-0, AL-1, and AL-4 markedly protected against hydrogen peroxide-induced damage, restoring cell viability up to 73%, while AL-7 achieved up to 85% protection against L-glutamate-induced excitotoxicity, outperforming caffeine. In silico SwissADME analysis indicated favorable oral bioavailability, with predicted gastrointestinal absorption and limited blood–brain barrier permeability. Overall, these findings highlight structurally modified caffeine derivatives as promising antioxidant and neuroprotective agents warranting further mechanistic and therapeutic investigation. Full article

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

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35 pages, 3230 KB

Open AccessReview

Timeless and Stainless Alcohol: Concentric Waves from Its Oxidative Metabolism and Related Oxidative Stress

by Riccardo Maccioni, Simone Tambaro, Laura Doro, Valentina Bassareo, Alessandra T. Peana and Elio Acquas

Antioxidants 2026, 15(2), 216; https://doi.org/10.3390/antiox15020216 - 6 Feb 2026

Abstract

Alcohol is a molecule whose multiple effects in living organisms exemplify how profound biological complexity can arise from an exceptionally simple chemical structure interacting with the cellular biochemical machinery. This review was conceived to provide an up-to-date synthesis of the current knowledge on [...] Read more.

Alcohol is a molecule whose multiple effects in living organisms exemplify how profound biological complexity can arise from an exceptionally simple chemical structure interacting with the cellular biochemical machinery. This review was conceived to provide an up-to-date synthesis of the current knowledge on the multifaceted consequences of alcohol oxidative metabolism and alcohol-derived oxidative stress, ranging from disruption of subcellular and cellular homeostasis to impairment of organ function. This study primarily focuses on the consequences of alcohol metabolism and on the mechanisms by which the rise of its main metabolite, acetaldehyde, and of reactive oxygen species (ROS), generates oxidative stress by-products and molecular adducts responsible for compromising cellular energy balance and antioxidant defense mechanisms. In particular, this review aims to provide an exhaustive representation of the mechanisms, causes, and consequences of alcohol oxidative metabolism: this is accomplished by taking into account alcohol-induced modifications of gene expression of cellular antioxidant determinants, the role of epigenetic mechanisms, and that of gene polymorphisms linked to alcohol-dependent oxidative stress and responsible for serious diseases such as, among others, alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma. In addition, this review highlights the role of alcohol oxidative metabolism in the brain, which, in the acute setting, activates the dopaminergic system mainly involved in alcohol reinforcing properties and, upon chronic exposure, contributes to neurodegenerative disorders. Finally, a dedicated paragraph explores autophagy as an integrative mechanism underlying the effects of alcohol-related oxidative stress across multiple organs, including the liver, heart, and brain. Full article

(This article belongs to the Special Issue Alcohol-Induced Oxidative Stress in Health and Disease, 2nd Edition)

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21 pages, 9195 KB

Open AccessArticle

BACH1–CHAC1–Glutathione Axis Aggravates Myocardial Ischemia–Reperfusion Injury by Enhancing Ferroptosis and Oxidative Stress

by Mingyue Sun, Zehao Feng, Zhaoqi Wang, Ruihao Wu, Ke Du, Jinhan Zhu, Ke Liu, Li Zhang, Min Zhang and Zhaohui Qiu

Antioxidants 2026, 15(2), 215; https://doi.org/10.3390/antiox15020215 - 6 Feb 2026

Abstract

Myocardial ischemia–reperfusion injury (MIRI) is a pathological process in which reperfusion-induced oxidative stress and metabolic derangement further aggravate myocardial damage and blunt the benefit of reperfusion. Ferroptosis is increasingly implicated in MIRI, with the glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis constituting a key [...] Read more.

Myocardial ischemia–reperfusion injury (MIRI) is a pathological process in which reperfusion-induced oxidative stress and metabolic derangement further aggravate myocardial damage and blunt the benefit of reperfusion. Ferroptosis is increasingly implicated in MIRI, with the glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis constituting a key antioxidant barrier. Although GSH depletion is recognized as a critical event, its upstream regulation in MIRI remains unclear. Against this background, we investigate the BACH1–CHAC1–GSH pathway as a putative upstream regulatory axis of ferroptosis in MIRI and a potential molecular target. Here, using an oxygen–glucose deprivation/reoxygenation (OGD/R) model in AC16 and the reversibility conferred by the ferrostatin-1, RNA sequencing identified the GSH-degrading enzyme CHAC1 as a modulator that is induced by stress and promotes ferroptosis. Experiments showed that CHAC1 overexpression aggravated OGD/R-induced injury, depleted GSH, suppressed GPX4 and enhanced lipid peroxidation, whereas CHAC1 knockdown was partially protective. N-acetylcysteine (NAC) replenished GSH, restored GPX4 activity and partially rescued CHAC1-driven injury. In a mouse myocardial I/R model, cardiotropic adeno-associated virus-mediated CHAC1 overexpression worsened cardiac dysfunction, enlarged infarct and fibrosis areas, and increased myocardial iron deposition. Dual-luciferase assays revealed that the transcription factor BACH1 activates the CHAC1 promoter, and BACH1 silencing attenuated ferroptosis by suppressing CHAC1 and restoring the GSH–GPX4 axis. Collectively, our data identify the BACH1–CHAC1–GSH axis as an upstream amplifier of ferroptosis in MIRI through glutathione depletion and impairment of GPX4-dependent antioxidant defense. These findings refine the mechanistic link between reperfusion-phase redox imbalance and ferroptosis and highlight BACH1/CHAC1 inhibition or augmentation of GSH precursors as potential cardioprotective strategies in ischemic heart disease. Full article

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

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21 pages, 590 KB

Open AccessReview

Glutathione-Mediated Redox Regulation of Immune Dysfunction in COVID-19 and Tuberculosis

by John Dawi, Scarlet Affa, Yura Misakyan, Edgar Gonzalez, Stephen Affa and Vishwanath Venketaraman

Antioxidants 2026, 15(2), 214; https://doi.org/10.3390/antiox15020214 - 6 Feb 2026

Abstract

Tuberculosis and coronavirus disease 2019, also known as COVID-19, remain major global health challenges that disproportionately affect individuals with metabolic disorders, chronic inflammation, and limited access to healthcare. Although these diseases are caused by different pathogens, they share important host-related determinants of severity, [...] Read more.

Tuberculosis and coronavirus disease 2019, also known as COVID-19, remain major global health challenges that disproportionately affect individuals with metabolic disorders, chronic inflammation, and limited access to healthcare. Although these diseases are caused by different pathogens, they share important host-related determinants of severity, including immune dysfunction, oxidative stress, endothelial injury, and maladaptive inflammatory responses. Glutathione, the primary intracellular antioxidant and a key regulator of redox balance, has emerged as an important host factor connecting these processes across infectious diseases. This review integrates experimental, translational, and clinical evidence supporting the role of glutathione in regulating immune function, oxidative stress, and tissue damage in tuberculosis and COVID-19. In tuberculosis, glutathione deficiency compromises macrophage antimicrobial activity, disrupts granuloma structure, and alters T helper cell responses, leading to impaired immune containment and disease progression. In COVID-19, reduced glutathione levels are associated with redox imbalance, excessive cytokine signaling, endothelial dysfunction, and thromboinflammatory complications, especially in high-risk populations. In both diseases, glutathione depletion reduces host resilience and increases vulnerability to severe outcomes through shared immune and vascular pathways. By unifying disease-specific findings within a host-directed framework, this review highlights glutathione and redox signaling as common vulnerability pathways that help explain overlapping risk profiles for severe tuberculosis and COVID-19. It also places glutathione biology within the broader context of host-directed immunotherapy, emphasizing its potential role in prevention-focused and resilience-based strategies that complement pathogen-targeted treatments. Although current evidence does not support simple claims of disease prevention, it provides strong mechanistic justification for further investigation of glutathione as a modifiable host factor in high-risk populations. Full article

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

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18 pages, 10482 KB

Open AccessArticle

Disruption of Calcium Homeostasis in Human Spermatozoa: Implications on Mitochondrial Bioenergetics, ROS Production, Phosphatidylserine Externalization, and Motility

by Anita Bravo, Ignacio Jofré-Fernández, Rodrigo Boguen, Raúl Sánchez, Fabiola Zambrano and Pamela Uribe

Antioxidants 2026, 15(2), 213; https://doi.org/10.3390/antiox15020213 - 6 Feb 2026

Abstract

The etiology of male infertility is linked to oxidative stress, which is an imbalance caused by an excess of reactive oxygen species (ROS) that can negatively impact sperm function. It is known that a strong stimulus to induce excessive ROS production by spermatozoa [...] Read more.

The etiology of male infertility is linked to oxidative stress, which is an imbalance caused by an excess of reactive oxygen species (ROS) that can negatively impact sperm function. It is known that a strong stimulus to induce excessive ROS production by spermatozoa is an intracellular calcium (Ca²⁺) overload; however, the link between Ca²⁺ dysregulation, ROS production, and impaired sperm function is still an area requiring further research. This investigation aimed to characterize the intracellular Ca²⁺ overload detrimental effects on human sperm quality. The intracellular Ca²⁺ overload was achieved by dose-dependent incubation with ionomycin, followed by analysis of key functional sperm parameters. Ca²⁺ overload caused an increase in cytosolic and mitochondrial ROS production, dissipation of mitochondrial membrane potential (ΔΨm), reduction in ATP content, cAMP levels, and motility. Furthermore, Ca²⁺ overload promoted phosphatidylserine externalization and a decrease in sperm viability. This study provides novel insights into the interplay between ROS and Ca²⁺ signaling, highlighting that disruption of homeostasis induces OS, leading to impairment of sperm quality. These findings not only contribute to the understanding of the mechanisms underlying male infertility but also provide an in vitro model for future research aimed at optimizing human sperm quality in patients with seminal OS. Full article

(This article belongs to the Special Issue The Role of Oxidative Stress in Male Infertility)

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18 pages, 17647 KB

Open AccessArticle

Three-Month Administration of PB125 Modifies Histopathology, Redox Homeostasis, and Mobility in the Hartley Guinea Pig Model of Primary Osteoarthritis

by Kendra M. Andrie, Robert V. Musci, Maureen A. Walsh, Sydney Bork, Zachary J. Valenti, Joseph Sanford, Margaret Campbell, Leila F. Afzali, Maryam F. Afzali, Karyn L. Hamilton and Kelly S. Santangelo

Antioxidants 2026, 15(2), 212; https://doi.org/10.3390/antiox15020212 - 5 Feb 2026

Abstract

The pathogenesis of primary osteoarthritis (OA) is complex and multifactorial. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor that regulates hundreds of genes involved with cytoprotection. The role of Nrf2 in OA remains undefined. We utilized the Hartley guinea pig model [...] Read more.

The pathogenesis of primary osteoarthritis (OA) is complex and multifactorial. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor that regulates hundreds of genes involved with cytoprotection. The role of Nrf2 in OA remains undefined. We utilized the Hartley guinea pig model of primary OA to investigate the role of a purported Nrf2 activator, PB125, in delaying the onset of knee OA. We hypothesized that three months of daily PB125 supplementation would modify structural, molecular, and in vivo functional outcomes characteristic of disease. Fifty-six 2-month-old animals (equal sexes) were treated orally with PB125 or vehicle control for 3 months; animals were sacrificed at 5 months, which represents mild OA and early disease. Outcome measures included knee histopathology, mRNA expression, immunohistochemistry, and in vivo mobility. Notably, PB125 treatment had differing effects in males and females. Female PB125-treated animals had significantly decreased distal femur OA scores, accompanied by differential gene and protein expression patterns in articular cartilage for markers related to redox homeostasis; decreases in one compulsory mobility metric were also seen. In contrast, males demonstrated a statistical difference in voluntary mobility patterns. In summary, PB125 may modify the molecular mechanisms involved in the initiation of early OA in a potential sex-dependent fashion. Full article

(This article belongs to the Special Issue Inflammation and Oxidative Stress in Articular Cartilage)

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26 pages, 2130 KB

Open AccessArticle

A Nose-to-Brain Delivery System for Taxifolin Ameliorates Alzheimer’s Disease via Synergistic Attenuation of Oxidative Stress and Mitochondrial Dysfunction

by Miao Zhang, Yusu Wang, Liangliang Zhu, Jianan Geng, Zhongmei He and Meisong Jin

Antioxidants 2026, 15(2), 211; https://doi.org/10.3390/antiox15020211 - 5 Feb 2026

Abstract

The blood–brain barrier (BBB) presents the principal obstacle to drug delivery for Alzheimer’s disease (AD), severely restricting brain bioavailability and therapeutic efficacy. Taxifolin (TF) is a potent natural antioxidant with significant therapeutic potential. To enhance its efficacy in treating AD, we developed a [...] Read more.

The blood–brain barrier (BBB) presents the principal obstacle to drug delivery for Alzheimer’s disease (AD), severely restricting brain bioavailability and therapeutic efficacy. Taxifolin (TF) is a potent natural antioxidant with significant therapeutic potential. To enhance its efficacy in treating AD, we developed a brain-targeted delivery system based on a taxifolin-loaded thermosensitive hydrogel (TF-Gel). This platform integrates TF with a poly(N-isopropylacrylamide)-based thermosensitive hydrogel to enhance brain delivery, tissue penetration, and intracerebral retention via intranasal administration. TF-Gel exhibits excellent structural stability and functional performance, enabling efficient bypass of the BBB through the nasal–brain pathway. Furthermore, it regulates mitochondrial dysfunction, reverses abnormal levels of adenosine triphosphate (ATP), reactive oxygen species (ROS), and malondialdehyde (MDA) in neuronal mitochondria, repairs mitochondrial energy metabolism, restores mitochondrial dynamic balance, improves oxidative stress damage, and blocks cell apoptosis pathways. Collectively, these results highlight the strong potential of the TF-Gel nasal delivery system as a mitochondria-targeted therapeutic strategy for AD. Full article

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22 pages, 3681 KB

Open AccessArticle

Alleviating Effects of Three Heat-Inactivated Enterococcus faecalis Strains Against Growth Suppression, Oxidative Stress and Gut Microbiome Dysbiosis in Macrobrachium rosenbergii Fed with Sesame Meal-Replaced Fish Meal Diet

by Xiu Fang, Ling Zhu, Xuwen Bing, Zhengzhong Li, Xin Liu, Bo Liu, Cunxin Sun, Xiaochuan Zheng and Bo Liu

Antioxidants 2026, 15(2), 210; https://doi.org/10.3390/antiox15020210 - 5 Feb 2026

Abstract

This study evaluated the alleviating effects of three heat-inactivated Enterococcus faecalis strains on growth suppression, oxidative stress, and gut microbiome dysbiosis in Macrobrachium rosenbergii-fed sesame meal-substituted fish meal diets. The trial comprised a control group (CT), low fish meal group (LF), and [...] Read more.

This study evaluated the alleviating effects of three heat-inactivated Enterococcus faecalis strains on growth suppression, oxidative stress, and gut microbiome dysbiosis in Macrobrachium rosenbergii-fed sesame meal-substituted fish meal diets. The trial comprised a control group (CT), low fish meal group (LF), and LF fed with three postbiotic-supplemented groups (LF+HK-448, LF+HK-798, LF+HK-804). Results demonstrated that compared with the CT group, the LF diet significantly decreased weight gain rate, specific growth rate, hepatopancreatic total nitric oxide synthase and inducible nitric oxide synthase, while increased feed conversion ratio, nitric oxide, and malondialdehyde contents. Among the postbiotics, LF+HK-804 group conferred the most pronounced compensatory growth and significantly improved oxidative stress and immune markers, as evidenced by elevated WGR, SGR, HSI, and flesh percentage, reduced MDA, and the down-regulation of Toll and Relish alongside the upregulation of peroxiredoxin-5. Intestinal microbiota analysis showed the group of LF+HK-804 improved microbial diversity and richness, specifically by increasing Firmicutes and decreasing Habeamium and Sphingomonas. Metabolomics identified 11 key differential metabolites related to amino acid, energy, and fatty acid metabolism. Correlation analysis further revealed that Gemmatimonadetes, WD2101_soil_group, and Sphingomonas were negatively correlated with phospholipids and positively correlated with glycoside and fatty acid metabolites. Moreover, immunometabolic correlation analysis segregated the metabolic response of microbiota into two distinct profiles: one potentiating a reactive oxygen/nitrogen species–antioxidant defense, and the other favoring a Dorsal/Relish-mediated transcriptional response. In conclusion, E. faecalis 804 can promote growth, alleviate oxidative damage, enhance immunity, and regulate intestinal microbiota and metabolic capacity in M. rosenbergii, showing great potential as a postbiotic. Full article

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23 pages, 3767 KB

Open AccessArticle

Time-Resolved Oxygen Dynamics Reveals Redox-Selective Apoptosis Induced by Cold Atmospheric Plasma in HT-29 Colorectal Cancer Cells

by Hamideh Mohammadi, Kamal Hajisharifi, Esmaeil Heydari, Hassan Mehdian, Sara Emadi, Yuri Akishev, Svetlana A. Ermolaeva, Augusto Stancampiano and Eric Robert

Antioxidants 2026, 15(2), 209; https://doi.org/10.3390/antiox15020209 - 4 Feb 2026

Abstract

Cold atmospheric plasma (CAP) has emerged as a promising anticancer approach because of its ability to selectively eliminate malignant cells. Among the proposed mechanisms of this selectivity, the Bauer theory emphasizes the synergistic action of plasma-derived hydrogen peroxide (H₂O₂) [...] Read more.

Cold atmospheric plasma (CAP) has emerged as a promising anticancer approach because of its ability to selectively eliminate malignant cells. Among the proposed mechanisms of this selectivity, the Bauer theory emphasizes the synergistic action of plasma-derived hydrogen peroxide (H₂O₂) and nitrite (NO₂⁻), leading to the transient generation of primary singlet oxygen (¹O₂). This early event inactivates membrane-bound catalase, allowing tumor cell-derived H₂O₂ and peroxynitrite to initiate a self-amplifying cycle that produces secondary ¹O₂, as a hallmark of CAP selectivity. To test this hypothesis, in this work, we monitored extracellular dissolved oxygen (DO) dynamics in HT-29 colorectal cancer cells treated with an argon plasma jet using time-resolved phosphorescence lifetime spectroscopy. Temporal variations in DO likely reflect the cumulative effect of rapid ¹O₂ production and its reactions with cells. A delayed surge in extracellular ¹O₂ was observed specifically in dying cancer cells within the 10–20 min window predicted by the model. Intracellular ROS imaging confirmed a strong correlation between intracellular ROS, extracellular ¹O₂ dynamics, and viability loss. Together, these results provide mechanistic validation of Bauer’s redox model and suggest that early oxygen dynamics after CAP exposure can serve as predictive markers for treatment efficacy in plasma or photodynamic therapies. Full article

21 pages, 1604 KB

Open AccessReview

Interplay Between Oxidative Stress and Inflammation in Aquatic Animals: Mechanisms, Consequences, and Implications for Aquaculture Health

by Zi-Yan Liu, Yang Yu and Xiao-Zheng Yu

Antioxidants 2026, 15(2), 208; https://doi.org/10.3390/antiox15020208 - 4 Feb 2026

Abstract

Oxidative stress and inflammation are two tightly interconnected processes that shape the physiological and pathological responses of aquatic animals to environmental and pathogenic challenges. Reactive oxygen species (ROS) act as key molecular mediators linking oxidative damage with immune activation, forming a bidirectional amplification [...] Read more.

Oxidative stress and inflammation are two tightly interconnected processes that shape the physiological and pathological responses of aquatic animals to environmental and pathogenic challenges. Reactive oxygen species (ROS) act as key molecular mediators linking oxidative damage with immune activation, forming a bidirectional amplification loop in which oxidative stress triggers inflammation, and inflammation further enhances ROS production. This vicious cycle disrupts immune homeostasis, damages vital organs such as the liver, intestine, and gills, and ultimately increases disease susceptibility in aquaculture species. Recent studies have revealed that breaking this ROS–inflammation loop through integrated strategies, combining antioxidant enhancement, inflammation modulation, and immune regulation, can significantly improve stress tolerance and survival. Particularly in viral diseases, targeting the ROS–inflammation–virus replication axis has emerged as a promising approach for effective control. This review systematically summarizes the mechanistic crosstalk between oxidative stress and inflammation, highlights their biological consequences, and proposes mechanism-based prevention strategies for sustainable aquaculture health management. Full article

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19 pages, 1627 KB

Open AccessArticle

Accelerated Solvent Extraction as an Alternative for the Recovery of Phenolic Compounds from Chestnut Bur: Optimization of Extraction Conditions

by Ana I. Paniagua-García, Lucía Gómez-González, Silvia González-Rojo and Rebeca Díez-Antolínez

Antioxidants 2026, 15(2), 207; https://doi.org/10.3390/antiox15020207 - 4 Feb 2026

Abstract

Chestnut bur (CB) is a solid waste product generated in large quantities during the harvesting of edible fruits. This by-product is rich in total phenolic content (TPC) with high antioxidant properties, making it suitable for use in a variety of industrial applications. In [...] Read more.

Chestnut bur (CB) is a solid waste product generated in large quantities during the harvesting of edible fruits. This by-product is rich in total phenolic content (TPC) with high antioxidant properties, making it suitable for use in a variety of industrial applications. In this study, the operational variables of accelerated solvent extraction (ASE) and conventional solvent extraction (CSE) of CB were optimized in order to obtain extracts with maximum levels of TPC. The analysis revealed that the extract obtained by ASE using 31.3% ethanol at 180 °C for 9 min achieved the highest value of TPC (8.37 ± 0.05 g gallic acid equivalents (GAE)/100 g dry matter (DM)). Moreover, this extract exhibited higher values of radical-scavenging activity for α,α-diphenyl-β-picrylhydrazyl (DPPH) (90.8 ± 0.3%) than those observed for catechin standard (88.7 ± 0.2%). In addition, its phenolic composition revealed high amounts of gallic acid (13.22 ± 1.01 mg/g DM), followed by 3,4-dihydroxybenzoic acid (2.96 ± 0.16 mg/g DM). This study demonstrates the potential for valorization of CB by ASE under feasible extraction conditions, thereby promoting the circular economy. Full article

(This article belongs to the Special Issue Agri-Food Wastes as Natural Source of Bioactive Antioxidants: Fourth Edition)

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14 pages, 884 KB

Open AccessArticle

Lipid Peroxidation Products 4-ONE and 4-HNE Modulate Voltage-Gated Sodium Channels in Neuronal Cell Lines and DRG Action Potentials

by Ming-Zhe Yin, Na Kyeong Park, Mi Seon Seo, Jin Ryeol An, Hyun Jong Kim, JooHan Woo, Jintae Kim, Min Yan, Sung Joon Kim and Seong Woo Choi

Antioxidants 2026, 15(2), 206; https://doi.org/10.3390/antiox15020206 - 4 Feb 2026

Abstract

Oxidative stress-induced lipid peroxidation products (LPPs), particularly 4-hydroxy-nonenal (4-HNE) and 4-oxo-nonenal (4-ONE), have recently gained attention for their direct regulation of ion channels essential for pain signaling. In this study, we investigated how these two LPPs affect the electrophysiological properties of neurons, specifically [...] Read more.

Oxidative stress-induced lipid peroxidation products (LPPs), particularly 4-hydroxy-nonenal (4-HNE) and 4-oxo-nonenal (4-ONE), have recently gained attention for their direct regulation of ion channels essential for pain signaling. In this study, we investigated how these two LPPs affect the electrophysiological properties of neurons, specifically voltage-gated sodium (Na_V) channels, thereby influencing sensory neuron excitability and pain pathways. Using human neuroblastoma (SH-SY5Y) and ND7/23 cells (a fusion cell line exhibiting partial sensory neuron properties), we measured changes in Na_V channel-mediated sodium currents following treatment with 4-HNE or 4-ONE. Whole-cell patch-clamp experiments showed that 4-ONE (10 µM) and 4-HNE (100 µM) did not significantly alter the peak sodium current amplitude in SH-SY5Y cells. However, in ND7/23 cells, both 4-HNE and 4-ONE induced a negative shift in Na_V channel activation voltage dependence, enabling sodium channel activation at lower membrane potentials. Furthermore, current-clamp recordings in primary mouse dorsal root ganglion neurons demonstrated that treatment with 4-ONE and 4-HNE reduced the current threshold required to elicit action potentials and significantly increased action potential firing frequency. These findings indicate that LPPs enhance pain sensitivity by modulating Na_V channels, which play a crucial role in pain transmission. In conclusion, 4-HNE and 4-ONE shift the voltage-dependent activation of sodium channels toward more negative potentials, thereby increasing the excitability of primary sensory neurons and amplifying pain signals. This study provides molecular insights into how oxidative stress-related lipid peroxidation contributes to sensory mechanisms and offers potential avenues for developing new treatments for oxidative stress- or inflammation-associated pain. Full article

(This article belongs to the Special Issue Lipid Peroxidation in Physiology and Chronic Inflammatory Diseases)

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22 pages, 6475 KB

Open AccessArticle

The Algal Antioxidant Carotenoid Diatoxanthin as a Modulator of Inflammation and Angiogenesis in Triple-Negative Breast Cancer Cells

by Danilo Morelli, Luana Calabrone, Luisa Di Paola, Giovanna Chiorino, Paola Ostano, Douglas M. Noonan, Giovanni Corso and Adriana Albini

Antioxidants 2026, 15(2), 205; https://doi.org/10.3390/antiox15020205 - 4 Feb 2026

Abstract

Algal carotenoids play a promising role in handling chronic diseases due to their diverse bioactive properties, including anti-inflammatory, antioxidant, and anticancer effects. This study assesses the activity of the antioxidant xanthophyll diatoxanthin (Dt), derived from marine diatoms, against triple-negative breast cancer (TNBC) cells [...] Read more.

Algal carotenoids play a promising role in handling chronic diseases due to their diverse bioactive properties, including anti-inflammatory, antioxidant, and anticancer effects. This study assesses the activity of the antioxidant xanthophyll diatoxanthin (Dt), derived from marine diatoms, against triple-negative breast cancer (TNBC) cells using in vitro models, gene expression evaluation, and explores its role in potentiating the cytotoxic effect of chemotherapy. Dt exhibited selective activity against MDA-MB-231 and BT-549 TNBC cells at concentrations ≥12.5 ng/mL, with maximal effects observed at 25 ng/mL while sparing human umbilical vein endothelial cells (HUVECs) at these doses. When combined with doxorubicin (0.1–0.5 μM), Dt enhanced the anti-tumor efficacy in both TNBC cell lines, further reducing cell viability compared with doxorubicin alone (p < 0.05–0.001). Dt also exerted its activity in inhibiting migration and chemotaxis by approximately 30–50% compared with the controls (p < 0.01) and suppressing 3D-tumor spheroid growth at day 12 (up to >50% reduction, p < 0.001). Notably, secretome analysis revealed Dt-induced changes in inflammatory, oxidative and angiogenic mediators, highlighting its ability to modulate the TNBC microenvironment. Dt also downregulated key pro-survival, pro-angiogenic and pro-tumorigenic genes in both TNBC cell lines, supporting its role in disrupting oncogenic pathways. Angiogenesis-related genes were significantly reduced. Dt also decreased the expression of angiogenic mediators in HUVECs, supporting Dt’s role in inhibiting tumor vascularization. Results on gene expression regulation were also confirmed by RNA-Seq analysis. These findings pose Dt as a promising chemopreventing candidate in the challenging fight against TNBC, a well-known type of cancer that is aggressive and resistant to conventional therapies, targeting critical pathways for tumor survival, such as inflammation, angiogenesis, tumor cell growth, and cell migration. Given its selective activity against TNBC cells, ability to enhance chemotherapy efficacy, and modulation of the tumor microenvironment, Dt holds promise as a complementary drug for cancer prevention and interception. Future studies should focus on validating these effects in vivo and exploring Dt’s potential in combinatorial treatment strategies for cancer. Full article

(This article belongs to the Special Issue Microalgae FoodOmics and FeedOmics: Antioxidant Enrichment, ROS Modulation, and Health-Boosting Applications)

35 pages, 1246 KB

Open AccessReview

Maqui as a Chilean Functional Food: Antioxidant Bioactivity, Nutritional Value, and Health Applications

by Caterina Tiscornia, Enrique Lorca, Carolina Estremadoyro, Valeria Aicardi and Fabián Vásquez

Antioxidants 2026, 15(2), 204; https://doi.org/10.3390/antiox15020204 - 3 Feb 2026

Abstract

Maqui (Aristotelia chilensis) is a berry native to southern Chile, recognized for its high content of phenolic compounds, particularly delphinidin-type anthocyanins, which confer strong antioxidant and anti-inflammatory properties and have generated growing interest as a functional food. Its scientific relevance has [...] Read more.

Maqui (Aristotelia chilensis) is a berry native to southern Chile, recognized for its high content of phenolic compounds, particularly delphinidin-type anthocyanins, which confer strong antioxidant and anti-inflammatory properties and have generated growing interest as a functional food. Its scientific relevance has increased due to advances in understanding its biological mechanisms, including the Nrf2 signaling pathway, modulation of systemic inflammation, improvement in mitochondrial function, and potential applications in cardiometabolic, renal, and vascular health. Objective: The objective of this study is to analyze the available evidence on maqui in relation to its nutritional composition, bioactive profile, antioxidant and anti-inflammatory mechanisms, bioavailability, and emerging clinical applications in the prevention and/or treatment of chronic non-communicable diseases. Main findings: Maqui is rich in delphinidins, dietary fiber, and antioxidant micronutrients and modulates key oxidative stress and inflammatory pathways, including Nrf2-HO-1 and NF-κB. Preclinical and early clinical evidence supports its cardiometabolic and nephroprotective effects, with improvements in glycemic control, lipid metabolism, oxidative stress, and endothelial function. Conclusions: Maqui shows considerable potential as a Chilean functional food with antioxidant and anti-inflammatory effects relevant to human health. However, robust clinical trials and formulations with enhanced bioavailability are required to consolidate its therapeutic application. Full article

(This article belongs to the Special Issue Antioxidant Research in Chile—2nd Edition)

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22 pages, 449 KB

Open AccessReview

Redox Homeostasis as a Therapeutic Target in Chronic Oxidative Diseases: Implications for Cancer Treatment

by Moon Nyeo Park, Min Choi, Rony Abdi Syahputra, Domenico V. Delfino, Seong-Gyu Ko and Bonglee Kim

Antioxidants 2026, 15(2), 203; https://doi.org/10.3390/antiox15020203 - 3 Feb 2026

Abstract

Reactive oxygen species (ROS) have traditionally been viewed as pathological by-products of metabolism that drive tissue damage through oxidative stress. However, accumulating evidence across chronic diseases, including metabolic, cardiovascular, neurodegenerative disorders, and cancer, indicates that ROS also function as tightly regulated signaling molecules [...] Read more.

Reactive oxygen species (ROS) have traditionally been viewed as pathological by-products of metabolism that drive tissue damage through oxidative stress. However, accumulating evidence across chronic diseases, including metabolic, cardiovascular, neurodegenerative disorders, and cancer, indicates that ROS also function as tightly regulated signaling molecules essential for cellular adaptation and survival. This paradigm shift from oxidative stress to redox signaling necessitates a fundamental re-evaluation of how redox imbalance contributes to chronic disease pathogenesis. In this review, we propose that chronic diseases should be understood as disorders of maladaptive redox homeostasis rather than simple consequences of excessive oxidative damage. We delineate the distinction between oxidative stress and redox signaling, emphasizing how chronic redox remodeling stabilizes pathological cellular states through coordinated regulation of key redox-sensitive transcriptional nodes, including KEAP1–NRF2, FOXO, HIFs, and NF-κB. Using cancer as a representative model, we illustrate how elevated but buffered ROS levels support oncogenic signaling, metabolic rewiring, and therapeutic resistance through redox addiction. We further discuss why non-specific antioxidant strategies have largely failed and argue that effective intervention requires context-dependent redox modulation rather than global ROS suppression. Finally, we introduce therapeutic redox reprogramming and outline future directions for precision redox medicine based on biomarker-guided stratification and disease stage-specific targeting strategies. Full article

(This article belongs to the Special Issue Redox Signaling in Chronic Diseases)

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27 pages, 13489 KB

Open AccessArticle

Optimization of Bioactive Compound Extraction from Prunus spinosa L. Fruits Using Ultrasound-Assisted Extraction with Food-Grade Glycerin: A Combined RSM–ANN Approach

by Asmaa Berkati, Nadir Ben Hamiche, Amina Kribeche, Louiza Himed, Salah Merniz, Maria D’Elia, Rita Celano and Luca Rastrelli

Antioxidants 2026, 15(2), 202; https://doi.org/10.3390/antiox15020202 - 3 Feb 2026

Abstract

Within the framework of green chemistry and wild fruit valorization, this study optimizes the extraction of bioactive compounds from Prunus spinosa L. fruits using glycerin-based ultrasound-assisted extraction (UAE). Response Surface Methodology (RSM) and Artificial Neural Networks (ANN) were comparatively employed to model the [...] Read more.

Within the framework of green chemistry and wild fruit valorization, this study optimizes the extraction of bioactive compounds from Prunus spinosa L. fruits using glycerin-based ultrasound-assisted extraction (UAE). Response Surface Methodology (RSM) and Artificial Neural Networks (ANN) were comparatively employed to model the process. Significant improvements in extraction efficiency were achieved, with total phenolic content increasing from 9.28 to 23.22 mg GAE/g DW, total flavonoid content from 6.53 to 21.65 mg CE/g DW, and antioxidant activity (DPPH assay) from 57.04% to 86.34%. While both models performed well, ANN demonstrated slightly higher predictive accuracy, highlighting its potential for capturing complex, non-linear relationships in the extraction process. We identified the optimal extraction conditions as 9 min extraction time, 100% ultrasonic amplitude, and 40% water in glycerin, and these conditions were experimentally validated. UHPLC-DAD-HRMS/MS profiling revealed a rich phytochemical fingerprint dominated by phenolic acids, caffeoylquinic acid derivatives, and flavonol glycosides, and revealed largely overlapping qualitative phytochemical profiles between hydroglyceric and ethanolic extracts. Comparative extraction using 70% ethanol under identical conditions resulted in lower TPC, TFC, and antioxidant activity, indicating the improved efficiency of glycerin under the investigated conditions. Overall, the optimized glycerin-based UAE provides a sustainable, food-safe approach for extracting bioactive compounds from underutilized P. spinosa fruits. These results support its application in functional foods and in nutraceutical and cosmetic formulations. Full article

(This article belongs to the Special Issue Green Extraction of Antioxidant from Natural Source)

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18 pages, 1533 KB

Open AccessHypothesis

A Pathophysiological Model of Parkinson’s Disease Based on Microvascular Flow Disturbance and Leukocyte-Mediated Oxidative Injury in Critical Pigmented Neuronal Niches

by Emilio Fernández-Espejo and Fernando Rodríguez de Fonseca

Antioxidants 2026, 15(2), 201; https://doi.org/10.3390/antiox15020201 - 3 Feb 2026

Abstract

The authors hypothesize that idiopathic Parkinson’s disease may result from an alteration in microvascular flow at a “critical point” in the nervous system that is characterized by pigmented cells that express neuromelanin and/or lipofuscin. “Critical points” include the olfactory epithelium/bulb, the autonomic nervous [...] Read more.

The authors hypothesize that idiopathic Parkinson’s disease may result from an alteration in microvascular flow at a “critical point” in the nervous system that is characterized by pigmented cells that express neuromelanin and/or lipofuscin. “Critical points” include the olfactory epithelium/bulb, the autonomic nervous system, the enteric nervous system, the prefrontal–cortico-pontine network, and the amygdala. Hypoxia–ischemia following blood flow disturbance would recruit and activate leukocytes and induce the infiltration of peripheral immune cells into neural tissue. The excess of toxic factors produced by hyperactive immune cells, such as myeloperoxidase and its derivatives, would cause the oxidation of lipids, proteins, and biogenic monoamines such as dopamine, which in turn would facilitate the accumulation and precipitation of neuromelanin, lipofuscin, and alpha-synuclein. In addition, neuromelanin and lipofuscin precipitates may accentuate the misfolding and aggregation of alpha-synuclein. This “amplification” mechanism could help explain the crucial role of pigmented neurons in the onset of Parkinson’s disease pathology, triggering abnormal neurotoxic alpha-synuclein spread throughout the nervous system from the “critical point” of origin, and enabling a self-perpetuating degenerative process. The proposed hypothesis may have implications for the identification of new therapeutic targets, early prevention strategies, and the development of vascular and/or immune biomarkers. Full article

(This article belongs to the Special Issue Oxidative Stress Mechanisms and Parkinson's Disease Treatment)

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17 pages, 2507 KB

Open AccessArticle

Annurca Apple By-Products at Different Ripening Stages Inhibit AGE Formation and Protect Against AGE-Induced Cytotoxicity Through Antioxidant Activity

by Maria Liccardo, Pasquale Perrone, Shana Perrella, Ivana Sirangelo, Stefania D’Angelo and Clara Iannuzzi

Antioxidants 2026, 15(2), 200; https://doi.org/10.3390/antiox15020200 - 3 Feb 2026

Abstract

Annurca apple extract is gaining growing attention for its beneficial properties, particularly its outstanding antioxidant activity. Using a combination of biophysical, cell, and molecular biology techniques, this study investigates the sustainable valorization of Annurca apple by-products at different ripening stages and their role [...] Read more.

Annurca apple extract is gaining growing attention for its beneficial properties, particularly its outstanding antioxidant activity. Using a combination of biophysical, cell, and molecular biology techniques, this study investigates the sustainable valorization of Annurca apple by-products at different ripening stages and their role in the formation of advanced glycation end-products (AGEs), as well as in protection against AGE-related cytotoxicity. AGEs are a class of compounds formed by non-enzymatic reactions between reducing sugars and proteins, lipids, or nucleic acids. They can be produced endogenously or ingested through dietary sources and tobacco smoke. AGEs accumulate in nearly all mammalian tissues and are linked to various health issues, such as diabetes and its related complications, cardiovascular disease, and neurodegenerative disorders. Our data show that Annurca apple by-products at different ripening stages differentially counteract AGEs’ formation by inhibiting protein glycation and protect against AGE-induced cytotoxicity in endothelial cells. In particular, the extracts reduce AGE-induced reactive oxygen species (ROS) production, thereby inhibiting MAPK signaling pathways and caspase-3 activation. Moreover, ripening significantly enhances the concentration of bioactive compounds and the extent of cellular protection. This study highlights new beneficial properties of Annurca apple extracts and suggests that adopting nutritional interventions may support health and potentially reduce the risk of complications associated with AGE accumulation. Full article

(This article belongs to the Special Issue Antioxidant Compounds and Health Benefits of Mediterranean Functional Food)

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14 pages, 781 KB

Open AccessArticle

Associations Between Gut Microbiota and Mitochondrial Metabolites, with Growth Differentiation Factor-15 as a Marker of Oxidative Stress in Heart Failure vs. Healthy Ageing

by Konstantinos Prokopidis, Adam Burke, Beyza Gulsah Altinpinar, Sima Jalali Farahani, Omid Khaiyat, Gregory Y. H. Lip, Rajiv Sankaranarayanan, Vanja Pekovic-Vaughan, Howbeer Muhamadali and Masoud Isanejad

Antioxidants 2026, 15(2), 199; https://doi.org/10.3390/antiox15020199 - 2 Feb 2026

Abstract

Growth differentiation factor-15 (GDF-15) is an established marker of oxidative stress and a general stress-response mitokines. In this study, we aim to investigate the association of GDF-15 with the metabolic signature of gut and mitochondrial activity in HF and ageing population. A total [...] Read more.

Growth differentiation factor-15 (GDF-15) is an established marker of oxidative stress and a general stress-response mitokines. In this study, we aim to investigate the association of GDF-15 with the metabolic signature of gut and mitochondrial activity in HF and ageing population. A total of 25 HF (67.9 ± 10.0 years) and 29 age-matched healthy participants (HPs) (67.8 ± 11.1 years) were recruited and underwent detailed body composition assessment via dual X-ray absorptiometry; total fat mass and appendicular lean soft tissue index (ALSTI/body mass index (BMI)) were calculated. Utilizing semi-targeted Gas Chromatography–Mass Spectrometry on fasting plasma, a panel of gut microbial-derived (e.g., hippuric acid, indole derivatives, and sarcosine) and tricarboxylic acid cycle metabolites was identified. Results showed higher GDF-15 tertiles were associated with greater HF prevalence, fat mass, NT-proBNP, and TNF-α (p < 0.05). Gut-derived metabolites exhibited phenotype-specific patterns; 3-hydroxyindole predicted higher fat mass in HP; hippuric acid was inversely related in HF; and sarcosine correlated with GDF-15 only in HP. In HF, GDF-15 was strongly driven by pyruvic and fumaric acid, indicating disease-specific mitochondrial stress. In conclusion, these observed associations could be evaluated in future mechanistic studies as sensitive biomarkers of systemic oxidative stress markers, informing potential microbiome-targeted therapeutic avenues. Full article

(This article belongs to the Special Issue Oxidative Stress in Age-Related Diseases)

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