Antioxidants

21 pages, 17539 KB

Open AccessArticle

Coenzyme Q10 Improves Functional and Structural Parameters of Dairy Goat Sperm During Cooling and Cryopreservation

by Ranadheer Narlagiri, Abdallah M. Shahat, Courtney Henry, Ashvini Pawar, Niki C. Whitley, Iman B. Shaheed, Mahipal Singh, Brou Kouakou, Irina A. Polejaeva and Adel R. Moawad

Antioxidants 2026, 15(6), 655; https://doi.org/10.3390/antiox15060655 - 22 May 2026

Abstract

Cryopreservation of gametes is crucial for conserving genetic diversity in livestock and endangered species, but the process can significantly impair sperm quality due to oxidative stress. Our aim was to evaluate the impacts of coenzyme Q10 (CoQ10) supplementation on the in vitro quality [...] Read more.

Cryopreservation of gametes is crucial for conserving genetic diversity in livestock and endangered species, but the process can significantly impair sperm quality due to oxidative stress. Our aim was to evaluate the impacts of coenzyme Q10 (CoQ10) supplementation on the in vitro quality of cooled and cryopreserved goat semen. Semen samples collected from six mature Saanen bucks were pooled then diluted with AndroMed^® semen extender to a final concentration of 800 × 10⁶ sperm/mL. Diluted semen was supplemented with 0, 1, 2, 5, 10, and 20 µM CoQ10. Extended semen was either cooled at 4 °C for 72 h or cryopreserved using a Styrofoam box in which the straws were arranged on the freezing rack and placed 4 cm over the liquid nitrogen (LN₂) for 10 min then stored in a LN₂ tank for one-week before being thawed at 37 °C for 30 sec. Sperm quality, including total and progressive motility, sperm kinematics, live sperm %, and sperm membrane integrity, was assessed at 0 h (fresh semen), and 24, 48, and 72 h post-cooling. For post-thaw sperm, we evaluated the same parameters plus acrosome integrity, mitochondrial activity, lipid peroxidation, and sperm ultrastructural changes using scanning electron microscopy (SEM). The pooled semen sample was considered the experimental unit for all treatments. Cooled semen data were analyzed using a General Linear Model (GLM) with univariate analysis, followed by Tukey’s test for multiple comparisons. In contrast, data from frozen–thawed semen were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s test. CoQ10 supplementation at 10 and 20 µM significantly (p < 0.05) improved sperm motility, viability, and membrane integrity in cooled and frozen–thawed semen in comparison with the control group (0 µM CoQ10). Moreover, the same concentrations significantly (p < 0.05) enhanced acrosome integrity, mitochondrial activity, and reduced the percentages of sperm with lipid peroxidation in frozen–thawed semen. Furthermore, 10 and 20 µM CoQ10 significantly mitigated the ultrastructural defects in frozen–thawed spermatozoa. In conclusion, CoQ10 supplementation during the cooling and cryopreservation of dairy goat semen significantly improved sperm quality. Among the tested concentrations, 10 and 20 µM exhibited the most favorable outcomes. Full article

(This article belongs to the Special Issue Redox Regulation in Animal Reproduction—2nd Edition)

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24 pages, 2493 KB

Open AccessSystematic Review

Clinical Evidence on the Health Effects of Aristotelia chilensis (Maqui Berry) Supplementation: A Systematic Review of Human Trials

by Patricio Arce-Johnson, Yohaily Rodríguez-Alvarez, Carolina Gabriela Vallejos Sierra, Jesús L. Romero-Romero, Luisbel González and Alain Manuel Chaple Gil

Antioxidants 2026, 15(6), 654; https://doi.org/10.3390/antiox15060654 - 22 May 2026

Abstract

Aristotelia chilensis (maqui berry) is a Chilean native fruit rich in anthocyanins with potential antioxidant, glycemic, cardiometabolic, and ocular benefits, but its clinical efficacy remains unclear. This systematic review synthesized and critically appraised human trials evaluating oral maqui supplementation in adults. Following PRISMA [...] Read more.

Aristotelia chilensis (maqui berry) is a Chilean native fruit rich in anthocyanins with potential antioxidant, glycemic, cardiometabolic, and ocular benefits, but its clinical efficacy remains unclear. This systematic review synthesized and critically appraised human trials evaluating oral maqui supplementation in adults. Following PRISMA 2020 and a PROSPERO-registered protocol, five databases were searched, and risk of bias and certainty of evidence were assessed using RoB 2/ROBINS-I and GRADE. Twelve clinical trials published between 2014 and 2023 were included. Acute studies consistently showed reduced postprandial glucose and modulation of insulin response, whereas chronic interventions showed modest and inconsistent effects on HbA1c, lipid profile, and other cardiometabolic markers. Favorable changes were also reported for oxidative stress biomarkers and autonomic parameters, although these findings were mainly based on surrogate endpoints. The most consistent evidence was observed in the ocular domain, where maqui supplementation improved tear production, dry eye symptoms, and tear inflammatory markers. The overall certainty of evidence ranged from moderate to very low because of methodological heterogeneity, small sample sizes, and short intervention duration. Maqui berry supplementation shows promise, particularly for acute glycemic control and ocular surface health, but larger long-term randomized trials using standardized formulations are needed before definitive clinical recommendations can be made. Full article

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

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20 pages, 4605 KB

Open AccessArticle

Caloric Restriction Attenuates Gentamicin-Induced Acute Kidney Injury and Is Associated with Changes in Oxidative Stress and Mitochondrial DNA Damage

by Xinyu Liao, Nadezda V. Andrianova, Ljubava D. Zorova, Irina S. Sadovnikova, Dmitry S. Semenovich, Vasily N. Manskikh, Irina B. Pevzner, Artem P. Gureev and Egor Y. Plotnikov

Antioxidants 2026, 15(6), 653; https://doi.org/10.3390/antiox15060653 - 22 May 2026

Abstract

Caloric restriction (CR) is known to activate a broad spectrum of cytoprotective signaling pathways and enhance tissue tolerance to various stressors, including those associated with the cytotoxic effects of pharmaceutical agents. Nephrotoxic drugs, such as aminoglycoside antibiotics, remain a major clinical concern due [...] Read more.

Caloric restriction (CR) is known to activate a broad spectrum of cytoprotective signaling pathways and enhance tissue tolerance to various stressors, including those associated with the cytotoxic effects of pharmaceutical agents. Nephrotoxic drugs, such as aminoglycoside antibiotics, remain a major clinical concern due to their frequent use and potential to cause acute kidney injury (AKI), for which effective preventive strategies are still limited. In this study, we investigated whether CR applied for 5 weeks (4-week pretreatment + 1-week concurrent with AKI induction) can alleviate AKI triggered by the antibiotic gentamicin, with a focus on evaluating changes in antioxidant-related parameters and autophagy-associated signaling during CR-mediated nephroprotection. CR’s nephroprotective effects were evaluated using diagnostic assays, Western blotting, and histological analysis. Additionally, oxidative stress markers and mitochondrial integrity were assessed to analyze the impact of CR on antioxidant-related pathways. CR significantly improved renal function and structure, with reduced kidney injury markers (KIM-1, NGAL) and alleviated histological damage. Critically, CR mitigated oxidative stress, evidenced by decreased thiobarbituric acid reactive substances (TBARS) and protein carbonylation, as well as increased levels of the reduced form of glutathione and activity of glutathione peroxidase (GPx). A lowered Bcl-X_L/X_S ratio was consistent with reduced apoptotic signaling, while reduced leukocyte infiltration reflected attenuated renal inflammation. Additionally, a reduction in mitochondrial DNA (mtDNA) lesions suggested that CR was associated with modulation of mitochondrial and metabolism-related pathways, with concurrent improvements in mitochondrial stability. Our findings demonstrate that CR attenuated gentamicin-induced AKI and was associated with changes in antioxidant-related parameters, reduced mtDNA damage, a decrease in inflammatory cell infiltration, and modulation of autophagy-related signaling. Full article

(This article belongs to the Special Issue The Role of Nutrition and Exercise in the Prevention and Treatment of Oxidative Stress-Associated Diseases—2nd Edition)

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17 pages, 3473 KB

Open AccessArticle

Esculetin Improves LPS/D-GalN Induced Acute Liver Injury Through AMPK/SIRT1/PGC-1α Signaling Pathway

by Haoyang Dai, Qinqin Zhang, Pei Chen and Suiqing Chen

Antioxidants 2026, 15(5), 652; https://doi.org/10.3390/antiox15050652 - 21 May 2026

Abstract

The pathogenesis of acute liver injury (ALI) involves the loss of hepatic detoxification function, massive death of liver parenchymal cells within a short period, and excessive inflammatory responses. Studies have shown that Esculetin (Esc) possesses potent anti-inflammatory, antioxidant, and anti-tumor properties. In this [...] Read more.

The pathogenesis of acute liver injury (ALI) involves the loss of hepatic detoxification function, massive death of liver parenchymal cells within a short period, and excessive inflammatory responses. Studies have shown that Esculetin (Esc) possesses potent anti-inflammatory, antioxidant, and anti-tumor properties. In this study, we investigate whether Esc has a protective effect against ALI in mice and its potential mechanism. Esculetin markedly decreased ROS, MitoSOX, and apoptosis levels in AML12 cells and restored MMP. H&E staining demonstrated that Esc alleviated hepatic histopathological injury, and its intervention reduced serum ALT and AST levels. Moreover, Esc diminished ROS and apoptosis levels in the liver. Hepatic proteomic profiling identified the AMPK signaling pathway. Esc reduced the protein levels of p-AMPK/AMPK, PGC-1α, p-SIRT1/SIRT1, and BAX and upregulated the levels of Bcl-2 in liver tissue. Concomitantly, we added inhibitor Compound C (CC) to the AML12 cells to assess whether Esc acted through the AMPK pathway. The results showed that CC exacerbated the degree of liver injury, whereas Esc was able to reverse these phenomena, thus exerting an anti-liver injury effect. These findings provide mechanistic insights into the protective effects of Esc against ALI and support its potential as a therapeutic candidate for ALI. Full article

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15 pages, 13547 KB

Open AccessArticle

Protective Effects of Vitis coignetiae Vine Stem Extract Against Carbon Tetrachloride-Induced Acute Liver Injury in Mice

by Nam-Kyu Yoon, Jeongjun Lee, Hunsuk Chung, Jae-Kwang Kim and Sae-Kwang Ku

Antioxidants 2026, 15(5), 651; https://doi.org/10.3390/antiox15050651 - 21 May 2026

Abstract

Vitis coignetiae Pulliat ex Planch, commonly referred to as “meoru” in Korea (crimson glory vine), is a grape species belonging to the Vitaceae family, native to East Asia. This study investigated the protective effects of a hot water extract prepared from the vine [...] Read more.

Vitis coignetiae Pulliat ex Planch, commonly referred to as “meoru” in Korea (crimson glory vine), is a grape species belonging to the Vitaceae family, native to East Asia. This study investigated the protective effects of a hot water extract prepared from the vine stems of V. coignetiae (CG) in a model of CCl₄-induced acute liver injury. Mice received oral administration of CG (100, 200, and 400 mg/kg) or silymarin (200 mg/kg) once daily for 7 consecutive days, followed by intraperitoneal injection of CCl₄ (0.5 mL/kg). CG attenuated CCl₄-induced oxidative stress, as indicated by reduced hepatic malondialdehyde production and decreased 4-hydroxynonenal-positive cells. These effects were accompanied by restoration of antioxidant defense systems, including increased glutathione levels and superoxide dismutase and catalase activities, along with increased nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression. Hepatic inflammatory responses were also attenuated by CG treatment, with reductions in TNF-α, interleukin (IL)-1β, and IL-6 levels, inflammatory cell infiltration, and nuclear factor-κB (NF-κB) mRNA expression. Furthermore, CG attenuated apoptotic cell death, as evidenced by decreased cleaved caspase-3-positive and cleaved poly(ADP-ribose) polymerase (PARP)-positive cells. CG also lowered serum aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transferase levels, and alleviated hepatocellular degeneration in histopathological analysis. Collectively, these findings suggest that CG may exert protective effects against CCl₄-induced liver injury by regulating oxidative stress, inflammation, and apoptosis. Full article

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

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9 pages, 979 KB

Open AccessEditorial

Antioxidant Activity of Natural Products: Recent Advances, Challenges, and Future Directions

by José Pinela, Maria Inês Dias, Alexandra Plácido and Carla Pereira

Antioxidants 2026, 15(5), 650; https://doi.org/10.3390/antiox15050650 - 21 May 2026

Abstract

Oxidative stress represents a fundamental paradox in biology [...] Full article

(This article belongs to the Topic Antioxidant Activity of Natural Products)

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23 pages, 17534 KB

Open AccessArticle

Feilike and Its Constituent Licochalcone B Trigger Caspase-3/GSDME-Mediated Pyroptosis in Triple-Negative Breast Cancer via Modulation of the Mutant p53–Calcium/ER Stress–ROS–MAPK Axis

by Jue Yang, Peng Zhao, Lianghong Zhou, Hui Song, Zili Feng, Hongjian Cui, Yanmei Li, Jianfei Qiu and Xiaojiang Hao

Antioxidants 2026, 15(5), 649; https://doi.org/10.3390/antiox15050649 - 21 May 2026

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options, underscoring the urgent need for novel treatment strategies. Feilike (FLK), a Traditional Chinese Medicine formula with heat-clearing and detoxifying properties, aligns with key pathological features implicated in [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options, underscoring the urgent need for novel treatment strategies. Feilike (FLK), a Traditional Chinese Medicine formula with heat-clearing and detoxifying properties, aligns with key pathological features implicated in breast cancer progression. In addition, several of its components have demonstrated anti-tumor activity, positioning FLK as a potential therapeutic candidate for TNBC. In this study, we employed an integrated approach combining network pharmacology, transcriptomic analysis, and experimental validation to investigate the anti-TNBC effects of FLK. Our results demonstrate that FLK significantly inhibits the proliferation of TNBC cell lines and patient-derived organoids and induces typical pyroptotic features, including cell swelling and increased lactate dehydrogenase (LDH) release. Mechanistically, FLK triggers a mutant p53 signaling cascade involving calcium dysregulation, endoplasmic reticulum stress (ERS) activation, mitochondrial dysfunction, and reactive oxygen species (ROS) accumulation, which collectively activate the P38/JNK–Caspase-3/GSDME pathway to induce pyroptosis. In vivo, FLK markedly suppresses tumor growth in a 4T1 orthotopic mouse model and enhances the anti-tumor efficacy of Cyclophosphamide. Furthermore, Licochalcone B (LCB) is identified as a key bioactive constituent that recapitulates the pyroptosis-inducing effects of FLK. Collectively, our findings uncover a previously unrecognized mutant p53–ERS–ROS–MAPK signaling axis underlying FLK-induced pyroptosis and provide mechanistic insight and experimental evidence supporting the repurposing of FLK as a potential therapeutic strategy for TNBC. Full article

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

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22 pages, 23239 KB

Open AccessArticle

Lycopene Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease via PINK1/Parkin-Mediated Mitophagy Activation and Apoptosis Attenuation

by Ze Xu, Xiao Wu, Lin Ye, Zeqi Li, Jian Zhao, Zhaofeng Zhang and Yongye Sun

Antioxidants 2026, 15(5), 648; https://doi.org/10.3390/antiox15050648 - 21 May 2026

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent global health concern. Although pharmacotherapies such as Resmetirom and semaglutide have recently gained approval by FDA/EMEA, therapeutic options remain limited, necessitating the exploration of novel natural compounds. Our previous research indicated that lycopene exerts [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent global health concern. Although pharmacotherapies such as Resmetirom and semaglutide have recently gained approval by FDA/EMEA, therapeutic options remain limited, necessitating the exploration of novel natural compounds. Our previous research indicated that lycopene exerts protective effects against MASLD; however, its underlying molecular mechanisms remain incompletely understood. The present study aimed to investigate whether lycopene alleviates MASLD by modulating mitophagy, with a focus on the PINK1/Parkin pathway. C57BL/6J mice were fed with high-fat diet for 12 weeks to induce MASLD and daily gavage of lycopene (10/40 mg/kg). In vitro, AML12 cells were treated with lycopene and Mdivi-1 to assess the role of PINK1/Parkin-mediated mitophagy against lipid accumulation, oxidative stress, and apoptosis. The results found that lycopene supplementation significantly ameliorated HFD-induced weight gain, dyslipidemia, hepatic steatosis, pathological liver injury, and elevated serum liver enzymes. It reduced hepatic reactive oxygen species (ROS) overproduction and suppressed the mitochondrial apoptotic pathway, as evidenced by decreased cytochrome c release and caspase cascade activation. Concurrently, lycopene restored ATP levels and mitochondrial membrane potential, improved ultrastructural integrity, and balanced mitochondrial dynamics by downregulating DRP1 and upregulating MFN2 and OPA1. Crucially, lycopene activated PINK1/Parkin-mediated mitophagy, leading to an increased LC3-II/LC3-I ratio and Beclin1 expression, alongside decreased levels of mitochondrial proteins TOM20 and COX IV. In vitro, the lycopene partially reversed the exacerbating effects of Mdivi-1 on lipid accumulation, ROS generation, apoptosis, and the suppression of the PINK1/Parkin pathway. Collectively, lycopene ameliorates MASLD by activating PINK1/Parkin-mediated mitophagy and improving mitochondrial homeostasis, thereby reducing hepatic lipid accumulation and attenuating hepatocyte apoptosis. Full article

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

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21 pages, 9685 KB

Open AccessArticle

Non-Erythropoietic EPO (EPO-R76E) Protects RPE Cells from Ferroptosis by Modulating the Labile Iron Pool and NRF2-GPX4 Axis

by Sundaramoorthy Gopi, George T. Prodanoff, Christopher L. Passaglia, Mark S. Kindy, Vijaykumar Sutariya, Ganesh V. Halade, Alfred S. Lewin and Manas R. Biswal

Antioxidants 2026, 15(5), 647; https://doi.org/10.3390/antiox15050647 - 20 May 2026

Abstract

Retinal pigment epithelium (RPE) degeneration remains a formidable challenge in dry age-related macular degeneration (AMD) research, primarily due to the toxic interplay between iron overload and ferroptosis. We investigated whether EPO-R76E, a non-erythropoietic modified variant of erythropoietin, could effectively interrupt this destructive cycle. [...] Read more.

Retinal pigment epithelium (RPE) degeneration remains a formidable challenge in dry age-related macular degeneration (AMD) research, primarily due to the toxic interplay between iron overload and ferroptosis. We investigated whether EPO-R76E, a non-erythropoietic modified variant of erythropoietin, could effectively interrupt this destructive cycle. Using ARPE-19 cells challenged with ferric ammonium citrate (FAC) to model iron-induced toxicity, we show that EPO-R76E confers protection against ferroptosis. Our results demonstrate that this variant significantly reduces the intracellular labile iron pool, directly quenching the lipid peroxidation that drives ferroptotic cell death. This resilience is fueled by a robust upregulation of Glutathione Peroxidase 4 (GPX4) and the broad transcriptional activation of the NRF2 (Nuclear factor erythroid 2-related factor 2) NRF2 antioxidant axis. Furthermore, we found that EPO-R76E enhances autophagic flux, ensuring that cells maintain essential proteostasis and “housekeeping” functions even under metabolic crisis. By integrating iron sequestration with reinforced antioxidant signaling and cellular clearing mechanisms, EPO-R76E stands out as a potent candidate for preserving RPE health. These findings uncover a novel molecular framework for protecting the retina against iron-mediated injury, positioning EPO-R76E as a versatile and targeted gene-based therapeutic for addressing the fundamental causes of retinal degeneration. Full article

(This article belongs to the Special Issue Novel Antioxidant Mechanisms for Health and Diseases, 2nd Edition)

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18 pages, 1365 KB

Open AccessArticle

Oxidative Stability and Kinetics of Oxidation of Rosehip, Sunflower, Olive and Jojoba Oils

by Carmen Fagoaga, Angela Moreno, Nayara Fernández-Julián and Gloria Castellano

Antioxidants 2026, 15(5), 646; https://doi.org/10.3390/antiox15050646 - 20 May 2026

Abstract

Lipid oxidation affects the quality and functionality of vegetable oils, and its progression depends largely on fatty acid composition and antioxidant content. Oxidation kinetics provide essential information about oxidative resistance in oils. The determination of activation parameters allows for the evaluation of oxidation [...] Read more.

Lipid oxidation affects the quality and functionality of vegetable oils, and its progression depends largely on fatty acid composition and antioxidant content. Oxidation kinetics provide essential information about oxidative resistance in oils. The determination of activation parameters allows for the evaluation of oxidation susceptibility under thermal stress. Oxidative stability and oxidation kinetics at different temperatures of rosehip, sunflower, olive and jojoba oils were studied using both Rancimat and BQC-Redox System methods, enabling the calculation of kinetic constants and thermodynamic activation parameters for the process. BRS measurements showed an increase in total antioxidant capacity (TAC) with temperature in all samples, with olive oil presenting the highest TAC and jojoba the lowest at 298 K, while rosehip oil showed the lowest TAC at 373 K. Kinetic analysis revealed negative ΔS^# values, indicating the formation of ordered transition states, and similar activation energies (ΔG^# ≈ 56–58 kJ/mol), although jojoba displayed the highest ΔH^# and ΔG^#. Rancimat analysis at 373 K showed clear differences in oxidative stability: jojoba oil had the longest induction period, followed by olive, sunflower, and rosehip. These results correlated with PUFA levels. Principal component analysis (PCA) confirmed strong associations between induction period, fatty-acid composition, and kinetic parameters, demonstrating good agreement between the two analytical methods. Full article

(This article belongs to the Special Issue Antioxidant Capacity of Natural Products—3rd Edition)

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25 pages, 15227 KB

Open AccessArticle

NFAT5: A Metabolic Time Capsule Encoding the History of Paternal Metabolic Oxidative Stress Within the Male Reproductive Tract

by Nicola Mosca, Antonella Migliaccio, Teresa Chioccarelli, Donato Cappetta, Antonella De Angelis, Marialucia Telesca, Liberato Berrino, Danila Valletta, Alice Luddi, Chiara Donati, Paola Piomboni, Charles Coutton, Guillaume Martinez, Gilda Cobellis, Chiara Schiraldi, Nicoletta Potenza, Rosanna Chianese and Francesco Manfrevola

Antioxidants 2026, 15(5), 645; https://doi.org/10.3390/antiox15050645 - 20 May 2026

Abstract

Leydig cells (LCs) represent a somatic testicular population responsible for testosterone synthesis, a hormone essential for spermatogenesis and male fertility. The obesity condition impairs LC steroidogenic activity, contributing to testicular oxidative stress and male reproductive dysfunctions. Using a high-fat-diet (HFD) murine model, we [...] Read more.

Leydig cells (LCs) represent a somatic testicular population responsible for testosterone synthesis, a hormone essential for spermatogenesis and male fertility. The obesity condition impairs LC steroidogenic activity, contributing to testicular oxidative stress and male reproductive dysfunctions. Using a high-fat-diet (HFD) murine model, we investigated the regulatory role of the nuclear factor of activated T cells 5 (NFAT5s) in the obesity-induced LC damage and the resulting alterations in intergenerationally inherited sperm circRNA cargo. Our findings reveal a significant upregulation of both circNFAT5 and NFAT5 protein levels in HFD testis. This molecular signature correlated with decreased antioxidant defense system, increased LC apoptosis, and impaired steroidogenesis. In vitro experiments, performed in TM3 cells, confirmed that NFAT5 nuclear shuttling drives proapoptotic gene activation, while NFAT5 silencing promotes LC survival. The analysis of HFD progeny (F1H) revealed a full recovery of testis oxidative status and LC apoptosis, linked with the recovery of NFAT5 expression. However, a steroidogenic deficiency persisted in F1H offspring. Notably, HFD and F1H epididymides exhibited NFAT5 overexpression concomitantly with impaired sperm morphology, motility, viability, and altered sperm circRNA profiles alongside a deregulated 4-hydroxy-2-nonenal (4HNE) profile, a marker of sperm oxidative stress. Lastly, an enhanced FUS-related amplification of circRNA perturbations was highlighted in F1H spermatozoa. Collectively, our findings reveal a dual functional role of NFAT5 as a testicular regulator of LC fate and an epididymal sentinel of metabolic stress, in turn linking paternal obesity to the persistent transmission of sperm epigenetic anomalies across the offspring. Full article

(This article belongs to the Special Issue Effect of Oxidative Stress on Reproduction and Development—3rd Edition)

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24 pages, 1527 KB

Open AccessArticle

Tomato Intake Improves Cognitive Performance and Modulates Functional Brain Networks in Healthy Adults: A Randomized Crossover Clinical Trial

by Ricardo López-Solís, Carolina Donat-Vargas, Patricia Ramírez-Carrasco, Rocío M. Gutiérrez-Romero, Maria Pérez, Magda Castellví, Beatriz Bosch, Camila Arancibia-Riveros, Alejandro Hinojosa-Moscoso, Carlos Laredo, Emma Muñoz-Moreno, Ana Maria Ruiz-Leon, Rosa Casas, Ramon Estruch, Anna Vallverdú-Queralt, Marina Corrado and Rosa M. Lamuela-Raventós

Antioxidants 2026, 15(5), 644; https://doi.org/10.3390/antiox15050644 - 19 May 2026

Abstract

Tomatoes are the major dietary source of lycopene, a carotenoid that crosses the blood–brain barrier and exerts antioxidant and anti-inflammatory effects. However, the impact of tomato consumption on cognitive function in healthy adults remains unclear. This study assessed the effects of concentrated tomato [...] Read more.

Tomatoes are the major dietary source of lycopene, a carotenoid that crosses the blood–brain barrier and exerts antioxidant and anti-inflammatory effects. However, the impact of tomato consumption on cognitive function in healthy adults remains unclear. This study assessed the effects of concentrated tomato paste on cognitive performance and explored potential mechanisms, including brain-derived neurotrophic factor (BDNF) and functional brain connectivity. A randomized, two-period crossover trial (ClinicalTrials.gov: NCT05891977) was conducted in 47 healthy adults aged 40–55 years assigned to two 3-month interventions separated by a 1-month washout: (a) daily consumption of concentrated tomato paste (0.5 g/kg body weight) and (b) a lycopene-restricted control diet. Cognitive performance was evaluated using validated neuropsychological tests (d2-R, Face-Name Associative Memory Exam, Modified Wisconsin Card Sorting Test), alongside plasma lycopene and BDNF, and resting-state functional magnetic resonance imaging (fMRI). Forty-two participants completed the study. Tomato intake improved selective attention (concentration performance: +7.2 points; processing speed: +8.3 points) and associative memory (face-name matching: +0.8 points). Plasma BDNF showed a borderline increase with tomato intake (mean difference 15.2 ng/mL). Resting-state fMRI revealed changes in brain networks, including reduced connectivity in frontoparietal and auditory networks, contrasting with reductions in the dorsal attention network during the control period. These findings provide evidence that tomato consumption may support cognitive function and modulate brain connectivity in healthy middle-aged adults. Full article

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

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30 pages, 39256 KB

Open AccessArticle

The Flavonoid Rutin Enhances Temozolomide Sensitivity in Glioblastoma Spheroids by Modulating Chemoresistance via PI3K/AKT, STAT3, Redox and Kynurenine Pathways, and Altering ECM Remodeling Associated with Reduced Migration

by Irlã Santos Lima, Fernanda Vidal Carvalho, Érica Novaes Soares, Monique Reis de Santana, Maria de Fátima Dias Costa, Carolina Kymie Vasques Nonaka, Bruno Solano de Freitas Souza, Henning Ulrich, Cleonice Creusa dos Santos and Silvia Lima Costa

Antioxidants 2026, 15(5), 643; https://doi.org/10.3390/antiox15050643 - 19 May 2026

Abstract

Introduction: Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system and is highly resistant to temozolomide (TMZ). Rutin is a potent antioxidant with immunomodulatory and anti-glioma effects in vitro, although its mechanisms of action remain incompletely understood. This study [...] Read more.

Introduction: Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system and is highly resistant to temozolomide (TMZ). Rutin is a potent antioxidant with immunomodulatory and anti-glioma effects in vitro, although its mechanisms of action remain incompletely understood. This study investigated the effects of rutin on morphology, viability, redox balance, and pro-tumoral signaling in GBM 2D cultures and 3D spheroids, as well as its association with TMZ sensitivity. Methods: GL15 and U343 human GBM cell lines and primary astrocytes were treated with rutin (5–30 μM) and/or TMZ (125–4000 μM). Cell metabolic activity and viability were assessed by MTT, PI/DiOC18(3) or PI/Hoechst. Cell migration was assessed from spheroid-derived cells, and extracellular matrix (ECM) components (fibronectin and laminin) were evaluated by immunofluorescence. Intracellular reactive oxygen species (ROS) were measured by DCFH-DA fluorescence. IL-6, STAT3, NOS2, and IDO1 gene expression were determined by RT-qPCR, and protein expression of MMP2, fibronectin, STAT3, PI3K, and AKT by Western blotting. Nitric oxide (NO) and L-kynurenine levels were quantified in the supernatant by colorimetric assays. Results: Rutin reduced cell viability and enhanced TMZ cytotoxicity in both 2D and 3D cultures, while exerting selective effects by increasing metabolic activity and attenuating TMZ-induced effects in non-tumoral primary astrocytes. In 3D spheroids, rutin affected structural organization and reduced spheroid-derived cell migration, accompanied by changes in ECM components, including MMP2, fibronectin, and laminin. Rutin decreased intracellular ROS levels and suppressed the TMZ-induced increase in ROS and NOS signaling. These effects were accompanied by modulation of IL-6/STAT3 signaling, along with reduced STAT3, PI3K, and AKT protein levels. Rutin also modulated immunometabolic parameters, including extracellular L-kynurenine and nitric oxide levels, and enhanced TMZ responsiveness following pre-sensitization. Conclusions: Rutin enhances TMZ responsiveness by modulating interconnected pro-tumoral mechanisms, including redox balance, pro-survival signaling, ECM remodeling and migratory behavior, and immunometabolic pathways linked to chemoresistance, supporting its potential as an adjuvant therapeutic strategy. Full article

(This article belongs to the Special Issue Anti-Cancer Potential of Plant-Based Antioxidants—2nd Edition)

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15 pages, 2729 KB

Open AccessArticle

Holotomography and Multivariate Analysis Reveal Donor-Specific Responses to Antioxidant Supplementation During Stallion Sperm Cryopreservation

by Graziano Preziosi, Raffaele Boni, Stefano Cecchini Gualandi and Maria Antonietta Ferrara

Antioxidants 2026, 15(5), 642; https://doi.org/10.3390/antiox15050642 - 18 May 2026

Abstract

Freeze–thaw procedures impair sperm morphology and function, affecting viability, motility, redox balance, and subcellular organization. Although antioxidants may mitigate these effects, their interaction with donor-specific variability remains unclear. We combined quantitative holotomography with conventional physiological assessments within a multivariate framework based on principal [...] Read more.

Freeze–thaw procedures impair sperm morphology and function, affecting viability, motility, redox balance, and subcellular organization. Although antioxidants may mitigate these effects, their interaction with donor-specific variability remains unclear. We combined quantitative holotomography with conventional physiological assessments within a multivariate framework based on principal component analysis (PCA) and nested cross-validated Linear Discriminant Analysis (LDA) to evaluate donor-specific responses to antioxidant-supplemented cryopreservation. Spermatozoa from ten stallions was analyzed before and after freezing under five conditions: fresh semen; frozen semen with INRA Freeze, frozen semen with HF-20, and HF-20 supplemented with matcha, spirulina, horseradish, or quercetin. For each condition, sperm kinetics, mitochondrial activity, oxidative stress, DNA integrity, and three-dimensional volumetric measurements of whole-cell and subcellular compartments derived from holotomography were integrated into a single dataset. LDA achieved 0.734 cross-validated accuracy for stallion classification, revealing strong donor-specific signatures. In contrast, classification by antioxidant treatment was near chance (0.248). Fresh semen was clearly distinct from all cryopreserved groups. Holotomography showed reduced whole-cell and post-acrosomal/midpiece volumes after freezing, while nuclear volume was unchanged. Antioxidant supplementation produced minor, inconsistent effects, with partial midpiece preservation in some donors but no global pattern. Overall, inter-stallion variability dominates post-thaw sperm phenotype. Antioxidant effects were detectable but modest, supporting individualized strategies to optimize equine semen cryopreservation protocols. Full article

(This article belongs to the Special Issue Redox Regulation in Animal Reproduction—2nd Edition)

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26 pages, 14667 KB

Open AccessReview

Oxidative Stress-Guided Gold Nanoparticles for Cancer Theranostics

by Yubin Jin, Jiaxuan Zhu, Yang Yang, Zhuhu Li and Yunzhi Qin

Antioxidants 2026, 15(5), 641; https://doi.org/10.3390/antiox15050641 - 18 May 2026

Abstract

Gold nanoparticles offer a versatile platform for cancer theranostics because their high atomic number can enhance X-ray energy deposition, their plasmonic properties support photothermal and photoacoustic applications, and their surfaces allow drug loading and molecular targeting. However, therapeutic benefit remains heterogeneous because tumor [...] Read more.

Gold nanoparticles offer a versatile platform for cancer theranostics because their high atomic number can enhance X-ray energy deposition, their plasmonic properties support photothermal and photoacoustic applications, and their surfaces allow drug loading and molecular targeting. However, therapeutic benefit remains heterogeneous because tumor uptake, intratumoral coverage, and subcellular localization determine whether deposited gold can be converted into biologically effective damage. Redox context further shapes this conversion by determining whether AuNP-triggered physical or catalytic events can overcome local buffering and propagate into durable injury. During radiotherapy, AuNPs increase local secondary electron release and ROS formation, which can intensify DNA damage when GSH-dependent peroxide detoxification, thioredoxin-related buffering, and KEAP1-NRF2-regulated antioxidant responses are insufficient to contain the redox burden. In catalytic systems, Au-containing nanozymes can convert endogenous H₂O₂ into highly reactive radicals and may simultaneously deplete glutathione, thereby amplifying mitochondrial dysfunction and lipid peroxidation. During photoactivation, plasmonic heating and photosensitizer coupling further reshape ROS generation in a time-dependent and location-dependent manner. On the diagnostic side, CT or spectral CT can quantify tumor gold burden and coverage, whereas ROS-responsive photoacoustic, SERS, or fluorescence probes can report treatment-related oxidants and verify whether redox activation has occurred within the tumor. Clinical translation will therefore depend on quantification-guided dosing, definition of spatial coverage and activation timing, standardized redox-response readouts, and long-term safety evaluation. Full article

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

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25 pages, 7060 KB

Open AccessArticle

Selective MIF Enolase Inhibitor TE-91 Regulates M1 Polarization and Associated Metabolic Reprogramming

by Péter Deák, Nikoletta Kálmán, Csenge Antus, Eva M. Böhm, Marcell Krekó, Eszter Vámos, Viola Bagóné Vántus, Katalin Böddi, Lilla Makszin, Tamás Lóránd, Ferenc Gallyas, Jr. and Balázs Radnai

Antioxidants 2026, 15(5), 640; https://doi.org/10.3390/antiox15050640 - 18 May 2026

Abstract

Macrophage migration inhibitory factor (MIF) has been shown to induce M1 macrophage polarization with oxidative stress and associated metabolic reprogramming. Several tautomerase inhibitors were shown to selectively inhibit either MIF’s ketonase or enolase sub-activities. In this study, we aimed to investigate the role [...] Read more.

Macrophage migration inhibitory factor (MIF) has been shown to induce M1 macrophage polarization with oxidative stress and associated metabolic reprogramming. Several tautomerase inhibitors were shown to selectively inhibit either MIF’s ketonase or enolase sub-activities. In this study, we aimed to investigate the role of enolase sub-activity in M1 polarization using the selective enolase inhibitor TE-91. We performed in silico molecular docking analysis and physicochemical characterization of TE-91. LPS + IFN-γ-induced RAW264.7 cells were applied as a model for M1 macrophage activation. We performed ROS and nitrite determinations, ELISA, qPCR, and immunoblot analysis, and measured mitochondrial oxygen consumption rate and extracellular acidification rate. Here, we reveal that TE-91 might directly bind to the MIF tautomerase active site. Furthermore, TE-91 reduces M1 activation by enhancing oxidative phosphorylation and reducing the glycolytic activity in LPS + IFN-γ-induced macrophage cells. In the same model, TE-91 reduces TNF-α, IL-6, CCL2, and iNOS mRNA transcription yet fails to modulate PARP1 and SOD2 mRNA transcription. It also decreases ROS, nitrite, and IL-6 production without influencing TNF-α and CCL2 protein production. TE-91 was unable to reduce either HIF-1α mRNA transcription or its protein expression. Finally, TE-91 reduced IL-1β cleavage, without affecting IL-1β protein expression. These results may highlight the importance of tautomerase sub-activities in M1 polarization. Full article

(This article belongs to the Special Issue Synthetic Compounds: Antioxidant and Anti-Inflammatory Activities, Biomedical Properties and Formulations)

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25 pages, 7419 KB

Open AccessArticle

Rhamnocitrin Ameliorates the Intestinal Fibrosis in DSS-Induced Colitis Mice by Modulating Host-Metabolites and Remodeling the Gut Microbiome

by Ming-Yu Zhang, Zhi-Zhu Ke, Pei-Lin Deng, Yi-Yan Qin, Shu-Lan Mo, Lin-Ting Qiu, Jie-Jing Xu, Chen-Xi Tong and Jia-Le Song

Antioxidants 2026, 15(5), 639; https://doi.org/10.3390/antiox15050639 - 18 May 2026

Abstract

Ulcerative colitis (UC) is characterized by barrier disruption, microbiota dysbiosis, fibrosis, and impaired autophagy. We investigated the effects of Rhamnocitrin (Rha) in dextran sulfate sodium (DSS)-induced chronic UC mice using histological analysis, molecular assays, and multiomics profiling. Rha alleviated weight loss and colon [...] Read more.

Ulcerative colitis (UC) is characterized by barrier disruption, microbiota dysbiosis, fibrosis, and impaired autophagy. We investigated the effects of Rhamnocitrin (Rha) in dextran sulfate sodium (DSS)-induced chronic UC mice using histological analysis, molecular assays, and multiomics profiling. Rha alleviated weight loss and colon shortening; improved mucus secretion and tight junction protein expression; suppressed NLRP3 inflammasome activation; activated autophagy via AMPK activation and consequent Akt/mTOR inhibition; and attenuated colonic fibrosis. Multiomics analysis integrating 16S rRNA sequencing, metagenomics, and metabolomics revealed that Rha remodels the gut microbiota and is associated with elevated levels of beneficial metabolites, including butyrate in the colon, glutamate and γ-aminobutyric acid in the liver, and α-linolenic acid in the serum. Correlation analysis revealed close associations between microbiota and metabolite alterations, and improved barrier integrity, reduced inflammation, and attenuated fibrosis. These findings suggest that Rha ameliorates chronic UC by modulating autophagy, microbiota composition, and host metabolism across the gut–liver axis. Full article

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21 pages, 339 KB

Open AccessReview

Translational Feasibility of Curcumin for Treatment of Alzheimer’s Disease: A Critical Appraisal of Clinical Challenges

by Jasmine Priya Virk, Malika G. Fernando, Prita Riana Asih and Ralph N. Martins

Antioxidants 2026, 15(5), 638; https://doi.org/10.3390/antiox15050638 - 18 May 2026

Abstract

The absence of robust and effective treatments for Alzheimer’s disease remains a major challenge in modern medicine. As one of the leading causes of death, its increasing prevalence and complex chronic pathogenesis impose a substantial societal and healthcare burden, intensifying the need for [...] Read more.

The absence of robust and effective treatments for Alzheimer’s disease remains a major challenge in modern medicine. As one of the leading causes of death, its increasing prevalence and complex chronic pathogenesis impose a substantial societal and healthcare burden, intensifying the need for effective therapeutic strategies. Current treatments remain limited, with minimal impact on cognitive decline in symptomatic patients. Curcumin, the bioactive ingredient in turmeric, has taken precedence over other natural products due to its potent antioxidative and anti-inflammatory properties. Numerous publications have extensively reported on the therapeutic effect of curcumin in animal models of Alzheimer’s disease. However, no curcumin formulation has demonstrated consistent clinical efficacy against Alzheimer’s or other neurodegenerative diseases to date. Over the years, many critics have argued that curcumin’s undesirable chemical properties, mainly low bioavailability and rapid metabolism, pose significant barriers to its therapeutic use to target the brain. Considerable funding and research effort on emerging technologies such as nanoparticles and intranasal delivery continue to drive curcumin preclinical and clinical trials, prompting reflection on the rationale for continued investment. This narrative review critically dissects this disconnect, arguing that many purported benefits remain insufficiently substantiated, and identifying important opportunities where future research may hold promise for an effective treatment. Full article

(This article belongs to the Special Issue Oxidative Stress and Its Mitigation in Neurodegenerative Disorders)

33 pages, 15781 KB

Open AccessArticle

Spermidine Targets Ovarian Granulosa Cells via Activating the FHC/SLC7A11 Axis to Regulate Iron Homeostasis and Ameliorate Iron Overload-Induced Ovarian Dysfunction

by Chun-Yang Niu, Dong-Mei Jiang, Xin Wang, Guan-Hua Chen, Shuo Li, Yong-Ni Guo, Cheng-Weng Ji, Xiao-Guang An, Wei-Kang Ling, Yu-Xin Qi, Xin-Yi Wang, Lu Lu, Xun Wang and Bo Kang

Antioxidants 2026, 15(5), 637; https://doi.org/10.3390/antiox15050637 - 18 May 2026

Abstract

Females with iron overload suffer from follicular dysplasia, and effective therapeutic strategies for preserving fertility remain lacking. As a natural aliphatic polyamine, spermidine exerts antioxidant activity and plays an anti-ferroptosis role in the pathogenesis of various diseases. However, the role and underlying mechanism [...] Read more.

Females with iron overload suffer from follicular dysplasia, and effective therapeutic strategies for preserving fertility remain lacking. As a natural aliphatic polyamine, spermidine exerts antioxidant activity and plays an anti-ferroptosis role in the pathogenesis of various diseases. However, the role and underlying mechanism of spermidine in iron overload-induced ovarian ferroptosis remain largely elusive. This study aimed to investigate the therapeutic potential of spermidine against iron overload-induced ferroptosis in ovarian granulosa cells and elucidate its molecular mechanism. As a result, iron overload models were established in female mice (in vivo, ferrous sulfate) and porcine ovarian granulosa cells (in vitro, ferric ammonium citrate), with spermidine administered at 3 mM (in vivo) or 150 μM (in vitro). Ferritin heavy chain (FHC) and solute carrier family 7 member 11 (SLC7A11) silencing were performed via siRNA transfection, and relevant controls were set. In vivo studies showed that spermidine elevated serum estradiol and progesterone levels, enhanced ovarian catalase (CAT) and superoxide dismutase (SOD) activities, improved granulosa cell mitochondrial morphology, and increased estrous cycle regularity from 35.6% (high-iron group) to 63.1%. In vitro, spermidine improved ferric ammonium citrate (FAC)-impaired cell viability; attenuated reactive oxygen species (ROS) accumulation; upregulated FHC, Nrf2/p-Nrf2/GPX4, SLC7A11 and anti-müllerian hormone (AMH) expression; and inhibited excessive autophagy (decreased LC3BII/I ratio). Mechanistically, spermidine activated AKT-mediated autophagy, modulated iron homeostasis and glutathione (GSH) synthesis via FHC, alleviated ferroptosis-related Nrf2/p-Nrf2/HO-1 pathway overactivation, reduced lipid peroxidation and DNA damage, and restored mitochondrial function. SLC7A11 silencing disrupted glutathione metabolism, induced mitochondrial ROS accumulation, and inhibited autophagy. Proteomic analysis identified microsomal glutathione S-transferase 3 (MGST3) as a potential key downstream target of spermidine in suppressing SLC7A11-mediated ferroptosis. This study reveals a novel therapeutic strategy wherein spermidine protects against ovarian ferroptosis and preserves ovarian function by regulating iron homeostasis through the FHC/SLC7A11 axis. Full article

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

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