Antioxidants

28 pages, 1186 KB

Open AccessReview

Antioxidants and Exercise: A Redox-Informed Framework for Training Adaptation, Performance, and Recovery

by Dan Cristian Mănescu, Andrei Tudor, Andreea Maria Mănescu, Iulius Radulian Mărgărit, Cătălin Octavian Mănescu, Ciprian Prisăcaru, Lucian Păun and Virgil Tudor

Antioxidants 2026, 15(4), 456; https://doi.org/10.3390/antiox15040456 - 7 Apr 2026

Abstract

Exercise-derived reactive oxygen species (ROS) are required for mitochondrial and hypertrophic adaptations, creating a practical trade-off: antioxidant strategies may support short-term performance and recovery yet blunt training signals when mis-timed or over-dosed. We performed a structured narrative review informed by transparent database searches [...] Read more.

Exercise-derived reactive oxygen species (ROS) are required for mitochondrial and hypertrophic adaptations, creating a practical trade-off: antioxidant strategies may support short-term performance and recovery yet blunt training signals when mis-timed or over-dosed. We performed a structured narrative review informed by transparent database searches of MEDLINE, Scopus, and SPORTDiscus (2000–2025), prioritizing human intervention studies and using mechanistic evidence to interpret plausibility. Evidence was mapped by antioxidant class, dose, timing, training modality, and context. Across trials, chronic high-dose vitamins C/E taken close to key sessions are most consistently associated with attenuation of redox-sensitive signaling, whereas food-first polyphenols and selected bioactives (e.g., tart cherry/anthocyanins, pomegranate, and curcumin) more often support recovery when positioned away from adaptation-critical workouts, without clear evidence of impaired training gains. N-acetylcysteine can acutely improve tolerance to repeated high-intensity exercise, but effects during prolonged training remain uncertain and appear context-dependent. We propose Redox-Adaptive Periodization, aligning antioxidant class, dose, and timing with the primary objective (adaptation vs. immediate readiness) and environmental constraints, and we outline methodological priorities to advance precision redox management. Full article

(This article belongs to the Special Issue The Role of Antioxidants in Enhancing Training Adaptation, Exercise Performance, and Post-exercise Recovery)

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15 pages, 6470 KB

Open AccessArticle

Oxidative Damage, Antioxidant Capacity, and Apoptotic Activation in Varicocele: Biochemical Evidence of Improvement After Surgical Repair

by Erdem Orman, Hakki Uzun, Merve Huner Yigit, Ertugrul Yigit, Huseyin Cinar Zihni and Gorkem Akca

Antioxidants 2026, 15(4), 455; https://doi.org/10.3390/antiox15040455 - 5 Apr 2026

Abstract

To evaluate seminal oxidative stress, antioxidant defense, apoptosis-related activity, and Sertoli cell biomarkers in infertile men with grade 3 varicocele versus normozoospermic controls, and to assess postoperative changes after varicocelectomy. This prospective observational case–control study included 39 infertile men with grade 3 clinical [...] Read more.

To evaluate seminal oxidative stress, antioxidant defense, apoptosis-related activity, and Sertoli cell biomarkers in infertile men with grade 3 varicocele versus normozoospermic controls, and to assess postoperative changes after varicocelectomy. This prospective observational case–control study included 39 infertile men with grade 3 clinical varicocele and 44 normozoospermic controls. Seminal plasma levels of Malondialdehyde (MDA), 8-hydroxy-2′-deoxyguanosine (8-OHdG), superoxide dismutase (SOD), glutathione peroxidase-1 (GPx-1), reduced glutathione (GSH), nuclear factor erythroid 2–related factor 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), caspase-3, anti-Müllerian hormone (AMH), and inhibin B were measured by ELISA. Testicular volume, semen parameters, and diagnostic performance were also evaluated. Compared with controls, patients with varicocele had lower testicular volumes and impaired semen parameters. Seminal 8-OHdG and caspase-3 levels were higher, whereas SOD and inhibin B levels were lower. Baseline MDA, GPx-1, GSH, NRF2, KEAP1, and AMH levels did not differ significantly. After varicocelectomy, sperm concentration, total sperm count, progressive and total motility, total motile sperm count, morphology, and round cell count improved significantly. Postoperatively, caspase-3, MDA, and KEAP1 decreased, whereas SOD, GPx-1, GSH, NRF2, and inhibin B increased significantly. 8-OHdG showed a borderline decrease, and AMH remained unchanged. SOD showed the best diagnostic performance. Grade 3 varicocele is associated with oxidative DNA damage, impaired antioxidant defense, increased apoptotic signaling, and altered Sertoli cell-related seminal biomarkers. Varicocelectomy partially restores redox homeostasis, which may contribute to improved spermatogenic function. Full article

(This article belongs to the Special Issue Oxidative Stress and Male Reproductive Health—2nd Edition)

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21 pages, 4284 KB

Open AccessArticle

Functionalization of 3D Printed Polylactic Acid by Supercritical CO₂ Impregnation with Mango Leaf Extract and Evaluation with Endothelial Colony-Forming Cells and Mesenchymal Stromal Cells

by Ismael Sánchez-Gomar, Mercedes Cáceres-Medina, Cristina Cejudo-Bastante, Casimiro Mantell-Serrano, Lourdes Casas-Cardoso and Mª Carmen Durán-Ruiz

Antioxidants 2026, 15(4), 454; https://doi.org/10.3390/antiox15040454 - 4 Apr 2026

Abstract

Poly(lactic acid) (PLA) devices can be functionalized with plant-derived bioactives to introduce antioxidant activity while maintaining manufacturability and cytocompatibility. Here, a polyphenol-rich mango leaf extract (MLE) was obtained by enhanced solvent extraction and incorporated into PLA using supercritical carbon dioxide-assisted impregnation. Two manufacturing [...] Read more.

Poly(lactic acid) (PLA) devices can be functionalized with plant-derived bioactives to introduce antioxidant activity while maintaining manufacturability and cytocompatibility. Here, a polyphenol-rich mango leaf extract (MLE) was obtained by enhanced solvent extraction and incorporated into PLA using supercritical carbon dioxide-assisted impregnation. Two manufacturing sequences were compared: impregnation after three-dimensional (3D) printing of discs and impregnation of filaments prior to printing. Extract yield and radical scavenging capacity were quantified, and impregnation efficiency was assessed as a function of pressure and temperature. Biological performance was evaluated using adipose tissue-derived endothelial colony-forming cells (ECFCs) and adipose tissue-derived mesenchymal stromal cells (MSCs), cultured separately and in co-culture on functionalized substrates. Impregnation after printing provided higher and more reproducible loading while preserving disc geometry, whereas impregnation before printing promoted swelling and printing-associated deformation that compromised structural fidelity. Cell-based analyses supported improved adhesion, spatial distribution, and proliferative status on discs produced by impregnation after printing under low-temperature and high-pressure conditions, without evidence of selective loss of either population in co-culture by flow cytometry. These results support post-print supercritical impregnation as a robust route to generate antioxidant, cell-supportive PLA scaffolds from agricultural by-products with potential relevance for vascular-oriented biomedical applications. Full article

(This article belongs to the Special Issue Bioactive Antioxidants from Agri-Food Wastes, 2nd Edition)

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Graphical abstract

26 pages, 1455 KB

Open AccessReview

ROS–SUMO Crosstalk in Oxidative Stress: Disease Mechanisms and Reproductive Health

by Ann-Yae Na, Hyun-Shik Lee and Hong-Yeoul Ryu

Antioxidants 2026, 15(4), 453; https://doi.org/10.3390/antiox15040453 - 4 Apr 2026

Abstract

Oxidative stress disrupts protein function through direct oxidation and triggers adaptive post-translational modifications. Among these, small ubiquitin-like modifier (SUMO)-ylation mediates fast and reversible remodeling of nuclear and cytoplasmic proteins. Redox regulation of the SUMO E1–E2 conjugation complex and specific SUMO proteases, such as [...] Read more.

Oxidative stress disrupts protein function through direct oxidation and triggers adaptive post-translational modifications. Among these, small ubiquitin-like modifier (SUMO)-ylation mediates fast and reversible remodeling of nuclear and cytoplasmic proteins. Redox regulation of the SUMO E1–E2 conjugation complex and specific SUMO proteases, such as SENP1 and SENP3, allows ROS to influence SUMO turnover and substrate selectivity. This defines SUMOylation as a versatile stress-response module under oxidative stress. In this review, we describe oxidative stress-induced remodeling of SUMO conjugation and deconjugation, with a focus on SUMO2/3 responses that transiently adjust transcription, DNA damage repair, and nuclear body dynamics. We discuss disease-relevant SUMO targets and pathological alterations in SUMO regulation across four major disease categories: neurodegenerative diseases, cardiovascular disease, cancer, and diabetes/metabolic diseases. In addition, we summarize emerging evidence connecting redox-sensitive SUMO remodeling to germ-cell function and reproductive health. Together, these perspectives highlight the dual role of SUMOylation as both a driver of stress adaptation and a tractable target for informing therapeutic strategies targeting the SUMO pathway. Full article

(This article belongs to the Special Issue Oxidative Stress in Fertility and Infertility)

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30 pages, 9530 KB

Open AccessArticle

Liposomal Myricetin Nanoantioxidants Attenuate Methotrexate-Induced Hepatotoxicity by Modulating Oxidative Stress, Inflammation, and Apoptosis in Rats

by Fahad Alshammari, Ekramy M. Elmorsy, Abdulrahman S. Aldaghmi, Fahd Alaajam, Eida M. Alshammari, Mona M. Elghareeb, Manal S. Fawzy and Noha M. Abd El-Fadeal

Antioxidants 2026, 15(4), 452; https://doi.org/10.3390/antiox15040452 - 4 Apr 2026

Abstract

Methotrexate (MTX) is widely used for its chemotherapeutic and immunosuppressive properties, but is limited by oxidative stress-mediated hepatotoxicity. Nanoantioxidant delivery systems can enhance the stability, solubility, and in vivo efficacy of natural antioxidants. This study investigated the hepatoprotective effects of myricetin (MYR), a [...] Read more.

Methotrexate (MTX) is widely used for its chemotherapeutic and immunosuppressive properties, but is limited by oxidative stress-mediated hepatotoxicity. Nanoantioxidant delivery systems can enhance the stability, solubility, and in vivo efficacy of natural antioxidants. This study investigated the hepatoprotective effects of myricetin (MYR), a flavonoid with potent antioxidant activity, and its liposomal nanoantioxidant formulation (MYR-loaded liposomal nanoparticles, MYR-LNPs) against MTX-induced liver injury in male albino Sprague Dawley rats. Sixty rats were randomly allocated to six groups: control, MTX, MYR, MYR-LNPs, and combinations of MTX with MYR-LNPs. MYR-LNPs were successfully formulated and physicochemically characterized, exhibiting a mean particle size of 95.6 nm, a zeta potential of −32 mV, and a narrow polydispersity index, collectively confirming their colloidal stability and suitability for hepatic delivery. MTX markedly disrupted liver function, increasing serum AST, ALT, ALP, and bilirubin and decreasing total protein, albumin, and globulin, whereas co-treatment with MYR-LNPs substantially restored these parameters and outperformed free MYR. MTX-induced oxidative stress, reflected by depleted hepatic GSH and antioxidant enzymes (GPx, SOD, CAT, GST), elevated reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyls and downregulated NRF2/HO-1, was significantly counteracted by MYR-LNPs. In addition, MYR-LNPs mitigated MTX-evoked inflammation and nitrosative stress by reducing NF-κB, TNF-α, IL-1β, nitric oxide, and iNOS expression. They corrected apoptotic imbalance by lowering Bax and caspase 3 while increasing Bcl-2. Histopathological and ultrastructural assessments confirmed that MYR-LNPs preserved hepatic architecture and mitochondrial integrity. These findings indicate that MYR-loaded liposomal nanoantioxidants provide superior protection against MTX-induced hepatotoxicity by modulating oxidative stress, inflammation, and apoptosis, supporting their potential as an advanced nanodrug delivery strategy for antioxidant therapy. Full article

(This article belongs to the Special Issue Recent Trends in Nanoantioxidants—2nd Edition)

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Graphical abstract

16 pages, 1289 KB

Open AccessReview

The Role of ER Stress in Bilirubin Neurotoxicity: A Complex Molecular Network

by Mohammed Qaisiya, Claudio Tiribelli and Cristina Bellarosa

Antioxidants 2026, 15(4), 451; https://doi.org/10.3390/antiox15040451 - 3 Apr 2026

Abstract

Although the molecular pathogenesis of bilirubin-induced neuronal cell injury is not completely understood, certain recurrent themes resonate in the literature on this topic and include the generally untoward effects of high unconjugated bilirubin (UCB) concentrations on membranes (plasma, mitochondrial, and endoplasmic reticulum (ER)), [...] Read more.

Although the molecular pathogenesis of bilirubin-induced neuronal cell injury is not completely understood, certain recurrent themes resonate in the literature on this topic and include the generally untoward effects of high unconjugated bilirubin (UCB) concentrations on membranes (plasma, mitochondrial, and endoplasmic reticulum (ER)), cellular bioenergetics, and intracellular calcium homeostasis. Only in the last decade, ER was discovered as an early target of bilirubin neurotoxicity. We will review the main features of bilirubin neurotoxicity from the point of view of ER and bilirubin-induced ER stress. Neuronal excitotoxicity, mitochondrial energy failure, and increased intracellular calcium concentration are three phenomena linked spatially and temporally in the pathogenesis of bilirubin-induced neurotoxicity. ER, being the main intracellular calcium storage organelle, is involved in the increase in the universal second messenger, calcium. This event leads to the activation of proteolytic enzymes, apoptotic pathways, and necrosis, the occurrence of which is likely a function of the degree and duration of bilirubin exposure. Full article

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

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20 pages, 17099 KB

Open AccessArticle

Augmenter of Liver Regeneration-Modified Adipose Mesenchymal Stem Cell-Derived Exosomes Repairs Liver Damage by Regulating Endoplasmic Reticulum Stress and Pyroptosis in a Minipig Model of Liver Injury

by Yajun Ma, Tao Liu, Lei Cao, Pujun Li, Xiangyu Lu, Yue Wang and Hongbin Wang

Antioxidants 2026, 15(4), 450; https://doi.org/10.3390/antiox15040450 - 3 Apr 2026

Abstract

Adipose mesenchymal stem cell-derived exosomes (ADSC-Exo) have demonstrated therapeutic effects in liver diseases and injuries. The Augmenter of Liver Regeneration (ALR), a novel hepatic trophic growth factor, promotes hepatic structural and functional recovery. In this study, we constructed ALR-overexpressing ADSC-Exo (ADSC-ALR-Exo) by harnessing [...] Read more.

Adipose mesenchymal stem cell-derived exosomes (ADSC-Exo) have demonstrated therapeutic effects in liver diseases and injuries. The Augmenter of Liver Regeneration (ALR), a novel hepatic trophic growth factor, promotes hepatic structural and functional recovery. In this study, we constructed ALR-overexpressing ADSC-Exo (ADSC-ALR-Exo) by harnessing the messaging capacity of ADSC-Exo, and analyzed the effects of ADSC-ALR-Exo on hepatic ischemia–reperfusion injury (IRI) combined with partial hepatectomy in a minipig model. Our results indicated that, compared to the ADSC-Exo group, the ADSC-ALR-Exo group exhibited a significant reduction in reactive oxygen species (ROS) levels, alongside a notable increase in the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Furthermore, there was a marked decrease in malondialdehyde (MDA) content. Concurrently, the concentrations of pro-inflammatory factors in the blood (IL-1β, IL-18, and TNF-α) and liver tissue (IL-1β, IL-18, IL-6, and TNF-α) were significantly lower in the ADSC-ALR-Exo group, while the level of the anti-inflammatory factor IL-10 in the blood was significantly elevated. Additionally, ALR enrichment enhanced the inhibitory effect of ADSC-ALR-Exo on endoplasmic reticulum stress-related pathways, specifically ATF6, IRE1α, and PERK. Compared to ADSC-Exo, the ADSC-ALR-Exo intervention was also more effective in reducing the expression levels of NLRP3, caspase-1, and GSDMD, thereby decreasing the incidence of pyroptosis. In conclusion, ADSC-ALR-Exo mitigated liver injury by inhibiting endoplasmic reticulum stress and cellular pyroptosis induced by liver injury. Full article

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20 pages, 13343 KB

Open AccessArticle

Chiglitazar Activates PPAR-α/γ to Suppress Oxidative Stress and Angiogenesis in Corneal Neovascularization

by Tao Tao, Jiyuan Ye, Ruifeng Li, Yan Ke, Xiaoqin Zheng, Qinghe Zhang, Lan Zheng, Shuwen Wang, Zhen Zhang, Le Wang and Cheng Li

Antioxidants 2026, 15(4), 449; https://doi.org/10.3390/antiox15040449 - 2 Apr 2026

Abstract

Purpose: Chiglitazar (Chi) is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with reported anti-oxidative effects in metabolic disorders. In this study, we investigate its therapeutic effects and potential mechanisms in corneal neovascularization (CNV). Methods: Scratch-wound and tube formation assays in human umbilical vein endothelial [...] Read more.

Purpose: Chiglitazar (Chi) is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with reported anti-oxidative effects in metabolic disorders. In this study, we investigate its therapeutic effects and potential mechanisms in corneal neovascularization (CNV). Methods: Scratch-wound and tube formation assays in human umbilical vein endothelial cells (HUVECs) were performed to evaluate the effects of Chi under recombinant human vascular endothelial growth factor (VEGF) stimulation. An oxidative stress model was established in human corneal epithelial cells (HCEs), and intracellular reactive oxygen species (ROS) levels were quantified by flow cytometry. A corneal alkali burn mouse model of CNV was established. Chi was then administered and compared with vehicle, pioglitazone, or fenofibrate. Corneal epithelial healing and neovascularization were assessed. Public drug–disease–target resources were integrated with RNA-seq data and single-cell transcriptomes to prioritize Chi-associated targets and pathways, which were examined by immunofluorescence, RT-PCR, and Western blotting. Ocular safety was evaluated by comprehensive ophthalmic evaluation. Results: Chi significantly inhibited migration and tube formation in VEGF-induced HUVECs, and flow cytometry confirmed effective ROS reduction. In vivo, Chi markedly improved corneal conditions compared with the vehicle and showed efficacy comparable to or superior to selective PPAR-α/γ agonists, depending on the outcome measures. Bioinformatic analyses predicted PPAR-γ as the dominant isoform, with PPAR-α secondary and PPAR-δ appearing less prominent, collectively implicating oxidative stress and VEGF pathways. Immunofluorescence verified PPAR-γ activation, predominantly localized to the corneal epithelium. RT-PCR and Western blotting supported activation of antioxidant pathways and suppression of angiogenic signals, with Western blotting confirming PPAR-γ and PPAR-α activation, whereas PPAR-δ activation appeared less evident under the present conditions. Ocular examinations demonstrated a favorable safety profile. Conclusions: Chi primarily activates PPAR-γ and PPAR-α, producing antioxidant and anti-angiogenic benefits, supporting its potential as a multi-target PPAR therapy for CNV. Full article

(This article belongs to the Topic Cell Signaling and Redox Biology: From Molecular Mechanisms to Therapeutic Applications)

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16 pages, 1400 KB

Open AccessArticle

In Vitro Evaluation of Redox-Associated Responses Induced by Mud Extract in L929 and RAW 264.7 Cells

by Hyeong Ho Kim, Sung Hun Jang, Jae-Sik Jeon and Jae Kyung Kim

Antioxidants 2026, 15(4), 448; https://doi.org/10.3390/antiox15040448 - 2 Apr 2026

Abstract

While natural muds are widely used in traditional balneotherapy and dermatological applications, the cellular basis of their redox-related effects remains insufficiently defined. In this study, we evaluated the effects of a mineral-rich mud extract on L929 fibroblasts and RAW 264.7 macrophages. This study [...] Read more.

While natural muds are widely used in traditional balneotherapy and dermatological applications, the cellular basis of their redox-related effects remains insufficiently defined. In this study, we evaluated the effects of a mineral-rich mud extract on L929 fibroblasts and RAW 264.7 macrophages. This study was designed as an initial in vitro exploratory investigation to evaluate the cellular responses induced by a complex mud-derived material containing multiple inorganic components under standardized extract conditions. The mud extract showed no overt cytotoxicity up to 1000 μg/mL under the tested conditions. Intracellular reactive oxygen species (ROS) levels remained near baseline across the measured time points, with limited cell type-dependent variation. In parallel, antioxidant-related responses were observed primarily in RAW 264.7 cells, including a transient early increase in superoxide dismutase (SOD)-associated activity and subsequent increases in catalase (CAT) and glutathione peroxidase (GPx) activities. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis further showed dose-dependent upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) transcripts, particularly in RAW 264.7 cells. Collectively, these findings suggest that the mud extract is associated with coordinated antioxidant-related responses under non-cytotoxic conditions. However, because the present study was conducted in two murine cell lines and relied partly on assay systems potentially susceptible to matrix effects, the results should be interpreted as supportive of redox-associated modulation rather than definitive proof of a therapeutic mechanism. Furthermore, these findings should be interpreted as preliminary evidence obtained from a standardized aqueous extract system and not as definitive proof of component-specific mechanisms or direct applicability. Full article

(This article belongs to the Special Issue Antioxidant Effects of Natural Compounds on Cell Metabolism)

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15 pages, 9214 KB

Open AccessArticle

Cytoprotective Effects of Lipid Emulsion Against Bupivacaine-Induced Cytotoxicity in Human Rotator Cuff Fibroblasts

by Ra Jeong Kim and Hyung Bin Park

Antioxidants 2026, 15(4), 447; https://doi.org/10.3390/antiox15040447 - 2 Apr 2026

Abstract

This study evaluated the protective effects of lipid emulsion (LE) against bupivacaine-induced cytotoxicity in human rotator cuff fibroblasts (hRCFs). hRCFs were divided into control, bupivacaine alone (Bupivacaine), LE alone (LE), LE-pretreated bupivacaine (LE + Bupivacaine), N-acetylcysteine alone (NAC), and NAC-pretreated bupivacaine (NAC + [...] Read more.

This study evaluated the protective effects of lipid emulsion (LE) against bupivacaine-induced cytotoxicity in human rotator cuff fibroblasts (hRCFs). hRCFs were divided into control, bupivacaine alone (Bupivacaine), LE alone (LE), LE-pretreated bupivacaine (LE + Bupivacaine), N-acetylcysteine alone (NAC), and NAC-pretreated bupivacaine (NAC + Bupivacaine). Cell viability was assessed by MTT and Live/Dead assays; ROS production by DCF-DA; apoptosis by Annexin V/PI staining and TUNEL assay; cleaved caspase-3 and PARP expression by Western blot; cell cycle by FACS; cell proliferation by Ki-67 staining; and wound healing. Cell viability decreased in a bupivacaine concentration-dependent manner (p < 0.001). Pretreatment with LE or NAC improved cell viability compared with bupivacaine alone (p < 0.001). ROS levels were elevated by bupivacaine, whereas LE and NAC pretreatments significantly reduced ROS (p < 0.001). Bupivacaine-induced apoptosis was significantly attenuated by LE and NAC, as evidenced by reductions in apoptosis rate, expression levels of cleaved caspase-3 and PARP-1, TUNEL-positive nuclei, and the subG1 population (p < 0.05). Cell proliferation and wound healing were suppressed by bupivacaine but restored by LE and NAC pretreatment. This study demonstrates bupivacaine-induced cytotoxicity in hRCFs and suggests that LE and NAC mitigate these effects by reducing oxidative stress and promoting cell survival and wound healing. Full article

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

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18 pages, 1225 KB

Open AccessSystematic Review

Antioxidants as Therapeutic Tools in the Management of COPD: A Systematic Review with Meta-Analysis

by Manuel López-Denis, Bernardo Cálamo-Guzmán, Silvia Castillo-Corullón, Joaquín Carrasco-Luna, María José Herrero, Cruz González-Villaescusa, Jaime Signes-Costa and Francisco Dasí

Antioxidants 2026, 15(4), 446; https://doi.org/10.3390/antiox15040446 - 2 Apr 2026

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Beyond established risk factors such as smoking and exposure to pollutants increasing evidence emphasizes the role of oxidative stress (OS) in COPD pathophysiology. OS contributes to chronic inflammation, to [...] Read more.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Beyond established risk factors such as smoking and exposure to pollutants increasing evidence emphasizes the role of oxidative stress (OS) in COPD pathophysiology. OS contributes to chronic inflammation, to the progression of the disease and affects both lung function and exacerbations, which opens a rationale for the use of antioxidant and redox-modulating substances in the treatment of the disease. Although numerous substances with antioxidant capacity have been evaluated in randomized clinical trials (RCTs), their clinical relevance remains uncertain. Therefore, a systematic review was conducted to evaluate the effects of these therapies in COPD. Also, a meta-analysis to evaluate the effects on exacerbations was performed. Nineteen RCTs meet the eligibility criteria and were included in the study. Quantitative analyses were performed using random-effects models. N-acetylcysteine-based interventions were associated with a significant reduction in exacerbation risk (risk ratio 0.80; 95% confidence interval 0.66–0.98), corresponding to a 20% relative reduction. No study reported serious adverse effects. These findings suggest that antioxidant-based strategies may have clinically meaningful benefits in COPD. However, larger, more robust RCTs are required to confirm these results and establish optimal therapeutic strategies. Full article

(This article belongs to the Special Issue Oxidative/Nitrosative Stress and Antioxidant Strategies in Inflammatory Respiratory Diseases)

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28 pages, 1876 KB

Open AccessArticle

Network Analysis of Convergent and Specific Molecular Pathways of Nutraceuticals with Antioxidant and Neuroprotective Potential in Glaucoma

by Pavlina Teneva, Sylvia Stamova, Kaloyan Varlyakov, Neli Ermenlieva, Emilia Georgieva and Todorka Kostadinova

Antioxidants 2026, 15(4), 445; https://doi.org/10.3390/antiox15040445 - 2 Apr 2026

Abstract

Optic neuropathy represents a leading cause of irreversible vision loss, in which oxidative stress, chronic inflammation, dysregulated lipid metabolism, and mitochondrial dysfunction contribute to the progressive degeneration of retinal ganglion cells (RGCs). In recent years, a number of nutraceuticals have been investigated as [...] Read more.

Optic neuropathy represents a leading cause of irreversible vision loss, in which oxidative stress, chronic inflammation, dysregulated lipid metabolism, and mitochondrial dysfunction contribute to the progressive degeneration of retinal ganglion cells (RGCs). In recent years, a number of nutraceuticals have been investigated as potential neuroprotective agents; however, the molecular mechanisms through which they exert their effects remain incompletely understood and are often considered in isolation. In the present in silico study, an integrative network-based approach was applied for a systematic analysis of the predicted molecular targets of selected nutraceuticals with antioxidant and anti-inflammatory potential. By combining target prediction, protein–protein interaction analysis, and functional enrichment, their functional convergence was assessed in the context of optic nerve pathophysiology. The results indicate that, despite their chemical and functional heterogeneity, the investigated nutraceuticals do not act through fully independent mechanisms but instead converge on interconnected regulatory axes. In particular, lipid–inflammatory signaling, epigenetic and stress-adaptive mechanisms, as well as nuclear-receptor mediated transcriptional regulation emerged as key pathways. These pathways form integrated molecular models potentially determining cellular susceptibility to injury and the adaptive capacity of RGCs. In conclusion, the present analysis provides a systems-level framework for understanding the neuroprotective potential of nutraceuticals, highlighting the importance of network convergence and multi-target activity. The obtained results support the conceptual shift from isolated antioxidant strategies towards integrative, network-oriented approaches in the study of optic neuropathy. Full article

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24 pages, 1257 KB

Open AccessArticle

Compositional Phenolic Signatures of Antioxidant-Relevant Compounds in Hop (Humulus lupulus L.) Varieties and Local Ecotypes Cultivated in Southern Chile

by Ignacio Matamala, Manuel Chacón-Fuentes, Daniel Martínez-Cisterna, Pablo Parra-Verdugo, Valeria Asencio-Cancino and Leonardo Bardehle

Antioxidants 2026, 15(4), 444; https://doi.org/10.3390/antiox15040444 - 1 Apr 2026

Abstract

Hop (Humulus lupulus L.) cones are increasingly recognized as sources of phenolic compounds relevant to antioxidant-oriented applications beyond their traditional brewing role; however, genotype-dependent chemical diversity remains poorly characterized under South American cultivation. This study evaluated phenolic composition and antioxidant-related chemical signatures [...] Read more.

Hop (Humulus lupulus L.) cones are increasingly recognized as sources of phenolic compounds relevant to antioxidant-oriented applications beyond their traditional brewing role; however, genotype-dependent chemical diversity remains poorly characterized under South American cultivation. This study evaluated phenolic composition and antioxidant-related chemical signatures in 22 hop accessions, including commercial varieties and Chilean local ecotypes, cultivated under homogeneous conditions in southern Chile. Total phenolic content (TPC), total flavonoid content (TFC), and condensed tannins were determined using spectrophotometric assays, while phenolic acids, catechin, and prenylated flavonoids were quantified by HPLC. Antioxidant capacity was evaluated using the ORAC assay, and principal component analysis (PCA) was applied to integrate chemical variables. TPC ranged from 4051 to 8124 mg gallic acid equivalents/100 g dry weight, TFC from 655 to 3011 mg quercetin equivalents/100 g, and condensed tannins from 11.0 to 60.1 mg catechin equivalents/g. ORAC values ranged from 96,405 to 161,815 µmol Trolox equivalents/100 g dry weight, indicating substantial genotype-dependent variation. PCA explained 69.5% of total variance and revealed distinct phenolic composition patterns among genotypes. Pearson correlation analysis showed that antioxidant capacity was strongly associated with condensed tannins and total phenolic content, whereas total flavonoids were not significantly related to ORAC values. Prenylated flavonoids were negatively associated with antioxidant capacity, suggesting a limited contribution to peroxyl radical scavenging activity. These findings highlight the importance of phenolic subclass composition, particularly condensed tannins, in determining antioxidant capacity and support the selection of hop genotypes based on specific phenolic profiles for functional applications. Full article

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

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21 pages, 5150 KB

Open AccessArticle

A Multi-Omics Integration Analysis Reveals That Mori Fructus Polysaccharide Ameliorates Liver Injury via Regulating Liver Metabolic Function Through Inhibiting Lipid Metabolism, Enhancing Glycolysis, and Promoting Amino Acid Utilization

by Qingfang Deng, Baitong Jing, Ruhai Chen, Yang Cao, Xiaomei Zhou, Yu Sun and Xin Zhou

Antioxidants 2026, 15(4), 443; https://doi.org/10.3390/antiox15040443 - 1 Apr 2026

Abstract

Alcohol-associated liver disease (ALD) is a prevalent chronic liver disease worldwide, with unclear pathogenesis and limited effective treatments. Mori Fructus polysaccharide (MFP-1) exhibits good therapeutic potential for ALD, but its mechanism remains unclear. This study aims to elucidate how MFP-1 mitigates ALD. An [...] Read more.

Alcohol-associated liver disease (ALD) is a prevalent chronic liver disease worldwide, with unclear pathogenesis and limited effective treatments. Mori Fructus polysaccharide (MFP-1) exhibits good therapeutic potential for ALD, but its mechanism remains unclear. This study aims to elucidate how MFP-1 mitigates ALD. An integrated multi-omics approach, encompassing quantitative proteomics, metabolomics, and lipidomics, was employed to systematically characterize the hepatic response to MFP-1 in ALD. MFP-1 coordinates metabolic reprogramming by regulating fatty acid synthesis and β-oxidation. It also enhances branched-chain amino acid catabolism via the 2-oxocarboxylic acid pathway, optimizing energy generation and amino acid utilization. MFP-1 protects against ALD by simultaneously targeting multiple metabolic vulnerabilities. These findings elucidate the mechanistic basis of MFP-1’s hepatoprotective effects and highlight its potential for improving ALD. Full article

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19 pages, 6065 KB

Open AccessArticle

Transcriptomic Analysis of Fermented Chinese Chive Selectively Attenuating Deoxynivalenol-Induced Ovarian Toxicity in Mice

by Hong Zou, Chun-Yan Qin, Teerath Kumar Suthar, Yupeng Xie, Koroloso Phomane Abednicco, Chun-Feng Wang, Min Kyu Kim, Shu-Min Zhang and Wu-Sheng Sun

Antioxidants 2026, 15(4), 442; https://doi.org/10.3390/antiox15040442 - 1 Apr 2026

Abstract

Deoxynivalenol (DON) is a common mycotoxin linked to ovarian oxidative stress, toxicity, and reduced reproductive performance. Fermented Chinese chive is known for its antioxidant properties and potential reproductive benefits, but their individual and combined effects on ovarian function remain unclear in post-pubertal mice. [...] Read more.

Deoxynivalenol (DON) is a common mycotoxin linked to ovarian oxidative stress, toxicity, and reduced reproductive performance. Fermented Chinese chive is known for its antioxidant properties and potential reproductive benefits, but their individual and combined effects on ovarian function remain unclear in post-pubertal mice. In this study, a 21-day oral gavage model in female Kunming mice was used to evaluate the effects of DON (2 mg/kg/day), fermented Chinese chive extract (LEEK; 0.2 mL/day), and their combined exposure (LKDON) on ovarian physiology, oocyte quality, and ovarian transcriptomic responses. The results showed that DON exposure significantly reduced the zygote cleavage rate, increased intracellular reactive oxygen species levels, and disrupted oocyte mitochondrial membrane potential. While histological examination revealed disturbed follicular architecture. Transcriptomic hub gene analysis showed that DON exposure down-regulate the key associated with innate immune responses and motile cilia/axonemal structure, including Rsph4a, Drc1, Zmynd10, Hydin, and Tmem212. In contrast, LEEK alone was associated with immunomodulatory upregulated genes, including Il5, Cd27, and Crp. Interestingly, LKDON and DON comparison revealed upregulation of a motile cilia/axoneme gene network (Dnah5, Dnah11, Tekt1, Zmynd10, Cfap44, and Spag6l), rather than a global reversal of DON-induced changes. Overall, finding suggest that DON disrupts ovarian immune and structural pathways, while fermented Chinese chive provides partial protection by modulating specific biological processes. Further studies are needed to confirm the underlying mechanisms. Full article

(This article belongs to the Special Issue Natural Antioxidants in Counteracting Mycotoxin and Heavy Metal Toxicity)

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11 pages, 705 KB

Open AccessPerspective

The Emerging Role of N-Lactoyl-Phenylalanine (Lac-Phe) in Metabolic Regulation and Disease: From Exercise-Induced Metabolite to Therapeutic Candidate

by Julia Chu-Ning Hsu, Chia-Hui Chen, Ming-Wei Chen, Wen-Hua Chen and Tzong-Shyuan Lee

Antioxidants 2026, 15(4), 441; https://doi.org/10.3390/antiox15040441 - 1 Apr 2026

Abstract

N-Lactoyl-phenylalanine (Lac-Phe), identified in 2022 as an exercise-inducible signaling metabolite, is formed by carnosine dipeptidase 2 via conjugation of lactate and phenylalanine. Its circulating levels rise sharply after intense exercise in mice, humans, and racehorses, reflecting increased glycolytic flux. Beyond exercise, Lac-Phe also [...] Read more.

N-Lactoyl-phenylalanine (Lac-Phe), identified in 2022 as an exercise-inducible signaling metabolite, is formed by carnosine dipeptidase 2 via conjugation of lactate and phenylalanine. Its circulating levels rise sharply after intense exercise in mice, humans, and racehorses, reflecting increased glycolytic flux. Beyond exercise, Lac-Phe also rises with feeding and metformin, positioning it as a potential integrator of energy intake, expenditure, and metabolic homeostasis. Centrally, Lac-Phe may contribute to appetite suppression by inhibiting hypothalamic orexigenic agouti-related protein neurons, primarily observed in obese rodent models, while sparing anorexigenic pro-opiomelanocortin neurons, thereby reducing food intake, promoting weight loss, and improving glucose tolerance in obese models without altering energy expenditure. Peripherally, it drives anti-inflammatory M2 macrophage polarization, ameliorating colitis and aiding recovery after spinal cord injury via NF-κB suppression and reactive oxygen species reduction. As a biomarker, Lac-Phe may offer advantages over lactate in reflecting mitochondrial dysfunction in conditions such as MELAS, sepsis, and NADH-reductive stress; however, these observations derive mainly from small-scale or exploratory studies and require prospective validation. Recent studies from 2024 to 2025 further reveal its partial and context-dependent role in mediating metformin’s effects, intensity- and sex-dependent responses, renal clearance via SLC17A1/3 transporters, and links to exercise-induced redox adaptations. The first human phase I trial (NCT06743009), launched in 2025, is assessing the metabolic effects of Lac-Phe in obesity. This Perspective summarizes Lac-Phe biosynthesis, physiological mechanisms, including its emerging but largely correlative connections to redox homeostasis, and therapeutic promise, underscoring its potential relevance for exercise-mimicking strategies in metabolic, inflammatory, and redox-related disorders. Full article

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

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4 pages, 155 KB

Open AccessEditorial

Novel Antioxidants for Animal Nutrition—2nd Edition

by Matteo Dell’Anno and Luciana Rossi

Antioxidants 2026, 15(4), 440; https://doi.org/10.3390/antiox15040440 - 1 Apr 2026

Abstract

Oxidative stress is widely recognized as a major biological challenge affecting animal health, productivity, and reproductive efficiency [...] Full article

(This article belongs to the Special Issue Novel Antioxidants for Animal Nutrition—2nd Edition)

26 pages, 2273 KB

Open AccessReview

Life-Course Regulation of Health and Disease by Nitric Oxide: Mechanistic Insights

by Chien-Ning Hsu and You-Lin Tain

Antioxidants 2026, 15(4), 439; https://doi.org/10.3390/antiox15040439 - 1 Apr 2026

Abstract

Nitric oxide (NO) functions as a master integrative regulator of cardiovascular–kidney–metabolic (CKM) homeostasis, yet it displays a profound Janus face, defined by concentration- and context-dependent roles in both health and disease. This narrative review examines NO signaling from a life-course perspective, beginning with [...] Read more.

Nitric oxide (NO) functions as a master integrative regulator of cardiovascular–kidney–metabolic (CKM) homeostasis, yet it displays a profound Janus face, defined by concentration- and context-dependent roles in both health and disease. This narrative review examines NO signaling from a life-course perspective, beginning with fetal programming, during which the NO–asymmetric dimethylarginine (ADMA) axis orchestrates placental development and nephron endowment. Perturbations during this critical window—such as maternal ADMA elevation—can imprint a maladaptive trajectory toward adult-onset hypertension and chronic kidney disease. In adulthood, this initially silent dysregulation of NO signaling is amplified by Western dietary patterns and environmental pollutants, culminating in the clinical manifestation of the CKM triad. This pathological transition is driven by eNOS uncoupling and ADMA accumulation, which shift redox balance toward peroxynitrite formation and precipitate mitochondrial bioenergetic failure. Moreover, while constitutive NO production is essential for vascular homeostasis, pathological induction of inducible NOS generates excessive NO fluxes that promote insulin resistance and tissue injury. With advancing age, a progressive loss of NO resilience further exacerbates multi-organ vulnerability. To mitigate the cumulative burden of CKM disease, this review highlights developmental reprogramming strategies—such as perinatal L-citrulline supplementation and ADMA-lowering interventions—as interventions to restore physiological NO signaling. Integrating such early-life strategies with contemporary pharmacological therapies offers a coherent framework for maintaining NO bioavailability and extending health span across the life course. Full article

(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)

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28 pages, 14728 KB

Open AccessArticle

Hepatic ACSL4 Loss Boosts Endogenous Gamma-Glutamylcysteine to Alleviate Alcoholic Liver Disease

by Ran Duan, Xin-Yi Wang, Xue Zhou, Jing-Wen Ding, Zhi-Sen Yang, Zhi-Lin Li, Yue-Yu Wang, Jia-Xin Yu and Jing-Jing Duan

Antioxidants 2026, 15(4), 438; https://doi.org/10.3390/antiox15040438 - 31 Mar 2026

Abstract

Alcoholic liver disease (ALD), secondary to chronic alcohol abuse, encompasses a spectrum of liver disorders that progress from steatosis and hepatitis to fibrosis, cirrhosis, and acute-on-chronic liver failure. It poses a considerable global health burden due to its elevated rates of associated morbidity [...] Read more.

Alcoholic liver disease (ALD), secondary to chronic alcohol abuse, encompasses a spectrum of liver disorders that progress from steatosis and hepatitis to fibrosis, cirrhosis, and acute-on-chronic liver failure. It poses a considerable global health burden due to its elevated rates of associated morbidity and mortality. The rising prevalence of ALD, coupled with the lack of approved pharmacotherapies, presents considerable unmet clinical needs. In this study, long-chain acyl-CoA synthetase 4 (ACSL4) was identified as a pathogenic driver in the context of chronic alcohol consumption. Hepatocyte Acsl4 ablation mitigated key pathological manifestations in Gao-Binge model mice, as evidenced by reduced inflammatory cell infiltration and attenuated lipid accumulation. Mechanistically, ACSL4 inhibition augmented cellular antioxidant defence through elevating gamma-glutamylcysteine (γ-GC) levels. In addition, γ-GC bound to and suppressed the expression of protein tyrosine phosphatase type IVA member 1 (PTP4A1). Both genetic silencing and pharmacological inhibition of PTP4A1 attenuated the activation of the downstream MAPK-NF-κB inflammatory cascade. Dronedarone, identified as a novel compound targeting ACSL4, demonstrated efficacy in ameliorating the progression of ALD. Overall, these findings elucidate a novel mechanism wherein ACSL4 modulates antioxidant responses via a small bioactive peptide, highlighting ACSL4 as a potential therapeutic target for ALD. Full article

(This article belongs to the Topic Oxidative Stress and Inflammation, 3rd Edition)

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