Antioxidants doi: 10.3390/antiox15111429

Authors: Dexin Zhao Linfeng Zhou Haoliang Chai Fengjie Ji Weiqi Peng Hongzhi Wu

Gut microbial metabolites can influence host redox regulation, but their relevance to precision animal nutrition depends on evidence linking microbial origin, tissue exposure, and a necessary host mechanism. This narrative review evaluates short-chain fatty acids, microbially modified bile acids, tryptophan derivatives, and sulfur metabolites across cellular, rodent, and livestock studies. Mechanisms are distinguished as direct chemical, metabolism-mediated, receptor-mediated, or associative, with receptor dependence assessed separately from redox dependence. Butyrate provides a strong metabolic example linking epithelial oxidation, oxygen consumption, hypoxia-inducible factor, and barrier function. Specific bile acid metabolites affect immune differentiation through mitochondrial reactive oxygen species, whereas necessary redox nodes remain less clearly established for indole derivatives. Sulfide can support mitochondrial electron transfer or inhibit respiration, depending on exposure and disposal capacity. Mechanistic evidence is strongest in experimental models; livestock studies commonly lack source attribution, tissue measurements, or targeted perturbation. Fermentable carbohydrate selection, balanced protein reduction, and defined bile acid or microbial preparations illustrate candidate nutritional applications rather than validated redox prescriptions. Translation requires species-specific exposure measurements, causal testing, processing stability, and independent evaluation of health, feed efficiency, and economic return. The framework prioritizes testable redox mechanisms while limiting claims unsupported by animal-level outcomes.

Antioxidants doi: 10.3390/antiox15111428

Authors: Shuai Zhu Jinli Wen Honglu Han Xiaona Pei Meihong Liu Xiuying Xu Hongjie Li Xiyang Zhao

Conifer needles are a renewable forestry biomass and a potential source of bioactive phenolic compounds. In this study, ultrasound-assisted extraction of polyphenols from Pinus banksiana needles was optimized, and the validated conditions were subsequently applied to six conifer species for comparative evaluation of phenolic composition, antioxidant capacity, and digestive enzyme inhibitory activity. Under the optimal conditions of 53% (v/v) ethanol, a liquid-to-solid ratio of 29 mL/g, 21 min, and 45 °C, the total phenolic content of P. banksiana reached 36.13 ± 0.89 mg GAE/g DW. Significant interspecific differences were observed in phenolic composition and bioactivity. Nine phenolic compounds were quantified by targeted HPLC-DAD analysis, with (+)-catechin being the most abundant among these analytes in all six extracts (1.523–9.974 mg/g DW). P. banksiana exhibited the strongest ABTS+ radical-scavenging activity (IC50 = 0.306 ± 0.010 mg/mL) and the strongest inhibition of both α-glucosidase (IC50 = 5.352 ± 0.113 μg/mL) and α-amylase (IC50 = 0.374 ± 0.003 mg/mL). Kinetic analysis suggested an apparent mixed-type inhibition pattern of α-glucosidase by P. banksiana extract, although a pure noncompetitive inhibition model could not be conclusively excluded. Mantel analysis revealed that (+)-catechin showed the strongest association with α-glucosidase inhibition, while molecular docking predicted favorable interactions of (+)-catechin with both human digestive enzyme models. These findings identify (+)-catechin as a potential contributor to α-glucosidase inhibition and highlight P. banksiana as a promising source of antioxidant phenolics with carbohydrate digestion-modulating potential.

Antioxidants doi: 10.3390/antiox15111427

Authors: Lavinia Țocu Bogdan Ioan Ștefănescu Raul Mihailov Valerii Luțenco Oana Mariana Mihailov Alina Pleșea Condratovici Mădălina Nicoleta Matei Loredana Stavăr Matei George Țocu

Myocardial infarction (MI) remains a major cause of death and heart failure despite reperfusion. Reopening an occluded coronary artery salvages viable myocardium but creates an ischemia–reperfusion environment in which reactive oxygen species (ROS) and reactive nitrogen species (RNS) can contribute to injury. Postinfarction redox responses continue through inflammation, repair, and remodeling. Their effects depend on species, concentration, source, compartment, timing, molecular targets, and local antioxidant capacity; controlled redox signaling is essential for normal vascular, metabolic, and immune function. This narrative review focuses primarily on type 1 MI, particularly reperfused ST-segment elevation MI. It examines mitochondrial and enzymatic oxidant sources, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidoreductase, nitric oxide synthases, and myeloperoxidase, alongside secondary lipid- and nitrogen-derived products. It considers their roles in microvascular dysfunction, cardiomyocyte injury and death, inflammatory amplification, fibrosis, ventricular dysfunction, heart failure, and arrhythmic vulnerability. Circulating oxidative-stress biomarkers may be associated with infarct severity or later outcomes, but generally provide indirect information and have limited validation for clinical decision-making. Broad antioxidant strategies have not yielded consistent clinical benefit. More precise therapeutic approaches require source- and compartment-specific targeting, appropriate timing and patient selection, reliable measures of target engagement, and benefit beyond contemporary MI care.

Antioxidants doi: 10.3390/antiox15111426

Authors: Huixing Guo Xiufei Cao Ting Chen Xi Wang Haokun Hua Xiaoyu Chu Zishang Liu Le Chang Junxiang Guan Guangzhen Jiang Wenbin Liu

With the global expansion of aquaculture, histamine, an emerging contaminant derived from microbial decarboxylation of histidine in aquafeed, poses a hidden threat to aquatic ecosystems owing to its obscure sources. This study employed Eriocheir sinensis (E. sinensis) as a model to clarify histamine’s ecological risks and toxic mechanisms. A 5-day oral gavage trial with four histamine doses (0, 50, 100, 200 μg/g body weight) was performed on 160 male crabs (initial weight: 20.0 ± 0.5 g) allocated to four replicate tanks of 10 individuals each. The results showed histamine significantly increased crab autotomy rate in a dose-dependent manner (p < 0.05), disturbed neuroendocrine factors, damaged hepatopancreas microstructure and reduced digestive-enzyme activities (p < 0.05). It triggered hepatopancreatic oxidative stress-related apoptosis and altered the expression of mitogen-activated protein kinase (MAPK) associated genes, with significant up-regulation of pro-apoptotic genes and down-regulation of BCL2 (p < 0.05). Metabolomics showed distinct metabolic perturbations; arachidonic-acid metabolism was markedly enriched at 200 μg/g histamine (p < 0.05). Combined reverse virtual screening, molecular docking and RNAi analyses support the involvement of the histamine H2 receptor (H2R) in crustacean histamine toxicity, and H2R silencing significantly alleviated histamine-induced tissue damage (p < 0.05). Collectively, histamine exerts multi-system toxicity in E. sinensis principally via H2R, disrupting the neuroendocrine–immune network, impairing hepatopancreatic integrity and disturbing metabolic homeostasis. This study provides novel insights into the toxic mechanism of histamine in crustaceans, and offers valuable implications for feed safety evaluation, nutritional risk control, and healthy aquaculture management.

Antioxidants doi: 10.3390/antiox15111425

Authors: Yuxin Jiang Huan Xie Hao Zhang Jinsong Zhang Yanfei Yu Yanan Chen Hao Wang Chenhuan Lai Qiang Yong

Background: Intestinal epithelial barrier dysfunction, a major consequence of inflammatory and oxidative stress, contributes to enteric disorder progression. Salvianolic acid B (SAB), a prominent water-soluble phenolic compound in Salvia miltiorrhiza, shows intestinal protective potential, but the underlying mechanisms remain unclear. Methods: This study investigated the protective effects of SAB on intestinal barrier function using a lipopolysaccharide (LPS)-challenged piglet model and LPS-stimulated IPEC-J2 cells. Results: SAB alleviated LPS-induced intestinal injury, evidenced by reduced plasma diamine oxidase and D-lactate levels, improved intestinal morphology, decreased pro-inflammatory cytokines, and enhanced antioxidant capacity. SAB also strengthened intestinal barrier integrity by increasing goblet cell number and mucin 2 levels and upregulating tight junction protein expression. Moreover, SAB restored epithelial proliferation–apoptosis balance and increased PI3K/AKT/mTOR phosphorylation. Molecular docking and molecular dynamics simulations predicted a stable SAB–PI3Kα/p110α interaction, whereas LY294002 treatment attenuated SAB-mediated restoration of epithelial renewal and barrier integrity in LPS-treated IPEC-J2 cells. SAB also altered the jejunal microbial composition, including higher relative abundance of Streptococcus and lower relative abundance of Escherichia-Shigella, together with increased jejunal acetate and lactate concentrations. Conclusions: SAB alleviates inflammation-associated intestinal barrier dysfunction by restoring epithelial proliferation–apoptosis balance and regulating the microbiota–metabolite profile.

Antioxidants doi: 10.3390/antiox15111424

Authors: Hyun Jin Yun Ha Young Kim Gaeun Seo Seung Hee Eom Tae Kyung Hyun

High temperature disrupts cellular redox homeostasis by enhancing reactive oxygen species production, requiring coordinated antioxidant regulation. Superoxide dismutases (SODs) are central to this response, but their molecular organization and heat-responsive regulation remain poorly understood in onion (Allium cepa L.). Here, we combined physiological, biochemical, transcriptional, and functional analyses to characterize the onion SOD family. Following exposure to 35 °C, H2O2 accumulation and proline content increased relative to baseline, whereas total SOD activity was significantly higher after 1 d but declined to near-baseline levels after 2 d. Native PAGE showed class-specific responses, with FeSOD and CZSOD activities increasing under heat stress, whereas MnSOD activity remained largely unchanged. Genome-wide analysis identified 12 AcSOD genes comprising nine CZSODs genes, one FeSOD gene, and two MnSODs genes. Most AcSOD genes were induced after 1 d of heat exposure, with AcCZSOD2 showing the strongest transcriptional response. Importantly, transcriptional changes were not always paralleled by isozyme activity, indicating distinct but complementary regulation at the transcript and enzyme levels. Transient expression of AcFeSOD, AcMnSOD1, AcCZSOD2, and AcCZSOD7 in Nicotiana benthamiana significantly increased total SOD activity by approximately 14–22% relative to the control, supporting their contribution to SOD activity in a heterologous plant system. These findings provide an integrated view of SOD regulation during heat exposure in onion and establish a basis for future studies of isoform-specific antioxidant functions.

Antioxidants doi: 10.3390/antiox15111423

Authors: Puja Laxmanrao Shinde Siddhartha Singh Vikas Kumar K. C. Sivakumar Amit Mishra Rashmi Mishra

Natural polyphenol-rich interventions are widely investigated for antioxidant protection, yet whether such interventions influence non-redox mechanisms of cardiac mechanoadaptation remains incompletely understood. Amalaki Rasayana (AR) is a traditional phytomedicine with antioxidant properties used for cardioprotection. Here, we investigated whether extracellular C-terminal-epitope-reactive Galectin-3 (Gal-3) species are associated with altered cardiomyocyte surface organization and mechanotransduction-associated signaling, and whether these responses are modulated by AR. In complementary mechanistic cardiomyocyte cell-culture experiments, we further examined whether gallic acid (GA), an analytically prominent and bioavailable constituent of AR, recapitulates selected AR-associated anti-hypertrophic effects. Using biologically aged and left ventricular pressure-overload rat models, followed by complementary in vitro cardiomyocyte mechanical-loading assays, biochemical and imaging approaches, and exploratory analyses of human serum and myocardial tissue, we examined epitope-resolved Gal-3 species, their compartmental distribution and surface-associated clustering, and associated mechanotransduction responses. Pressure overload increased extracellular and surface-associated C-terminal-epitope-reactive Gal-3 species, including a higher-molecular-weight population distinct from full-length Gal-3, accompanied by reduced intracellular Gal-3 and hypertrophic remodeling. C-terminal-epitope-enriched human serum induced surface-associated Gal-3 clustering and altered calcium responses, RhoA–ROCK1-F-actin organization, the NFATC2–MEF2A hypertrophic transcriptional axis, and nuclear stress responses. AR attenuated hypertrophic remodeling while shifting Gal-3 distribution away from extracellular and surface-associated C-terminal-epitope-reactive species toward intracellular retention. In complementary mechanical-loading experiments, GA recapitulated selected AR-associated effects. Additional mechanistic experiments supported roles for Gal-3 C-terminal-epitope (carbohydrate-recognition domain, CRD)-dependent surface engagement and Ser6-phosphorylation-sensitive regulation of intracellular Gal-3. Together, these findings support a potentially non-canonical, Gal-3-centered mechanism through which a polyphenol-rich antioxidant intervention may modulate pathological cardiac mechanoadaptation by regulating Gal-3 compartmentalization and surface engagement.

Antioxidants doi: 10.3390/antiox15111422

Authors: Ziyin Hong Xin Tong Ziyi Ji Xinyi Wang Zhongjing Su

Redox signaling is a key regulator of lymphocyte activation and adaptation, in which reactive oxygen species (ROS) function not only as mediators of oxidative stress but also as context-dependent signaling molecules. G protein-coupled estrogen receptor (GPER1) is an estrogen-responsive receptor with emerging roles in immune regulation, yet how GPER1 signaling intersects with cellular redox networks in lymphocytes remains incompletely understood. Evidence from different biological systems supports a relationship between GPER1 signaling and redox regulation, whereas direct evidence connecting GPER1 to mitochondrial ROS (mtROS) regulation in lymphocytes remains to be established. This review examines the potential intersection between GPER1 signaling, redox regulation, and lymphocyte immunity. We first summarize current evidence regarding GPER1 expression and immunomodulatory functions, followed by a discussion of signaling mechanisms through which GPER1 may influence ROS generation, antioxidant responses, and mitochondrial function. Particular emphasis is placed on mitochondrial redox signaling and its context-dependent roles in lymphocyte activation, metabolic adaptation, and functional states. We propose that GPER1-associated redox regulation may influence lymphocyte adaptation to changing signaling and metabolic demands, although this potential relationship has not been directly established in normal lymphocytes. Further investigation of this potential relationship may provide insights into the role of GPER1-associated redox signaling in lymphocyte function and chronic inflammatory diseases.

Antioxidants doi: 10.3390/antiox15111421

Authors: Khawar Hayat Canyu Wang Wang Tao Rongjin Zheng Zunzhong Ye Jinming Pan

Embryonic environmental conditions can influence post-hatch physiology in poultry. This study evaluated whether green-light incubation modifies post-hatch redox homeostasis, peripheral endocrine responses, and hypothalamic proteomic remodeling in Roman Pink and Hy-Line Brown chickens. Yolk hormone profiles were screened in 16 breeder strains, revealing clear strain-specific differences in serotonin (5-HT), dopamine (DA), testosterone (TES), and corticosterone (CORT). Roman Pink and Hy-Line Brown chickens were selected for further experimentation, as they showed contrasting yolk endocrine status. A total of 296 eggs from each strain (148 eggs per treatment having four replicates of 37) were incubated under light-emitting diode (LED) green-light or control incubation. Post-hatch antioxidant status, humoral immune response, endocrine indices and hypothalamic proteomes were evaluated. Strain- and age-dependent post-hatch changes in antioxidant status and endocrine profiles were noticed. Green-light incubation enhanced total antioxidant capacity by enhancing total antioxidant capacity (T-AOC), catalase (CAT) and superoxide dismutase (SOD) activity in both strains, and reduction of CORT and TES was observed in Roman Pink chickens (p < 0.05). Proteomic analysis indicated regulation of mitochondrial oxidative phosphorylation, peroxisomal metabolism, antioxidant-related pathways, and monoamine-associated proteins including tryptophan hydroxylase 2 (TPH2), solute carrier family 6 member 4 (SLC6A4), and catechol-O-methyltransferase (COMT). Correlation analyses further linked mitochondrial and antioxidant-related proteins with physiological redox and endocrine indices. These findings suggest that embryonic green-light exposure influences post-hatch antioxidant status, hepatic endocrine profiles, and hypothalamic protein abundance in a strain-dependent manner.

Antioxidants doi: 10.3390/antiox15111420

Authors: Jing Han Xiaoyu Fu Yu Xia Boning Zhang Xichen Li Chenggang Zhang

A high-salt and high-sugar (HS) diet is a major contributor to metabolic disorders, including lipid accumulation and oxidative stress. Lithocholic acid (LCA), as a key secondary bile acid, plays a crucial role in regulating metabolism and delaying aging. However, the specific molecular mechanisms underlying LCA’s protective effects against HS-induced metabolic damage remain unclear. In this study, using Caenorhabditis elegans as a model organism, we systematically investigated the protective effects of different concentrations of LCA against HS-induced metabolic damage and their regulatory mechanisms through lifespan analysis, oxidative stress phenotype testing, mitochondrial function assessment, intestinal barrier integrity evaluation, and molecular pathway validation. The aim was to explore the benefits of LCA against HS-induced metabolic abnormalities and to elucidate its potential molecular mechanisms. Result: In HS model, LCA treatment significantly improves overall health in nematodes, enhances motility, and extends lifespan. LCA effectively boosts antioxidant stress resistance in HS conditions, reduces reactive oxygen species (ROS) accumulation, positively regulates mitochondrial membrane potential to maintain stable mitochondrial function, and activates the AMPK signaling pathway. Furthermore, LCA mitigates HS-induced intestinal barrier damage, reduces intestinal permeability, and preserves gut structure and homeostasis. Concurrently, LCA alleviates HS-induced metabolic dysregulation by regulating the sbp-1/nhr-49 metabolic axis, ultimately exerting systemic protective effects through multiple targets and pathways. Conclusion: LCA may have anti-aging qualities, antioxidant properties and the capacity to raise metabolic levels when exposed to HS.

Antioxidants doi: 10.3390/antiox15111418

Authors: Isabel Viña Consuelo Borrás Juan R. Viña Federico V. Pallardó Cristina Mas-Bargues

Ketone bodies (acetoacetate, AcAc, and β-hydroxybutyrate, βOHB) have traditionally been regarded as alternative energy substrates produced when the glucagon-to-insulin ratio rises, as occurs during fasting, time-restricted eating, carbohydrate restriction, ketogenic diets, and endurance exercise. Growing evidence indicates that their functions extend beyond fuel provision. This review brings these functions together and assesses the strength of the evidence supporting each of them. We organize the evidence along three axes: ketone bodies as oxidative fuels, as receptor and epigenetic signals, and as modulators of redox homeostasis. As fuels, hepatic ketogenesis converts adipose-derived lipid carbon into water-soluble substrates that reach tissues that cannot oxidize long-chain fatty acids, with the mitochondrial isoform of HMG-CoA synthase (HMGCS2) controlling production and SCOT/OXCT1 controlling utilization. As a signaling molecule, βOHB engages HCAR2, inhibits class I and IIa histone deacetylases, suppresses NLRP3 inflammasome activation, and donates the acyl group for histone lysine β-hydroxybutyrylation. The strength of the supporting evidence is uneven across these mechanisms, and we indicate for each one the experimental system, the concentration range, and whether the effect has been shown for βOHB, for AcAc, or for both. As redox modulators, ketone oxidation reduces the mitochondrial NAD+/NADH couple while oxidizing the coenzyme Q pool, and βOHB-dependent HDAC inhibition and Nrf2 activation induce FOXO3A, catalase, MnSOD, NQO1, and glutathione synthesis. We argue that this response is best described as hormetic and context-dependent rather than as a universal antioxidant effect, since a transient pro-oxidant signal appears to initiate the defense program and AcAc behaves as a pro-oxidant at supraphysiological concentrations. A recurrent difficulty in the field is that fasting, caloric restriction, and exercise also engage most of the pathways involved, independent of ketone bodies, and that human redox data from endogenous physiological ketosis remain scarce. We therefore propose a shortlist of measurable human endpoints, including Nrf2 and FOXO target genes, SOD and catalase activity, and the GSH/GSSG ratio, to test the ketone-specific component of these effects.

Antioxidants doi: 10.3390/antiox15111419

Authors: Shuo Chang Yuyan Liu Zhilong Yan Tianhao Yang Yang Wang Tianqi Jin Ye Gong Jiarui Zhang Fangrong Liu Fangxia Yang Zifang Wu Wuzi Dong

Wulingzhi (WLZ), a traditional Chinese medicine with diverse chemical constituents, has shown antioxidant and cytoprotective activities; however, its potential to protect spermatogonial stem cells against chemotherapy-induced oxidative injury remains unclear. In this study, a busulfan-induced oxidative injury model was established in porcine spermatogonial stem cells (PSSCs) to investigate the protective effects of WLZ and explore potential bioactive compounds and associated molecular mechanisms by integrating ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS)-based chemical profiling, network pharmacology, molecular docking, and in vitro experiments. Chemical profiling of WLZ by UHPLC–MS/MS, followed by integration with constituents retrieved from BATMAN-TCM and HERB, established an integrated library of 89 candidate compounds. Network pharmacology and molecular docking computationally prioritized ursolic acid (UA) as a candidate WLZ-associated constituent and AKT1 as a candidate regulatory target for subsequent experimental evaluation. Experimental evaluation showed that both WLZ and UA attenuated busulfan-induced oxidative injury, as evidenced by improved cell viability, reduced ROS accumulation, and restored antioxidant capacity. The protective effects of UA were associated with changes in AKT1 transcript expression and were attenuated by the AKT inhibitor Miransertib. In contrast, the PI3K–AKT pathway agonist Recilisib independently improved antioxidant-related parameters in busulfan-exposed PSSCs in the absence of UA. UA treatment was also accompanied by increased transcript levels of Nrf2 and the antioxidant genes SOD, CAT, and GPX1. These findings indicate that UA, prioritized from the integrated WLZ candidate compound library, independently attenuates busulfan-induced oxidative injury in PSSCs and suggest a possible involvement of AKT-related signaling in the observed antioxidant responses. This study provides preliminary in vitro evidence that WLZ and UA attenuate busulfan-induced oxidative injury in PSSCs and supports further investigation of their potential protective effects against chemotherapy-associated male reproductive toxicity.

Antioxidants doi: 10.3390/antiox15111417

Authors: Tzu Ting Weng Adam Clark Paola Corti

Nitric oxide (NO) is an important regulator of motile cilia. Coordinated ciliary beating moves mucus, extracellular fluids, or cells across tissue surfaces and, during embryonic development, drives the establishment of correct organ left–right asymmetry. The connection between NO and cilia function is particularly evident in primary ciliary dyskinesia (PCD), where reduced nasal NO is a diagnostic hallmark, although whether it contributes to or results from ciliary dysfunction remains unclear. Studies of PCD and other airway diseases also show that NO levels do not necessarily correlate with nitric oxide synthase (NOS) expression or activity, indicating that NO bioavailability in ciliated tissues is regulated by additional mechanisms. Despite decades of evidence linking NO to ciliary function, fundamental questions remain regarding how NO is produced and regulated within ciliated cells, how NO signaling is spatially organized within the ciliary microenvironment, and how it reaches the axoneme to regulate ciliary structure and motility. In this review, we examine these questions focusing on soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling, S-nitrosylation, and emerging redox-dependent mechanisms regulating NO bioavailability in motile cilia.

Antioxidants doi: 10.3390/antiox15111416

Authors: Tingshuo Yang Nan Zhang Guodong Ren Yixin Chen Ziyang Sheng Renlong Lv Hanlin Zhou Hailing Luo

Heat exposure can affect intestinal physiology, but the intestinal effects of dietary Piper sarmentosum Roxb. extract (PSE) in goats remain incompletely characterized. During this summer trial in Hainan, the temperature–humidity index generally exceeded 70. Thirty-six male Hainan black goats were randomly assigned to receive 0 (CON), 200, 400, or 600 mg/kg PSE on a dietary dry-matter basis for 90 days after a 15-day adaptation period. At slaughter, small-intestinal tissues and contents were collected for histomorphometry, microbial profiling, and ileal biochemical assays. Exploratory ileal metabolomics compared CON and PSE400 following inspection of morphological and microbial results. Ileal catalase (CAT) activity was higher in PSE400 and PSE600 than in CON, whereas the other measured redox indices showed no significant overall treatment effects in the primary ANOVA. PSE400 also showed a higher duodenal villus height-to-crypt depth ratio, lower ileal crypt depth, and higher ileal lipase activity and microbial richness than CON (p < 0.05). Metabolomics identified relative feature differences and candidate carbohydrate- and lipid-related annotations. These findings associate dietary PSE with higher ileal CAT activity and accompanying morphological and microbial differences under summer conditions. Metabolomic associations remain exploratory and require independent validation.

Antioxidants doi: 10.3390/antiox15111415

Authors: Rushan Lakshitha Adrian Owens Kevin Kantono Thao T. Le Swapna Gannabathula Nazimah Hamid

Honey bioactivity is a multi-constituent property often oversimplified by single-marker analysis. This study applied an exploratory multiblock integrative framework to map the systems-level architecture of bioactivity in New Zealand thyme, mānuka, kānuka, and clover honeys. Sugars, minerals, targeted phenolics, and bioactive indices were profiled alongside a functional panel (ferric reducing antioxidant power, FRAP; cupric ion reducing antioxidant capacity, CUPRAC; 1,1-diphenyl-2-picrylhydrazyl radical scavenging, DPPH; and anti-tyrosinase). Univariate analysis revealed a distinct functional gradient (p ≤ 0.004), with thyme showing the highest mean activity across the four in vitro endpoints within this cohort. Beyond univariate comparison, data integration analysis for biomarker discovery using latent components (DIABLO), supervised by categorical honey type, and sparse partial least squares regression (sPLS-REG), using the continuous assay panel as the response, identified a bioactivity-associated signature spanning multiple chemical domains. The high-bioactivity axis co-varied with vitamin C, syringic acid, phosphorus, and sucrose; these associations do not establish biochemical synergy or soil causation. Botanical adjustment weakened or reversed several pooled associations; vitamin C–CUPRAC depended on the inference method and within-thyme support, and no pair passed within-type permutation BH correction. Lumichrome showed a kānuka-associated pattern within the present cohort, consistent with previous reports, but its specificity requires confirmation in larger, independently sourced cohorts. The contribution is the within-cohort integration of complementary compositional domains with multiple functional endpoints. The findings are hypothesis-generating and require external validation.

Antioxidants doi: 10.3390/antiox15111414

Authors: Desh Deepak Singh Dharmendra Kumar Yadav Dongyun Shin

Hypoxia profoundly reshapes tumor metabolism, promoting glycolytic dependence and lactate accumulation within the tumor microenvironment. Once regarded primarily as a metabolic waste product, lactate is increasingly recognized as a signaling metabolite that links metabolic adaptation to epigenetic regulation through histone lysine lactylation. This emerging mechanism may be particularly important in tumor-associated macrophages (TAMs), where lactate-rich conditions can remodel transcriptional programs and influence macrophage–cancer cell communication. Hypoxia-inducible factor (HIF)-dependent glycolysis, lactate dehydrogenase A (LDHA) activity, and monocarboxylate transporter (MCT)-mediated lactate exchange collectively establish spatial lactate gradients that may facilitate macrophage lactate uptake and histone lactylation, including H3K18la. Emerging evidence implicating p300/CBP, AARS1/AARS2, and histone deacetylases further indicates that lactylation is dynamically written and erased. Lactylation-associated macrophage states may promote immune suppression, angiogenesis, extracellular-matrix remodeling, and tumor plasticity through cytokine and growth-factor networks converging on STAT3, PI3K–AKT–mTOR, NF-κB, and HIF signaling. These reciprocal interactions support a metabolic–epigenetic circuit in which cancer-derived lactate reprograms macrophage chromatin, while altered TAM functions reinforce malignant adaptation and immune escape. This review critically examines the molecular, spatial, and functional organization of the lactate–histone lactylation axis and discusses emerging therapeutic opportunities to disrupt this bidirectional macrophage–cancer cell circuitry. The integrated feedback model is presented as a testable hypothesis: evidence for individual steps is stronger than evidence for the entire closed circuit. Redox-dependent control of glycolysis and the potential of antioxidant interventions are discussed with explicit attention to mechanistic uncertainty.

Antioxidants doi: 10.3390/antiox15111413

Authors: Muhammad Yaseen Ashlee J. Medica Róisín A. Griffin Ceilidh Jenkins Afshin Seifi-Jamadi Aleona Swegen Zamira Gibb

Environmental and biochemical factors can compromise the DNA integrity of equine spermatozoa. Several sperm DNA damage assays exist, but their relative prognostic value has not been assessed in the horse. This study compared four assays for detecting DNA damage in stallion spermatozoa: the sperm chromatin structure assay (SCSA), the sperm chromatin dispersion assay (SCD), the single-cell gel electrophoresis (comet) assay, and the 8-hydroxy-2′-deoxyguanosine (8-OHdG) ELISA. Experiment 1 assessed the effect of hydrogen peroxide (H2O2), a driver of oxidative stress, on sperm DNA damage across increasing concentrations and incubation times. Experiment 2 assessed arachidonic acid (AA), an upstream driver of endogenous oxidative stress. Experiment 3 evaluated the prognostic value of each assay using semen from Thoroughbred stallions during periods of high and low fertility. Across experiments, the comet assay detected DNA damage at lower stressor doses and shorter incubation times than the other assays and was the only assay to distinguish semen from low-fertility stallions from that of high-fertility stallions. The SCSA, SCD, and 8-OHdG ELISA were comparatively less sensitive in detecting significant differences under the same conditions. In conclusion, the comet assay demonstrated the most consistent responsiveness in detecting sperm DNA damage in stallions under the tested conditions.

Antioxidants doi: 10.3390/antiox15111411

Authors: Melissa Terruzzi Luis Reyes-García Angeleth Pacheco-Alfaro Paulina Rivas-Reyes Jaime Ortiz-Viedma Camila Benavides-Delmonte Francisco González-Vidal Christopher Sanhueza-Vergara Marcos Flores-García Roberto Lemus-Mondaca Jorge Barros-Velázquez

This study developed a biorefinery process based on clean, sequential extraction using supercritical carbon dioxide and pressurized liquids to recover lipophilic and hydrophilic (phenolic) bioactive fractions from calafate (Berberis microphylla) pomace. This process was then applied to inhibit lipoxidation and retain total carotenoids, expressed as astaxanthin and PUFAs, in 3D-printed salmon paste baked at 200 °C. For this purpose, phenolic extract doses of 100, 500, and 1000 ppm were applied to the 3D-printed salmon paste. It was determined that all extract doses improved the relative carotenoid content after baking, especially the 100 ppm dose, while the 500 ppm dose reduced secondary alteration indices (K270). Texture profile analysis revealed that applied doses could have involved protein-polyphenol interactions that, under thermal conditions, would stabilize the myofibrillar protein matrix, modulating anisotropic contraction, texture, and the fidelity of the food’s 3D geometry. The results demonstrate the viability of this biorefinery approach as a sustainable strategy for developing natural ingredients applicable to healthy marine matrices with high structural and nutritional complexity.

Antioxidants doi: 10.3390/antiox15111412

Authors: Boxuan Liu Xijin Yu Rou Qi Hongtao Bi Min Zhao Jinwen Du Hongyan Yuan Weihua Ni

In a previous study, we isolated a water-soluble heteropolysaccharide (CRWP-S) from the edible lichen Cladina rangiferina (L.) Nyl., which exhibited potent free radical-scavenging capacities. However, its protective efficacy against ultraviolet B (UVB)-induced skin photoaging and the underlying molecular mechanisms remain to be fully elucidated. In this study, we established a UVB-induced photoaging model in BALB/c mice and cell senescence model in HaCaT keratinocytes to evaluate the photoprotective effects and mechanisms of CRWP-S. Microneedle-assisted topical application of CRWP-S effectively attenuated UVB-induced macroscopic photoaging phenotypes, while mitigating dermal collagen degradation and restored NRF2 expression in vivo. CRWP-S treatment enhanced HaCaT cell viability, reduced intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and restored the activities of superoxide dismutase (SOD) and catalase (CAT). Mechanistically, CRWP-S inhibited senescence-associated β-galactosidase (SA-β-Gal) activity and downregulated the expression of senescence markers p53 and p21. Furthermore, CRWP-S promoted NRF2 nuclear translocation and upregulated downstream heme oxygenase-1 (HO-1) while downregulating KEAP1 expression. Pharmacological inhibition of NRF2 using ML385 largely abolished the ROS-scavenging and cytoprotective effects of CRWP-S. Taken together, these findings demonstrate that CRWP-S protects against UVB-induced skin photoaging via activation of the KEAP1–NRF2 signaling pathway, highlighting its strong potential as a functional bioactive ingredient for anti-photoaging formulations.

Antioxidants doi: 10.3390/antiox15111410

Authors: Chaewon Park Hwamok Oh Chang-Young Jang Tae Hyun Kim

Oxidative stress and redox dysregulation are widely implicated in drug-induced liver injury (DILI), yet their roles vary considerably according to the initiating insult, cellular context, and stage of injury. Rather than representing a single pathogenic mechanism, redox disturbances may function as initiating contributors, injury amplifiers, adaptive responses, or downstream consequences of tissue injury. This review examines these context-dependent roles using hepatocellular and cholestatic DILI as complementary settings for distinguishing shared and divergent redox mechanisms. We discuss how mitochondrial oxidant stress, glutathione- and thioredoxin-dependent defenses, nuclear factor erythroid 2-related factor 2 (NRF2)-mediated adaptation, redox-sensitive signaling, lipid peroxidation, and inflammatory oxidants occupy different positions within the injury cascade across representative DILI settings. This review focuses particularly on the sources, spatial organization, timing, molecular targets, and consequences of redox events, all of which are considered together with their magnitude. This perspective may help reconcile apparently inconsistent findings across experimental models and improve the mechanistic interpretation of redox biomarkers and therapeutic interventions in DILI.

Antioxidants doi: 10.3390/antiox15111409

Authors: Marwa M. El-Said Ahmed M. Mabrouk Mostafa Elaaser Marwa A. Kamel Amira A. Gamal Eman S. Abou-Amra Sally S. Sakr Hassan Barakat

Red prickly pear (Opuntia ficus-indica) fruit as a potential source of phenolic compounds with biological and functional-food applications was investigated. The present study aimed at the detailed characterization of red prickly pear pulp fruit phenolic extract (RPPP-PE), determination of its antimicrobial and anti-hepatitis A virus (HAV) activities, elucidation of the molecular interactions of the identified phytochemicals with HAV 3C protease using docking and ADME analyses, and development of a liposomal formulation associated with chitosan–maltodextrin for yogurt fortification. RPPP-PE was obtained by ultrasound-assisted ethanol–water extraction and analyzed by HPLC-DAD. The most abundant phenolics were epicatechin and catechin (148.40 and 137.58 µg/g, respectively). The RPPP-PE showed antimicrobial activity against several tested microorganisms and anti-HAV activity in Vero cells (IC50 = 59.42 ± 2.34 μg/mL; SI = 3.98). Docking of 15 identified phytochemicals against two HAV 3C protease structures (2CXV and 2HAL) revealed rosmarinic acid, apigenin-7-glucoside, and epicatechin gallate as favorable binders. ADME analysis showed an affinity–permeability trade-off for the leading candidates. RPPP-PE was then loaded into lecithin liposomes complexed with chitosan and maltodextrin. The chosen formulation, PEL-0.50-CS/MD, had a particle size of 199.0 nm, a zeta potential of −30.47 mV, and an encapsulation efficiency of 86.46%. Adding PEL-0.50-CS/MD significantly increased phenolic content and antioxidant capacity and improved syneresis during refrigerated storage. The 5% supplementation level showed starter culture viability closest to the control. However, higher inclusion levels declined more sharply over time. These results confirm the biological relevance of RPPP-PE and its use in a chitosan–maltodextrin-associated liposomal system for functional yogurt development.

Antioxidants doi: 10.3390/antiox15111408

Authors: Alena Korencikova Jakub Sofranko Marian Grendar Matej Gazdarica Milan Grofik Ivana Pilchova Norbert Zilka Michaela Skorvanova Natalia Hunarova Andrea Izarik Verespejova Li-Sheng Chien Jaroslava Guzikova Christian Terkanic Nada Labajova Peter Bednarcik Egon Kurca Martin Kolisek

Parkinson’s disease (PD) is associated with systemic proteostatic failure, chronic neuroinflammation, and mitochondrial abnormalities linked to severe oxidative stress. This exploratory longitudinal study mapped the deep-coverage plasma proteome (~6000 proteins via SOMAmer technology) in 32 patients with mild-to-moderate PD following a 21-day intensive, multimodal physiological stimulus framework. This hormetic intervention combined balneo- and hydropinic therapy (incorporating mineral water with 7.48 mg/L H2S and peloid mud with 6.14% S2− of dry matter), neurophysiotherapy, a neuroprotective MIND diet, mindfulness meditation, and clinical aromatherapy. Systems-level pathway analysis was leveraged to evaluate alterations in functional biological networks. Gene Set Enrichment Analysis (GSEA) resolved a negative enrichment of the Parkinson’s disease pathway hsa05012 (FDR = 0.0053). Network topology modeling revealed a highly coordinated proteostatic and antioxidant alteration pattern involving interferon-gamma (IFN-γ) and polyubiquitin-B (UBB) protein clusters (p = 2.2 × 10−5), accompanied by the downregulation of protein clearance markers (UBB, p62, and UCHL1). Concurrently, upregulation of the phase-II detoxification modifier sulfotransferase 1C2 (SULT1C2; log2FC = 0.42) and a reduction of circulating mitochondrial respiratory subunits (NDUFB6, COX5A, NDUFB11) were observed. These exploratory findings may suggest that multimodal hormetic interventions trigger systemic, redox-responsive changes in protein signatures. However, because the distinct volatile chemical and organoleptic properties of the intervention prevent a sham control, these open-label findings must be treated as hypothesis-generating. These tentative models require verification in future parallel-controlled trials before definitive causal interpretations can be established.

Antioxidants doi: 10.3390/antiox15111407

Authors: Syed Arman Rabbani Mohamed El-Tanani Rakesh Kumar Manita Saini Shrestha Sharma Mohamedanas Mohamedfaruk Patni

Despite considerable breakthroughs in renoprotective medicines, chronic kidney disease (CKD) and diabetic kidney disease (DKD) remain the predominant causes of end-stage renal disease and cardiovascular morbidity. Growing evidence shows that oxidative stress is not simply a result of renal injury but a crucial pathogenic element interconnecting metabolic dysregulation, mitochondrial dysfunction, inflammation, endothelial dysfunction, and fibrogenesis. Physiological ROS mediate cellular signaling, mitochondrial homeostasis, and adaptive responses. Persistent redox imbalance, by contrast, results in excessive production of ROS by dysfunctional mitochondria, NADPH oxidases, uremic toxins, and hyperglycemia-driven metabolic pathways that drive self-amplifying oxidative circuits that accelerate nephron loss. This review provides a comprehensive synthesis of the existing knowledge on the molecular causes of oxidative stress in CKD and DKD, with a focus on disease-specific pathways such as mitochondrial dysfunction, AGE–RAGE signaling, metabolic memory, insulin resistance, and lipotoxicity. It also describes cell-specific oxidative injury in podocytes, mesangial cells, tubular epithelial cells, and endothelial cells, and how these contribute to glomerular dysfunction, tubulointerstitial fibrosis, and disease progression. Emerging redox-targeted strategies, such as mitochondria-targeted antioxidants, NADPH oxidase inhibitors, Nrf2 activators, and sirtuin modulation, are reviewed in terms of experimental rationale and clinical evidence. We discuss established renoprotective therapies, such as RAAS inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists, separately to distinguish demonstrated clinical benefits from the still incompletely established contribution of redox mechanisms. The clinical use of circulating and urinary oxidative stress biomarkers is also critically evaluated. Finally, we discuss new research directions in precision redox medicine, including cell-specific antioxidant delivery, redox-sensitive molecular imaging, integration of multi-omics, artificial intelligence-assisted biomarker discovery, and human-relevant translational models, as well as the current stages of development and barriers to clinical application. The present review combines mechanistic evidence with biomarker and translational studies to prioritize research in biomarker-informed risk stratification and mechanism-guided redox therapies in CKD and DKD. However, their clinical utility remains to be proven and requires independent validation and prospective evidence of improved patient outcomes. These advances provide a foundation for biomarker-informed risk stratification and mechanism-guided therapy in CKD and DKD, but clinical use requires further validation and evidence of improved patient outcomes.

Antioxidants doi: 10.3390/antiox15111406

Authors: Siyi Li Fuqiang Shi Xiangsheng Guan Shuai Chen Xuyan He Ziwen Zhang Ruyi Zi Jiayi Guo Esi Domi Massimo Ubaldi Roberto Ciccocioppo Hongwu Li

The use of ginseng has long been documented in classical texts of traditional Chinese medicine, where it is commonly used to treat conditions involving physical weakness and depletion, as well as pain-related disorders. Ginsenosides, as the primary active components of ginseng, are the focus of modern pharmacological research. Ginsenoside Rb1 (abbreviated as G-Rb1) is a tetracyclic triterpenoid compound that is abundantly distributed in ginseng. It exhibits multiple pharmacological activities, including antioxidant, analgesic, anti-inflammatory, and neuroprotective effects, and has been proven to exert notable therapeutic efficacy in the treatment of neurological disorders, cardiovascular diseases, metabolic disorders, and as an anti-cancer therapeutic agent. Neuropathic pain (NP) involves complex mechanisms. Owing to its diverse pharmacological properties and potential to modulate multiple signaling pathways, G-Rb1 has emerged as a promising natural compound for investigating novel strategies for NP management. This review analyzes the possible mechanisms by which G-Rb1 may treat various diseases, explores its interactions with different signaling pathways, and demonstrates its feasibility in the treatment of NP. Based on a comprehensive analysis of the existing literature, G-Rb1 shows promise as a novel analgesic or as a complementary component for use in combination with other analgesic drugs. This paper provides a reference for further in-depth research on the application of G-Rb1 in the treatment of NP.

Antioxidants doi: 10.3390/antiox15111405

Authors: Jocelyn Fuentes Catalina Cornejo-Coronado Mario Aranda Lina Patiño-Arias Hernán Speisky

Exposure of quercetin (Que) or kaempferol (Kae) to a nitrous-acid containing pseudo-gastric fluid (PGF) leads to their oxidative conversion into their respective hydroxylated-benzoyl-benzofuranones (BZFs), Que-BZF and Kae-BZF. This study evaluated the implications that the referred conversion could have on the antioxidant properties, cellular metabolic activity, and membrane integrity of such fluids when added to Caco-2 cells exposed to the ROS-generator, indomethacin. The addition of PGF containing either Que-BZF or Kae-BZF to the cells concentration-dependently (10–100 nM) prevented indomethacin-induced oxidative stress (dichlorodihydrofluorescein oxidation), mitochondrial-dependent metabolic dysfunction (MTT reduction), and plasma membrane disruption (LDH leakage). To achieve a level of intracellular antioxidant protection (80%), metabolic preservation (100%), and membrane integrity protection (100%) comparable to that induced by 10 nM of Que-BZF or Kae-BZF in the PGF, concentrations of quercetin or kaempferol of 10 µM, that is, three-orders of magnitude higher, were required. At 100 nM, the BZFs contained in the PGF promoted Nrf2 nuclear translocation and induced a near five-fold increase in the levels of the antioxidant enzymes HO-1 and NQO1, regardless of indomethacin treatment. Therefore, the present in vitro chemical simulation and cellular model of intestinal epithelium study demonstrates that the oxidative conversion that quercetin and kaempferol undergo following their incubation in a nitrous acid-containing PGF results in a substantial amplification of their original antioxidant and cytoprotective capabilities and suggests that the latter effects arise from the extremely potent ability of the hydroxylated-benzoyl-benzofuranones to activate the Nrf2-Keap1 pathway.

Antioxidants doi: 10.3390/antiox15111404

Authors: Tom Ryu Junsouk Yoon Jaejun Lee Ji Won Han Hyun Yang Keungmo Yang

Albumin and bilirubin contribute to endogenous antioxidant defenses, but their circulating concentrations also reflect hepatic and systemic processes. We examined their mutually adjusted associations with mortality in probable metabolic dysfunction-associated steatotic liver disease (MASLD). This UK Biobank analysis included 73,099 participants with fatty liver index ≥ 60, cardiometabolic risk, quantifiable low alcohol intake, and complete covariates. Albumin and total bilirubin were modeled simultaneously using restricted cubic splines. During 1,079,873 person-years, 10,467 deaths occurred. The fully adjusted hazard ratio for albumin 42 versus 46 g/L was 1.21 (95% confidence interval 1.15–1.27). For bilirubin 12 versus 6 µmol/L, it was 0.96 (0.91–1.02), attenuated from 0.89 (0.84–0.94) after age and sex adjustment. The low-albumin/low-bilirubin profile had a hazard ratio of 1.18 (1.10–1.28) relative to the middle/middle profile, without evidence of interaction (p = 0.810). Albumin associations with cardiovascular and non-liver cancer mortality survived correction for six secondary comparisons; the liver mortality association did not. Sensitivity analyses, including a post-review model allowing adjustment-covariate effects to vary across follow-up, supported the albumin finding. Lower albumin was consistently associated with mortality, whereas an independent bilirubin association was not established. Antioxidant function was not measured; these observational associations do not demonstrate antioxidant protection or therapeutic benefit.

Antioxidants doi: 10.3390/antiox15111403

Authors: Marta Lewoc-Magnuszewska Barbara Choromańska Mateusz Maciejczyk Agata Kolanek Julia Grymuza Radosław Sielawa Kamil Waczyński Dariusz Średziński Piotr Radziwon Anna Zalewska Małgorzata Żendzian-Piotrowska Jacek Dadan Piotr Myśliwiec

Data on redox homeostasis and matrix metalloproteinase (MMP) activity in parathyroid adenoma are limited, although chronic inflammation and oxidative stress may contribute to the pathophysiology of primary hyperparathyroidism. In this prospective pre–post study, we assessed systemic redox status, nitrosative stress markers, and circulating MMP activity in 52 patients with parathyroid adenoma before and six months after parathyroidectomy and in 52 age- and sex-matched controls. Before surgery, patients had lower total antioxidant capacity (TAC), and higher total oxidant status (TOS) and oxidative stress index (OSI) compared to the controls. Six months after surgery, TAC returned to control levels, whereas TOS and OSI remained elevated. Nitric oxide (NO) levels decreased after parathyroidectomy, and peroxynitrite (ONOO−) levels at follow-up were higher than in controls. Postoperatively, the plasma activity of all six investigated MMPs (MMP-1, -2, -7, -9, -11, and -13) was lower than in the controls, whereas significant pre- to postoperative decreases were observed only for MMP-7 and MMP-11. Thus, six months after parathyroidectomy, several systemic redox, nitrosative, and MMP parameters still differed from those in the controls. Longer follow-up is required to determine whether these abnormalities normalize and to establish their clinical significance.

Antioxidants doi: 10.3390/antiox15111402

Authors: Honghui Guo Siqi Chen Manman Liao Mingwang Zhang Liang Ke Guiwei Zou Haifen Tian Hongwei Liang

The rice field eel (Monopterus albus) is a commercially significant freshwater fish. However, the persistent shortage of fry has therefore become a major constraint on the sustainable development of the eel aquaculture industry. The causes of mortality are generally associated with aquaculture practices, stocking density, and water quality. Therefore, there is an urgent need to optimize stocking density for M. albus fingerlings in indoor aquaculture to improve survival and support sustainable development of M. albus aquaculture. This study aimed to determine the optimal stocking density for M. albus fry (0.6–0.7 g) by evaluating growth, cannibalism, antioxidant status, and transcriptome responses. Four initial densities were tested over 80 days: 500 (D1), 1000 (D2), 1500 (D3), and 2000 (D4) individuals per square meter (inds/m2). Fry reared at 1500 inds/m2 (D3) achieved the lowest cannibalism-induced mortality and the highest survival and growth rates. Conversely, low-density groups (D1 and D2) exhibited increased spontaneous aggression and oxygen consumption rates, suggesting higher metabolic costs linked to agonistic interactions. Oxidative stress analysis revealed tissue-specific responses between liver and muscles: high density significantly increased hepatic malondialdehyde (MDA) levels and activated hepatic superoxide dismutase (SOD) and glutathione peroxidase (GPx) while activating an SOD-catalase (CAT) response in muscles. Transcriptome profiling supported these findings, showing enrichment in pathways related to neuroactive ligand–receptor interaction and tissue damage in cannibalistic low-density groups, while the D3 group showed enrichment in O-glycan biosynthesis and detoxification pathways (cytochrome P450), reflecting a metabolically healthy adaptation. In conclusion, stocking density markedly influences behavior, physiological status and molecular responses in M. albus. An intermediate density of 1500 inds/m2 optimizes survival and reduces cannibalism, providing a practical reference for improving welfare and productivity in indoor eel aquaculture.

Antioxidants doi: 10.3390/antiox15111401

Authors: Maria Ester Canepa Isabella Panfoli Sara Mangini Andrea Calandrino Francesco Vinci Mariya Malova Pasquale Striano Luigi Gagliardi Luca Antonio Ramenghi

Glucose is more than an energetic substrate: its homeostasis emerges from continuous interactions between peripheral glucose-regulatory organs and the brain, where glucose availability, sensing, and utilisation must be dynamically matched to metabolic demands. This narrative review examines how disruption of this balance may intersect with oxidative stress, inflammation, and brain vulnerability at the extremes of life. In preterm neonates, the definition of pathological glycaemic states remains heterogeneous, while hypoglycaemia, hyperglycaemia, and particularly glycaemic variability may represent different manifestations of dysglycaemia within an immature homeostatic system. Experimental and clinical evidence links these disturbances, with different degrees of certainty, to oxidative stress, inflammatory responses, adverse neurological outcomes, and white matter vulnerability. The developing brain is particularly susceptible to redox imbalance because of maturation-dependent antioxidant defences and the vulnerability of developing white matter. At the opposite extreme of life, ageing is accompanied by alterations in cerebral glucose and energy metabolism, while neurodegenerative disorders show disturbances in glucose transport and utilisation together with mitochondrial dysfunction, oxidative stress, inflammation, and neuronal and white matter abnormalities. We propose the Biochemical and Physiological Mirror as a conceptual interpretation of these apparently distant conditions: developmental immaturity and age-related decline represent distinct biological trajectories that may converge on partially shared glucose–redox–inflammatory intersections. Within the Crossword Effect, glucose therefore acquires biological meaning not as an isolated concentration but through its context-dependent relationships with metabolic, redox, inflammatory, cellular, and developmental information. Viewing dysglycaemia as a systems-level disturbance rather than solely as deviation from a numerical threshold may provide a more integrated framework for understanding brain vulnerability across the lifespan.

Antioxidants doi: 10.3390/antiox15111400

Authors: Damian Mielecki Elżbieta Salińska

Neonatal hypoxic–ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term neurological disability. Although therapeutic hypothermia (TH) improves outcomes in eligible infants with moderate-to-severe HIE, its efficacy is incomplete, highlighting the need for additional neuroprotective strategies. Endogenous neuroprotective compounds are particularly attractive candidates because they participate in intrinsic cellular defense mechanisms and can modulate components of the hypoxic–ischemic injury cascade. This review focuses on five endogenous molecules—carnosine, citicoline, kynurenic acid (KYNA), lactoferrin, and N-acetylaspartylglutamate (NAAG)—whose neuroprotective effects have been demonstrated in experimental models of neonatal hypoxia-ischemia (HI). These molecules act through distinct but partly overlapping mechanisms involving modulation of glutamatergic neurotransmission, antioxidant defense, mitochondrial protection, anti-inflammatory signaling, and inhibition of regulated cell death. Their complementary actions suggest that they may represent components of a broader endogenous neuroprotective network rather than independent protective mechanisms. However, differences in blood–brain barrier accessibility, pharmacokinetics, therapeutic windows, and the predominantly preclinical nature of the available evidence remain important limitations to translation. Future studies should define optimal dosing, establish safety in the developing brain, and determine whether rational combinations of these compounds, particularly as adjuncts to TH, can provide more effective protection against neonatal hypoxic–ischemic brain injury.

Antioxidants doi: 10.3390/antiox15111399

Authors: Ana Asenjo-Bueno Ariadna Moreno-Piedra Maria Martos-Elvira Javier Sanz-Zamora Gemma Olmos Maria Piedad Ruíz-Torres Elena Alcalde-Estévez Susana López-Ongil

Hyperlipidemia-associated atherosclerosis promotes plaque formation and extracellular matrix accumulation in the vascular media, increasing also the production of reactive oxygen species (ROS), inflammation, and the oxidation of LDL to oxidized-LDL, through mechanisms that remain unknown. Our objective was to determine whether oxidizedLDL-induced oxidative stress drives fibrosis in the arterial media during atherosclerosis and whether antioxidants can prevent or reduce this effect. Experiments were conducted in vascular smooth muscle cells (VSMCs) and in apolipoproteinE-knockout (KO-apoE) mice. ROS production was measured by confocal microscopy and fibrosis by immunofluorescence, Western and RT-qPCR in VSMCs and by Sirius red staining and RT-qPCR in mice. In VSMCs, oxidized-LDL treatment significantly increased the expression of TGF-beta, fibronectin and collagen-I, indicating fibrosis. Additionally, oxidized-LDL enhanced ROS production and NF-κB activation. The fibrotic response was prevented by treatment with the antioxidant N-acetylcysteine (NAC) and an NF-κB inhibitor, suggesting that the ROS-NF-κB axis mediates these effects in VSMCs. In vivo, KO-apoE mice exhibited higher cholesterol levels and increased ROS production compared with wild-type controls. These mice also showed enhanced aortic fibrosis. Importantly, NAC administration reduced both ROS production and fibrosis in KO-apoE mice. Overall, the findings suggest that both oxidized-LDL-induced vascular fibrosis and hyperlipidemia-induced fibrosis are mediated by ROS.

Antioxidants doi: 10.3390/antiox15111398

Authors: Yong-Guy Kim Paramasivam Nithyanand MinHwi Sim Jin-Hyung Lee Jintae Lee

Antifungal resistance in Candida species, particularly in biofilm-associated infections, poses a major clinical challenge. We evaluated a series of halogenated 1,4-naphthoquinones for their antifungal, antibiofilm, and antivirulence activities against drug-resistant Candida species. Among the derivatives tested, 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (compound #10) emerged as the most potent, exhibiting strong activity against both C. albicans and non-albicans Candida strains. Notably, #10 at 1 μg/mL showed rapid fungicidal activity, with no viable cells detected within 15 min, and inhibited biofilm formation at the same concentration. Cell aggregation and hyphal development were also reduced at the sub-MIC of 0.5 μg/mL. Structure–activity comparisons suggest that hydroxyl substitution further enhances activity beyond halogenation alone. Mechanistically, #10 induced intracellular reactive oxygen species (ROS) production at low concentrations and was associated with rapid fungicidal activity and suppression of virulence-associated gene expression, including those involved in adhesion, hyphal morphogenesis, and biofilm regulation. Toxicity was further evaluated across plant, invertebrate, mammalian cell, and rat models. These findings identify #10 as a promising lead candidate for the development of antifungal agents targeting biofilm-associated and drug-resistant Candida infections.

Antioxidants doi: 10.3390/antiox15111396

Authors: Yağmur Özhan Etil Güzelmeriç Dilara Güreşçi Elif Begüm Yıldırım Rengin Reis Muhammed Hamitoğlu Ahmet Aydın Hande Sipahi

Iron overload induces oxidative stress, lipid peroxidation, and inflammatory responses, collectively contributing to cellular and tissue injury. Although synthetic iron chelators are widely used in clinical practice, their associated adverse effects and treatment-related costs highlight the need to investigate naturally derived compounds as potential alternative therapeutic agents. This study comprehensively evaluated the iron-chelating, antioxidant, and anti-inflammatory properties of hazelnut samples encompassing Giresun-quality (Beşikdüzü, Vakfıkebir, and Çarşıbaşı), Levant-quality (Araklı, Arsin, and Yomra), and Pikola-type varieties, alongside extracts derived from defatted hazelnut pulp. Following qualitative and quantitative phytochemical characterization, antioxidant capacity was assessed using DPPH, CUPRAC, FRAP, and TOAC assays, while iron-binding capacity was evaluated under simulated gastric (pH 2) and intestinal (pH 6) conditions using atomic absorption spectroscopy and the ferrozine assay. To investigate hepatic protection, the iron-chelating potential of the extracts was examined in Hep3B cells exposed to iron overload. Extract C (80% ethanolic extract of ground hazelnuts) exhibited the most pronounced iron-chelating activity, achieving iron-binding efficiencies of 77–88% under simulated gastrointestinal conditions and 90% in the ferrozine assay, while decreasing intracellular iron accumulation in Hep3B cells by approximately 83–84%. Furthermore, Extract C effectively mitigated iron-induced oxidative stress, as evidenced by reduced malondialdehyde (MDA) levels and the restoration of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). In lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, the extracts additionally suppressed nitrite accumulation and decreased prostaglandin E2 (PGE2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels. Our findings highlight the potential of hazelnut-based extracts as therapeutic candidates for the management of iron overload owing to their iron-chelating, antioxidant, and anti-inflammatory properties.

Antioxidants doi: 10.3390/antiox15111397

Authors: Fen Xiong Kaiyuan Jiang Xiaoqing Yan Tian Tang Xinran Wang Yiwen Peng Ruoxin Guan Xi Zhang Chen Li Hongchang Gao

Background: Cognitive impairment is a clinically relevant neurological complication of diabetes, yet its metabolic mechanisms remain incompletely understood. This study aimed to determine whether fibroblast growth factor 21 (FGF21), a fasting-responsive metabolic hormone, mediates the neuroprotective effects of intermittent fasting (IF) in diabetes-associated cognitive impairment, and to explore the underlying mechanisms. Methods: Streptozotocin (STZ)-induced type 1 diabetes-associated cognitive impairment (T1DCI) mice were used together with FGF21 genetic deletion and exogenous FGF21 supplementation. Cognitive function, neuronal injury, hippocampal lipid metabolism, mitochondrial function, protein acetylation, and SIRT3-associated deacetylation were evaluated. Results: IF significantly increased FGF21 levels in serum and hippocampus and improved cognitive deficits, whereas these effects were attenuated in FGF21-deficient mice. FGF21 supplementation improved cognitive performance and attenuated neuronal damage, accompanied by MAPK-related signaling changes. Lipidomic analysis revealed decreased phosphatidylcholine and triacylglycerols in the hippocampus of T1DCI mice, which were partially restored by FGF21. Consistently, FGF21 increased the expression of LPIN3, DGAT2, and CHPT1, key enzymes involved in PC and TAG biosynthesis. FGF21 also improved mitochondrial function and was associated with reduced protein acetylation, while SIRT3 inhibition attenuated these effects. Conclusions: These findings suggest that FGF21 contributes to the neuroprotective effects of IF in diabetes-associated cognitive impairment, potentially through coordinated regulation of lipid metabolism and mitochondrial function.

Antioxidants doi: 10.3390/antiox15111395

Authors: Umut Kaan Özbaş Halil İbrahim Yavuz

Hydrogels that remove reactive oxygen species (ROS) are now a standard design response to the oxidative environment of a bone defect, and the supporting literature has grown quickly across polyphenols, metal–phenolic networks, inorganic nanozymes, ROS-cleavable polymers, and oxygen-generating composites. The evidence offered for these systems almost always takes one form: a percentage of a synthetic radical scavenged in a cuvette, a reduction in intracellular probe fluorescence, and an increase in bone volume in a rodent defect. We argue that this chain has a missing link. The first measurement is a capacity-an equilibrium property of a material sample-while the quantity that determines a biological effect is a dose: an amount of oxidant removed, per unit volume of tissue, over a defined interval, at a defined position. Capacity and dose are different physical quantities with different units, and no published transformation connects them. The problem is sharpened by the fact that ROS in bone are not purely pathological: osteoclast differentiation, hypoxia-driven angiogenic signalling and macrophage transition all depend on them, so the therapeutic target is a moving setpoint rather than zero. We review the redox biology of the healing defect as a design specification, reclassify the available chemistries by turnover mode and localization rather than by chemical family, and show by unit analysis why percentage scavenging cannot specify a design. We propose two reportable quantities-scavenging flux density and redox residence time-identify the integrated oxidant burden of a healing defect as the field’s central unmeasured denominator, and close with a reporting checklist.

Antioxidants doi: 10.3390/antiox15111394

Authors: Guilherme da Silva Rodrigues Ivo Vieira de Sousa Neto Ana Paula Pinto Andressa Crystine da Silva Sobrinho Eliézer Lucas Pires Ramos Jonas Benjamim Carlos Roberto Bueno Júnior

Exercise may influence redox homeostasis and epigenetic plasticity, but longitudinal evidence linking redox-related DNA methylation to functional adaptation is limited. We examined time-dependent functional and methylation changes during 14 weeks of combined exercise training. Methods: In this single-arm longitudinal study, 45 physically inactive women participated in supervised aerobic and resistance exercise three times weekly. Functional outcomes and whole blood DNA methylation (Illumina EPIC array) were assessed at baseline and weeks 7 and 14. Repeated-measures models evaluated temporal changes, and redox-related CpGs were analyzed using limma with false-discovery-rate control. Results: Blood pressure, muscle strength, agility, and 6 min walk distance improved over time. Across different contrasts, hypomethylated CpGs were detected in CAT, SOD1, TXNRD1, TGFB1, and NFE2L2. Several CpGs remained significant after false-discovery-rate adjustment in the week-14-versus-baseline contrast. cg06295404 in SOCS1 was identified in two sequential contrasts. Methylation at cg07613405 in NFE2L2 was associated with 6 min walk distance, while exploratory public transcriptomic analyses showed concordant redox-gene expression patterns. Conclusion: Combined training was accompanied by early functional improvements and time-dependent redox-related methylation changes. Controlled studies with independent replication are needed to establish causality.

Antioxidants doi: 10.3390/antiox15111393

Authors: Feng Gao Chu Chen Ruyue Yang Haichen Xu Qianqian Dong Qiqi Han Xiaowen Feng Jiqing Ye

Myeloperoxidase (MPO) has emerged as a promising therapeutic target for heart failure (HF) because of its pathogenic roles in oxidative stress, inflammation, and myocardial fibrosis. However, the clinical development of MPO inhibitors remains limited, and most candidates have failed in advanced trials. Here, we report the discovery of novel MPO inhibitors through an integrated computational pipeline combining machine-learning-based virtual screening with structure-based consensus docking. This approach screened ~3.1 million compounds and yielded 25 candidates for experimental evaluation. Among these, compound 16 exhibited potent MPO inhibition (IC50 = 0.297 ± 0.097 mM) and conferred significant cardioprotection in H9c2 cells subjected to oxygen-glucose deprivation, preserving cell viability to 66.19% at 25 mM. Mechanistic investigations revealed that compound 16 reduced lactate dehydrogenase release, decreased reactive oxygen species accumulation, and suppressed hypoxia/reoxygenation-induced a-SMA upregulation in a neutrophil-conditioned medium model. In addition, molecular dynamics simulations and MM-PBSA/MM-GBSA calculations suggested stable binding to MPO, primarily through p-stacking with the heme prosthetic group and hydrophobic contacts with key active-site residues. Compound 16 showed favorable predicted permeability and low predicted hERG liability, but poor metabolic stability in rat liver microsomes (T1/2 = 1.34 min), indicating that metabolic optimization is required. Collectively, this study establishes a computationally efficient strategy for MPO inhibitor discovery and identifies compound 16 as an MPO inhibitor that protects cardiomyocytes in vitro, providing a starting point for future in vivo studies aimed at heart failure therapy.

Antioxidants doi: 10.3390/antiox15111392

Authors: Zhihui Huang Benhe Ma Xin’an Wang Ruiyu Deng Qi Liu Guohong Yu Guohua Ke Haihua Wang Aijun Ma

Selenium (Se) is an essential trace element for aquatic animals, but its narrow margin between nutritional requirement and toxicity necessitates precise supplementation strategies. Nano-selenium (Nano-Se) has emerged as a promising alternative, yet its dose- and time-dependent effects on the Paramisgurnus dabryanus remain poorly understood. This study employed a central composite design (CCD) within response-surface methodology (RSM) to systematically investigate the interactive effects of dietary Nano-Se concentration (0–4 mg Se/kg diet) and feeding duration (20–60 days) on growth performance, and further evaluated hepatic antioxidant parameters as well as expression profiles of 12 selenoprotein- and glutathione-metabolism-related genes. The RSM models for weight-gain rate (WGR) and specific growth rate (SGR) were highly significant (R2_Adj = 0.972 and 0.855, respectively; p < 0.001), revealing that the two factors act independently (TS term not significant, p > 0.05). Optimal growth was achieved at 1.0 mg/kg Nano-Se, with feeding duration showing a continuous positive effect on WGR (maximum at 60 d) but a plateau effect on SGR after 30 days. The medium dose (1.0 mg/kg) maintained stable antioxidant capacity and induced the strongest gene–enzyme coupling at 40 days (e.g., selenoprotein O1 (selenoo1) vs. SOD: ρ = 0.90, p < 0.001). The low dose (0.5 mg/kg) suppressed SOD and GSH-Px activities, whereas the high dose (3.0 mg/kg) disrupted positive coupling and caused an “uncoupling” phenomenon with up-regulation of antioxidant enzymes but down-regulation of transaminases. Twelve functional genes were clustered into three response modules: selenoprotein synthesis (Cluster I, including glutathione peroxidase 1 (gpx1) and tRNA-selenocysteine-1-associated protein (trnau1ap)), GSH-dependent secondary defense (Cluster II), and GSH regeneration/metabolism (Cluster III). Notably, gpx1 and other antioxidant-defense genes were prioritized under adequate Se supply, whereas trnau1ap (SECp43), a potential master switch for selenoprotein translation, was globally down-regulated under long-term high-Se exposure. In conclusion, the optimal Nano-Se supplementation for juvenile P. dabryanus is 1.0 mg/kg for 40 days, providing a theoretical basis for precision selenium nutrition in farmed fish.

Antioxidants doi: 10.3390/antiox15111391

Authors: Yu Zhang Haoyang Hu Yang Zhang Xiao Liang Bao Lou

Paracoccus marcusii is an astaxanthin-synthesizing bacterium with antioxidant potential, but its mechanisms mitigating intestinal oxidative injury in fish remain unclear. Herein, we explored the protective function of P. marcusii IHA034 (CGMCC No. 25301) in juvenile Larimichthys polyactis, combining an in vivo oxidized-fish-oil challenge model and an in vitro H2O2-stimulated primary intestinal cell model. A 51-day feeding trial showed that 1.0 g/kg dietary P. marcusii supplementation improved growth performance, enhanced intestinal antioxidant enzyme activities, and restored epithelial ultrastructural damage. A strikingly high relative abundance of Paracoccus (90.50%) was detected in the gut digesta of the PM1.0 group, accompanied by reduced microbial α-diversity. In vivo intestinal transcriptomics and qPCR showed downregulated nrf2 mRNA, alongside activated complement and anti-apoptotic responses. However, P. marcusii pigment-rich crude extracts activated the Keap-1/Nrf2 pathway and rescued H2O2-induced cell injury in vitro. These findings demonstrate multi-modal protective effects of P. marcusii IHA034 and uncover contrasting Keap-1/Nrf2 regulatory patterns between in vivo intestinal tissue and in vitro cell models, providing mechanistic support for the application of this astaxanthin-producing bacterial resource in aquaculture.

Antioxidants doi: 10.3390/antiox15111390

Authors: Khyati Alagh Rudy N. Zalzal Akshay Kumar Ying Xiong Zhiqiu Xia Kajal Kamra

Nitric oxide (NO) is a central regulator of cardiovascular function, influencing vascular tone, platelet activity, and inflammatory signaling. Despite decades of work defining its molecular pathways, translation into consistent clinical application has remained uneven, with findings across experimental, biomarker, and therapeutic studies often appearing inconsistent. Part of this variability reflects how NO behaves under different biological conditions. Its effects are shaped by where it is produced, how much is generated, and the biochemical environment in which it operates. Under some conditions, NO supports vascular homeostasis, while in others it contributes to oxidative and nitrosative stress, a pattern we refer to as the nitric oxide paradox. This review revisits commonly used NO-related biomarkers, including nitrate/nitrite (NOx), asymmetric dimethylarginine (ADMA), and 3-nitrotyrosine, and considers why their clinical interpretation remains inconsistent. It also examines the limitations of NO-based therapies, where short half-life, systemic exposure, and limited control over delivery continue to constrain outcomes. Rather than viewing these findings as conflicting, this article considers them as reflections of how NO signaling shifts across different physiological contexts. We organize NO signaling according to four interacting determinants: enzymatic source, magnitude and duration of production, cellular compartment, and the surrounding redox environment. Framing NO biology in this way may help explain variability in both diagnostic and therapeutic settings and clarify where current approaches remain limited.

Antioxidants doi: 10.3390/antiox15111389

Authors: Agnieszka Zgoła-Grześkowiak

Plant-derived bioactive compounds continue to attract considerable scientific interest because of their chemical diversity and their potential to modulate oxidative processes in biological and food systems [...]

Antioxidants doi: 10.3390/antiox15111388

Authors: M. Firoze Khan Hui Wang

Systemic lupus erythematosus (SLE) is a complex autoimmune disease (AD) characterized by chronic inflammation and multi-organ damage, driven by a combination of genetic, hormonal and environmental factors. Ample evidence links specific environmental agents, such as solvents, PFAS, microplastics, bisphenol A, mercury, pesticides, smoking and silica, to the development of SLE. Despite growing evidence highlighting the pivotal role of these environmental agents in initiating, modulating or exacerbating autoimmune responses, substantial gaps remain in our understanding of their precise role and mechanisms driving disease pathogenesis. Oxidative stress (OS) plays an important role in the pathogenesis of a variety of ADs, including SLE, and many environmental factors actively participate in this process. Furthermore, with the recent surge in microbiome research, numerous studies have provided insight into how changes in the gut microbiota contribute to the onset and progression of the disease. Importantly, understanding the interplay among OS, gut dysbiosis, and immune dysregulation will not only deepen our insight into environmental pathophysiology but also open new avenues for microbiota-targeted prevention and therapy in SLE. This review aims to provide an updated overview of the existing literature concerning the role of gut microbiome-OS-host interactions in the pathogenesis of SLE, while also exploring potential novel therapies.

Antioxidants doi: 10.3390/antiox15111387

Authors: Jessica L. Nicholson Yujia Qin Mark F. Boktor Christine N. S. C. Lau Pamela Toh Stella Maris A. Remigio Kescher K. Nakahara-Akita Alyssa M. Vetter Youping Deng Marla J. Berry Daniel J. Torres

Long-term elevation of glucocorticoid levels is detrimental to neurological function, causing disturbances in mood and memory. Multiple molecular mechanisms of action have been implicated, including the disruption of antioxidant defense systems. This study focused on the impact of glucocorticoids on selenoproteins, which include selenoenzymes with antioxidant functions, some of which are essential for proper brain function. We exposed C57/BL6 mice to long-term glucocorticoid administration and measured changes in selenoprotein levels and gene expression. To study the underlying mechanism of selenoprotein regulation, we used an immortalized mouse hippocampal cell line. We found that Glutathione peroxidase 1 and Selenoprotein S levels are altered by glucocorticoids in a manner that is dependent on selenium availability and differential activation of the glucocorticoid and mineralocorticoid receptors. Spatial transcriptomic analysis of mouse hippocampal sections suggests spatial and cell-specific changes to the selenoprotein transcriptome. Finally, brain selenoprotein levels may be indirectly decreased by glucocorticoids due to insufficient distribution of selenium to the brain. Thus, glucocorticoids demonstrate an ability to control selenoprotein levels both by acting directly on hippocampal cells as well as indirectly by disrupting the delivery of dietary selenium to the brain. Future work will determine the impact of selenium intake on glucocorticoid-induced neurological dysfunction and damage.

Antioxidants doi: 10.3390/antiox15111386

Authors: Avinash Kumar Vishal Gill Vishal Verma Shailendra Pratap Singh

The effects of nutraceuticals β-glucan, taurine, and L-arginine under hypoxia, and their significance for athletes, remain unknown. We evaluated these compounds in vitro and tested β-glucan supplementation in athletes. H9c2 cardiomyoblasts were subjected to CoCl2-induced chemical hypoxia to assess metabolic activity, morphology, transcript profiles, and mitochondrial/glycolytic function. In an uncontrolled, single-arm pre–post trial, 50 male athletes received β-glucan-rich mushroom extract (320 mg/day) for 40 days. Body composition, complete blood count, and cardiopulmonary exercise testing were assessed pre- and post-supplementation. CoCl2 decreased MTT metabolic activity to 67.29 ± 0.87% of control. The three compounds significantly increased MTT metabolic activity (83.65–97.40%; p < 0.001 vs. positive control). Taurine, β-glucan, and L-arginine all reduced Hif1a transcript (FC = 0.44, 0.58, and 0.47, respectively; all p < 0.001 vs. positive control). Seahorse examination revealed partial preservation of mitochondrial parameters and improved glycolytic reserve, with L-arginine (120.4%) and taurine (105.1%) numerically higher than the negative control (86.0 ± 20.2%), but neither difference was statistically significant. The transcriptional alterations were compound-specific and exploratory. Athletes who supplemented with multi-mushroom extract for 40 days had higher relative VO2/kg (46.26 ± 2.33 to 53.12 ± 3.75 mL/min/kg; +14.8%; p < 0.001), absolute VO2 (3138.46 ± 313.38 to 3503.82 ± 371.73 mL/min; +11.6%; p < 0.001), and peak RQ (1.096 ± 0.048 to 1.308 ± 0.082; p < 0.001). HCT dropped (44.53 ± 2.81% to 42.10 ± 2.64%; p < 0.001), MCV increased (86.37 ± 2.20 to 89.67 ± 2.32 fL; p < 0.001), and MCHC fell (35.10 ± 0.80 to 33.78 ± 0.53 g/dL; p < 0.001). WBC levels reduced (7.53 ± 1.31 to 6.80 ± 1.02 × 103/µL; p = 0.004), neutrophils fell (61.00 ± 8.34% to 52.02 ± 5.66%; p < 0.001), lymphocytes rose (27.80 ± 3.67% to 35.17 ± 1.65%; p < 0.001), and monocytes increased (2.75 ± 0.44% to 4.35 ± 0.64%; p < 0.001). The human component was an uncontrolled, single-arm, pre–post study with no placebo, randomization, or blinding; hence, the results are hypothesis-generating. In CoCl2-treated H9c2 cells, the compounds improved metabolic activity and partially preserved bioenergetics. The uncontrolled human trial suggests β-glucan supplementation improves aerobic performance and alters hematological indices, though randomized controlled trials are needed to confirm these preliminary findings.

Antioxidants doi: 10.3390/antiox15111385

Authors: Huigang Han Likai Wang Zhenhua Xue Zixia Shen Pengyun Ji Chenyun Guo Jiarui Gao Bingyuan Wang Xuguang Wang Guoshi Liu

Intrauterine growth restriction (IUGR) frequently leads to abnormal fetal liver development and an elevated risk of long-term hepatic metabolic disorders. In this study, primiparous Landrace × Large White sows were used as a model to investigate the protective effects of melatonin supplementation during mid-gestation (days 60–90) on the liver of IUGR fetal pigs. The results showed that melatonin reduced the incidence of IUGR, improved fetal body weight and liver index, and alleviated hepatic structural disorganization, collagen deposition, and hepatic stellate cell activation. Meanwhile, melatonin decreased malondialdehyde levels, restored superoxide dismutase activity and total antioxidant capacity, and effectively mitigated oxidative stress. Transcriptomic validation revealed that melatonin partially counteracted IUGR-induced upregulation of extracellular matrix genes (e.g., COL1A2, COL3A1) and downregulation of antioxidant genes (e.g., GSTA1, GPX3), thereby shifting hepatic transcriptional profiles toward those observed in normal fetuses. In vitro experiments further confirmed that melatonin inhibited LX-2 cell activation and collagen overexpression. In conclusion, gestational melatonin supplementation can attenuate IUGR-associated fibrogenic alterations in IUGR fetal pigs by alleviating oxidative stress and remodeling the transcriptome, providing a novel basis for prenatal intervention.

Antioxidants doi: 10.3390/antiox15111384

Authors: Habaragoda Dewage Tharushi Udayangani Wijerathne Dinusha Shiromala Dissanayake Kalu Kapuge Asanka Sanjeewa Do-Young Jung Cheol-Yeong Yoo Hyo-Geun Lee Soo-Jin Heo Hyun-Soo Kim

The seafood processing industry generates significant amounts of solid waste, including boiled tuna skin, a major byproduct with limited commercial use. Antioxidant activities of Flavourzyme hydrolysate derived from boiled Skipjack tuna (Katsuwonus pelamis) skin byproduct were assessed for their ability to reduce AAPH-induced oxidative stress in In Vitro and In Vivo. The functional properties were improved by enzymatic hydrolysis with Flavourzyme at pH 7.0 to produce an antioxidant hydrolysate. Antioxidant activity was evaluated for boiled tuna skin Flavourzyme hydrolysate (BTSFH) using Hydrogen Peroxide Scavenging activity and ABTS radical scavenging activity. The IC50 values for H2O2 and ABTS radical-scavenging activities were 2.91 mg/mL and 7.52 mg/mL. BTSFH treatment increased cell viability, significantly reduced ROS production under AAPH-induced oxidative stress, and protected against AAPH-induced apoptotic DNA damage. BTSFH exhibited potent antioxidant activity by upregulating endogenous antioxidant enzymes (SOD and Catalase) in AAPH- stimulated Vero cells. An in vivo zebrafish assay demonstrated its antioxidant potential effects by reducing ROS generation, lipid peroxidation, and cell death, thereby supporting its potential as a bioactive compound. These in vitro and in vivo studies’ findings showed that the BTSFH sample represented strong antioxidant activity, making it preliminary evidence for use in pharmaceuticals and health supplements. Marine byproducts as a source of functional ingredients help reduce waste and promote better resource management, aligning with broader goals for a more sustainable circular bioeconomy.

Antioxidants doi: 10.3390/antiox15111383

Authors: Jinli Wen Shuai Zhu Yuxi Li Meihong Liu Hongjie Li Xiyang Zhao

Pinus koraiensis needles (PKNs) are a valuable natural source of high-quality antioxidants, and their health benefits are strongly linked to secondary metabolites. This study thoroughly evaluated the antioxidant activity and metabolite profile of PKNs from three provenances—Lushuihe (LSH), Dongfanghong (DFH), and Dailing (DL)—through chemical antioxidant assays and widely targeted metabolomics. A total of 2948 secondary metabolites were obtained, predominantly flavonoids, terpenoids, alkaloids, and phenolic acids. In vitro antioxidant assays (DPPH, ABTS, FRAP, and hydroxyl radical scavenging) showed that PKNs from LSH exhibited the highest antioxidant capacity, with an overall trend of LSH > DL > DFH. Correlation analysis further indicated that polyphenols play a significant role in the antioxidant properties of PKNs. Network pharmacology analysis suggested that the antioxidant effects of PKNs may involve 207 components, 191 signaling pathways, and 183 related targets. The potential active ingredients could participate in a variety of metabolic pathways in vivo, including PI3K/AKT, MAPK, and cancer pathways. Additionally, molecular docking showed that the key active ingredients bind to the core targets through hydrophobic interactions and hydrogen bonds. Finally, a network pharmacology approach was used to predict potential active ingredients of PKNs for treating cancer, cardiovascular diseases, and liver disorders. This study enhances the understanding of the bioactive compounds and health benefits of PKNs, providing a theoretical foundation for their further development and application.

Antioxidants doi: 10.3390/antiox15111382

Authors: Allan Langlois Nadia Benkirane-Jessel Karim Bouzakri

Pancreatic β-cell dysfunction plays a central role in the development and progression of diabetes. For decades, numerous studies have placed mitochondria at the core of this process. In β-cells, mitochondrial metabolism couples glucose sensing to insulin secretion through ATP production, calcium handling, redox signaling and metabolic coupling factors. Conversely, defects in oxidative phosphorylation, mitochondrial dynamics, mitophagy and redox homeostasis impair glucose-stimulated insulin secretion, promote β-cell stress, the loss of β-cell identity and survival. Moreover, inflammation and metabolic stresses amplify mitochondrial dysfunction in both type 1 and type 2 diabetes, highlighting mitochondria as therapeutic targets. In this review, we aimed to summarize main mitochondrial mechanisms governing β-cell function and to discuss how their disruption contributes to diabetes onset. We also explored emerging strategies aimed at restoring mitochondrial homeostasis, including antioxidant defenses, mitophagy modulation and bioenergetic improvement. Finally, we discussed the impact of skeletal muscle/pancreas crosstalk in insulin secretion. In particular, we emphasized how exercise-induced mitochondrial adaptation and myokines release may influence β-cell survival, insulin secretion and mitochondrial activity. Finally, understanding how β-cell intrinsic mitochondrial quality control integrates with systemic signals from skeletal muscle may open new therapeutic perspectives to preserve β-cell function and improve metabolic control in diabetes.

Antioxidants doi: 10.3390/antiox15111381

Authors: Beibei Chen Yanbin Wang Qi Huang Liang He Dan Liu

Given the prevalence of oxidative stress–driven chronic diseases and the poor targeting of synthetic antioxidants, novel natural antioxidant peptides were systematically identified from Ganoderma lucidum spore proteins using an integrated strategy combining peptidomics, bioinformatics, molecular docking, quantum chemical calculations, and in vitro cellular validation. Among the 6369 identified peptide sequences, three candidate peptides, including CDLDIR, FEQPR and PPSDFAK demonstrated superior performance. They exhibited strong binding affinities toward the Keap1 Kelch domain with the lowest binding energies of −75.00, −73.09 and −72.01 kcal/mol, respectively, driven by stable interactions with key residues Arg415, Arg483 and Tyr334. Density functional theory (DFT) calculations revealed that CDLDIR possessed the narrowest HOMO–LUMO energy gap (3.3163 eV) with its Arg-6 guanidinium group acting as the primary active site for radical scavenging. Subsequently, the antioxidant activity of the three peptides was validated, providing robust experimental confirmation for the computational results. In vitro cellular assays confirmed that CDLDIR was non-cytotoxic from 50 up to 500 μg/mL. Moreover, it remarkably reduced intracellular MDA and ROS levels while upregulating SOD, CAT and GPx activities in a concentration-dependent manner. These computational and experimental findings demonstrate that CDLDIR would be a promising natural antioxidant peptide from G. lucidum spores, offering a strong theoretical foundation for further investigation of their antioxidant and cytoprotective potential and for the development of functional food ingredients or nutraceuticals.

Antioxidants doi: 10.3390/antiox15111380

Authors: Hamid Arazi Ahmad Hematabadi Mohamad Motevalli Markus Schauer Elena Pocecco Katsuhiko Suzuki

Reactive oxygen species generated during physical exercise have traditionally been regarded as detrimental by-products of aerobic metabolism, contributing to the widespread use of antioxidant supplementation to attenuate oxidative stress, facilitate post-exercise recovery, and improve performance outcomes. Recent systematic reviews and meta-analyses demonstrate considerable heterogeneity in the efficacy of antioxidant interventions. This inconsistency appears to reflect differences in intervention characteristics and study designs, as well as substantial inter-individual biological variability. The present narrative review adopts a multidimensional perspective to examine the biological factors and mechanisms underlying heterogeneous responses to antioxidant supplementation in generally healthy physically active individuals, with particular emphasis on sex-related redox regulation, hormonal influences, baseline redox phenotype, training status, and other modifiers of antioxidant responsiveness. The core evidence comprises 21 publications, including 10 original human studies addressing hormonal status, age, physical activity, and redox-related outcomes, and 11 systematic reviews with or without meta-analysis examining supplementation in exercise settings; additional human and mechanistic evidence informs the narrative synthesis. Collectively, the findings support the rationale for precision antioxidant supplementation that accounts for individual biological characteristics, including sex and hormonal status, as well as exercise context and antioxidant-specific properties. Based on the current mechanistic and human evidence, we propose a conceptual framework in which antioxidant supplementation is tailored to individual biological characteristics, exercise demands, and compound-specific mechanisms while preserving adaptive redox signaling and limiting excessive oxidative stress.

Antioxidants doi: 10.3390/antiox15111379

Authors: Yuki Ogasawara Hiroki Morii Kaho Arai Tasuku Kayama Shin Koike

Human plasma contains trace amounts of bound sulfane sulfur (BS) and hydrogen sulfide ions (HS−), but reported concentrations vary widely depending on the analytical method used. Extremely high values have been obtained in methods that use alkaline treatment. To identify the underlying mechanism, human serum albumin (HSA) was incubated at various pH values, and the formation of BS and HS− was analyzed. Incubating HSA in PBS or buffer at pH 8.0–10.0 resulted in no significant changes, whereas BS formed rapidly under strongly alkaline conditions, followed by the generation of free HS− and a continuous increase in their concentrations. In contrast, when the number of thiol (–SH) groups derived from cysteine residues involved in intramolecular disulfide bonds in HSA was quantified after complete reduction, it decreased significantly by an amount corresponding to the total amount of BS and HS− formed. This indicates that the C–S bonds of the cysteine residues that originally formed intramolecular disulfides in HSA were cleaved by β-elimination, resulting in the formation of cysteine persulfide groups. Moreover, SDS–PAGE and SEC analyses revealed obvious structural changes which were indicative of fragmentation and degradation. Further, LC–MS/MS analysis revealed that some cysteine residues were converted to dehydroalanine (Dha) residues. These results suggest that the millimolar levels of polysulfide detected in plasma after alkaline treatment are likely artificial products resulting from the alkaline-induced degradation of intramolecular disulfide bonds within HSA. Therefore, strongly alkaline conditions should be avoided when analyzing BS and HS− in biological samples containing disulfide bonds.

Antioxidants doi: 10.3390/antiox15111378

Authors: Xingyu Wu Haiyan Shen Wenjie Li Ting Feng Ying Luo

Talinum paniculatum exhibits significant antioxidant capacity, however the specific bioactive metabolites and molecular mechanisms underlying this capacity remain to be elucidated. In this study, ethanol extracts from the underground parts (roots, TP-ER) and aerial parts (stems and leaves, TP-ESL) of T. paniculatum were prepared to determine total phenolic and flavonoid contents, as well as to conduct in vitro antioxidant assays, and evaluate the cytoprotective effect against H2O2-induced oxidative stress in HepG2 cells. In all assays, TP-ER exhibited higher activity than TP-ESL under the tested conditions. Subsequently, widely targeted metabolomics analysis was conducted on the two extracts to annotate their metabolites. Genes associated with oxidative damage were screened computationally using the Gene Expression Omnibus (GEO) database. Three p53 pathway genes (CDKN1A, JUN, and PMAIP1) were prioritized as candidate targets for further investigation. Quantitative Structure–Activity Relationship (QSAR) models were constructed as exploratory pooled classifiers using reported activity datasets from ChEMBL to prioritize annotated metabolites with potential activity within the combined p53-related target dataset. This classifier does not assign activity to individual targets. Three annotated metabolites were predicted to be potentially active, including two steroids and one alkaloid. Molecular docking prioritized N-Caffeoyl-4-O-methyldopamine and norflickinflimiod F as candidate metabolites with favorable predicted binding to PCNA/NFAT1 and the NOXA BH3 interface, respectively. These findings provide a preliminary chemical basis for further investigation of the antioxidant and cytoprotective effects of T. paniculatum and generate testable mechanistic hypotheses that require experimental validation in future studies.

Antioxidants doi: 10.3390/antiox15111377

Authors: Melinee D’Silva Christina Signoretti Monika Dzieciatkowska Angelo D’Alessandro Michael S. Wolin Sachin A. Gupte

Extracellular vesicles (EVs) released by cells carry a diverse molecular cargo, including proteins, lipids, nucleic acids, and mitochondria. In addition, EVs carry antioxidants and free radical-producing enzymes like NADPH oxidases or other oxidases. Growing evidence suggests that EV cargo plays a critical role in intercellular communication and disease pathogenesis. In pulmonary hypertension (PH), circulating EV levels are elevated; however, whether EVs transmit mitochondria and the composition of their protein cargo remain poorly understood. To address this knowledge gap, we characterized the cargo of EVs in a rat model of Sugen5416 (SU; 20 mg/kg, S.C.)- and hypoxia (10% O2)-induced PH. EVs were isolated from blood collected from the left ventricles of SU/hypoxia (SU/Hx) and SU/normoxia (SU/Nx) rats and analyzed using quantitative mass spectrometry-based proteomics and flow cytometry. Proteomic profiling revealed that EVs contain proteins involved in coagulation, complement, and immune signaling, metabolism, receptor signaling, and cytoskeletal organization. EVs from SU/Hx rats contained specific proteins involved in cytoskeletal structure, metabolism, immune signaling, and cell adhesion that were preferentially enriched and contained post-translational modifications. These molecular changes are possibly linked to underlying PH progression. Importantly, EVs from SU/Hx rats contained a significantly greater abundance of mitochondrial protein components, detected by mass spectrometry and a more hyperpolarized mitochondrial membrane potential as determined by the MitoTracker Red-to-MitoTracker Green signal ratio, while exhibiting lower levels of mitochondrial superoxide anions, as determined by MitoSOX fluorescence. Together, these findings demonstrate, for the first time, the presence of mitochondrial content and protein cargo in circulating EV-enriched preparations from an experimental PH model.

Antioxidants doi: 10.3390/antiox15111376

Authors: Seda Çelikel Taşci Bülent Bayraktar

Background: With its steadily rising global prevalence posing a profound public health challenge, obesity represents a complex disorder sustained by reciprocal disturbances in energy partitioning, glycemic control, adipokine–neuroendocrine signaling, cellular redox equilibrium, and organ integrity. The aim of this study was to evaluate the dose-dependent therapeutic effects of Garcinia mangostana pericarp extract (GME) in a high-fat-diet (HFD)-induced obesity model, focusing on adipokine patterns, redox balance, organ injury, and hepatic Nrf2/HO-1 levels. Methods: Sixty-four male Wistar albino rats were allocated into a 16-week 2 × 4 factorial design (n = 8/group): standard basal diet or 60%-kcal fat HFD, each concurrently administered vehicle or GME via daily oral gavage at 100, 200, or 300 mg/kg. Somatic growth parameters and fasting glycometabolic indices (glucose, insulin, HOMA-IR) were quantified. Circulating lipids, hepatorenal injury enzymes, regulatory peptides (spexin, asprosin, adiponectin, BDNF, irisin, GLP-1), and systemic/tissue redox markers (TAS, TOS, OSI, MDA, 4-HNE, 8-OHdG, enzymatic antioxidants) were determined via automated clinical chemistry analyzers, spectrophotometry, and specific ELISA kits. Hepatorenal histopathology, epididymal adipocyte morphometry, and hepatic nuclear Nrf2 and HO-1 abundance were quantitatively analyzed. Statistical evaluations were conducted using two-way factorial ANOVA assessing diet, treatment, and diet-by-treatment interactions, followed by Tukey’s post hoc test for multiplicity-adjusted comparisons (p < 0.05). Results: HFD feeding significantly increased final body weight, energy intake, fasting glucose, and marked insulin resistance (HOMA-IR: 7.89 vs. 1.69; p < 0.001), precipitating atherogenic dyslipidemia and hepatorenal injury relative to controls. This pathophysiology coincided with elevated circulating asprosin, alongside marked depletion of spexin, adiponectin, BDNF, enzymatic antioxidant defenses (SOD, CAT, GPx; all p < 0.001), and Nrf2/HO-1 levels. GME produced dose-dependent improvements across these metabolic disturbances (diet × treatment interaction: p < 0.001 for all primary outcomes). Relative to HFD controls, the 300 mg/kg dose reduced final body weight by 15.3% (p < 0.05), HOMA-IR by 69.5% (p < 0.001), triglycerides by 47.6% (p < 0.001), serum MDA by 55.4% (p < 0.001), and adipocyte diameter by 49.1% (p < 0.001), providing the most prominent improvements in hepatic steatosis, renal injury scores, and upregulation of nuclear Nrf2 (3.81-fold) and liver HO-1 (4.74-fold). Conversely, the 200 mg/kg dose was distinguished by maximizing neurotrophic support (peak BDNF elevation, +84.8% vs. HFD controls; p < 0.05) and effectively restoring circulating metabolic peptides (spexin and adiponectin) toward physiological levels. Conclusions: These findings indicate that GME supplementation dose-dependently attenuates high-fat-diet-induced metabolic dysfunction, a response accompanied in part by a concomitant reduction in daily energy intake. Among the evaluated regimens, the 300 mg/kg dose exhibited the most potent efficacy in improving glycemic control (HOMA-IR), circulating lipid profiles (triglycerides, total cholesterol, LDL-C), and parenchymal organ injury (hepatic steatosis and renal vacuolation). In contrast, the 200 mg/kg dose was distinguished by optimizing neurotrophic support and restoring suppressed adipokines toward physiological concentrations. Consequently, GME is anticipated and considered to provide valuable support to medical nutrition therapy and clinical dietetic management as a promising functional nutraceutical for counteracting diet-induced metabolic abnormalities; prospective clinical trials remain necessary to establish safety, bioavailability, and therapeutic dosing.

Antioxidants doi: 10.3390/antiox15111375

Authors: Yijie Ren Nan Huang Zheng Yuan Siya Peng Ying Liu Shuai Shao Qinqiu Zhang Wen Qin

Houttuynia cordata is used as food and medicine, yet integrated comparisons of the non-volatile chemical profiles and in vitro antioxidant capacities of its rhizomes and leaves remain limited. Ten rhizome (RZ) and ten leaf (LF) samples from 10 batches were compared using ultra-high-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UHPLC–Q-TOF–MS)-based untargeted metabolomics, Functional Analysis of full peak tables, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, total phenolic and flavonoid content assays, and four antioxidant assays. Clear separation occurred in both modes. In the original exploratory Welch-based screening, variable importance in projection (VIP) > 1, absolute log2 fold change > 1, and Benjamini–Hochberg-adjusted q < 0.05 yielded 436 and 232 differential features with putative annotations in positive and negative modes, respectively, with LF-enriched features predominating. Sixty-four of 65 flavonoid-related features were LF-enriched. Functional and KEGG analyses suggested that differences may involve amino acid metabolism, flavone and flavonol biosynthesis, and lipid-related processes. LF had higher total phenolic and flavonoid contents and greater radical-scavenging and ferric-reducing capacities than RZ (all q < 0.001). Prioritization based on LF enrichment, chemical class, and annotation quality yielded 20 phenolic and flavonoid features assigned to nine candidate annotation groups. These findings support differentiated quality evaluation and utilization of RZ and LF.

Antioxidants doi: 10.3390/antiox15111374

Authors: Baraa. Hamze Engin Sümer Alev Cumbul Ela Naz Köprülü Muhammed Hamitoğlu Hande Sipahi Issam Kassab Fouad Dabboussi Ahmet Aydın

Atorvastatin, a widely prescribed HMG-CoA reductase inhibitor, causes statin-associated muscle symptoms and, less commonly, hepatic and renal toxicity, effects attributed to mitochondrial dysfunction and oxidative stress; strategies to prevent this multisystem injury are needed. This study evaluated whether N-acetylcysteine (NAC) and coenzyme Q10 (CoQ10), alone and in combination, protect against atorvastatin-induced toxicity in male BALB/c mice and C2C12 myoblasts. Mice (n = 30) received, by oral gavage once daily for 14 days, vehicle, atorvastatin (100 mg/kg/day), atorvastatin plus NAC (200 mg/kg/day), atorvastatin plus CoQ10 (100 mg/kg/day), or the triple combination. Outcomes included survival, body weight, rotarod performance, serum creatine kinase, erythrocyte oxidative-stress markers, semi-quantitative histopathology, TUNEL apoptosis, and VEGF immunohistochemistry in liver, kidney, and skeletal muscle, complemented by in vitro atorvastatin cytotoxicity and antioxidant cytoprotection assays in C2C12 myoblasts (atorvastatin 50–200 µg/mL; CoQ10 12.5–50 µg/mL; NAC 100–400 µg/mL). Atorvastatin produced significant histopathological injury and increased apoptotic and VEGF immunoreactivity in all three tissues (p < 0.0001–0.005), effects markedly attenuated by combined NAC plus CoQ10. Glutathione peroxidase activity was significantly reduced by atorvastatin and restored by combination therapy (p < 0.05); catalase, malondialdehyde, and superoxide dismutase showed non-significant favorable trends. In C2C12 myoblasts, atorvastatin produced concentration-dependent cytotoxicity (IC50 ≈ 65 µg/mL), substantially reversed by NAC plus CoQ10 (≈89% viability restoration, p = 0.0025). These findings indicate that combined NAC and CoQ10 confer structural, apoptotic, and cytoprotective protection against atorvastatin-induced toxicity, supporting further mechanistic and translational investigation of combined antioxidant strategies in this high-dose supratherapeutic model; extrapolation to routine clinical statin intolerance will require confirmation at clinically relevant exposures.

Antioxidants doi: 10.3390/antiox15111373

Authors: Panfeng Yao Wenlin Li Yongwei Zhao Zhanshu Song Jianguo Wei Ying Wang Chao Sun Zhenzhen Bi Zhen Liu Han Wang Jiangping Bai Junmei Cui Yuhui Liu

Drought stress triggers an excessive reactive oxygen species burst, disturbs cellular redox homeostasis, and impairs potato (Solanum tuberosum L.) growth, tuber yields, and quality. Exogenous betaine (Bet) is an effective osmoprotectant mitigating abiotic stress injury in many crops; however, the systematic evaluation of Bet application conditions and its molecular mechanisms in drought-stressed potato remains limited. In this study, morphological and physiological assays were used to screen the optimal Bet concentration and effective foliar-spraying growth stage. Foliar 10 mM Bet exerted the strongest protection, restoring plant growth, enhancing antioxidant enzyme activities, and strengthening antioxidant defense to limit the further progression of drought-associated oxidative injury. Relative to the drought-only control, 10 mM Bet applied at the maturation stage markedly improved photosynthetic performance, tuber yields, and nutritional quality. Transcriptomic profiling revealed that Bet reversed drought-triggered transcriptional perturbations and activated antioxidant, cell-wall remodeling, and hormone signal-transduction pathways. Weighted gene co-expression network analysis identified three key modules linked to drought tolerance and Bet-mediated mitigation. Six hub genes, including StGS2 (antioxidant-associated function), StXTH5 (cell-wall modification), StLOX1 (stress signaling), and StCERK1 (stress perception), were validated via RT-qPCR as candidate genes associated with the betaine-responsive drought response. Mechanistically, Bet strengthened reactive oxygen species-scavenging capacity to limit the further progression of drought-associated oxidative injury, alleviated drought-induced photosynthetic inhibition and maintained photosynthetic functions, and modulated stress-related hub-gene expression. These findings show that exogenous Bet alleviates drought damage by coordinating multi-level physiological and molecular pathways, providing a feasible agronomic practice for water-limited potato production and a molecular reference for Bet-regulated drought tolerance in tuber crops.

Antioxidants doi: 10.3390/antiox15111372

Authors: Napapan Kangwan Wittaya Chaiwangyen Sarawut Kongkarnka Pilaiporn Thippraphan Amnart Onsa-Ard Piyawan Nuntaboon Thanawat Pattananandecha Young-Joon Surh Chalermpong Saenjum

Houttuynia cordata is commonly consumed as an herb and traditional medicinal ingredient in Asian regions. Although fermented products of H. cordata are gaining popularity as natural health products, their effects in experimental models of colitis remain unclear. This study investigated the protective effects of fermented H. cordata extract (FHE) and fermented H. cordata juice (FHJ) in dextran sulfate sodium (DSS)-induced colitis mice. The bioactive compounds in FHE and FHJ were analyzed via HPLC, confirmed via MS, and compared with those in non-fermented H. cordata extract. The fermented products contained higher levels of gallic acid, quercetin, isoquercitrin, and organic acids, including lactic, glucuronic, butyric, and acetic acids, whereas their caffeic acid, rutin, total phenolic, and total flavonoid contents were lower. In an animal study, male C57BL/6 mice were administered 500 or 1000 mg/kg of FHE and 200 or 400 mg/kg of FHJ as low and high doses for 23 days, with 2.5% DSS in the drinking water on days 15–21 followed by drinking water without DSS on days 22–23. Pretreatment with FHE and FHJ ameliorated the severity of the induced colitis, as indicated by reduced weight loss, decreased disease activity index, restored colon length (8.82 ± 0.29 cm with FHJ 400 mg/kg versus 7.53 ± 0.08 cm in the DSS group, p < 0.001), and protection against histopathological injury, most evidently with the FHE 500 mg/kg and FHJ 400 mg/kg treatments. Intestinal barrier integrity was maintained as shown by decreased permeability to FITC-dextran (570 ± 56 ng/mL with FHJ 400 mg/kg versus 1963 ± 183 ng/mL with DSS group, p < 0.001), elevated levels of colonic Muc2 mRNA (with FHJ at both doses), and upregulation of the tight junction proteins ZO-1 (with FHE at 1000 mg/kg) and claudin-1 (with FHE at both doses and FHJ at 400 mg/kg). Moreover, pretreatment with both FHE and FHJ diminished colonic mRNA expression of TNF-α and IL-1β, whereas IL-6 was reduced under the FHE treatment only, accompanied by reduced colonic TLR4 expression with FHE at 1000 mg/kg and with FHJ at both doses. The phosphorylated-total ratios of IκB-α and NF-κB p65 did not differ significantly between groups. FHE and FHJ played protective roles against DSS-induced colitis, which is associated with the preservation of gut barrier function and reduced colonic TLR4 expression.

Antioxidants doi: 10.3390/antiox15111371

Authors: Mohammed Zayed Hadeer Khaled Hilal Tayara Byung-Hoon Jeong

Tendinopathy is a complex disorder involving inflammation, oxidative stress, extracellular matrix damage, and changes in cellular metabolism. Cuproptosis is a type of regulated cell death that depends on copper and is associated with mitochondrial protein lipoylation and proteotoxic stress. This study investigated whether IL-1β-induced dysfunction of tendon progenitor cells (TPCs) is accompanied by changes in cuproptosis-associated genes and whether pharmacological modulation of copper availability alters this phenotype. Rat TPCs were stimulated with IL-1β, exposed to copper chloride (CuCl2) and the copper ionophore elesclomol (ES), and cotreated with the copper chelator tetrathiomolybdate (TTM). Cellular metabolic activity, gene expression, and reactive oxygen species (ROS) production were assessed. Bulk RNA-sequencing data from IL-1β-treated rat TPCs (GSE253913) and single-cell RNA-sequencing data from cultured human tendon-derived progenitor cells (GSE150482) were analyzed. In rats, transcriptomic analysis showed mainly an inflammatory response to IL-1β, with only slight changes in genes associated with copper and mitochondrial functions. IL-1β decreased TPC metabolic activity and the expression of tenogenic markers such as Scx, Col1a1, and Col3a1, while it increased inflammatory and catabolic markers, ROS production, and the expression of Dld and Lipt1. TTM attenuated these effects, restoring metabolic activity and some tenogenic markers, and reducing ROS, Dld, and Lipt1 levels. Exposure to ES + Cu triggered a TTM-sensitive phenotype characterized by reduced metabolic activity, decreased expression of tenogenic genes, increased ROS levels, and altered expression of cuproptosis-related genes. The human single-cell dataset analysis also revealed condition-dependent changes in mitochondrial lipoylation genes, including DLAT and DLST. Overall, these findings suggest that inflammatory TPC dysfunction is linked to copper-sensitive mitochondrial stress and gene changes related to cuproptosis pathways.

Antioxidants doi: 10.3390/antiox15111370

Authors: Woo Ri Cho Tae-Yong Koh Ji-Seok Yoon Hye-Yoon Jeon Juha Lee Minsoo Kim Sunyoung Park Kwon-Soo Ha

Diabetic retinopathy (DR) is a metabolic disease of the neurovascular unit, in which retinal microvascular dysfunction and neurodegeneration are interconnected processes that contribute to disease progression. Oxidative stress is a major pathogenic driver of DR; however, whether reactive oxygen species (ROS)-mediated microvascular leakage directly contributes to retinal neurodegeneration remains unclear. Here, we investigated whether targeting ROS-mediated microvascular leakage through inhibition of the ROS–transglutaminase 2 (TGase2) pathway can ameliorate hyperglycemia-induced retinal neurodegeneration in human retinal endothelial cells (HRECs) and diabetic mice. In HRECs, ROS-dependent activation of TGase2 was required for endothelial hyperpermeability. In diabetic mouse retinas, hyperglycemia induced TGase2 activation, stress fiber formation, vascular endothelial-cadherin disassembly, and microvascular leakage, all of which were effectively suppressed by pharmacological inhibition of the ROS-TGase2 pathway or TGase2-specific siRNA. Consistently, diabetic TGase2-null mice exhibited complete protection against retinal microvascular leakage. In contrast, pharmacological inhibition or genetic deletion of TGase2 failed to suppress hyperglycemia-induced inflammatory responses, reactive gliosis, retinal ganglion cell apoptosis, or retinal thinning in diabetic mice. These findings reveal that oxidative stress induces distinct downstream responses in the retinal vasculature and neural retina. TGase2 is a critical effector of ROS-dependent microvascular leakage but is dispensable for hyperglycemia-induced retinal neurodegeneration. Thus, suppression of ROS–TGase2-mediated microvascular dysfunction alone is insufficient to prevent retinal neurodegeneration, indicating that vascular leakage and neurodegeneration are mechanistically dissociable consequences of oxidative stress in DR.

Antioxidants doi: 10.3390/antiox15111369

Authors: Agnieszka Polecka Urszula Cwalina Ewa Olszewska

Obstructive sleep apnea (OSA) and heart failure (HF) share pathways involving intermittent hypoxia and oxidative stress. This randomized clinical trial with blinded endpoint assessment evaluated systemic oxidative balance during sequential treatment with empagliflozin and continuous positive airway pressure (CPAP). Seventy adults with HF and predominantly obstructive OSA were randomized to empagliflozin 10 mg daily plus background HF therapy (n = 37) or background therapy alone (n = 33). Assessments were performed at baseline, month 3, and month 6; CPAP was initiated in both groups after month 3. The primary endpoint was the between-group difference in AHI change from baseline to month 3, estimated using a baseline-adjusted linear mixed-effects model. TOS, TAS, and OSI were exploratory outcomes. Median AHI (IQR) in the study and control groups was 58.9 (28.5–70.3) and 55.0 (29.9–67.8) at baseline, and 44.2 (22.4–59.3) and 52.2 (30.8–70.2) at month 3, respectively. The baseline-adjusted between-group difference in AHI change from baseline to month 3 was −11.04 (95% CI −16.72 to −5.35; p < 0.001). The exploratory mixed-effects models showed lower TOS and OSI and higher TAS in the study group at both follow-up visits (all p < 0.001). Empagliflozin initiation was associated with early reductions in AHI and improvements in exploratory markers of systemic oxidative balance before CPAP initiation. Although the shared CPAP phase did not allow separation of drug and CPAP effects, these findings support further investigation of the respiratory and redox effects of empagliflozin in patients with coexisting HF and OSA.

Antioxidants doi: 10.3390/antiox15101367

Authors: Dong-Hee Choi In-Ae Choi

Cognitive impairment is a major non-motor manifestation of Parkinson’s disease (PD); however, evidence linking specific NADPH oxidase (NOX) isoforms to cognition-related outcomes remains incompletely integrated. In this evidence-focused narrative review, a structured four-database search identified 12 studies for study-level synthesis: 10 rodent studies involving cognitive assessment in PD-relevant models and 2 contextual studies. The 10 core studies were appraised according to the directness with which NOX involvement was examined in relation to cognitive outcomes. The most direct experimental support centered on hippocampal NOX4- and NOX2/gp91phox-associated microglial signaling. Dentate-gyrus-targeted NOX4 knockdown attenuated learning and memory deficits, with concurrent reductions in proteinopathy-related changes. CD68-driven gp91phox knockdown similarly attenuated these deficits alongside reductions in inflammatory responses and neuronal and synaptic injury. Apocynin was classified as a NOX-targeted pharmacological intervention and improved learning and memory performance. However, its lack of target and isoform specificity precluded definitive attribution of the behavioral effect to NOX inhibition. Other studies contributed partial or supportive evidence, while complementary pathway-level evidence linked cognition-related inflammatory signaling to NOX1/NOX2 dependence. Human postmortem and canine biomarker studies have provided clinicopathological and comparative peripheral biomarker context, respectively, but they have not established a NOX–cognition relationship in human PD. Overall, the evidence suggests that NOX-related oxidative stress contributes to the development of learning and memory deficits in PD-relevant models. Because the principal NOX4 and gp91phox genetic interventions preceded model induction, the observed effects are best interpreted as protection during deficit development rather than reversal of established cognitive impairment. Cross-model validation, NOX-directed interventions initiated after cognitive impairment has been confirmed, and studies in cognitively characterized human PD cohorts are needed to establish translational relevance.

Antioxidants doi: 10.3390/antiox15101368

Authors: Sophia Rusch Patricia Mester Fabian Möller Martina Müller Karsten Gülow

Acute respiratory distress syndrome (ARDS) is the final common phenotype of diverse insults, but the route to alveolar–capillary barrier failure matters. Sepsis and severe acute pancreatitis provide an informative contrast: sepsis begins with infection and pathogen-associated molecular patterns, whereas pancreatitis is initially driven by sterile acinar-cell injury, necrosis and damage-associated molecular patterns, before infected necrosis can superimpose sepsis biology. These differences are clinically relevant since they determine whether redox-related signals must be interpreted in the context of pathogen burden and antimicrobial host defense or of initially sterile necrosis with subsequent risk of infected necrosis. In this review, we discuss how these distinct pathophysiological contexts engage NADPH oxidase (NOX)-derived oxidants, mitochondrial reactive oxygen species, reactive nitrogen species (RNS), lipid peroxidation, regulated cell death and impaired antioxidant defenses. We focus on the pulmonary endothelium and epithelium as compartments in which inflammatory and redox signals converge to disrupt barrier integrity, impair alveolar fluid clearance and promote immunothrombosis. We also discuss coronavirus disease 2019 (COVID-19)-associated ARDS as a viral comparator, the analytical limitations of redox biomarkers, and the value of serial, compartment-aware measurements. The central message is that oxidative stress is not a single systemic deficiency that can be corrected by generic antioxidants. Its biological and therapeutic significance depends on oxidant source, cellular compartment, microbial burden and disease phase. However, evidence for many specific redox pathways remains predominantly preclinical, and their clinical relevance requires further validation. At present, no validated redox-directed treatment-selection strategy exists; future approaches will therefore require validated target-engagement markers and phenotype- and time-specific trial designs.

Antioxidants doi: 10.3390/antiox15101366

Authors: Wenzhuo Ma Joseph Owusu-Sarfo Zhiqi Zhang Scarlett M. Silvia Brenda Cordeiro Lauren F. Bazinet Thomas Mancini Benison C. Aguocha Ahmed Aboulgheit Jin O-Uchi Bong Sook Jhun Afshin Ehsan Gaurav Choudhary Frank W. Sellke Jun Feng Martin Kolodziejczack Dmitry Terentyev Neel R. Sodha Richard T. Clements

Cardiac surgery or transplant using cardioplegic arrest and cardiopulmonary bypass (CP/CPB) subjects the heart to mild reversible ischemic injury that results in pronounced myocardial stunning. Mitochondrial large conductance calcium-activated K+ channels (BKCa) in cardiomyocytes are potently cardioprotective and beneficially modulate respiration and ROS post-I/R injury. However, how BKCa-dependent K+ flux regulates ROS and respiration is unclear. We evaluated the BKCa activator rottlerin in a preclinical large animal pig CP/CPB model of myocardial stunning and evaluated BKCa-dependent cardioprotective mechanisms in vitro and in vivo. BKCa activation with the small molecule rottlerin significantly improved LV cardiac functional recovery and contractility at 1 h reperfusion. TEM showed larger mitochondria in the rottlerin group consistent with K+ influx. We also found that pigs with rottlerin treatment had increased electron transport chain supercomplexes (mSCs), which are thought to improve respiratory efficiency and reduce ROS. Consistent with increased mSC, rottlerin reduced ROS-dependent protein modification in CP/CPB pigs. In complementary studies, rottlerin and/or adenoviral overexpression of a mutant mito-BKCa increased respiration, altered mitochondrial morphology, increased mSC assembly, and significantly reduced ROS following in vitro CP/reoxygenation, similar to CP/CPB pigs. In summary, mito-BKCa activation increases mSCs and respiration while reducing ROS, suggesting that mSC-dependent improved respiratory efficiency promotes robust cardioprotection.

Antioxidants doi: 10.3390/antiox15101365

Authors: Dinu Stefan Justine Lequesne Frédéric Pouzoulet Ludovic De Marzi Frédérique Mégnin-Chanet François Christy Cyril Moignier Bénédicte Clarisse Victor Barraux Mathilde Lechevrel Stéphanie Gente François Sichel Carine Laurent

Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor with established radiosensitizing properties, is a candidate for combination with radiotherapy, yet its multi-organ oxidative toxicity when combined with photon versus proton irradiation has not been characterized. In the ToxIP3 project, C57BL/6 male mice were allocated to six groups (n = 10 per group) receiving whole-body irradiation at 7.5 Gy by photons (TrueBeam™) or protons (190.6 MeV, Institut Curie, Orsay), with or without concurrent oral olaparib (50 mg/kg/day). Seventy-four biomarkers spanning protein carbonylation, lipid peroxidation, antioxidant enzyme activities, glutathione redox status, PARP activity, total protein, TGF-β1, and 13 plasma cytokines were quantified across nine compartments. The principal comparison (protons + olaparib vs. photons + olaparib) used two-sided Wilcoxon–Mann–Whitney tests with Benjamini–Hochberg false discovery rate (FDR) correction; time-shifted comparisons used rank-based ANCOVA adjusted for the day of sacrifice. Combination arms showed markedly increased lethality (median survival 9 days for photons + olaparib and 8 days for protons + olaparib in all 60 randomized animals); 54 mice were available for biomarker analysis. Of 74 biomarkers, 18 differed between combination arms after FDR correction; seven hepatic protein-normalized measurements were considered non-interpretable, leaving 11. Protons + olaparib was associated with higher intestinal GPx and GSH/GSSG, higher erythrocyte GSH, GSSG and SOD, higher cerebral SOD (+75.1%, q = 0.010), and a higher hepatic GSH/GSSG ratio (+108.2%, q < 0.001), whereas skin showed a lower GSH/GSSG ratio (−77.6%) and higher protein carbonylation (+142.9%). These exploratory findings, obtained in a near-lethal whole-body irradiation model, show modality-associated differences in redox biomarkers but do not establish differences in normal-tissue toxicity.

Antioxidants doi: 10.3390/antiox15101364

Authors: Manuel Castillejos-López Ulises Barrera-Elizalde Edgar Flores-Soto Luz A. Colín-Godínez Luz María Torres-Espíndola Bianca S. Romero-Martinez Joel Guzmán-Castillo Georgina González-Avila Erika Rubí Luis-García Fausto Rojas-Duran Jesús Antonio Lara-Reyes Víctor Ruiz Arnoldo Aquino-Gálvez

Lung adenocarcinoma (LUAD) exhibits metabolic flexibility that transcends the classical interpretation of the Warburg effect. This review proposes the concept of “adaptive mitochondrial specialization (AMS)”, an integrative framework in which mitochondria undergo coordinated, context-dependent remodeling of bioenergetic metabolism, redox homeostasis, architecture and dynamics, proteostasis, mitochondrial genome maintenance and translation, and inter-organelle communication in response to hypoxia and other tumor-associated stressors. We examine how hypoxia can promote this adaptive state through HIF-dependent metabolic reprogramming together with intrinsic mitochondrial stress responses, including respiratory-chain remodeling, proteostatic regulation, and context-dependent control of reactive oxygen species (ROS). We further discuss mitochondrial genome and translational maintenance, fusion/fission dynamics, apoptotic susceptibility, and mitochondria-associated membrane (MAM) signaling as mechanisms through which mitochondrial function can be adjusted to environmental and therapeutic stress. Beyond tumor cells, we examine how mitochondrial quality-control alterations accompany systemic metabolic remodeling during cancer cachexia and how impaired mitophagy and intercellular mitochondrial transfer can influence antitumor T-cell function. These tumor–host manifestations are considered consequences or interacting mechanisms of cancer-associated mitochondrial remodeling rather than defining criteria of AMS. Finally, we discuss how context-dependent mitochondrial and redox dependencies may expose therapeutic vulnerabilities and provide a rationale for bioenergetic stratification in precision oncology.

Antioxidants doi: 10.3390/antiox15101363

Authors: André Felipe Câmara Amaral Karen Chrockatt de Sá Dantas Maria Luíza Soccio Bezerra Vera Lúcia Perussi Polez Luciano Paulino Silva

Oxidative stress and industrial water pollution represent critical global challenges that demand the development of sustainable, multitarget remediation platforms. This study addresses the existing knowledge gap regarding the modulation of green-synthesized iron nanostructures by secondary transition metals through the fabrication of silver–iron (AgFe), cobalt–iron (CoFe), and copper–iron (CuFe) bimetallic oxide formulations using Anacardium occidentale L. pericarp extracts as dual-functional reducing and capping agents. Characterization was performed using UV-Vis, DLS, AFM, Raman, FTIR, and XRD techniques to elucidate their structural properties. Our results demonstrate that phytochemicals within the agro-industrial byproduct facilitated the formation of stable, spherical bimetallic oxide nanostructures. The CuFe formulation exhibited the highest catalytic activity, achieving 99.1% conversion/reduction of 4-nitrophenol within 6.3 min. Furthermore, all bimetallic oxide formulations demonstrated superior radical scavenging capacity, as evidenced by FRAP/DPPH assays, confirming the synergistic effect of the secondary metals on electron-transfer kinetics. These findings indicate that the integration of secondary metals significantly enhances the performance of biogenic iron-based oxide nanoparticles. Consequently, this study establishes an eco-friendly protocol for the production of bimetallic oxide nanostructures, providing a robust, dual-purpose platform for both environmental remediation and advanced biomedical antioxidant applications.

Antioxidants doi: 10.3390/antiox15101362

Authors: Hongjie Cui Yingyi Wu Chuhan Shao Cheng Zhang Shuying Lin Kaizhao Zhang Xiaohong Huang

Ochratoxin A (OTA) damages renal epithelial cells and disrupts redox homeostasis. We examined whether curcumin (Cur) reduces OTA-induced injury in porcine kidney epithelial PK-15 cells and whether protection accompanies changes in antioxidant expression. Preliminary concentration screening gave an OTA half-maximal inhibitory concentration (IC50) of 10.83 μg/mL. Cells received OTA (8 μg/mL), Cur (10 μmol/L), their combination, or control treatment. Cell viability, apoptosis, oxidant burden, mitochondrial membrane potential, and biochemical markers were assessed alongside quantitative reverse-transcription PCR (qRT-PCR) and Western blotting. A previously published RNA-sequencing dataset was reanalyzed to examine redox-related responses. OTA reduced viability and mitochondrial membrane potential, increased apoptosis, and impaired antioxidant defenses. Cur attenuated these changes, lowered oxidant-associated fluorescence, malondialdehyde, and lactate dehydrogenase release, and improved glutathione status. The shared RNA-sequencing dataset contained 11,707 differentially expressed genes in OTA versus control and 498 in OTA+Cur versus OTA, with 380 genes common to both comparisons. Targeted assays showed higher Nrf2, NQO1, and HO-1 mRNA and total-protein abundance with Cur than with OTA alone. These results associate Cur-mediated protection with recovery of antioxidant expression in PK-15 cells. They do not establish Nrf2 activation or a causal requirement for this pathway.

Antioxidants doi: 10.3390/antiox15101361

Authors: Sang-Yong Han Su-Jin Kim Geun-Ah Jo Se-Geon Oh Ji-Ye Kee

Santalol (STL), a sesquiterpene alcohol extracted from sandalwood oil, has reported antioxidant, anti-inflammatory, and anticancer effects. Nevertheless, the influence of this compound on lung metastasis of colorectal cancer (CRC) cells has not been insufficiently elucidated. In this study, we investigated the anticancer activity of STL in metastatic CRC cells. STL significantly reduced cell viability and clonogenic capacity in a dose-dependent manner. This compound induced mitochondria-mediated apoptosis of CRC cells by regulating caspases and PARP. In addition, it reduced total antioxidant capacity and increased reactive oxygen species (ROS) levels. These results indicate that STL can enhance mitochondrial depolarization and activate the mitochondrial apoptotic pathway. Using an in vivo murine model, we further demonstrated that STL restricted the pulmonary dissemination of CRC cells. Taken together, these findings reveal that STL hinders lung metastasis of CRC cells via the induction of apoptosis and mitochondrial dysfunction driven by intracellular ROS accumulation. Our findings support STL as a promising therapeutic candidate for metastatic CRC.

Antioxidants doi: 10.3390/antiox15101360

Authors: Hugo S. Díaz Katherine V. Pereyra Karla G. Schwarz Rodrigo Iturriaga Rodrigo Del Rio

Background: It is not well-known whether cardiovascular alterations elicited by adolescent binge drinking (ABD) are reversible or if they persist following long-term abstinence until adult life. Thus, we studied the long-term impact of ABD on oxidative stress, inflammation and cardiovascular function. Methods: Twenty-four adolescent Sprague-Dawley rats underwent a controlled or ABD-like protocol, (ethanol 3.00 g/kg i.p.) starting at postnatal day 25 (PND25) to PND38, followed by long-term abstinence until PND70 (adulthood). Results: ABD resulted in overt cardiac dysfunction in adult rats. We found a decreased left ventricular compliance as evidenced by a marked reduction in the early-to-late mitral valve blood flow (E/A: 1.23 ± 0.14 vs. 1.51 ± 0.09, control vs. ABD, p < 0.05). Importantly, cardiac dysfunction was closely linked to adverse cardiac remodeling and fibrosis in ABD animals compared to control animals. Furthermore, we found that ABD resulted in a significant increase in cardiac arrhythmogenesis. Indeed, ABD rats showed a 2-fold increase in the incidence of cardiac arrhythmias compared to control rats (53.6 ± 12.7 vs. 21.7 ± 5.7 events/h, Control vs. ABD, p < 0.05). Finally, we found that cardiac functional impairments were accompanied by increases in cardiac tissue oxidative stress and upregulated levels of pro-inflammatory cytokines (i.e., IL-1β and TNF-α). Conclusions: Present results show that ABD drives long-lasting cardiac dysfunction that persists during early adulthood. Oxidative stress and inflammation may contribute to long-term cardiovascular alterations induced by ABD.

Antioxidants doi: 10.3390/antiox15101359

Authors: Yanting Lu Mengchao Zhang Shuang Liang Mingming Wu Jing Ye Shenghai Ye Bingkui Wang

To investigate the effects of exogenous growth regulators on the growth of rice seedlings from irradiated seeds and to provide a reference for mutation breeding, Zhejing 100 rice seeds were irradiated with gamma rays at the median lethal dose and then soaked in solutions containing naphthalene acetic acid (NAA), indolebutyric acid (IBA), or NAA and IBA. Soaking seeds in a solution containing NAA alone or combined with IBA significantly decreased superoxide anion (O2•−), hydrogen peroxide (H2O2), and malondialdehyde contents in rice seedlings. Treatments with exogenous growth regulators at appropriate concentrations significantly enhanced antioxidant enzyme activities (e.g., superoxide dismutase, peroxidase, and ascorbate peroxidase) as well as proline, ascorbic acid, and glutathione contents, thereby increasing seedling survival rates after radiation-induced mutagenesis. Non-targeted metabolomic analyses revealed that in seedlings from irradiated seeds treated with NAA, IBA, or NAA and IBA, the two most abundant metabolite categories were lipids/lipid-like molecules and phenylpropanoids/polyketides, both of which are closely associated with antioxidant metabolism in plants. NAA and IBA also participated in the regulation of flavone and flavonol biosynthesis, flavonoid biosynthesis, purine metabolism, and zeatin biosynthesis, with positive effects on the ability of seedlings to repair damage due to irradiation. Soaking irradiated seeds in an NAA solution (0.2–0.4 mg/L) or a solution containing both NAA (0.1–0.4 mg/L) and IBA (0.25–1.0 mg/L) yielded the best results.

Antioxidants doi: 10.3390/antiox15101358

Authors: Jun-Ho Lee Inkyou Seo Seung-Ug Hong Sungyoul Choi

Trigeminal neuralgia is classically explained by neurovascular compression, focal demyelination, and pathological hyperexcitability, but emerging evidence suggests that oxidative stress may form a modifiable molecular layer within this framework. Cerebrospinal fluid from patients contains elevated lipid-peroxidation products capable of activating transient receptor potential ankyrin 1 (TRPA1), a redox-sensitive pain-sensing ion channel, while experimental trigeminal injury studies show that manipulation of nuclear factor erythroid 2-related factor 2 (NRF2) signaling and its downstream effector heme oxygenase-1 can reduce allodynia, oxidative injury, pyroptosis, and satellite glial-cell activation. This review organizes trigeminal redox biology around NRF2-centered antioxidant signaling, in which Kelch-like ECH-associated protein 1 regulates NRF2-dependent transcription through antioxidant response elements, and examines its intersection with TRPA1 and the voltage-gated sodium channel Nav1.7. We then evaluate plant-derived compounds and herbal medicines against this framework. The available evidence remains asymmetric: compounds tested in trigeminal models rarely include causal redox endpoints, whereas compounds with strong NRF2-linked analgesic evidence have largely been studied outside the trigeminal system. A limited multiscale network-pharmacology case study prioritizes Cistanchis Herba as a redox-relevant herbal candidate. Independent pharmacological evidence further identifies its constituent echinacoside as the primary translational compound for trigeminal evaluation, whereas hydroxytyrosol is better regarded as a secondary metabolite-exposure hypothesis. These findings define testable hypotheses rather than established treatments and support experimental evaluation of NRF2-targeted, plant-derived adjunctive strategies in trigeminal neuropathic pain.

Antioxidants doi: 10.3390/antiox15101357

Authors: Irene Patrono Margherita Sonnessa Marco Trerotola Anna Maria Giudetti Simona De Summa Francesco Alfredo Zito Concetta Saponaro Daniele Vergara

The transition from physiological cellular senescence to malignancy is not an isolated event, but a gradual, systemic remodeling of the biological landscape orchestrated by the persistent state of inflammaging. As detailed in this review, senescent populations do not remain passive. Through the chronic deployment of the senescence-associated secretory phenotype (SASP), they actively dismantle tissue architecture and convert healthy organs into a highly permissive pro-tumorigenic “soil”. This cross-talk is mediated by a complex network of signaling cascades including the IL-1 family, IL-6 and TNF-α, CXCL10 and CCL2-CCR2 chemokine axes, and MMPs. Crucially, this cellular decay is reinforced by a profound metabolic shift toward a hyper-glycolytic “metabolic SASP,” where extracellular lactate accumulation and prostaglandin synthesis permanently sustain the senescent state. Cellular senescence through the persistent accumulation of senescent cells and the accompanying age-related decline in immune surveillance drive “inflammaging”, a chronic, low-grade systemic inflammation that serves as a primary mechanistic bridge fueling the aging–cancer cycle.

Antioxidants doi: 10.3390/antiox15101356

Authors: Yuankun Deng Chengming Wang Yunlong Meng Yulong Yin Jing Wang Qiuping Ye

Oxidative stress (OS) is closely associated with intestinal dysfunction, gut microbial dysbiosis, and metabolic disturbances in weaned piglets. Ellagic acid (EA) is a dietary polyphenol with antioxidant properties. This study investigated the effects of EA supplementation and ampicillin (AMP)-induced microbial perturbation on OS, gut microbiota, and tryptophan (Trp) metabolism in paraquat (PQ)-challenged piglets. Twenty-four weaned piglets were assigned to four treatments in a 2 × 2 factorial design (±EA, ±AMP), followed by a PQ challenge. Neither EA nor AMP affected growth performance or most serum biochemical parameters. EA significantly decreased malondialdehyde (MDA) in AMP-treated piglets. AMP altered ileal morphology and reshaped the microbial community in both the ileum and colon. Moreover, EA and AMP differentially affected Trp metabolism in serum and intestinal segments; AMP altered kynurenine-pathway and microbiota-associated indole metabolites, with significant EA × AMP interactions for some metabolites. Spearman analysis further revealed distinct associations between gut microbiota and Trp metabolites along the intestinal tract. Collectively, AMP-induced microbial perturbation was accompanied by substantial Trp-metabolism alterations and distinct microbiota–Trp associations, whereas EA modulated MDA levels and selected microbial and metabolic responses under AMP treatment. These observations suggest that EA effects under OS may be associated with gut microbiota-Trp metabolism axis modulation, although causality remains to be established.

Antioxidants doi: 10.3390/antiox15101355

Authors: Remigio López-Solís Eliana Seguel-Rubio Claudio Muñoz-Pérez Mónica Vergara-López Rocío Belmar-Díaz Marcela Medel-Marabolí Danilo Aros-Orellana Jaime Laqui-Estaña Elías Obreque-Slier

This comparative literature review evaluated the polyphenolic profiles in seeds, skins, and wines of nine Vitis vinifera L. cultivars. The data compilation revealed that total tannins and catechin exhibited comparatively more homogeneous phenolic profiles in seeds than skins, suggesting differential tissue regulation of specific phenolic biosynthetic pathways within the berry. However, this pattern did not extend to total phenols or epicatechin. Furthermore, the results confirmed wide inter- and intra-cultivar polyphenolic variations, with intra-cultivar dispersion frequently reaching a magnitude comparable to, or exceeding, that observed between cultivars. These variations are likely related to the multifactorial effect of environmental, genetic, and cultural contexts on polyphenol concentration in grapes and wines due to methodological differences (extraction protocols, various quantification techniques and winemaking practices) and biological factors (edaphic and climatic conditions). Furthermore, this high inter- and intra-cultivar variability leads to overlapping concentration ranges, preventing strict varietal categorization. This demonstrates that each study represents only a snapshot of specific environmental and agricultural conditions. Consequently, this review underscores that standardized analytical protocols, rigorous experimental designs, and robust biological replication are essential to distinguish between experimental noise and biological variability, reinforcing the value of comprehensive phenolic profiles for genotypic characterization and targeted winemaking decisions.

Antioxidants doi: 10.3390/antiox15101354

Authors: Jialing Zhang Ting Zhang Azhar Dzulhadj B. Arafah Sora Lee Michelle Yam Jingwen Zeng Chen-Chin Chang Xiaosuo Wang Mark C. Gillies Ling Zhu

MAFF is a small MAF family transcription factor involved in antioxidant signaling and cytoprotective gene regulation. MAFF is differentially expressed across retinal regions, with particularly low expression in macular Müller cells, which play a central role in retinal redox balance. Reduced MAFF expression may weaken macular resilience to oxidative stress (OS), increasing susceptibility to age-related macular degeneration (AMD) and macular telangiectasia type 2. However, the function of MAFF in Müller cells remains unclear. Human primary Müller cells (huPMCs) from non-diseased human donor eyes were used to investigate MAFF modulation under stress. Cells were transfected with MAFF plasmid DNA to evaluate intracellular reactive oxygen species (ROS) following H2O2-induced stress. For functional and proteomic analyses, MAFF was overexpressed using mRNA or knocked down using siRNA and validated by Western blot. huPMCs were exposed to light stress and cell viability was assessed using the AlamarBlue assay. Molecular changes were characterized by liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based quantitative proteomics. MAFF upregulation significantly reduced intracellular ROS following H2O2-induced stress. MAFF protein expression decreased following siRNA-mediated knockdown (KD) and increased following mRNA-mediated overexpression (OE). MAFF OE improved Müller cell viability under light stress, whereas MAFF KD reduced viability. Exploratory proteomic profiling quantified 5907 proteins and identified candidate molecular changes associated with MAFF expression. Pathway analyses suggested that reduced MAFF expression was associated with oxidative-stress response signatures, whereas elevated MAFF expression was associated with changes in mitochondrial and immune/inflammatory pathways. KEAP1, BMP2K, VPS28, and PDCD4 were negatively associated with MAFF expression, suggesting potential regulation of antioxidant defense, vesicle trafficking, and apoptosis-related processes. Elevated MAFF expression was associated with reduced ROS accumulation and improved cell viability, while exploratory proteomic analysis identified changes in mitochondrial, oxidative-stress, and immune/inflammatory pathways. These findings support further investigation of MAFF as a contributor to macular stress susceptibility and as a candidate for future therapeutic studies.

Antioxidants doi: 10.3390/antiox15101353

Authors: Sandra Budziak Monika Kloza Przemysław Baranowski Oskar Antoniak Aniqa Saiyara Marta Żarczyńska-Buchowiecka Marcin Hellmann Barbara Kutryb-Zając Marta Baranowska-Kuczko

Hypertension is a multifactorial cardiovascular disorder characterized by oxidative stress, endothelial dysfunction, chronic inflammation, mitochondrial impairment, and accelerated vascular aging, all of which contribute to hypertension-mediated target organ damage. Among the molecular pathways involved in these processes, sirtuin-1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, has emerged as a potential regulator of vascular and metabolic homeostasis. This review summarizes current evidence on the role of SIRT1 in the pathophysiology of hypertension, with particular emphasis on its interactions with oxidative stress, mitochondrial function, endothelial integrity, inflammation, fibrosis, and cellular senescence. Experimental studies suggest that SIRT1 modulation can improve endothelial function and mitochondrial homeostasis, attenuate oxidative stress, inflammation, and vascular remodeling, and limit organ damage in several models. Effects on blood pressure are less consistent and appear to depend on the model and intervention used. Although clinical evidence remains limited, altered SIRT1 expression or activity has been reported in association with hypertension and preeclampsia, while preliminary studies suggest that interventions proposed to activate SIRT1 may improve vascular function and inflammatory status. However, changes in SIRT1 expression might not necessarily reflect changes in its enzymatic activity, and the effects of pharmacological interventions cannot always be attributed specifically to SIRT1. Overall, SIRT1 represents a potential therapeutic target whose value as a biomarker remains uncertain; however, well-designed clinical studies are required to establish its prognostic value and determine whether SIRT1 modulation can improve long-term cardiovascular outcomes.

Antioxidants doi: 10.3390/antiox15101352

Authors: Thierres H. D. Pontes Gabriela Brandao Eder A. Rodrigues Ricardo C. Damatto Lidiane M. Souza Mariana J. Gomes Felipe C. Damatto Luana U. Pagan Élida P. B. Ojopi Anna C. C. Santos Ana P. S. Marreiros Gilson M. Murata Leonardo A. M. Zornoff Katashi Okoshi Marina P. Okoshi

Introduction: High-intensity interval training (HIIT) has been recommended in post-myocardial infarction (MI) cardiac rehabilitation; however, its effects on MI-induced cardiac remodeling and skeletal muscle remain unclear. This study evaluated the effects of HIIT on functional capacity, cardiac remodeling, and the soleus skeletal muscle in rats after long-term MI. Methods: Three months after MI induction, Wistar rats were assigned to Sham, MI, and MI subjected to HIIT (MI-HIIT) groups. HIIT was performed three times per week for three months on a treadmill. Cardiac function and functional capacity were assessed before and after training. Oxidative stress markers, energy metabolism enzyme activities, and trophism were analyzed in the soleus. The statistical analysis included ANOVA and Bonferroni or Kruskal–Wallis and Dunn tests. Results: HIIT improved functional capacity compared to the Sham and MI groups. The infarcted groups had left ventricular dilation, hypertrophy, and systolic dysfunction, which were not modulated by HIIT. Soleus fiber cross-sectional areas did not differ between the groups. Catalase activity was lower in the MI and MI-HIIT groups than in the Sham group, while other oxidative stress markers were unchanged. HIIT increased citrate synthase activity compared to the Sham and MI groups, and phosphofructokinase and carnitine palmitoyltransferase-1 activities compared to the MI group. Conclusions: High-intensity interval training improves functional capacity despite unchanged cardiac remodeling in long-term infarcted rats. Enhanced physical capacity is associated with the increased activity of the enzymes involved in the energy metabolism of the soleus muscle.

Antioxidants doi: 10.3390/antiox15101351

Authors: Tatsuya Mimura Hidetaka Noma

Age-related macular degeneration (AMD) is a multifactorial retinal disease in which genetic susceptibility, aging, metabolic dysfunction, and environmental factors interact to determine disease onset and progression. Although environmental exposures are increasingly recognized as modifiable risk factors for AMD, the molecular mechanisms linking cumulative environmental stress to retinal degeneration remain incompletely understood. In this review, we examine the environmental exposome relevant to AMD and propose oxidative stress as a central molecular link connecting diverse environmental exposures with retinal aging and AMD susceptibility. Epidemiological evidence linking air pollution, particulate matter, cigarette smoke, and other environmental stressors to AMD is reviewed, followed by an analysis of their effects on redox homeostasis and the retinal pigment epithelium (RPE)–Bruch’s membrane–choriocapillaris complex. We further discuss how chronic oxidative stress promotes mitochondrial dysfunction, lipid peroxidation, ferroptosis, autophagy and mitophagy impairment, cellular senescence, and senescence-associated inflammation. These processes interact with complement activation, microglial activation, and chronic retinal inflammation, ultimately contributing to RPE dysfunction, choriocapillaris and Bruch’s membrane abnormalities, photoreceptor degeneration, and AMD progression. Integrating these mechanisms, we propose an environmental exposome–oxidative stress–retinal aging axis in which cumulative environmental exposures progressively reduce retinal resilience and increase susceptibility to AMD. We also evaluate antioxidant and redox-modulating strategies, including the established evidence for AREDS/AREDS2 supplementation and emerging approaches targeting Nrf2 signaling, glutathione homeostasis, mitochondria, and ferroptosis. Importantly, antioxidant supplementation should not be equated with primary prevention of environmentally induced AMD. Future studies integrating individual exposure monitoring, oxidative stress biomarkers, genetic susceptibility, and retinal phenotyping may enable precision prevention and personalized redox-based interventions. This framework positions environmental exposure as a potentially modifiable driver of retinal biological aging and provides a mechanistic basis for understanding and preventing environmentally driven AMD.

Antioxidants doi: 10.3390/antiox15101350

Authors: Haotian Yuan Ling Long Yelin Zeng Long Huang Yaoyu Chen Yongsheng Wang

Grass carp are prone to excessive fat deposition in intensive aquaculture, which impairs their health and reduces economic returns. Here, we investigated the effects of replacing soybean meal with ultrafine pulverized mulberry leaves combined with multi-enzyme preparations on lipid metabolism in grass carp using phenotypic and multi-omics approaches. A total of 480 grass carp (8.45 ± 0.17 g) were fed a basal diet and two experimental diets (6% and 12%) containing mulberry leaf for 60 d. Replacing soybean meal with ultrafine pulverized mulberry leaf with multi-enzyme preparations reduced serum triglyceride, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and dorsal muscle ether extract levels, downregulated hepatic glycolysis (gk, pfk, pk) and lipogenesis (fas and acc) genes and increased intestinal lipase activity. Intestinal omics identified the lysine degradation pathway as a key pathway that regulates lipid metabolism. Reduced levels of multiple differential metabolites and enhanced microbial metabolic functions are closely associated with inhibition of lipid metabolism in grass carp. The reduction in fat deposition, particularly polyunsaturated fatty acids, the downregulation of antioxidant capacity, as indicated by decreased glutathione peroxidase and superoxide dismutase activities and reduced total antioxidant capacity, along with a decrease in malondialdehyde levels, suggests that the lipid-lowering effects could alleviate oxidative stress. Replacing soybean meal with ultrafine pulverized mulberry leaves combined with multi-enzyme preparations reduced lipid deposition and alleviated oxidative stress in grass carp by regulating the gut–liver axis. When replacing soybean meal, a 12% proportion of ultrafine pulverized mulberry leaves combined with multi-enzyme preparations in the diet is recommended.

Antioxidants doi: 10.3390/antiox15101349

Authors: Jieqiong Ma Yuhan Jiang Ming Zhou Ruiqi Li Chanmin Liu

Renal damage is closely related to oxidative stress, inflammation, ferroptosis, and fibrosis. Renal fibrosis is closely related to oxidative stress, inflammation, and ferroptosis. Isochlorogenic acid C (IaC) has been demonstrated to have a protective effect against kidney injury in both in vivo and in vitro studies. Nonetheless, it remains uncertain whether IaC can mitigate kidney dysfunction induced by carbon tetrachloride (CCl4). In this study, we examined the protective effects of IaC on renal inflammation, ferroptosis, and fibrosis, as well as the underlying regulatory mechanisms. An experimental model of kidney injury was developed using ICR mice (in vivo) and HK-2 cells (in vitro), which were treated with CCl4 or TGFβ1. Gene/protein expressions were detected using RT-qPCR, Western blotting, and immunohistochemistry assays. In addition, to identify the potential mechanisms involved in this process, we conducted RNA interference and signaling pathway inhibition analysis. IaC alleviated CCl4-induced renal dysfunction and fibrosis. It resulted in the down-regulation of fibrosis-associated markers, specifically collagen I and α-SMA. Furthermore, IaC mitigated CCl4-induced renal inflammation by reducing the activities of TNF-α, IL-6, and NF-κB p65. IaC led to an up-regulation in the activities of GSH, SOD, and GPx in the renal tissues of mice. IaC effectively inhibited the elevation of renal ferroptosis-associated markers induced by CCl4, as evidenced by the reduced Fe2+ levels and the increased expression of GSH, GPX4, and SLC7A11. Moreover, IaC significantly enhanced the activation of Sestrin2 (SESN2). IaC resulted in a down-regulation of the expression levels of TGFβ1, YAP, TAZ, p-ERK, p-JNK, and p-p38 in the kidneys. Furthermore, IaC demonstrated an inhibitory effect on inflammation and fibrosis within an in vitro model of TGFβ-induced fibrosis. However, treatment with the inhibitors of MAPKs and YAP significantly enhanced the effects of IaC in TGFβ-stimulated HK-2 cells. Sestrin2 silencing also reversed the effects of IaC in TGFβ-stimulated HK-2 cells. IaC demonstrated effective docking with the active sites of the target proteins SESN2, GPX4, and YAP, thereby corroborating the predicted compatibility of interactions between IaC and these proteins. Our study demonstrates that IaC ameliorates CCl4-induced renal inflammation and fibrosis through modulation of the Hippo pathway and the SESN2/MAPKs pathways. IaC is a promising natural compound that can be used to treat kidney damage.

Antioxidants doi: 10.3390/antiox15101348

Authors: Shuhua Liu Ruolin Wang Chenhaoyu Liu Jiachun Huang Xiaoyun Li Haomin Qian Hongxing Huang Lei Wan

Postmenopausal osteoporosis (PMOP) is associated with estrogen deficiency and oxidative stress (OS), which impair osteoblast survival and osteogenic function. Formononetin (FMN) is a phytoestrogen with antioxidant properties, but its protective effects on osteoblasts under OS and the signaling pathways associated with these effects remain incompletely understood. Here, we evaluated the effects of FMN in ovariectomized (OVX) mice and in a tert-butyl hydroperoxide (t-BOOH)-induced oxidative injury model in MC3T3-E1 cells. Bone microarchitecture, histology, serum OS markers, cell viability, reactive oxygen species (ROS) production, apoptosis, mitochondrial morphology, and osteogenic differentiation were assessed. Network pharmacology, molecular docking, molecular dynamics simulations, RNA sequencing, Western blotting, and pharmacological pathway-modulation experiments were used to investigate signaling changes associated with FMN treatment. FMN attenuated trabecular bone deterioration and systemic oxidative imbalance in OVX mice. In MC3T3-E1 cells, FMN improved cell viability, reduced ROS accumulation and apoptosis, alleviated mitochondrial damage, and preserved osteogenic differentiation following t-BOOH exposure. FMN treatment was accompanied by reduced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK), together with reduced expression of activator protein 1 (AP-1)-related proteins, including c-Fos, c-Jun, and phosphorylated c-Jun. Pharmacological reactivation of p38/JNK signaling with anisomycin attenuated several antioxidant, anti-apoptotic, and pro-osteogenic effects associated with FMN treatment, whereas nuclear factor erythroid 2-related factor 2 (NRF2) inhibition partially diminished FMN-mediated protection. Collectively, these findings support an association between the protective effects of FMN and modulation of mitogen-activated protein kinase (MAPK)/AP-1 and NRF2-associated signaling.

Antioxidants doi: 10.3390/antiox15101347

Authors: Jhazmin Quizhpe Rocío Peñalver Pablo Ayuso Leilei Zhang Pascual García-Pérez Luigi Lucini Gema Nieto

The growing demand for gluten-free (GF) products has highlighted nutritional limitations in commercial bakery products, particularly low fiber, mineral, and bioactive compound content. This study evaluated the valorization of Pleurotus ostreatus by-products as nutritionally valuable ingredients for GF cookies, focusing on the nutritional and metabolomic effects of ultrasound-assisted extraction (UAE). Untreated and UAE-treated by-products were incorporated into GF cookies at 4% and 8% (w/w). Proximate composition, mineral content, antioxidant capacity, untargeted phenolic profile, and sensory characteristics were assessed. UAE modified the nutritional and metabolomic profiles of mushroom by-products, increasing soluble dietary fiber, protein, and essential minerals such as Zn, Cu, and Mn. Untargeted metabolomic analysis revealed that UAE selectively promoted low-molecular-weight phenolic acids. Compared with a commercial GF reference, reformulated cookies exhibited higher protein and total dietary fiber contents, fulfilling the “high fiber” nutritional claim, together with a more balanced mineral profile. All reformulated cookies also showed higher iron content than the commercial GF reference, allowing the “source of iron” nutritional claim. Metabolomic profiling confirmed greater phenolic diversity and abundance in reformulated cookies, while UAE-treated by-products enhanced phenolic acids. Overall, UAE-treated mushroom by-products represent a clean-label strategy to enhance the nutritional quality and bioactive compound profile of GF bakery products.

Antioxidants doi: 10.3390/antiox15101346

Authors: Aikebaier Aihemaiti Alimire Niyazi Kuanfeng Zhu Weijian Li Depeng Yin Bingyuan Wang Xuguang Wang Lu Zhang Guoshi Liu

Oxidative stress impairs gamete development and embryonic competence in female mammals. We compared four melatonin (MT) dose regimens (vehicle control and 20, 40, and 80 mg per injection) in FSH-superovulated ewes during in vivo ovum pick-up. The 40 mg regimen significantly reduced follicular atresia and increased high-quality oocytes and transferable blastocysts. Pregnancy and lambing rates after in vivo embryo transfer were numerically higher in the 40 mg group but did not reach statistical significance. The favorable responses observed with the 40 mg regimen were not maintained at the 80 mg dose. Oocyte transcriptomics and follicular fluid metabolomics revealed multilevel molecular responses associated with MT treatment. Systemically, 40 mg MT was associated with changes in serum reproductive hormones, including significant increases in MT, E2, and IGF-1. At the cellular and molecular levels, MT treatment was associated with changes in follicular development and oocyte quality, together with altered redox status and candidate changes in energy metabolism; MT1-related signaling was identified as a candidate pathway. MT treatment was associated with increased MT1 and Ki-67 expression in granulosa cells, an increased Bcl-2/Bax ratio, and reduced follicular fluid ROS and MDA levels, indicating improved redox homeostasis and granulosa cell proliferation. MT treatment was associated with altered redox status, including significantly increased GSH and reduced intracellular ROS, while ATP and mitochondrial superoxide showed non-significant changes. Hypoxia-inducible factor 1 (HIF-1) signaling and the tricarboxylic acid (TCA) cycle were identified as candidate pathways potentially associated with follicular energy–redox remodeling. These observations provide a basis for further investigation of MT dose regimens to mitigate disadvantages associated with FSH superovulation in ewes and other species.

Antioxidants doi: 10.3390/antiox15101345

Authors: Brian Enrique Rojo-Ruvalcaba Montserrat Maldonado-González Bertha Ruiz-Madrigal Erika Martínez-López Rocío García-Becerra Pedro Ernesto Sánchez-Hernández Juan Florencio Gómez-Leyva Teresa Arcelia García-Cobián María Guadalupe Ramírez-Dueñas Andrea Carolina Machado-Sulbaran Héctor Flores-Martínez Itzel Viridiana Reyes-Pérez Eduardo Huerta-García Cristina Estefanía Rizo-Estrada Alejandro Ulises Centeno-Torres Trinidad García-Iglesias

Background/Objectives: Breast cancer (BC), particularly aggressive subtypes such as triple-negative TNBC, remains a significant clinical challenge due to treatment resistance and therapeutic toxicity. This study evaluated the antitumor potential, antioxidant activity, and anti-inflammatory effect of Mexican Oregano (Lippia graveolens) infusion (MoI) and its bioactive constituent, carvacrol (Cv), in diverse BC cell lines (MCF-7, HCC-1954, and MDA-MB-231). Methods: Cellular responses were assessed by quantifying apoptosis, profiling cytokines (IL-4, IL-6, IL-10), and analyzing the gene expression of antioxidant enzymes (CAT, SOD2, GPX1) and their enzymatic activities. Results: Cv exhibited potent, subtype-independent pro-apoptotic activity, while MoI demonstrated significant efficacy with attenuated cytotoxicity in non-tumoral HaCaT cells. Both treatments mediated complex modification of cytokine signaling, characterized by reduction in the extracellular concentration of tumor-promoting IL-4, IL-6, and IL-10, an effect most pronounced in the highly aggressive MDA-MB-231 cell line. Transcriptional and functional analyses further revealed that these agents alter the expression and activity of antioxidant enzymes, thereby promoting pro-oxidant environments conducive to cancer cell death. Conclusions: These findings indicate that MoI and Cv exert antitumor effects through coordinated pathways of apoptosis induction, extracellular cytokine levels and redox disruption. Consequently, MoI emerges as a promising candidate for complementary therapeutic strategies in BC management, particularly for aggressive subtypes, owing to its impact on inflammatory networks and redox vulnerabilities. At the same time, Cv serves as a compelling lead compound for targeted oncological research.

Antioxidants doi: 10.3390/antiox15101344

Authors: Changhua Zhang Yong Zhang

Macleaya cordata, which is widely distributed in nature, exhibits pronounced anti-inflammatory, antioxidant, and anti-colitis potential. However, its therapeutic mechanism on DSS-induced ulcerative colitis (UC) remains unknown; therefore, we aimed to evaluate the protective effect of Macleaya cordata extract (MCE) on UC and investigate its active monomer component. In a mouse colitis model induced by DSS, MCE markedly alleviated pathological characteristics. 16S rRNA sequencing indicated a significant reduction in the relative abundance of pathogenic Streptococcus, while increasing that of beneficial genera Dubosiella and Akkermansia. Furthermore, flow cytometry analysis indicated the protective role of MCE on DSS-induced macrophage polarization in the colon (32.6% reduction in M1 macrophage compared to the DSS group; 5.3% increase in M2 macrophage compared to the DSS group) and spleen tissue (36.8% reduction in M1 macrophage compared to the DSS group; 22.3% increase in M2 macrophage compared to the DSS group). In addition, we found that sanguinarine (SAN) (27.9% reduction in body weight compared to the DSS group; p < 0.01) exhibited a superior anti-colitis effect compared to chelerythrine (CHE) (19.8% reduction in body weight compared to the DSS group) by inhibiting NF-κB activation and ROS production than CHE in LPS-induced RAW 264.7 macrophages. In conclusion, MCE ameliorates UC by reshaping gut microbiota and suppressing M1 polarization.

Antioxidants doi: 10.3390/antiox15101343

Authors: Pallab Sarker Manuel Labbe Benjamin V. Schoffstall Anne R. Kapuscinski Brandi McKuin Devin Fitzgerald Connor Greenwood Kira O’Shelski Emily Noelle Pasion Duncan Gwynne Diego Gonzalez Orcajo

As global demand for affordable, high-quality protein continues to rise, commercial aquaculture has emerged as a critical solution. The industry’s reliance on ocean-derived fishmeal (FM) and fish oil (FO) for aquafeed poses sustainability concerns. Marine microalgae offer a promising alternative due to their comparable nutrient profiles and potential for large-scale, sustainable production. We conducted a feeding trial with juvenile rainbow trout to evaluate fish-free, microalgae-based diets as alternatives to FM and FO. Diets were formulated using Nannochloropsis oculata (N. oculata) by-product as a protein source and Schizochytrium sp. (whole-cell or oil) as a source of DHA and key antioxidants. Diets included a reference formulation containing FMFO and three experimental diets: 75% replacement of FMFO using N. oculata and Schizochytrium whole-cell (NSW75), 100% replacement using both (NSW100), and 100% replacement using N. oculata and Schizochytrium oil (NSO100). The NSW100 diet supported growth and feed conversion comparable to the FMFO control; the NSO100 had lower growth than the FMFO control. Cost analysis revealed that fish-free diets had the numerically lowest, though not significantly different, values for formulated feed costs and economic conversion ratios, highlighting their commercial potential. These findings demonstrate that microalgae-based aquafeeds combining N. oculata and Schizochytrium sp. can viably replace FMFO.

Antioxidants doi: 10.3390/antiox15101342

Authors: Soo-Jin Park Hee Jae Lee Su Ui Lee Jae-Won Lee

Emerging paradigms in systemic immunology have illuminated the intricate, bidirectional communication networks linking distant organ systems, which are conceptualized as the gut–lung–brain axis. The homeostasis of this anatomical triad is primarily disrupted by localized and systemic oxidative stress, which serves as a potent driver of chronic inflammatory cascades. This comprehensive narrative review comprehensively delineates the redox-sensitive molecular cross-talk between peripheral tissue-resident macrophages (alveolar and intestinal) and central nervous system microglia. Environmental insults or microbial dysbiosis trigger the overproduction of reactive oxygen species (ROS), which compromise epithelial and endothelial barrier integrity, thereby allowing inflammatory mediators to breach the blood–brain barrier and trigger neuroinflammation. Herein, we systematically evaluate the mechanistic evidence demonstrating how this systemic redox disequilibrium drives coordinated myeloid hyperactivation. Rather than operating as isolated cellular responses, peripheral macrophage activation establishes a self-perpetuating feedback loop that systematically lowers the activation threshold of central microglia. We focus on the molecular convergence of the classical nuclear factor kappa B (NF-κB) pathway and the NOD-like receptor protein 3 (NLRP3) inflammasome within these myeloid lineages, which orchestrates the transcription of cytotoxic cytokines and gasdermin D-mediated pore formation. Crucially, within the architecture of systemic immunology, baseline intracellular ROS production serves as an essential physiological redox signaling molecule requisite for maintaining homeostatic cellular responses, whereas the transition into unmitigated pathological oxidative distress acts as the primary orchestrator of multi-organ barrier collapse. To counteract this multi-organ deterioration, we highlight the translational and therapeutic potential of well-characterized antioxidant phytochemicals—acting as multi-target molecular rheostats capable of neutralizing free radical bursts, rescuing barrier junctions, and systematically reprogramming hyperactive myeloid phenotypes. Furthermore, this review examines the progressive functional impairment and exhaustion of the endogenous cytoprotective Nrf2/HO-1 signaling axis, which functions as the primary molecular rheostat failure under persistent and unmitigated oxidative distress. Finally, we address the strategic implementation of advanced biomimetic multi-organ-on-a-chip technologies designed to model this intercellular dialog, establishing a robust conceptual framework for understanding multi-organ inflammatory decay driven by synchronized macrophage and microglia hyperactivation.

Antioxidants doi: 10.3390/antiox15101341

Authors: Marta Pawłowska Celestyna Mila-Kierzenkowska Marek Jóźwiak Jarosław Nuszkiewicz

Oxidative stress is a fundamental driver of carcinogenesis and tumor progression, arising from an imbalance between reactive oxygen or nitrogen species and antioxidant defense mechanisms. This redox disruption contributes to genomic instability, metabolic reprogramming, inflammation, immune modulation, and therapy resistance processes that together influence the biological behavior of cancer. A broad spectrum of oxidative stress biomarkers has been evaluated in oncology, including markers of lipid peroxidation, protein oxidation, DNA oxidation, and enzymatic or non-enzymatic antioxidant systems. This review integrates current mechanistic knowledge of the formation and functional significance of these biomarkers and evaluates clinical evidence regarding their diagnostic, prognostic, and predictive usefulness across multiple cancer types. We examine whether oxidative stress biomarkers could complement established measures of risk and describe treatment-related changes in systemic oxidative status, while distinguishing these potential applications from validated clinical uses. Despite promising findings, biomarker implementation remains limited by analytical variability, lack of standardized reference ranges, and insufficient prospective validation. Beyond biomedical considerations, the review also highlights key organizational and quality-related factors that may influence the integration of oxidative stress biomarkers into clinical practice. These include laboratory quality assurance requirements, methodological standardization, workflow and data management needs, and broader health system implications. By integrating mechanistic, clinical, analytical, and organizational evidence, this review identifies the validation and quality requirements that must be met before oxidative stress biomarkers can inform routine oncology decisions.

Antioxidants doi: 10.3390/antiox15101340

Authors: Ariti Tsinari Stefanos Roumeliotis Ioannis Eleftherios Neofytou Athanasios Roumeliotis Garyfallia Varouktsi Aikaterini Stamou Ioannis Kontogiorgos Konstantinos Leivaditis Andrej Veljkovic Gordana Kocic Vassilios Liakopoulos

Oxidative stress (OS) is highly prevalent in chronic kidney disease (CKD), yet its clinical significance and association with cardiovascular disease (CVD) has not been yet clearly demonstrated. In this cohort study, 477 adults with CKD at various stages and 20 healthy controls were enrolled. In all participants, an extensive panel of OS biomarkers was measured. Malondialdehyde (MDA) was correlated with glomerular filtration rate (eGFR) and carotid intima media thickness (cIMT) (p = 0.008 and p = 0.024, respectively, according to Spearman’s rho). Advanced oxidation protein products (AOPPs) were correlated with the urine protein-to-creatinine ratio (uPCR), parathormone (PTH) and eGFR (p = 0.048, p = 0.025 and p = 0.045 respectively, according to Spearman’s rho) and oxidized albumin (oxALB) was correlated with PTH (p = 0.032) and pulse wave velocity (PWV) (p = 0.017). The antioxidant enzyme superoxide dismutase (SOD) was correlated with PWV (p = 0.042), urea (p < 0.001), uPCR (p = 0.024), and eGFR (p < 0.001). Meanwhile, catalase (CAT) was correlated with eGFR (p = 0.029) and indices of central pressure. Xanthine oxidase (XO) was correlated with the duration of CVD and PWV. Multivariate analysis showed that kidney function and/or arterial stiffness and CVD were independent predictors of all OS markers.

Antioxidants doi: 10.3390/antiox15101339

Authors: Li-Yan Hou Ying Zhou Ya-Xuan Li Shu-Hao Fan Zong-Jun Yin

Resveratrol (RES) is a natural polyphenolic compound that protects the organism against oxidative stress and various metabolic injuries. Ochratoxin A (OTA) is a widely occurring mycotoxin with established reproductive toxicity in monogastric animals, including pigs. Nevertheless, its molecular mechanisms remain elusive. This study aimed to investigate OTA-induced cellular injury and the protective role of RES using porcine granulosa cells as an in vitro model. OTA treatment significantly reduced cell viability, increased lactate dehydrogenase release, induced oxidative damage, and promoted apoptosis. Transcriptomic analysis revealed that OTA markedly activated the NF-κB inflammatory pathway while suppressing the expression of HIF-1 signaling-related genes. Consistently, RT-qPCR showed that OTA upregulated the mRNA levels of TNF-α, p50, p65, IL-6, and CXCL-14. Furthermore, ELISA demonstrated that OTA increased the protein secretion of IL-1β, IL-8, TNF-α, MCP-1, and IL-6. Western blot analysis indicated that OTA decreased IκBα protein levels but did not alter p65 expression. Notably, RES co-treatment effectively reversed all the above-mentioned alterations and restored the aberrant expression of NF-κB and HIF-1 pathway genes to levels close to those of the control group. In conclusion, RES alleviates OTA-induced damage in porcine ovarian granulosa cells via modulating oxidative stress, inflammation response and apoptosis.

Antioxidants doi: 10.3390/antiox15101338

Authors: Xiaoxu Zhang Tingyu Feng Mengjia Zhu Jiangbo Xiang Guanghua Xia Xiaoming Jiang Xiang Gao

Hippocampus abdominalis (H. abdominalis) is an important marine teleost fish with diverse functional activities. Accordingly, the present research was designed to isolate and prepare innovative antioxidant peptides derived from H. abdominalis and to assess the protective and restorative impacts of its protein hydrolysates (HAPH) against reproductive injury caused by triptolide (TP) in male mice. Notably, pepsin was ultimately identified as the optimal protease among seven screened proteases. High hydrostatic pressure (HHP) pretreatment significantly increased peptide yield and antioxidant activity of pepsin hydrolysates. Subsequently, the optimal enzymatic hydrolysis conditions were established as E/S of 3% (w/w), hydrolysis time of 3 h, S/L of 1:25 (w/v), HHP pressure of 200 MPa, and 9 min of HHP time using single-factor experiments and response surface methodology. The peptide fraction with a molecular weight below 3 kDa (HAPH-1) exhibited stronger antioxidant activity and excellent stability against pH, temperature, and simulated gastrointestinal digestion. Furthermore, animal experiments revealed that HAPH-1 alleviated triptolide-induced impaired spermatogenesis and testicular tissue damage in mice, and the underlying mechanisms involve the regulation of the Keap1-Nrf2 pathway and the Bcl-2/Bax/caspase-3 apoptotic signaling pathway. Finally, through LC-MS/MS analysis, molecular docking, and in vitro activity validation, three novel peptides with high antioxidant activity (GPAPWGF, FPALLF, and LPLPLF) were successfully screened. Collectively, this study provides new insights into the high-value utilization of H. abdominalis and the development of novel antioxidant functional components.

Antioxidants doi: 10.3390/antiox15101337

Authors: Yunbo Yan Songmei Hu Mingxin Chen Yanlin Wen Xinyu He Aoli Ding Chengyuan Tang Junxiang Chen

Acute kidney injury (AKI) lacks effective pharmacological therapies, and ferroptosis-associated lipid peroxidation contributes to renal tubular injury. Here, we investigated the protective effects of dendrobine against AKI and its mechanisms. Dendrobine was evaluated in murine cisplatin-induced AKI and renal ischemia–reperfusion (I/R) models and in cisplatin- and erastin-challenged HK-2 cells using functional, histological, biochemical, and molecular analyses. Dendrobine improved renal function, alleviated tubular injury, reduced oxidative stress and lipid peroxidation, and preserved the GPX4/SLC7A11 antioxidant defense system in cisplatin-induced AKI and renal tubular cells. Dendrobine also attenuated erastin-associated lipid peroxidation and glutathione depletion, supporting an effect on ferroptosis-associated redox stress. Consistent renoprotective effects were observed in the renal I/R model. Mechanistically, target-engagement and protein-interaction analyses supported cellular engagement of KEAP1 by dendrobine and showed reduced KEAP1–NRF2 association and NRF2 ubiquitination, accompanied by enhanced NRF2 stabilization and nuclear accumulation. NRF2 inhibition attenuated the protective effects of dendrobine. Moreover, the KEAP1 R415A substitution attenuated dendrobine-associated KEAP1 engagement, NRF2 activation, and cytoprotection, supporting a functional contribution of Arg415 to these responses. Collectively, these findings support KEAP1–NRF2-regulated antioxidant defense as an important component of dendrobine-mediated protection against renal tubular injury and ferroptosis-associated stress in AKI.

Antioxidants doi: 10.3390/antiox15101336

Authors: Maria Czernicka Sebastian Such

Natural products are important sources of redox-active phytochemicals, but meaningful interpretation of their biological effects requires accurate botanical and chemical characterization. The vernacular label “lotus” is applied to botanically distinct taxa belonging to the genera Nymphaea (Nymphaeaceae) and Nelumbo (Nelumbonaceae), despite their substantial taxonomic and phytochemical divergence. This review critically evaluates authenticated evidence on botanical identity, phenolic and alkaloid composition, antioxidant activity, redox-modulating mechanisms, translational relevance, and safety across selected species of both genera. Particular emphasis is placed on organ-specific phytochemical specialization, the contrasting distribution of flavonoids and benzylisoquinoline alkaloids, and the limitations of comparing antioxidant activity across heterogeneous extraction and assay systems. Available mechanistic studies implicate interconnected antioxidant-response, inflammatory, metabolic, autophagy, and glucose-handling pathways, but the evidence remains predominantly preclinical. Nelumbo nucifera is substantially better characterized than Nymphaea species, especially with respect to alkaloid chemistry, pharmacology, and toxicology, whereas evidence for Nymphaea remains more fragmented and species dependent. Botanical authentication, chemical standardization, pharmacokinetic characterization, and preparation-specific safety assessment are therefore essential for meaningful translation. Overall, the therapeutic potential of Nymphaea and Nelumbo is scientifically plausible, but current evidence is insufficient for broad clinical generalization or interchangeable use of materials marketed as “lotus”.

Antioxidants doi: 10.3390/antiox15101335

Authors: Xiangyu Lu Pujun Li Lei Cao Tao Liu Yajun Ma Jiantao Zhang Hongbin Wang

Hepatic ischemia–reperfusion injury (HIRI) involves multiple forms of regulated cell death, but the relationship between copper-associated alterations and ferroptosis-related responses remains incompletely understood. This study investigated whether pharmacological modulation of intracellular copper homeostasis was accompanied by corresponding changes in ferroptosis-associated responses, and vice versa, during HIRI, and evaluated whether adipose-derived mesenchymal stem cell-derived exosomes (ADSCs-Exo) attenuate injury-associated alterations under OGD/R and HIRI conditions. Primary piglet hepatocytes were subjected to oxygen–glucose deprivation/reoxygenation (OGD/R), followed by bidirectional pharmacological modulation of copper homeostasis and ferroptosis-associated responses. The major response patterns were further evaluated in a laparoscopic miniature pig model of HIRI combined with partial hepatectomy. OGD/R induced copper and iron dyshomeostasis, mitochondrial dysfunction, redox imbalance, alterations in cuproptosis-related markers, and ferroptosis-associated changes. Relative to the OGD/R group, ADSC-Exo treatment attenuated these injury-associated abnormalities. Pharmacological reduction in intracellular copper loading was accompanied by decreased Fe2+ accumulation and restoration of GSH, AIFM2, SLC7A11, and GPX4, whereas increased copper loading produced the opposite pattern. Conversely, pharmacological enhancement in ferroptosis-associated responses increased Cu2+ accumulation and aggravated alterations in the cuproptosis-related markers SLC31A1, FDX1, LIAS, and DLAT, whereas pharmacological suppression of ferroptosis-associated responses attenuated these changes. These bidirectional pharmacological response patterns are consistent with a potential reciprocal association between copper-associated alterations and ferroptosis-related responses but do not establish bona fide cuproptosis, direct molecular interaction, or target-specific causality. In miniature pigs, HIRI was accompanied by hepatic injury, mitochondrial dysfunction, hepatic copper accumulation, alterations in cuproptosis-related markers, ferroptosis-associated changes, and reduced GPX4 expression. Relative to untreated IRI animals, ADSC-Exo administration was associated with attenuation of these injury-related abnormalities. The coordinated changes in GPX4, TAX1BP1, and MAP1LC3B are hypothesis-generating and support the working hypothesis that TAX1BP1/MAP1LC3B-associated autophagic processes may contribute to GPX4 homeostasis; however, autophagic flux, GPX4 turnover, and direct TAX1BP1–GPX4 interaction were not assessed. Because a non-injured ADSC-Exo-only control was not included, the present study does not determine the independent effects of ADSCs-Exo under baseline conditions. Thus, the observed ADSC-Exo-associated effects should be interpreted specifically within the OGD/R and HIRI settings examined here.

Antioxidants doi: 10.3390/antiox15101334

Authors: Faruk Danış Murat Alışık

Clinical redox studies usually sample a single compartment. In a single-centre, cross-sectional case–control study, we measured serum thiol-disulfide homeostasis, a bulk extracellular thiol measure, and erythrocyte glutathione, an intracellular measure, in the same blood draw from 82 patients presenting to an emergency department with non-ST-elevation myocardial infarction and 75 controls. Cases and controls differed substantially in sex and in cardiovascular risk profile. All nine redox indices differed between groups in the direction consistent with greater oxidation in patients. The standardized case–control difference was larger for erythrocyte reduced glutathione (Hedges g 1.14) than for serum native thiol (0.56). The post hoc bootstrap ratio of the two was 2.04 (95% confidence interval [CI] 1.31 to 4.08) before adjustment and 1.60 (0.99 to 3.23) after adjustment for age, sex and smoking, and no asymmetry was seen in the small subgroup free of recorded risk factors. In exploratory analyses within patients, serum indices were associated with the Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) score and reduced glutathione with ejection fraction. Each assay reports its own pool and is not a global measure of oxidative stress. In this sample, the compartment chosen determined the size of the observed case–control difference, a result that needs confirmation in a design with comparable groups.

Antioxidants doi: 10.3390/antiox15101333

Authors: Yusong Zhang Hongxia Long Li Qiao Huiling Zhang Dingyuan Chen Jingjing Chen Bo Wei Wei Li Haiyan Zhou

Oxidative stress is a major contributor to cardiomyoblast injury and cardiovascular disease progression. Huperzine A (HupA), a natural Lycopodium alkaloid, exhibits antioxidant and anti-inflammatory properties, but its cardioprotective mechanisms remain unclear. This study aimed to investigate the effects of HupA on oxidative stress-induced H9c2 cardiomyoblast injury and elucidate the underlying molecular mechanisms. Network pharmacology, molecular docking, molecular dynamics simulations, and cellular thermal shift assay (CETSA) were integrated to predict and investigate AKT1 involvement. An in vitro model of tert-butyl hydroperoxide (tBHP)-induced injury in H9c2 rat cardiomyoblasts was established. Oxidative stress status, mitochondrial function, and AKT-associated signaling were evaluated. The involvement of AKT signaling was examined using MK-2206. HupA significantly improved cell viability in a dose-dependent manner and markedly reduced lipid peroxidation and intracellular and mitochondrial ROS accumulation. In addition, HupA restored antioxidant defenses by increasing superoxide dismutase activity and glutathione levels. Mitochondrial dysfunction induced by tBHP was effectively alleviated, as evidenced by preserved mitochondrial membrane potential and reduced mitochondrial superoxide production. Furthermore, HupA enhanced AKT phosphorylation and MCL-1 expression while inhibiting extracellular HMGB1 release. Importantly, pharmacological inhibition of AKT largely abolished these protective effects, including antioxidant restoration, mitochondrial preservation, and anti-cell death activity. HupA protects H9c2 cardiomyoblasts against oxidative injury through AKT-associated survival signaling, thereby attenuating oxidative stress and preserving mitochondrial integrity. These findings suggest HupA as a promising therapeutic candidate in H9c2 cardiomyoblasts under oxidative stress conditions.

Antioxidants doi: 10.3390/antiox15101331

Authors: Ha-il Jung Myung-Sook Kim Eun-Jin Lee Tae-Gu Lee Theint Thandar Latt Jinwook Lee Chaw Su Lwin Bok-Rye Lee

Arsenic (As) contamination poses a serious threat to rice production and food safety. Although sulfur (S) nutrition is known to alleviate As toxicity through thiol-based detoxification, the mechanisms underlying the relationship between S-induced As accumulation and tolerance remain poorly understood. We investigated the effects of contrasting S levels (0, 1, and 4 mM) on As accumulation, translocation, oxidative stress responses, thiol metabolite pools, and mineral nutrient profiles in hydroponically grown rice seedlings exposed to 15 µM As for 15 days. S supplementation alleviated As-induced growth inhibition in a dose-dependent manner despite increasing total As accumulation in both roots and shoots, demonstrating that S-mediated tolerance is independent of reduced As accumulation. Elevated S supply reduced oxidative stress markers (O2•–, H2O2, and MDA), while markedly enlarged the pools of γ-glutamylcysteine (γ-EC), glutathione, and phytochelatins (PCs), particularly in roots. S supplementation also improved the uptake of major essential nutrients, including nitrogen and potassium in shoots, while selectively modulating micronutrient distributions under As stress. Correlation analysis showed that root As content was strongly and positively correlated with γ-EC and PC2–PC4, and principal component analysis separated the treatments along the S gradient in both roots and shoots. Collectively, these results suggest that S enhances As tolerance in rice seedlings through thiol-dependent detoxification, thereby decoupling As tolerance from As accumulation rather than by restricting As accumulation.

Antioxidants doi: 10.3390/antiox15101332

Authors: Hafiz Abdul Kareem Sana Saleem Muhammad Bilal Hafeez Naeem Ahmad Da-Chuan Yin

Soil salinity and drought can restrict oxygen availability in the root zone, adding hypoxic stress to the ionic, osmotic, and hydraulic constraints experienced by crops. Nanobubble (NB) water offers a chemical-free approach for delivering highly dispersed oxygen and sustaining dissolved oxygen during irrigation. This review connects the physicochemical behavior of NBs with plant responses to salinity- and drought-associated hypoxia. It examines restoration of aerobic respiration and ATP homeostasis, modulation of ethylene response factor group VII and hypoxia-responsive gene signaling, recovery of ion transport and aquaporin function, redox regulation, hormonal cross-talk, and rhizosphere microbiome responses. Evidence from rice, maize, wheat, cotton, and controlled-environment systems is evaluated alongside opportunities for nanoparticle co-delivery, nanofertilizers, seed priming, and sensor-guided irrigation. The review also outlines how transcriptomics, proteomics, metabolomics, epigenomics, ionomics, and phenomics can resolve NB-mediated mechanisms across the plant–soil continuum. Current evidence supports NB irrigation as a promising precision-aeration platform, but field-scale validation, standardized NB characterization, dose–response studies, energy and cost assessments, and long-term environmental safety analyses remain necessary before broad agricultural deployment.

Antioxidants doi: 10.3390/antiox15101330

Authors: Yanlu Yu Boyuan Liu Jing Wu Ji Wu Linguo Sheng Tao Xu Yuqi Wang Shuangchi Liu Roman A. Surmenev Kai Zheng Bin Xue

Partial hepatectomy (PH) causes bleeding and oxidative stress, which can slow early liver recovery. To address this, we made cerium-doped bioactive glass fibers (Ce-BGFs) using sol–gel electrospinning. We tested these fibers both in vitro and in a 70% PH mouse model. The fibers showed sustained ion release and lowered H2O2-induced ROS in hepatocytes. In vivo, Ce-BGFs lowered hepatic ROS fluorescence on postoperative day 1 compared to untreated PH controls (4.17 ± 1.20 vs. 34.52 ± 1.47). Serum AST levels decreased (66.42 ± 15.93 vs. 89.62 ± 16.66 U/L). Ce-BGFs also reduced blood loss (0.039 ± 0.016 vs. 0.102 ± 0.038 g) and bleeding times (13.67 ± 3.21 vs. 37.00 ± 1.73 s). By day 3, we observed more Ki67-positive cells, suggesting better early hepatocyte proliferation (3.92 ± 1.25% vs. 1.14 ± 0.29%). However, liver-to-body weight ratios were not significantly different at this stage. Proteomic profiling showed enrichment in pathways for oxidative stress, inflammation, and pentose phosphate metabolism. Ce-BGF treatment also led to time-dependent cytokine changes and helped preserve liver glycogen after PH. In addition, the PAS-positive area at postoperative day 1 was higher with Ce-BGF treatment than with untreated PH (10.27 ± 1.31% vs. 3.50 ± 1.03%), indicating greater hepatic glycogen preservation. These results show that Ce-BGFs provide local hemostasis and are associated with reduced oxidative stress, attenuated liver injury, enhanced early hepatocyte proliferation, and greater glycogen preservation after PH.