Antioxidants doi: 10.3390/antiox15070873

Authors: Bissih Fred Kaimin Cheng Agyenim Godfred Boateng Junming Deng Beiping Tan Asare Derrick Shuyan Chi

This study investigated the effects of high-lipid diets (HLD) with methionine (Met) supplementations on golden pompano (Trachinotus ovatus). T. ovatus (initial weight 82 ± 0.04 g) were fed with a normal lipid control diet (11.30% crude lipid and 1.04% Met, NLM) and HLDs (18% crude lipid) supplemented with varying Met levels (1.04%, 1.14%, 1.24%, 1.34%, 1.44%, 1.54% and 1.64%) namely HLM1, HLM2, HLM3, HLM4, HLM5, HLM6 and HLM7, respectively. After 56 days of feeding trial, the growth performance such as weight gain rate was significantly elevated in the HLM3 (p < 0.05). The liver lipid droplets area, sum of n-3 and n-6 poly-unsaturated fatty acids and fatty acid synthesis genes were elevated in the HLM1 and HLM7, while the genes for lipid breakdown were elevated in the HLM3. Based on the groups NLM, HLM1, and HLM3, the transcriptome sequence data revealed critical associated lipid metabolism, classic antioxidant pathway nrf2 and ferroptosis markers were influenced by Met and higher lipid. The fish livers in HLD groups with lower or higher Met showed the phenomenon of lipid oxidation obviously, while the reactive oxygen species and malondialdehyde were considerably lowered in the liver of fish in group HLM3 (p < 0.05). The hepatic Met was significantly reduced while cysteine was elevated in the HLM3 compared to HLM7 (p < 0.05). Fe and ferroptosis inducers were significantly upregulated in the liver of HLM1 and HLM7. HLM3 elevated anti-ferroptosis and anti-inflammation markers. In conclusion, Met inclusion in the HLD was associated with nrf2/keap1 and critical anti-ferroptosis-related transcriptional responses and regulated lipid metabolism in T. ovatus. The quadratic regression model revealed the optimal dietary Met in the HLD as 1.32%, which will help formulators make more rational and effective use of dietary lipid to support the better growth of golden pompano.

Antioxidants doi: 10.3390/antiox15070872

Authors: Rachit Sood Sanjay Hae-Jeung Lee

Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by inflammation, oxidative stress, tear film instability, and secretory dysfunction. This study investigated the protective effects of Lute-gen®, a lutein and zeaxanthin-based formulation, in both in vitro and in vivo DED models. Human corneal epithelial (HCE-T) cells were stimulated with TNF-α, while dry eye was induced in female Sprague–Dawley rats using subcutaneous scopolamine (SCP) administration. In HCE-T cells, Lute-gen® showed no cytotoxicity, restored cell viability, reduced intracellular ROS, and was associated with increased expression of antioxidant-related markers (Nrf2, HO-1, SOD, CAT, and GPx), reduced expression of inflammatory mediators (TLR4/MyD88/NF-κB/NLRP3), and increased expression of AQP3 and AQP5. In SCP-induced rats, Lute-gen® significantly improved tear secretion and reduced corneal fluorescein staining. Histopathological analyses revealed restoration of conjunctival goblet cells, mucin staining, corneal epithelial integrity, acinar area and cell density, and lacrimal gland architecture, with reduced inflammatory infiltration. Immunofluorescence further demonstrated reduced TLR4 and MMP9 immunoreactivity and decreased CD68+ inflammatory cell infiltration. Molecular analyses showed reduced expression of inflammatory cytokines and NF-κB/MAPK/MMP signaling-related inflammatory mediators, together with restoration of AQP1, AQP3, and AQP5 expression in corneal tissues. Collectively, these findings suggest that Lute-gen® treatment was associated with improvements in dry eye-related pathological changes, including restoration of antioxidant-related markers, attenuation of inflammatory responses, restoration of aquaporin expression, and preservation of ocular surface and lacrimal gland integrity. These preclinical findings support further mechanistic investigations and the future clinical evaluation of Lute-gen® as a potential nutritional intervention for dry eye disease.

Antioxidants doi: 10.3390/antiox15070871

Authors: Hye Ji Choi Hyo Lim Lee Yeong Hyeon Ju Yu Mi Heo Hwa Rang Na Chae Eun Yoon Young Hee Son Do-Yoon Kim Yu-Jin Kim Hui-Seok Jeong Seung-Hwan Park Hyun-Jin Kim Ho Jin Heo

Since lung cancer remains a leading cause of cancer-related mortality, effective adjunct strategies against this disease are needed. This study evaluated an extract prepared from organically cultivated Capsicum annuum treated with deep-seawater-derived ion minerals during cultivation (ODSW-CE) in Lewis lung carcinoma (LLC1) cells and LLC1 tumor-bearing mice. Targeted HPLC-DAD analysis identified and quantified lutein and β-carotene as representative carotenoids. ODSW-CE reduced MTT-derived cell viability and colony-forming ability in vitro and suppressed tumor growth in vivo. In tumor-bearing mice, ODSW-CE was associated with lower hematological inflammatory indices, reduced TNF-α and IL-1β levels in plasma and lung tissue, and attenuated histopathological alterations in tumor and lung tissues. These changes were accompanied by reduced expression of proteins associated with TLR4/MyD88/NF-κB signaling. ODSW-CE also modulated survival and apoptosis-related proteins, decreasing PI3K, p-Akt, and p-mTOR expression, increasing Bax and cleaved caspase-3 expression, and decreasing Bcl-2 expression. Additionally, in tumor tissue, Keap1 expression increased, whereas Nrf2, xCT, and GPX4 expression decreased. Overall, ODSW-CE suppressed LLC1 tumor growth and was associated with coordinated modulation of tumor-associated inflammatory signaling, survival pathways, apoptosis-related proteins, and redox defense.

Antioxidants doi: 10.3390/antiox15070870

Authors: Domantas Armonavičius Audrius Maruška Kristina Bimbiraitė-Survilienė Mantas Stankevičius Baltramiejus Jakštys Tomas Drevinskas Ugnė Gabrytė Elżbieta Skrzydlewska Ona Ragažinskienė Vilma Kaškonienė Saulius Šatkauskas Inga Pečiulienė Arvydas Kanopka

Medicinal plants are a rich source of biologically active compounds, including phenolic acids, flavonoids, ellagitannins and other secondary metabolites. However, the contribution of specific groups of phenolic compounds to antiproliferative activity remains insufficiently clarified. This study extends our previous crude-extract screening by evaluating whether C18 solid-phase extraction (SPE) fractions with different phenolic profiles are associated with different antiproliferative responses. In parallel, extraction strategies were compared to assess method-dependent changes in phenolic recovery and antioxidant capacity, and an additional single-species vegetation-stage analysis of Chamaenerion angustifolium L. Holub was performed to evaluate harvest-stage effects. Phytochemical characterisation was performed using spectrophotometric assays and high-performance liquid chromatography (HPLC) analyses. Among the tested extraction methods, 75% (v/v) methanol in water was the most effective conventional solvent, and ultrasound-assisted extraction yielded the highest overall TPC (total phenolic content), TFC (total flavonoid content), and RSA (radical scavenging activity) values. Vegetation stage analysis of C. angustifolium L. Holub revealed significant variation in phenolic content and antioxidant activity, with the highest levels observed at the beginning of the flowering. Antiproliferative activity was assessed against five cancer cell lines (4T1, A549, Caki-1, HCT116 and MCF7), while HEK-293 cells were used as an immortalised non-cancerous reference model for general cytotoxicity evaluation. Linear mixed-model analysis confirmed a significant incubation-time effect in all tested cancer cell lines, with IC50 values generally decreasing after prolonged exposure. Statistically significant F2-F3 differences were plant-dependent. The 30% (v/v) methanol in water fraction (F2), enriched in oenothein B in C. angustifolium L., showed stronger antiproliferative activity, whereas the 60% (v/v) methanol in water fraction (F3) showed stronger activity in Quercus robur L., Juglans nigra L., Juglans regia L., and Solidago canadensis L. These findings indicate that antiproliferative activity was associated with the qualitative and quantitative composition of the selected phenolic-rich SPE fractions rather than with a single universal fraction effect. All tested fractions exhibited lower cytotoxicity toward HEK-293 cells under the applied conditions; however, claims of selectivity should be confirmed using additional normal or primary cell models. Overall, the findings clarify the role of extraction strategy, harvest stage and targeted fractionation in linking phenolic composition with biological activity.

Antioxidants doi: 10.3390/antiox15070869

Authors: Tariq G. Alsahli Khushhaal Sami I. Alzarea Hesham A. M. Gomaa Muhammad Afzal

Excessive ethanol consumption is a cause of gastric ulceration. This study aimed to identify the gastroprotective action of rufigallol, an anthraquinone, against ethanol-induced gastric ulcers and assess its antioxidant and anti-inflammatory properties. Healthy rats were grouped into five groups (n = 8); the control group received sterile saline orally; the ethanol group received ethanol (5 mL/kg) to generate gastric ulcers on the last day of the experiment; the pretreated rufigallol group was administered 10 or 20 mg/kg rufigallol orally for a week before gastric ulcer initiation; and the drug control group received omeprazole (20 mg/kg) for a week with ethanol treatment. The results showed that oral rugalallol significantly reduced gastric ulcers, as indicated by decreased gastric juice volume and increased preventive percentage, gastric pH value, and pepsin activity. Histopathology confirmed a reduction in the gastric ulcer index following rufigallol treatment. Rufigallol pre-treatment significantly increased antioxidant levels (CAT, SOD, and GSH) and decreased MDA levels compared to the ethanol group. Furthermore, rufigallol treatment decreased MPO, pro-inflammatory cytokines, and mediator levels. It also reduced COX-2, IFN-γ, and NLRP3 expression and restored NO and PGE2 levels. In vitro experiments using HT-29 and HaCaT cell lines confirmed that rufigallol reduced cytokine production and exhibited anti-inflammatory activity in response to lipopolysaccharide stimulation. These results suggested that rufigallol administration may provide gastroprotective benefits against ethanol-induced gastric ulcers, potentially by reducing oxidative stress and gastric inflammation.

Antioxidants doi: 10.3390/antiox15070868

Authors: Ainsley Barisoff Max Walton-Raaby Paula Jofily Nelaine Mora-Diez

The physiological implications of chronic oxidative stress motivate research on antioxidant activity: the cellular defence and repair mechanism for oxidative damage. Through evaluation of thermodynamic and kinetic quantities of hydroperoxyl (•OOH) and methylperoxyl (•OOCH3) radical scavenging reactions, the primary antioxidant activity of twenty phenolic compounds, previously investigated for tertiary antioxidant activity, is evaluated at the M06-2X(SMD)/6-31++G(d,p) level of theory in water and pentyl ethanoate. The formal-hydrogen atom transfer (f-HAT) and single electron transfer (SET) mechanisms are considered. In aqueous environments, SET proves to be the dominant mechanism for most phenols studied, as nearly half of the phenols produced rate constants within the diffusion limit, implicating biochemical relevance. Only three of the phenols also exhibited significant activity via f-HAT. The phenols show greater SET scavenging of •OOH than •OOCH3, but the more efficient f-HAT target is variable. Through comparison with their tertiary activity, we show that thermodynamics are a better predictor for antioxidant activity when the radical is a less complex species (i.e., •OOH versus protein radical); however, several inconsistencies in the Bell–Evans–Polanyi principle still appear between and within solvents and phenolic compounds. This work examines the differences that appear when studying primary versus tertiary antioxidant activity and highlights the importance of using kinetic strategies to investigate antioxidant activity.

Antioxidants doi: 10.3390/antiox15070867

Authors: Zixiong Zhou Xi Zeng Yuqi Guo Zhengyi Tan Xin Zhang Xuyang Liu Shuyu Zheng Wenwen Liu Haiyan Wang Jing Qi

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe, progressive liver disease lacking effective therapies. Disulfiram (DSF), an FDA-approved medication for alcohol dependence, exhibits diverse biological activities beyond its primary indication. This study aimed to evaluate whether DSF holds intervention promise for MASH and to unravel the underlying molecular mechanism. The efficacy of DSF was assessed in a mouse model of MASH induced by a choline-deficient, L-amino acid-defined diet, as well as in hepatocytes exposed to free fatty acids (FFAs) to trigger lipotoxicity. RNA-seq analysis combined with bioinformatic approaches was performed to identify key pathways and hub genes. Mechanistic validation was carried out using Western blotting and qPCR. Computational predictions suggested that DSF may influence insulin resistance, inflammation, autophagy-related markers, and lipid metabolism. In FFAs-treated hepatocytes, DSF administration dose-dependently reduced lipid accumulation and lipotoxicity. Consistently, in MASH mice, DSF administration significantly lowered elevated serum ALT (35%) and AST (40%) levels and the absolute hepatic triglyceride content (reduced from 1 to 0.5 μg/mg protein), and markedly attenuated hepatic steatosis, inflammation, fibrosis, and oxidative stress. Of note, RNA-seq analysis revealed that DSF modulated autophagy-related pathways and identified Aurora kinase A (AURKA) as a central downregulated hub gene. Mechanistically, DSF suppressed AURKA expression, which in turn led to changes in autophagy-related markers. These changes in autophagy-related markers were functionally coupled to a reduction in lipotoxicity. Collectively, DSF alleviates MASH by inhibiting AURKA, thereby relieving AURKA-mediated suppression of autophagy-related markers, which was associated with diminishing lipotoxicity, and ultimately achieving broad suppression of disease progression. Thus, DSF represents a promising hepatoprotective candidate for the intervention of MASH.

Antioxidants doi: 10.3390/antiox15070866

Authors: Yiming Luo Chengbin Feng Mengze Liu Pengfei Zhao Danfei Huang

Selenium nanoparticles (SeNPs), which are nanoscale particles of elemental selenium (Se0), combine the biological activity of selenium with the distinctive properties inherent in nanomaterials, thereby making SeNPs a more promising candidate for advancing selenium-based resources. In this work, several strains of Bacillus with sodium selenite-reducing ability were isolated from selenium-rich soils. Bacillus subtilis ESNS-2 with high selenium tolerance was selected as the target strain. Under culture conditions supplemented with 5 mmol/L sodium selenite, this strain exhibited a reduction efficiency of 75.4 ± 0.6% over 24 h. The produced bioSeNPs were purified, decorated using polysaccharides from the seeds of Plantago asiatica L. (PLP), and subsequently systematically characterized using various means. The results revealed that the prepared PLP-bioSeNPs were regularly spherical elemental selenium particles, with an average particle size of 96.9 ± 1.1 nm, a PDI of 0.108 ± 0.003, and a zeta potential of −19.7 ± 0.4 mV. Characterization confirmed that they exhibited excellent dispersibility and stability. In vitro antioxidant assays, both bioSeNPs and the PLP-bioSeNP complex demonstrated pronounced dose-dependent scavenging activity against DPPH• and ABTS+• radicals. In a D-galactose-induced aging mouse model, both bioSeNPs and PLP-bioSeNPs alleviated D-galactose-induced hepatic and cerebral damage, as well as associated behavioral deficits, through the modulation of oxidative stress balance and suppression of inflammation. This study successfully accomplished the efficient production of SeNPs utilizing Bacillus subtilis ESNS-2. The modification of PLP provided innovative strategies for the development of macromolecular drugs, with a specific emphasis on enhancing stability.

Antioxidants doi: 10.3390/antiox15070865

Authors: Jiaqi Liu Wenjing Liu Lu Li Qianqian Zhang Jun Zhang Wenjie Yan

Oxidative stress contributes to retinal neurovascular injury through inflammation, mitochondrial dysfunction, blood–retinal barrier (BRB) disruption, microcirculatory impairment, and regulated cell death. Hydroxysafflor yellow A (HSYA), a water-soluble quinochalcone C-glycoside derived from safflower (Carthamus tinctorius L.), modulates oxidative and inflammatory signaling, apoptosis, mitochondrial injury, endothelial barrier dysfunction, and neurovascular damage in experimental ischemic, inflammatory, and metabolic disorders. This review critically evaluates the direct ocular evidence for HSYA in diabetic retinopathy and examines the systemic-to-ocular pharmacokinetic and delivery barriers that constrain its ophthalmic translation. Current ocular evidence is limited and concentrated mainly in DR models, in which HSYA attenuates oxidative stress, inflammation, BRB disruption, and apoptosis, potentially through Nrf2/HO-1 signaling. Evidence in retinal photic injury is limited, whereas the proposed relevance of HSYA to retinal ischemia–reperfusion injury, glaucoma, and AMD remains largely hypothesis-generating. The principal translational challenge is whether HSYA can achieve pharmacologically relevant exposure in ocular target tissues. Future studies should integrate dose, plasma and ocular exposure, target engagement, retinal structure, local safety, and visual function in disease-specific models. Accordingly, evidence from non-DR models is discussed primarily to define mechanistic hypotheses and experimental priorities rather than to establish ophthalmic efficacy.

Antioxidants doi: 10.3390/antiox15070864

Authors: Yihang Cai Kehan Li Huibo Ma Jianqiang Wu Yuehong Zheng

The pathogenesis of cardiovascular diseases (CVDs) is intimately linked to cholesterol dysregulation. While high-density lipoprotein cholesterol (HDL-C) is classically considered cardioprotective, contemporary epidemiological evidence reveals a noncausal, often U-shaped, relationship with CVD risk. Static measurements of HDL-C obscure the structural and functional heterogeneity of circulating HDL particles. Under pathological stress, HDL undergoes extensive structural remodeling into dysfunctional HDL, thereby losing its vasculoprotective properties and instead mediating proatherogenic and proinflammatory responses. This review critically evaluates the biogenesis, maturation, and metabolic trajectory of HDL. By integrating recent advancements in proteomics and lipidomics, we map the intricate compositional shifts within HDL subpopulations and clarify the regulatory roles of HDL-associated microRNAs in intercellular communication. We investigate the specific drivers of HDL dysfunction, which is often exacerbated by comorbidities such as diabetes and chronic kidney disease. Furthermore, we outline the methodological transition from automated homogeneous HDL-C quantification to multidimensional profiling. Shifting the clinical focus from HDL quantity to functional quality resolves the HDL-C paradox, helping to drive the development of precision lipidology and targeted therapies to reverse HDL dysfunction in CVDs.

Antioxidants doi: 10.3390/antiox15070863

Authors: Rethabile Banda-Lesole Ipeleng Kopano Rosinah Kgosiemang Tshepiso Jan Makhafola

Vitiligo is a multifactorial depigmentation disorder involving complex interactions among oxidative stress, immune dysregulation, inflammatory signaling, and programmed cell death pathways, which act as a central driver of melanocyte dysfunction and loss, interacting with immune-mediated cytotoxicity and intrinsic cellular susceptibility. Excessive reactive oxygen species (ROS) disrupt mitochondrial integrity, impair redox homeostasis, suppress microphthalmia-associated transcription factor (MITF)-dependent melanogenesis, and induce melanocyte apoptosis. Concomitant dysfunction of the nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element (ARE) axis further exacerbates oxidative injury by limiting endogenous antioxidant capacity. Current therapeutic approaches, including corticosteroids, phototherapy, and targeted immunomodulators, achieve partial repigmentation but do not adequately resolve melanocyte-intrinsic redox imbalance. This structured narrative review comprehensively integrates mechanistic and translational evidence to define phytocompounds as redox-active, multi-target modulators in vitiligo. Plant-derived polyphenols, flavonoids, terpenoids, and related metabolites are shown to attenuate ROS accumulation, preserve mitochondrial function, activate NRF2-dependent antioxidant signaling, and restore MITF-mediated expression of tyrosinase and associated melanogenic enzymes. Furthermore, coordinated modulation of MAPK, PI3K/Akt, and JAK/STAT pathways highlights their capacity to regulate immune–oxidative crosstalk and promote melanocyte survival. Despite promising preclinical and emerging clinical evidence of repigmentation efficacy, translational progress remains limited by poor phytochemical standardization, insufficient transcriptional and proteomic validation, suboptimal stability and dermal bioavailability, and a lack of rigorously designed clinical trials. Collectively, this review provides a mechanistic framework linking redox dysregulation to melanocyte failure and positions phytocompounds as rational candidates for adjunctive or stand-alone antioxidant-based therapies, while defining critical priorities for clinical translation.

Antioxidants doi: 10.3390/antiox15070862

Authors: Beining Xue Pengchi Zhang Hanwen Yang Liusuo Zhang

Ocean acidification poses a critical threat to marine invertebrate survival and diversification, yet the post-transcriptional regulatory mechanisms underlying acid stress responses remain poorly understood. Here, we employed Oxford Nanopore long-read RNA sequencing to systematically characterize transcriptional and post-transcriptional responses to acidic pH stresses in the marine nematode Litoditis marina. Our analysis revealed 912 upregulated and 728 downregulated genes enriched in autophagy, fatty acid metabolism, and peroxisome activation, alongside 327 differential alternative splicing events and 1512 transcripts with significant usage changes under severe acidic pH stress. By integrating weighted gene co-expression network analysis with databases such as WormExp2, we found that acidic pH stress response exhibited resemblance to oxidative stress response. Specifically, we identified genes involved in the oxidative stress response, such as gpx-1, cyp-13A11, trxr-1, cyc-1, and key regulators, including hlh-30/TFEB. Genes such as gpx-1, trxr-1, and cyp-23A1 might protect L. marina from oxidative stress under acidic pH. Moreover, several ferroptosis-related genes, such as gpx-5, fat-2, and smf-1, might render L. marina vulnerable to acidic pH stress. Among the genes with splicing changes, we identified oxidative stress responding genes such as sod-4, prx-2, coq-2, coq-3, prx-10, ctl-2, gst-7, trx-1, mdt-15, and fat-2. Additionally, we discovered the preference for proximal 3′ UTR under acidic pH stress. Genes related to ferroptosis, including cyp-23A1, C07E3.9/PLA2G1B, and C53D5.5/GGT1, exhibited differential 3′ UTR usage under acidic pH stress. Our findings shift the focus from traditional gene-centric analyses to capturing the full breadth of post-transcriptional diversity, providing novel insights into post-transcriptional gene regulation in marine metazoans under environmental stress, as well as revealing that alleviating oxidative stress might increase resistance to acid pH stress.

Antioxidants doi: 10.3390/antiox15070861

Authors: Antón Cruces-Sande Néstor Vázquez-Agra Óscar Seoane-Casqueiro Emma López-Prado Estefanía Méndez-Álvarez Ramón Soto-Otero Antonio Pose-Reino Álvaro Hermida-Ameijeiras

Background/Objectives: Lipid peroxidation is a relevant oxidative–inflammatory mechanism in essential hypertension and cardiovascular disease. Plasma thiobarbituric acid reactive substances (TBARS), commonly reported as malondialdehyde-equivalent values, provide an operational index of lipid peroxidation-related aldehydic reactivity, but blood-based assessment is limited by venipuncture and preanalytical handling requirements. Urine is an attractive non-invasive matrix for redox biomarker development, although whether urinary TBARS reflect plasma lipid peroxidation in hypertensive patients remains insufficiently characterized. This study aimed to evaluate whether matrix-specific normalization—total cholesterol for plasma TBARS and creatinine for urinary TBARS—reveals a measurable intra-individual relationship between these matrices in essential hypertension. Methods: In this paired observational study, plasma and urine samples were obtained from 39 treated patients with essential hypertension under standardized fasting conditions. TBARS were quantified using a colorimetric thiobarbituric acid reaction assay. Plasma TBARS were normalized to total cholesterol and expressed as TBARSp, while urinary TBARS were normalized to creatinine and expressed as TBARSu. Associations were assessed using Spearman’s rank correlation, exploratory receiver operating characteristic (ROC) analyses based on internally derived plasma TBARS percentile thresholds, and Bayesian bootstrap inference. Results: Cholesterol-normalized plasma TBARS and creatinine-normalized urinary TBARS showed a moderate-to-strong positive monotonic association (Spearman’s ρ = 0.717, p < 0.001). Bayesian bootstrap analysis supported this relationship, with a 95% credible interval of 0.57–0.83 and a Bayes factor > 300 for ρ ≥ 0.5. Urinary TBARS showed exploratory within-cohort discriminatory capacity for identifying elevated plasma TBARS using internally derived thresholds, with an AUC of 0.892 for the median-based classification. Conclusions: Creatinine-normalized urinary TBARS showed a moderate-to-strong association with cholesterol-normalized plasma TBARS in treated essential hypertension. These findings provide hypothesis-generating paired-sample evidence that urinary TBARS may serve as a low-burden, non-invasive proxy of plasma lipid peroxidation-related redox alterations. Further validation in larger and clinically diverse cohorts, ideally including more specific lipid peroxidation markers and renal-function-aware analyses, is required to define their translational and clinical utility.

Antioxidants doi: 10.3390/antiox15070860

Authors: Birandra K. Sinha

Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a promising strategy for targeting therapy-resistant cancers. However, both intrinsic and acquired resistance to ferroptosis-inducing agents (FINs) limit their clinical efficacy. Here, we propose an integrated framework in which ferroptosis resistance arises from coordinated redox, metabolic, lipid, iron, and transport adaptations that collectively suppress lipid peroxidation and promote tumor survival. Central to this network is the cysteine–glutathione–GPX4 axis, supported by parallel GPX4-independent systems including FSP1–CoQ10, DHODH–CoQ10, GCH1–BH4, and NQO1–NADPH pathways. These antioxidant systems are reinforced by NRF2-driven transcriptional programs, iron sequestration mechanisms, lipid remodeling that reduces polyunsaturated fatty acid availability, and ATP-binding cassette (ABC) transporters that regulate drug and glutathione flux. Tumor heterogeneity further enhances ferroptosis resistance by generating metabolically distinct cellular subpopulations that differ in their susceptibility to lipid peroxidation. We discuss emerging therapeutic strategies designed to overcome these coordinated defense mechanisms, including simultaneous targeting of GPX4 and FSP1, metabolic reprogramming, iron-directed therapies, and nanoparticle-based delivery systems. Collectively, these observations support a systems-level model in which durable ferroptosis-based cancer therapy will require disruption of multiple interconnected resistance mechanisms rather than inhibition of a single molecular target.

Antioxidants doi: 10.3390/antiox15070859

Authors: Francesca Giordano Martina Roberta Nastasi Vitaliy B. Borisov Elena Forte

Bacterial terminal oxidases are essential for growth and may provide protection against environmental stressors. Bacteria often have to cope with ammonia, which, although an essential nutrient, is toxic at high concentrations. Here, we studied the influence of ammonia on the cell growth of three different Escherichia coli respiratory mutants, each possessing a single terminal oxidase: cytochrome bd-I, cytochrome bd-II, or cytochrome bo3. We also investigated the effect of ammonia on O2 consumption in cytochrome bd-II-only cells and membranes, as well as in the isolated bd-II enzyme. Using microcalorimetry, spectrophotometry and high-resolution respirometry, the following new results were obtained: (i) At pH 8.3, the addition of ammonia to both bd-I-only and bd-II-only cell cultures has virtually no effect on growth. In contrast, the growth of bo3-only cells is significantly impaired. (ii) The addition of ammonia to bd-II-only intact cells at pH 8.3 not only fails to inhibit their respiration but also accelerates O2 consumption. The same is observed with bd-II-only isolated membranes and detergent-solubilized bd-II enzyme. The maximum increase in cytochrome bd-II O2 consumption rate is approximately 150%. Physiological aspects of the findings are discussed, and molecular mechanisms for ammonia-induced acceleration of O2 consumption by cytochrome bd-II are suggested.

Antioxidants doi: 10.3390/antiox15070858

Authors: Sonia Eligini Lisa Brocca Alice Mallia Arianna Valeriano Erica Gianazza Cristina Banfi

Whole blood (WB) storage induces biochemical and biomechanical alterations that may compromise red blood cell (RBC) quality. Since oxidative stress is a major driver of storage lesions, we investigated whether N-acetylcysteine (NAC) could attenuate these changes during refrigerated storage. WB from healthy donors was stored at 4 °C for 42 days with or without NAC, added either once at baseline or every 10 days. Plasma albumin proteoforms were assessed by liquid chromatography–mass spectrometry, free hemoglobin species by spectrophotometry, plasma proteomic changes by proximity extension assay, and RBC hemorheological properties by LORRCA analysis. Storage decreased reduced albumin (HSA-SH) and increased oxidized albumin (HSA-Cys), indicating plasma oxidation. Free oxyhemoglobin, deoxyhemoglobin, and methemoglobin increased, consistent with hemoglobin oxidation and hemolysis. Storage also induced plasma proteomic alterations and impaired RBC osmotic and deformability parameters. NAC preserved albumin redox status, limited free hemoglobin accumulation, and attenuated storage-induced proteomic changes. Moreover, NAC partially preserved RBC osmotic and rheological properties, particularly parameters related to osmotic fragility and hydration. No clear advantage of 20 mM over 10 mM NAC was observed. Overall, NAC attenuated oxidative and functional alterations associated with refrigerated whole blood storage, supporting further investigation of antioxidant supplementation as a strategy to mitigate storage lesions under ex vivo conditions.

Antioxidants doi: 10.3390/antiox15070857

Authors: Lidia Ciccone Giovanni Petrarolo Ilaria D’Agostino Fabio Scianò Bianca Laura Bernardoni Manuela Leri Jihyae Ann Susanna Nencetti Jeewoo Lee Monica Bucciantini Concettina La Motta

Alzheimer’s disease (AD) involves oxidative stress, metal dyshomeostasis, and toxic oligomers of the amyloid-β peptide (Aβ1-42), calling for multifunctional agents. We investigated a panel of imidazo[1,2-a]pyridines bearing catechol or resorcinol motifs previously designed as SIRT1-activating agents. Their antioxidant profile was evaluated using in vitro DPPH and ABTS assays, which revealed promising radical scavenging activities, and TBARS assays on rat brain homogenates showing inhibition of lipid peroxidation, strictly dependent on the phenolic pattern. UV–Vis studies revealed metal-binding properties, particularly Cu2+ and Fe2+ interactions. In Aβ1-42 aggregation assays, the most active derivatives appeared to promote fibril maturation and the growth of large, ThT-low aggregates with distinct morphological features observed by TEM. Notably, Aβ1-42 aggregates generated in the presence of these compounds exhibited reduced cytotoxicity, preserved cell viability, and induced lower ROS levels in RA-differentiated SH-SY5Y cells compared to aggregates formed in their absence. Imaging and FRET analyses further indicated reduced formation of membrane-binding toxic species. Overall, our data suggest that polyphenolic imidazo[1,2-a]pyridines can remodel Aβ1-42 aggregation, redirecting it toward structurally distinct and less toxic assemblies, while also counteracting oxidative and metal-associated damage. These findings highlight their potential as multifunctional agents capable of addressing several pathological hallmarks of AD.

Antioxidants doi: 10.3390/antiox15070856

Authors: Wenshu Liu Lun Chen Wencai Liu Jingjing Lu Yuzhu Wang Xiaoze Guo Lingya Li Xu Han Chuang Mei Siming Li Zirui Wang

This study was designed to assess the protective efficacy of dihydromyricetin (DHM) against intestinal injury in Chinese soft-shelled turtles (Pelodiscus sinensis) caused by partial replacement of fishmeal (FM) with fermented rapeseed meal (FRM), and to uncover the molecular mechanisms involved. Turtles were fed an FM-based control diet, an FRM-substituted diet, or FRM diets supplemented with DHM at 0.5‰ (DHMT1), 1.0‰ (DHMT2) or 2.0‰ (DHMT3) for 8 weeks. Growth performance, digestive enzyme activities, antioxidant parameters, inflammatory cytokines, and intestinal histomorphology were assessed, and intestinal transcriptomics and metabolomics were also performed. FRM replacement significantly improved growth performance; however, this beneficial effect was accompanied by notable intestinal mucosal oxidative damage, as evidenced by decreased villus height, increased lumen space, and lamina propria edema, along with elevated pro-inflammatory cytokines (IL-1β and TNF-α) and MDA content, alongside reduced GSH and CAT activities. DHM supplementation dose-dependently ameliorated these adverse effects by restoring mucosal integrity, digestive enzyme activities, redox homeostasis, and inflammatory balance, ultimately improving growth performance. Transcriptomic KEGG analysis revealed that DHM enriched pathways related to glycerophospholipid metabolism, glutathione metabolism, drug metabolis-cytochrome P450, and polyunsaturated fatty acid metabolism. Metabolomics further confirmed dose-dependent remodeling of phospholipids and bile acids. Integrated omics demonstrated that DHM likely regulates detoxification, anti-inflammatory, membrane repair, and antioxidant pathways. In conclusion, DHM demonstrates a protective effect against FRM-induced intestinal mucosal oxidative damage in P. sinensis, which may be mediated by a synergistic combination of enhanced detoxification, anti-inflammatory modulation, restoration of phospholipid membrane integrity, and reinforcement of antioxidant defenses.

Antioxidants doi: 10.3390/antiox15070855

Authors: Yue Chang Yanzhuo Song Naveed Ahmad Chao Song Yuhang Chu Yuru Zhang Lufei Feng Wei Wei Min Zhang Xiuming Liu

Cisplatin-induced acute kidney injury (AKI) remains a dose-limiting complication in cancer chemotherapy with restricted preventive measures. Carthamus tinctorius L. (safflower) is known to exhibit effective antioxidant and anti-inflammatory properties; however its potential in renoprotective mechanisms remains poorly understood. The present study utilized a cisplatin-induced AKI mouse model to evaluate the renoprotective potential of CT (Carthamus tinctorius) extract. Integrated multi-omics along with in silico and in vivo approaches were used to elucidate the underlying mechanisms of action. The results initially demonstrated a rich phytochemical profile of CT extract characterized by abundant polysaccharides and flavonoids, with Hydroxysafflor Yellow A as a dominant bioactive constituent. In a cisplatin-induced acute kidney injury (AKI) mouse model, CT extract noticeably ameliorated the abnormalities of renal injury, as suggested by improved histopathology, reduced serum creatinine and BUN levels, and regulation of redox homeostasis. Metabolically, CT extract partially reversed AKI-associated disturbances by affecting 21 key metabolites, likely associated with histidine and alanine-aspartate-glutamate biosynthesis, and modulating amino acid and energy metabolism pathways. Concurrently, CT extract improved gut microbial homeostasis, increasing microbial diversity, normalizing the Firmicutes/Bacteroidota ratio, suppressing pathogens, and enriching beneficial Ligilactobacillus. Network pharmacology and molecular docking identified AKT1, RELA, MAPK, and TP53 as central targets of core compounds (rutin and kaempferol derivatives), apparently targeting the PI3K-AKT and RELA (NF-kappaB) hubs. These results suggested that the renoprotective effects of CT extract are associated with transcriptional upregulation of the PI3K/Akt/Nrf2 pathway-related genes, increased expression of antioxidant genes (Ho-1, Sod1), and reduced expression of pro-inflammatory mediators (RelA, Cdk2) in the cisplatin-induced AKI mouse model.

Antioxidants doi: 10.3390/antiox15070854

Authors: Hisano Ujiie Hiroyuki Kanzaki Mao Katayama Tomomi Ida Syunnosuke Tohyama Miho Shimoyama Yuta Katsumata Chihiro Arai Misao Ishikawa Hiroshi Tomonari

Mandibular condylar cartilage (MCC) exhibits greater susceptibility to mechanical stress-induced degeneration than tibial articular cartilage (TAC). This study investigated whether differential epigenetic regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant responses, is associated with distinct antioxidant capacities between these cartilage types. Cartilage tissues from 5-week-old male ICR mice (n = 16 for gene analyses, n = 8 for protein analyses) were obtained using laser microdissection. Gene and protein expression was analyzed by microarray, real-time RT-PCR, and immunohistochemistry. DNA methylation of the Nrf2 promoter was evaluated using pyrosequencing and high-resolution melting analysis. Nrf2 expression in MCC was approximately 1/10 that in TAC at mRNA level and only 5% at protein level. Downstream antioxidant enzymes (NQO1, G6PD, HO-1) showed significantly reduced expression in MCC. Oxidative DNA damage marker 8-OHdG was significantly elevated in MCC compared to TAC (20.0% vs. 10.7%, p < 0.05). The Nrf2 promoter region showed higher DNA methylation levels in MCC, confirmed by high-resolution melting analysis. Higher Nrf2 promoter methylation in MCC is associated with reduced antioxidant capacity and elevated oxidative damage. This epigenetic–antioxidant relationship may contribute to MCC’s vulnerability to mechanical stress-induced degeneration and represents a potential therapeutic target for temporomandibular joint disorders.

Antioxidants doi: 10.3390/antiox15070853

Authors: Jung-Wook Yang Ho Soo Kim Yun-Hee Kim

Root-knot nematodes (RKNs; Meloidogyne spp.) are among the most destructive plant parasites, causing severe yield losses in diverse crops. Reactive oxygen species (ROS), particularly superoxide radicals (O2•−) and hydrogen peroxide (H2O2), are central regulators of plant–RKN interactions. This review synthesizes current molecular, biochemical, genetic, transcriptomic, and translational evidence showing that the outcome of infection is determined by the spatiotemporal regulation of H2O2 rather than by ROS abundance alone. In resistant interactions, nematode perception activates PTI-associated signaling through selected cell-surface receptor complexes, including some BAK1/SERK3-associated pathways, together with BIK1, Ca2+ signaling, and RBOHD/F, generating a sustained oxidative activity associated with salicylic acid-dependent immune signaling and reduced H2O2-scavenging capacity and coupled to hypersensitive response, lignin and callose deposition, and feeding site restriction. In susceptible interactions, RKNs deploy ROS-targeting effectors such as Mi-CRT, MjTTL5, CATLe, Mj-NEROSs, and CMII to suppress ROS production, enhance antioxidant scavenging, or weaken SA-dependent defense. Evidence from a cyst-nematode system suggests that RBOH-derived ROS can restrict excessive cell death around syncytia; whether an analogous lower-redox requirement exists in RKN-induced giant cells remains unresolved. Finally, redox-based strategies, including CRISPR/Cas editing, host-induced gene silencing, chemical priming, and biocontrol, are discussed as promising approaches for durable and sustainable nematode resistance.

Antioxidants doi: 10.3390/antiox15070852

Authors: Viet H. Dinh Magda Descorbeth Francis Zamora Jo-Wen Liu Cono Badalamenti Salvador Soriano Johnny D. Figueroa Marino De León Alfonso M. Durán

Neuropathic pain (NP) arises from diverse conditions, including peripheral nerve injury, spinal cord injury (SCI), and painful diabetic neuropathy, yet these disorders share oxidative stress, mitochondrial dysfunction, lipid dysregulation, and altered neuronal excitability. We investigated whether dietary omega-3 polyunsaturated fatty acids modulate ferroptotic stress-associated pathways, defined as lipid peroxidation susceptibility and impaired antioxidant defense rather than overt ferroptotic cell death. Female Sprague–Dawley rats received either a soy oil control diet (SOD) or fish oil omega-3-enriched diet (FOD) before chronic constriction injury (CCI). Behavioral outcomes were assessed using Hargreaves and CatWalk testing, followed by dorsal root ganglion (DRG) RNA sequencing, RT-PCR, and GPX4 ELISA. Previously generated SCI metabolomics and human diabetic serum metabolomic/lipidomic datasets were re-analyzed for shared pathways. FOD attenuated CCI-induced thermal hypersensitivity and improved gait parameters. DRG transcriptomics showed reduced injury-associated transcriptional disruption, enrichment of selenoamino acid metabolism, nonsense-mediated decay, and ribosomal quality-control pathways, and reduced mitochondrial dysfunction pathway activity. Omega-3 increased Gpx1/Gpx4 expression and GPX4 protein, reduced pain-associated genes including Scn10a, Piezo2, Trpa1, and Oprm1, and aligned with selenoamino acid enrichment in SCI and human datasets. Human lipidomics showed MG/DG/PC/PE pathway remodeling. These findings support ferroptotic stress as a plausible shared downstream mechanism modulated by omega-3 supplementation across NP models.

Antioxidants doi: 10.3390/antiox15070851

Authors: Begoña M. Escribano Manuel E. Valdelvira Ana Muñoz-Jurado Montse Feijóo Eduardo Agüera-Morales Javier Caballero-Villarraso Abel Santamaría Isaac Túnez

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method with neuromodulatory capacity in neurodegenerative diseases such as multiple sclerosis (MS). Its therapeutic value is linked to its activity against oxidative stress by activation of antioxidant defenses. The sex hormones, estrogens (E), progesterone (P) and testosterone (T), have demonstrated their power as adjuvants to TMS, improving cortical excitability. The aim of this study was to evaluate the effect of these hormones as adjuvants to extremely low-frequency electromagnetic fields (ELFEFs) in the treatment of experimental autoimmune encephalomyelitis (EAE), the experimental model of MS. The effect of these hormones as replacement therapy was also evaluated in ovariectomized rats treated with ELFEFs. Sixty-five female Dark Agouti rats were divided into 13 groups (5 rats/group), in which biomarkers of oxidative stress and the glutathione redox cycle in non-nervous organs (kidney, liver, heart, intestines and blood) were analyzed. The results show that ELFEFs alone are more effective against oxidative stress. However, P and E were more effective than ELFEFs, both as adjuvants and in hormone replacement therapy, in activating the glutathione system. Therefore, it could be concluded that sex hormones play an important role against MS, enhancing the antioxidant effect of ELFEFs.

Antioxidants doi: 10.3390/antiox15070850

Authors: Yukun Zhang Amina Moss Saichiro Yokoyama

Global aquaculture is expanding to meet the increasing demand for high-quality aquatic protein, with projections indicating that the total production of aquatic animals will reach 205 million tonnes by 2032 [...]

Antioxidants doi: 10.3390/antiox15070849

Authors: Tianzi Wang Wenling Shi Xingyue Song Jinglei Huang Youqing Cheng Xiaofan Zhang Wei Xie Guoqing Wan

Ulomoides dermestoides (Yangchong) is a tenebrionid beetle used in traditional medicine across Asia and Latin America. While crude extracts show effects on inflammation, oxidative stress, and other conditions, systematic integration of its bioactive substances, mechanisms, and translational potential is lacking. This review consolidates its chemical basis, comprising volatile benzoquinones, terpenes, and alkenes, alongside non-volatile fatty acids, proteins (antioxidant enzymes, glycoproteins), and phenolics. Pharmacological evidence indicates multi-target modulation of reactive oxygen species (ROS), cytokines, leukocyte recruitment, endothelial activation, and thromboinflammation. Recent advances include proteomic identification of antioxidant protein complexes, neuroprotection in a Parkinson’s disease model, chromosome-level genome assembly, and isolation of the UDP-glucose pyrophosphorylase 2a (UGP2A) glycoprotein, which alleviates thrombosis partly via toll-like receptor 4/myeloid differentiation primary response 88 (TLR4/MyD88)-mediated endothelial anti-inflammatory effects. However, most evidence remains preclinical, relying on non-standardized crude extracts, and benzoquinone-containing fractions display potential cytotoxicity and genotoxicity. Future research should integrate bioassay-guided isolation, structural characterization, multi-omics, pharmacokinetic/pharmacodynamic (PK/PD) analysis, standardized quality markers, and rigorous safety evaluation to transform U. dermestoides from an empirical insect-derived medicinal resource into a scientifically validated source of preclinical antioxidant and anti-inflammatory candidate substances.

Antioxidants doi: 10.3390/antiox15070848

Authors: Qiwen Liu Yunxia Liang Dongli Xie Yiming Xu Dianliang Wang Xiaogang Luo

Mitochondrial alterations, including mitochondrial DNA (mtDNA) loss and defects in maintenance pathways, have been recognized as an important driver for toxic effects of environmental pollutants. Therefore, exposure to nano-sized particles (1–100 nm in diameter; a new source of environmental pollution) may also result in these mitochondrial impairments; however, controversial results have been reported. Available studies collected from three electronic databases through July 2025 were pooled for a comprehensive assessment. Meta-analysis of 19 in vitro studies (69 datasets) showed exposure to nano-sized particles significantly reduced mtDNA content [standardized mean difference = −1.08; p-value = 0.001). The expression levels of mtDNA-encoded (ND1, COX1,2, CYTB, ATP6), mitochondrial biogenesis (SIRT1, PGC-1α, TFAM) and fusion genes (MFN1, MFN2, OPA1) were found to be significantly down-regulated, while fission genes DRP1 and FIS1 were up-regulated following nano-sized particle exposure after meta-analysis of corresponding in vitro and in vivo studies. Accordingly, mtDNA depletion and expression disruption in mtDNA-encoded and maintenance genes may represent important contributors to nano-sized particle exposure-induced diseases.

Antioxidants doi: 10.3390/antiox15070847

Authors: Ana Maria Ciupitu Gina Cecilia Pistol Valeria Cristina Bulgaru Iulian Alexandru Grosu Alexandra Gabriela Oancea Norica Branza-Nichita Ionelia Taranu

Carrot processing for juice generates substantial pomace residues rich in bioactive compounds, which represent both an environmental challenge and an unexploited resource. This study investigated the protective effects of a polyphenolic extract derived from carrot pomace (CP) against Escherichia coli lipopolysaccharide (LPS)-induced damage. For that, we used IPEC-1 (Intestinal Porcine Epithelial Cells) as an in vitro model of the intestinal epithelium. The total phenolic content of the CP polyphenolic extract (CPE) was 1.017 mg GAE/mL, with flavan-3-ols (epicatechin, catechin, epigallocatechin) accounting for 71.3% of that value. Before being exposed to LPS (10 μg/mL) for 24 h, the cells were pre-treated with CP extract (20.34 µg and 10.17 µg polyphenols/mL of extract corresponding to 1/50 and 1/100 dilution) for 4 h. Epithelial renewal (cell viability, cell proliferation and apoptosis), monolayer/barrier integrity (TEER, FD4 permeability, LDH release), as well as epithelial functionality (synthesis of pro-inflammatory cytokines: TNF-α, IL-1β, IL-6, reactive oxygen species (ROS), nitric oxide (NO) production), MAPK signalling and mitochondrial morphology and function were assessed. The results showed that CP extract had no cytotoxic effects and successfully counteracted LPS-induced loss of cell viability and proliferation. The pre-treatment with CPE at both dilutions significantly reduced LPS-induced apoptosis and cell death. Barrier integrity was preserved with TEER values maintained near baseline: −0.43% and −0.24% for 1/50 and 1/100 dilutions of CPE vs. −53.47% at 72 h for LPS alone, and paracellular FD4 passage was restored to control levels. At the molecular level, CP extract reduced pro-inflammatory cytokine gene expression (IL-6 by 40%, TNF-α by 50–56%) and suppressed LPS-induced MAPK activation by 62.9% and 46.5%, for 1/50 and 1/100 dilutions of CPE, respectively. The pre-treatment of cells with CP extract normalised LPS-induced ROS production and protected mitochondrial morphology and function. These in vitro findings demonstrate that CP extract exerts a protective effect on intestinal epithelial cells, acting through anti-inflammatory, antioxidant and barrier-preserving mechanisms. This supports the hypothesis for valorisation of carrot agro-industrial by-products as functional feed additives for promoting intestinal health. Further in vivo studies are needed to validate this hypothesis and to establish the concentration/rate of inclusion of carrot by-products to achieve the maximal positive effects.

Antioxidants doi: 10.3390/antiox15070846

Authors: Xue Yu Yujie Wu Wei Zhang Gaosen Zhang Shiyu Wu Xiaomin Niu Liguo Yang Qi Feng Tuo Chen Guangxiu Liu

Water-soluble blue microbial pigments with antioxidant activity remain rare, and their host-level protective mechanisms are poorly understood. Here, we identified the genetic basis of blue pigment biosynthesis in the glacier-derived strain Arthrobacter antioxidans QL17. Heavy-ion mutagenesis yielded a hyperpigmented mutant (M157) and a pigment-deficient mutant (M186), and pigment yield was positively associated with hydrogen peroxide (H2O2) tolerance. Genome mining identified MWM45_RS16760 as the sole core biosynthetic gene in a candidate nonribosomal peptide synthetase (NRPS)-like cluster. The encoded protein displayed an adenylation–peptidyl carrier protein–thioesterase (A-PCP-TE) architecture with a predicted L-glutamine-specific A domain, and its transcript abundance paralleled pigment production across the three strains. Phylogenetic analysis placed MWM45_RS16760 in a distinct actinomycete-associated indigoidine-like lineage separated from the characterized BpsA and IndC branches. Heterologous expression in Escherichia coli reconstructed a blue-pigment-producing phenotype, increased H2O2 tolerance, and was accompanied by enhanced extracellular DPPH and ABTS radical-scavenging activities in the culture supernatant. Comparative transcriptomics further revealed coordinated activation of oxidative-stress and proteostasis responses alongside repression of tryptophan biosynthesis and flagellar assembly. These findings identify MWM45_RS16760 as a candidate indigoidine-like NRPS associated with blue pigment biosynthesis and oxidative-stress resistance, with heterologous expression linked to enhanced radical scavenging and coordinated transcriptional reprogramming, expanding the phylogenetic and functional diversity of indigoidine-like systems.

Antioxidants doi: 10.3390/antiox15070845

Authors: Wenrui Zhang Yijia Zhang Xinyuan Wang Yujuan Chen Yixuan Li Yanan Sun

Chronic ultraviolet B (UVB) radiation drives cutaneous photoaging—clinically manifesting as erythema, edema, scaling, deep wrinkling, loss of elasticity, and barrier disruption—through mitochondrial reactive oxygen species (mtROS) overproduction and quality-control failure. Here we identify α-ketoglutarate (AKG; also known as 2-oxoglutarate), a TCA-cycle intermediate and essential co-substrate for α-ketoglutarate-dependent dioxygenases (α-KGDDs), as a metabolic corrector of mitochondrial redox homeostasis in UVB-induced photoaging. In a 10-week chronic UVB SKH1 hairless mouse model, microneedle-assisted transdermal delivery of AKG dose-dependently attenuated macroscopic erythema, scaling, and erosive lesions, restored skin barrier function and dermal elasticity, preserved epidermal–dermal architecture, and protected collagen and elastic fiber integrity, with efficacy comparable to all-trans retinoic acid. Mechanistically, AKG reactivated α-KGDD/prolyl hydroxylase (PHD) catalytic function and promoted proteasomal clearance of aberrantly stabilized HIF-1α under normoxia; this was accompanied by restored AMPK Thr172 phosphorylation downstream of constitutive LKB1 and recovery of PGC-1α-driven mitochondrial biogenesis. AKG preferentially attenuated mitochondrial superoxide over total cellular ROS through a co-substrate-mediated mechanism distinct from direct radical scavenging, and its protective effects were largely abrogated by DMOG (an α-KGDD inhibitor) or compound C (an AMPK inhibitor). These findings position AKG, delivered via microneedle-assisted topical application, as a candidate metabolite-based intervention targeting the α-KGDD/HIF-1α/AMPK axis for photoaging.

Antioxidants doi: 10.3390/antiox15070844

Authors: Sabrina Tini Stefano Celano Stella Pigni Elena De Palma Hilal Irem Ozdemir Tommaso Raiteri Alessandro Antonioli Jessica Baima Valentina Antoniotti Marina Caputo Paolo Marzullo Flavia Prodam

Background: Oxidative stress and chronic inflammation contribute to the pathogenesis of obesity and type 2 diabetes (T2D), yet the effects of dietary interventions on endogenous antioxidant defences remain poorly defined. This is a non-randomized study evaluates the effects of very-low-energy ketogenic therapy (VLEKT), compared with a Mediterranean diet (MedD) and a control group, on antioxidants, metabolic, and inflammatory markers. Materials and Methods: Thirty adults with obesity and T2D were assigned to VLEKT (n = 10), MedD (n = 10), or control (n = 10) for 90 days. Metabolic parameters, inflammatory cytokines, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were assessed. Longitudinal changes were analyzed using linear mixed models. Results: VLEKT exhibited significant reductions in body weight, fat mass, HbA1c, and HOMA-IR. SOD activity increased in the VLEKT group, whereas no significant changes were observed in MedD. Changes in SOD were inversely associated with changes in HOMA-IR. GPx showed a less consistent response pattern, while inflammatory markers did not differ between groups. Conclusions: VLEKT was associated with substantial metabolic improvement accompanied by a selective modulation of antioxidant enzyme activity. The increase in SOD activity and its association with HOMA-IR suggest a link between metabolic and redox adaptations in subjects with obesity and T2D.

Antioxidants doi: 10.3390/antiox15070843

Authors: Caterina Lonati Michele Battistin Andrea Carlin Michela Ripolone Francesco Fortunato Valentina Fonsato Alessia Brossa Alberto Zanella Giovanni Camussi Daniele Eliseo Dondossola

Despite advances in liver machine perfusion (MP), ischemia–reperfusion injury (IRI) remains a major challenge in liver transplantation, with energetic stress and mitochondrial dysfunction recognized as key drivers of damage exacerbation. We investigated whether fractions enriched with extracellular vesicles (EVs) derived from mesenchymal stromal cells can preserve energetic homeostasis in rat livers undergoing normothermic MP (NMP). An established NMP rat model was used (n = 5 per group). After procurement, livers underwent NMP for 4 h, preceded or not by 30 min cold ischemia (CI). EVs (NMP + EVs and CI + NMP + EVs) or saline (NMP and CI + NMP) were randomly administered to the perfusion fluid. Perfusate samples were collected throughout the procedure, and biopsies were taken at the end of NMP. Ischemic livers exhibited succinate accumulation, flavin mononucleotide (FMN) release, activation of reverse electron transport, and adenosine triphosphate (ATP) depletion. EV treatment effectively counteracted these effects, restoring a metabolic profile comparable to that of non-ischemic livers. Moreover, EVs improved adenosine monophosphate/ATP ratios and prevented AMP-activated protein kinase activation, a key energy-stress sensor. Furthermore, EVs reduced oxidative stress markers, cell death mediators, and pro-inflammatory cytokines, indicating a broad cytoprotective and anti-inflammatory effect. These findings support the potential of EVs to preserve mitochondrial function, restore energy balance, and reduce inflammation, thereby improving liver cell viability during NMP.

Antioxidants doi: 10.3390/antiox15070842

Authors: Diana-Maria Mateescu Dragos-Mihai Gavrilescu Adelina-Raluca Marinescu Ovidiu Rosca Voichita Elena Lazureanu Adrian-Cosmin Ilie Camelia-Oana Muresan Alexandra Enache

(1) Background: Reactive oxygen species (ROS) act as physiological signaling mediators but contribute to oxidative damage, cellular dysfunction, and age-related disease when redox homeostasis fails. Forkhead box O4 (FOXO4) has emerged as a redox-sensitive regulator linking stress adaptation, antioxidant defense, and cellular senescence. This structured narrative review critically evaluates which redox- and aging-related conclusions are supported directly for FOXO4 and which remain inferred from other FOXO isoforms. (2) Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to May 2026; Google Scholar was used only for supplementary citation tracking and did not contribute a separate platform-level count. Of 420 records, 300 remained after deduplication, 110 full texts were assessed, and 89 publications were retained. FOXO4-related evidence was classified as directly FOXO4-specific (n = 18), FOXO-family/conserved (n = 24), or extrapolated predominantly from FOXO1/FOXO3/DAF-16 (n = 20); 27 contextual publications on redox biology, senescence, disease, and NRF2 were tracked separately. (3) Results: The strongest FOXO4-specific evidence supports three mechanistic axes: cysteine-dependent redox sensing, stress-regulated nuclear trafficking and coactivator engagement through transportin-1 and p300/CBP, and FOXO4–p53-mediated survival of senescent cells. By contrast, direct FOXO4 regulation of commonly cited antioxidant targets, including SOD2, catalase, sestrins, and GADD45, remains insufficiently demonstrated and is inferred mainly from FOXO3 or broader FOXO-family studies. FOXO4-DRI has shown senolytic activity in preclinical models, including vascular endothelium, but has not been clinically validated. (4) Conclusions: FOXO4 is a redox-responsive transcriptional regulator with well-supported roles in cysteine-based signaling and senescent-cell survival, whereas its target-gene-level antioxidant program remains incompletely resolved. Clinical translation of FOXO4–p53 disruption requires isoform- and tissue-specific validation, pharmacokinetic and delivery studies, long-term toxicology, and explicit assessment of p53-dependent tumor surveillance.

Antioxidants doi: 10.3390/antiox15070841

Authors: Inês C. C. Costa Joana Silva Isabel Oliveira Abreu Juliana Antunes Gaspar Susete Pinteus Celso Alves Maria L. S. Cristiano Rui Pedrosa

Skin functionalities are instrumental in four main domains: protection, regulation, sensation, and support. However, excessive exposure to ultraviolet (UV) radiation can compromise skin integrity and, in turn, affect its functions, by generating reactive oxygen species (ROS). Aiming to protect skin from UV radiation, sunscreens incorporate UV filters and antioxidants that absorb/reflect UV rays and neutralise free radicals, respectively. Nevertheless, undesired side and ecological effects of conventional UV filters have spurred the search for safer alternatives. Among synthetic antioxidants, thioethers have attracted attention for their redox power and potential medicinal properties. In this context, a library of aminopyrimidine–arylthioether conjugates was synthesised and evaluated for their antioxidant, enzyme-inhibitory and antibacterial activities, as well as for their cytotoxicity in HaCaT cells and potential photoprotective properties. Among the aminopyrimidine-thioethers studied, compound C5 stood out for its antioxidant potential, exhibiting a value of 566.39 mM FeSO4 equivalents per mM of the compound, while compound C2 showed the highest anti-enzymatic potential, inhibiting elastase (45.58%) and tyrosinase activities (34.66%). Regarding photoprotective activity, compound C13 reduced by 33.74% the ROS production induced by UV radiation exposure, at 100 μM, a non-cytotoxic concentration. Finally, compound C7 inhibited the growth of Staphylococcus epidermidis, Staphylococcus hominis and Cutibacterium acnes, at 30 μM. These preliminary results demonstrate that aminopyrimidine–arylthioethers constitute a new class of compounds warranting further investigation for skin protection. Compound C5 showed antioxidant activity in the FRAP assay, comparable to that of the positive control, BHT.

Antioxidants doi: 10.3390/antiox15070840

Authors: Kyung-Hyun Cho Krismala Djayanti Ashutosh Bahuguna Yunki Lee Sang Hyuk Lee Seung Hee Baek

This study compares the efficacy of ozonated sunflower oil (OSO) and ozonated olive oil (OOO) in terms of antioxidant properties, modulation of high-density lipoprotein (HDL) functionality, and protective effects against carboxymethyllysine (CML)-mediated stress in zebrafish embryos and adults. The spectral and electronic nose (e-nose) analyses revealed that OSO and OOO possessed markedly distinct physicochemical characteristics and volatile and olfactory constituents compared with non-ozonated sunflower (SO) and olive oil (OO). The fluorescence spectrum analysis of HDL treated with OOO and OSO exhibited a red shift (2.6~3.3 nm) in the wavelength maximum fluorescence (WMF), accompanied by pronounced quenching of tryptophan fluorescence. Additionally, a significant increase in HDL-associated paraoxonase (PON) and ferric ion reduction (FRA) activity was observed in the OSO- and OOO-treated HDL. However, compared to OOO, significantly higher PON and FRA activities were observed in HDL treated with OSO. Also, compared to OOO, OSO effectively reverses CML-induced oxidative stress, altered heart rate, and reduced embryo survival. Similarly, in adult zebrafish, CML-compromised survival, swimming impairment, and disturbed antioxidant parameters were prevented by treatment with OOO and OSO. Nonetheless, OSO showed significantly higher efficacy than OOO. Consistently, OSO substantially reduced the CML-elevated blood glucose, total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels with a marked increase in high-density lipoprotein cholesterol (HDL-C) levels. Notably, no significant effect of OOO was observed on the reduction in and augmentation of LDL-C and HDL-C, respectively. Both OOO and OSO significantly protect against CML-triggered liver and kidney damage. However, compared with OOO, OSO significantly reduced neutrophil infiltration, interleukin-6 (IL-6) production, liver steatosis, ROS generation, and cellular senescence in the kidneys. The study concludes that OSO exerts significantly higher beneficial effects than OOO on HDL functionality and antioxidant defense, thereby attenuating CML-induced inflammatory and oxidative damage.

Antioxidants doi: 10.3390/antiox15070839

Authors: Asad Abbas Iqra Tabassum Saeed Vohra Ralf Weiskirchen Areesha Shoukat Muhammad Khurram Afzal Adan Ijaz Nimra Anees Anis Ahmad Chaudhary Abdulrahman Mohammed Alhudhaibi

Momordica charantia L. is a medicinal plant rich in bioactive compounds, including steroidal glycosides, flavonoids, phenolics, triterpenoids, saponins, and polysaccharides, which exhibit antidiabetic, antioxidant, anti-inflammatory, hepatoprotective, and anticancer activities. This review summarizes its nutritional and phytochemical composition, green extraction technologies, molecular mechanisms, and industrial applications based on literature from Google Scholar, PubMed, Scopus, Web of Science, ScienceDirect, and other scientific databases. Ultrasound-assisted extraction is an efficient and eco-friendly method that provides higher recovery of bioactive compounds from M. charantia and improved bioavailability compared with enzyme-assisted, microwave-assisted, and conventional methods. The phytochemicals of M. charantia regulate oxidative stress, inflammation, lipid peroxidation, and glucose homeostasis. Studies show that its antidiabetic effects involve improved insulin sensitivity, enhanced glucose uptake, and inhibition of carbohydrate-digesting enzymes. These compounds also exhibit antioxidant activity through free radical scavenging and anti-inflammatory effects via inhibition of the NF-κB and MAPK pathways. M. charantia further demonstrates anticancer activity by inducing apoptosis, causing cell-cycle arrest, and downregulating proliferation pathways in several cancer cell lines, including MCF-7, HCT-116, HepG2, A549, and PANC-1. Beyond medicinal uses, it is applied in the food industry as a functional ingredient in products such as yogurt, cookies, pickles, bread, juice, oil, and beverages. Overall, M. charantia shows strong potential for therapeutic applications, including functional foods and pharmaceutical formulations targeting diabetes, inflammation, liver diseases, and cancer; however, further studies are needed to confirm its clinical efficacy.

Antioxidants doi: 10.3390/antiox15070838

Authors: Shuang Xiao Xueqing Liu Yanming Wang Yuesen Yue Juying Wu Haifeng Wen Hui Zhang Xifeng Fan

Carex is among the most species-rich genera of angiosperms and plays important ecological roles in wetlands, alpine regions, and temperate ecosystems worldwide. However, research on this genus has long been challenged by pronounced phenotypic plasticity, reduced floral morphology, frequent hybridization, and complex chromosomal evolution. Although recent advances in molecular phylogenetics, comparative genomics, reproductive biology, and ecophysiology have substantially expanded the knowledge of Carex, these findings remain fragmented across disciplines. Here, we synthesize current evidence on Carex taxonomy and phylogeny, genomic and karyotypic evolution, reproductive and life history strategies, abiotic stress responses, ecosystem functions, and bioresource potential within a cross-scale framework. This review emphasizes how genomic architecture, life history variation, and ecophysiological adaptation jointly shape species diversification and ecosystem functioning, while clarifying their implications for habitat restoration and the sustainable use of Carex resources. Finally, we identify key priorities for future research, including improved phylogenomic resolution, comparative functional studies, climate-resilience assessment, and germplasm conservation and sustainable use.

Antioxidants doi: 10.3390/antiox15070837

Authors: Qian Gao Yayun Mao Shu Xie Wendi Wang Jun Xia Weibing Wu

Skeletal muscle dysfunction (SMD) is a critical extrapulmonary comorbidity in chronic obstructive pulmonary disease (COPD), contributing to exercise intolerance, poor quality of life, and increased mortality. Building upon and extending the disuse model, this review synthesizes evidence establishing COPD-induced SMD as a distinct myopathy with intrinsic disease drivers. Its pathophysiology is driven by a self-reinforcing network: mitochondrial energetic crisis featuring bioenergetic failure and dysregulated dynamics, chronic oxidative stress and inflammation fueling catabolic drive via ubiquitin–proteasome system activation, and epigenetic dysregulation through alterations in key histone deacetylases (HDACs) and microRNA expression, which collectively orchestrate a pro-atrophic phenotype. We further explore how these molecular insights are translating into novel diagnostic tools, including circulating biomarkers like myomiRs and C-terminal agrin fragment, and imaging techniques such as shear wave elastography. Although exercise training remains the cornerstone of management, its limited efficacy underscores the need for adjunctive and targeted therapies. We discuss promising strategies from pharmacological and nutritional support to emerging agents targeting specific pathways, including the IL-36 receptor, lipoprotein-associated phospholipase A2, aryl hydrocarbon receptor, and mitsugumin 53. Effective management of COPD-related SMD will hinge on a precision medicine framework, leveraging biomarker-guided stratification to deploy personalized combinatorial interventions aimed at preserving muscle mass and function.

Antioxidants doi: 10.3390/antiox15070836

Authors: Congying Guo Sheng Ai Jun Chen

This study investigated the mechanism of TGF-β1-induced Nox4 expression in pulmonary fibrosis (PF) and the anti-fibrotic effects of Tanshinone IIA (Tan-IIA). In a bleomycin-induced pulmonary fibrosis mouse model and in TGF-β1-stimulated fibroblasts, Tan-IIA attenuated fibrosis, oxidative stress, and fibroblast activation. Pharmacological inhibition revealed that the JNK/c-Jun and Smad3 pathways cooperatively mediate TGF-β1-induced expression of Nox4 and fibrotic markers (Collagen I/III, α-SMA). Tan-IIA exerted these effects by dually inhibiting the JNK/c-Jun and Smad2/3 pathways, reducing their phosphorylation and nuclear signaling, which consequently suppressed Nox4 transcription and protein expression. The combination of Tan-IIA with JNK or Smad3 inhibitors synergistically enhanced these effects. We identified a tandem c-Jun/Smad binding element in the Nox4 promoter that is critical for TGF-β1 response. Reporter assays and CUT&RUN experiments confirmed that TGF-β1-induced transcriptional activation depends on an intact c-Jun/Smad binding element and recruitment of c-Jun and Smad2/3. Moreover, Tan-IIA inhibited the enrichment of c-Jun and Smad2/3 at the Nox4 promoter. Collectively, our findings demonstrate that a c-Jun/Smad element integrates profibrotic JNK and Smad signaling to drive Nox4 expression. Tan-IIA presents a novel therapeutic strategy for fibrosis by simultaneously targeting these two key pathways, thereby mitigating Nox4-dependent oxidative stress and fibroblast activation.

Antioxidants doi: 10.3390/antiox15070835

Authors: Jiacheng Xu Lujia Sun Miaomiao Chen Bingdi Chao Jie He Hongli Liu Dongni Huang Jie Wang Lumei Xie Philip N. Baker Yubin Ding Hongbo Qi Xin Luo

Preeclampsia (PE) is a major pregnancy complication characterized by placental dysfunction and metabolic disturbances. Although mitochondrial abnormalities are frequently observed in PE, the upstream regulatory mechanisms remain incompletely understood. Here, we investigated the potential involvement of BACH1 in trophoblast dysfunction in PE and explored its association with mitochondrial metabolic alterations and protein succinylation. BACH1 expression was assessed in placental tissues and plasma samples from patients with PE, its functional effects were examined in trophoblast cell lines and BACH1 overexpression mouse models, and metabolic, bioenergetic, and succinylation-related alterations were evaluated using multi-omics and functional analyses. BACH1 expression was elevated in PE placentas and correlated with disease severity. In trophoblasts, BACH1 overexpression impaired proliferation, invasion, and trophoblast-mediated angiogenesis and was accompanied by mitochondrial and metabolic abnormalities, while quantitative succinylproteomic analysis revealed widespread alterations in mitochondrial protein succinylation. In vivo, BACH1 overexpression induced key PE-like features, including hypertension, fetal growth restriction, and placental abnormalities, and glycine supplementation partially rescued the trophoblast dysfunction associated with BACH1 overexpression. Together, evidence from clinical samples and experimental models suggests that BACH1 is associated with mitochondrial succinylation remodeling and trophoblast dysfunction in PE, supporting the hypothesis that BACH1-associated metabolic dysregulation and mitochondrial succinylation remodeling may contribute to PE pathogenesis. Further studies are required to establish the causal relevance and clinical significance of these mechanisms in human PE.

Antioxidants doi: 10.3390/antiox15070834

Authors: Rahmatullah Jan Shahzad Iqbal Sajad Ali Muhammad A. Almalki Mohammad Alfredan Sajjad Asaf Kyung-Min Kim

Soil salinity severely limits plant growth by disrupting cellular homeostasis and inducing oxidative damage. Although ethylene-responsive transcription factors (ERFs) are central regulators of stress responses, the function of ERF013 in salt stress responses remains poorly understood. In this study, we investigated the role of ERF013 in Arabidopsis thaliana using ERF013 overexpression lines (OE-ERF013) and genome-edited (ge-erf013) under 250 mM NaCl stress, in comparison with wild-type control (CK) and salt-treated wild-type (WT) plants. Under salinity stress, OE-ERF013 plants maintained vigorous shoot and root growth, exhibiting a 17% increase in shoot fresh weight and a 100% in root fresh weight relative to WT-T plants, whereas ge-erf013 mutants displayed severe growth inhibition. Salt stress markedly elevated superoxide (O2−) and hydrogen peroxide (H2O2) levels in WT-T (62% and 134%) and ge-erf013 plants (122% and 193%) compared with CK, while OE-ERF013 plants showed a significant reduction in O2−·and H2O2 levels, which decreased by 34% and 64%, respectively, relative to WT-T. Improved redox homeostasis in OE-ERF013 plants was associated with enhanced catalase (CAT) and superoxide dismutase (SOD) activities (55% and 44%), increased DPPH radical-scavenging activity (62%), maintained total antioxidant capacity (ABTS), and reduced lipid peroxidation, whereas ge-erf013 plants exhibited a 47% increase in malondialdehyde (MDA) content relative to WT-T. Furthermore, OE-ERF013 plants displayed reduced electrolyte leakage and sustained higher relative water content (RWC), with only a 15% decline under salt stress. Transcript analysis revealed strong upregulation of key ion homeostasis genes (SOS1, SOS2, NHX1, and HKT1) in OE-ERF013 plants, while their expression was suppressed in ge-erf013 mutants relative to WT-T. Additionally, OE-ERF013 plants accumulated higher abscisic acid (ABA) levels and showed increased expression of ABA biosynthesis-related genes (ATAO3 and ATABA3), accompanied by enhanced osmotic adjustment through elevated proline, soluble sugars, and sucrose accumulation, as well as improved chlorophyll stability. Collectively, these results demonstrate that ERF013 acts as a positive regulator of responses to salinity by coordinating ABA signaling, antioxidant defense, ion homeostasis, and osmotic regulation in Arabidopsis thaliana.

Antioxidants doi: 10.3390/antiox15070833

Authors: Katarzyna Gawlik Dorota Pawlica-Gosiewska Tomasz Milewicz Krystyna Słowińska-Solnica Justyna Brodowicz Dominik Żurek Bogdan Solnica

Gestational diabetes mellitus (GDM) is characterized by metabolic disturbances in which oxidative stress may play an important role. Most existing studies have examined individual biomarkers rather than their interrelationships. The present study evaluated selected oxidative stress, metabolic, and antioxidant markers, as well as their associations, in women with GDM compared with healthy pregnant controls. A total of 160 pregnant women (87 with GDM and 73 controls) were included. Biomarkers were measured, and their associations were assessed using correlation and interaction analyses. Women with GDM demonstrated higher levels of malondialdehyde (p < 0.001), leptin (p = 0.007), and ferric reducing antioxidant power (p < 0.001). The difference in the correlation between catalase activity and uric acid remained statistically significant after false discovery rate correction (q = 0.006), with a negative association in women with GDM and a positive association in controls. Interaction analysis further supported a group-dependent relationship between uric acid and catalase activity (p = 0.007; FDR-adjusted q = 0.007). These findings suggest that GDM may be associated not only with changes in individual biomarkers but also with alterations in selected redox-related relationships, indicating differences in redox regulation in GDM.

Antioxidants doi: 10.3390/antiox15070832

Authors: Cristian J. Gomes-Lobo Wendy Franco Mario Faundez Óscar Martínez-Álvarez José R. Pérez-Correa

Lactic fermentation modulates polyphenol composition in plant matrices, yet how compositional shifts translate into functional outcomes across extractable (EP) and hydrolyzable (HP) fractions remains unclear. Here, we apply a phenolic–bioactivity connectivity framework to fermented murta (Ugni molinae Turcz) juice, integrating compositional profiling with three functional axes: antimicrobial activity (against Escherichia coli, Salmonella enterica, and Staphylococcus aureus), inhibition of carbohydrate-hydrolyzing enzymes (α-amylase, α-glucosidase) and DPP-IV, and modulation of oxidative stress in Caco-2 cells. Murta juice was fermented with Lactobacillus acidophilus, Lactiplantibacillus plantarum, and a 1:1 coculture under two optimized strategies (GDF and SAW). Principal component analysis separated fermented from unfermented samples (89.7% variance explained) and identified coculture fermentation (MIX-GDF) as the most compositionally distinct treatment. EP fractions drove antimicrobial and α-glucosidase inhibition, whereas HP fractions contributed preferentially to DPP-IV inhibition and intracellular reactive oxygen species (ROS). A bipartite correlation network revealed a dual-functional architecture: specific flavonoid–bioactivity associations governed enzyme inhibition, while diffuse collective interactions shaped antimicrobial responses. These results demonstrate that fermentation-induced phenolic remodeling yields structured, functional outcomes, providing a rational basis for designing fermentation strategies targeting specific bioactivity profiles.

Antioxidants doi: 10.3390/antiox15070831

Authors: Zhixi Wei Xinyu Luo Yi Xia Mingyang Cui Peng An Junjie Luo Yongting Luo

Aortic dissection (AD) is a life-threatening vascular disease characterized by progressive vascular remodeling, oxidative stress, and inflammation. Among them, severe oxidative stress and systemic inflammation are important driving factors causing vascular integrity damage. Cistanche deserticola polysaccharides (CTPs) have definite deserticola anti-inflammatory and antioxidant properties. However, their influence on the progression of AD remains to be studied. In this study, we investigated the protective effects of CTP in a BAPN-induced mouse model of aortic dissection and explored the underlying mechanisms. CTP administration significantly attenuated aortic dilation and reduced the incidence of aortic dissection, accompanied by suppression of oxidative stress and inflammatory responses, preservation of extracellular matrix integrity, and maintenance of the contractile phenotype of vascular smooth muscle cells. Most importantly, CTP inhibits oxidative stress responses, as evidenced by the recovery of endogenous antioxidant enzyme activity and the reduction in lipid peroxidation. At the same time, CTP also suppresses systemic inflammatory responses. In addition, CTP markedly reshaped gut microbiota composition, characterized by enrichment of Akkermansia and Lachnospiraceae and reduction in Desulfovibrio and Escherichia-Shigella. Correlation analyses revealed close associations between gut microbial alterations and antioxidant, vascular remodeling, and smooth muscle cell phenotypic modulation. Collectively, these findings suggest that CTP confers vascular protection against aortic dissection through coordinated regulation of oxidative stress, inflammation, and vascular remodeling. The observed changes in gut microbiota composition may represent an additional mechanism associated with the beneficial effects of CTP and warrant further investigation.

Antioxidants doi: 10.3390/antiox15070830

Authors: Jingmin Che Ye Sun Fang Wang Qing Feng Cuixiang Xu Xuhui Li

Background: Mitochondria are the primary organelles that regulate cellular bioenergetic metabolism and maintain homeostasis, providing essential structural support for optimal cell survival. Nonetheless, advancing age leads to cumulative damage to mitochondrial structure and functional integrity, which is a defining characteristic of biological aging and is closely linked to the emergence and progression of numerous age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders. Scope of review: This article offers a thorough summary and review of mitochondrial quality control (MQC), emphasizing numerous critical processes, including mitochondrial biosynthesis, dynamic remodeling (fusion and fission), and mitophagy. We thoroughly elucidate the molecular pathways that regulate MQC and demonstrate how age-related dysregulation precipitates cellular senescence, highlighting the transition from physiological maintenance to pathological malfunction, which ultimately culminates in cellular aging. Conclusions and implications: This study systematically elaborates the pathophysiological mechanisms in the field, comprehensively evaluates the clinical translational potential of targeting the MQC pathway, highlights the key objectives of “restoring mitochondrial plasticity and removing dysfunctional mitochondria”, and explores novel intervention strategies. The restoration of normal mitochondrial function in cells throughout aging is a very promising path for precision medicine therapeutics with great translational potential, according to recent state-of-the-art research. The development of novel therapeutic approaches to improve functional healthy mitochondria can effectively delay aging and reduce the rising global burden of age-related diseases.

Antioxidants doi: 10.3390/antiox15070829

Authors: Tengfei Zhu Yongxin Liu Mingshi Chen Yamin Wang Wenjie Chu Shuling Bai Qi Li Zhipeng Zheng Hao Chen Jiandong Zhu Yingying Yu Dianchang Zhang

Nanoplastics (NPs) are emerging aquatic pollutants that may threaten farmed fish health. This study evaluated whether dietary nanocurcumin (NCUR) modulates NP-associated biological disturbances in largemouth bass (Micropterus salmoides). A total of 480 fish (initial weight 11.52 ± 0.02 g) were assigned to four treatments for 21 days: control, 0.2% NCUR, 100 μg/L NPs, and 0.2% NCUR + 100 μg/L NPs. NP exposure significantly reduced growth and feed intake (p < 0.05) and was accompanied by gill, hepatic and intestinal tissue alterations, disturbed serum lipid parameters, changes in hepatic antioxidant enzyme activities, and altered mRNA expression of antioxidant- and metabolism-related genes. Dietary NCUR was associated with partial modulation of several NP-associated responses, including hepatic and intestinal structural alterations, serum lipid changes, adaptive antioxidant enzyme responses, and transcriptional changes in Nrf2/Keap1- and SIRT1/FoxO1-associated genes. However, NCUR did not alleviate NPs-induced gill damage, and NCUR alone also caused branchial histopathological alterations. Therefore, 0.2% NCUR may partially mitigate selected NPs-induced disturbances in M. salmoides, but its independent effects, branchial safety, and pathway-level mechanisms require further investigation.

Antioxidants doi: 10.3390/antiox15070828

Authors: Xuan Leng Bo-Jing Liu Ren An Si-Ying Chen Kang Li Dong Wang Yun-Wei Pang

Carnosine is a naturally occurring endogenous dipeptide with great potential to improve reproductive function and fertility. In this study, supplementation of 1 μg/mL carnosine during in vitro maturation (IVM) significantly enhanced the developmental competence and quality of the resulting bovine embryos. Carnosine treatment effectively elevated mitochondrial membrane potential, mitochondrial activity, and ATP content in oocytes. Moreover, it strengthened the antioxidant and anti-apoptotic capacities of oocytes, as evidenced by reduced intracellular reactive oxygen species (ROS) levels, lowered DNA damage and an early apoptosis rate, alongside increased glutathione (GSH) content, an elevated BCL2/BAX mRNA ratio, and upregulation of antioxidant genes SOD1, CAT, GPx1, and GPx4. Notably, combined application of 1 μg/mL carnosine during IVM and 10−7 M melatonin during in vitro culture (IVC) synergistically improved both blastocyst development and quality. Collectively, these findings provide novel evidence supporting the therapeutic potential of carnosine in optimizing in vitro embryo production in bovine, and highlight the value of stage-specific supplementation strategies to further improve embryonic development efficiency.

Antioxidants doi: 10.3390/antiox15070827

Authors: Shengli Fu Kun Qian Tuo Yao Jie Lu Lingtong Ye Jianmin Ye

Lead (Pb) is a persistent aquatic pollutant that disrupts redox homeostasis in fish. This study investigated hepatic Pb accumulation, reactive oxygen species (ROS) production, antioxidant responses, lipid peroxidation, and transcriptomic alterations in juvenile pufferfish (Takifugu obscurus) exposed to waterborne Pb. Juvenile pufferfish were exposed to 5.98 mg/L waterborne Pb, corresponding to 10% of the 96 h LC50, for 96 h. Liver, blood, and hepatocyte samples were collected at 0, 12, 24, 48, and 96 h, with four biological replicates at each sampling time point. Hepatic Pb accumulation increased over time and reached the highest level at 96 h. ROS levels in blood cells and hepatocytes increased rapidly and peaked at 12 h. Superoxide dismutase (SOD) and catalase (CAT) activities showed early activation followed by late suppression, whereas glutathione peroxidase (GSH-Px) displayed partial adaptive recovery. Malondialdehyde (MDA) content increased progressively and reached approximately 2.8-fold of the control level at 96 h, indicating persistent lipid peroxidation. RNA-seq analysis identified 167, 460, 1398, and 2580 differentially expressed genes at 12, 24, 48, and 96 h, respectively. Enrichment, temporal trend, and weighted gene co-expression analyses indicated that Pb exposure shifted hepatic responses from early redox regulation to later metabolic adaptation, protein processing in the endoplasmic reticulum, proteasome function, and oxidative phosphorylation. qRT-PCR validation of 12 hub genes supported the RNA-seq results. These findings provide integrated biochemical and transcriptomic evidence for oxidative-stress-mediated hepatic toxicity in pufferfish exposed to waterborne Pb.

Antioxidants doi: 10.3390/antiox15070826

Authors: Mirjana S. Jankulovska Raquel Sánchez-Romero Gabriela Guillena José Luis Todolí-Torró

Deep eutectic solvents (DES) emerge as sustainable alternatives for antioxidant polyphenol extraction; however, their analytical performance and compatibility with antioxidant assays remain insufficiently characterized. A choline chloride-urea-water DES (1:2:4) was compared with 70% ethanol for extracting polyphenols from onion bulbs and peels from cultivars grown in Spain and North Macedonia. Extraction conditions were selected through a comparative evaluation of vortex- and ultrasound-assisted extraction and benchmarked against conventional ethanolic stirring (2 h). Two-way ANOVA identified solvent composition as the main determinant of total phenolic content (F(1,20) = 1526.28, p < 0.001), while extraction method significantly influenced recovery under DES conditions (F(2,30) = 408.52, p < 0.001). The selected UAE-DES protocol increased TPC up to 2.2-fold and reduced extraction time to <5 min. TPC ranged from 25 to 44 mg GAE/g dw in bulbs and 42–62 mg GAE/g dw in peels, with red cultivars showing the highest values. UHPLC-MS/MS revealed solvent-dependent selectivity: ethanol favored flavonols (quercetin 5–11 mg/g dw), whereas DES enhanced phenolic acids (gallic acid up to 0.3 mg/g dw; protocatechuic acid up to 7 mg/g dw). FRAP correlated with TPC (r = 0.64–0.92), while ABTS was incompatible with DES extracts. Storage reduced TPC by 45–75% but preserved cultivar ranking. These findings demonstrate that UAE-DES enables rapid and efficient polyphenol recovery while highlighting the need to validate antioxidant assays in non-conventional solvents.

Antioxidants doi: 10.3390/antiox15070825

Authors: Chia-Hui Lin I-Ning Tsai Ai-Ting Jou Chau-Jong Wang Ming-Chih Chou Hui-Pei Huang Chien-Ning Huang

Diabetic cardiomyopathy (DCM) under glucolipotoxic stress is sustained by a reactive oxygen species (ROS)-driven circuit in which oxidative DNA damage and nitrosative injury prime NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly, triggering caspase-1 activation, gasdermin D (GSDMD) cleavage, and pyroptotic cardiomyocyte death that propagates apoptosis and fibrotic remodeling. Whether melatonin can disrupt this oxidative-pyroptotic axis when both hyperglycemia and dyslipidemia coexist, the metabolic context most refractory to current therapy has not been established. Apolipoprotein E-deficient (ApoE−/−) mice were subjected to streptozotocin-induced hyperglycemia and high-fat diet-induced dyslipidemia, then treated with oral melatonin (20 mg/kg/day) for 8 weeks. Despite unchanged fasting glycemia, melatonin attenuated cardiac oxidative stress, reducing 8-OHdG and inducible nitric oxide synthase while restoring Nrf2. Suppression of nuclear factor-κB and NLRP3 was accompanied by lowered interleukin-1β, caspase-1, and GSDMD, indicating disrupted inflammasome priming and pyroptotic execution. Downstream pathology was concurrently attenuated, with reduced TUNEL-positive cardiomyocytes, normalized Bax/Bcl-2 ratio, lower natriuretic peptide expression, diminished interstitial fibrosis, and improved electrocardiographic parameters. These findings position melatonin as a cardioprotective agent that operates despite persistent fasting hyperglycemia, acting through combined attenuation of lipid burden, cumulative glycemic stress, oxidative stress, and inflammatory signaling to arrest downstream apoptotic and fibrotic remodeling under glucolipotoxic conditions, providing a mechanistic rationale for adjunctive melatonin therapy in DCM.

Antioxidants doi: 10.3390/antiox15070824

Authors: Xiaoqing Feng Xiao Zhou Shushan Jia Jingzhen Chen Peiwang Li Yan Yang Wei Wu Lijuan Jiang Wenbin Zeng Changzhu Li Qiang Liu Yunzhu Chen

Camelliasaponins, bioactive constituents abundant in the by-products of Camellia oleifera oil production, exhibit diverse biological activities. However, their potential in regulating neuroprotective mitophagy remains largely unexplored. This study identifies camelliasaponin B1 (CSB1) as an abundant component in C. oleifera seeds and investigates its cytoprotective mechanisms against oxidative stress. Using an in vitro model of H2O2-induced oxidative damage in PC12 cells, we found that CSB1 pretreatment significantly alleviated oxidative stress, as evidenced by reduced reactive oxygen species (ROS) accumulation and enhanced antioxidant enzyme activities (SOD, CAT, GSH-Px). CSB1 also preserved mitochondrial function, restoring membrane potential (ΔΨm), ultrastructure, and respiratory capacity. Mechanistically, CSB1 reduces the expression of BNIP3/NIX-LC3B pathway-related proteins, suggesting a modulatory effect on mitophagy, as supported by transcriptomic analysis, Western blotting, and immunofluorescence. Molecular docking computationally predicted potential interactions between CSB1 and BNIP3/NIX proteins, which require experimental validation. Collectively, these findings suggest that CSB1 acts as a cytoprotective agent that enhances antioxidant defenses, safeguards mitochondrial integrity, and is associated with reduced BNIP3/NIX-LC3B expression and co-localization, offering a potential molecular basis for its development as a neuroprotective agent targeting oxidative stress-related mitochondrial dysfunction.

Antioxidants doi: 10.3390/antiox15070823

Authors: Pierfrancesco Mastroeni Alfonso Trezza Anna Visibelli Michela Geminiani Annalisa Santucci

Alkaptonuria (AKU) is a rare metabolic disorder caused by homogentisate 1,2-dioxygenase deficiency, leading to systemic accumulation of homogentisic acid (HGA) and progressive tissue degeneration characterized by dark urine, ochronosis, and severe osteoarthropathy. Chronic exposure to HGA promotes oxidative stress, chondroptosis, secondary amyloidosis, and impaired autophagy, an essential process for maintaining chondrocyte homeostasis. This study investigated the mechanisms potentially involved in autophagy dysregulation in AKU using the human C20/A4 chondrocyte line treated with 0.1 mM HGA, an established in vitro model of the disease. The findings were then verified using chondrocyte cells and cartilage tissue obtained from AKU biopsies. HGA treatment induced a time-dependent increase in oxidative stress, evidenced by elevated ROS levels, 4-HNE accumulation, and overproduction of mitochondrial superoxide. Autophagy assessment showed an early increase in autophagy-related markers, with increased LC3 and p62 expression and enhanced lysosomal biogenesis (LAMP1). However, prolonged HGA exposure was associated with reduced LC3/LAMP1 colocalization, persistent p62 accumulation, altered acidic compartment staining, and accumulation of autophagy-related structures, supporting a dysregulation of the autophagy–lysosomal pathway. Live-cell imaging further supported a transition from functional autophagy to lysosomal failure under chronic oxidative stress. Overall, this study suggests that prolonged HGA exposure disrupts the interplay between oxidative stress and autophagic flux. The progressive collapse of these adaptive mechanisms may contribute to chondrocyte degeneration and to the pathogenesis of cartilage damage in AKU.

Antioxidants doi: 10.3390/antiox15070822

Authors: Cheng-Chun Wu Hao-Kuang Wang Yu-Ting Su Yu-Cheng Ho Yuan-Chin Hsieh Cheng-Loong Liang Yung-Kuo Lee Tian-Huei Chu Yun-Shin Lin Jui-Sheng Chen

Parkinson’s disease (PD) is characterized by progressive dopaminergic neurodegeneration driven by oxidative stress, mitochondrial dysfunction, synaptic loss, and impaired neurotrophic signaling; however, the role of integrin α5β1 in neuronal vulnerability remains unclear. Here, the data show that rotenone-induced stress reduces integrin α5 expression in a dose- and time-dependent manner, leading to increased ROS accumulation, glutathione imbalance, synaptic degeneration, senescence-like β-gal activity, and apoptosis, whereas integrin α5 knockdown further exacerbates these deficits, supporting a protective role of α5β1. In contrast, treatment with the fibronectin-derived α5β1-activating peptide Ac-PHSRN-NH2 restores integrin signaling by engaging the FAK–PI3K–AKT/ERK cascade and NRF2-mediated antioxidant responses, thereby reducing oxidative stress, suppressing cell death, and improving redox homeostasis. Moreover, PHSRN enhances NGF and BDNF levels, preserves synaptic integrity, and promotes dopaminergic neuronal activity and dopamine release. Consistently, in MPTP-lesioned mice, PHSRN preserves nigral TH-positive neurons, reduces apoptosis, restores neurotrophic support, and improves motor function. Collectively, these findings identify integrin α5β1 as a critical protective axis and support PHSRN as a potential disease-modifying therapeutic strategy for PD.

Antioxidants doi: 10.3390/antiox15070821

Authors: Bo Hu Jiansen Li Shen Zhu Zhe Ning Yangyan Jin Xiaoqiong Shi Zexuan Zhang Rui Liu Xinyuan Wang Lanbing Wu Yi Cao Ying He Haobing Yu

Ultraviolet B (UVB) radiation-induced corneal injury poses a significant public health challenge. However, its underlying molecular mechanisms remain incompletely understood, hindering the development of effective interventions. This study identified a key molecular pathway in UVB-induced corneal damage, revealing that UVB exposure triggers a rapid intracellular burst of reactive oxygen species (ROS), which in turn upregulates and aberrantly activates the receptor tyrosine kinase Ephrin type-A receptor 2 (EphA2), thereby collectively accelerating DNA damage and photoaging in corneal epithelial cells. Based on this mechanism, we developed the natural compound Penicophenone F (PP-F), which was screened and identified from the Arctic fungus Penicillium sp. MYA5, as a novel therapeutic strategy against UVB-induced corneal damage. In vitro and in vivo experiments suggest that PP-F may mediate its therapeutic effects via a dual mechanism. On one hand, it may counteract UVB damage by modulating ROS levels through regulation of endogenous antioxidant enzymes, inhibiting aberrant EphA2 activation, and promoting cellular proliferation and DNA repair. On the other hand, it may upregulate IRF6 to activate the cGAS pathway, which could enhance antioxidant defenses and significantly contribute to the restoration of epithelial barrier integrity and overall corneal physiology. These results underscore the safety and potential of PP-F in treating UVB-induced corneal damage and other oxidative stress-related ocular surface diseases.

Antioxidants doi: 10.3390/antiox15070820

Authors: Antonella Porrello Alessia Sordillo Giusy Castagliuolo Dario Antonini Gianfranco Fontana Natale Badalamenti Mario Varcamonti Maurizio Bruno Vincenzo Ilardi Anna Zanfardino

The complex genus Achillea L. comprises more than 140 species distributed widely throughout the Northern Hemisphere. Several species are widely used in traditional medicine for their therapeutic properties, yet few studies have correlated their biological properties with the plant’s phytochemical composition. Among these, Achillea setacea Waldst. & Kit. is a perennial species traditionally used to treat digestive and inflammatory disorders. In this study, the essential oil of A. setacea, collected wild in North Macedonia, was analyzed spectrometrically and spectroscopically by GC-MS and NMR, respectively. A total of nineteen compounds were identified, with camphor (31.3%), 4-terpineol (11.3%), and eucalyptol (10.6%) being the main constituents. Furthermore, the biological activities of pure oil were evaluated, showing notable antioxidant properties, as well as antimicrobial effects against a panel of clinically relevant microorganisms, including Gram-positive and Gram-negative bacteria. Furthermore, its impact on human intestinal epithelial (Caco-2) cells was assessed, highlighting its potential relevance for gastrointestinal applications, in agreement with the traditional use of Achillea species for digestive disorders.

Antioxidants doi: 10.3390/antiox15070819

Authors: Irwin K. Cheah Lik Hang Wu Richard M. Y. Tang Ulrike Rieprecht Leroy Sivappiragasam Pakkiri Arthur Mark Richards Chester Lee Drum Barry Halliwell

High circulating levels of trimethylamine-N-oxide (TMAO), largely produced by hepatic oxidation of gut-microbiota-derived trimethylamine (TMA), are associated with increased risk of cardiometabolic and neurodegenerative diseases. In contrast, the diet-derived compound ergothioneine (ET) possesses cytoprotective and neuroprotective properties, and higher circulating ET levels have been linked to a lower risk of cardiovascular, neurodegenerative, and other age-related disorders. However, concerns have been raised that microbial degradation of ET may also contribute to the TMAO pool. In this study, we examined the relationship between ET and TMAO. Bioinformatic analyses indicated that ergothionase, the enzyme responsible for ET degradation to trimethylamine (TMA), is restricted to a limited number of bacterial genera and is far less prevalent than choline trimethylamine lyase, which generates TMA from choline. In a randomised, placebo-controlled human study, ET supplementation (25 mg/day for 7 days) significantly increased plasma ET levels but did not increase TMAO concentrations. Similarly, in a heart failure cohort, plasma ET showed no correlation with TMA or TMAO levels, whereas TMAO was clearly correlated with TMA. Collectively, these findings suggest that ET is unlikely to contribute significantly to systemic TMAO levels.

Antioxidants doi: 10.3390/antiox15070818

Authors: Soojin Jeon Jihye Maeng Jiwon Lee Young-Min Kim Gaewon Nam

Atopic dermatitis (AD) is a chronic skin disorder driven by Th2 immune dysregulation, persistent inflammation, and epidermal barrier defects. Oxidative stress acts as a major upstream factor in this process, amplifying inflammatory signals and worsening disease severity. While current treatments relieve acute symptoms, long-term application is often constrained by side effects and poor barrier restoration, pointing to a need for safer, multifaceted alternatives. Here, we formulated a complex of Torilis japonica extract (TJE) and GHK-Cu (Glycyl-L-histidyl-L-lysine copper(II)) complex and examined its anti-atopic and skin-regenerative properties using a TNF-α (Tumor necrosis factor-α)/IFN-γ (Interferon-γ)-stimulated HaCaT cell model. TJE decreased the expression of AD-related chemokines (TARC(Thymus and activation-regulated chemokine (CCL17)) and CTACK(Cutaneous T-cell-attracting chemokine (CCL27)) as well as IgE production, confirming the suppression of Th2-driven inflammation. An optimized 6:4 ratio (TJE:GHK-Cu) yielded the highest efficacy compared to individual treatments, indicating a synergistic interaction. TJE–GHK-Cu complex suppressed the transcription of key Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) and promoted keratinocyte migration during wound healing assays. The formulation also displayed strong radical scavenging activity without compromising cell viability. These results demonstrate that the TJE–GHK-Cu complex provides simultaneous anti-inflammatory, antioxidant, and regenerative benefits, presenting a formulation warranting further investigation for managing AD.

Antioxidants doi: 10.3390/antiox15070817

Authors: Muhammad Imran Muhammad Shoaib Rana Xiangru Tang

2-acetyl-1-pyrroline (2-AP), the key volatile compound responsible for aroma in aromatic rice, is highly susceptible to abiotic stresses such as cadmium (Cd) toxicity. However, the potential role of molybdenum disulfide nanoflakes (MoS2FL) in regulating antioxidant defense and 2-AP biosynthesis under Cd stress remains largely unexplored. In this study, a pot experiment was conducted to evaluate the effects of foliar MoS2FL application on antioxidant defense, aroma formation, and Cd-stress mitigation in two fragrant rice cultivars, Meixiangzhan-2 and Basmati, grown in Cd-contaminated soil (50 mg kg−1). Cadmium stress significantly reduced key enzymes and precursors involved during 2-AP biosynthesis, including Δ1-pyrroline-5-carboxylate synthetase (P5CS), Δ1-pyrroline, pyrroline-5-carboxylic acid (P5C), diamine oxidase (DAO) and proline dehydrogenase (PRODH), along with downregulation of their associated genes. In contrast, foliar application of MoS2FL was associated with reduced Cd-induced oxidative stress, as indicated by increased antioxidant enzyme activities (SOD, POD, and CAT) and decreased malondialdehyde (MDA) accumulation. Moreover, MoS2FL increased precursor accumulation, enzymatic activities, and transcript abundance of genes associated with 2-AP biosynthesis, whereas gamma-aminobutyric acid (GABA) content, betaine aldehyde dehydrogenase (BADH) activity, and BADH2 gene expression were significantly reduced. Consequently, MoS2FL application significantly increased 2-AP content by 44.47% in Meixiangzhan-2 and 39.94% in Basmati under Cd stress. These findings suggest that MoS2 nanoflakes may serve as a promising nano-enabled strategy to enhance antioxidant defense, improve aroma quality, and mitigate cadmium stress in fragrant rice, potentially through changes associated with the 2-AP biosynthesis pathway. This study highlights the potential application of nanomaterials in improving crop quality and stress resilience in sustainable agricultural systems.

Antioxidants doi: 10.3390/antiox15070816

Authors: Ting-Yu Tsai Pei-Hsuan Lu Eddy Owaga Yi-Sheng Tsai Chia-Wen Chen Rong-Hong Hsieh

Microplastic exposure is an emerging environmental risk factor for cardiovascular health; however, whether cardiovascular alterations can be detected after exposure cessation remains unclear. This study investigated subclinical cardiovascular alterations following repeated oral exposure to polystyrene microplastics (PSMPs), with particular emphasis on redox imbalance and mitochondrial function in delayed cardiovascular alterations. Male Sprague-Dawley rats were administered 0.5 μm PSMPs via oral gavage at varying dosages of 5 or 20 mg/kg every 5 days for 70 days, followed by a 35-day exposure-free period. Repeated exposure to PSMPs did not affect body or organ weights but altered cardiac serum biochemical markers. Cardiac tissue exhibited elevated NADPH oxidase 4 (NOX4) expression and decreased superoxide dismutase 1 (SOD1), SOD2, and catalase (CAT) activities, whereas malondialdehyde (MDA) levels remained unchanged, indicating a state of chronic, low-level oxidative stress. Mitochondrial respiratory chain activities, including nicotinamide adenine dinucleotide cytochrome c reductase (NCCR) and succinate cytochrome c reductase (SCCR), were significantly reduced. Ultrastructural analysis revealed mitochondrial swelling and cristae disruption. In parallel, mitochondrial biogenesis-related proteins, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM), were downregulated, while mitophagy markers, including PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (Parkin), microtubule-associated protein 1 light chain 3 (LC3), and sequestosome 1 (p62), were upregulated. Notably, most significant alterations were primarily observed in the high-dose group. Furthermore, the aorta showed increased oxidative stress markers without overt structural remodeling. These findings suggest that repeated exposure to PSMP is associated with subclinical cardiac redox–mitochondrial dysregulation, potentially involving redox imbalance, impaired mitochondrial respiratory chain activity, reduced mitochondrial biogenesis, and altered mitochondrial quality-control markers.

Antioxidants doi: 10.3390/antiox15070815

Authors: Guo-Dong Zhuang Wen-Ting Gu Hua-Ze Wu Ao Li Dan Tang Yong-Sheng Chen

Background/Objectives: This study investigated the effects of different roasting levels on bound phenolic composition and antioxidant activity in barley malts. Methods: Bound phenolics from raw, fried, and dark malts were characterized using UPLC-Q-Orbitrap HRMS/MS combined with multivariate analysis. Potential antioxidant-active compounds were screened by DPPH/AAPH-incubating UPLC-DAD and further evaluated by in vitro antioxidant assays. Results: A total of 44 bound phenolic compounds were tentatively characterized. Distinct differences in bound phenolic profiles were observed among the three malts, with raw malt exhibiting relatively higher levels of bound phenolics. PCA analysis revealed compositional differences among samples. Activity-guided screening identified epicatechin gallate, trans-ferulic acid, and cis-ferulic acid as compounds exhibiting pronounced radical-scavenging activity, which was further supported by in vitro assays. Conclusions: Different roasting levels were associated with changes in bound phenolic composition and antioxidant properties of barley malts, providing insights into the relationship between thermal processing and the functional quality of malt-based products.

Antioxidants doi: 10.3390/antiox15070814

Authors: Haotian Li Man Han Rouman Zhang Congmin Xia Jianqin Yang Yanjun Liu Yuping Zhao Quan Jiang

Background: Autoimmune diseases such as primary Sjögren’s syndrome and type 1 diabetes are frequently complicated by hepatic injury, yet therapies that simultaneously target inflammation and parenchymal damage remain limited. Mitochondrial dysfunction with excessive reactive oxygen species (ROS) production drives a self-amplifying pathogenic loop by activating the cGAS-STING innate immune pathway. We previously observed that a Chinese herbal formula preserved mitochondrial ultrastructure in autoimmune NOD mice, and computational screening identified trifolirhizin—a natural pterocarpan flavonoid—as the candidate active constituent mediating this protection. Here, we investigated the hepatoprotective effects and underlying mechanisms of trifolirhizin in autoimmune-associated liver injury. Methods: Female NOD mice received trifolirhizin (5, 10, or 20 mg/kg/day) for four weeks, with C57BL/6J mice as healthy controls. Hepatic histopathology, inflammatory cytokines, mitochondrial ultrastructure (TEM), mitochondrial membrane potential (ΔΨm), and ROS levels were evaluated. Integrated transcriptomic and metabolomic profiling was performed to unbiasedly characterize protective mechanisms. In vitro, H2O2-induced oxidative stress was established in HepG2 cells. Cells were treated with trifolirhizin (15–25 µM) and assessed for antioxidant enzyme activities, ΔΨm, ROS production, glycolytic and mitochondrial respiration (Seahorse analysis), and cGAS-STING pathway protein expression. Pharmacological rescue experiments using the cGAS agonist cGAMP were conducted to test pathway dependency. Results: Trifolirhizin dose-dependently alleviated hepatic pathological damage and reduced pro-inflammatory cytokine levels in NOD mice. Multi-omics profiling revealed that oxidative stress responses, the mitochondrial electron transport chain, and glutathione metabolism were the most significantly restored pathways. Trifolirhizin preserved mitochondrial ultrastructure, restored ΔΨm, and attenuated ROS accumulation both in vivo and in vitro. Functionally, Seahorse analysis demonstrated that trifolirhizin rescued overall cellular bioenergetics, restoring both glycolytic capacity and mitochondrial respiratory parameters (basal respiration, ATP production, maximal respiration, and spare respiratory capacity). Mechanistically, trifolirhizin suppressed the cGAS-STING-TBK1-IRF3 axis, as evidenced by reduced expression of cGAS, p-STING, ZBP1, p-TBK1, and p-IRF3. Importantly, the cGAS agonist cGAMP abrogated the protective effects of trifolirhizin, confirming that the cGAS-STING pathway is functionally required for its action downstream of mitochondrial protection. Conclusion: Trifolirhizin attenuates liver injury in the nod mouse by preserving mitochondrial integrity, maintaining cellular energy metabolism, and thereby suppressing the ROS/cGAS-STING inflammatory cascade. These findings position trifolirhizin as a promising mitochondria-targeted therapeutic candidate for pSS-related hepatic complications and provide a mechanistic framework for discovering active compounds from mitochondrially active herbal formulations.

Antioxidants doi: 10.3390/antiox15070813

Authors: Jiaxuan Song Guanghuan Kong Xinling Wang Yunfei Zhai Jiajie Wang Jie Xu Chongjun Li Wudong Liu Yaodi Han Zhaoyu Han

High-yielding dairy cows are highly susceptible to lactational oxidative stress, which compromises mammary barrier integrity and elevates mastitis risk. This study investigated the potential biological mechanisms by which dietary hydroxy-selenomethionine (HMSeBA) alleviates oxidative stress and improves health in dairy cows. Forty Holstein cows were assigned to a basal control group (0.32 mg Se/kg DM) or an HMSeBA-supplemented group (0.64 mg Se/kg DM) for 105 days. HMSeBA significantly enhanced selenium bioavailability in both milk and blood, comprehensively strengthening antioxidant defenses (increased glutathione peroxidase activity, decreased malondialdehyde) and elevated serum immunoglobulins (IgA, IgM, IgG), accompanied by a reduction in milk somatic cell count, without significantly affecting milk yield, feed intake, or milk production efficiency. Multi-omics analysis revealed that HMSeBA supplementation altered the rumen microenvironment by enriching fiber-degrading genera (Prevotellaceae_Ga6A1_group, Xylanibacter, Segatella) and shifting metabolites, including feed flavonoids, peptides, 1-deoxy-D-xylulose-5-phosphate, and 3-OH-C6-HSL. The positive correlation of ruminal 3-OH-C6-HSL with both blood selenium and these enriched taxa suggests a potential link between microbial activity and host selenium status. These findings indicate that HMSeBA supplementation improves the antioxidant and immune status of dairy cows, accompanied by exploratory, hypothesis-generating shifts in the ruminal microbiome and metabolome. Collectively, these findings highlight HMSeBA as a promising nutritional strategy to produce selenium-enriched milk while safeguarding udder health.

Antioxidants doi: 10.3390/antiox15070812

Authors: Wenli Huang Fen Zhou Shuo Wang Meng Shu Zhongchun Liu Ling Gao

The recently conceptualized Cardiovascular–Kidney–Metabolic (CKM) syndrome represents a pressing global health burden, characterized by a vicious cycle of dysfunction among the cardiac, renal, and metabolic systems. Growing evidence suggests that gut microbiota dysbiosis, specifically, a loss of butyrate-producing bacteria (BPB) and the resulting systemic butyrate deficiency, may be an important but previously overlooked driver of CKM progression. In this review, we synthesize available evidence linking butyrate to the integrated, multi-organ pathophysiology of CKM and propose a conceptual framework we term the gut-butyrate-CKM axis. We discuss the multiple mechanisms by which butyrate and BPB exert protective effects, including targeting key pathophysiological features of CKM, such as insulin resistance (IR), metabolic inflammation, oxidative stress, endothelial dysfunction, renin–angiotensin–aldosterone system (RAAS) overactivation, and gut dysbiosis itself. Through a critical appraisal of human studies, we bring together findings from direct butyrate supplementation, dietary interventions, and microbiota-directed strategies. Based on this, we argue that butyrate serves as a central hub linking gut homeostasis to systemic metabolic and cardiorenal health. By integrating previously fragmented observations into a coherent framework, this review addresses a conceptual gap in our understanding of CKM pathogenesis and points to actionable, microbiota-targeted therapeutic strategies that could help break the disease cycle. Given the current lack of integrated management options for CKM, our work offers insights for future translational research and clinical practice, highlighting butyrate-centered approaches as a potential paradigm shift in CKM care.

Antioxidants doi: 10.3390/antiox15070811

Authors: Xiaoyu Yang Xiaoxiao Jiang Zijun Liu Jiawei Zhang Jinyu Yang Shuangzhi Zhao Dafeng Jiang Xiangyan Chen Qingxin Zhou Leilei Chen

Solid-state fermentation of burdock roots with Eurotium cristatum was performed to enhance their functional properties. Fermentation induced marked compositional remodeling, resulting in a 1.37-fold increase in protein content compared to unfermented controls. Antioxidant capacities were markedly enhanced. DPPH and ABTS radical-scavenging activities both exceeded 90%, and intracellular ROS levels in Caenorhabditis elegans were reduced by 62.7%. Phenolic profiling via UPLC-ESI-MS/MS identified and quantified 74 phenolic compounds across samples; notably, 10 flavonoids were exclusively detected in fermented burdock roots, indicative of microbial biotransformation. Correlation analysis integrating phenolic abundance with all three antioxidant endpoints revealed 11 compounds significantly associated with enhanced bioactivity. Among these, sinapic acid, 3-hydroxyflavone, liquiritigenin, and sakuranetin exhibited positive correlations with all three antioxidant measures. Prostaglandin G/H synthase 1 (PTGS1) and PTGS2 were identified as shared antioxidant-relevant targets, with PTGS1 highlighted due to its constitutive role in prostaglandin biosynthesis. Importantly, 3-hydroxyflavone, liquiritigenin, and sakuranetin were newly emerged following fermentation, providing direct evidence that E. cristatum mediates the synthesis or structural modification of key flavonoids, thereby augmenting the antioxidant chemical profile and functional efficacy of burdock roots.

Antioxidants doi: 10.3390/antiox15070810

Authors: Stephany Abigail Tadeo-Cuenca Silvia Marquina-Bahena Gabriel Alfonso Gutiérrez-Rebolledo María Crystal Columba-Palomares Araceli Guerrero-Alonso Valeri Domínguez-Villegas Francisco Cruz-Sosa Mariana Sánchez-Ramos

Due to Ludwigia octovalvis’ aquatic habitat’s vulnerability to climate change, this study developed an in vitro regeneration system using indirect organogenesis to ensure sustainable production of biomass and secondary metabolites. Treatment T16 (0.1 mg/L BAP and 1.0 mg/L NAA) was identified as the optimal hormonal regimen for callus induction and shoot differentiation. Phytochemical analysis by GC-MS revealed that seedlings regenerated under treatment T16 exhibited a diverse profile of 18 phytoconstituents, enhancing the accumulation of phytosterols, terpenes, and tocopherols. In vitro biological evaluation demonstrated that T16 extract possesses significant antibacterial activity (MIC < 62.5 µg/mL) against methicillin-resistant Staphylococcus aureus, and moderate antioxidant capacity. T16 extract showed anti-inflammatory effects superior to indomethacin at a low quantity (0.5 mg/ear) in adult CD1 mice of both sexes. In conclusion, the indirect organogenesis of L. octovalvis not only conserves the species but also optimizes its pharmacological potential, consolidating it as an efficient biotechnological platform for the development of advanced phytopharmaceuticals.

Antioxidants doi: 10.3390/antiox15070809

Authors: Pierrick Martinez Enrique A. Martinez Mosqueira Lionel Gillot William Makis Casey Peavler Antonio Vega-Galvez Fabrice Joulia William B. Grant

Supplements are widely perceived as safe and beneficial; yet in oncology, this assumption is questionable. Clinical trials over the past few decades have often produced disappointing results, raising a critical question: are these agents used correctly, or could they inadvertently cause harm? This review examines supplements frequently used in cancer care—such as oral vitamin C, berberine, N-acetylcysteine, vitamin D, vitamin E, melatonin, polyphenols, alpha-lipoic acid, selenium, and coenzyme Q10—which can act as tumor suppressors or promoters depending on dose, route, and disease stage. We examine their dual antioxidant and pro-oxidant properties, revealing that therapeutic outcomes are shaped not only by the molecule itself, but also by bioavailability, dosing thresholds, and the tumor redox environment. Building on these insights, we propose that four factors may be considered to guide clinical use: ensure that anticancer effects are not overshadowed by antioxidant activity, achieve sufficient bioavailability, confirm pro-oxidant concentrations where possible, and prioritize supplements that target the respiration-supported non-OxPhos pathways. By framing supplements as context-dependent redox modulators rather than universally beneficial agents, this review provides a mechanistically grounded framework for informing future research and safer, more effective integrative oncology strategies.

Antioxidants doi: 10.3390/antiox15070808

Authors: Huwei Yuan Qinyuan Shen Ye Zheng Mingzheng Duan Junhan Guo Yihui Li Jiashuang Qiao Liangye Huang Maryam Tahira Yanyan Yin Jiaxin Hu Jianfang Zuo Daoliang Yan Bingsong Zheng Muhammad Junaid Rao

Drought stress imposes oxidative damage on plants, yet the tissue-specific roles of salicylic acid (SA) in modulating phenolic metabolism remain poorly understood in woody species. Using Ilex rotunda seedlings, we investigated whether exogenous SA (100 µM) mitigates drought-induced oxidative damage and reshapes phenolic profiles in different tissues. Drought alone increased leaf total phenolics by 32% but depleted root phenolics by 29%, whereas combined drought + SA (DSA) treatment partially restored root phenolic levels, coinciding with elevated malondialdehyde (MDA) (2.2-fold in leaves, 2.6-fold in roots) and H2O2. Leaf antioxidant capacity increased under drought (DPPH by 73%, •OH by 33%), whereas root DPPH declined by 27% despite a 26% rise in •OH scavenging. SA alone induced mild oxidative responses and selectively upregulated caffeoylquinic and galloyl derivatives, notably 1-Caffeoylquinic acid (log2FC = 6.38) in leaves. DSA treatment mitigated oxidative damage—reducing leaf MDA by 44% and root H2O2 by 38%. Metabolomics revealed tissue-specific reprogramming leaves accumulated dicaffeoylshikimic acid (log2FC = 10.66) and trilobatin D (log2FC = 11.18) under DSA, whereas roots showed contrasting patterns with up-accumulation of vanillate (log2FC = 5.77) and suppression of 3,5-dicaffeoylquinic acid (log2FC = −7.21) under drought, with stronger metabolic reprogramming in leaves than roots. Our findings indicate that SA-mediated drought tolerance is associated with tissue-specific phenolic reprogramming, identifying candidate indicators that advance the mechanistic understanding of woody plant resilience to drought. These results provide a framework for translating metabolomic signatures into practical strategies for stress mitigation in medicinal perennials facing climate change.

Antioxidants doi: 10.3390/antiox15070807

Authors: Xiaolong Gu Yuan Fu Yongli Zhao Zhenyi Liu Yixiao Yang Qi Xie Peng Ma Zhiwei Peng Zhizhen Liu Jianting Li Jun Xie

High homocysteine levels are a key risk factor for cognitive impairment, a major public health concern in aging societies. Although betaine is known to reduce Hcy levels, its effects on hyperhomocysteinemia (hHcy)-induced cognitive impairment and the underlying mechanisms remain unclear. Here, we established an hHcy-induced cognitive impairment mouse model by feeding mice a high-methionine diet for 8 weeks, followed by betaine supplementation for 14 days. Betaine treatment attenuated hHcy-induced cognitive impairment. This improvement was accompanied by alleviation of neuropathological alterations and enhancement of antioxidant capacity. Notably, betaine suppressed reactive oxygen species (ROS) accumulation, neuronal apoptosis, and Tau hyperphosphorylation at Ser396 and Thr231 in both mouse hippocampus and HT-22 cells. Mechanistically, betaine-induced activation of the PI3K/AKT/GSK-3β pathway was effectively blocked by the PI3K inhibitor LY294002. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) alone phenocopied this activation, suggesting that ROS functions as an upstream regulator of this signaling cascade. Collectively, our data demonstrate that betaine attenuates hHcy-induced cognitive impairment by suppressing oxidative stress-driven apoptosis and Tau pathology through modulation of the PI3K/AKT/GSK-3β signaling pathway. These findings suggest that betaine may hold promise for further preclinical and clinical studies, although long-term efficacy and safety evaluations remain necessary.

Antioxidants doi: 10.3390/antiox15070806

Authors: Madeleine C. Nankivell Franklin Rosenfeldt Jeffery M. Reddan Judy B. de Haan Cherry Zhang Ping Beaudan Campbell-Brown Andrew Pipingas Matthew P. Pase Ruchong Ou Matthew B. Cooke David L. Hare Con Stough

Older age is typically characterized by decrements in cognitive performance relative to younger adults, though it may not necessarily reach clinical impairment. Dietary supplementation with ubiquinol, the reduced form of the antioxidant and cellular energizer CoQ10, may support cognitive function in older individuals. In the current randomized clinical trial of 111 adults aged 60 years and older (ubiquinol, n = 61; placebo, n = 50), 90 days of ubiquinol (200 mg) supplementation resulted in plasma CoQ10 levels being four times that of the placebo group at study end (p < 0.001). We found that ubiquinol supplementation did not facilitate group differences (controlling for baseline values and relevant demographics) in cognitive function, blood biomarkers reflective of oxidative stress or inflammation, measures of cardiovascular health, or subjective mood at study end. However, regression analyses revealed a positive association between change in plasma CoQ10 and memory performance, as well as a negative association between change in oxidative stress and memory performance at study end in those who received ubiquinol but not placebo. We conclude that adequately powered future clinical trials should examine whether long-term supplementation with ubiquinol can support cognitive function in older adults at risk of cognitive decline or with health conditions predisposing them to risk factors associated with decline.

Antioxidants doi: 10.3390/antiox15070805

Authors: Weican Zhang An Tao Xingping Chen Xin Li Tiande Zou Jun Chen Jinming You

Early weaning can disrupt the intestinal function and microbial community balance of piglets, and trigger inflammation and oxidative stress, thereby affecting their production performance. In recent years, butyric acid has gained considerable interest as a functional feed additive. However, practical limitations such as its pungent odor and low absorption efficiency in the digestive tract have led to the development of more stable forms, including sodium butyrate, coated butyrate, and butyrate glycerides, etc. Research has shown that butyric acid and its derivatives can serve as effective feed additives by enhancing pigs’ resistance to pathogenic colonization, stabilizing the intestinal microbiota, and alleviating oxidative stress to mitigate challenges such as weaning stress and pathogenic infections. This review systematically highlights the role of butyric acid and its derivatives as dietary supplements for weaned piglets. Importantly, it underscores the potential of butyric acid and its derivatives may contribute to antibiotic-reduction strategies in weaned piglet nutrition, while also highlighting the need for optimized supplementation strategies and further investigation into synergistic effects with other feed additives. This review aims to offer both theoretical and practical insights for the application of butyric acid in weaned piglet nutrition.

Antioxidants doi: 10.3390/antiox15070804

Authors: Su Yeon Kim Eun Hye Han Hyun Su Park Jae-Kwang Kim Sae-Kwang Ku

The present study evaluated the protective effects of Oralis SB® (Osb), a commercial multi-strain probiotic formulation, in a ligature-induced experimental periodontitis (EPD) Sprague–Dawley rat model. Male rats were subjected to ligature placement and orally administered Osb (1.25 × 108, 1.25 × 109, and 6.25 × 109 CFU/head) or received single-strain treatments with each of the four constituent strains (1.25 × 109 CFU/head) for 10 days. Periodontal changes were assessed by microbiological, biochemical, histological, and bone-related analyses. Ligature placement markedly increased anaerobic bacterial counts, neutrophil-associated myeloperoxidase activity, and inflammatory mediator production in gingival tissues, accompanied by elevated gingival IgA levels and impaired expression of epithelial tight junction-related genes, including claudin-1, claudin-5, occludin, and zonula occludens-1. Osb administration significantly attenuated bacterial overgrowth, restored gingival IgA contents, and suppressed the production of inflammatory mediators. Osb also reduced malondialdehyde level and inducible nitric oxide synthase activity, as markers of oxidative and nitrosative stress, and decreased metalloproteinase-8 expression in gingival tissue. In addition, Osb effectively prevented alveolar bone deterioration by improving focal bone mineral density, reducing osteoclast numbers, and restoring the receptor activator of nuclear factor-κB/osteoprotegerin balance. Histological evaluation further confirmed that Osb alleviated gingival inflammation and alveolar bone loss. Notably, the lowest dose of Osb (1.25 × 108 CFU/head) consistently produced significantly greater protective effects than each of the four individual component strains across all measured parameters. Osb exerted protective effects against EPD by modulating anaerobic microbial overgrowth, inflammatory and oxidative responses, epithelial barrier integrity, and alveolar bone resorption. These findings support the therapeutic potential of Osb in periodontitis.

Antioxidants doi: 10.3390/antiox15070803

Authors: Yirui Chen Jingzhi Zhu Hongxin Gui Mingyuan Liu Ye Zhang Zimu Wu Chang Liu Mengyang Wang

Cardiometabolic diseases are increasingly understood as disorders involving compartment-specific redox disruption rather than a uniform excess of reactive oxygen species. This narrative review synthesizes evidence for a proposed gut microbiota–mitochondria ferroptosis framework in which dysbiosis-derived lipopolysaccharide, trimethylamine N-oxide, short-chain fatty acids, bile acids, and tryptophan metabolites may modulate mitochondrial reactive species production, antioxidant defenses, iron handling, lipid peroxide detoxification, and inflammatory signaling. The reference set was assembled through searches of PubMed and Web of Science Core Collection, supplemented by targeted Google Scholar searches and citation chaining during manuscript preparation and revision through June 2026 and was organized around microbial metabolites, mitochondrial redox biology, ferroptosis pathways, disease-specific evidence, and redox-targeted interventions. Because this is a narrative synthesis rather than a systematic review, the framework should be interpreted as hypothesis-generating rather than as a systematically validated pathological model. Across atherosclerosis, diabetic cardiomyopathy, metabolic dysfunction-associated steatotic liver disease, obesity-associated insulin resistance, chronic kidney disease, and cardiorenal metabolic injury, the most consistent mechanistic links involve mtROS, impaired mitophagy, glutathione/GPX4 and SLC7A11 dysfunction, ACSL4-dependent lipid peroxidation, Nrf2 signaling, NLRP3 activation, and cGAS-STING-associated inflammation, although human causal evidence remains uneven. Importantly, much of the current literature supports local links within this sequence rather than a fully verified dysbiosis–metabolite–mitochondria ferroptosis–organ dysfunction chain in the same study. We therefore emphasize evidence tiers, terminology discipline, and biomarker requirements when interpreting ferroptosis-sensitive injury. Polyphenols, flavonoids, probiotics, postbiotics, melatonin, CoQ10-related strategies, mitochondria-targeted antioxidants, and ferroptosis-sensitive approaches may be most translatable when paired with microbiome, metabolomic, lipidomic, pharmacokinetic, and redox biomarkers.

Antioxidants doi: 10.3390/antiox15070801

Authors: Ming-Hung Shen Pei-Hsuan Lu Ting-Yu Tsai Eddy Owaga Yi-Sheng Tsai Chia-Wen Chen Rong-Hong Hsieh

Global plastic production has led to widespread contamination by micro- and nanoplastics, with polystyrene nanoplastics (PSNPs) increasingly being detected in human biological samples, including blood and cardiac tissue. Given the critical role of mitochondria in cardiac energy metabolism, this study investigated whether 100 nm PSNPs interact with mitochondria and affect mitochondrial function in H9c2 cardiomyoblasts. Cellular uptake and intracellular distribution were examined, followed by an evaluation of mitochondrial ultrastructure, intracellular and mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential, mitochondrial dynamics and mitophagy-related gene expression, mitochondrial DNA copy number, and metabolic function. PSNPs were internalized but did not directly localize to mitochondria within 24 h. No significant cytotoxicity, increase in intracellular or mitochondrial ROS production, or alteration in basal metabolic activity was observed. However, PSNP exposure resulted in intracellular accumulation, an altered mitochondrial ultrastructure characterized by crista loosening and vacuole-like structural changes. These changes were accompanied by reduced mitochondrial membrane potential; the upregulation of mitochondrial dynamics-related genes, including optic atrophy 1 (Opa1) and dynamin-related protein 1 (Drp1); the suppression of PTEN-induced kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (Parkin)-mediated mitophagy-related genes; and decreased maximal respiratory capacity. Lactate production and the extracellular acidification rate remained unchanged, suggesting that compensatory glycolysis was not activated. These findings indicate that PSNP exposure induces early mitochondrial structural and functional alterations without substantial cell damage, suggesting a potential reduction in cardiac adaptive capacity under PSNP-induced stress conditions.

Antioxidants doi: 10.3390/antiox15070802

Authors: Rossella Tatoli Rossella Donghia Gianluigi Casimo Pasqua Letizia Pesole Caterina Bonfiglio

Background: MASLD is characterised by chronic inflammation and oxidative stress, which contribute to disease progression. Currently, no effective pharmacological treatment is available, and the first-line treatment remains lifestyle modification, including dietary changes and physical activity. This study aimed to assess the effect of dietary antioxidants, anthocyanins, on the risk of MASLD in a cohort from Southern Italy. Methods: The sample of this study comprised 1, 297 individuals aged between 54 and 64 years from a larger cohort, the NUTRIHEP study cohort. Data on anthocyanin intake were collected using a food-frequency questionnaire. MASLD is diagnosed when fatty liver disease is present in conjunction with at least one cardiometabolic risk factor. Results: Anthocyanin intake was inversely associated with MASLD risk. In Model b, adjusted for adjusted for age, sex, Fasting Glucose, Triglycerides, Diastolic Blood Pressure, Job, Alcohol consumption (g/day), daily energy intake, adherence to the Relative Mediterranean Diet (rMED), Available Carbohydrates, fibre intake, the third quartile (Q3) and the highest intake group (Q4) of anthocyanins showed a negative correlation with MASLD. Analysis of Anthocyanin intake as a continuous variable showed a modest negative association with MASLD risk (OR = 0.990, 95% CI 0.989–0.999), suggesting that higher anthocyanin intake may slightly lower the risk of MASLD. Conclusions: Our study highlights the protective effects of dietary anthocyanins against MASLD. These findings confirm the potential preventive role of dietary polyphenols in MASLD and identify anthocyanins as novel targets for intervention.

Antioxidants doi: 10.3390/antiox15070800

Authors: Huairuo Shi Qingyun Guan Zixu Wang Jing Cao Yulan Dong Yaoxing Chen

Artificial light at night (ALAN) has emerged as a pervasive environmental stressor that disrupts immune homeostasis. This study examined the association between nocturnal dim blue light (dBL) exposure and splenic immune alterations, with particular attention to the corticosterone-glucocorticoid receptor, or CORT-GR, signalling pathway in a high-fat diet-fed mouse model. Male C57BL/6 mice were exposed to dBL (~5 lx) during the dark phase for 12 weeks while maintained on a high-fat diet (HFD). Chronic dBL exposure was associated with splenic atrophy, impaired splenocyte proliferative responses, elevated circulating CORT, and increased splenic GR expression. dBL exposure also coincided with increased NF-κB activation, reduced Nrf2/HO-1 signalling, oxidative stress, and cytokine imbalance in the spleen. Furthermore, in an independent pharmacological cohort, inhibition of CORT synthesis or GR signalling partially attenuated these alterations. Together, these findings suggest that, within an HFD-fed mouse model, dBL exposure is associated with splenic redox-inflammatory imbalance and impaired proliferative responses, a process to which dysregulated CORT-GR signalling appears to contribute.

Antioxidants doi: 10.3390/antiox15070799

Authors: Shujie Wang Qiang Yu Junwen Zhang Yingfeng Wang Guilian Zhang Huabing Deng Xiong Liu Xuedan Lu Qiuhong Chen Feng Wang Wenbang Tang Yunhua Xiao

Heat stress has emerged as one of the major environmental factors constraining rice growth. In our previous studies, OsPUP1, a member of the purine transporter protein family in rice, has been verified to be involved in the transport of cytokinin (CK). Unfortunately, the role of the OsPUP1 gene in the heat stress response has not been fully elucidated to date. In this study, we show that overexpression of OsPUP1, encoding a purine permease in rice, leads to severe growth inhibition and oxidative damage under heat stress. OsPUP1 overexpression lines exhibited increased accumulation of peroxides and malondialdehyde (MDA), along with significantly reduced activities of superoxide dismutase (SOD) and peroxidase (POD). Together with previous findings, these results suggest that OsPUP1 modulates CK transport, thereby influencing the spatial distribution of CK within the plant, which in turn regulates antioxidant defense mechanisms and heat stress response. This study uncovers a key role for OsPUP1 in controlling thermotolerance in rice and highlights the importance of CK distribution in plant adaptation to heat stress.

Antioxidants doi: 10.3390/antiox15070798

Authors: Mariapia Vietri Enza Napolitano Maria Rosaria Miranda Carmen Marino Simona Musella Veronica Di Sarno Carmine Ostacolo Michele Manfra Pietro Campiglia Mario Felice Tecce Anna Maria D’Ursi Ornella Moltedo Alessia Bertamino Tania Ciaglia Vincenzo Vestuto

Ferroptosis has emerged as a critical mechanism linking iron dysregulation, oxidative stress, and neurodegeneration in amyloid-associated pathologies. Building on our previous work, which identified compound 20 as a promising antioxidant and neuroprotective agent, the present study investigates the molecular mechanisms underlying its protective activity against amyloid-induced ferroptosis in human neuroblastoma SH-SY5Y cells exposed to Aβ(25–35). Compound 20 (3-(((4-hydroxybenzyl)(methyl)amino)methyl)-1-methyl-N-(2-(piperazin-1-yl)ethyl)-1H-indole-5-carboxamide) markedly counteracted Aβ(25–35)-induced ferroptotic damage by restoring intracellular glutathione levels, depleting the labile iron pool, and suppressing lipid peroxidation. In parallel, the compound significantly rescued mitochondrial membrane potential and attenuated endoplasmic reticulum (ER) expansion associated with ER stress, thereby preserving cellular homeostasis under oxidative challenge. These protective effects were further corroborated by real-time PCR analysis, which revealed the modulation of key genes involved in the oxidative stress response, endoplasmic reticulum stress, and inflammatory pathways. To gain a systems-level insight into these mechanisms, untargeted 1H-NMR metabolomic profiling was performed. This analysis confirmed the activation of antioxidant pathways and disclosed a significant modulation of energy metabolism and GABA-related pathways, both of which are closely linked to redox balance and neuronal resilience. Overall, these findings demonstrate that compound 20 drives metabolic reprogramming that orchestrates its multifactorial protective effect against Aβ(25–35)-induced ferroptosis by coordinating antioxidant defense, iron homeostasis, and ER stress mitigation.

Antioxidants doi: 10.3390/antiox15070797

Authors: Paweł Gać Michał Fułek Monika Michałek Piotr Macek Małgorzata Poręba Helena Martynowicz Rafał Poręba

Aim: The aim of this observational cross-sectional study was to evaluate whether blood renalase concentration, total antioxidant status (TAS), main cardiovascular risk factors, and obstructive sleep apnea severity are associated with the anatomical severity of coronary artery disease assessed by CCTA in patients with suspected OSA. Materials and methods: The study included 93 patients with suspected OSA. All patients were assessed for main risk factors for cardiovascular disease. Polysomnography was performed to verify the suspicion of OSA, as well as coronary computed tomography angiography (CCTA) with a systematic assessment of the severity of coronary artery disease using the CAD-RADS classification. Blood renalase concentration and total antioxidant status (TAS) were determined. Results: The apnea–hypopnea index (AHI) in the study group was 16.57 ± 17.17 /h. OSA was diagnosed in 73.1% of the study group. In CCTA examinations, significant coronary artery disease (CAD-RADS ≥ 3) was suspected in 22.6% of the subjects, including 16.1% classified as CAD-RADS 3, 4.3% as CAD-RADS 4, and 2.1% as CAD-RADS 5. Patients with AHI ≥ median were significantly more often classified as CAD-RADS ≥ 3 than patients with AHI < median. Patients with blood renalase concentration ≥ median were significantly less often classified as CAD-RADS ≥ 3 than patients with blood renalase concentration < median. Similarly, patients with TAS ≥ median were significantly less often classified as CAD-RADS ≥ 3 than those with TAS < median. Older age, higher systolic blood pressure, higher blood cholesterol levels, and lower TAS were independently associated with CAD-RADS ≥ 3 in logistic regression analysis. In multivariable regression analysis, higher pack-years of smoking, higher AHI, and lower blood renalase concentration were independently associated with lower TAS. Conclusions: Higher pack-years of smoking, higher AHI values, and lower blood renalase concentration were associated with lower total antioxidant status, which, along with older age, higher systolic blood pressure, and higher total cholesterol concentration, was independently associated with suspected anatomically significant coronary artery disease on CCTA.

Antioxidants doi: 10.3390/antiox15070796

Authors: Hyovin Ahn June Lee Jeong-Ho Park Jae Sang Barn Yejin Kim Jae Seung Kang

Natural killer (NK) cells are crucial components of innate immunity and rapidly eliminate abnormal cells through ligand–receptor signaling without prior sensitization. Vitamin C is known to enhance NK cell function; however, its susceptibility to oxidation may limit its efficacy in NK cell activation. This study evaluated the efficacy of Aptamin C, a stabilized conjugate of vitamin C and an aptamer, in enhancing NK cell activation. In the in vivo randomized placebo-controlled study, 120 participants were randomized to receive either Aptamin C or placebo, and 109 participants were included in the final analysis. Participants received Aptamin C at a dose of 36.057 mg/day or placebo for 4 weeks. The results showed significant increases in NK cell cytotoxicity after 2 and 4 weeks in the Aptamin C group. Additionally, serum levels of cytokines and cytotoxic granules associated with NK cell activity peaked 4 weeks after Aptamin C intake. Subgroup analysis showed that the enhancing effect of Aptamin C on NK cell activity was mainly observed in participants older than 40 years, whereas no significant effects were detected in participants aged <40 years. In the in vitro study, NK-92 cells treated with Aptamin C were compared with NK-92 cells treated with vitamin C. Aptamin C treatment enhanced proliferation, survival, cytotoxicity, and cytotoxic granule production in NK-92 cells compared with vitamin C treatment. These findings indicate that Aptamin C may effectively promote NK cell activation, particularly in middle-aged and older adults, and suggest its potential as an immunomodulatory supplement for supporting NK cell function.

Antioxidants doi: 10.3390/antiox15070795

Authors: Sijia Wang Jacqueline Pui Wah Chung David Yiu Leung Chan

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critical modulators of male reproductive health, influencing sperm function, hormonal regulation, and overall fertility. While physiological levels of ROS and RNS are essential for processes such as sperm capacitation and acrosome reaction, their overproduction leads to oxidative and nitrosative stress, contributing to male infertility. Excessive ROS and RNS can damage sperm DNA, proteins, and lipids, impairing motility, viability, and fertilizing capacity. Moreover, these reactive species disrupt the hypothalamic-pituitary-gonadal (HPG) axis, leading to hormonal imbalances that further compromise reproductive function. Environmental factors, lifestyle choices, and underlying health conditions exacerbate the production of ROS and RNS, highlighting the need for preventive and therapeutic strategies. Clinically, ROS- and RNS-mediated redox imbalance has been implicated in several male reproductive disorders, including varicocele, genital tract infection and inflammation, obesity, diabetes and other metabolic disorders, and toxicant-related reproductive dysfunction. Antioxidant supplementation has shown promise in mitigating oxidative stress; however, its efficacy varies, and further research is necessary to establish standardized treatment protocols. These findings underscore the clinical relevance of integrating oxidative stress assessment with conventional semen analysis to improve risk stratification and guide targeted interventions in male infertility. This review synthesizes current knowledge on the molecular mechanisms by which ROS and RNS affect male reproduction and discusses potential clinical interventions to address oxidative and nitrosative stress in male infertility.

Antioxidants doi: 10.3390/antiox15070794

Authors: Shiyi Chen Yang Jiao Wen Shen Xingru Hu Guoyue Yuan Jue Jia

Metabolic and cardiometabolic diseases are closely associated with mitochondrial dysfunction and redox imbalance. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2), a non-catalytic structural core subunit of mitochondrial respiratory chain Complex III, is increasingly recognized as a regulator of Complex III integrity, electron transfer, oxidative phosphorylation, and mitochondrial redox homeostasis. Under metabolic stress, reduced expression or functional impairment of UQCRC2 may promote electron leakage, mitochondrial reactive oxygen species (mtROS) generation, lipid peroxidation, impaired antioxidant defense, and disrupted glucose–lipid metabolism. These alterations may contribute to insulin resistance (IR), metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and cardiovascular disease (CVD). This review summarizes current evidence linking UQCRC2 dysfunction to mitochondrial bioenergetic failure, oxidative stress, inflammatory signaling, and cardiometabolic injury. We further discuss redox-regulatory pathways, including Nrf2, AMPK–SIRT1–PGC-1α, glutathione metabolism, and mitophagy, as well as pharmacological agents and natural compounds that may modulate UQCRC2-related mitochondrial responses. Collectively, these findings highlight UQCRC2 as a redox-sensitive mitochondrial node linking Complex III dysfunction to cardiometabolic injury and targeted redox-based interventions.

Antioxidants doi: 10.3390/antiox15070793

Authors: Hsu-Hung Chang Phebe Ting Syuan Chang Chung-Che Tsai Chan-Yen Kuo

Mitochondrial Lon peptidase 1 (LONP1) is an ATP-dependent AAA+ (ATPases associated with diverse cellular activities) protease that has emerged as a key regulator of mitochondrial proteostasis, with functions extending beyond protein quality control. In addition to degrading misfolded and oxidized proteins, LONP1 coordinates mitochondrial DNA maintenance, metabolic remodeling, and stress-responsive signaling. Recent structural and functional advances have expanded the biological significance of LONP1 beyond protein quality control, highlighting its roles in mitochondrial metabolism, genome maintenance, and stress responses. LONP1 dysregulation is increasingly implicated in cancer, metabolic disorders, neurodegeneration, and aging, where it exerts context-dependent effects on cell survival and disease progression. In cancer, LONP1 supports metabolic plasticity, redox adaptation, and therapeutic resistance, whereas in degenerative conditions, its decline contributes to mitochondrial dysfunction and tissue damage. Here, we synthesize recent insights into the structure, mechanisms, and biological functions of LONP1 and discuss their implications for human disease. We further discuss emerging therapeutic strategies and key challenges for targeting LONP1 in human disease.

Antioxidants doi: 10.3390/antiox15070792

Authors: Monika Stompor-Gorący Robert Ostatek Agata Bajek-Bil Małgorzata Kus-Liśkiewicz Agnieszka Gala-Błądzińska Maciej Machaczka

Methoxyflavones, along with chalcones and phenolic acids, belong to natural polyphenols. Apart from their antioxidant function, in plants, they act as pigments and are a part of plant chemical defense system. A member of this group is pedalitin, which expresses a range of interesting biological properties. The compound acts as an anticancer agent, strengthens the immune system, improves insulin sensitivity, protects internal organs, and also shows anti-inflammatory and neuroprotective activity. Due to the constant need for alternative therapies for treatment and prevention of lifestyle diseases, O-methylated flavonoids, including pedalitin, may serve as natural lead molecules in designing new structures with significant pharmacological potential. This review summarizes the literature reports on obtaining pedalitin and assessing its biological activity, also in the context of further functionalization of this compound and potential new applications.

Antioxidants doi: 10.3390/antiox15070791

Authors: Xingke Wang Ruiying Bao Qingchao Yang Qian Yang Sheng Gao Qingying Cai Yang Zhang Haiwen Zhang Huiyu Shi Xuemei Wang

Intestinal oxidative stress severely compromises the health and growth of weaned piglets. The fly maggot-derived antioxidant peptide FMP was previously identified, but its protective mechanisms remain unclear. Here, we explored how FMP alleviates oxidative intestinal injury. In IPEC-J2 cells, FMP pretreatment significantly attenuated H2O2-induced cytotoxicity, ROS accumulation, and apoptosis, while enhancing antioxidant enzyme activities and activating Nrf2 signaling (p < 0.05). Co-treatment with the Nrf2 inhibitor ML385 abolished FMP-mediated mitophagy enhancement and cytoprotection, revealing that FMP enhances PINK1/Parkin-dependent mitophagy via Nrf2 activation. In diquat-challenged weaned piglets, oral FMP administration restored serum SOD and GSH-Px activities, reduced MDA and DAO levels (p < 0.05), upregulated jejunal tight junction proteins, and enriched Lactobacillus populations. These findings demonstrate that FMP targets the Nrf2-mitophagy axis to protect against intestinal oxidative damage, supporting its application as a green feed additive.

Antioxidants doi: 10.3390/antiox15070790

Authors: Álvaro Becerra Felipe Soto Daniela Millán Juan José Valenzuela-Fuenzalida Maria P. Moya José E. León-Rojas Manuel E. Cortés

Background: Buddleja globosa Hope (matico) is a Chilean medicinal plant traditionally used in Mapuche and Aymara ethnomedicine. However, no systematic synthesis of its phytochemical composition and pharmacological evidence has been previously reported. Methods: A PRISMA 2020-compliant systematic review was conducted using Google Scholar, PubMed, EBSCOhost, and Springer Nature databases from inception to March 2026. Studies reporting phytochemical characterization and/or biological activities of B. globosa were included. Methodological quality was assessed using an adapted five-criterion tool for non-clinical studies. The protocol was registered in OSF. Results: Fourteen studies (1989–2026), mainly from Chilean research groups, identified 27 bioactive compounds across leaves, roots, and flowers. These included phenylethanoid glycosides (e.g., verbascoside/acteoside, echinacoside, forsitoside B, and linarin), flavonoids (luteolin 7-O-glucoside, apigenin 7-O-glucoside, myricetin, catechin, and epicatechin), pentacyclic triterpenes (α/β-amyrins and β-sitosterol), iridoid glycosides, and clerodane diterpenoids (buddledines A–C), as well as four newly reported phenylethanoids. Antioxidant activity was the most frequently evaluated endpoint (11/14 studies), mainly mediated through hydrogen atom transfer and single-electron transfer mechanisms linked to caffeoyl and flavonoid structures. Anti-inflammatory effects (five studies) involved COX and 5-LOX inhibition and reduced PGE2 production in LPS-stimulated macrophages. Additional reported activities included antihepatotoxic, antiplatelet, wound-healing, antibacterial, and antifungal effects. Conclusions:B. globosa exhibits a coherent phytochemical profile supporting strong preclinical antioxidant and anti-inflammatory activities. The main limitation for clinical translation is the low oral bioavailability of phenylethanoid glycosides. Nanoformulation strategies, investigation of colonic metabolites, and topical delivery systems represent promising approaches to bridge the preclinical-to-clinical gap.

Antioxidants doi: 10.3390/antiox15070789

Authors: Aggeliki Alibade Vassilis Athanasiadis Martha Mantiniotou Eleni Bozinou Stavros I. Lalas

The current research investigates the extraction efficiency of an emerging green technology, pressurized liquid extraction (PLE), compared to traditional stirring extraction (STE) in order to recover higher antioxidant capacity from three plant species of the Asteraceae family, namely Solidago virgaurea, Tussilago farfara, and Helichrysum stoechas. The optimal PLE conditions were achieved through a combined response surface methodology (RSM) approach. The resulting optimized PLE parameters (40% ethanol, 160 °C, 25 min, 1700 psi) were experimentally verified and directly contrasted with STE (40% ethanol, 80 °C, 60 min, 500 rpm). Despite having the same solvent polarity, the two methods showed significant variations in mass transfer kinetics and heat intensity. Across all species, PLE significantly boosted the ascorbic acid antioxidant capacity (p < 0.05), thereby showing enhanced recovery of compounds that contribute to the overall antioxidant capacity. STE generated noticeably increased total polyphenolic content and DPPH radical scavenging activity (p < 0.05), indicating that some phenolic subclasses might be susceptible to PLE at higher temperatures. Values for ferric-reducing antioxidant power were largely similar among approaches. Overall, PLE was shown to be highly effective in maximizing the total antioxidant capacity in shorter extraction times, while STE can better preserve specific polyphenolic fractions, as demonstrated through analysis of the optimal extracts by HPLC-DAD. The integration of experimental validation with chemometric modeling supports the reliability and practical applicability of the optimized PLE protocol.

Antioxidants doi: 10.3390/antiox15070788

Authors: Anca Daniela Raiciu Mihaela Carmen Eremia Amalia Stefaniu

Inulin-type fructans are widely recognized as functional polysaccharides with prebiotic properties, while plant polyphenols represent one of the most important classes of natural antioxidants. Increasing evidence demonstrates that interactions between dietary fibers such as inulin and phenolic compounds significantly influence antioxidant capacity, bioavailability, and physiological activity. The present review integrates recent advances regarding the chemical structure of inulin, extraction sources, molecular interactions with polyphenols, and implications for antioxidant activity in functional foods and nutraceuticals. Experimental studies indicate correlations between inulin concentration and antioxidant parameters such as DPPH, FRAP, SOD and CAT activities. Furthermore, physicochemical interactions between cell wall polysaccharides and polyphenols influence the stability, release kinetics and bioefficacy of antioxidant compounds. These findings support the potential development of optimized functional formulations combining inulin-rich plant extracts with polyphenol sources for improved health benefits. The literature was identified through searches of PubMed, Scopus and Web of Science databases (2000–2026).

Antioxidants doi: 10.3390/antiox15070787

Authors: Edén A. Luna-Zapién Jorge A. Zegbe Andrea de J. Campos-Badillo Jolanta E. Marszalek Juan R. Esparza-Rivera Jorge A. Meza-Velázquez

The prickly pear is a crop of socioeconomic relevance in arid regions, and its productivity and chemical composition depend on water availability. The effect of irrigation on the crop’s biochemical quality was evaluated. Cladodes of cultivars: ‘Amarilla Olorosa’, ‘Cristalina’, ‘Dalia Roja’, and ‘Roja Lisa’, were subjected to three treatments: no irrigation (NI), supplemental irrigation (SI), equivalent to 50% of the crop’s evapotranspiration, and full irrigation (FI). Subsequently, cladodes were collected, and total polyphenols and flavonoids, polyphenol profile, and antioxidant capacity were determined. Cladodes under NI had the highest concentrations of flavonoids, although the lowest values of total polyphenols. In the cladode extracts, myricetin, rutin, catechin, as well as caffeic, chlorogenic, dihydroxybenzoic, and vanillic acids were identified. Overall, cladodes grown under FI and SI showed higher levels of phenolic acids (caffeic, chlorogenic, and vanillic), while concentrations of catechin, myricetin, and rutin were higher under SI and NI. Antioxidant capacity was higher in NI cladodes assessed by ABTS and DPPH, while the FRAP assay showed higher values under SI. Among the cultivars, ‘Amarilla Olorosa’ stood out for its high content of bioactive compounds, confirming the potential of nopal cladodes as a source of antioxidant metabolites with agro-industrial applications.

Antioxidants doi: 10.3390/antiox15070786

Authors: Andrea Borghini Mariangela Palazzo Alessandro Tonacci Fabrizio Minichilli Haotian Wu Francesca Gorini

Micro- and nanoplastics (MPs/NPs) are ubiquitous environmental contaminants increasingly detected in air, food, drinking water, and human tissues, raising concerns about their potential long-term health effects. Accumulating evidence indicates that these particles can enter the human body, cross biological barriers, and elicit cellular and molecular responses relevant to disease development. This review synthesizes current mechanistic evidence linking MP/NP exposure to cardiovascular disease (CVD) and cancer, two leading global causes of morbidity and mortality that share interconnected pathogenic pathways. Key mechanisms include chronic inflammation, oxidative stress, gut microbiota dysbiosis, genotoxicity, and epigenetic alterations, all of which are widely implicated in both conditions. However, the available evidence is still largely derived from in vitro and animal studies, with limited human epidemiological data. Important uncertainties remain regarding real-world exposure characterization, dose–response relationships, and long-term clinical outcomes, underscoring the need for standardized analytical approaches, validated exposure and effect biomarkers, and large-scale longitudinal studies to clarify causal associations for both cancer and CVD. Taken together, current evidence suggests that MPs/NPs may represent emerging environmental contributors to shared pathogenic pathways linking CVD and cancer; however, establishing causality in humans will require well-designed longitudinal studies that integrate exposure assessment and clinical outcomes.

Antioxidants doi: 10.3390/antiox15070785

Authors: Chuyu Song Cui Deng Tengyue Zhang Wei Yao Dapeng Li Xiangming Wang

Alzheimer’s disease (AD) lacks effective disease-modifying therapeutics. Probiotics, promising neuroprotective candidates, exert benefits mainly by modulating gut-brain-axis (GBA) signaling. This study explored the anti-AD effects and mechanisms of Rhodopseudomonas pseudopalustris (R. pse). Using Caenorhabditis elegans (C. elegans) AD models, we evaluated AD-related phenotypes (learning deficits, paralysis) after R. pse administration, and performed genetic analysis and metabolomic profiling to clarify its regulatory pathways and metabolites. Mechanistically, R. pse significantly alleviated AD-related phenotype in C. elegans. It upregulated γ-glutamylcysteine synthetase (GCS-1) to enhance the glutathione (GSH)-dependent antioxidant defense. Knockout of the oxidation repair enzyme methionine sulfoxide reductase A-1 (MSRA-1) abolished the neuroprotective effects of R. pse, which was rescued by methionine. R. pse also activated activating transcription factor 7 (ATF-7)-mediated innate immunity and transforming growth factor β (TGF-β) signaling, with pantothenic acid as its functional metabolite. Collectively, R. pse is a potential anti-AD bacterium that mitigates AD model pathogenesis by enhancing the cellular antioxidant capacity, providing experimental evidence for bacteria-based AD interventions.

Antioxidants doi: 10.3390/antiox15070784

Authors: Thangasrinivasan Samyuktha Sridharan Yukta Kumar Ganesan Kunka Mohanram Ramkumar

Endothelial dysfunction (ED) is an early event in cardiovascular and metabolic diseases, including atherosclerosis, diabetes, and hypertension. Emerging evidence highlights the interplay between chronic inflammation and oxidative stress, collectively termed OxInflammation, as a major driver of vascular injury and impaired tissue repair. Among the key mediators of this response is the Nod like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex that promotes the release of inflammatory cytokines, including Interleukin 1β (IL-1β) and Interleukin-18 (IL-18), and induces gasdermin D-mediated pyroptotic cell death. Activation of NLRP3 disrupts endothelial function, reduces nitric oxide availability, and accelerates vascular inflammation and injury. This review discusses current evidence on pharmacological strategies targeting NLRP3 inflammasome signaling using both natural and synthetic inhibitors. Studies have shown that inhibiting NLRP3 can reduce inflammation and oxidative stress, preserve endothelial integrity, improve vascular function, and support tissue repair. Several NLRP3-targeting compounds have advanced into early-phase clinical trials, showing encouraging safety profiles and efficacy in individuals with cardiovascular risk factors. By integrating the emerging concept of OxInflammation with endothelial dysfunction, this review critically evaluates the therapeutic and translational potential of NLRP3 inflammasome inhibition in cardiovascular and metabolic disorders. Collectively, the available evidence supports NLRP3 as a promising therapeutic target for restoring endothelial homeostasis and promoting vascular repair. However, further clinical studies are needed to establish long-term efficacy, optimal dosing strategies, and appropriate patient selection criteria.

Antioxidants doi: 10.3390/antiox15070783

Authors: Martyna Szydłowska Aneta Wojdyło Paulina Nowicka

Blackcurrant (Ribes nigrum L.) fruits and their by-products represent valuable sources of bioactive compounds. This study compared fruits, juice, seeds, oil, and leaves with respect to their content of selected bioactive components, potential intestinal availability of polyphenols estimated by dialysis, and in vitro biological activities. Blackcurrant leaves contained several-fold higher levels of polyphenols in the dialyzable fraction (651.3 mg/100 g) than fruits (255.1 mg/100 g) and juice (261.4 mg/100 g). Seeds exhibited the strongest antioxidant activity among all matrices, reaching 13.3, 10.9 and 11.4 mmol Trolox/100 g in the ABTS, FRAP and ORAC assays, respectively. Hydrophilic fractions of juice and seeds showed notably stronger α-amylase inhibition (IC50 < 0.01 mg/mL) than the antidiabetic drug acarbose (IC50 = 0.35 mg/mL). Juice also demonstrated higher pancreatic lipase inhibition (IC50 = 0.01 mg/mL) compared with Orlistat (IC50 = 0.15 mg/mL) and effectively inhibited acetylcholinesterase, butyrylcholinesterase, and 15-lipoxygenase (IC50 = 0.11, 0.03, and 0.02 mg/mL, respectively). These results indicate that various blackcurrant matrices possess strong biological activity and may serve as promising functional food ingredients or sources of health-promoting compounds.

Antioxidants doi: 10.3390/antiox15060782

Authors: Dawon Kang

Ionizing radiation induces reactive oxygen species (ROS) and inflammatory signaling that contribute to both therapeutic efficacy and normal tissue toxicity. While the effects of high-dose radiation are well characterized, responses to low-dose-rate radiation (LDRR) remain inconsistent and are not adequately explained by conventional linear dose–response models. To address this gap, we conducted a narrative review of recent experimental studies across multiple biological systems, including body fluids, joint microenvironments, and reproductive tissues, focusing on redox and immune-related responses under LDRR conditions (dose rates: 0.39–3.49 mGy/h). Literature was identified through PubMed/MEDLINE, Web of Science, and Google Scholar, with emphasis on studies published between 2015 and 2026. These studies demonstrate that LDRR elicits nonlinear, dose-dependent effects that vary across biological compartments and involve coordinated changes in oxidative stress, immune signaling, and metabolic regulation. Based on this synthesis, we propose a unifying framework of nonlinear redox–immune coupling, in which oxidative stress functions as a threshold-dependent regulator and immune responses follow a biphasic trajectory characterized by activation at lower dose rates and attenuation or adaptation at higher levels. These responses are strongly influenced by the local microenvironment, resulting in compartment-specific variability. This integrated perspective supports a shift from dose-centric to systems-level interpretations of radiation biology and provides a basis for improving biomarker development, risk assessment, and therapeutic strategies in chronic low-dose radiation exposure settings. Future research priorities include time-resolved mechanistic studies to define compartment-specific redox thresholds, validation of candidate biomarkers under identical multi-compartment experimental conditions (e.g., GSH/GSSG ratio, 8-OHdG, circulating cytokine panels including IL-10/TNF-α ratio), and integration of subject-specific biological variables (e.g., age, sex, and baseline redox capacity) into predictive models of LDRR response.

Antioxidants doi: 10.3390/antiox15060781

Authors: Eugenio Caradonna Fulvio Ferrara Lucy Costantino Fortuna Iannuzzo Nicola Testa Luca Giordano Alice Faversani Carlo Setacci Ettore Novellino Emilio Vanoli

Clonal hematopoiesis of indeterminate potential (CHIP) and the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) are both linked to NLRP3-mediated cardiovascular inflammation, but their interaction has not previously been explored. This work proposes the CHIDT axis (clonal hematopoiesis–dysbiosis–TMAO), a feed-forward mechanism in which TET2 loss-of-function CHIP- and TMAO-generating Gram-negative gut dysbiosis mutually enhance cardiovascular risk. The model proceeds in three nodes. CHIP-associated intestinal immune dysregulation promotes luminal expansion of Gammaproteobacteria, which produce both trimethylamine via CntA/CntB-mediated L-carnitine oxidation and ADP-heptose as an obligate LPS biosynthetic intermediate. TMAO amplifies NLRP3 inflammasome activation through the SIRT3 → SOD2 → mtROS pathway. The evidence base of the CHIDT model is strongest for TET2-CHIP; the proposed extension to DNMT3A-CHIP rests on indirect, associative data and requires dedicated experimental confirmation before it can be considered established. TXNIP cascade, with predicted disproportionate potency in macrophages epigenetically primed by TET2 haploinsufficiency. High concentrations of TMAO have also been shown to suppress TET2 expression in endothelial cells through CYTB promoter hypermethylation, inducing NLRP3–GSDMD-dependent pyroptosis, although it remains unclear whether physiological TMAO levels can trigger this effect. Concurrently, ADP-heptose activates the ALPK1–TIFA–NF-κB pathway in bone marrow progenitors, favoring the expansion of mutant hematopoietic stem and progenitor cells. The model identifies three potential therapeutic strategies: NLRP3 inhibition, microbial TMA lyase inhibition, and microbiome-targeted reduction in Gram-negative bacteria. None has been tested in CHIP carriers stratified by plasma TMAO. Further studies in preclinical models and human cohorts integrating CHIP genotyping and TMAO quantification are needed to validate the CHIDT axis as a target for precision cardiovascular prevention.

Antioxidants doi: 10.3390/antiox15060780

Authors: Miaomiao Li Xiaojun Deng Haibo Wang

Radiation-induced liver injury (RILI) is a major complication of abdominal radiotherapy, originating from mitochondrial oxidative stress, and effective radioprotectants are lacking. We designed an antioxidant intended to target mitochondria, TPP-C6-NIT, by conjugating a triphenylphosphonium cation to an imidazole nitroxide radical. Its protective effects were evaluated through in vitro assays, studies on irradiated L-02 and Huh-7 cells, a mouse model of whole-body irradiation, combined with metabolomics, molecular docking, and assessments of mitochondrial function, apoptosis, and inflammation. TPP-C6-NIT exhibited potent radical scavenging activity in vitro. In L-02 cells, it reduced oxidative stress, preserved mitochondrial function (membrane potential, ATP, respiratory capacity), and improved viability. In mice, pretreatment with TPP-C6-NIT significantly improved survival, alleviated liver injury (reduced serum ALT/AST and histopathological damage), and suppressed systemic inflammation. Mechanistic exploration suggested TPP-C6-NIT treatment was associated with increased Nrf2/GPX4 expression and reversal of lipid metabolic changes. Notably, TPP-C6-NIT did not confer significant protection in Huh-7 cells, indicating selective cytoprotection. By reducing oxidative stress and preserving mitochondrial function, TPP-C6-NIT demonstrates potent protection against radiation-induced liver injury in a whole-body irradiation mouse model, presenting a promising candidate for further development.

Antioxidants doi: 10.3390/antiox15060779

Authors: Wang Liu Jiang Zhao Changlin Li Haixia Xu Ruibao Chen Xing Zeng Jun Yang Cuncong Zhong Xiangwei Wang Benyi Li

SQSTM1/p62 is a multifunctional scaffold protein that plays important roles in selective autophagy and cellular redox homeostasis. While phosphorylation-dependent regulation of p62 has been extensively studied, the functional significance of oxidative modification remains incompletely understood. Our previous studies showed that the natural small compound Alternol induces cancer cell-specific killing via a xanthine oxidase-mediated strong oxidative stress. In this study, we investigated p62-associated oxidative responses under Alternol-induced oxidative stress conditions in prostate cancer cells. Using biochemical assays and cell-based models, we found that Alternol treatment was associated with the accumulation of oxidized and high-molecular-weight p62 species, accompanied by altered KEAP1 association and increased Nrf2-associated signaling. Furthermore, Alternol-induced p62 oxidative modification was associated with autophagy-related responses and adaptive cellular survival under oxidative stress conditions. Disruption of the Cys105/113-dependent oxidative modification response attenuated Nrf2-associated transcriptional activity and increased cellular sensitivity to Alternol treatment. Collectively, our findings support an association between p62 oxidative modification and redox-responsive autophagy- and antioxidant-associated signaling pathways under Alternol-induced oxidative stress conditions, providing new insight into adaptive stress responses in prostate cancer cells.

Antioxidants doi: 10.3390/antiox15060778

Authors: Sandro La Vignera Rosita A. Condorelli

Male reproductive health has experienced an unprecedented decline over the past five decades, characterized by substantial reductions in sperm count and testosterone levels. This review provides a comprehensive synthesis of current evidence on the global decline in sperm count and testosterone levels, examining epidemiological trends, underlying mechanisms, environmental drivers, and clinical implications. Sperm concentration declined by 51.6% globally between 1973 and 2018, with an accelerating trajectory post-2000 (from 1.16% to 2.64% per year). Concurrently, multiple independent studies document an age-independent secular decline in testosterone, averaging 1–2% per year across diverse populations. The etiology is multifactorial, involving endocrine-disrupting chemicals (bisphenol A, phthalates, pesticides, dioxins), lifestyle factors (obesity, sedentary behavior, smoking, heat exposure), and disruption of the hypothalamic–pituitary–gonadal axis. At the cellular level, mechanisms include Sertoli and Leydig cell dysfunction, oxidative stress, mitochondrial impairment, and sperm DNA fragmentation. Integrated clinical management combining lifestyle optimization, antioxidant therapy, and targeted endocrine interventions is essential. Prevention through environmental policy and public health initiatives represents the most promising long-term strategy.

Antioxidants doi: 10.3390/antiox15060777

Authors: Francisco J. Corpas Rosa M. Rivero José M. Palma

Although hydrogen peroxide (H2O2) and nitric oxide (NO) are widely recognized for their signaling functions [...]

Antioxidants doi: 10.3390/antiox15060776

Authors: Khanittha Chinarak Pudthaya Kumnerdsiri Anurak Uchuwittayakul Kanrawee Hunsakul Jaksuma Pongsetkul Samart Sai-ut Supatra Karnjanapratum Saroat Rawdkuen Passakorn Kingwascharapong

Gelatin capsule waste (GCW), a protein-rich by-product, represents a promising substrate for the generation of potential bioactive substances, including free amino acids and other soluble substances generated during enzymatic hydrolysis. In this study, gelatin hydrolysates with degrees of hydrolysis (DH) ranging from 10% to 40% were produced using the commercial enzymes NS AC0106 (endopeptidase) and NS AC0107 (aminopeptidase) to enhance their functional properties. Increasing DH significantly improved antioxidant activity, surface hydrophobicity, and emulsifying capacity (p < 0.05), while sterilization further enhanced antioxidant capacity. Structural analyses confirmed extensive protein degradation and conformational modifications, as evidenced by SDS–PAGE (formation of low-molecular-weight substances), FTIR (shifts in the amide I region), and NMR (release of free amino acids). Electronic tongue analysis indicated that enzymatic hydrolysis enhanced umami and salty taste attributes. Notably, hydrolysis using NS AC0107 at 40% DH resulted in the highest antioxidant activity, together with pronounced umami taste and low bitterness. Overall, GCW-derived hydrolysates show considerable potential as functional ingredients and provide a sustainable strategy for the valorization of protein-rich industrial by-products.

Antioxidants doi: 10.3390/antiox15060775

Authors: Xinxin Chen Han Di Gang Wang Yanhong Wang Feng Guan

Daidzein is a naturally occurring isoflavone phytoestrogen, mainly found in leguminous plants. This component exerts anti-inflammatory effects by regulating inflammatory cells via multiple targets, blocking core inflammatory pathways, and inhibiting the release of inflammatory factors. It also scavenges reactive oxygen species, activates the antioxidant enzyme system, and regulates antioxidant signaling pathways to achieve antioxidant effects. By regulating these two core pathological processes, it exerts protective effects in diseases such as cancer, cardiovascular disease, and acute kidney injury, based on preclinical evidence. The development of nanodelivery systems has effectively improved the physicochemical properties of daidzein, enhanced its bioavailability, and enabled disease-targeted delivery. Most previous reviews have either focused exclusively on daidzein or broadly covered the pharmacological activities of isoflavones, yet have largely overlooked the dual anti-inflammatory and antioxidant mechanisms specific to daidzein. This review summarizes these mechanisms and their preclinical effects on various diseases, including cancer, cardiovascular diseases, and acute kidney injury. It also reviews the pharmacokinetic limitations of daidzein and recent progress in nanodelivery strategies aimed at enhancing its bioavailability and bioactivity. Overall, this review serves as a reference for the future standardized comparison of nanocarriers, targeted therapies, and clinical applications.

Antioxidants doi: 10.3390/antiox15060774

Authors: Victor Ferrer Tomás Oñate-Valdés Cecilia Fuentealba Gastón Bravo-Arrepol Solange Torres Vicente Hernández Moisés Vásquez Priscila Moraga-Suazo Jorge Santos Danilo Escobar-Avello

In Chile, Eucalyptus globulus stands out as a significant forest species, yielding around 2 million tonnes of bark; this by-product is a valuable source of phenolic compounds. This research evaluated the valorization of E. globulus bark using alkali-assisted extraction (AAE) and obtained extracts intended to protect the wood against fungal degradation and ultraviolet (UV) radiation. The chemical and thermal properties of the extracts were characterized using total phenolic content (TPC), antioxidant capacity, FTIR spectroscopy, LC-LTQ-Orbitrap-MS, and thermal analyses (TGA and DSC). Pine wood samples were impregnated using the Bethel process, and their absorption, retention, leaching, UV resistance, gloss, and antifungal efficacy were evaluated. The AAE showed an extraction yield of 8.79%, almost double that of aqueous extraction, with a phenolic content of 970 mg GAE/100 g dry bark and good antioxidant capacity. The MS/MS analysis tentatively identified low-molecular-weight organic acids, phenolic acids, a hydrolyzable tannin derivative, ellagic acid, methylated flavonol glycosides, and an iridoid non-phenolic metabolite. Thermal analysis indicated greater stability of the alkaline extracts, with a mass loss of less than 10% up to 200 °C, and significant degradation between 220 and 300 °C. Leaching tests showed a lower release of polyphenols from alkali-treated wood, indicating reduced mobility and/or greater retention of the extractives within the wood structure. Biological assays demonstrated effective inhibition of stain fungi and strong resistance to brown rot. Furthermore, UV aging tests showed less color change (Delta E*) and greater resistance to surface degradation. These results demonstrate the potential of alkaline extracts from E. globulus bark as sustainable additives for wood protection.