Antioxidants

14 pages, 1906 KB

Open AccessArticle

Succinate Dehydrogenase Subunit D as a Redox-Responsive Mitochondrial Component Linked to Aquaporin-Associated Hydrogen Peroxide Signaling in Glioblastoma Cells

by Kuen-Jang Tsai, Kuan-Tso Chen, Chin-Chuan Tsai, Zi-Xuan Hong, Li-Ying Qiu, Chan-Chuan Liu, Kwang-Yu Chang, Pin-Yuan Chen and Chia-Hung Chien

Antioxidants 2026, 15(9), 1125; https://doi.org/10.3390/antiox15091125 (registering DOI) - 5 Sep 2026

Abstract

Glioblastoma (GBM) frequently recurs after temozolomide (TMZ) therapy and exhibits substantial redox plasticity. Our previous work showed that the effects of hydrogen peroxide (H₂O₂) vary with its level and between parental and TMZ-resistant GBM cells. Succinate dehydrogenase subunit D [...] Read more.

Glioblastoma (GBM) frequently recurs after temozolomide (TMZ) therapy and exhibits substantial redox plasticity. Our previous work showed that the effects of hydrogen peroxide (H₂O₂) vary with its level and between parental and TMZ-resistant GBM cells. Succinate dehydrogenase subunit D (SDHD), a membrane-anchoring component of mitochondrial complex II, is positioned at the interface of electron transport and redox homeostasis, but its regulation in GBM remains unclear. We therefore examined whether SDHD expression changes across distinct H₂O₂-responsive contexts involving aquaporins (AQPs) and AKT. TCGA transcriptomic analysis showed higher SDHD mRNA expression in WHO grade IV than in grade II/III gliomas, whereas paired primary/recurrent high-grade glioma samples showed heterogeneous SDHD changes at recurrence. TMZ reduced SDHD, and SDHD knockdown decreased intracellular reactive oxygen species. Combined redox perturbation reduced SDHD, whereas AKT inhibition restored SDHD expression. Under receptor-associated signaling conditions, EGFRvIII expression or CXCL12 stimulation increased measured H₂O₂ together with AQP3, AKT Ser473 phosphorylation, and SDHD. In TMZ-resistant cells, pharmacological perturbation of aquaporin-associated signaling decreased AQP9 together with AKT Ser473 phosphorylation and SDHD. An AQP3-targeting compound further reduced cell density when combined with TMZ. Together, these findings suggest that changes in SDHD expression are consistent with a compensatory redox response in GBM cells and that its regulation varies with the nature of H₂O₂-associated signaling during TMZ-related stress. Full article

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

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13 pages, 1522 KB

Open AccessArticle

Low-Grade Endotoxemia Is Associated with NOX2-Mediated Oxidative Stress and Endothelial Dysfunction in Takotsubo Syndrome: A Cross-Sectional Study

by Lorenzo Loffredo, Enrico Maggio, Simona Bartimoccia, Vito Cantisani, Antonio Angeloni, Aurora Paraninfi, Paolo Ciacci, Simona Battaglia, Federica Armeli, Ilaria Maria Palumbo, Mariaelena Malvasi, Giancarlo D’Ambrosio, Pasquale Pignatelli, Roberto Carnevale, Francesco Violi, Francesco Barillà and Gaetano Tanzilli

Antioxidants 2026, 15(9), 1124; https://doi.org/10.3390/antiox15091124 (registering DOI) - 5 Sep 2026

Abstract

Takotsubo syndrome (TTS) is an acute and reversible heart failure condition characterized by transitional left ventricular systolic dysfunction without obstructive coronary artery disease. Although sympathetic hyperactivation is considered a key pathogenic mechanism, the contribution of gut-derived endotoxemia and oxidative stress is still unclear. [...] Read more.

Takotsubo syndrome (TTS) is an acute and reversible heart failure condition characterized by transitional left ventricular systolic dysfunction without obstructive coronary artery disease. Although sympathetic hyperactivation is considered a key pathogenic mechanism, the contribution of gut-derived endotoxemia and oxidative stress is still unclear. Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, may translocate from the gut into the bloodstream and increase oxidative stress through activation of NADPH oxidase 2 (NOX2), nitric oxide (NO) depletion and endothelial dysfunction. This study aimed to evaluate circulating LPS levels in TTS and investigate their association with NOX2 activation, oxidative stress, and endothelial dysfunction. Twenty consecutive patients with TTS and 20 age- and sex-matched healthy controls were included. Within 48 h of admission, fasting blood samples were collected to assess soluble NOX2-derived peptide (sNOX2-dp), hydrogen peroxide (H₂O₂), NO metabolites (NOx), LPS, and zonulin. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD). Compared with controls, TTS patients had significantly higher serum levels of sNOX2-dp, H₂O₂, LPS, and zonulin, lower NOx and impaired FMD. sNOX2-dp was positively correlated with LPS (Rs = 0.539, p < 0.001) and zonulin (Rs = 0.331, p = 0.037) and inversely correlated with FMD (Rs = −0.462, p = 0.003). NOx correlated negatively with H₂O₂, zonulin and LPS. In multivariable analysis, LPS was the only independent predictor of FMD (β = 0.498, SE = 0.126, p = 0.001) and sNOX2-dp (β = −0.572, SE = 0.034 p < 0.001); FMD (β = −0.347, SE = 0.455, p = 0.005), H₂O₂ (β = 0.445, SE = 0.155, p < 0.001), and zonulin (β = 0.298, SE = 2.309, p = 0.016) emerged as independent predictors of LPS (adjusted R² = 0.585). TTS is associated with low-grade endotoxemia, NOX2-driven oxidative stress, reduced NO bioavailability, and endothelial dysfunction. The independent association between LPS and NOX2 activation supports a potential gut–vascular axis in TTS pathophysiology. Full article

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19 pages, 1113 KB

Open AccessArticle

Vaginal Infection in Pregnancy Is Associated with Amniotic Oxidative Stress: Insights from AOPP and MDA on Neonatal Outcomes

by Meryem Kececi Oguzhanoglu, Icten Olgu Bafali, Kursat Oguzhanoglu, Senem Karacabey Cakmak, Busra Seker Atas, Muhammed Oguz Yildiz and Ali Cetin

Antioxidants 2026, 15(9), 1123; https://doi.org/10.3390/antiox15091123 - 4 Sep 2026

Abstract

Amniotic oxidative stress in women with vaginal infection but no documented intra-amniotic infection has received little attention. In this prospective cohort study of 90 women undergoing elective cesarean delivery, 45 had symptomatic, culture- or Nugent-confirmed vaginal infection and 45 were asymptomatic controls. Amniotic [...] Read more.

Amniotic oxidative stress in women with vaginal infection but no documented intra-amniotic infection has received little attention. In this prospective cohort study of 90 women undergoing elective cesarean delivery, 45 had symptomatic, culture- or Nugent-confirmed vaginal infection and 45 were asymptomatic controls. Amniotic fluid advanced oxidation protein products (AOPP) and malondialdehyde (MDA) were measured by commercial ELISA. Both were higher in the infection group (median 7.96 versus 5.77 ng/mL and 12.49 versus 7.73 nmol/mL, both p < 0.001), with lower cord blood pH (p = 0.003) and more frequent neonatal intensive care unit (NICU) admission (26.7% versus 4.4%, p = 0.007). AOPP was associated with NICU admission (area under the curve 0.917, 95% CI 0.777 to 0.999), although this rests on 14 events with thresholds derived and evaluated in the same sample. Elevations were largest in the bacterial vaginosis and aerobic bacterial subgroups, but the etiologies did not differ. Both kits were designed for serum and are not validated for amniotic fluid, and 16.7% of MDA measurements fell outside the calibration range, so the MDA results are semi-quantitative. Vaginal infection at cesarean delivery is associated with higher amniotic oxidative stress markers; these findings are exploratory and require external validation. Full article

(This article belongs to the Special Issue Oxidative Stress in Pregnant Women and Fetuses)

27 pages, 7480 KB

Open AccessArticle

Targeting SQLE-Mediated Cholesterol Metabolism to Promote Oxidative Stress and Attenuate Drug Resistance in Osteosarcoma

by Amonnat Sukhamwang, Dumnoensun Pruksakorn, Pornngarm Dejkriengkraikul, Michael A. Dengler and Supachai Yodkeeree

Antioxidants 2026, 15(9), 1122; https://doi.org/10.3390/antiox15091122 - 4 Sep 2026

Abstract

High-grade osteosarcoma presents a significant clinical challenge due to unpredictable therapeutic responses and aggressive progression. This study aimed to identify the critical molecular pathways driving chemotherapy resistance and aggressive phenotypes in osteosarcoma patients. Through transcriptomic and bioinformatic analyses, we identified cholesterol biosynthesis as [...] Read more.

High-grade osteosarcoma presents a significant clinical challenge due to unpredictable therapeutic responses and aggressive progression. This study aimed to identify the critical molecular pathways driving chemotherapy resistance and aggressive phenotypes in osteosarcoma patients. Through transcriptomic and bioinformatic analyses, we identified cholesterol biosynthesis as a key upregulated metabolic pathway in poor chemotherapy responders, where squalene epoxidase (SQLE) emerged as an exploratory candidate hub gene whose elevated expression significantly correlates with shortened survival in the TCGA cohort. We validated these findings by administering terbinafine, a known SQLE inhibitor. In highly chemoresistant SaOS-2 cells exhibiting the highest baseline SQLE expression, terbinafine synergistically sensitized cells to doxorubicin by driving cell death partly through apoptosis, as confirmed by caspase inhibition. The combination also promoted ferroptosis, indicated by elevated ROS and MDA along with decreased FSP1 and GPX4 expression. Furthermore, the co-treatment effectively suppressed clonogenic potential, induced G2/M phase cell cycle arrest, and inhibited metastatic progression. These effects were mediated by the modulation of cell proliferation, metastasis, and survival genes through the coordinated regulation of the PI3K/AKT/mTOR, ERK, and JNK signaling cascades. Together, these results highlight the therapeutic potential of targeting the SQLE pathway to overcome doxorubicin resistance and suppress aggressive progression in high-grade osteosarcoma. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Carcinogenesis: A Multifaceted Approach—2nd Edition)

17 pages, 752 KB

Open AccessArticle

Antioxidant, Antibacterial, and Antivirulence Activities of a Bioactive Fraction from Lycopus lucidus Against Porphyromonas gingivalis

by Jung Min Park, Sohae Park, Dae Youn Hwang, Heeseob Lee and Jumin Park

Antioxidants 2026, 15(9), 1121; https://doi.org/10.3390/antiox15091121 - 4 Sep 2026

Abstract

Porphyromonas gingivalis (Pg) is a keystone periodontal pathogen associated with biofilm formation and gingipain-mediated virulence. This study evaluated the antioxidant, antibacterial, antibiofilm, and antivirulence activities of a hexane extract of Lycopus lucidus (LLH) and its eight chromatographic fractions (H1–H8). Antioxidant activity was assessed [...] Read more.

Porphyromonas gingivalis (Pg) is a keystone periodontal pathogen associated with biofilm formation and gingipain-mediated virulence. This study evaluated the antioxidant, antibacterial, antibiofilm, and antivirulence activities of a hexane extract of Lycopus lucidus (LLH) and its eight chromatographic fractions (H1–H8). Antioxidant activity was assessed using DPPH and ABTS radical-scavenging assays, whereas antibacterial activity, biofilm formation, and virulence-associated gene expression were evaluated using corresponding in vitro assays. LLH exhibited antioxidant and antibacterial activities, while H4 showed the strongest overall biological activity among the fractions. The DPPH IC₅₀ values of LLH and H4 were 98.33 ± 2.05 and 60.67 ± 3.09 µg/mL, respectively, and the corresponding ABTS IC₅₀ values were 89.24 ± 1.67 and 28.15 ± 1.21 µg/mL, respectively. H4 also showed greater inhibition of biofilm formation than LLH and more pronounced downregulation of several virulence-associated genes. LC–MS/MS analysis tentatively identified α-cyperone as a constituent of H4. Overall, chromatographic fractionation of LLH yielded H4 with enhanced biological activity across several measured endpoints, including radical-scavenging, antibacterial, and antibiofilm effects, together with more pronounced suppression of several virulence-associated genes. However, the contribution of α-cyperone or other individual constituents to these effects remains to be established. Full article

(This article belongs to the Section Extraction and Industrial Applications of Antioxidants)

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34 pages, 31728 KB

Open AccessArticle

Mitochondrial Transplantation Suppresses mtDNA-cGAS/STING-Mediated Innate Immunity by Enhancing PINK1/Parkin-Dependent Mitophagy to Attenuate Keloid Fibrosis

by Wenjing Wang, Yuanbo Liu, Jipeng Song, Zouzou Yu, Zixiang Chen and Hu Jiao

Antioxidants 2026, 15(9), 1120; https://doi.org/10.3390/antiox15091120 - 4 Sep 2026

Abstract

Keloids are characterized by fibrosis and chronic inflammation, but links between mitochondrial dysfunction and keloid pathogenesis remain unclear. This study examined whether impaired PINK1/Parkin-dependent mitophagy is associated with mitochondrial DNA (mtDNA)-mediated innate immune activation and fibrosis in keloids, and evaluated mitochondrial transplantation as [...] Read more.

Keloids are characterized by fibrosis and chronic inflammation, but links between mitochondrial dysfunction and keloid pathogenesis remain unclear. This study examined whether impaired PINK1/Parkin-dependent mitophagy is associated with mitochondrial DNA (mtDNA)-mediated innate immune activation and fibrosis in keloids, and evaluated mitochondrial transplantation as a potential therapeutic strategy. Primary keloid fibroblasts (KFs), normal skin fibroblasts (NFs), adipose-derived stem cells (ADSCs), human keloid tissues, and human keloid xenografts in immunodeficient BALB/c nude mice were analyzed using ultrastructural, molecular, and functional approaches. Freshly isolated NF-derived mitochondria (nMito) and ADSC-derived mitochondria (aMito) were compared at protein-equivalent doses. KFs exhibited mitochondrial abnormalities, impaired oxidative phosphorylation, increased reactive oxygen species, mtDNA leakage, and cGAS/STING pathway activation. Elevated PINK1 expression, reduced Parkin expression and p62 accumulation were consistent with impaired downstream mitophagic clearance. Both nMito and aMito were associated with improved mitochondrial function, changes in mitophagy-related markers, reduced cytosolic mtDNA and cGAS/STING signaling, and attenuated fibroblast activation, with greater aMito-associated changes in selected endpoints. In xenografts, intralesional administration of either mitochondria improved collagen organization and reduced fibrotic and inflammatory signaling. Together, these findings link altered PINK1/Parkin-dependent mitophagy to mtDNA-driven inflammation and fibrosis and support mitochondrial transplantation as a potential organelle-based therapeutic approach. Full article

(This article belongs to the Special Issue Antioxidant Therapies, Mitochondrial Function, and Transplantation Strategies: Mechanisms and Emerging Therapeutics)

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24 pages, 4494 KB

Open AccessArticle

Mung Bean Seed Coat Extract Promotes Diabetic Wound Healing in High-Glucose-Exposed HaCaT Keratinocytes

by Sineenad Teerapatpaisan, Alisa Naladta, Kamonpan Wanichsri, Penpimol Ponchunchoovong, Suthasinee Thapphasaraphong and Natsajee Nualkaew

Antioxidants 2026, 15(9), 1119; https://doi.org/10.3390/antiox15091119 - 4 Sep 2026

Abstract

Mung bean seed coat (MBSC) is a byproduct of commercial vermicelli production that possesses essential activities capable of delaying diabetic wound progression. This study aimed to evaluate the potential of MBSC extracts to promote diabetic wound healing, an effect that has not yet [...] Read more.

Mung bean seed coat (MBSC) is a byproduct of commercial vermicelli production that possesses essential activities capable of delaying diabetic wound progression. This study aimed to evaluate the potential of MBSC extracts to promote diabetic wound healing, an effect that has not yet been reported. The hypoglycemic effect was assessed by glucose uptake stimulation in L6 myotubes and by an α-glucosidase inhibition assay. Antiglycation was determined by BSA-glucose and BSA-methylglyoxal assays. Intracellular reactive oxygen species (ROS) reduction and wound healing were assessed in human keratinocytes (HaCaT) exposed to high glucose (HG), and gene expression in HG-wounded cells was analyzed by qPCR. The results demonstrated that the ethanolic extract (EE) from MBSC exhibited glucose-lowering effects and suppressed glycation reactions at the early and intermediate stages, with IC₅₀ values of 75 and 140 µg/mL, respectively. EE reduced ROS by 70%, stimulated cell proliferation by 57% in the high-glucose (HG)-exposed HaCaT cells, and accelerated cell migration to close the HG-exposed wound. EE increased the gene expression of Nrf2, NQO-1, SOD2, and CAT. It also downregulated TNF-α, upregulated TGF-β1, and downregulated MMP-9. In conclusion, EE has the potential to delay the progression of diabetic wounds by lowering blood glucose levels, inhibiting AGE and ROS formation, and enhancing cell proliferation and migration in HG-exposed HaCaT cells. The gene regulatory effects of EE were demonstrated as an Nrf2 activator that reduced oxidative stress, exerted anti-inflammatory effects, and regulated ECM balance. The preparation of oral and topical products could be further developed. Full article

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

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32 pages, 5564 KB

Open AccessReview

Natural Histidine Derivatives—From Basic Research to Potential Applications in Cosmetics and Nutricosmetics

by Edyta Gołaś and Mateusz Maciejczyk

Antioxidants 2026, 15(9), 1118; https://doi.org/10.3390/antiox15091118 - 4 Sep 2026

Abstract

Skin aging is a complex process influenced by oxidative stress, protein glycation, chronic inflammation, and increased extracellular matrix remodeling. Intensive research is underway on new anti-aging substances with multi-target mechanisms of action while maintaining safety and efficacy. Ergothioneine, selenoneine, and ovothiol A are [...] Read more.

Skin aging is a complex process influenced by oxidative stress, protein glycation, chronic inflammation, and increased extracellular matrix remodeling. Intensive research is underway on new anti-aging substances with multi-target mechanisms of action while maintaining safety and efficacy. Ergothioneine, selenoneine, and ovothiol A are natural histidine derivatives of marine origin, in which the oxygen atom of the hydroxyl group has been replaced with sulphur or selenium. In recent years, a broad spectrum of their biological activity has been demonstrated. Despite the well-documented antioxidant potential of these compounds, their anti-aging effects, particularly in terms of antiglycation and anti-inflammatory activity, remain insufficiently understood. This study presents the current state of knowledge regarding the biological activity of ergothioneine, selenoneine, and ovothiol A, and discusses available cosmetic preparations and dietary supplements containing these compounds. Meanwhile, significant research gaps have been identified regarding their potential use in the prevention and treatment of skin aging. Full article

(This article belongs to the Special Issue Natural Antioxidants for Cosmetic Applications)

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19 pages, 9459 KB

Open AccessArticle

Carnosine Potentiates a Compensatory Mitochondrial–Synaptic Proteomic Response in the ALS Cerebellum

by Hellen P. Valerio, Valeria Oliveira, Stephanie Y. Ferreira, Isabel R. Pereira, Giuseppe Palmisano, Mariana P. Massafera, Vanderson S. Bispo, Fernanda M. Prado, Paolo Di Mascio and Marisa H. G. Medeiros

Antioxidants 2026, 15(9), 1117; https://doi.org/10.3390/antiox15091117 - 4 Sep 2026

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and chronic neuroinflammation in the brain and spinal cord, involving complex interactions between neurons and immune cells. Carnosine (β-alanyl-L-histidine) has pathophysiological relevance due to its ability to detoxify [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and chronic neuroinflammation in the brain and spinal cord, involving complex interactions between neurons and immune cells. Carnosine (β-alanyl-L-histidine) has pathophysiological relevance due to its ability to detoxify reactive carbonyl species, including α,β-unsaturated aldehydes, scavenge free radicals, and chelate zinc, and has also been proposed to function in the central nervous system as a histidine reservoir for histamine synthesis. Here, we investigated the effects of carnosine supplementation on the cerebellar proteome of SOD1^G93A ALS rats using quantitative proteomics. Carnosine treatment extensively remodeled mitochondrial, antioxidant, and synaptic vesicle-trafficking protein networks and increased the abundance of glutamatergic and GABAergic receptor subunits relative to untreated ALS animals, with several of these changes exceeding wild-type levels. Pathway enrichment analyses identified significant up-regulation of Rab-mediated vesicle trafficking, synaptic vesicle cycling, and neurotransmitter transport/secretion pathways, alongside a partial reduction in RNA splicing and proteasomal subunits that were elevated in untreated ALS animals. Cross-comparison with the ALS-associated proteomic signature revealed that most carnosine-responsive proteins followed, rather than reversed, the direction of disease-associated change, indicating that carnosine predominantly potentiates an endogenous compensatory program rather than restoring a wild-type-like proteome. Collectively, these findings show that carnosine drives systems-level remodeling of mitochondrial and synaptic networks in the ALS cerebellum, identifying candidate compensatory pathways and supporting further functional validation of carnosine as a component of multimodal therapeutic strategies in ALS. Full article

(This article belongs to the Special Issue Carnosine: A Multifaceted Antioxidant and Anti-Inflammatory Peptide—Molecular Mechanisms and Biological Relevance)

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35 pages, 2797 KB

Open AccessReview

Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease: From Molecular Mechanisms to Biomarkers and Targeted Therapies

by Federica De Luca, Dario Troise, Valentina Camporeale, Giorgia Leccese, Federica Galloso, Roberto Cuttano, Barbara Infante, Giovanni Stallone, Elena Ranieri and Giuseppe Stefano Netti

Antioxidants 2026, 15(9), 1116; https://doi.org/10.3390/antiox15091116 - 4 Sep 2026

Abstract

Chronic kidney disease (CKD) represents a major global health challenge, affecting more than 10% of the population and contributing substantially to morbidity and premature mortality. Growing evidence identifies oxidative stress and mitochondrial dysfunction as central drivers of renal injury and disease progression across [...] Read more.

Chronic kidney disease (CKD) represents a major global health challenge, affecting more than 10% of the population and contributing substantially to morbidity and premature mortality. Growing evidence identifies oxidative stress and mitochondrial dysfunction as central drivers of renal injury and disease progression across diverse etiologies. The kidney is one of the most mitochondria-rich organs in the body, reflecting the high bioenergetic demands required for tubular reabsorption and metabolic homeostasis. Disruption of mitochondrial oxidative phosphorylation, excessive production of reactive oxygen species (ROS), and impaired mitochondrial quality control mechanisms promote tubular injury, inflammation, and fibrosis. In particular, dysfunction of the electron transport chain, activation of NADPH oxidase isoforms—especially NOX4—and alterations in mitochondrial dynamics create a vicious cycle of oxidative damage and bioenergetic failure. Emerging evidence highlights the importance of mitochondrial quality control pathways, including fusion–fission balance, PINK1/Parkin-mediated mitophagy, and mitochondrial biogenesis regulated by PGC-1α and TFAM. Additional mechanisms include ferroptosis, epigenetic regulation, mitochondrial DNA-mediated innate immune activation, and Na⁺/K⁺-ATPase-linked redox signaling. At the translational level, redox and mitochondrial biomarkers and targeted therapies are biologically compelling, but the evidence is uneven: most candidate biomarkers remain insufficiently standardized, and direct mitochondria-targeted interventions are supported predominantly by preclinical studies or small human proof-of-concept trials. This review therefore emphasizes not only mechanistic advances but also conflicting findings, model limitations, and the barriers that currently separate experimental efficacy from clinically meaningful CKD outcomes. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Kidney Diseases)

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30 pages, 27851 KB

Open AccessArticle

Gelatin Methacryloyl Hydrogel Encapsulating CiMECs-Derived Extracellular Vesicles Ameliorates Lactation Function via Alleviating Mammary Oxidative Stress

by Guodong Wang, Jiawen Duan, Longfei Sun, Tao Xu, Jianwei Chen, Aihao Xu, Quanhui Liu, Mengqin Qin, Shouyu Huo, Weiqing Li, Xiaozhen Li, Quanqing Zou, Prasanna Kallingappa, Dandan Zhang and Ben Huang

Antioxidants 2026, 15(9), 1115; https://doi.org/10.3390/antiox15091115 - 4 Sep 2026

Abstract

Background: Postpartum hypogalactia is a prevalent obstetric complication worldwide, closely associated with excessive oxidative stress and impaired antioxidant defense in mammary tissue. Current hormone-based therapies carry endocrine disruption risks, while natural antioxidant bioactive agents such as extracellular vesicles (EVs) are largely limited [...] Read more.

Background: Postpartum hypogalactia is a prevalent obstetric complication worldwide, closely associated with excessive oxidative stress and impaired antioxidant defense in mammary tissue. Current hormone-based therapies carry endocrine disruption risks, while natural antioxidant bioactive agents such as extracellular vesicles (EVs) are largely limited by rapid in vivo clearance and poor tissue retention. Methods: We constructed an injectable gelatin methacryloyl (GelMA) hydrogel system to encapsulate chemically induced mammary epithelial cell-derived EVs (CiMECs-EVs) and systematically evaluated their antioxidant and lactogenic activities via multi-omics analysis, cellular functional assays and a bromocriptine-induced murine hypogalactia model. Results: CiMECs-EVs induced a functional mammary epithelial-like phenotype in fibroblasts in a dose-dependent manner with functional cargo enriched in glutathione metabolism and redox-regulatory miRNAs. The GelMA matrix protected EV integrity and enabled sustained release, and the composite system significantly ameliorated mammary duct structure and lactation function in vivo with specific mammary tropism and no systemic toxicity, outperforming free EV treatment. Conclusions: This study presents a safe protein biomacromolecule-based antioxidant delivery platform that effectively restores mammary redox balance and antioxidant defenses, providing a promising non-hormonal therapeutic strategy for postpartum hypogalactia. Full article

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30 pages, 42890 KB

Open AccessArticle

Blastocyst-Derived Lactic Acid Regulates Uterine Epithelial Receptivity and Stromal Decidualization via the HIF1α-HO-1-Heme Metabolic Axis

by Wen-Xu Yao, Yao-Dan Ma, Shi-Yao Ding, Jian Lu, Hao-Lan Tang and Zeng-Ming Yang

Antioxidants 2026, 15(9), 1114; https://doi.org/10.3390/antiox15091114 - 4 Sep 2026

Abstract

Successful embryo implantation requires intimate crosstalk between the blastocyst and the uterine epithelium within a defined window of receptivity. However, the metabolic signals that mediate this process in mammals remain poorly understood. In this study, pregnant mice, primary uterine cell culture and uterine [...] Read more.

Successful embryo implantation requires intimate crosstalk between the blastocyst and the uterine epithelium within a defined window of receptivity. However, the metabolic signals that mediate this process in mammals remain poorly understood. In this study, pregnant mice, primary uterine cell culture and uterine epithelial organoids were used to examine the regulation and function of heme oxygenase-1 (HO-1) during mouse embryo implantation and decidualization. We demonstrate that embryo-derived lactic acid drives heme catabolism and regulates epithelial receptivity in mice through a hypoxia-inducible factor 1α (HIF1α) -heme oxygenase-1 (HO-1) signaling axis. Specifically, lactic acid stabilizes HIF1α to induce HO-1 expression in uterine epithelial cells by promoting von Hippel-Lindau (VHL) nucleolar sequestration and downregulating PHD2/3. Additionally, lactic acid suppresses the transcriptional repressor BACH1, further facilitating HO-1 induction. At physiological heme levels, HO-1-derived bilirubin promotes epithelial receptivity by increasing phosphorylated STAT3 (p-STAT3) and downregulating MUC1. A low dose of hemin promotes epithelial receptivity and decidualization, whereas a high dose of hemin suppresses these processes. Pharmacological inhibition of HO-1 in mice markedly reduces implantation sites, establishing the functional necessity of this pathway. However, when heme levels exceed the regulatory capacity of HO-1, epithelial dysfunction ensues, characterized by reduced p-STAT3 and elevated MUC1, which ultimately disrupts implantation. Consistent with this, chronic heme exposure by oral gavage in mice increases uterine heme levels and upregulates BACH1, thereby suppressing HO-1 and trapping the uterus in a non-receptive state, causing implantation failure. Our findings define a lactic acid-HIF1α-HO-1-heme metabolic checkpoint that couples glycolytic signaling to heme regulation and endometrial receptivity. Dysregulation of this checkpoint may contribute to implantation disorders associated with heme stress, providing mechanistic insights into heme stress-related uterine receptivity failure. Full article

(This article belongs to the Special Issue Oxidative Stress in Animal Reproduction and Nutrition—2nd Edition)

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25 pages, 458 KB

Open AccessArticle

Antioxidant Properties and Bioactive Compounds of Oregano, Sage, Basil, Rosemary, and Herbal Mixtures

by Julia Płatkiewicz, Joanna Wróbel, Magdalena Jeszka-Skowron, Robert Frankowski, Zuzanna Grześkowiak, Beata Czarczyńska-Goślińska, Anna Maria Jeszka and Agnieszka Zgoła-Grześkowiak

Antioxidants 2026, 15(9), 1113; https://doi.org/10.3390/antiox15091113 - 4 Sep 2026

Abstract

Herbs and spices are traditionally added to food in cuisines around the world. Antioxidant activity and content of bioactive compounds were compared in oregano, sage, basil, rosemary, and herbal mixtures. After optimization of ultrasound-assisted extraction of the ethanol–water extracts, the content of reducing [...] Read more.

Herbs and spices are traditionally added to food in cuisines around the world. Antioxidant activity and content of bioactive compounds were compared in oregano, sage, basil, rosemary, and herbal mixtures. After optimization of ultrasound-assisted extraction of the ethanol–water extracts, the content of reducing compounds of the herb extracts was tested using the Folin–Ciocalteu method, and antioxidant capacity was evaluated with ABTS (2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt) and DPPH (2,2-diphenyl-1-picrylhydrazyl radical) assays. Oregano showed the highest antioxidant activity in all tests used (2.6 mg of gallic acid equivalent (GAE) per mL in the Folin–Ciocalteu test, 4.6 mg Trolox/mL in the ABTS assay, and 3.3 mg Trolox/mL in the DPPH assay) while rosemary had the lowest antioxidant activity (1.2 mg GAE/mL (Folin–Ciocalteu), 1.5 mg Trolox/mL (ABTS), and 1.3 mg Trolox/mL (DPPH)). Apart from antioxidant properties, the content of bioactive compounds was determined with the use of high-performance liquid chromatography–tandem mass spectrometry (LC-MS/MS). It was found that in all tested Lamiaceae herbs and the herbal mixes, rosmarinic acid widely predominates as a major non-volatile phenolic constituent, and its content varies from 1121 µg/g in rosemary to 10,255 µg/g in herbes de Provence. High concentrations were also observed for quinic acid in both oregano and rosemary. Interestingly, the concentrations of rosmarinic acid in the group of herbs studied are positively correlated with the results obtained in the Folin–Ciocalteu, ABTS, and DPPH tests (Spearman’s correlation coefficient 0.7030, 0.6657, and 0.7188, respectively), whereas no such correlation is observed for quinic acid. Overall, the findings indicate that these herbs share a common hydroxycinnamate-based phytochemical framework but display clear species-specific differences reflecting their intrinsic metabolism. Furthermore, the concentration of 3-caffeoylquinic acid in the Sicilian herbs (1021 µg/g) was approximately 10 times higher compared to the samples of Dalmatian herbs, herbes de Provence, and pure herbs, which demonstrates the unique chemical composition of that mixture, including the presence of dried tomatoes and tarragon, which were not included in other tested herbal mixtures. Full article

(This article belongs to the Special Issue Phytochemical Analysis and Evaluation of Antioxidant Properties in Medicinal Plants)

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28 pages, 9791 KB

Open AccessArticle

Trans-Vitisin B Targets Neuroinflammation, Oxidative Stress, and Tau Pathology to Improve Behavioral Outcomes in a Mouse Model of Parkinson’s Disease

by Evgeny Pislyagin, Igor Manzhulo, Irina Agafonova, Anna Starinets, Ekaterina Menchinskaya, Ekaterina Chingizova, Darya Tarbeeva, Sergey Fedoreyev and Dmitry Aminin

Antioxidants 2026, 15(9), 1112; https://doi.org/10.3390/antiox15091112 - 3 Sep 2026

Abstract

Current Parkinson’s disease (PD) therapies like Levodopa (L-DOPA) only provide symptomatic relief, highlighting the need for multi-target neuroprotective agents. This study investigates the mechanisms and preclinical effects of trans-vitisin B (tVB), an oligomeric stilbene, in PD models. In LPS-stimulated HMC3 and RAW 264.7 [...] Read more.

Current Parkinson’s disease (PD) therapies like Levodopa (L-DOPA) only provide symptomatic relief, highlighting the need for multi-target neuroprotective agents. This study investigates the mechanisms and preclinical effects of trans-vitisin B (tVB), an oligomeric stilbene, in PD models. In LPS-stimulated HMC3 and RAW 264.7 cells, tVB (0.1–10.0 µM) significantly suppressed reactive oxygen species (ROS), nitric oxide (NO), COX-2, and pro-inflammatory cytokines (IL-1β, TNF-α), while restoring HSP70 chaperone levels to normalize proteostasis. These findings were validated in vivo using C57BL/6 mice with rotenone-induced chronic PD. Administration of tVB attenuated motor deficits (Cylinder test) and reduced pathological freezing (Open Field) and working memory impairments (Y-maze) in this model, without inducing the dyskinesia-like side effects of L-DOPA treatment in rodents. Histologically, tVB mitigated the loss of dopaminergic neurons (TH⁺) in the substantia nigra, reduced microglial activation (IBA-1⁺) and neuronal NO synthase, and suppressed pathological phosphorylated Tau protein (p-TauSer202) accumulation. Unlike L-DOPA’s direct dopaminergic stimulation, tVB’s neuroprotective efficacy is mediated through multilevel regulation of key PD pathogenetic pathways, including neuroinflammation, oxidative stress, and impaired proteostasis. Full article

(This article belongs to the Topic Targeting Metabolic Pathways: Oxidative Stress, Autophagy, and Inflammation in Neurological Diseases)

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31 pages, 1382 KB

Open AccessReview

Edible Fungi and Skin Redox Homeostasis: Bioactive Diversity, Processing, Oral Exposure, and Evidence Gaps

by Caizhen Wang, Ying Wang, Hongyu Chen, Bing Li, Youran Shao and Gen Zou

Antioxidants 2026, 15(9), 1111; https://doi.org/10.3390/antiox15091111 - 2 Sep 2026

Abstract

Oxidative stress drives skin aging, barrier impairment, and inflammatory amplification, making dietary antioxidants potential systemic contributors to cutaneous redox homeostasis. Edible fungi are distinctive sources of redox-active metabolites, particularly ergothioneine, a stable sulfur-containing antioxidant whose cellular uptake is mediated by the ergothioneine transporter [...] Read more.

Oxidative stress drives skin aging, barrier impairment, and inflammatory amplification, making dietary antioxidants potential systemic contributors to cutaneous redox homeostasis. Edible fungi are distinctive sources of redox-active metabolites, particularly ergothioneine, a stable sulfur-containing antioxidant whose cellular uptake is mediated by the ergothioneine transporter OCTN1 (SLC22A4). This review evaluates ergothioneine, polysaccharides and β-glucans, cordycepin, phenolics, and Ganoderma triterpenoids as processing-sensitive dietary bioactives with redox relevance rather than topical cosmetic ingredients. We examine how cultivation, drying, cooking, extraction, fermentation, and microbial biomanufacturing determine antioxidant formation, retention, oral bioaccessibility, and dose realism, and how antioxidant response, inflammatory, mitochondrial, and gut microbiota-mediated pathways connect intake to skin endpoints. The strongest oral evidence concerns biomarker-linked ergothioneine-rich Pleurotus. Smaller Flammulina velutipes and Sparassis crispa trials report hydration or transepidermal water loss signals without comparable exposure biomarkers, whereas purified ergothioneine provides provisional non-mushroom food evidence. Compared with better-established oral ingredients, edible fungi offer distinctive food technology advantages but a narrower human evidence base. Priorities include processing-aware quality and safety markers, contaminant control, standardized digestion models, dose-realistic exposure estimates, and biomarker-anchored randomized human trials. Full article

(This article belongs to the Special Issue Antioxidants in Cosmetics)

16 pages, 616 KB

Open AccessReview

The Oxidative–Mitochondrial–Inflammatory Axis in Retinitis Pigmentosa: Extracellular mtDNA as Biomarker and Therapeutic Read-Out

by Rossella Grimaldi, Francesca Franco and Enzo Maria Vingolo

Antioxidants 2026, 15(9), 1110; https://doi.org/10.3390/antiox15091110 - 2 Sep 2026

Abstract

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy (prevalence ~1:4000) and a leading Mendelian cause of working-age blindness. Despite marked genetic heterogeneity, its progression converges on a common secondary cascade of outer-retinal hyperoxia, increased reactive oxygen species (ROS), and mitochondrial dysfunction [...] Read more.

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy (prevalence ~1:4000) and a leading Mendelian cause of working-age blindness. Despite marked genetic heterogeneity, its progression converges on a common secondary cascade of outer-retinal hyperoxia, increased reactive oxygen species (ROS), and mitochondrial dysfunction that drives cone degeneration and central vision loss. Because this oxidative cascade is largely genotype-independent and pharmacologically tractable, oxidative stress is a cross-cutting therapeutic target. Within it, mitochondrial DNA (mtDNA) is a key element: once released from damaged photoreceptors—free or within exosomes—it may act as a damage-associated molecular pattern (DAMP), engaging TLR9, cGAS–STING, and the NLRP3 inflammasome and sustaining chronic neuroinflammation. Extracellular mtDNA is therefore a potential integrative marker, simultaneously reflecting oxidative stress, mitochondrial dysfunction, cell death, and innate-immune activation. A central knowledge gap, however, remains: the mechanistic steps linking mtDNA to inflammation and to photoreceptor death have not been demonstrated in RP itself, and extracellular mtDNA has never been quantified in the ocular fluids of RP patients. In this review we appraise oxidative biomarkers in RP, propose extracellular mtDNA as a candidate biomarker of disease activity, and examine antioxidant and redox-modulating therapies—from N-acetylcysteine and elamipretide trials to DAMP-sensor inhibition—across experimental and clinical models. Finally, we propose extracellular mtDNA as a candidate pharmacodynamic endpoint and outline a path toward its validation. Full article

(This article belongs to the Special Issue Role of Oxidative Stress in Eye Diseases)

18 pages, 590 KB

Open AccessPerspective

The TMAO Metabolic Axis in Vascular Disease: A Position Paper on Redox Mechanisms and Priorities for Clinical Translation

by Francesca Miceli, Eugenio Caradonna, Claudia Panzano, Wassim Mansour, Fulvio Ferrara, Lucy Costantino, Carlo Setacci and Luca di Marzo

Antioxidants 2026, 15(9), 1109; https://doi.org/10.3390/antiox15091109 - 2 Sep 2026

Abstract

Background: Trimethylamine N-oxide (TMAO) arises from the interaction of diet, gut microbial metabolism, hepatic oxidation, and renal clearance. Experimental work links TMAO exposure to mitochondrial oxidative stress, NLRP3 inflammasome activation, impaired nitric oxide signaling, vascular smooth muscle cell dysfunction, and thrombosis. How far [...] Read more.

Background: Trimethylamine N-oxide (TMAO) arises from the interaction of diet, gut microbial metabolism, hepatic oxidation, and renal clearance. Experimental work links TMAO exposure to mitochondrial oxidative stress, NLRP3 inflammasome activation, impaired nitric oxide signaling, vascular smooth muscle cell dysfunction, and thrombosis. How far these findings explain human vascular disease remains uncertain. Purpose: We examine TMAO and related metabolites in carotid atherosclerosis, aortic disease (abdominal aortic aneurysm, AAA, and dissection), and peripheral artery disease (PAD), focusing on redox biology and the obstacles that still limit clinical translation. Position: Current evidence makes the pathway biologically credible, but it does not support routine TMAO measurement, a universal cutoff, or treatment decisions based on a single metabolite. The recent association between γ-butyrobetaine and limb outcomes also suggests that TMAO may not always be the most informative component of the pathway. Most causal evidence remains preclinical, and no TMAO-lowering or redox-directed intervention has improved a vascular clinical endpoint. Conclusions: For now, the TMAO pathway remains investigational. Progress will depend on multicenter studies that measure several pathway metabolites with harmonized assays and carefully account for renal function, diet, and sex. Interventional studies are premature until safety and biological target engagement have been established. Full article

24 pages, 22647 KB

Open AccessArticle

Palmitic Acid Inhibits the Proliferation and Hypertrophy of Antler Chondrocytes by Disrupting Mitochondria-Associated Endoplasmic Reticulum Membrane Function

by Qiaoling Zhang, Zhanqing Yang, Xueyuan Yao, Yinfei Xing, Chenhao Wang, Baiyu Li, Zhanpeng Yue and Bin Guo

Antioxidants 2026, 15(9), 1108; https://doi.org/10.3390/antiox15091108 - 2 Sep 2026

Abstract

As the only mammalian appendage capable of complete regeneration, deer antlers serve as an invaluable model to investigate cartilage regrowth, but the underlying mechanism remains unclear. This study revealed that addition of palmitic acid (PA), an abundant long-chain saturated free fatty acid, inhibited [...] Read more.

As the only mammalian appendage capable of complete regeneration, deer antlers serve as an invaluable model to investigate cartilage regrowth, but the underlying mechanism remains unclear. This study revealed that addition of palmitic acid (PA), an abundant long-chain saturated free fatty acid, inhibited the proliferation and hypertrophy of antler chondrocytes while promoting chondrocyte apoptosis. PA treatment activated NOTCH1 signaling and restrained the transport of Ca²⁺ from the cytosol to the endoplasmic reticulum (ER) via RBPJ (recombination signal-binding protein for immunoglobulin kappa J region)-targeted TMTC4 (transmembrane O-mannosyltransferase targeting cadherins 4), resulting in a reduction in ER Ca²⁺. Meanwhile, PA disrupted the structure and function of mitochondria-associated ER membranes (MAMs) via TGM2 (transglutaminase 2) through the cytosolic Ca²⁺-mediated PPP3CB (protein phosphatase 3 catalytic subunit beta)-NFATC2 (nuclear factor of activated T cells cytoplasmic 2) pathway. Further analysis demonstrated that PA induced mitochondrial dysfunction via MAM-mediated mitochondrial Ca²⁺ insufficiency, thereby restricting mitophagy and attenuating lysosomal acidification. This caused the leakage of mitochondrial reactive oxygen species (mtROS) from depolarized mitochondria into the cytosol via the mitochondrial permeability transition pore, thereby inducing lipid peroxidation, while the addition of ROS scavengers prevented the negative effects of chondrocyte proliferation and hypertrophy and protected chondrocytes from apoptosis in the context of PA. Collectively, PA treatment regulated the proliferation, apoptosis and hypertrophy of antler chondrocytes by disrupting MAM function. Full article

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

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30 pages, 13280 KB

Open AccessArticle

Comprehensive Characterization of Cytochrome P450s Reveals Candidate Enzymes Involved in the Metabolic Fate of Absorbed Volatile Organic Compounds in Potato

by Milica D. Bogdanović, Nina Devrnja, Katarina B. Ćuković Janićijević, Sofija Stupar, Slađana I. Todorović and Jelena Savić

Antioxidants 2026, 15(9), 1107; https://doi.org/10.3390/antiox15091107 - 2 Sep 2026

Abstract

Plants are continuously exposed to volatile organic compounds (VOCs) emitted by neighbors. Although the mechanisms governing VOC uptake and metabolism remain unclear, cytochrome P450 monooxygenases (CYP450s) are thought to participate in the detoxification and metabolic conversion of absorbed VOCs. Data from previously conducted [...] Read more.

Plants are continuously exposed to volatile organic compounds (VOCs) emitted by neighbors. Although the mechanisms governing VOC uptake and metabolism remain unclear, cytochrome P450 monooxygenases (CYP450s) are thought to participate in the detoxification and metabolic conversion of absorbed VOCs. Data from previously conducted cDNA microarray transcriptomic profiling in potato exposed to French marigold essential oil (FM-EO) was here used to filter differentially expressed sequences, and identified 54 unique CYP450 transcripts. Among the 10 most highly expressed sequences, two CYP81D1-like (81D1-1 and 81D1-2) and one CYP81D11-like (81D11-1) transcripts were found. RT-qPCR confirmed their strong induction within 8 h of volatile exposure. Comprehensive bioinformatics identified the most highly induced 81D1-1 gene as a CYP450 containing a predicted N-terminal hydrophobic signal or membrane-anchor region, the conserved heme-binding signature motif, and regulatory elements associated with oxidative stress responses. The other 81D11-1 gene, exhibiting a comparable expression level, was annotated only as a heme-binding protein but possessed seven distinct cis-regulatory elements, suggesting high transcriptional plasticity. Machine learning predictions assigned the highest interaction probability to (Z)-β-ocimene, whereas structure-based docking yielded the most favorable mean score for piperitone. This study provides the first characterization of the potato CYP450 superfamily in the context of volatile-mediated plant–plant interactions and identifies two CYP81D members as strong candidates for the oxidative metabolism of absorbed VOCs. The results support a proposed detoxification pathway in which CYP81-mediated oxidation precedes glutathione conjugation and intracellular sequestration of VOCs. These candidate genes provide a valuable foundation for future functional studies and may facilitate the development of sustainable crop protection strategies based on volatile-mediated plant defense. Full article

(This article belongs to the Special Issue Advances in Plant Redox Biology Research)

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