Antioxidants

20 pages, 6269 KiB

Open AccessArticle

Reduced Glutathione Promoted Growth Performance by Improving the Jejunal Barrier, Antioxidant Function, and Altering Proteomics of Weaned Piglets

by Zhimei Tian, Yiyan Cui, Miao Yu, Dun Deng, Zhenming Li, Xianyong Ma and Mingren Qu

Antioxidants 2025, 14(1), 107; https://doi.org/10.3390/antiox14010107 (registering DOI) - 17 Jan 2025

Abstract

Reduced glutathione (GSH) is a main nonenzymatic antioxidant, but its effects and underlying mechanisms on growth and intestinal health in weaned piglets still require further assessment. A total of 180 weaned piglets were randomly allotted to 5 groups: a basal diet (CON), and [...] Read more.

Reduced glutathione (GSH) is a main nonenzymatic antioxidant, but its effects and underlying mechanisms on growth and intestinal health in weaned piglets still require further assessment. A total of 180 weaned piglets were randomly allotted to 5 groups: a basal diet (CON), and a basal diet supplemented with antibiotic chlortetracycline (ABX), 50 (GSH1), 65 (GSH2), or 100 mg/kg GSH (GSH3). Results revealed that dietary GSH1, GSH2, and ABX improved body weight and the average daily gain of weaned piglets, and ABX decreased albumin content but increased aspartate aminotransferase (AST) activity and the ratio of AST to alanine transaminase levels in plasma. GSH2 significantly decreased glucose content but increased the content of triglyceride and cholesterol in the plasma. Both GSH1 and GSH2 improved the jejunal mucosa architecture (villus height, crypt depth, and the ratio of villus height to crypt depth), tight junction protein (ZO-1 and Occludin), and antioxidant capacity (CAT and MDA), and the effects were superior to ABX. Dietary GSH improved the jejunal barrier by probably inhibiting the myosin light chain kinas pathway to up-regulate the transcript expression of tight junction protein (ZO-1 and Occludin) and Mucins. Through the proteomics analysis of the jejunal mucosa using 4D-DIA, the KEGG pathway enrichment analysis showed that differentiated proteins were significantly enriched in redox homeostasis-related pathways such as glutathione metabolism, cytochrome P450, the reactive oxygen species metabolic pathway, the oxidative phosphorylation pathway, and the phosphatidylinositol 3-kinase-serine/threonine kinase pathway in GSH2 vs. CON and in GSH2 vs. ABX. The results of proteomics and qRT-PCR showed that GSH supplementation might dose-dependently promote growth performance and that it alleviated the weaning stress-induced oxidative injury of the jejunal mucosa in piglets by activating SIRTI and Akt pathways to regulate GPX4, HSP70, FoxO1. Therefore, diets supplemented with 50–65 mg/kg GSH can promote the growth of and relieve intestinal oxidative injury in weaned piglets. Full article

20 pages, 6357 KiB

Open AccessArticle

(−)-Epigallocatechin-3-Gallate and Quercetin Inhibit Quiescin Sulfhydryl Oxidase 1 Secretion from Hepatocellular Carcinoma Cells

by Lumin Yang, Yuying Fang, Yufeng He and Jinsong Zhang

Antioxidants 2025, 14(1), 106; https://doi.org/10.3390/antiox14010106 - 17 Jan 2025

Abstract

Liver cancer is one of the most prevalent cancers worldwide. The first-line therapeutic drug sorafenib offers only a moderate improvement in patients’ conditions. Therefore, an approach to enhancing its therapeutic efficacy is urgently needed. It has been revealed that hepatocellular carcinoma (HCC) cells [...] Read more.

Liver cancer is one of the most prevalent cancers worldwide. The first-line therapeutic drug sorafenib offers only a moderate improvement in patients’ conditions. Therefore, an approach to enhancing its therapeutic efficacy is urgently needed. It has been revealed that hepatocellular carcinoma (HCC) cells with heightened intracellular quiescin sulfhydryl oxidase 1 (QSOX1) exhibit increased sensitivity to sorafenib. QSOX1 is a secreted disulfide catalyst, and it is widely recognized that extracellular QSOX1 promotes the growth, invasion, and metastasis of cancer cells through its participation in the establishment of extracellular matrix. Inhibiting QSOX1 secretion can increase intracellular QSOX1 and decrease extracellular QSOX1. Such an approach would sensitize HCC cells to sorafenib but remains to be established. Since (−)-epigallocatechin-3-gallate (EGCG) has been demonstrated to be an effective inhibitor of α-fetal protein secretion from HCC cells, we screened QSOX1 secretion inhibition using polyphenolic compounds. We examined eight dietary polyphenols (EGCG, quercetin, fisetin, myricetin, caffeic acid, chlorogenic acid, resveratrol, and theaflavin) and found that EGCG and quercetin effectively inhibited QSOX1 secretion from human HCC cells (HepG2 or Huh7), resulting in high intracellular QSOX1 and low extracellular QSOX1. The combination of EGCG or quercetin, both of which change the cellular distribution of QSOX1, with sorafenib, which has no influence on the cellular distribution of QSOX1, exhibited multiple synergistic effects against the HCC cells, including the induction of apoptosis and inhibition of invasion and metastasis. In conclusion, our current results suggest that dietary EGCG and quercetin have the potential to be developed as adjuvants to sorafenib in the treatment of HCC by modulating the cellular distribution of QSOX1. Full article

(This article belongs to the Special Issue Anti-cancer Potential of Plant-Based Antioxidants)

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15 pages, 586 KiB

Open AccessArticle

Excessive Weight Gain During Pregnancy Increased Ponoxarase 1 Level in Neonatal Cord Blood

by Serhat Ege, Hasan Akduman, Ayşegül Aşır and Tuğcan Korak

Antioxidants 2025, 14(1), 105; https://doi.org/10.3390/antiox14010105 - 17 Jan 2025

Abstract

Maternal obesity is increasingly recognized as a risk factor for adverse fetal outcomes, primarily through its association with heightened oxidative stress. This study aimed to evaluate oxidative stress markers in umbilical cord blood of neonates born to obese mothers. Sixty-three pregnant women, who [...] Read more.

Maternal obesity is increasingly recognized as a risk factor for adverse fetal outcomes, primarily through its association with heightened oxidative stress. This study aimed to evaluate oxidative stress markers in umbilical cord blood of neonates born to obese mothers. Sixty-three pregnant women, who were of normal weight at the start of pregnancy but classified as obese at term, were included. Umbilical cord blood samples were collected immediately post-delivery and analyzed for serum oxidative stress markers (total oxidant status (TOS), total antioxidant status (TAS), paraoxanase (PON), aryl esterase, thiol, and catalase activities). Protein interaction networks were generated using Cytoscape (v3.10.3), and the overlapping proteins were further analyzed for functional annotations with ShinyGO (0.80). The top ten significantly enriched pathways were identified with a false discovery rate (FDR) threshold of <0.05. Significant associations were found between maternal BMI change and paraoxonase 1 (PON1) levels in umbilical cord blood, while no correlation was observed with other oxidative (total oxidant status) and antioxidant markers (total antioxidant status, aryl esterase, thiol, and catalase). Additionally, the correlation analysis showed a significant relationship between BMI change and fetal gestational age, but not with other demographic or clinical features. A total of 24 common protein interactors associated with PON1, obesity, and oxidative stress were identified. Functional annotation analysis revealed significant enrichment in antioxidant and oxidoreductase activities, along with pathways involved in insulin resistance, AGE-RAGE signaling, and atherosclerosis. Maternal obesity may specifically affect PON1 activity, potentially serving as a compensatory response to oxidative stress in neonates, suggesting PON1 as a possible biomarker for oxidative stress-related metabolic disturbances in neonates of obese mothers, with implications for monitoring and managing pregnancy outcomes in obese populations. Full article

(This article belongs to the Special Issue Effect of Oxidative Stress on Reproduction and Development—2nd Edition)

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27 pages, 2157 KiB

Open AccessReview

Role of Oxidative Stress in the Occurrence, Development, and Treatment of Breast Cancer

by Rui Dong, Jing Wang, Ruiqi Guan, Jianwei Sun, Ping Jin and Junling Shen

Antioxidants 2025, 14(1), 104; https://doi.org/10.3390/antiox14010104 - 17 Jan 2025

Abstract

Breast cancer is one of the most prevalent cancers worldwide. Recent studies have increasingly emphasized the role of oxidative stress in the initiation and progression of breast cancer. This article reviews how oxidative stress imbalance influences the occurrence and advancement of breast cancer, [...] Read more.

Breast cancer is one of the most prevalent cancers worldwide. Recent studies have increasingly emphasized the role of oxidative stress in the initiation and progression of breast cancer. This article reviews how oxidative stress imbalance influences the occurrence and advancement of breast cancer, elucidating the intricate mechanisms through which reactive oxygen species (ROS) operate in this context and their potential therapeutic applications. By highlighting these critical insights, this review aims to enhance our understanding of oxidative stress as a potential target for innovative therapeutic strategies in the management of breast cancer. Full article

(This article belongs to the Special Issue Oxidative Stress and Redox Signaling in Cancer Progression and Therapy)

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18 pages, 637 KiB

Open AccessArticle

Multicomponent Dietary Supplementation: Impact on Tear Secretion and Ocular Surface Inflammation in Dry Eye Syndrome Patients

by Shih-Chien Huang, Yen-Ping Lei, Min-Chien Hsiao, Yu-Kai Hsieh, Quei-Ping Tang, Connie Chen and Min-Yen Hsu

Antioxidants 2025, 14(1), 103; https://doi.org/10.3390/antiox14010103 - 16 Jan 2025

Abstract

Dry eye syndrome (DES) is a prevalent ocular condition characterized by tear film instability, inflammation, and discomfort, affecting millions worldwide. DES is related to oxidative stress imbalance and ocular surface inflammation, which are important factors in the development of the condition. Recent studies [...] Read more.

Dry eye syndrome (DES) is a prevalent ocular condition characterized by tear film instability, inflammation, and discomfort, affecting millions worldwide. DES is related to oxidative stress imbalance and ocular surface inflammation, which are important factors in the development of the condition. Recent studies have demonstrated that fish oil, lutein, and zeaxanthin possess anti-inflammatory and antioxidant properties. This study investigated the efficacy of a multicomponent dietary supplement in improving tear secretion and mitigating ocular surface inflammation in patients with DES. It was an open-label intervention trial. In total, 52 participants were randomly assigned to control (n = 23) and supplement (45 mg/day eicosapentaenoic acid, 30 mg/day docosahexaenoic acid, 30 mg/day lutein, and 1.8 mg/day zeaxanthin; n = 29) groups for 12 weeks. The participants were evaluated using Schirmer’s test and the ocular surface disease index (OSDI) as ocular surface parameters. Moreover, blood or tear oxidative stress, antioxidant capacities, and tear inflammatory indicators were measured at weeks 0 and 12. The results indicated a significant increase in tear secretion and a significant reduction in OSDI scores in the supplement group. Additionally, inflammatory markers, such as interleukin (IL)-6 and IL-8, significantly decreased after the intervention. However, the OSDI of the supplement group significantly improved by 6.60 points (β = −6.60, p = 0.01). These findings support the potential of targeted nutritional supplementation as a safe and effective strategy for alleviating DES symptoms, offering an alternative to conventional treatments that exclusively focus on symptom management. This study highlights the role of specific nutrients in modulating tear production and inflammation, thereby providing a foundation for dietary approaches to DES treatment. Future research should explore the long-term benefits of such interventions and their impact on overall ocular health. Full article

(This article belongs to the Special Issue Effect of Dietary Antioxidants in Chronic Disease Prevention)

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17 pages, 3682 KiB

Open AccessArticle

Pyrroloquinoline Quinone Improved Boar Sperm Quality via Maintaining Mitochondrial Function During Cryopreservation

by Shanpeng Wang, Qi Wang, Lingjiang Min, Hailiang Cao, Adedeji O. Adetunji, Kaifeng Zhou and Zhendong Zhu

Antioxidants 2025, 14(1), 102; https://doi.org/10.3390/antiox14010102 - 16 Jan 2025

Abstract

Due to oxidative damage and mitochondrial dysfunction, boar semen cryopreservation remains a significant challenge. This study investigates the effects of pyrroloquinoline quinone (PQQ), a mitochondrial-targeted antioxidant, on the post-thaw boar sperm quality during cryopreservation. Boar semen was diluted in a freezing extender containing [...] Read more.

Due to oxidative damage and mitochondrial dysfunction, boar semen cryopreservation remains a significant challenge. This study investigates the effects of pyrroloquinoline quinone (PQQ), a mitochondrial-targeted antioxidant, on the post-thaw boar sperm quality during cryopreservation. Boar semen was diluted in a freezing extender containing different concentrations of PQQ (0, 10, 100, 1000, 10,000 nM). After freezing–thawing, the sperm motility, viability, acrosome integrity, mitochondrial activity, adenosine triphosphate (ATP) levels, DNA integrity, malondialdehyde (MDA) levels, reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, mitochondrial transcription proteins levels, and fertilization capacity were assessed. The results show that 1000 nM PQQ supplementation to the freezing extender significantly enhanced post-thaw sperm motility, viability, and acrosome integrity compared to the control (p < 0.05). Additionally, 1000 nM PQQ increased mitochondrial membrane potential (MMP) and ATP levels, while decreasing MDA and mitochondrial ROS levels, and reducing DNA damage (p < 0.05). Furthermore, the levels of mitochondrial-encoded proteins were significantly elevated in the 1000 nM PQQ group compared to the control (p < 0.05). Interestingly, sperm in the 1000 nM PQQ group showed a higher binding rate to oviductal epithelial cells and the zona pellucida (ZP), indicating higher fertilization potential. These findings suggest that the use of mitochondria-target antioxidant, PQQ, can improve post-thaw boar sperm quality and fertilization via its capacity to reduce oxidative stress and protect mitochondrial function. Full article

(This article belongs to the Special Issue Redox Regulation in Animal Reproduction)

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13 pages, 1205 KiB

Open AccessReview

Dual Roles of Reducing Systems in Protein Persulfidation and Depersulfidation

by Zhichao Liu, Nicolas Rouhier and Jérémy Couturier

Antioxidants 2025, 14(1), 101; https://doi.org/10.3390/antiox14010101 - 16 Jan 2025

Abstract

The oxidative modification of specific cysteine residues to persulfides is thought to be the main way by which hydrogen sulfide (H₂S) exerts its biological and signaling functions. Therefore, protein persulfidation represents an important thiol-switching mechanism as other reversible redox post-translational modifications. [...] Read more.

The oxidative modification of specific cysteine residues to persulfides is thought to be the main way by which hydrogen sulfide (H₂S) exerts its biological and signaling functions. Therefore, protein persulfidation represents an important thiol-switching mechanism as other reversible redox post-translational modifications. Considering their reductase activity but also their connections with proteins that generate H₂S and its related molecules, the glutaredoxin (GRX) and thioredoxin (TRX)-reducing systems have potential dual roles in both protein persulfidation and depersulfidation. In this review, we will first focus on recent advances describing the physiological pathways leading to protein persulfidation before discussing the dual roles of the physiological TRX and glutathione/GRX-reducing systems in protein persulfidation/depersulfidation. Full article

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

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19 pages, 7322 KiB

Open AccessArticle

Peroxiredoxin 5 Acts as a Negative Regulator of the Sodium-Chloride Cotransporter Involved in Alleviating Angiotensin II-Induced Hypertension

by Hoon-In Choi, In Ae Jung and Soo Wan Kim

Antioxidants 2025, 14(1), 100; https://doi.org/10.3390/antiox14010100 - 16 Jan 2025

Abstract

Chronic kidney disease (CKD) and hypertension are interconnected, worsening each other. Recent studies have shown that the reduction of peroxiredoxin 5 (Prdx5) accelerates kidney fibrosis, a hallmark of CKD. This study aims to observe whether the deficiency of Prdx5 also contributes to the [...] Read more.

Chronic kidney disease (CKD) and hypertension are interconnected, worsening each other. Recent studies have shown that the reduction of peroxiredoxin 5 (Prdx5) accelerates kidney fibrosis, a hallmark of CKD. This study aims to observe whether the deficiency of Prdx5 also contributes to the worsening of CKD-related hypertension. Angiotensin II (Ang II, 1000 ng/kg/day) was infused into Prdx5 wild-type (WT) and Prdx5 knock out (KO) mice (each group; n = 6). The blood pressure was higher in the Ang-II-infused Prdx5 KO mice than in the WT mice. Ang-II-induced ROS/RNS generation and fibrotic marker expressions were also higher in the Prdx5 KO mice. In particular, the expression of the sodium-chloride cotransporter (NCC), an ion transport protein important for sodium retention in the distal convoluted tubule, and the NCC’s phosphorylation at Thr53 were increased in the kidney of Ang-II-infused Prdx5 KO. The activity of an WNK4-SPAK/OSR1, upstream activator of the NCC, was also increased. In 209/mDCT cells, the knockdown of Prdx5 (siPrdx5) increased the activity of Ang-II-mediated WNK4-SPAK/OSR1-NCC signaling and Ang-II-mediated ROS generation, whereas Prdx5 overexpression showed opposite results. In conclusion, Prdx5 negatively regulates the WNK4-SPAK/OSR1-NCC signaling axis, indicating its potential as a candidate for antihypertensive drug development through NCC regulation. Full article

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36 pages, 2119 KiB

Open AccessReview

Treating Metabolic Dysregulation and Senescence by Caloric Restriction: Killing Two Birds with One Stone?

by Lara Russo, Serena Babboni, Maria Grazia Andreassi, Jalil Daher, Paola Canale, Serena Del Turco and Giuseppina Basta

Antioxidants 2025, 14(1), 99; https://doi.org/10.3390/antiox14010099 - 16 Jan 2025

Abstract

Cellular senescence is a state of permanent cell cycle arrest accompanied by metabolic activity and characteristic phenotypic changes. This process is crucial for developing age-related diseases, where excessive calorie intake accelerates metabolic dysfunction and aging. Overnutrition disturbs key metabolic pathways, including insulin/insulin-like growth [...] Read more.

Cellular senescence is a state of permanent cell cycle arrest accompanied by metabolic activity and characteristic phenotypic changes. This process is crucial for developing age-related diseases, where excessive calorie intake accelerates metabolic dysfunction and aging. Overnutrition disturbs key metabolic pathways, including insulin/insulin-like growth factor signaling (IIS), the mammalian target of rapamycin (mTOR), and AMP-activated protein kinase. The dysregulation of these pathways contributes to insulin resistance, impaired autophagy, exacerbated oxidative stress, and mitochondrial dysfunction, further enhancing cellular senescence and systemic metabolic derangements. On the other hand, dysfunctional endothelial cells and adipocytes contribute to systemic inflammation, reduced nitric oxide production, and altered lipid metabolism. Numerous factors, including extracellular vesicles, mediate pathological communication between the vascular system and adipose tissue, amplifying metabolic imbalances. Meanwhile, caloric restriction (CR) emerges as a potent intervention to counteract overnutrition effects, improve mitochondrial function, reduce oxidative stress, and restore metabolic balance. CR modulates pathways such as IIS, mTOR, and sirtuins, enhancing glucose and lipid metabolism, reducing inflammation, and promoting autophagy. CR can extend the health span and mitigate age-related diseases by delaying cellular senescence and improving healthy endothelial–adipocyte interactions. This review highlights the crosstalk between endothelial cells and adipocytes, emphasizing CR potential in counteracting overnutrition-induced senescence and restoring vascular homeostasis. Full article

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3 pages, 145 KiB

Open AccessEditorial

Something Is Rotten in the State of Redox

by Ahmad Yaman Abdin, Mohamad Jawad Nasim and Claus Jacob

Antioxidants 2025, 14(1), 98; https://doi.org/10.3390/antiox14010098 - 16 Jan 2025

Abstract

Some say that science is an art, a craft, and a passion—and, one may add these days, often also a business [...] Full article

(This article belongs to the Special Issue Something is Rotten in the State of Redox)

52 pages, 10706 KiB

Open AccessArticle

Enhancement of Cognitive Benefits and Anti-Anxiety Effects of Phytolacca americana Fruits in a Zebrafish (Danio rerio) Model of Scopolamine-Induced Memory Impairment

by Lucia-Florina Popovici, Ion Brinza, Florentina Gatea, Georgiana Ileana Badea, Emanuel Vamanu, Simona Oancea and Lucian Hritcu

Antioxidants 2025, 14(1), 97; https://doi.org/10.3390/antiox14010097 - 15 Jan 2025

Abstract

Phytolacca americana fruits exhibit a wide range of biological activities, including antimicrobial, anti-inflammatory, and anticancer properties. This study aims to investigate the phenolic profile of hydroethanolic extracts from both fresh (PEC) and dried (PEU) fruits of P. americana using high-performance liquid chromatography (HPLC) [...] Read more.

Phytolacca americana fruits exhibit a wide range of biological activities, including antimicrobial, anti-inflammatory, and anticancer properties. This study aims to investigate the phenolic profile of hydroethanolic extracts from both fresh (PEC) and dried (PEU) fruits of P. americana using high-performance liquid chromatography (HPLC) and to evaluate their impact on anxiety-like behavior, memory, oxidative stress, and cholinergic status in zebrafish (Danio rerio, Tübingen strain) treated with scopolamine (SCO, 100 μM). Acute administration of PEC and PEU (0.1, 0.5, and 1 mg/L) was conducted for one hour per day. In silico analyses were performed to evaluate the pharmacokinetic characteristics of the phenolic compounds discerned in the two extracts, using platforms such as SwissAdme, Molinspiration, ProToX-III, AdmetLab 3.0, PKCSM, and PASS. Anxiety-like behavior and memory performance were assessed through specific behavioral assays, including the novel tank test (NTT), light/dark test (LD), novel approach test (NAT), Y-maze, and novel object recognition (NOR). Subsequently, the activity of acetylcholinesterase (AChE) and the extent of oxidative stress in the zebrafish brain were investigated. Our findings suggest that both PEC and PEU possess anxiolytic effects, alleviating SCO-induced anxiety and enhancing cognitive performance in amnesic zebrafish. Furthermore, these extracts demonstrated the ability to mitigate cholinergic deficits by inhibiting AChE activity and supporting antioxidant defense mechanisms through increased activity of antioxidant enzymes and reduced lipid and protein peroxidation. These results highlight the potential use of P. americana fruit extracts in managing anxiety and cognitive impairments related to dementia conditions. Full article

(This article belongs to the Special Issue Antioxidant Capacity of Bioactive Plant Compounds for Therapeutic Purpose—2nd Edition)

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25 pages, 11151 KiB

Open AccessArticle

Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq

by Christophe Desterke, Yuanji Fu, Jenny Bonifacio-Mundaca, Claudia Monge, Pascal Pineau, Jorge Mata-Garrido and Raquel Francés

Antioxidants 2025, 14(1), 96; https://doi.org/10.3390/antiox14010096 (registering DOI) - 15 Jan 2025

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can [...] Read more.

Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. Using two independent medulloblastoma RNA-sequencing cohorts (MB-PBTA and MTAB-10767), we investigated the expression of ferroptosis-related molecules through multiple approaches, including Weighted Gene Co-Expression Network Analysis (WGCNA), molecular subtype stratification, protein–protein interaction (PPI) networks, and univariable and multivariable overall survival analyses. A prognostic expression score was computed based on a cross-validated ferroptosis signature. In training and validation cohorts, the regulation of the ferroptosis transcriptional program distinguished the four molecular subtypes of medulloblastoma. WGCNA identified nine gene modules in the MB tumor transcriptome; five correlated with molecular subtypes, implicating pathways related to oxidative stress, hypoxia, and trans-synaptic signaling. One module, associated with disease recurrence, included epigenetic regulators and nucleosome organizers. Univariable survival analyses identified a 45-gene ferroptosis prognostic signature associated with nutrient sensing, cysteine and methionine metabolism, and trans-sulfuration within a one-carbon metabolism. The top ten unfavorable ferroptosis genes included CCT3, SNX5, SQOR, G3BP1, CARS1, SLC39A14, FAM98A, FXR1, TFAP2C, and ATF4. Patients with a high ferroptosis score showed a worse prognosis, particularly in the G3 and SHH subtypes. The PPI network highlighted IL6 and CBS as unfavorable hub genes. In a multivariable overall survival model, which included gender, age, and the molecular subtype classification, the ferroptosis expression score was validated as an independent adverse prognostic marker (hazard ratio: 5.8; p-value = 1.04 × 10⁻⁹). This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma. Full article

(This article belongs to the Special Issue Oxidative Stress in Rare Diseases: Mechanisms, Implications, and Therapeutic Opportunities)

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22 pages, 5843 KiB

Open AccessReview

Unveiling the Emerging Role of Xanthine Oxidase in Acute Pancreatitis: Beyond Reactive Oxygen Species

by Chenxia Han, Yaling Wu, Juan Rong, Qing Xia and Dan Du

Antioxidants 2025, 14(1), 95; https://doi.org/10.3390/antiox14010095 - 15 Jan 2025

Abstract

Acute pancreatitis (AP) is a potentially fatal acute digestive disease that is widespread globally. Although significant progress has been made in the previous decade, the study of mechanisms and therapeutic strategies is still far from being completed. Xanthine oxidase (XO) is an enzyme [...] Read more.

Acute pancreatitis (AP) is a potentially fatal acute digestive disease that is widespread globally. Although significant progress has been made in the previous decade, the study of mechanisms and therapeutic strategies is still far from being completed. Xanthine oxidase (XO) is an enzyme that catalyzes hypoxanthine and xanthine to produce urate and is accompanied by the generation of reactive oxygen species (ROS) in purine catabolism. Considerable preclinical and clinical studies have been conducted over many decades to investigate the role of XO in the pathogenesis of AP and its potential targeting therapeutic value. There is no doubt that the ROS generated by irreversibly activated XO participates in the local pancreas and multiple organ failure during AP. However, the optimal timing and doses for therapeutic interventions targeting XO in animal studies and the clinic, as well as the additional molecular mechanisms through which XO contributes to disease onset and progression, including metabolic regulation, remain to be elucidated. This review summarized the benefits and contradictions of using XO inhibitors in animal models, offered mechanisms other than ROS, and discussed the difficulties faced in clinical trials. We hope to provide a perspective on the future worthwhile basic and clinical research on XO by analyzing its chemical and biological characteristics, as well as the progress of its regulatory mechanisms in AP. Full article

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20 pages, 681 KiB

Open AccessReview

Hypoxia-Induced Reactive Oxygen Species: Their Role in Cancer Resistance and Emerging Therapies to Overcome It

by Eleicy Nathaly Mendoza, Maria Rosa Ciriolo and Fabio Ciccarone

Antioxidants 2025, 14(1), 94; https://doi.org/10.3390/antiox14010094 - 15 Jan 2025

Abstract

Normal tissues typically maintain partial oxygen pressure within a range of 3–10% oxygen, ensuring homeostasis through a well-regulated oxygen supply and responsive vascular network. However, in solid tumors, rapid growth often outpaces angiogenesis, creating a hypoxic microenvironment that fosters tumor progression, altered metabolism [...] Read more.

Normal tissues typically maintain partial oxygen pressure within a range of 3–10% oxygen, ensuring homeostasis through a well-regulated oxygen supply and responsive vascular network. However, in solid tumors, rapid growth often outpaces angiogenesis, creating a hypoxic microenvironment that fosters tumor progression, altered metabolism and resistance to therapy. Hypoxic tumor regions experience uneven oxygen distribution with severe hypoxia in the core due to poor vascularization and high metabolic oxygen consumption. Cancer cells adapt to these conditions through metabolic shifts, predominantly relying on glycolysis, and by upregulating antioxidant defenses to mitigate reactive oxygen species (ROS)-induced oxidative damage. Hypoxia-induced ROS, resulting from mitochondrial dysfunction and enzyme activation, exacerbates genomic instability, tumor aggressiveness, and therapy resistance. Overcoming hypoxia-induced ROS cancer resistance requires a multifaceted approach that targets various aspects of tumor biology. Emerging therapeutic strategies target hypoxia-induced resistance, focusing on hypoxia-inducible factors, ROS levels, and tumor microenvironment subpopulations. Combining innovative therapies with existing treatments holds promise for improving cancer outcomes and overcoming resistance mechanisms. Full article

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

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18 pages, 23483 KiB

Open AccessArticle

DNA Methylation and Transcriptome Profiling Reveal the Role of the Antioxidant Pathway and Lipid Metabolism in Plectropomus leopardus Skin Color Formation

by Yang Liu, Linna Wang, Zhentong Li, Linlin Li, Tangtang Ding, Shuai Chen, Pengfei Duan, Xinyi Wang, Yishu Qiu, Xiaoyu Ding and Yongsheng Tian

Antioxidants 2025, 14(1), 93; https://doi.org/10.3390/antiox14010093 - 15 Jan 2025

Abstract

Leopard coral grouper (Plectropomus leopardus), possessing a distinct red body color, is an important species in commercial markets; however, the high ratio of black individuals under intensive cultivation has limited the commercial value of the species. To dissect the regulatory mechanisms [...] Read more.

Leopard coral grouper (Plectropomus leopardus), possessing a distinct red body color, is an important species in commercial markets; however, the high ratio of black individuals under intensive cultivation has limited the commercial value of the species. To dissect the regulatory mechanisms underlying the red skin trait in P. leopardus, gene expression and DNA methylation modifications were compared between red and black skin tissues after astaxanthin treatment. Astaxanthin effectively increased the redness value a* and body weight. Multi-omics analyses revealed the crucial roles of pathways related to antioxidants and lipid metabolism, particularly “Tyrosine metabolism”, “Melanogenesis”, “Fatty acid metabolism”, “Fatty acid elongation”, and “Biosynthesis of unsaturated acids”, in red skin coloration. A molecular network for the regulation of red skin coloration in P. leopardus was constructed, and pmel, tyr, tyrp1a, tyrp1b, dct, slc24a5, wnt1, acsl4, elovl1, elovl6l.1, elovl6l.2, and elovl7 were identified as key genes. Notably, pmel, acsl4, and elovl7 were negatively regulated by differential DNA methylation. Our results provide new insight into the molecular and epigenetic mechanisms of body color variation, representing a significant step towards breeding for the red skin trait in P. leopardus. Full article

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14 pages, 3436 KiB

Open AccessArticle

Cobalt Protoporphyrin Downregulates Hyperglycemia-Induced Inflammation and Enhances Mitochondrial Respiration in Retinal Pigment Epithelial Cells

by Peng-Hsiang Fang, Tzu-Yu Lin, Chiu-Chen Huang, Yung-Chang Lin, Cheng-Hung Lai and Bill Cheng

Antioxidants 2025, 14(1), 92; https://doi.org/10.3390/antiox14010092 - 15 Jan 2025

Abstract

Diabetic retinopathy is characterized by hyperglycemic retinal pigment epithelial cells that secrete excessive pro-inflammatory cytokines and VEGF, leading to retinal damage and vision loss. Cobalt protoporphyrin (CoPP) is a compound that can reduce inflammatory responses by inducing high levels of HO-1. In the [...] Read more.

Diabetic retinopathy is characterized by hyperglycemic retinal pigment epithelial cells that secrete excessive pro-inflammatory cytokines and VEGF, leading to retinal damage and vision loss. Cobalt protoporphyrin (CoPP) is a compound that can reduce inflammatory responses by inducing high levels of HO-1. In the present study, the therapeutic effects of CoPP were examined in ARPE-19 cells under hyperglycemia. ARPE-19 cells were incubated in culture media containing either 5.5 mM (NG) or 25 mM (HG) glucose, with or without the addition of 0.1 µM CoPP. Protein expressions in samples were determined by either Western blotting or immunostaining. A Seahorse metabolic analyzer was used to assess the impact of CoPP treatment on mitochondrial respiration in ARPE-19 cells in NG or HG media. ARPE-19 cells cultured in NG media displayed different cell morphology than those cultured in HG media. CoPP treatment induced high HO-1 expressions and significantly enhanced the viability of ARPE-19 cells under hyperglycemia. Moreover, CoPP significantly downregulated expressions of inflammatory and apoptotic markers and significantly upregulated mitochondrial respiration in APRPE-19 cells under hyperglycemia. CoPP treatment significantly enhanced cell viability in ARPE-19 cells under hyperglycemia. The treatment also downregulated the expressions of pro-inflammatory and upregulated mitochondrial respiration in the hyperglycemic cells. Full article

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20 pages, 10707 KiB

Open AccessArticle

Structure–Antioxidant Activity Relationship of Polysaccharides Isolated by Microwave/Ultrasonic-Assisted Extraction from Pleurotus ferulae

by Hongjin Zhou, Zhongxiong Fan, Yuan Li, Xuelian Liu, Bo Wang, Jianguo Xing, Jiang He, Ruifang Zheng and Jinyao Li

Antioxidants 2025, 14(1), 91; https://doi.org/10.3390/antiox14010091 - 14 Jan 2025

Abstract

To investigate the structure–antioxidant activity relationship, Pleurotus ferulae polysaccharides were extracted using ultrasonic (U-PFPS) and microwave/ultrasonic-assisted methods (MU-PFPS). Compared to U-PFPS with a molecular weight of 1.566 × 10³ kDa, MU-PFPS exhibited a lower molecular weight of 89.26 kDa. In addition, unlike [...] Read more.

To investigate the structure–antioxidant activity relationship, Pleurotus ferulae polysaccharides were extracted using ultrasonic (U-PFPS) and microwave/ultrasonic-assisted methods (MU-PFPS). Compared to U-PFPS with a molecular weight of 1.566 × 10³ kDa, MU-PFPS exhibited a lower molecular weight of 89.26 kDa. In addition, unlike U-PFPS, which is primarily composed of glucose (Glu:Man:Gal = 91.1:3.5:5.4), MU-PFPS has a more balanced composition of Glu:Man:Gal in the ratio of 39.4:27.8:32.8 and contains more branched chains. Furthermore, antioxidant analysis revealed that high concentration (at concentrations above 600 μg/mL) MU-PFPS demonstrated stronger protective effects against oxidative damage in RAW264.7 cells than U-PFPS did. Collectively, these data suggest that lower molecular weight and higher branching degree of polysaccharides at appropriate concentrations may correlate with enhanced antioxidant enzyme activities. Our work provides a method for isolating polysaccharides with higher antioxidant activity and offers insights into the structure–activity relationship of polysaccharides, laying the foundation for future applications in polysaccharide modification and structural characterization. Full article

(This article belongs to the Special Issue Antioxidant Capacity of Natural Products—2nd Edition)

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17 pages, 1877 KiB

Open AccessArticle

A Comparative Analysis of the Antioxidant Profiles Generated by the RoXsta^TM System for Diverse Biological Fluids Highlights the Powerful Protective Role of Human Seminal Plasma

by Robert J. Aitken, Alexandra Wilkins, Natasha Harrison, Mohammad Bahrami, Zamira Gibb, Kaitlin McIntosh, Quan Vuong and Sarah Lambourne

Antioxidants 2025, 14(1), 90; https://doi.org/10.3390/antiox14010090 - 14 Jan 2025

Abstract

(1) Background: The RoXsta^TM system has been developed as a rapid, effective means of profiling different types of antioxidant activity. The purpose of this study was to examine its performance utilizing a diverse array of biological fluids including semen, blood plasma, serum, [...] Read more.

(1) Background: The RoXsta^TM system has been developed as a rapid, effective means of profiling different types of antioxidant activity. The purpose of this study was to examine its performance utilizing a diverse array of biological fluids including semen, blood plasma, serum, urine, saliva, follicular fluid and plant extracts. (2) Methods: The RoXsta^TM system was used to assess the ability of different fluids to suppress free radical formation as well as scavenge a variety of toxic oxygen metabolites including free radicals and both hydrogen and organic peroxides. (3) Results: Human semen was shown to have significantly (p < 0.001) more peroxide scavenging power than any other fluid tested (10–14 mM vitamin C equivalent compared with 1–2 mM for blood serum or plasma), while urine was particularly effective in scavenging free radicals and preventing free radical formation (p < 0.001). The powerful antioxidant properties of human semen were shown to reside within the seminal plasma (SP) fraction, rather than the spermatozoa, and to be resistant to snap freezing in liquid nitrogen. Moreover, comparative studies demonstrated that human SP exhibited significantly (p < 0.001) higher levels of antioxidant potential than any other species examined (stallion, bull, dog) and that this intense activity reflected the relative vulnerability of human spermatozoa to peroxide attack. (4) Conclusions: The RoXsta^TM system provides valuable information on the antioxidant profile of complex biological fluids, supporting its diagnostic role in conditions associated with oxidative stress. Based on the results secured in this study, human semen is identified as a particularly rich source of antioxidants capable of scavenging both hydrogen and organic peroxides, in keeping with the high susceptibility of human spermatozoa to peroxide-mediated damage. Full article

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

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17 pages, 3825 KiB

Open AccessArticle

Shrimp White Spot Viral Infections Are Attenuated by Organic Acids by Regulating the Expression of HO-1 Oxygenase and β-1,3-Glucan-Binding Protein

by Ioan Pet, Igori Balta, Nicolae Corcionivoschi, Tiberiu Iancu, Ducu Stef, Lavinia Stef and Iuliana Cretescu

Antioxidants 2025, 14(1), 89; https://doi.org/10.3390/antiox14010089 - 14 Jan 2025

Abstract

The absence of efficient on-farm interventions against white spot syndrome viral (WSSV) infections can cause significant economic losses to shrimp farmers. With this exploratory study we aimed to test, both in vitro and in vivo, the efficacy of an organic acid mixture (Aq) [...] Read more.

The absence of efficient on-farm interventions against white spot syndrome viral (WSSV) infections can cause significant economic losses to shrimp farmers. With this exploratory study we aimed to test, both in vitro and in vivo, the efficacy of an organic acid mixture (Aq) against WSSV infections in shrimp. In vitro, using shrimp gut primary cells (SGP), 2% Aq significantly reduced WSSV infection and the amounts of H₂O₂ released but had no impact on CAT and SOD expression. In vivo, in a shrimp challenge test, 2% Aq significantly downregulated the expression of proteins involved in WSSV virulence, such as the lipopolysaccharide-β-1,3-glucan-binding protein (LGBP) and the TLR signalling pathway (LvECSIT), and increased the expression of HO-1 oxygenase. Additionally, at 2% Aq, the expression of the digestive-related enzyme carboxypeptidase B was upregulated in the gut, alongside a significant decrease in IL-22 expression, a cytokine usually increased during WSSV infection in shrimp. A low mortality rate (7.33%) was recorded in infected shrimp treated with 2% Aq compared to the 96.66% mortality in the absence of Aq. The peritrophic membrane (PM) was proven essential to ensure Aq efficacy, as the infected and treated PM deficient shrimp (PM−) had a mortality rate of 27.8%, compared to only 9.34% mortality in the infected shrimp at 2% Aq and in the presence of PM (PM+). Aq significantly increased the expression of mucin-1, mucin-2, mucin-5AC, mucin-5B, and mucin-19 in both PM+ and PM− shrimp. Conclusively, organic acid in mixtures can protect farmed shrimp against WSSV infection and increase their survivability through a mediated gut health effect which includes resistance to oxidative stress and improved immunity. Full article

(This article belongs to the Special Issue Antioxidants and Aquaculture: A Synergistic Approach for Sustainable Aquatic Production)

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