Antioxidants

4 pages, 173 KiB

Open AccessEditorial

Reactive Oxygen Species and the Lung Cancer Tumor Microenvironment: Emerging Therapeutic Opportunities

by Kostas A. Papavassiliou, Amalia A. Sofianidi and Athanasios G. Papavassiliou

Antioxidants 2025, 14(8), 964; https://doi.org/10.3390/antiox14080964 (registering DOI) - 5 Aug 2025

Lung cancer is the principal cause of cancer-related mortality globally, accounting for the high number of cancer-associated deaths amongst both men and women [...] Full article

(This article belongs to the Special Issue Role of Reactive Oxygen Species (ROS) in Tumor Microenvironment Modulation)

16 pages, 12012 KiB

Open AccessArticle

Complement Receptor 3 Regulates Microglial Exosome Release and Related Neurotoxicity via NADPH Oxidase in Neuroinflammation Associated with Parkinson’s Disease

by Yu Ma, Xiaomeng Zhang, Jiaqi Xu, Runnan Luo, Sheng Li, Hong Su, Qingshan Wang and Liyan Hou

Antioxidants 2025, 14(8), 963; https://doi.org/10.3390/antiox14080963 (registering DOI) - 5 Aug 2025

Abstract

Microglia-mediated chronic neuroinflammation is a common pathological feature of Parkinson’s disease (PD). Strong evidence suggests that activated microglia can lesion neurons by releasing exosomes. However, the mechanisms of exosome release from activated microglia remain unclear. We recently revealed a key role of complement [...] Read more.

Microglia-mediated chronic neuroinflammation is a common pathological feature of Parkinson’s disease (PD). Strong evidence suggests that activated microglia can lesion neurons by releasing exosomes. However, the mechanisms of exosome release from activated microglia remain unclear. We recently revealed a key role of complement receptor 3 (CR3) in regulating microglial activation in the process of progressive neurodegeneration. This study aimed to investigate whether CR3 can regulate exosome release from activated microglia, as well as the underlying mechanisms. We found that LPS, an inducer of microglial M1 activation, induced exosome release from activated microglia. Inhibition of exosome synthesis suppressed LPS-induced microglial activation, gene expression of proinflammatory factors, and related neurotoxicity. Silencing or knocking out CR3 attenuated LPS-induced exosome release in microglia. NADPH oxidase (NOX2) was further identified as a downstream signal of CR3, mediating microglial exosome release and related neurotoxicity. CR3 silencing blocked LPS-induced NOX2 activation and superoxide production through inhibition of p47^phox phosphorylation and membrane translocation. Moreover, NOX2 activation elicited by PMA or supplementation of H₂O₂ recovered exosome release from CR3-silenced microglia. Subsequently, we demonstrated that the CR3-NOX2 axis regulates syntenin-1 to control microglial exosome release. Finally, we observed that the expression of CR3 was increased in the brain of LPS-treated mice, and genetic ablation of CR3 significantly reduced LPS-induced NOX2 activation, microglial M1 polarization, and exosome production in mice. Overall, our findings revealed a critical role of the CR3-NOX2 axis in controlling microglial exosome release and related neurotoxicity through syntenin-1, providing a novel target for the development of a therapeutic strategy for neuroinflammation-mediated neurodegeneration. Full article

(This article belongs to the Section Antioxidant Enzyme Systems)

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18 pages, 5256 KiB

Open AccessArticle

Impact of Alginate Oligosaccharides on Ovarian Performance and the Gut Microbial Community in Mice with D-Galactose-Induced Premature Ovarian Insufficiency

by Yan Zhang, Hongda Pan, Dao Xiang, Hexuan Qu and Shuang Liang

Antioxidants 2025, 14(8), 962; https://doi.org/10.3390/antiox14080962 (registering DOI) - 5 Aug 2025

Abstract

Premature ovarian insufficiency (POI) is an important factor in female infertility and is often associated with oxidative stress. Alginate oligosaccharides (AOSs), derived from the degradation of alginate, have been demonstrated to have protective effects against various oxidative stress-related diseases. However, the impact of [...] Read more.

Premature ovarian insufficiency (POI) is an important factor in female infertility and is often associated with oxidative stress. Alginate oligosaccharides (AOSs), derived from the degradation of alginate, have been demonstrated to have protective effects against various oxidative stress-related diseases. However, the impact of AOSs on POI has not been previously explored. The current study explored the effects of AOSs on ovarian dysfunction in a mouse model of POI induced by D-galactose (D-gal). Female C57BL/6 mice were randomly divided into five groups: the control (CON), POI model (D-gal), and low-, medium-, and high-dose AOS groups (AOS-L, 100 mg/kg/day; AOS-M, 150 mg/kg/day; AOS-H, 200 mg/kg/day). For 42 consecutive days, mice in the D-gal, AOS-L, AOS-M, and AOS-H groups received daily intraperitoneal injections of D-gal (200 mg/kg/day), whereas those in the CON group received equivalent volumes of sterile saline. Following D-gal injection, AOSs were administered via gavage at the specified doses; mice in the CON and D-gal groups received sterile saline instead. AOS treatment markedly improved estrous cycle irregularities, normalized serum hormone levels, reduced granulosa cell apoptosis, and increased follicle counts in POI mice. Moreover, AOSs significantly reduced ovarian oxidative stress and senescence in POI mice, as indicated by lower levels of malondialdehyde (MDA), higher activities of catalase (CAT) and superoxide dismutase (SOD), and decreased protein expression of 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), 8-hydroxydeoxyguanosine (8-OHdG), and p16 in ovarian tissue. Analysis of the gut microbiota through 16S rRNA gene sequencing and short-chain fatty acid (SCFA) analysis revealed significant differences in gut microbiota composition and SCFA levels (acetic acid and total SCFAs) between control and D-gal-induced POI mice. These differences were largely alleviated by AOS treatment. AOSs changed the gut microbiota by increasing the abundance of Ligilactobacillus and decreasing the abundance of Clostridiales, Clostridiaceae, Marinifilaceae, and Clostridium_T. Additionally, AOSs mitigated the decline in acetic acid and total SCFA levels observed in POI mice. Notably, the total SCFA level was significantly correlated with the abundance of Ligilactobacillus, Marinifilaceae, and Clostridium_T. In conclusion, AOS intervention effectively mitigates ovarian oxidative stress, restores gut microbiota homeostasis, and regulates the microbiota–SCFA axis, collectively improving D-gal-induced POI. Therefore, AOSs represent a promising therapeutic strategy for POI management. Full article

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

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19 pages, 1492 KiB

Open AccessReview

Ginseng Nanosizing: The Second Spring of Ginseng Therapeutic Applications

by Jian Wang, Huan Liu, Xinshuo Ding, Tianqi Liu, Qianyuan Li, Runyuan Li, Yuan Yuan, Xiaoyu Yan and Jing Su

Antioxidants 2025, 14(8), 961; https://doi.org/10.3390/antiox14080961 (registering DOI) - 5 Aug 2025

Abstract

Plant-derived vesicles offer several advantages, including high yield, low cost, ethical compatibility, safety, and potential health benefits. These advantages enable them to overcome technological limitations associated with vesicles of mammalian origin. Ginseng, a prominent example of a natural botanical plant, is known for [...] Read more.

Plant-derived vesicles offer several advantages, including high yield, low cost, ethical compatibility, safety, and potential health benefits. These advantages enable them to overcome technological limitations associated with vesicles of mammalian origin. Ginseng, a prominent example of a natural botanical plant, is known for its abundant bioactive components. Recent studies confirmed that ginseng-derived vesicles offer significant advantages in the treatment of human diseases. Therefore, this study reviews the extraction and purification processes of ginseng-derived vesicle-like nanoparticles (GDVLNs), their therapeutic potential, and the active ingredients in GDVLNs that may exert pharmacological activities. Furthermore, this study evaluates the research and applications of nanosized ginseng extracts, with a primary focus on ginsenosides. Full article

(This article belongs to the Special Issue Antioxidant and Protective Effects of Plant Extracts—2nd Edition)

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18 pages, 8203 KiB

Open AccessArticle

Puerarin Enhances Eggshell Quality by Mitigating Uterine Senescence in Late-Phase Laying Breeder Hens

by Zhenwu Huang, Guangju Wang, Mengjie Xu, Yanru Shi, Jinghai Feng, Minhong Zhang and Chunmei Li

Antioxidants 2025, 14(8), 960; https://doi.org/10.3390/antiox14080960 (registering DOI) - 5 Aug 2025

Abstract

The deterioration of uterine calcium transport capacity induced by aging is a common problem for late-laying period hens, causing decline in eggshell quality. This study aimed to investigate the effects and possible regulatory mechanisms of dietary puerarin (PU) on calcium transport and eggshell [...] Read more.

The deterioration of uterine calcium transport capacity induced by aging is a common problem for late-laying period hens, causing decline in eggshell quality. This study aimed to investigate the effects and possible regulatory mechanisms of dietary puerarin (PU) on calcium transport and eggshell quality in aged hens. Two hundred eighty-eight Hubbard Efficiency Plus broiler breeder hens (50-week-old) were randomly allocated to three dietary treatments containing 0, 40, or 200 mg/kg puerarin (PU), with 8 replicates of 12 birds each, for an 8-week trial. The results demonstrated that dietary PU ameliorated the eggshell thickness and strength, which in turn reduced the broken egg rate (p < 0.05). Histological analysis showed that PU improved uterus morphology and increased epithelium height in the uterus (p < 0.05). Antioxidative capacity was significantly improved via upregulation of Nrf2, HO-1, and GPX1 mRNA expression in the uterus (p < 0.05), along with enhanced total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-PX) activity, and decreased levels of the oxidative stress marker malondialdehyde (MDA) (p < 0.05). Meanwhile, PU treatment reduced the apoptotic index of the uterus, followed by a significant decrease in expression of pro-apoptotic genes Caspase3 and BAX and the rate of BAX/BCL-2. Additionally, calcium content in serum and uterus, as well as the activity of Ca²⁺-ATPase in the duodenum and uterus, were increased by dietary PU (p < 0.05). The genes involved in calcium transport including ERα, KCNA1, CABP-28K, and OPN in the uterus were upregulated by PU supplementation (p < 0.05). The 16S rRNA gene sequencing revealed that dietary PU supplementation could reverse the age-related decline in the relative abundance of Bacteroidota within the uterus (p < 0.05). Overall, dietary PU can improve eggshell quality and calcium transport through enhanced antioxidative defenses and mitigation of age-related uterine degeneration. Full article

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25 pages, 1951 KiB

Open AccessReview

Antioxidant Capacity and Therapeutic Applications of Honey: Health Benefits, Antimicrobial Activity and Food Processing Roles

by Ivana Tlak Gajger, Showket Ahmad Dar, Mohamed Morsi M. Ahmed, Magda M. Aly and Josipa Vlainić

Antioxidants 2025, 14(8), 959; https://doi.org/10.3390/antiox14080959 (registering DOI) - 4 Aug 2025

Abstract

Honey is a natural product of honeybees that has been consumed for centuries due to its nutritional value and potential health benefits. Recent scientific research has focused on its antioxidant capacity, which is linked to a variety of bioactive compounds such as phenolic [...] Read more.

Honey is a natural product of honeybees that has been consumed for centuries due to its nutritional value and potential health benefits. Recent scientific research has focused on its antioxidant capacity, which is linked to a variety of bioactive compounds such as phenolic acids, enzymes (e.g., glucose oxidase, catalase), flavonoids, ascorbic acid, carotenoids, amino acids, and proteins. Together, these components work synergistically to neutralize free radicals, regulate antioxidant enzyme activity, and reduce oxidative stress. This review decisively outlines the antioxidant effects of honey and presents compelling clinical and experimental evidence supporting its critical role in preventing diseases associated with oxidative stress. Honey stands out for its extensive health benefits, which include robust protection against cardiovascular issues, notable anticancer and anti-inflammatory effects, enhanced glycemic control in diabetes, immune modulation, neuroprotection, and effective wound healing. As a recognized functional food and dietary supplement, honey is essential for the prevention and adjunct treatment of chronic diseases. However, it faces challenges due to variations in composition linked to climatic conditions, geographical and floral sources, as well as hive management practices. The limited number of large-scale clinical trials further underscores the need for more research. Future studies must focus on elucidating honey’s antioxidant mechanisms, standardizing its bioactive compounds, and examining its synergistic effects with other natural antioxidants to fully harness its potential. Full article

(This article belongs to the Special Issue Antioxidant and Antimicrobial Activity of Honey Bee Products—2nd Edition)

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16 pages, 1287 KiB

Open AccessReview

Oxidative Stress in the Regulation of Autosis-Related Proteins

by María Guerra-Andrés, Inés Martínez-Rojo, Alejandra Piedra-Macías, Elena Lavado-Fernández, Marina García-Macia and Álvaro F. Fernández

Antioxidants 2025, 14(8), 958; https://doi.org/10.3390/antiox14080958 (registering DOI) - 4 Aug 2025

Abstract

Physiological levels of reactive oxygen species (ROS) play a crucial role as intracellular signaling molecules, helping to maintain cellular homeostasis. However, when ROS accumulate excessively, they become toxic to cells, leading to damage to lipids, proteins, and DNA. This oxidative stress can impair [...] Read more.

Physiological levels of reactive oxygen species (ROS) play a crucial role as intracellular signaling molecules, helping to maintain cellular homeostasis. However, when ROS accumulate excessively, they become toxic to cells, leading to damage to lipids, proteins, and DNA. This oxidative stress can impair cellular function and lead to various forms of cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, paraptosis, parthanatos, and oxeiptosis. Despite their significance, the role of ROS in autosis (an autophagy-dependent form of cell death) remains largely unexplored. In this review, we gather current knowledge on autotic cell death and summarize how oxidative stress influences the activity of Beclin-1 and the Na⁺,K⁺-ATPase pump, both of which are critical effectors of this pathway. Finally, we discuss the theoretical potential for ROS to modulate this type of cell death, proposing a possible dual role for these species in autosis regulation through effectors such as HIF-1α, TFEB, or the FOXO family, and highlighting the need to experimentally address cellular redox status when working on autotic cell death. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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16 pages, 2073 KiB

Open AccessArticle

Physiological Mechanisms of the Enhanced UV-B Radiation Triggering Plant-Specific Peroxidase-Mediated Antioxidant Defences

by Yijia Gao, Ling Wei, Chenyu Jiang, Shaopu Shi, Jiabing Jiao, Hassam Tahir, Minjie Qian and Kaibing Zhou

Antioxidants 2025, 14(8), 957; https://doi.org/10.3390/antiox14080957 (registering DOI) - 4 Aug 2025

Abstract

In this study, an artificially simulated enhanced UV-B radiation treatment of 96 kJ/m²·d⁻¹ was applied with natural sunlight as the control. By observing changes in biological tissue damage, peroxidase (POD) enzyme activity, and hormone content, combined with transcriptome analysis and [...] Read more.

In this study, an artificially simulated enhanced UV-B radiation treatment of 96 kJ/m²·d⁻¹ was applied with natural sunlight as the control. By observing changes in biological tissue damage, peroxidase (POD) enzyme activity, and hormone content, combined with transcriptome analysis and quantitative fluorescence PCR validation, this study preliminarily elucidated the physiological mechanisms of plant-specific peroxidase (POD) in responding to enhanced UV-B radiation stress. Enhanced UV-B treatment significantly inhibited biological tissue growth, particularly during the rapid growth stage. At this stage, the treatment exhibited higher malondialdehyde (MDA) content, indicating increased oxidative stress due to the accumulation of reactive oxygen species (ROS). Despite the inhibition in growth, the treatment showed improvements in the accumulation of organic nutrients as well as the contents of abscisic acid (ABA), salicylic acid (SA), and methyl jasmonate (MeJA). Additionally, an increase in POD activity and lignin content was observed in the treatment, especially during the middle period of the rapid growth period. Transcriptome analysis revealed that two POD multigene family members, LOC123198833 and LOC123225298, were significantly upregulated under enhanced UV-B radiation, which was further validated through qPCR. In general, enhanced UV-B radiation triggered a defence response in biological tissue by upregulating POD genes, which can effectively help to scavenge excess ROS. Full article

(This article belongs to the Special Issue Oxidative Stress in Plant Stress and Plant Physiology)

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27 pages, 2005 KiB

Open AccessArticle

Glyoxalase 1 Inducer, trans-Resveratrol and Hesperetin–Dietary Supplement with Multi-Modal Health Benefits

by Mingzhan Xue, Naila Rabbani and Paul J. Thornalley

Antioxidants 2025, 14(8), 956; https://doi.org/10.3390/antiox14080956 (registering DOI) - 4 Aug 2025

Abstract

A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose [...] Read more.

A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose and low-grade inflammation in overweight and obese subjects in a clinical trial. The aim of this study was to explore, for the first time, health-beneficial gene expression other than Glo1 induced by tRES+HESP in human endothelial cells and fibroblasts in primary culture and HepG2 hepatoma cell line and activity of cis-resveratrol (cRES) as a Glo1 inducer. We measured antioxidant response element-linked gene expression in these cells in response to 5 µM tRES+HESP by the NanoString method. tRES+HESP increases gene expression linked to the prevention of dicarbonyl stress, lipid peroxidation, oxidative stress, proteotoxicity and hyperglycemia-linked glycolytic overload. Downstream benefits were improved regulation of glucose and lipid metabolism and decreased inflammation, extracellular matrix remodeling and senescence markers. The median effective concentration of tRES was ninefold lower than cRES in the Glo1 inducer luciferase reporter assay. The GlucoRegulate supplement provides a new treatment option for the prevention of type 2 diabetes and metabolic dysfunction–associated steatotic liver disease and supports healthy aging. Full article

(This article belongs to the Special Issue Redox Biology of Glyoxalases and Advanced Glycation End Products in Health and Diseases)

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20 pages, 2361 KiB

Open AccessArticle

Abelmoschus esculentus Ameliorates Cognitive Impairment in Hyperlipidemic ApoE^−/− Mice via Modulation of Oxidative Stress and Neuronal Differentiation

by Chiung-Huei Peng, Hsin-Wen Liang, Chau-Jong Wang, Chien-Ning Huang and Huei-Jane Lee

Antioxidants 2025, 14(8), 955; https://doi.org/10.3390/antiox14080955 (registering DOI) - 4 Aug 2025

Abstract

Cardiovascular disease (CVD) and dementia may share common pathogenic factors such as atherosclerosis and hyperlipoproteinemia. Dyslipidemia-induced oxidative stress contributes to dementia comorbidity in CVD. Abelmoschus esculentus (AE, okra) potentiates in alleviating hyperlipidemia and diabetes-related cognitive impairment. This study evaluated the effects of AE [...] Read more.

Cardiovascular disease (CVD) and dementia may share common pathogenic factors such as atherosclerosis and hyperlipoproteinemia. Dyslipidemia-induced oxidative stress contributes to dementia comorbidity in CVD. Abelmoschus esculentus (AE, okra) potentiates in alleviating hyperlipidemia and diabetes-related cognitive impairment. This study evaluated the effects of AE in hyperlipidemic ApoE^−/− mice treated with streptozotocin (50 mg/kg) and fed a high-fat diet (17% lard oil, 1.2% cholesterol). AE fractions F1 or F2 (0.65 mg/kg) were administered for 8 weeks. AE significantly reduced serum LDL-C, HDL-C, triglycerides, and glucose, improved cognitive and memory function, and protected hippocampal neurons. AE also lowered oxidative stress markers (8-hydroxy-2′-deoxyguanosine, 8-OHdG) and modulated neuronal nuclei (NeuN) and doublecortin (DCX) expression. In vitro, AE promoted neurite outgrowth and neuronal differentiation in retinoic acid (RA)-differentiated human SH-SY5Y cells under metabolic stress (glucose and palmitate), alongside the upregulation of heme oxygenase-1 (HO-1), Nuclear factor-erythroid 2-related factor 2 (Nrf2), and brain-derived neurotrophic factor (BDNF). These findings suggest AE may counter cognitive decline via oxidative stress regulation and the enhancement of neuronal differentiation. Full article

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16 pages, 5537 KiB

Open AccessArticle

Different Light Wavelengths Differentially Influence the Progression of the Hypersensitive Response Induced by Pathogen Infection in Tobacco

by Bao Quoc Tran, Anh Trung Nguyen and Sunyo Jung

Antioxidants 2025, 14(8), 954; https://doi.org/10.3390/antiox14080954 (registering DOI) - 3 Aug 2025

Abstract

Using light-emitting diodes (LEDs), we examined how different light wavelengths influence the hypersensitive response (HR) in tobacco plants infected with Pseudomonas syringae pv. tomato (Pst). Pst-infiltrated plants exhibited greater resistance to Pst infection under green and blue light compared to white and red [...] Read more.

Using light-emitting diodes (LEDs), we examined how different light wavelengths influence the hypersensitive response (HR) in tobacco plants infected with Pseudomonas syringae pv. tomato (Pst). Pst-infiltrated plants exhibited greater resistance to Pst infection under green and blue light compared to white and red light, as indicated by reduced HR-associated programmed cell death, lower H₂O₂ production, and up to 64% reduction in membrane damage. During the late stage of HR, catalase and ascorbate peroxidase activities peaked under green and blue LEDs, with 5- and 10-fold increases, respectively, while superoxide dismutase activity was higher under white and red LEDs. Defense-related genes CHS1, PALa, PR1, and PR2 were more strongly induced by white and red light. The plants treated with green or blue LEDs during Pst infection prompted faster degradation of phototoxic Mg-porphyrins and exhibited smaller declines in F_v/F_m, electron transport rate, chlorophyll content, and LHCB expression compared to those treated with white or red LEDs. By contrast, the induction of the chlorophyll catabolic gene SGR was 54% and 77% lower in green and blue LEDs, respectively, compared to white LEDs. This study demonstrates that light quality differentially affects Pst-mediated HR, with green and blue light more effectively suppressing HR progression, mainly by reducing oxidative stress through enhanced antioxidative capacity and mitigation of photosynthetic impairments. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidant Defense in Crop Plants, 2nd Edition)

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16 pages, 1961 KiB

Open AccessArticle

A Novel Glycosylated Ferulic Acid Conjugate: Synthesis, Antioxidative Neuroprotection Activities In Vitro, and Alleviation of Cerebral Ischemia–Reperfusion Injury (CIRI) In Vivo

by Jian Chen, Yongjun Yuan, Litao Tong, Manyou Yu, Yongqing Zhu, Qingqing Liu, Junling Deng, Fengzhang Wang, Zhuoya Xiang and Chen Xia

Antioxidants 2025, 14(8), 953; https://doi.org/10.3390/antiox14080953 (registering DOI) - 3 Aug 2025

Abstract

Antioxidative neuroprotection is effective at preventing ischemic stroke (IS). Ferulic acid (FA) offers benefits in the treatment of many diseases, mostly due to its antioxidant activities. In this study, a glycosylated ferulic acid conjugate (FA-Glu), with 1,2,3-triazole as a linker and bioisostere between [...] Read more.

Antioxidative neuroprotection is effective at preventing ischemic stroke (IS). Ferulic acid (FA) offers benefits in the treatment of many diseases, mostly due to its antioxidant activities. In this study, a glycosylated ferulic acid conjugate (FA-Glu), with 1,2,3-triazole as a linker and bioisostere between glucose at the C6 position and FA at the C4 position, was designed and synthesized. The hydrophilicity and chemical stability of FA-Glu were tested. FA-Glu’s protection against DNA oxidative cleavage was tested using pBR322 plasmid DNA under the Fenton reaction. The cytotoxicity of FA-Glu was examined via the PC12 cell and bEnd.3 cell tests. Antioxidative neuroprotection was evaluated, in vitro, via a H₂O₂-induced PC12 cell test, measuring cell viability and ROS levels. Antioxidative alleviation of cerebral ischemia–reperfusion injury (CIRI), in vivo, was evaluated using a rat middle cerebral artery occlusion (MCAO) model. The results indicated that FA-Glu was water-soluble (LogP −1.16 ± 0.01) and chemically stable. FA-Glu prevented pBR322 plasmid DNA cleavage induced via •OH radicals (SC% 88.00%). It was a non-toxic agent based on PC12 cell and bEnd.3 cell tests results. FA-Glu significantly protected against H₂O₂-induced oxidative damage in the PC12 cell (cell viability 88.12%, 100 μM) and inhibited excessive cell ROS generation (45.67% at 100 μM). FA-Glu significantly reduced the infarcted brain areas measured using TTC stain observation, quantification (FA-Glu 21.79%, FA 28.49%, I/R model 43.42%), and H&E stain histological observation. It sharply reduced the MDA level (3.26 nmol/mg protein) and significantly increased the GSH level (139.6 nmol/mg protein) and SOD level (265.19 U/mg protein). With superior performance to FA, FA-Glu is a safe agent with effective antioxidative DNA and neuronal protective actions and an ability to alleviate CIRI, which should help in the prevention of IS. Full article

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24 pages, 1718 KiB

Open AccessArticle

Exploring the Impact of Bioactive Compounds Found in Extra Virgin Olive Oil on NRF2 Modulation in Alzheimer’s Disease

by Marilena M. Bourdakou, Eleni M. Loizidou and George M. Spyrou

Antioxidants 2025, 14(8), 952; https://doi.org/10.3390/antiox14080952 (registering DOI) - 2 Aug 2025

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, blood–brain barrier dysfunction, oxidative stress (OS), and neuroinflammation. Current treatments provide symptomatic relief, but do not halt the disease’s progression. OS plays a crucial role in AD pathogenesis [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, blood–brain barrier dysfunction, oxidative stress (OS), and neuroinflammation. Current treatments provide symptomatic relief, but do not halt the disease’s progression. OS plays a crucial role in AD pathogenesis by promoting Aβ accumulation. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the antioxidant response, influencing genes involved in OS mitigation, mitochondrial function, and inflammation. Dysregulation of NRF2 is implicated in AD, making it a promising therapeutic target. Emerging evidence suggests that adherence to a Mediterranean diet (MD), which is particularly rich in polyphenols from extra virgin olive oil (EVOO), is associated with improved cognitive function and a reduced risk of mild cognitive impairment. Polyphenols can activate NRF2, enhancing endogenous antioxidant defenses. This study employs a computational approach to explore the potential of bioactive compounds in EVOO to modulate NRF2-related pathways in AD. We analyzed transcriptomic data from AD and EVOO-treated samples to identify NRF2-associated genes, and used chemical structure-based analysis to compare EVOO’s bioactive compounds with known NRF2 activators. Enrichment analysis was performed to identify common biological functions between NRF2-, EVOO-, and AD-related pathways. Our findings highlight important factors and biological functions that provide new insight into the molecular mechanisms through which EVOO consumption might influence cellular pathways associated with AD via modulation of the NRF2 pathway. The presented approach provides a different perspective in the discovery of compounds that may contribute to neuroprotective mechanisms in the context of AD. Full article

(This article belongs to the Special Issue Inhibition of Oxidative Stress and Related Signaling Pathways in Neuroprotection—2nd Edition)

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21 pages, 2302 KiB

Open AccessArticle

Antioxidant Effects of Exogenous Mitochondria: The Role of Outer Membrane Integrity

by Sadab Sipar Ibban, Jannatul Naima, Ryo Kato, Taichi Kuroda and Yoshihiro Ohta

Antioxidants 2025, 14(8), 951; https://doi.org/10.3390/antiox14080951 (registering DOI) - 2 Aug 2025

Abstract

The administration of isolated mitochondria is a promising strategy for protecting cells from oxidative damage. This study aimed to identify mitochondrial characteristics that contribute to stronger protective effects. We compared two types of mitochondria isolated from C6 cells with similar ATP-producing capacity but [...] Read more.

The administration of isolated mitochondria is a promising strategy for protecting cells from oxidative damage. This study aimed to identify mitochondrial characteristics that contribute to stronger protective effects. We compared two types of mitochondria isolated from C6 cells with similar ATP-producing capacity but differing in outer membrane integrity. To evaluate their stability in extracellular conditions, we examined their behavior in serum. Both types underwent mitochondrial permeability transition to a similar extent; however, under intracellular-like conditions after serum incubation, mitochondria with intact membranes retained more polarized mitochondria. Notably, mitochondria with intact outer membranes were internalized more efficiently than those with damaged membranes. In H9c2 cells, both types of mitochondria similarly increased intracellular ATP levels 1 h after administration under all tested conditions. When co-administered with H₂O₂, both suppressed oxidative damage to a comparable degree, as indicated by similar H₂O₂-scavenging activity in solution, comparable intracellular ROS levels, and equivalent preservation of electron transport chain activity. However, at higher H₂O₂ concentrations, cells treated with mitochondria possessing intact outer membranes exhibited greater survival 24 h after co-administration. Furthermore, when mitochondria were added after H₂O₂-induced damage and their removal, intact mitochondria conferred superior cell survival compared to damaged ones. These findings suggest that while both mitochondrial types exert comparable antioxidant effects, outer membrane integrity prior to administration plays a critical role in enhancing cell survival under conditions of oxidative stress. Full article

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

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13 pages, 1608 KiB

Open AccessArticle

Enhanced Antioxidant and Anti-Inflammatory Activities of Diospyros lotus Leaf Extract via Enzymatic Conversion of Rutin to Isoquercitrin

by Yeong-Su Kim, Chae Sun Na and Kyung-Chul Shin

Antioxidants 2025, 14(8), 950; https://doi.org/10.3390/antiox14080950 (registering DOI) - 2 Aug 2025

Abstract

Isoquercitrin, a monoglucoside form of quercetin, exhibits superior antioxidant, anti-inflammatory, and cardiovascular protective effects in comparison to its precursor, rutin. However, its natural abundance is limited. This study aimed to increase the functional value of Diospyros lotus leaf extract through enzymatic conversion of [...] Read more.

Isoquercitrin, a monoglucoside form of quercetin, exhibits superior antioxidant, anti-inflammatory, and cardiovascular protective effects in comparison to its precursor, rutin. However, its natural abundance is limited. This study aimed to increase the functional value of Diospyros lotus leaf extract through enzymatic conversion of rutin to isoquercitrin using α-l-rhamnosidase and to evaluate the changes in biological activities after conversion. A sugar-free D. lotus leaf extract was prepared and subjected to enzymatic hydrolysis with α-l-rhamnosidase under optimized conditions (pH 5.5, 55 °C, and 0.6 U/mL). Isoquercitrin production was monitored via high-performance liquid chromatography. Antioxidant and anti-inflammatory activities were assessed using the 2,2-diphenyl-1-picrylhydrazyl radical scavenging and lipoxygenase (LOX) inhibition assays, respectively. The enzymatic reaction resulted in complete conversion of 30 mM rutin into isoquercitrin within 180 min, increasing isoquercitrin content from 9.8 to 39.8 mM. The enzyme-converted extract exhibited significantly enhanced antioxidant activity, with a 48% improvement in IC₅₀ value compared with the untreated extract. Similarly, LOX inhibition increased from 39.2% to 48.3% after enzymatic conversion. Both extracts showed higher inhibition than isoquercitrin alone, indicating synergistic effects of other phytochemicals present in the extract. This study is the first to demonstrate that α-l-rhamnosidase-mediated conversion of rutin to isoquercitrin in D. lotus leaf extract significantly improves its antioxidant and anti-inflammatory activities. The enzymatically enhanced extract shows potential as a functional food or therapeutic ingredient. Full article

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23 pages, 3297 KiB

Open AccessArticle

Phenotypic Changes and Oxidative Stress in THP-1 Macrophages in Response to Vanilloids Following Stimulation with Allergen Act d 1 and LPS

by Milena Zlatanova, Jovana Grubač, Jovana Trbojević-Ivić and Marija Gavrović-Jankulović

Antioxidants 2025, 14(8), 949; https://doi.org/10.3390/antiox14080949 (registering DOI) - 1 Aug 2025

Abstract

Activation of macrophages plays a key role in both inflammation and oxidative stress, key features of many chronic diseases. Pro-inflammatory M1-like macrophages, in particular, contribute to pro-oxidative environments and are a frequent focus of immunological research. This research examined the effects of kiwifruit [...] Read more.

Activation of macrophages plays a key role in both inflammation and oxidative stress, key features of many chronic diseases. Pro-inflammatory M1-like macrophages, in particular, contribute to pro-oxidative environments and are a frequent focus of immunological research. This research examined the effects of kiwifruit allergen Act d 1, in comparison to LPS, on THP-1 macrophages in vitro differentiated under optimized conditions, both in the presence and in the absence of selected vanilloids. THP-1 monocyte differentiation was optimized by varying PMA exposure and resting time. Act d 1 induced M1-like phenotypic changes comparable to LPS, including upregulation of CD80, IL-1β and IL-6 secretion, gene expression of iNOS and NF-κB activation, in addition to increased reactive oxygen species (ROS) and catalase activity. Treatment with specific vanilloids mitigated these responses, primarily through reduced oxidative stress and NF-κB activation. Notably, vanillin (VN) was the most effective, also reducing CD80 expression and IL-1β levels. These results suggest that vanilloids can affect pro-inflammatory signaling and oxidative stress in THP-1 macrophages and highlight their potential to alter inflammatory conditions characterized by similar immune responses. Full article

(This article belongs to the Section Natural and Synthetic Antioxidants)

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29 pages, 28078 KiB

Open AccessArticle

Long-Term Neuroprotective Effects of Hydrogen-Rich Water and Memantine in Chronic Radiation-Induced Brain Injury: Behavioral, Histological, and Molecular Insights

by Kai Xu, Huan Liu, Yinhui Wang, Yushan He, Mengya Liu, Haili Lu, Yuhao Wang, Piye Niu and Xiujun Qin

Antioxidants 2025, 14(8), 948; https://doi.org/10.3390/antiox14080948 (registering DOI) - 1 Aug 2025

Abstract

Hydrogen-rich water (HRW) has shown neuroprotective effects in acute brain injury, but its role in chronic radiation-induced brain injury (RIBI) remains unclear. This study investigated the long-term efficacy of HRW in mitigating cognitive impairment and neuronal damage caused by chronic RIBI. Fifty male [...] Read more.

Hydrogen-rich water (HRW) has shown neuroprotective effects in acute brain injury, but its role in chronic radiation-induced brain injury (RIBI) remains unclear. This study investigated the long-term efficacy of HRW in mitigating cognitive impairment and neuronal damage caused by chronic RIBI. Fifty male Sprague Dawley rats were randomly divided into five groups: control, irradiation (IR), IR with memantine, IR with HRW, and IR with combined treatment. All but the control group received 20 Gy whole-brain X-ray irradiation, followed by daily interventions for 60 days. Behavioral assessments, histopathological analyses, oxidative stress measurements, ¹⁸F-FDG PET/CT imaging, transcriptomic sequencing, RT-qPCR, Western blot, and serum ELISA were performed. HRW significantly improved anxiety-like behavior, memory, and learning performance compared to the IR group. Histological results revealed that HRW reduced neuronal swelling, degeneration, and loss and enhanced dendritic spine density and neurogenesis. PET/CT imaging showed increased hippocampal glucose uptake in the IR group, which was alleviated by HRW treatment. Transcriptomic and molecular analyses indicated that HRW modulated key genes and proteins, including CD44, CD74, SPP1, and Wnt1, potentially through the MIF, Wnt, and SPP1 signaling pathways. Serum CD44 levels were also lower in treated rats, suggesting its potential as a biomarker for chronic RIBI. These findings demonstrate that HRW can alleviate chronic RIBI by preserving neuronal structure, reducing inflammation, and enhancing neuroplasticity, supporting its potential as a therapeutic strategy for radiation-induced cognitive impairment. Full article

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17 pages, 2287 KiB

Open AccessArticle

Gender-Dependent Cognitive and Metabolic Benefits Due to Glyoxalase 1 (Glo1) Overexpression in Age-Accelerated SAMP8 Mice

by Alcir Luiz Dafre, Taketo Taguchi, Yelena Dayn, Antonio Currais and Pamela Maher

Antioxidants 2025, 14(8), 946; https://doi.org/10.3390/antiox14080946 (registering DOI) - 1 Aug 2025

Abstract

As the size of the elderly population increases, the need for an improved understanding of what leads to the age-related decline in physiological function continues to grow. SAMP8 mice were selected for their accelerated aging phenotype. The low levels of glyoxalase 1 (Glo1), [...] Read more.

As the size of the elderly population increases, the need for an improved understanding of what leads to the age-related decline in physiological function continues to grow. SAMP8 mice were selected for their accelerated aging phenotype. The low levels of glyoxalase 1 (Glo1), the main enzyme that removes the reactive dicarbonyl methylglyoxal (MGO), in the cerebral cortex of SAMP8 mice prompted us to produce the first transgenic mice overexpressing Glo1 against the SAMP8 background, aimed at rescuing the accelerated aging phenotype. Selected health and biochemical endpoints were assessed in ten-month-old SAMP8 mice overexpressing Glo1. Glo1 overexpression increased median survival in males (21%) and females (4.6%), which was associated with better memory performance. Glo1 overexpression also increased synaptic markers (synaptophysin and SNAP25) as well as markers of mitochondrial function (NDUFB8, SDHB) and negative modulators of oxytosis/ferroptosis (NQO1, FTH1, and GPx4) in the cerebral cortex. For all parameters analyzed, the effect of Glo1 overexpression was more pronounced in males. Overall, the data support the beneficial effects of overexpressing Glo1 in multiple tissues, especially in SAMP8 males, suggesting a possible gender effect of MGO in aging. Both modulation of oxytosis/ferroptosis and mitochondrial metabolism warrant further investigation as potential mechanisms underlying the improved health span of Glo1 mice. Full article

(This article belongs to the Special Issue Redox Biology of Glyoxalases and Advanced Glycation End Products in Health and Diseases)

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24 pages, 6731 KiB

Open AccessArticle

Combined Impacts of Acute Heat Stress on the Histology, Antioxidant Activity, Immunity, and Intestinal Microbiota of Wild Female Burbot (Lota Lota) in Winter: New Insights into Heat Sensitivity in Extremely Hardy Fish

by Cunhua Zhai, Yutao Li, Ruoyu Wang, Haoxiang Han, Ying Zhang and Bo Ma

Antioxidants 2025, 14(8), 947; https://doi.org/10.3390/antiox14080947 (registering DOI) - 31 Jul 2025

Abstract

Temperature fluctuations caused by climate change and global warming pose a threat to fish. The burbot (lota lota) population is particularly sensitive to increased water temperature, but the systematic impacts of high-temperature exposure on their liver and intestinal health remain unclear. [...] Read more.

Temperature fluctuations caused by climate change and global warming pose a threat to fish. The burbot (lota lota) population is particularly sensitive to increased water temperature, but the systematic impacts of high-temperature exposure on their liver and intestinal health remain unclear. In January of 2025, we collected wild adult burbot individuals from the Ussuri River (water temperature: about 2 °C), China. The burbot were exposed to 2 °C, 7 °C, 12 °C, 17 °C, and 22 °C environments for 96 h; then, the liver and intestinal contents were subsequently collected for histopathology observation, immunohistochemistry, biochemical index assessment, and transcriptome/16S rDNA sequencing analysis. There was obvious liver damage including hepatocyte necrosis, fat vacuoles, and cellular peripheral nuclei. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were elevated and subsequently decreased. Additionally, the malondialdehyde (MDA) level significantly increased with increasing temperature. These results indicate that 7 °C (heat stress temperature), 12 °C (tipping point for normal physiological metabolism status), 17 °C (tipping point for individual deaths), and 22 °C (thermal limit) are critical temperatures in terms of the physiological response of burbot during their breeding period. In the hepatic transcriptome profiling, 6538 differentially expressed genes (DEGs) were identified, while KEGG enrichment analysis showed that high-temperature stress could affect normal liver function by regulating energy metabolism, immune, and apoptosis-related pathways. Microbiomics also revealed that acute heat stress could change the intestinal microbe community structure. Additionally, correlation analysis suggested potential regulatory relationships between intestinal microbe taxa and immune/apoptosis-related DEGs in the liver. This study revealed the potential impact of environmental water temperature changes in cold habitats in winter on the physiological adaptability of burbot during the breeding period and provides new insights for the ecological protection of burbot in the context of global climate change and habitat warming. Full article

(This article belongs to the Special Issue Antioxidant Response in Aquatic Animals)

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