Antioxidants最新文献

{"title":"Ferulic Acid Promotes Hematopoietic Stem Cell Maintenance in Homeostasis and Injury Through Diminishing Ferroptosis Susceptibility.","authors":"Shuzhen Zhang, Yimin Zhang, Jiacheng Le, Kuan Yu, Xinliang Chen, Jun Chen, Mo Chen, Yiding Wu, Yang Xu, Song Wang, Chaonan Liu, Junping Wang, Changhong Du","doi":"10.3390/antiox14091053","DOIUrl":"10.3390/antiox14091053","url":null,"abstract":"<p><p>Redox balance is essential for maintenance of the hematopoietic stem cell (HSC) pool, which ensures the lifelong hematopoiesis. However, oxidative attack induced by various physiopathological stresses always compromises HSC maintenance, while there remains lack of safe and effective antioxidative measures combating these conditions. Here, we show that ferulic acid (FA), a natural antioxidant abundantly present in Angelica sinensis which is a traditional Chinese herb commonly used for promotion of blood production, distinctively and directly promotes HSC maintenance and thereby boosts hematopoiesis at homeostasis, whether supplemented over the long term in vivo or in HSC culture ex vivo. Using a mouse model of acute myelosuppressive injury induced by ionizing radiation, we further reveal that FA supplementation effectively safeguards HSC maintenance and accelerates hematopoietic regeneration after acute myelosuppressive injury. Mechanistically, FA diminishes ferroptosis susceptibility of HSCs through limiting the labile iron pool (LIP), thus favoring HSC maintenance. In addition, the LIP limitation and anti-ferroptosis activity of FA is independent of nuclear-factor erythroid 2-related factor 2 (NRF2), probably relying on its iron-chelating ability. These findings not only uncover a novel pharmacological action and mechanism of FA in promoting HSC maintenance, but also provides a therapeutic rationale for using FA or FA-rich herbs to treat iron overload- and ferroptosis-associated pathologies such as acute myelosuppressive injury.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Hydrogen as an Antioxidant and Radioprotector: Mechanistic Insights from Monte Carlo Radiation-Chemical Simulations.","authors":"Sumaiya Akhter Ria, Jintana Meesungnoen, Jean-Paul Jay-Gerin","doi":"10.3390/antiox14091054","DOIUrl":"10.3390/antiox14091054","url":null,"abstract":"<p><p>(1) Background: Water, comprising about 70-80% of cellular mass, is the most abundant constituent of living cells. Upon exposure to ionizing radiation, water undergoes radiolysis, generating a variety of reactive species, including free radicals and molecular products. Among these, hydroxyl radicals (^•OH) are particularly damaging due to their very high reactivity and their capacity to induce oxidative injury to vital biomolecules such as DNA, membrane lipids, and proteins. From a radiation-chemical perspective, this study investigates the selective scavenging ability of molecular hydrogen (H₂) toward ^•OH radicals, with the aim of evaluating its potential as an antioxidant and radioprotective agent; (2) Methods: We employed our Monte Carlo track chemistry simulation code, IONLYS-IRT, to model the time-dependent yields of ROS in a neutral, aerated aqueous environment. The simulations included varying concentrations of dissolved H₂ and, for comparison, cystamine-a well-known sulfur-containing radioprotector and antioxidant. Irradiation was simulated using 300 MeV protons, chosen to mimic the radiolytic effects of low linear energy transfer (LET) radiation, such as that of ⁶⁰Co γ-rays or fast (>1 MeV) electrons; (3) Results: Our simulations quantitatively demonstrated that H₂ selectively scavenges ^•OH radicals. Nevertheless, its scavenging efficiency was consistently lower than that of cystamine, which produced a faster and more pronounced suppression of ^•OH due to its higher reactivity and superior radical-quenching capacity; (4) Conclusions: Molecular hydrogen offers several unique advantages, including low toxicity, high diffusivity, selective scavenging of ^•OH radicals, and well-documented anti-inflammatory effects. Although it is less potent than cystamine in terms of radical-scavenging efficiency, its excellent safety profile and biological compatibility position H₂ as a promising radioprotector and antioxidant for therapeutic applications targeting radiation-induced oxidative stress and inflammation.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dystonia Versus Redox Balance: A Preliminary Assessment of Oxidative Stress in Patients.","authors":"Jan Koptielow, Emilia Szyłak, Anna Koptielowa, Magdalena Sarnowska, Katarzyna Kapica-Topczewska, Edyta Adamska-Patruno, Katarzyna Socha, Jan Kochanowicz, Alina Kułakowska, Monika Chorąży","doi":"10.3390/antiox14091052","DOIUrl":"10.3390/antiox14091052","url":null,"abstract":"<p><p>Dystonia is defined as a movement disorder, the etiology of which may be linked to oxidative stress. The objective of this study was to evaluate the serum levels of zinc, copper, and selenium, as well as oxidative stress parameters, in patients diagnosed with focal dystonia, in comparison to a control group. The study comprised 39 patients and 30 healthy subjects. Patients demonstrated a marked decrease in Total Antioxidant Status (TAS) (<i>p</i> = 0.0002) and an increase in Total Oxidant Status (TOS) and Oxidative Stress Index (OSI) (both <i>p</i> < 0.0001), suggesting a redox imbalance. Of the elements examined, only copper exhibited a significant elevation (<i>p</i> = 0.0061), while zinc and selenium levels remained unchanged. The results of this study suggest that oxidative stress may play a significant role in the pathophysiology of dystonia and represent a potential target for adjunctive therapy.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of PM2.5 Emitted by Wood Smoke on the Expression of Glucose Transporter 1 (GLUT1) and Sodium-Dependent Vitamin C Transporter 2 (SVCT2) in the Rat Placenta: A Pregestational and Gestational Exposure Study.","authors":"Francisca Villarroel, Eder Ramírez, Nikol Ponce, Francisco Nualart, Paulo Salinas","doi":"10.3390/antiox14091050","DOIUrl":"10.3390/antiox14091050","url":null,"abstract":"<p><p>Fine particulate matter (PM2.5) emitted by wood smoke is a significant environmental pollutant associated with oxidative stress and hypoxia. These conditions can disrupt placental function by altering the expression of key nutrient transporters, such as glucose transporter 1 (GLUT1) and sodium-dependent vitamin C transporter 2 (SVCT2), which are essential for fetal development. This study evaluates the effects of pregestational and gestational exposure to PM2.5 on GLUT1 and SVCT2 expression in the rat placenta. Pregnant Sprague-Dawley rats were exposed to either filtered air (FA) or non-filtered air (NFA) containing PM2.5 from wood combustion in a controlled exposure system. Four experimental groups were established: FA/FA (control), FA/NFA (gestational exposure), NFA/FA (pregestational exposure), and NFA/NFA (continuous exposure). Immunofluorescence and confocal microscopy were used to quantify the expression of GLUT1 and SVCT2 in the placental labyrinth zone. Statistical analyses were performed using Kruskal-Wallis and post hoc Dunn's test (<i>p</i> < 0.05). Gestational exposure to PM2.5 (FA/NFA) significantly reduced GLUT1 and SVCT2 expression, compromising glucose transport and antioxidant protection in the placenta. Pregestational exposure (NFA/FA) induced a compensatory increase in SVCT2 expression, suggesting an adaptive response to oxidative stress. Continuous exposure (NFA/NFA) resulted in GLUT1 redistribution within the syncytiotrophoblast and decreased membrane localization, potentially impairing glucose uptake. PM2.5 exposure disrupts the expression and localization of GLUT1 and SVCT2 in the placenta, with differential effects depending on the timing of exposure. The gestational phase appears to be particularly vulnerable, as reduced GLUT1 and SVCT2 levels may impair fetal nutrition and antioxidant defense. These findings underscore the need for preventive measures to mitigate air pollution-related risks during pregnancy.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative Stress and Inflammation in Uterine-Vascular Adaptation During Pregnancy.","authors":"Maurizio Mandalà","doi":"10.3390/antiox14091051","DOIUrl":"10.3390/antiox14091051","url":null,"abstract":"<p><p>During pregnancy, uterine circulation undergoes profound structural and functional adaptations to accommodate the dramatically increased metabolic demands of the growing fetus. Oxidative stress (OS) and inflammation have emerged as central regulators both physiologically, to drive vascular remodeling and angiogenesis, and pathologically, when dysregulated, to promote endothelial dysfunction, maladaptive extracellular matrix (ECM) remodeling, and heightened arterial stiffness. This review synthesizes insights into the molecular sources of reactive oxygen species (ROS) in the uterine vasculature, endothelial and immune-mediated inflammatory pathways, the bidirectional crosstalk between OS and inflammation, and their combined impact on vascular stiffness. We further discuss clinical implications for conditions such as preeclampsia and intrauterine growth restriction (IUGR), highlight circulating and imaging biomarkers of redox-inflammatory imbalance, and evaluate antioxidant and anti-inflammatory therapeutic strategies. Finally, we identify critical knowledge gaps and propose future research directions aimed at translating mechanistic understanding into personalized maternal-fetal care. For this narrative review, we searched the PubMed and Web of Science databases to identify all human and animal studies investigating OS and inflammation on uterine vasculature remodeling during pregnancy.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidants, Gut Microbiota, and Cardiovascular Programming: Unraveling a Triad of Early-Life Interactions.","authors":"Chien-Ning Hsu, Ying-Jui Lin, Chih-Yao Hou, Yu-Wei Chen, Guo-Ping Chang-Chien, Shu-Fen Lin, You-Lin Tain","doi":"10.3390/antiox14091049","DOIUrl":"10.3390/antiox14091049","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) remains the leading cause of global mortality, despite advances in adult-focused prevention and therapy. Mounting evidence supports the Developmental Origins of Health and Disease (DOHaD) paradigm, which identifies early-life exposures as critical determinants of long-term cardiovascular health. Among the key mechanistic pathways, oxidative stress and gut microbiota dysbiosis have emerged as central, interrelated contributors to cardiovascular programming. Prenatal and postnatal insults can induce sustained redox imbalance and disrupt microbial homeostasis. This disruption creates a feed-forward loop that predisposes offspring to CVD later in life. Antioxidants offer a promising reprogramming strategy by targeting both oxidative stress and gut microbiota composition. Preclinical studies demonstrate that maternal antioxidant interventions-such as vitamins, amino acids, melatonin, polyphenols, N-acetylcysteine, and synthetic agents-can restore redox homeostasis, modulate gut microbial communities, and attenuate cardiovascular risk in offspring. This review synthesizes current evidence on how oxidative stress and gut microbiota act together to shape cardiovascular trajectories. It also examines how antioxidant-based therapies may disrupt this pathological axis during critical developmental windows. Although human data remain limited due to ethical and practical constraints, advancing microbiota-targeted antioxidant interventions may offer a transformative approach to prevent CVD at its origins.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Hyssopus cuspidatus Boriss</i> Volatile Extract (SXC): A Dual-Action Antioxidant and Antifungal Agent Targeting <i>Candida albicans</i> Pathogenicity and Vulvovaginal Candidiasis via Host Oxidative Stress Modulation and Fungal Metabolic Reprogramming.","authors":"Yun-Dan Guo, Ming-Xuan Zhang, Quan-Yong Yu, Lu-Lu Wang, Yan-Xing Han, Tian-Le Gao, Yuan Lin, Cai Tie, Jian-Dong Jiang","doi":"10.3390/antiox14091046","DOIUrl":"10.3390/antiox14091046","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and purpose: &lt;/strong&gt;Vulvovaginal candidiasis (VVC), caused by &lt;i&gt;Candida albicans&lt;/i&gt; (&lt;i&gt;C. albicans&lt;/i&gt;), is exacerbated by oxidative stress and uncontrolled inflammation. Pathogens like &lt;i&gt;C. albicans&lt;/i&gt; generate reactive oxygen species (ROS) to enhance virulence, while host immune responses further amplify oxidative damage. This study investigates the antioxidant and antifungal properties of &lt;i&gt;Hyssopus cuspidatus Boriss&lt;/i&gt; volatile extract (SXC), a traditional Uyghur medicinal herb, against fluconazole-resistant VVC. We hypothesize that SXC's bioactive volatiles counteract pathogen-induced oxidative stress while inhibiting fungal growth and inflammation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;GC-MS identified SXC's major bioactive components, while broth microdilution assays determined minimum inhibitory concentrations (MICs) against bacterial/fungal pathogens, and synergistic interactions with amphotericin B (AmB) or fluconazole (FLC) were assessed via time-kill kinetics. Anti-biofilm activity was quantified using crystal violet/XTT assays, and in vitro studies evaluated SXC's effects on &lt;i&gt;C. albicans&lt;/i&gt;-induced cytotoxicity (LDH release in A431 cells) and inflammatory responses (cytokine production in LPS-stimulated RAW264.7 macrophages). A murine VVC model, employing estrogen-mediated pathogenesis and intravaginal &lt;i&gt;C. albicans&lt;/i&gt; challenge, confirmed SXC's in vivo effects. Immune modulation was assessed using ELISA and RT-qPCR targeting inflammatory and antioxidative stress mediators, while UPLC-MS was employed to profile metabolic perturbations in &lt;i&gt;C. albicans&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Gas chromatography-mass spectrometry identified 10 key volatile components contributing to SXC's activity. SXC exhibited broad-spectrum antimicrobial activity with MIC values ranging from 0.125-16 μL/mL against bacterial and fungal pathogens, including fluconazole-resistant Candida strains. Time-kill assays revealed that combinations of AmB-SXC and FLC-SXC achieved sustained synergistic bactericidal activity across all tested strains. Mechanistic studies revealed SXC's dual antifungal actions: inhibition of &lt;i&gt;C. albicans&lt;/i&gt; hyphal development and biofilm formation through downregulation of the Ras1-cAMP-Efg1 signaling pathway, and attenuation of riboflavin-mediated energy metabolism crucial for fungal proliferation. In the VVC model, SXC reduced vaginal fungal burden, alleviated clinical symptoms, and preserved vaginal epithelial integrity. Mechanistically, SXC modulated host immune responses by suppressing oxidative stress and pyroptosis through TLR4/NF-κB/NLRP3 pathway inhibition, evidenced by reduced caspase-1 activation and decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;SXC shows promise as a broad-spectrum natural antimicrobial against fungal pathogens. It inhibited &lt;i&gt;C. albicans&lt;/i&gt; hyphal growth, adhesion, biofilm formation, and invasion in vitro, while reducing ","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mangosteen Pericarp Extract Mitigates Diquat-Induced Hepatic Oxidative Stress by NRF2/HO-1 Activation, Intestinal Barrier Integrity Restoration, and Gut Microbiota Modulation.","authors":"Weichen Huang, Yujie Lv, Chenhao Zou, Chaoyue Ge, Shenao Zhan, Xinyu Shen, Lianchi Wu, Xiaoxu Wang, Hongmeng Yuan, Gang Lin, Dongyou Yu, Bing Liu","doi":"10.3390/antiox14091045","DOIUrl":"10.3390/antiox14091045","url":null,"abstract":"<p><p>Poultry production exposes birds to diverse environmental and physiological stressors that disrupt redox balance, impair gut-liver axis function, and undermine health and productivity. This study investigated the hepatoprotective and antioxidative effects of mangosteen pericarp extract (MPE) in an experimental model of diquat-induced oxidative stress in laying hens. A total of 270 Hy-Line White laying hens were randomly assigned to three groups: control group (CON), diquat-challenged group (DQ), and MEP intervention with diquat-challenged group (MQ), with six replicates of 15 birds each. The results showed that MPE supplementation effectively mitigated the hepatic oxidative damage caused by diquat, as evidenced by the increased ALT and AST activity, improved lipid metabolism, and reduced hepatic fibrosis. Mechanistically, MPE activated the NRF2/HO-1 antioxidant pathway, thus enhancing the liver's ability to counteract ROS-induced damage and reducing lipid droplet accumulation in liver tissue. MPE supplementation restored intestinal barrier integrity by upregulating tight junction protein expression (Occludin-1 and ZO-1), enhancing MUC-2 expression, and thereby decreasing gut microbiota-derived LPS transferring from the intestine. Additionally, MPE also modulated gut microbiota composition by enriching beneficial bacterial genera such as <i>Lactobacillus</i> and <i>Ruminococcus</i> while suppressing the growth of potentially harmful taxa (e.g., <i>Bacteroidales</i> and <i>UCG-010</i>). Fecal microbiota transplantation (FMT) from MPE-treated donors into diquat-exposed recipients reproduced these beneficial effects, further highlighting the role of gut microbiota modulation in mediating MPE's systemic protective actions. Together, these findings demonstrated that MPE alleviated DQ-induced liver injury and oxidative stress through a combination of antioxidant activity, protection of intestinal barrier function, and modulation of gut microbiota, positioning MPE as a promising natural strategy for mitigating oxidative stress-related liver damage by regulating the gut microbiota and gut-liver axis in poultry.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Electrophilic Activation of NRF2 in Neurological Disorders: Therapeutic Promise of Non-Pharmacological Strategies.","authors":"Chunyan Li, Keren Powell, Luca Giliberto, Christopher LeDoux, Cristina d'Abramo, Daniel Sciubba, Yousef Al Abed","doi":"10.3390/antiox14091047","DOIUrl":"10.3390/antiox14091047","url":null,"abstract":"<p><p>Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master transcriptional regulator of cellular antioxidant responses through orchestration of cytoprotective gene expression, establishing its significance as a therapeutic target in cerebral pathophysiology. Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency, underscoring the imperative for innovative therapeutic strategies to harness this cytoprotective pathway. Non-pharmacological interventions, including neuromodulation, physical exercise, and lifestyle modifications, activate NRF2 through non-canonical, non-electrophilic pathways involving protein-protein interaction inhibition, KEAP1 degradation, post-translational and transcriptional modulation, and protein stabilization, though mechanistic characterization remains incomplete. Such interventions utilize multi-mechanistic approaches that synergistically integrate multiple non-electrophilic NRF2 pathways or judiciously combine electrophilic and non-electrophilic mechanisms while mitigating electrophile-induced toxicity. This strategy confers neuroprotective effects without the contraindications characteristic of classical electrophilic activators. This review comprehensively examines the mechanistic underpinnings of non-pharmacological NRF2 modulation, highlighting non-electrophilic activation pathways that bypass the limitations inherent to electrophilic activators. The evidence presented herein positions non-pharmacological interventions as viable therapeutic approaches for achieving non-electrophilic NRF2 activation in the treatment of cerebrovascular and neurodegenerative pathologies.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative Stress, Advanced Glycation End Products (AGEs), and Neurodegeneration in Alzheimer's Disease: A Metabolic Perspective.","authors":"Virginia Boccardi, Francesca Mancinetti, Patrizia Mecocci","doi":"10.3390/antiox14091044","DOIUrl":"10.3390/antiox14091044","url":null,"abstract":"<p><p>Neurodegenerative diseases such as Alzheimer's disease (AD) are closely linked to oxidative stress and advanced glycation end products (AGEs), two interrelated processes that exacerbate neuronal damage through mitochondrial dysfunction, protein aggregation, and chronic inflammation. This narrative review explores the metabolic interplay between reactive oxygen species (ROS) and AGEs, with a focus on the AGE-RAGE (receptor for advanced glycation end products) signaling axis as a driver of neurodegeneration. Evidence from preclinical and clinical studies highlights their combined role in disease progression and underscores potential therapeutic targets. Strategies including mitochondria-targeted antioxidants, AGE inhibitors, RAGE antagonists, and metabolic interventions are discussed, along with future directions for biomarker development and personalized treatments. This review integrates current molecular insights into a unified metabolic-inflammatory model of AD, highlighting translational therapeutic opportunities.</p>","PeriodicalId":7984,"journal":{"name":"Antioxidants","volume":"14 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}