Search Results (433)

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide. CVDs are associated with multiple factors, including oxidative stress, mediated endothelial dysfunction, vascular inflammation, and atherothrombosis. Although traditional antioxidant supplementation (such as vitamins C, E, and β-carotene) has shown promising results in rigorous animal model studies, it has consistently failed to demonstrate clinical benefit in most human trials. Consequently, there is a substantial unmet need for novel paradigms involving mechanistically and biologically relevant pharmaceutical-grade antioxidant therapies (“next-generation antioxidants”). Rapid advancements in redox biology, nanotechnology, genetic modulation of redox processes, and metabolic regulation have enabled the development of new antioxidant therapeutics, including mitochondrial-targeted agents, NADPH oxidase (NOX) inhibitors, selenoprotein and Nrf2 activators, engineered nanoparticles, catalytic antioxidants, and RNA-based and gene-editing strategies. These interventions have the potential to modulate specific oxidative pathways that contribute to CVD pathogenesis. This review provides a comprehensive assessment of current oxidative stress–modulating modalities and their potential to inform personalized cardiovascular prevention and treatment strategies. Full article

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management. Full article

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with oxidative stress and mitochondrial dysfunction. NRF1 and NRF2 are transcription factors that regulate mitochondrial activity and antioxidant defense. This study investigated their expression patterns in placentas from preeclamptic and severe preeclamptic pregnancies by immunohistochemical and bioinformatical methods. Methods: Placentas from 40 healthy controls, 40 PE, and 40 sPE patients were analyzed by histological and immunohistochemical techniques. Protein–protein interaction networks for NRF1, NRF2, and PE-related proteins were constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape software, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis performed via ShinyGO, with significance set at false discovery rate (FDR) < 0.05. Results: NRF1 expression was significantly decreased in PE and sPE groups compared to controls, with notably negative staining in syncytial knots and fibrinoid areas. Conversely, NRF2 expression significantly increased, showing intense positivity in syncytiotrophoblasts, stromal cells, and vascular structures. Pathway analysis revealed that decreased NRF1 expression was associated with glutathione metabolism, hypoxia inducible factor-1 (HIF-1) signaling, and AMP-Activated Protein Kinase (AMPK) signaling pathways. Increased NRF2 expression was associated predominantly with inflammatory and immune response pathways, including AGE-RAGE signaling and pathogen–response pathways. Conclusions: Differential expressions of NRF1 and NRF2 in preeclamptic placentas reflect distinct yet interconnected responses to oxidative stress and inflammation. These transcription factors have potential clinical relevance as biomarkers for PE severity assessment and as targets for future therapeutic interventions. Full article

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s disease represent a major challenge in neuroscience due to their complex, multifactorial nature and the absence of curative treatments. These disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, proteostasis collapse, calcium dyshomeostasis, chronic neuroinflammation, and the prion-like propagation of misfolded proteins. Together, these processes trigger a cascade of cellular damage that culminates in synaptic dysfunction and programmed neuronal death. This review integrates current evidence on the sequential stages of neurodegeneration, emphasizing the convergence of oxidative, inflammatory, and proteotoxic pathways that drive neuronal vulnerability. Moreover, it explores emerging therapeutic strategies aimed at restoring cellular homeostasis, such as Nrf2 activation, modulation of the unfolded protein response (UPR), enhancement of autophagy, immunotherapy against pathological proteins, and gene therapy approaches. The dynamic interplay among mitochondria, endoplasmic reticulum, and glial cells is highlighted as a central element in disease progression. Understanding these interconnected mechanisms provides a foundation for developing multi-targeted interventions capable of halting or delaying neuronal loss and improving clinical outcomes in neurodegenerative disorders. This work provides an integrative and introductory overview of the convergent mechanisms underlying neurodegeneration rather than an exhaustive mechanistic analysis. Full article

Alcoholic liver injury (ALI) is a major global public health issue, with oxidative stress imbalance as its core pathological mechanism. The Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2–heme oxygenase-1/glutathione peroxidase 4 signaling pathway (Keap1–Nrf2–HO-1/GPX4) signaling pathway is a key target for regulating hepatic antioxidant defense. This study integrated Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS), Global Natural Products Social Molecular Networking (GNPS) molecular networking, network pharmacology, and animal experiments to systematically explore the hepatoprotective effect and mechanism of Cornus officinalis yeast-fermentation (COF). Component characterization identified 25 bioactive components, including flavonoids, triterpenic acids, and other fermentation-derived metabolites. Network pharmacology identified 441 common targets and 36 core targets of COF and ALI, which were enriched in oxidative stress regulation, inflammatory response, and the Keap1–Nrf2 pathway via Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Molecular docking showed that icariin and other components had stable interactions with Keap1 and Nrf2 (binding energy < −5 kcal/mol). Animal experiments confirmed that COF reduced the liver index of ALI mice, downregulated serum Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) activities, and ameliorated liver pathological damage. Western blot verified that COF inhibited Keap1 expression, promoted Nrf2 nuclear translocation, and upregulated HO-1/GPX4 expression. In conclusion, COF alleviates hepatic oxidative stress by regulating the Keap1–Nrf2–HO-1/GPX4 pathway, providing a scientific basis for its development as a functional food or candidate drug against ALI and a technical paradigm for fermentation-enhanced medicinal plant research. Full article

Skin aging is driven largely by oxidative stress, chronic inflammation, and mitochondrial dysfunction, processes closely linked to cellular senescence and declining NRF2 activity. Numerous dietary phytochemicals—such as curcumin (from turmeric), resveratrol (from grapes), sulforaphane (from cruciferous vegetables), zerumbone, and salvianolic acid B—abundant in fruits, vegetables, herbs, and traditional food sources, exhibit potent antioxidant and anti-inflammatory properties. This review systematically elucidates the molecular mechanisms by which these compounds mitigate skin aging, primarily through modulating the NRF2 signaling pathway. We further integrate insights from clinical trials of NRF2-targeting agents to inform the translational potential of these dietary bioactives. Molecular docking analyses confirm that these food-derived compounds interact directly with the KEAP1-NRF2 complex, promoting NRF2 activation. Transcriptomic analyses of skin-related datasets (GSE35160, GSE71910, GSE185129) further validate the downregulation of key NRF2-regulated cytoprotective genes (e.g., FTH1, FTL, HMOX1, SLC7A11) involved in antioxidant defense and the suppression of pro-inflammatory mediators. Based on this mechanistic foundation, we discuss the translational potential of these food-derived bioactives and the rationale for their future incorporation into skin-health-promoting nutraceuticals. We highlight how these food-derived phenolics and other bioactives may be incorporated into functional foods or nutraceuticals to support skin health from within, offering a dietary strategy to delay aging. We acknowledge that key translational challenges, such as oral bioavailability and optimal formulation, require further investigation. Further research is warranted to bridge these mechanistic insights into effective human applications. Full article

This review synthesizes research on nuclear factor erythroid 2-related factor 2 (Nrf2) in intestinal health across human, livestock, and mouse models. The Nrf2 signaling pathway serves as a master regulator of cellular antioxidant defenses and a key therapeutic target for intestinal inflammatory disorders, including ulcerative colitis and Crohn’s disease. The interplay between oxidative stress, Nrf2 signaling, and NF-κB inflammatory cascades represents a critical axis in the pathogenesis and resolution of intestinal inflammation. Under normal physiological conditions, Nrf2 remains sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which facilitates its ubiquitination and proteasomal degradation. However, during oxidative stress, reactive oxygen species (ROS) and electrophilic compounds modify critical cysteine residues on Keap1, disrupting the Keap1-Nrf2 interaction and enabling Nrf2 nuclear translocation. Once in the nucleus, Nrf2 binds to antioxidant response elements (ARE) in the promoter regions of genes encoding phase II detoxifying enzymes and antioxidant proteins, including heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase. This comprehensive review synthesizes current evidence demonstrating that activation of Nrf2 signaling confers protection against intestinal inflammation through multiple interconnected mechanisms: suppression of NF-κB-mediated pro-inflammatory cascades, enhancement of cellular antioxidant capacity, restoration of intestinal barrier integrity, modulation of immune cell function, and favorable alteration of gut microbiota composition. We systematically examine a diverse array of therapeutic agents targeting Nrf2 signaling, including bioactive peptides, natural polyphenols, flavonoids, terpenoids, alkaloids, polysaccharides, probiotics, and synthetic compounds. The mechanistic insights and therapeutic evidence presented underscore the translational potential of Nrf2 pathway modulation as a multi-targeted strategy for managing intestinal inflammatory conditions and restoring mucosal homeostasis. Full article

The therapeutic potential of functional nutrients has garnered considerable attention for enhancing resilience signaling and counteracting the damage to human health caused by microplastic pollutants. The intricate interactions between microplastics (MPs) and nanoplastics (NPs) and functional nutrients, including polyphenols, flavonoids, phenylpropanoids, phenolic acids, diterpenoids, and triterpenoids, have been shown to improve blood–brain barrier (BBB) homeostasis and brain function by inhibiting oxidative stress, ferroptosis, and inflammation linked to the pathogenesis of metabolic and brain disorders. Interestingly, nutrients exhibit biphasic dose–response effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and stress-resilience proteins at minimum doses, thereby preventing or blocking MP and NP-induced damage. Notably, chronic exposure to environmental pollutants causes aberrant regulation of NFE2L2 gene and related antioxidant signaling, which can exacerbate selective susceptibility to brain insulin resistance under inflammatory conditions. This, in turn, impairs glucose metabolism and facilitates β-amyloid (Aβ) plaque synthesis leading to the onset and progression of Alzheimer’s disease (AD), also known as “Type 3 diabetes”. This pathological process triggered by oxidative stress, inflammation, and ferroptosis creates a vicious cycle that ultimately contributes to neuronal damage and loss. The review aims to investigate the therapeutic potential of functional nutrients targeting the Nrf2 pathway and stress resilience proteins to regulate epigenetic alterations, and to explore the underlying molecular mechanisms using innovative in vitro platforms for the development of promising preventive strategies and personalized nutritional interventions to attenuate oxidative stress, ferroptosis, and inflammation, with the goal of ultimately improving clinical outcomes. Full article

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in regulating cellular defense against oxidative stress and maintaining redox homeostasis. In the context of viral infections, Nrf2 signaling emerges as a double-edged sword. On one hand, it activates a broad spectrum of antioxidant and cytoprotective genes, contributing to host defense and antiviral immunity. On the other hand, certain viruses exploit the Nrf2 pathway to create a favorable environment for replication, persistence, or immune evasion. This review summarizes the current understanding of Nrf2’s antiviral and proviral roles in both RNA and DNA virus infections, delineates the underlying mechanisms, and discusses the therapeutic implications of targeting Nrf2. We emphasize the need for context-dependent modulation of Nrf2 activity and highlight future directions in precision antiviral strategies. Full article

Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2–KEAP1 antioxidant system, the cGAS–STING innate immune pathway, and the PINK1–Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD⁺ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases. Full article

Nonalcoholic fatty liver disease (NAFLD) associated with high-fat diet (HFD) intake involves oxidative stress, inflammation, apoptosis, and genotoxicity. Carvacrol, a natural monoterpenoid phenol, exhibits potent antioxidant, anti-inflammatory, and cytoprotective properties, but its clinical application is limited by poor solubility and bioavailability. Chitosan nanoparticles, known for their biocompatibility and ability to enhance drug delivery, offer a promising nanotherapeutic platform for carvacrol delivery in NAFLD. Given the limited therapeutic options for NAFLD, there is a growing interest in nanotherapeutic strategies to enhance the delivery and efficacy of natural antioxidants. This study examined carvacrol-loaded chitosan nanoparticles (CRV-CNPs) in HFD-induced NAFLD. Sixty rats were assigned to six groups: control, CRV-treated (100 mg/kg), CRV-CNP-treated (100 mg/kg), HFD-fed, and two combination groups receiving HFD with either CRV or CRV-CNPs (100 mg/kg) for six weeks after 14 weeks on HFD. Liver function, metabolic markers, oxidative stress parameters, antioxidant enzyme levels, inflammatory and fibrotic mediators, apoptotic gene expression, genotoxicity indices, and histopathological changes were evaluated. CRV-CNPs showed greater efficacy than free carvacrol in ameliorating hepatic dysfunction and metabolic disturbances in HFD-fed rats. CRV-CNPs significantly reduced malondialdehyde, upregulated Nrf2, and elevated hepatic glutathione peroxidase, superoxide dismutase, catalase, and reduced glutathione. Inflammatory markers (NF-κB, iNOS, IL-1β, CRP) and transforming growth factor-beta were suppressed. Pro-apoptotic genes (Bax, Caspase-3) were downregulated, while antiapoptotic Bcl-2 was upregulated. CRV-CNPs also reduced DNA fragmentation and 8-hydroxy-2′-deoxyguanosine levels, indicating strong antigenotoxic effects. Histopathological and ultrastructural assessments revealed mitigated steatosis, preserved hepatic architecture, and maintained mitochondrial integrity. In conclusion, CRV-CNPs provide potent hepatoprotection by targeting oxidative stress, inflammation, apoptosis, and genotoxicity in NAFLD, demonstrating enhanced bioavailability, solubility, and sustained release, which support their potential as an advanced nanotherapeutic strategy for NAFLD management. Full article

Background/Objectives: Changes in glucose metabolism impact central nervous system (CNS) homeostasis and, consequently, can lead to cognitive impairment and an increased risk for neurodegenerative and neuropsychiatric disorders. Astrocytes are glial cells that act as key regulators of brain glucose metabolism, thus representing important cellular targets for studies of different pathophysiological conditions, including hyperglycemia. Resveratrol, a natural polyphenol, has emerged as a potential protective strategy against diabetes and its complications; however, its glioprotective effects remain unclear. Based on these observations, we evaluated whether resveratrol could modify the inflammatory response in astroglial cells exposed to experimental hyperglycemic conditions. Methods: After reaching confluence, C6 astroglial cells were pre-incubated with 10 µM resveratrol in serum-free DMEM with 6 mM glucose for 24 h. The medium was then replaced with serum-free DMEM containing 12 mM glucose and 10 µM resveratrol for another 24 h. Controls were maintained in 6 mM glucose. Analyses included cell viability, metabolic activity, glucose and glutamate uptake, cytokine quantification by ELISA, and gene expression by RT-qPCR. Results: We show that high glucose levels modulate glucose and glutamate metabolism, and increase neuroinflammation, through the modulation of inflammatory mediators. In addition, high glucose upregulated the gene expressions of inducible nitric oxide synthase (iNOS), nuclear factor κB (NFκB), cyclooxygenase 2 (COX2), and Toll-like receptor 4 (TLR4) while decreasing mRNA levels of NLR family pyrin domain containing 3 (NLRP3) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). However, resveratrol was able to prevent most of these effects, particularly the high glucose-triggered inflammatory response. Resveratrol also modulated heme oxygenase 1 (HO-1) and nuclear factor erythroid-derived 2-like 2 (Nrf2), important targets associated with cellular protection. Conclusions: Our findings reinforce resveratrol as a potential glioprotective strategy against diabetes-related brain toxicity. Full article

Background/Objectives: Atrazine (ATZ) is a widely used herbicide, and most studies of its reproductive toxicity have been conducted in vivo using animal models, where ATZ disrupts redox homeostasis, leading to male reproductive dysfunction. However, its molecular mechanisms of action in human spermatogenic cells remain poorly understood. Huntington’s disease (HD), an autosomal dominant disorder caused by abnormal CAG repeat expansion in the HTT gene, exhibits heightened oxidative stress sensitivity and mitochondrial dysfunction, which may further impair reproductive function. This study investigated ATZ effects on human spermatogenesis using an in vitro spermatogenesis (IVS) model derived from human induced pluripotent stem cells (hiPSCs), focusing on Nrf2-mediated oxidative responses and apoptotic regulation during spermatogonial stem cell-like cell (SSCLC) differentiation in wild-type (WT) and HD hiPSC lines. Methods: Two WT and two HD hiPSC lines carrying 44 (HD1) and 180 (HD2) CAG repeats were treated with ATZ (0, 0.01, 1, or 10 μM) for 30 days, followed by differentiation into SSCLCs for 15 days under continuous exposure. Expression of pluripotency (OCT4, SOX2), oxidative stress (NFE2L2, SOD1, GPX1, NQO1), cell cycle (CDK1), apoptosis (BCL2, BAX, CASP3, CASP9, FAS, FASLG), and spermatogenic markers (DAZL, ZBTB16, GFRA1, PIWIL2) were assessed by immunocytochemistry and qRT-PCR. Results: Long-term ATZ exposure affected pluripotency markers in hiPSCs and SSCLC differentiation in a cell line–dependent manner. WT cells exhibited early differentiation suppression without significant apoptosis. HD1 cells were highly sensitive: low ATZ doses (0.01–1 μM) partially activated intrinsic and extrinsic apoptotic pathways, whereas high-dose ATZ (10 μM) reduced Nrf2-target and spermatogenic gene expression, strongly impairing SSCLC maturation. HD2 cells showed pronounced oxidative stress with robust Nrf2-driven antioxidant responses and BCL2 that supported differentiation at low doses. However, excessive oxidative or proliferative signaling, including CDK1 upregulation at high ATZ concentrations, disrupted redox balance and SSCLC differentiation in HD2 cells. Conclusions: ATZ exerts dose- and genotype-dependent effects on IVS through coordinated regulation of oxidative stress and apoptosis. These findings highlight the interplay between Nrf2-mediated antioxidant defenses, apoptotic signaling, and genetic background in shaping spermatogenic outcomes, providing mechanistic insight into ATZ-induced reproductive toxicity in a human-relevant in vitro spermatogenesis model. Full article

Astrocytes play a key role in maintaining redox balance and supporting neuronal survival within the central nervous system (CNS). Their antioxidant machinery, primarily involving the Nrf2–ARE (nuclear factor erythroid 2-related factor 2–antioxidant response element) pathway, glutathione (GSH) metabolism, and mitochondrial function, enables the removal of reactive oxygen and nitrogen species (ROS and RNS) and supports neuronal resistance to oxidative stress. Effective communication between neurons and astrocytes coordinates metabolic and antioxidative responses via glutamate-, nitric oxide-, and calcium-dependent signalling. Disruption of this crosstalk during traumatic injury, ischemia, or neurodegenerative disease causes redox imbalance, neuroinflammation, and excitotoxicity, which contribute to progressive neurodegeneration. Astrocytic Nrf2 activation reduces oxidative damage and inflammation, while its suppression encourages a neurotoxic glial phenotype. Current evidence emphasizes various therapeutic strategies targeting astrocytic redox mechanisms, including small-molecule Nrf2 activators, GSH precursors, mitochondria-targeted antioxidants (MTAs), and RNA- and gene-based approaches. These interventions boost the antioxidant ability of astrocytes, influence reactive cell phenotypes, and support neuronal recovery in preclinical models. Although there are still challenges in delivery and safety, restoring neuron–glia redox signalling offers a promising strategy for neuroprotective treatments aimed at reducing oxidative stress-related CNS injury and disease progression. Full article

Ischemic stroke (IS) is a leading cause of mortality and long-term disability, underpinned by complex molecular mechanisms, such as oxidative stress, neuroinflammation, and apoptosis. The flavonoid Engeletin exhibits promising neuroprotective properties, but its mechanism of action remains largely unknown. In this study, we employed a systems biology approach, combined with artificial intelligence (AI), to uncover the multitarget mechanisms of Engeletin in IS. Potential targets were predicted using SwissTargetPrediction and PharmMapper and were found to intersect with IS-related genes from multiple disease databases. Functional enrichment analyses (GO/KEGG) revealed significant involvement in three classical neuroprotective pathways: PI3K-Akt-mTOR/Caspase/BCL2 (anti-apoptotic), TLR4/NF-κB (anti-inflammatory), and NRF2/KEAP1/HO-1 (antioxidant). Notably, we integrated six machine learning models (RF, SVM, GLM, KNN) to identify robust IS-specific biomarkers from the GSE22255 transcriptomic database. We used CIBERSORTx to characterize immune cell infiltration patterns in IS, revealing elevated populations of CD8⁺ T cells, M0 macrophages, and other PBMC-derived immune cells, suggesting the presence of an immunologically dynamic microenvironment. Molecular docking predicted favorable binding affinities of Engeletin to core targets (e.g., EGFR, IGF1R, KEAP1, JAK2). Finally, in vitro experiments using a Na₂S₂O₄-induced PC12 cell model confirmed Engeletin’s efficacy in reducing oxidative stress, modulating calcium overload, and regulating apoptosis- and inflammation-related genes. Overall, our study establishes a comprehensive pharmacological mechanistic framework for Engeletin in combating IS and reveals the multitarget and multi-pathway neuroprotective mechanisms, thus providing preliminary support for using Engeletin in combating ischemic stroke. Full article