Search Results (534)

Myocardial infarction (MI) is characterized by sudden cardiomyocyte death due to impaired blood supply and remains a leading cause of mortality despite advances in management. Aloe vera, a plant rich in over 75 bioactive compounds, including vitamins, minerals, polysaccharides, and anthraquinones, has been widely used in traditional medicine and modern healthcare. Increasing evidence supports its cardioprotective potential through multiple mechanisms. Aloe vera and its derivatives have demonstrated antioxidative, anti-apoptotic, anti-inflammatory, antimicrobial, immunomodulatory, and vasodilatory effects relevant to MI pathophysiology. Compounds such as aloe-emodin, emodin, aloin, barbaloin, and selenium-enriched polysaccharides have been shown to modulate pathways including Nrf2/HO-1, TGF-β/SMAD, ERK, ferroptosis inhibition, ionic pump activity, and microRNA regulation. These molecular effects translate into reductions in oxidative damage, apoptotic signaling, inflammatory cytokine release, calcium imbalance, and creatine kinase/LDH leakage, while preserving myocardial structure and function in preclinical models. Collectively, preclinical studies suggest the potential cardioprotective effects of Aloe vera-derived preparations and compounds; however, robust clinical evidence in myocardial infarction is lacking, and their therapeutic relevance remains uncertain. Full article

Background/Objectives: Manganese (Mn) is a neurotoxic trace element whose excessive accumulation in the brain can induce hippocampal damage via oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. This study investigated whether honokiol (HNK) and its liposomal nanoformulation (HNK-LNPs) can ameliorate Mn-induced hippocampal neurotoxicity by modulating key antioxidant and mitochondrial regulatory pathways. Methods: Male Wistar rats were subjected to Mn exposure to induce hippocampal neurotoxicity and were treated with HNK or HNK-LNPs. We assessed oxidative status via NRF2/HO-1 signaling, antioxidant defenses (glutathione, GPx, SOD, CAT), and oxidative indices (ROS, MDA). Neuroinflammatory markers (NF-κB, TNF-α, IL-1β, IL-6, Iba-1), mitochondrial respiratory chain function and ATP levels, SIRT1/PGC-1α signaling, and neurotransmitter homeostasis were evaluated. We analyzed apoptosis using Bax, Bcl-2, caspase-3, and cytochrome c, along with histopathological and ultrastructural examination of the hippocampus. Results: Mn exposure was associated with NRF2/HO-1 downregulation, depleted endogenous antioxidants, increased ROS and MDA levels, and increased NF-κB–driven neuroinflammation and microglial Iba-1 expression. Mn was further associated with reduced ATP synthesis, dysregulation of SIRT1/PGC-1α signaling, and disrupted neurotransmitter balance, with a pro-apoptotic shift (elevated Bax, caspase-3, cytochrome c; reduced Bcl-2) and neuronal degeneration. Co-treatment with HNK, and more prominently with HNK-LNPs, was associated with reversing these alterations, restoring antioxidant and mitochondrial pathways, dampening inflammatory cascades, normalizing neurotransmitters, and favoring neuronal survival, with many indices approaching control values and consistently surpassing free HNK. Conclusions: Liposomal encapsulation significantly enhances honokiol’s neuroprotection against Mn-induced hippocampal neurotoxicity, likely via improved CNS bioavailability and coordinated modulation of NRF2/HO-1 and SIRT1/PGC-1α pathways. These findings support HNK-LNPs as a promising multi-mechanistic therapeutic strategy for metal-induced and related neurotoxic brain disorders. Full article

Background: Oxidative stress is an important contributor to brain abnormalities in Down syndrome (DS), but the status of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway during early postnatal development remains poorly understood. The current study aimed to investigate whether an impairment of the NRF2 pathway is already present in the Ts65Dn mouse model of trisomy 21 at neonatal life stages and whether early treatment with astaxanthin-loaded stealth solid lipid nanoparticles (AST-SSLNs) positively impacts NRF2 signaling and reduces oxidative stress. Methods: Hippocampal NRF2 pathway components and oxidative stress markers were analyzed in neonate Ts65Dn and euploid mice. From postnatal day (P)3 to P15, mice received daily subcutaneous injections of AST-SSLNs or unloaded nanoparticles. NRF2 pathway activation, reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and safety parameters were evaluated. Results: Untreated Ts65Dn mice exhibited early impairment of the NRF2 pathway, characterized by increased BACH1, reduced NRF2 activation, and decreased HO-1 expression. Neonatal AST-SSLN treatment enhanced NRF2 activation, improved HO-1 levels, and normalized ROS accumulation, lipid peroxidation, and protein carbonylation in the hippocampus, a brain region critically impaired in DS. Treatment had no adverse effects on survival, body weight, or brain weight. Conclusions: These findings demonstrate that NRF2 pathway dysfunction is an early event in trisomy 21 and identify the neonatal period as a potential therapeutic window to counteract oxidative stress. AST-SSLNs represent a promising nanomedicine-based strategy to activate the impaired NRF2 pathway and reduce early hippocampal oxidative damage in DS. Full article

Background Aflatoxin B1 (AFB1) is a potent hepatotoxic mycotoxin that induces severe oxidative liver damage. Kaempferol (Kae), a natural flavonoid with known antioxidant properties, has unclear protective effects against AFB1-induced hepatotoxicity. This study aimed to evaluate the hepatoprotective role of Kae and elucidate its underlying mechanism using integrated in vivo, in silico, and in vitro approaches. Methods: In vivo (AFB1-challenged mice) and in vitro (hepatocyte) models were employed, combined with network pharmacology, molecular docking, and molecular dynamics simulations. Liver injury indices, oxidative stress markers, antioxidant enzyme activities, and Keap1/Nrf2 pathway expression were assessed. Results: Kae co-treatment reversed AFB1-induced increases in liver index, serum ALT/AST, histological lesions, and reduced antioxidant capacity in mice. Network pharmacology revealed 59 common targets, with NFE2L2 (Nrf2) as a key node. In vitro, Kae pretreatment significantly lowered AFB1-elevated ROS, MDA, ALT, and AST, while restoring GSH and total antioxidant capacity. Kae reversed AFB1-induced Keap1 upregulation and Nrf2 downregulation, and increased mRNA levels of HO-1, NQO1, SOD, GPX1, and CAT. Molecular docking and simulation showed stable Kae–Keap1 binding (−9.6 kcal/mol) with critical hydrogen bonds (VAL-606) and van der Waals contacts. Conclusions: Kae directly binds Keap1, activates Nrf2 signaling, upregulates antioxidant gene expression, and mitigates AFB1-induced oxidative liver injury. These findings support Kae as a promising candidate for preventing AFB1 hepatotoxicity. Full article

Quercetin is a plant-derived flavonol positioned at the interface of metabolic health and food preservation. This review integrates quercetin chemistry, plant biosynthesis and metabolism, production-relevant extraction and microbial synthesis, bioavailability, mechanisms of action, preclinical and clinical evidence in metabolic syndrome (MetS), and applications in clean-label food preservation. Experimental studies indicate that quercetin modulates obesity-associated inflammation, dyslipidemia, hepatic steatosis, insulin resistance, hypertension, endothelial dysfunction, and gut-barrier impairment through interconnected Nrf2/HO-1, NF-κB/NLRP3, AMPK/SIRT1, PI3K/Akt, eNOS/NO, lipid metabolism, and microbiota-related pathways. Human evidence is narrower and heterogeneous: modest reductions in systolic blood pressure constitute the most consistent signal, whereas effects on fasting glucose, lipids, inflammatory markers, endothelial function, liver fat, and body weight vary by population, formulation, dose, and duration. In food systems, quercetin has been investigated as an antioxidant, antimicrobial, antibiofilm agent, and photodynamic photosensitizer. It is incorporated into edible films, coatings, freshness indicators, and controlled-release packaging, although most evidence remains laboratory-scale. Key translational challenges include limited aqueous solubility, variable bioavailability, incomplete long-term safety evidence, matrix-dependent efficacy, sensory constraints, manufacturing scale-up, migration, and regulation. Overall, quercetin is promising, but clinical use and industrial deployment require formulation-specific, adequately powered human studies and validation in clinically relevant populations and under commercially realistic processing conditions. Full article

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological pathways, highlighting its potential as a multi-target therapeutic candidate in ophthalmology. However, current evidence regarding kaempferol-based ophthalmic applications remains fragmented across different ocular diseases and mechanistic investigations, and a comprehensive evaluation of its therapeutic potential, translational challenges, and existing limitations is still lacking. This review systematically summarizes the research progress on kaempferol in the treatment of eye diseases, encompassing its source distribution, structural characteristics, ocular delivery strategies, disease spectrum coverage, molecular mechanisms, and safety profile. By critically evaluating currently available evidence, this review further identifies unresolved issues and translational barriers that hinder the clinical application of kaempferol in ophthalmology. Regarding delivery strategies, carriers such as gelatin nanoparticles, porous bovine serum albumin membranes, platelet-derived extracellular vesicles, and polyvinylpyrrolidone-based nanocomposites have preliminarily improved ocular surface retention and corneal permeability of kaempferol in models of corneal neovascularization and alkali burns. In terms of therapeutic indications, kaempferol has demonstrated protective effects in diverse experimental models, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic cataract, dry eye disease, fungal keratitis, corneal transplant rejection, acute glaucoma, and retinoblastoma. At the mechanistic level, kaempferol exerts comprehensive pharmacological actions—anti-inflammatory, antioxidant, metabolic regulation, anti-angiogenic, and immunomodulatory—by modulating multiple signaling pathways, including MAPK, NF-κB, STAT1/IRF7, Nrf2/HO-1, VEGF/PI3K/Src/Akt/ERK, aldose reductase, estrogen-related receptor alpha (ERRα), and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Available safety assessments suggest that kaempferol exhibits a generally favorable safety profile across ocular, cellular, systemic, and genetic evaluations. Despite these advances, the clinical translation of kaempferol in ophthalmology remains limited by insufficient clinical and pharmacokinetic evidence, underdeveloped targeted delivery strategies, and a lack of integrated understanding of its molecular basis in ocular protection. By systematically integrating evidence from ocular disease models, molecular mechanisms, delivery strategies, and safety evaluations, this review bridges fragmented knowledge regarding kaempferol-based ophthalmic applications and provides an integrated framework for understanding its therapeutic potential and translational prospects. Overall, this review highlights kaempferol as a promising multi-target therapeutic candidate for ocular diseases and provides insights into its future translational development. Full article

Objective: To evaluate whether human adipose-derived mesenchymal stem cells (ADSCs) protect against ᴅ-galactose (ᴅ-gal)-induced aging-like testicular injury and to investigate the involvement of the Keap1/Nrf2 pathway and NLRP3-associated pyroptosis. Methods: A mouse model of aging-like testicular injury was established by subcutaneous administration of ᴅ-gal for 8 weeks, followed by tail vein injection of ADSCs. Testicular morphology, blood–testis barrier (BTB) integrity, and senescence-associated markers (p16, p21) were assessed. In vitro, TM4 Sertoli cells were used to establish a senescence model and Tranwell co-cultured with ADSCs. Oxidative stress, inflammatory responses, and pyroptosis-related markers were evaluated using biochemical assays, immunofluorescence, Western blotting, and RT-qPCR. The involvement of the Keap1/Nrf2-NLRP3 axis was further examined using pharmacological inhibitors. Results: ADSC treatment significantly alleviated ᴅ-gal-induced testicular atrophy and histopathological injury, accompanied by reduced expression of the senescence markers p16 and p21 and partial restoration of BTB-related structures. ADSCs also attenuated oxidative stress, as evidenced by decreased ROS and MDA levels, increased SOD activity, and enhanced expression of Nrf2 and its downstream antioxidant targets, including HO-1 and NQO1. In parallel, ADSC administration suppressed NLRP3 activation, reduced caspase-1 cleavage, and lowered the expression of pro-inflammatory cytokines. In TM4 cells, inhibition of Nrf2 weakened the protective effects of ADSCs and was accompanied by reactivation of NLRP3-associated signaling, whereas inhibition of NLRP3 attenuated senescence- and inflammation-related changes without restoring Nrf2 activity. Conclusions: ADSCs alleviate ᴅ-gal-induced aging-like testicular injury, at least in part, by restoring redox balance, preserving BTB-associated structure, and suppressing NLRP3-associated pyroptosis through the Keap1/Nrf2 pathway. These findings suggest that ADSC-based therapy may represent a promising strategy for age-related male reproductive dysfunction, while further studies using genetic models and functional fertility endpoints are needed to confirm causality and translational relevance. Full article

Despite the traditional application of Sophora moorcroftiana seeds (SMS) in Tibetan medicine for heat-clearing, damp-drying, anti-inflammatory and detoxifying properties, the anti-inflammatory mechanisms of SMS remain insufficiently understood and warrant systematic investigation. This study evaluated the protective effects of an ethanolic SMS extract against lipopolysaccharide (LPS)-induced oxidative stress and inflammation in RAW 264.7 macrophages, with emphasis on the p62/Keap1/Nrf2 signaling pathway. In vitro, the extract exhibited significant DPPH, ABTS and ·OH radical scavenging activities, as well as ferric-reducing antioxidant power, in a clear concentration dependent manner. An inflammatory model was established by stimulating RAW 264.7 cells with LPS, followed by treatment with graded concentrations of the ethanolic SMS extract. The extract significantly reduced LPS-induced nitric oxide production and decreased the secretion of TNF-α, IL-6 and IL-1β, while suppressing iNOS and COX-2 expression at both mRNA and protein levels. In parallel, the extract alleviated oxidative stress, as evidenced by reduced intracellular reactive oxygen species (ROS) and MDA levels, increased antioxidant defenses including SOD, GSH and CAT, and decreased LDH release. At the protein-expression level, SMS treatment was accompanied by differential changes in p62, Keap1, total Nrf2 and HO-1 expression, suggesting that its effects may involve regulatory processes associated with cellular stress and antioxidant defense. Collectively, the ethanolic extract of SMS attenuated LPS-induced inflammatory and oxidative stress responses in RAW 264.7 macrophages. These effects may be associated with the suppression of inflammatory mediator production, reduction in the cellular oxidative stress burden and modulation of proteins involved in cellular stress responses and antioxidant defense. Full article

Background: Doxorubicin-induced cardiotoxicity (DIC) is a major limitation of anthracycline chemotherapy and is characterized by oxidative stress, apoptosis, and myocardial remodeling. Dysregulation of AMP-activated protein kinase (AMPK) and its downstream effector sirtuin-1 (SIRT1) has been implicated in the molecular pathogenesis of DIC. Vardenafil (Var), a selective phosphodiesterase-5 inhibitor, has shown cardiovascular benefits; however, its impact on AMPK/SIRT1 signaling during DIC remains unclear. Methods: DIC was induced in rats by cumulative doxorubicin administration. Cardiac function, serum injury biomarkers, oxidative stress indices, histopathological alterations, apoptosis, fibrosis, and molecular markers associated with the AMPK/SIRT1 pathway were evaluated. In addition, molecular docking was performed to assess the potential interaction of Var with AMPK. Results: Var significantly improved cardiac function and reduced serum levels of lactate dehydrogenase, creatine kinase, and blood urea nitrogen. Treatment attenuated myocardial oxidative stress, restored glutathione content, reduced lipid peroxidation, and alleviated histopathological damage. Furthermore, Var suppressed caspase-3 and TGF-β1 expression while enhancing HO-1 levels. Var treatment was associated with restoration of cardiac phosphorylated AMPK (p-AMPK) expression and increased SIRT1, Nrf2, and PPARγ levels in doxorubicin-treated rats, consistent with modulation of an AMPK/SIRT1-associated cytoprotective network. Molecular docking demonstrated favorable interactions between Var and AMPK, providing supportive in silico evidence for the observed molecular findings. Conclusions: These findings demonstrate that Var attenuates doxorubicin-induced cardiotoxicity, and its cardioprotective effects are associated with restoration of the p-AMPK/SIRT1/Nrf2/PPARγ signaling pathway, together with reductions in oxidative stress, apoptosis, and fibrosis. Collectively, these findings suggest that Var attenuates early Dox-induced cardiac injury, potentially through modulation of the AMPK/SIRT1 signaling pathway, warranting further validation in long-term and dose–response studies. Full article

Chlorfenapyr (CFP) is a widely used pesticide associated with nephrotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. This study investigated the protective effects of limonene (LM) and its nano-liposomal formulation (LM-LNPs) against CFP-induced renal injury in rats. Animals were divided into six groups—control, LM, LM-LNPs, CFP, CFP + LM, and CFP + LM-LNPs—and treated orally for 30 days. CFP exposure resulted in marked renal dysfunction, histopathological and ultrastructural damage, suppression of the NRF2/HO-1/NQO1 antioxidant pathway, depletion of endogenous antioxidants excessive generation of reactive oxygen and nitrogen species, lipid peroxidation products, and DNA damage. These changes were accompanied by activation of NF-κB/COX-2-mediated inflammation, mitochondrial respiratory impairment, disrupted energy metabolism, and induction of apoptosis. Co-treatment with LM significantly ameliorated these alterations, whereas LM-LNPs produced greater improvements in renal function, tissue architecture, redox homeostasis, mitochondrial function, and inflammatory and apoptotic signaling. Immunohistochemical analyses further confirmed enhanced NRF2 expression and reduced NF-κB immunoreactivity in LM-LNP-treated kidneys. Overall, nano-liposomal delivery enhanced the renoprotective efficacy of limonene, highlighting its potential as a therapeutic strategy against pesticide-induced kidney injury. Full article

Ulcerative colitis (UC) is a chronic inflammatory disorder associated with cytokine imbalance, epigenetic alterations, and metabolic–redox dysfunction. Despite the widespread use of mesalazine (5-ASA), therapeutic limitations remain. Norcantharidin (NCTD), a synthetic cantharidin analogue, may provide multi-target protection against UC. Experimental colitis was induced in male Sprague-Dawley rats by intrarectal administration of 4% acetic acid (AA). Rats received oral NCTD (10 mg/kg), 5-ASA (100 mg/kg), or their combination for 8 days. Disease severity was assessed by disease activity index, body weight, colon length, colon weight/length ratio, and histopathology. Colonic biomarkers were evaluated using ELISA, qRT-PCR, Western blotting, and immunohistochemistry. Fe²⁺ and malondialdehyde (MDA) were measured as indicators of iron accumulation and lipid peroxidation. Molecular docking suggested that NCTD may adopt plausible binding poses within the binding pockets of AMPK, SIRT1, and DNMT1, providing structural support for potential protein–ligand interactions. NCTD significantly ameliorated AA-induced colitis, improving clinical and histological outcomes. These effects were associated with reduced IL-6, TNF-α, DNMT1, Fe²⁺, and MDA levels, restoration of SOCS3, activation of p-AMPK/SIRT1/FOXO3a signaling, and enhancement of Nrf2/HO-1 defenses. Combined NCTD/5-ASA treatment produced greater clinical and histological protection, with differential effects on molecular markers. Docking studies suggested favorable interactions of NCTD with AMPK, SIRT1, and DNMT1. NCTD treatment was associated with protection against experimental colitis, linked to modulation of inflammatory, epigenetic, metabolic, and antioxidant pathways. Full article

Acute kidney injury (AKI) is a major global health challenge associated with substantial morbidity, mortality, and progression to chronic kidney disease. Increasing evidence indicates that oxidative stress, mitochondrial dysfunction, inflammatory signaling, regulated cell death, and maladaptive tissue repair play central roles in AKI pathogenesis, yet effective disease-modifying pharmacological therapies remain unavailable. This narrative review critically evaluated current evidence regarding the pharmacological characteristics, molecular mechanisms, and translational potential of alpha-mangostin (AM), the principal prenylated xanthone isolated from the pericarp of Garcinia mangostana L., through a comprehensive synthesis of experimental and mechanistic studies. Available preclinical evidence consistently demonstrates that AM improves renal function and attenuates histopathological injury, particularly in cisplatin-induced nephrotoxicity and glycerol-induced rhabdomyolysis models. These renoprotective effects are primarily associated with suppression of oxidative stress, activation of the Nrf2/HO-1 antioxidant pathway, inhibition of NF-κB-mediated inflammatory signaling, preservation of mitochondrial function, and attenuation of apoptosis. Several emerging pathways may also contribute to AM-mediated renoprotective effects; however, current evidence remains indirect, and their roles require validation in kidney-specific models. Clinical translation remains limited by poor oral bioavailability, insufficient pharmacokinetic data, lack of standardized formulations, and the absence of human clinical trials. Overall, current evidence suggests that AM has preliminary renoprotective potential in experimental AKI models. However, the limited number of available studies, predominance of cisplatin-induced nephrotoxicity models, insufficient pharmacokinetic and safety data, and absence of human clinical studies preclude conclusions regarding its clinical efficacy or translational readiness. Further validation in diverse and clinically relevant AKI models is required before clinical investigation can be considered. Full article

Background and Objectives: Acute cerebral ischemia is characterized by excessive oxidative stress and impaired antioxidant defense mechanisms, in which the nuclear factor erythroid 2–related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) signaling pathway plays a pivotal regulatory role. This study aimed to investigate serum levels of Nrf2–Keap1 pathway components and associated oxidative stress biomarkers in patients with acute ischemic stroke. Materials and Methods: Eighty-eight patients diagnosed with ischemic stroke who presented within 24 h of the onset of neurological deficit and met the inclusion criteria, along with 72 healthy control subjects without a history of acute ischemic stroke, were included in the study. Serum levels of Nrf2, Keap1, glycogen synthase kinase-3β (GSK-3β), heme oxygenase-1 (HO-1), glutathione (GSH), and 4-hydroxynonenal (4-HNE) were quantified using enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance of the biomarkers. Results: Compared with controls, patients exhibited significantly reduced Nrf2 levels and markedly elevated Keap1 and 4-HNE levels. HO-1 and GSH concentrations were also significantly increased in the patient group, whereas GSK-3β levels did not differ significantly between groups. ROC analysis demonstrated that 4-HNE and Nrf2 possessed the highest discriminative capacity for acute ischemic stroke. Conclusions: These findings suggest that acute cerebral ischemia is associated with dysregulation of the Nrf2–Keap1 axis accompanied by enhanced lipid peroxidation and oxidative burden. Although increased HO-1 and GSH levels may reflect a compensatory antioxidant response, elevated 4-HNE levels indicate persistent oxidative injury. Full article

Background/Objectives: Oxidative and electrophilic stress-response pathways contribute to cellular resilience across various chronic diseases, including neurodegenerative, hepatic, and metabolic disorders. Pharmacological activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is a validated strategy to counteract oxidative damage, as evidenced by the clinical approval of dimethyl fumarate (DMF) and monomethyl fumarate (MMF) for relapsing forms of multiple sclerosis; both electrophilic compounds activate Nrf2 via covalent Keap1 (Kelch-like ECH-associated protein 1) modification. Cynara scolymus L. contains structurally related electrophilic metabolites; however, their contribution to Nrf2-associated signaling remains undefined. This study aimed to identify and characterize the constituents responsible for Nrf2-inducing activity and benchmark their potency against DMF and MMF. Methods: Bioactivity-guided fractionation combining Soxhlet extraction, Nrf2/ARE luciferase reporter screening, semi-preparative HPLC, and spectroscopic identification was employed. Functional validation included extracellular thiol quantification, H₂O₂ cytoprotection assays, and Western blot analysis of heme oxygenase-1 (HO-1). Results: The dichloromethane extract exhibited the highest Nrf2-inducing activity (54.4-fold). Fractionation yielded five guaianolide sesquiterpene lactones (1–5), four of which were active. The α-methylene-γ-lactone moiety was essential for activity. Aguerin B (3) exhibited the highest activity (39.14 ± 11.13-fold), while TBA analysis identified cynaropicrin (2) as the dominant extract-level contributor (62.9% of total activity). Notably, aguerin B (3) and cynaropicrin (2) induced greater reporter activity than DMF and MMF. Downstream pathway induction was confirmed by concentration- and time-dependent HO-1 upregulation, elevated extracellular glutathione and cysteinylglycine levels, and significant protection against H₂O₂-induced cytotoxicity without intrinsic toxicity. Conclusions: Guaianolide sesquiterpene lactones are the primary mediators of Nrf2-associated antioxidant signaling in C. scolymus. Cynaropicrin (2) exhibited stronger in vitro ARE-reporter induction than fumarates, supporting its relevance for further pharmacological investigation. Full article

Intracerebral hemorrhage (ICH) is a devastating stroke subtype in which secondary brain injury is driven by oxidative stress, iron overload, ferroptosis, neuroinflammation, blood–brain barrier disruption, and defective hematoma clearance. Nrf2 is a redox-sensitive transcription factor that coordinates antioxidant defense, iron handling, inflammatory regulation, and neurovascular unit protection through downstream effectors such as HO-1, NQO1, GPX4, and SLC7A11. Plant-derived natural compounds have been widely investigated in experimental ICH models; however, increased Nrf2 expression or nuclear translocation alone does not establish Nrf2-dependent neuroprotection. Here, we critically appraise preclinical evidence linking plant-derived natural compounds to Nrf2-centered signaling in ICH and classify the evidence into three levels: causal Nrf2-dependent evidence, Nrf2-associated evidence, and indirect or context-transferred evidence. Representative flavonoids, phenolics, terpenoids, lignans, steroidal lactones, and other bioactive compounds are evaluated with attention to ICH-model relevance, causal pathway validation, pharmacokinetic limitations, brain exposure, and therapeutic window. Current evidence indicates that only a limited subset of compounds has been validated by genetic or pharmacological Nrf2 inhibition, whereas most remain supported by pathway association rather than causality, and preclinical studies rely predominantly on young healthy rodent models with early post-ICH intervention. Notably, no compound currently reaches relatively high translational priority because perihematomal brain exposure, delayed-treatment efficacy, and long-term safety evidence remain largely unavailable. We therefore propose an evidence-based prioritization framework integrating Nrf2 causality, ICH-specific efficacy, brain bioavailability, and translational readiness. This review clarifies the mechanistic boundaries of Nrf2-targeted natural compounds and outlines priorities for rigorous translational research in ICH. Full article