Search Results (705)

Background/Objectives: Ischemic stroke remains a major global health challenge, yet therapeutic options are severely restricted by narrow treatment windows and the risk of hemorrhagic transformation. Natural small molecules represent a valuable reservoir for discovering novel neuroprotective leads with favorable safety profiles. Cinchonidine, a natural quinoline alkaloid, has shown anti-inflammatory and cytoprotective properties, but its potential in treating ischemic stroke is largely unexplored. This study aimed to evaluate the neurovascular protective effects and hemostatic safety of cinchonidine in preclinical stroke models. Methods: We evaluated cinchonidine using a mouse model of middle cerebral artery occlusion (MCAO) and in vitro oxygen–glucose deprivation (OGD) models in cerebral endothelial cells (CECs) and Neuro2A cells. Infarct volume, brain edema, and neurological recovery were assessed. Blood–brain barrier (BBB) integrity was measured via Evans blue extravasation. Mechanistic markers, including microglial activation, pro-inflammatory mediators (iNOS, COX-2), and apoptosis-related signaling, were examined. Additionally, cinchonidine’s effect on platelet aggregation was also tested. Results: Cinchonidine significantly reduced infarct volume and brain edema while improving neurological functional recovery. It effectively preserved BBB integrity and enhanced cell viability under OGD conditions. Furthermore, cinchonidine suppressed microglial activation and decreased the expression of pro-inflammatory mediators. These protective effects were associated with the modulation of apoptotic signaling pathways. These protective effects were accompanied by reduced p53-associated stress signaling in endothelial cells and ischemic brain tissue. Importantly, cinchonidine did not significantly interfere with platelet aggregation, suggesting a potentially favorable hemostatic profile. Conclusions: Cinchonidine attenuates ischemic brain injury and is associated with endothelial protection, preservation of BBB integrity, and modulation of inflammatory and apoptotic responses. As a natural lead compound that does not compromise hemostasis, cinchonidine represents a promising lead compound for further development as a neurovascular protective strategy in ischemic stroke. Full article

Moyamoya disease is a progressive steno-occlusive cerebrovascular disorder in which cerebral perfusion may become highly dependent on systemic arterial pressure, arterial carbon dioxide tension, and collateral flow. Encephaloduroarteriosynangiosis (EDAS) is an indirect revascularization procedure that promotes neovascularization over weeks to months but does not immediately augment cerebral blood flow intraoperatively. Anesthetic management therefore requires preservation of cerebral oxygen delivery during a period of persistent physiologic vulnerability. This narrative review presents a practical perioperative framework for EDAS anesthesia, emphasizing maintenance of mean arterial pressure near baseline or modestly above baseline, avoidance of hypotension and hypovolemia, normoxia, normothermia, and careful regulation of carbon dioxide. Hyperventilation should be avoided because hypocapnia can reduce cerebral blood flow through vasoconstriction, while excessive hypercapnia may contribute to regional maldistribution or steal physiology. Raw electroencephalography may provide cortical ischemia surveillance where available, whereas somatosensory evoked potentials, motor evoked potentials, near-infrared spectroscopy, and transcranial Doppler should be considered adjunctive and institution-dependent. A structured algorithm that integrates hemodynamics, ventilation, oxygen delivery, anesthetic depth, neuromonitoring, and surgical communication may support the timely recognition and correction of intraoperative hypoperfusion. Full article

Background:Scutellaria baicalensis (Scu) extract has been traditionally used in the treatment of stroke-related syndromes, yet its underlying molecular mechanisms, particularly those involving ferroptosis, remain to be fully elucidated. Purpose: This study aims to validate the hypothesis that Scu extract improves cerebral ischemia-reperfusion injury (CIRI) by inhibiting ferroptosis through the PI3K/AKT signaling pathway. Methods: This study employed middle cerebral artery occlusion (MCAO) in male Sprague-Dawley (SD) rats and oxygen–glucose deprivation/reoxygenation (OGD/R) models to evaluate the protective effects of Scu extract against CIRI. Multiple approaches were integrated to elucidate the underlying mechanisms. Furthermore, a range of experimental techniques, including neurological function assessment, TTC staining, histopathological analysis, biochemical assays, qPCR, transmission electron microscopy (TEM), reactive oxygen species (ROS) detection, Western blotting, and immunofluorescence, were used to comprehensively validate its neuroprotective effects. Results: Scu extract significantly improved neurological outcomes and attenuated brain injury in MCAO rats. Proteomic analysis revealed significant enrichment of ferroptosis-related pathways, which was supported by reduced mitochondrial damage, decreased iron accumulation, and restoration of the SLC7A11/GPX4 axis. Subsequently, UPLC/Q-TOF-MS analysis revealed that four major bioactive components were absorbed in MCAO rats. KEGG pathway analysis based on network pharmacology further indicated that the PI3K/AKT signaling pathway is a key regulatory target. Notably, pharmacological inhibition of PI3K with LY294002 markedly abolished the anti-ferroptotic effects of Scu extract, which was further confirmed in vitro. Conclusions: This study demonstrates that Scu extract confers neuroprotection against CIRI in MCAO rats potentially through inhibiting ferroptosis via activation of the PI3K/AKT pathway. Full article

Background: Stroke significantly increases morbidity and mortality in patients receiving extracorporeal membrane oxygenation (ECMO). This study evaluates the prognostic impact of stroke subtypes, acute ischemic stroke (AIS) and hemorrhagic stroke (HS), and neurologic injury severity in a contemporary adult population. Methods: We conducted a retrospective cohort study using the TriNetX federated electronic health record network, including adult patients who underwent ECMO between 1 October 2015 and 31 December 2025. Stroke was defined as a first-instance diagnosis of AIS, HS, or unspecified cerebrovascular event occurring within 24 h of ECMO cannulation during the index hospitalization. Propensity score matching (1:1 nearest neighbor) was performed to balance baseline demographics, comorbidities, anticoagulant use, and ECMO modality between the stroke and non-stroke cohorts. Primary outcomes included all-cause mortality at 30 days, 90 days, and 1 year. Secondary outcomes included cardiac arrest, seizures, palliative care utilization, and hospital readmission. Kaplan–Meier survival analysis and multivariable Cox proportional hazards modeling were performed. Results: Among 18,981 ECMO patients, 1481 (7.8%) developed a stroke within 24 h of ECMO cannulation, including 814 AIS (54.9%), 454 HS (30.6%), and 213 unspecified cerebrovascular events (14.4%). After propensity score matching, stroke was associated with significantly higher all-cause mortality at 30 days (RR 1.16), 90 days (RR 1.18), and 1 year (RR 1.18), all p < 0.05. Stroke was also associated with higher rates of cardiac arrest, seizures, hospital readmission, and palliative care utilization (all p < 0.001). AIS was associated with significantly lower mortality than HS at 30 days, 90 days, and 1 year (all p < 0.0001). In multivariable Cox regression, only HS was independently associated with increased 30-day mortality compared with no stroke. Markers of neurologic injury severity, including cerebral edema, brain compression, and coma, were among the strongest independent predictors of mortality. Conclusions: Stroke occurring early after ECMO cannulation is associated with substantially worse short- and long-term survival, with hemorrhagic subtype and markers of neurologic injury severity driving the strongest prognostic signals. These findings support early stroke recognition and subtype-informed prognostic discussions in ECMO patients. Full article

Objective: The objectives of this study were to characterise induction-phase regional cerebral oxygen saturation (rSO₂)–mean arterial pressure (MAP) dynamics during near-infrared spectroscopy (NIRS)-guided selective carotid endarterectomy (CEA) and to examine whether the Awake→Intubated pressure–oxygenation pattern may represent an early adjunctive physiological signal of subsequent cross-clamp-related ipsilateral cerebral desaturation. Methods: In this retrospective observational cohort study, 322 consecutive elective CEAs managed with an NIRS-guided selective shunting protocol between October 2019 and February 2025 were analysed, after excluding patients considered for routine pre-emptive shunting because of contralateral internal carotid artery occlusion or ≥70% stenosis. Standardised MAP and bilateral rSO₂ values were extracted at the Awake, Intubated, and Clamp stages, defined as 3 min after carotid cross-clamping. Awake→Intubated ipsilateral ΔrSO₂/ΔMAP was evaluated as a continuous, exploratory pressure–oxygenation index, with MAP–rSO₂ directional change classified as concordant or discordant. Clamp-related desaturation was defined as a ≥20% ipsilateral rSO₂ decrease from Awake to Clamp. Discrimination and adjusted associations were evaluated using receiver operating characteristic analysis and multivariable logistic regression, respectively. Results: Clamp-related ≥20% ipsilateral rSO₂ desaturation occurred in 43 patients (13.4%). The Awake→Intubated ipsilateral ΔrSO₂/ΔMAP ratio differed significantly between patients with and without ≥20% desaturation and showed significant discrimination on receiver operating characteristic analysis, with an area under the curve (AUC) of 0.799 (95% confidence interval [CI] 0.723–0.876; p < 0.001). Concordant pressure–oxygenation change was more frequent among patients with ≥20% desaturation (31/43, 72.1%), whereas discordant change predominated among those without desaturation (228/279, 81.7%; p < 0.001). In multivariable analysis, Awake→Intubated ipsilateral ΔrSO₂/ΔMAP remained associated with clamp-related ≥20% desaturation after adjustment (adjusted odds ratio [OR] 1.63, 95% CI 1.15–2.33; p = 0.006), along with symptomatic presentation and 50–69% contralateral stenosis. Postoperative stroke occurred in 4/322 patients (1.2%), and no 30-day mortality occurred. Conclusions: During NIRS-guided selective CEA, induction-phase rSO₂–MAP dynamics were associated with subsequent cross-clamp-related ipsilateral cerebral desaturation. As the outcome was a NIRS-defined desaturation rather than an independent clinical, neurological, or imaging endpoint, these findings indicate association with a surrogate marker rather than prediction of clinically relevant cerebral ischaemia. The Awake→Intubated ΔrSO₂/ΔMAP ratio and directional pressure–oxygenation pattern may represent early adjunctive physiological signals associated with clamp-related desaturation. These findings are hypothesis-generating and require prospective validation with systematic multimodal monitoring. Full article

Background: Mitochondrial dysfunction is a central event in the pathogenesis of ischemic stroke. The roles of specific mitochondrial complex subunits, such as NDUFA4 and NDUFB3, in cerebral ischemia–reperfusion injury remain poorly defined. This study aims to investigate the dynamic expressions and functional impact of NDUFA4 and NDUFB3 in ischemic stroke. Methods: A transient middle cerebral artery occlusion (MCAO) model was established in male C57BL/6J mice. Label-free quantitative proteomics and Western blotting were employed to analyze protein expression in the ischemic penumbra. Highly differentiated PC12 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) or glutamate excitotoxicity to mimic ischemic injury in vitro. The functional consequences of NDUFB3 knockdown and overexpression were assessed by measuring ATP levels, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptosis. The involvement of the JNK-mediated mitochondrial apoptotic pathway was also examined. Results: Proteomic analysis revealed a significant upregulation of NDUFA4 and NDUFB3 in the ischemic penumbra of MCAO mice, as verified by western blot. In highly differentiated PC12 cells, both OGD/R and glutamate exposure induced a time-dependent increase in these proteins in mitochondrial fractions. Functional studies demonstrated that NDUFB3 knockdown significantly rescued OGD/R-induced mitochondrial dysfunction, as indicated by restored ATP production, reduced ROS generation, and stabilized ΔΨm. Furthermore, NDUFB3 silencing attenuated apoptosis by inhibiting JNK phosphorylation and decreasing BAX levels. Conversely, overexpression of NDUFB3 alone was sufficient to induce mitochondrial abnormalities, including loss of ΔΨm and elevated oxidative stress in highly differentiated PC12 cells. Conclusions: Ischemic injury triggers the upregulation of mitochondrial complex subunits NDUFA4 and NDUFB3. While this may initially act as a compensatory response, our findings identify NDUFB3 as a critical mediator of ischemic stroke pathology, whose overexpression drives mitochondrial dysfunction and apoptosis. In contrast, the suppression of NDUFB3 provides protection against ischemic injury. Therefore, NDUFB3 may be a potential candidate therapeutic target for reducing mitochondrial damage in ischemic stroke, but this role requires further validation in additional experimental and translational models. Full article

Background and Objectives: We investigate whether a preoperative autonomic vulnerability phenotype and intraoperative regional cerebral oxygen saturation (rcSO₂) variables are associated with postoperative delirium (POD) in elderly patients undergoing non-cardiac, non-neurological surgery, and whether autonomic vulnerability modifies the association between cerebral desaturation and POD. Materials and Methods: This retrospective propensity score–matched cohort study included patients aged 65 years or older who underwent general anesthesia with intraoperative rcSO₂ monitoring. The preoperative autonomic vulnerability phenotype was defined using clinical features documented before surgery, including autonomic neuropathy, diabetic autonomic neuropathy, orthostatic hypotension, syncope or presyncope suggestive of autonomic dysfunction, and unexplained resting bradycardia or chronotropic incompetence not attributable to rate-limiting medication. The primary outcome was POD within 5 postoperative days. Patients were matched 1:1 using nearest-neighbor propensity score matching with a caliper of 0.2 standard deviations of the logit of the propensity score, and conditional logistic regression was used in the matched cohort. Results: A total of 412 patients were included; 112 had the phenotype and 300 did not. After matching, 98 pairs were analyzed. POD occurred in 27.6% of patients with the phenotype and 14.3% of patients without it. In the matched cohort, the phenotype (odds ratio [OR] 2.12, 95% confidence interval [CI] 1.18–3.82, p = 0.012), rcSO₂ decrease ≥20% (OR 2.45, 95% CI 1.31–4.58, p = 0.005), and longer duration of rcSO₂ < 80% of baseline (OR 1.02 per min, 95% CI 1.01–1.04, p = 0.008) were independently associated with POD. The phenotype-by-desaturation interaction was exploratory (OR 2.10, p = 0.032) and was not uniformly robust across sensitivity analyses. Conclusions: A preoperative autonomic vulnerability phenotype and intraoperative cerebral desaturation were independently associated with POD. The association between rcSO₂ decrease and POD appeared stronger in patients with autonomic vulnerability, but this interaction should be interpreted as hypothesis-generating rather than confirmatory. Full article

We previously demonstrated that fatty acid-binding protein 3 (FABP3) is significantly upregulated in ischemic neurons, and its inhibition mitigates ischemic brain injury in mice and attenuates mitochondrial damage under rotenone-induced oxidative stress. These findings suggest a potential role for FABP3 in mitochondrial dysfunction in ischemic neurons, although the underlying mechanism remains unclear. In this study, we further investigated the role of FABP3 in mitochondrial injury and apoptosis in ischemic neurons. Our findings indicated that FABP3 deficiency significantly decreased infarct volume following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice, improved cognitive and spontaneous activity deficits, and suppressed BAX activation and mitochondrial translocation, caspase-3 activation, and cytochrome c release. In HT22 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), FABP3 deficiency increased cell viability, reduced apoptosis, and alleviated the loss of mitochondrial membrane potential. Conversely, FABP3 overexpression further exacerbated mitochondrial dysfunction and apoptosis, effects that were partially reversed by the BAX inhibitor BAI1. Furthermore, FABP3 overexpression promoted abnormal mitochondrial lipid accumulation and increased lipid peroxidation. Both the mitochondria-targeted antioxidant MitoQ and the ferroptosis inhibitor Ferrostatin-1 alleviated FABP3 overexpression-induced mitochondrial damage and apoptotic signaling. Collectively, our findings suggest that FABP3 is an important promoter of cerebral ischemia–reperfusion injury. FABP3 may aggravate ischemic neuronal injury by promoting abnormal mitochondrial lipid accumulation and lipid peroxidation, thereby enhancing BAX-dependent mitochondrial apoptotic signaling. Targeting FABP3 may provide a potential therapeutic strategy for neuroprotection in ischemic stroke. Full article

T-2 toxin is widely present in agricultural products and poses a significant neurotoxicity threat. Betulinic acid (BA), a natural triterpenoid, exhibits strong antioxidant and anti-inflammatory properties. However, its protective role against T-2 toxin-induced neuroinflammation remains poorly understood. This study aimed to elucidate the mechanisms underlying T-2 toxin-induced neurotoxicity and evaluate the therapeutic potential of BA. Our results demonstrated that T-2 toxin (1 mg/kg/bw) exposure caused significant pathological damage in the hippocampus and cerebral cortex. T-2 toxin also induced marked oxidative stress, reflected by elevated reactive oxygen species (ROS) accumulation. At the inflammatory level, T-2 toxin upregulated the mRNA expression of pro-inflammatory cytokines (Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6)) and altered anti-inflammatory IL-10 expression. In addition, T-2 toxin exhibited strong binding affinity for the tight junction proteins Occludin and Claudin-1 (docking energies of −4.41 and −5.53 kcal/mol, respectively), and molecular dynamics simulations confirmed stable protein–ligand interactions. At the molecular level, T-2 toxin suppressed Nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression, increased Kelch-like ECH-associated protein 1 (Keap1) expression, and activated the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway. Furthermore, molecular docking analysis revealed that BA displayed strong binding affinity to proteins associated with the blood–brain barrier and the Nrf2/NLRP3 signaling pathway. Collectively, these findings indicate that BA mitigates T-2 toxin-induced neuroinflammation through regulating the Nrf2/NLRP3 signaling pathway in mice. Not only do these results clarify a key mechanism of T-2 toxin-induced central nervous system injury, but they also highlight BA as a promising candidate for developing interventions targeting mycotoxin-related neurological disorders. Full article

Traditional surgical decision-making in traumatic brain injury (TBI) has relied on static intracranial pressure (ICP) thresholds and fixed volumetric criteria, an approach that inadequately reflects the dynamic physiological nature of secondary brain injury. These conventional metrics fail to capture the critical determinant of clinical deterioration: the progressive loss of intracranial compliance, the brain’s capacity to buffer additional volume without harmful pressure escalation. This manuscript proposes a practical, compliance-based framework for selecting precise, personalized surgical strategies using real-time physiological, imaging, and neuromonitoring indicators. Based on the Intracranial Compartment Syndrome (ICCS) model, this approach translates the loss of compensatory reserve into actionable operative decisions. Compliance is assessed through multimodal tools, including ICP waveform morphology, cerebral oxygenation, and complementary noninvasive neuromonitoring. ICCS staging delineates three operative contexts: Stage 1, preserved compliance; Stage 2, compliance failure with maintained oxygenation requiring physiology-guided interventions to restore buffering capacity; and Stage 3, global decompensation with lost of compliance plus oxygenation failure requiring immediate, aggressive intervention for partial or total brain tissue survival. By shifting surgical reasoning from fixed anatomical thresholds to a physiology-centered assessment of intracranial compliance, this framework aims to enhance the timing, selection, and overall effectiveness of neurosurgical interventions in TBI. Full article

Pterostilbene (Pts), a small molecule stilbenoid and a dimethyl analogue of the star molecule resveratrol, exerts significant blood–brain barrier protection on cerebral ischemia-reperfusion injury and has received extensive attention. This study performed structural optimizations on Pts to obtain a series of derivatives and investigated their anti-ischemic activities both in vitro and in vivo, aiming to identify candidates with high safety and improved efficacy compared with Pts. The ADMET method was used to predict the drug-likeness of a series of Pts derivatives, and in vitro MTT cell viability analysis was conducted on neuroblastoma cells (SH-SY5Y) and brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation/reperfusion (OGD/R) injury. On the basis of the cytotoxicity results, four derivatives (NO. 1, NO. 3, NO. 5, and NO. 7) were selected for subsequent in vitro and in vivo biological activities evaluation. These compounds exhibited significantly higher TI values (18.29–30.61) in OGD/R-injured hBMECs compared with Pts (7.63) and effectively suppressed apoptosis, promoted cell migration, and enhanced tube formation capacity. In vivo, NO. 3 (5 mg/kg, ip., 7 d) demonstrated superior efficacy compared to Pts in improving cerebral blood flow, reducing infarction volume, enhancing neurological function, and modulating serum biomarker levels in middle cerebral artery occlusion/reperfusion (MCAO/R) rats, whereas NO. 1 and NO. 7 showed comparable efficacy to Pts. The acute intraperitoneal toxicity of NO. 3 was conducted and showed that the LD₅₀ of NO. 3 was estimated to be more than 300 mg/kg. In this study, the rational design and comprehensive evaluation of Pts derivatives were reported. Compound NO. 3 demonstrated superior pharmacological efficacy to Pts both in vitro and in vivo, and it may be a promising therapeutic candidate for ischemic stroke intervention. Full article

Background: Cerebral arteriovenous malformations (AVMs) are high-flow shunts in which abnormal arteriovenous connections expose draining veins to venous hypertension, arterialization, and altered oxygenation. While digital subtraction angiography (DSA) remains the reference standard for dynamic angioarchitecture, it does not directly characterize venous oxygenation or microhemorrhagic tissue changes. Objective: To synthesize current evidence on susceptibility-based MRI-susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) for characterization, risk-related features, and treatment monitoring in cerebral AVMs. Methods: Narrative review of the foundational and contemporary literature on AVM pathophysiology, SWI and QSM technical principles, and clinical applications including venous drainage depiction, microhemorrhage detection, oxygenation-related biomarkers, and post-treatment surveillance. Results: SWI provides high-resolution, non-contrast depiction of venous drainage and perinidal hemorrhagic/calcific components, improving visualization of draining veins and microhemorrhages compared with conventional MRI and complementing TOF-MRA. Arterialized draining veins may show altered SWI signal consistent with elevated venous oxygen saturation, though interpretation is indirect and influenced by flow and orientation. QSM extends susceptibility imaging by quantifying tissue susceptibility and enabling indirect estimation of venous oxygenation (SvO₂), offering a potential physiological biomarker of shunt severity and treatment response after radiosurgery or embolization. Key limitations include lack of dynamic flow timing, flow-related artifacts, orientation dependence, confounding from hemorrhage/calcification, and limited standardization and prospective validation. Conclusions: Susceptibility-based MRI does not replace DSA but meaningfully enriches multimodal AVM assessment by adding structural and physiological information-particularly venous mapping, microhemorrhage detection, and oxygenation-sensitive biomarkers. Standardized acquisition/reconstruction and prospective studies are needed to validate susceptibility-derived metrics for risk stratification and longitudinal monitoring. Full article

Background/Objectives: Contrast enhancement (CE) on T1-weighted MRI is routinely used to guide therapy in the management of glioblastoma, although adjacent non-contrast-enhancing (non-CE) T2/FLAIR abnormalities can also harbor viable tumor tissue. The differences between these radiographic compartments remain incompletely characterized beyond conventional structural imaging. We therefore compared CE and non-CE compartments in untreated IDH-wildtype glioblastoma using dynamic susceptibility contrast (DSC) and diffusion-weighted MRI derived indices. Methods: Adults with untreated glioblastoma imaged preoperatively between January 2021 and September 2024 on multi-vendor 1.5 T and 3 T scanners were retrospectively included. Regions of interest were placed in CE tumor, adjacent non-CE T2/FLAIR hyperintense tissue, and contralateral normal-appearing white matter (NAWM). Mean apparent diffusion coefficient (rADC), cerebral blood volume (rCBV), capillary transit time heterogeneity (rCTH), oxygen extraction fraction (rOEF), and a cerebral metabolic rate of oxygen index (rCMRO₂) were extracted and harmonized for scanner effects and normalized to NAWM. Paired CE–non-CE differences were tested using Wilcoxon signed-rank tests and summarized by Hodges–Lehmann differences with bootstrap 95% confidence intervals. Spearman correlations were used to assess coupling within contrast-enhancing tumor regions. Results: Seventy-two participants were analyzed (median age 67 years; 34 women); 66 had paired CE and non-CE data. rCMRO₂ and rCBV were higher in CE than non-CE (both p < 0.001), while rADC was lower (p = 0.003). rOEF (p = 0.12) and rCTH (p = 0.52) did not differ significantly between compartments. Conclusions: CE in untreated IDH-wildtype glioblastoma predominantly reflects higher perfusion capacity (rCBV) along with a higher model-derived rCMRO₂ index, while capillary-function indices (rCTH and rOEF) are not consistently compartment-restricted. These findings may refine the physiological interpretation of CE in glioblastoma and support further validation of DSC-derived indices. Full article

Parkinson’s disease (PD) lacks effective disease-modifying therapies (DMTs). While oxidative stress drives PD pathogenesis, broad-spectrum antioxidants frequently fail in clinical trials due to limited specificity and poor cerebral bioavailability. In PD, reactive oxygen species (ROS) arise from multiple intracellular sources, among which mitochondrial dysfunction is widely recognized as a fundamental driver, while nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), a constitutively active NOX isoform that predominantly generates hydrogen peroxide (H₂O₂), has emerged as an important enzymatic contributor in the central nervous system. This review systematically examines the important role of NOX4 in PD and proposes a mechanistic framework by which NOX4-derived ROS contribute to PD progression. NOX4-derived ROS may directly promote mitochondrial dysfunction, proteostasis disruption, neuroinflammation, and ferroptosis. More importantly, NOX4-derived ROS may aggravate mitochondrial dysfunction to increase mitochondrial ROS production, thereby promoting PD progression indirectly. We systematically summarize the emerging NOX4-targeted strategies, including highly selective small-molecule inhibitors, natural products, gene therapies, and blood–brain barrier-penetrating nanodrug delivery systems. NOX4 should be viewed as an important regulator and potential amplifier that can affect multiple pathogenic processes in PD, thereby representing a promising avenue for the development of DMTs for PD. Full article

Neuronal ferroptosis is a key contributor to secondary brain injury following cerebral ischemia, yet the metabolic mechanisms governing this process remain poorly understood. Enriched environment (EE) is a housing paradigm that provides enhanced sensory, cognitive, and social stimulation through complex physical surroundings and increased opportunities for voluntary activity. Our preliminary data indicate that EE confers cerebroprotection against ischemia-induced ferroptosis; however, whether this effect is associated with glycogen metabolic regulation and the underlying molecular pathways has not been elucidated. This study aimed to determine whether EE may influence ferroptosis-associated pathways, potentially via Sirtuin 1 (SIRT1)/protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β)-related mechanisms of glycogen metabolism. Using a mouse model of middle cerebral artery occlusion (MCAO) and an oxygen–glucose deprivation/reoxygenation (OGD/R) cellular model, we performed behavioral assessments, molecular and biochemical analyses, and pharmacological interventions to elucidate mechanistic pathways. EE was associated with improved neurological outcomes and reduced infarct volume after ischemia. Mechanistically, EE appeared to activate the SIRT1/AKT pathway and increase the inhibitory phosphorylation of GSK3β and relieving its suppressive effect on glycogen synthase, which may underlie the observed increase in glycogen levels within ischemic brain tissue. Pharmacological inhibition of SIRT1 largely diminished these metabolic and neuroprotective benefits. Consistently, at the cellular level, SIRT1 overexpression contributed to the restoration of glycogen metabolism and robustly attenuated ferroptosis under ischemic conditions. Collectively, these findings suggest that EE may attenuate ferroptosis-related pathways possibly involving SIRT1/AKT/GSK3β-dependent glycogen metabolic remodeling, providing a novel metabolic perspective on EE-induced cerebroprotection and highlighting SIRT1-centered regulation of glycogen metabolism as a potential therapeutic target for ischemic stroke. Full article