Search Results (232)

Background: Ischemic stroke remains a leading cause of mortality and long-term disability worldwide. Reperfusion therapies, such as intravenous thrombolysis and mechanical thrombectomy, are crucial for restoring cerebral blood flow but may also trigger ischemia–reperfusion injury and systemic inflammatory activation, associated with poorer clinical outcomes. Methods: We retrospectively analyzed medical records of 8833 patients hospitalized for acute ischemic stroke between January 2014 and May 2025. Of these, 2242 (25.38%) underwent reperfusion therapy (mechanical thrombectomy ± intravenous thrombolysis), and 6591 (74.62%) were treated conservatively. Laboratory parameters, including leukocyte count, C-reactive protein (CRP), and albumin, and composite inflammatory indices (e.g., neutrophil-to-lymphocyte ratio (NLR), systemic immune–inflammation index (SII), systemic-inflammation response index (SIRI), and neutrophil percentage-to-albumin ratio (NPAR)), were assessed at admission. Clinical outcomes included in-hospital mortality and functional scale results (e.g., National Institutes of Health Stroke Scale, modified Rankin score (mRS), Barthel scale, and Glasgow Coma Scale (GCS)). Results: Patients treated with reperfusion therapy had higher inflammatory indices (white blood cells, CRP, NLR, SII, and NPAR) compared to patients treated conservatively. In multiple regression analysis, these indices were significantly determined only by GCS and mRS scores, but age, gender, comorbidities, biochemical determinations, and type of ischemic stroke treatment (reperfusion or conservative) remained non-statistically significant. Conclusions: Patients with acute ischemic stroke undergoing reperfusion therapy exhibited a stronger inflammatory response and higher in-hospital mortality than those treated conservatively. However, multivariate analysis showed that a stronger inflammatory response following reperfusion therapy results more from the severity of the patients’ state than the kind of therapy. Full article

Background: Cerebral ischemia/reperfusion injury (CIRI) is a major challenge in ischemic stroke treatment. Phloretin (PHL), despite its potent antioxidant and anti-inflammatory properties, has limited clinical application due to poor oral bioavailability. This study aimed to develop an orally administered phloretin-loaded nanoemulsion (NE-PHL) to enhance brain delivery and neuroprotective efficacy against CIRI. Methods: NE-PHL was optimized via an orthogonal experimental design combined with ultrasonication. The optimized formulation was characterized for physicochemical properties and evaluated for pharmacokinetics and brain bioavailability. Its therapeutic efficacy was assessed in middle cerebral artery occlusion (MCAO) rats by measuring infarct volume, neurological scores, oxidative stress markers, and inflammatory cytokines. RNA sequencing analysis was performed to elucidate the underlying mechanisms. Results: The optimized NE-PHL exhibited a small droplet size (96.26 ± 0.86 nm), high encapsulation efficiency (84.58 ± 3.03%), and good storage stability over a period of 120 days. Pharmacokinetic studies showed a 2.72-fold increase in AUC _0–12h for NE-PHL compared to free PHL. In MCAO rats, NE-PHL treatment significantly improved neurological function, reduced cerebral infarct volume, attenuated oxidative stress, and modulated inflammatory responses by suppressing pro-inflammatory cytokines and enhancing anti-inflammatory activity. RNA sequencing analysis further confirmed coordinated downregulation of key pathways related to oxidative stress and inflammation. Conclusions: NE-PHL represents a promising oral nanotherapeutic strategy for the effective management of CIRI, offering enhanced bioavailability and significant neuroprotection. Full article

Ischemic stroke remains one of the leading causes of disability and mortality worldwide, and effective therapeutic options are still limited. Therefore, this study aimed to evaluate the neuroprotective effect of the aqueous extract of Bacopa procumbens (B. procumbens) in a murine model of ischemia/reperfusion induced by middle cerebral artery occlusion (MCAO). This widely used model is generated by the transient intraluminal insertion of a nylon filament through the external carotid artery to occlude the middle cerebral artery, allowing controlled induction and subsequent reperfusion. Wistar rats underwent 2 h MCAO, followed by tail vein administration of B. procumbens extract (40 mg/kg) or Edaravone (0.45 mg/kg) before reperfusion. Neurological, histological, and molecular parameters were assessed 48 h later. Additionally, in silico analyses were performed to predict the antioxidant activity of the extract’s major metabolites and to explore Nrf2-related signaling. B. procumbens treatment improved neurological condition, reduced the volume of the infarct lesion, increased the expression and activation of Akt and Nrf2, reduced lipid peroxidation (4-HNE), and downregulated AQP4, the main water channel involved in cerebral edema formation. These molecular effects were associated with enhanced neuronal survival and collectively resulted in significant neuroprotection in the MCAO model. In silico analysis identified key metabolites with high antioxidant potential through free radical scavenging, lipid peroxidation inhibition, and redox enzyme modulation. Nrf2-centered interactome analysis revealed eighty-two proteins linked to ischemia, neuroinflammation, neuronal death regulation, and oxidative stress response. These findings support the therapeutic potential of B. procumbens metabolites as neuroprotective agents against ischemic cerebral injury. Full article

Objective: Ischemic stroke (IS) is an acute neurologic injury in which inflammatory responses play a key role. Yinchen, a common medicinal plant used in Traditional Chinese Medicine (TCM), has been proven to possess strong anti-inflammatory effects. However, its efficacy in treating IS remains unclear. In this study, we aimed to investigate the therapeutic potential of Yinchen for IS and the material basis of this potential. Methods: The main active components in Artemisia scoparia extract (ASE, the extract of Yinchen), were identified by HPLC and MS. The targets of Yinchen and IS were obtained from public databases. Network pharmacology, molecular docking, and experimental investigation were further applied to acquire the core constituents in Yinchen that work against the neuroinflammation that occuring during IS. The neurological outcomes were evaluated in a transient Middle Cerebral Artery Occlusion (tMCAO) rat model. Additionally, the changes in the inflammatory responses in both the ischemic brain and in lipopolysaccharide (LPS)-treated microglial cells were examined using real-time qPCR. Results: Four active compounds of ASE, including isochlorogenic acid C (ICGA-C), isochlorogenic acid B (ICGA-B), isochlorogenic acid A (ICGA-A), and chlorogenic acid (CGA), were identified by HPLC and MS. Network pharmacology predicted that 103 compounds of Yinchen had 198 intersection targets with IS. The top five of these targets were TNF, STAT3, IL1B, AKT1, and SRC. Molecular docking results demonstrated that the abovementioned four compounds detected in ASE showed good interaction with all of the above five core targets. Moreover, both the four compounds and ASE were observed to attenuate NO release and suppress the release of various inflammatory factors (TNF-α, IL-1β, IL-6, and MCP-1) in a dose-dependent manner in LPS-induced BV2 microglial cells. ASE was further found to exert neuroprotective effects against ischemia–reperfusion (I/R) injury and inhibit the production of inflammatory factors in tMCAO rats. Conclusions: Yinchen exerts an anti-neuroinflammatory effect on IS, and its constituents with high scores binding to five core targets contribute to this effect. This supports its potential as an anti-inflammatory agent for the treatment of IS. Full article

Background/Objectives: Cerebral ischemia–reperfusion injury (CIRI) remains a major challenge in the treatment of ischemic stroke, characterized by intertwined oxidative stress and neuroinflammation. Existing monotherapies often fail to address this dual pathology effectively. We developed PLSCZ, a biomimetic nanoplatform integrating a catalytic core of imidazolate framework-8 (ZIF-8)-encapsulated superoxide dismutase (SOD) and catalase (CAT) enzymes with a hybrid platelet membrane shell. This design strategically employs metal–organic frameworks (MOFs) to effectively overcome the critical limitations of enzyme instability and provide a cascade catalytic environment, while the biomimetic surface modification enhances targeting capability, thereby enabling dual-pathway intervention against CIRI. Methods: PLSCZ was engineered by co-encapsulating SOD and CAT within a ZIF-8 core to form a cascade antioxidant system (SCZ). The core was further coated with a hybrid membrane composed of rapamycin-loaded phospholipids and natural platelet membranes. The nanoparticle was characterized by size, structure, enzyme activity, and targeting capability. In vitro and in vivo efficacy was evaluated using oxygen–glucose deprivation/reoxygenation (OGD/R) models and a transient middle cerebral artery occlusion/reperfusion (tMCAO/r) rat model. Results: In vitro, PLSCZ exhibited enhanced enzymatic stability and cascade catalytic efficiency, significantly scavenging reactive oxygen species (ROS) and restoring mitochondrial function. The platelet membrane conferred active targeting to ischemic brain regions and promoted immune evasion. PLSCZ effectively polarized microglia toward the anti-inflammatory M2 phenotype, reduced pro-inflammatory cytokine levels, restored autophagic flux, and preserved blood–brain barrier integrity. In vivo, in tMCAO/r rats, PLSCZ markedly targeted the ischemic hemisphere, reduced infarct volume, improved neurological function, and attenuated neuroinflammation. Conclusions: By synergistic ROS scavenging and anti-inflammatory action, the PLSCZ nanozyme overcomes the limitations of conventional monotherapies for CIRI. This biomimetic, multi-functional platform effectively reduces oxidative stress, modulates the phenotype of microglia, decreases infarct volume, and promotes neurological recovery, offering a promising multi-mechanistic nanotherapeutic for CIRI and a rational design model for MOF-based platforms. Full article

Ischemia–reperfusion is a rapidly evolving cascade that involves a variety of metabolic shifts whose precise timing and sequential order are still poorly understood. Clarifying these dynamics is critical for understanding the core injury trajectory of stroke and for refining time-delimited therapeutic interventions. More broadly, continuous in situ monitoring of the middle-cerebral-artery occlusion process at the system level has not yet been achieved. Here, we report the first single-subject high-resolution spatiotemporal resolution metabolic maps of the ultra-early phase of ischemic stroke in a rodent model. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging mapped a metabolic abnormality area in the ischemic hemisphere that propagates from the striatum to the cortex. Microdialysis probes were then stereotaxically implanted within this metabolic abnormality area, capturing 10,429 metabolites that resolved into 16 temporally distinct trajectories aligned with probe insertion, ischemic injury, and reperfusion injury. Analysis of specific metabolic pathways mainly revealed that the delayed clearance of metabolic waste (urea and tryptamine) during early reperfusion, the transient attenuation of the citrate-to-oxaloacetate buffering gradient within the TCA cycle, and the accumulation of extracellular branched-chain amino acids all play crucial roles in shaping the injury trajectory. Simultaneously, the depletion of cellular repair mechanisms (pyrimidine synthesis) in the early phase of reperfusion also warrants our attention. These findings provide novel insights into the molecular basis and mechanisms of ischemia–reperfusion and offer a comprehensive resource for further investigation. Full article

Background/Objectives: Cerebral ischemia and reperfusion injury, induced by bilateral common carotid artery occlusion and reperfusion (BCCAO/R), cause extensive neuronal damage and cognitive impairment. Bouvardia ternifolia (BtD), a plant known for its anti-inflammatory and neuroprotective effects, may offer therapeutic benefits against ischemic injury. This study aimed to evaluate the neuroprotective effects of BtD root extract on neuronal integrity, oxidative stress, and p53 protein expression following global cerebral ischemia in rats. Methods: Adult male Sprague Dawley rats were subjected to the BCCAO/R procedure for 60 min, followed by six days of reperfusion. Experimental groups included BCCAO/R+BtD, BCCAO/R+silymarin (reference control), BCCAO/R+vehicle, and sham controls. Neuronal morphology in the cortex, striatum, hippocampus, and cerebellum was assessed histologically. Oxidative stress markers, including reactive oxygen species (ROS), lipid peroxidation (LPO), reduced glutathione (GSH), and superoxide dismutase (SOD), were measured, along with the expression of p53 protein. Results: Treatment with BtD significantly decreased oxidative stress markers—LPO (82.2%), ROS (88.2%), GSH (66.5%), and SOD (54%)—and reduced p53 expression levels by 75%. Histological evaluation revealed that neurons in the BCCAO/R+BtD and BCCAO/R+silymarin groups maintained normal morphology, characterized by elongated cells and well-defined nuclei. In contrast, the BCCAO/R+vehicle group exhibited marked neuronal damage, including pyknosis, nuclear fragmentation, and interstitial edema, particularly in the hippocampal CA1 and cortical regions. BtD treatment significantly preserved neuronal structure and enhanced antioxidant defenses. Conclusions:Bouvardia ternifolia extract demonstrates neuroprotective potential in cerebral ischemia by maintaining neuronal architecture, reducing oxidative stress, and modulating p53 expression, supporting its therapeutic relevance in ischemia–reperfusion injury. Full article

Cerebral ischemic reperfusion injury (CIRI) induces irreversible neurological dysfunction with high morbidity and mortality, yet effective clinical interventions remain limited. This study focused on ferroptosis in CIRI and explored the neuroprotective components and mechanisms of Pomelo peel essential oil (PPEO)—a product derived from Guangxi’s characteristic Shatian pomelo. Sprague-Dawley rats were used to establish two CIRI models: focal CIRI via Middle Cerebral Artery Occlusion (MCAO) and global CIRI via Cardiac Arrest/Cardiopulmonary Resuscitation (CA/CPR). Analyses were conducted using metabolomics, transcriptomics, histopathological staining, biochemical assays, RT-qPCR, Western blotting (WB), and molecular docking. Metabolomic results showed altered lipid-related metabolites in both models, predominantly unsaturated fatty acids and components of the arachidonic acid (AA) metabolic pathway. Transcriptomic analysis revealed significant upregulation of PTGS1/2 in the MCAO model. Nootkatone and β-pinene improved neuronal morphology, increased glutathione peroxidase 4 (GPX4) levels, and enhanced neurological scores. Notably, Nootkatone exhibited strong binding affinity to ALOX15, and reduced lipid metabolic disturbances in the CA/CPR model. AA metabolism varies with CIRI severity: it is inflammation-driven in focal CIRI and ferroptosis-associated in global CIRI. As a key component of PPEO, Nootkatone antagonizes ferroptosis via the ACSL4-LPCAT3-ALOX15 axis, offering a novel therapeutic target for global CIRI after CA/CPR. Full article

Circular RNAs (circRNAs) are non-coding RNAs that can significantly influence the regulation of gene expression in health and disease, including ischemic stroke. We identified 597 differentially expressed circRNAs (DECs) (fold change > 1.5; Padj < 0.05) in the striatum region encompassing the ischemic lesion and penumbra 24 h after ischemia–reperfusion injury (tMCAO) in rats, according to high-throughput RNA sequencing data (RNA-Seq). The DECs predominantly increased expression levels relative to those in sham-operated animals. In this study, we also compared these data with DECs we previously identified in the frontal cortex region containing the penumbra and healthy tissue. Furthermore, we bioinformatically constructed a network of competitive circRNA-microRNA-mRNA interactions characterizing the possible functions of DECs in brain areas with varying degrees of ischemic injury. We found that in both tissues, the identified DECs were involved in regulating the expression of genes associated with inflammation and neurotransmission. Moreover, in the striatum, most DECs decreased their expression, while in the frontal cortex, most DECs increased their expression. Thus, we demonstrated different circRNA activities in brain areas with varying degrees of injury. This result may indicate a role for these molecules in regulating brain cell responses, including those important for functional recovery after cerebral ischemia. Full article

Cerebral ischemia–reperfusion (I/R) injury is a leading cause of death and long-term disability worldwide, characterized by a complex interplay of pathophysiological mechanisms and currently limited therapeutic options. This critical unmet need underscores the importance of exploring novel multi-targeted neuroprotective agents. Marine algae represent a rich and underexplored source of structurally diverse bioactive compounds with promising therapeutic potential against cerebral I/R injury. This comprehensive review systematically summarizes the preclinical evidence on the neuroprotective effects and underlying mechanisms of key bioactive compounds found in marine algae, including polysaccharides (e.g., fucoidan, laminarin, porphyran), carotenoids (e.g., astaxanthin, fucoxanthin, lutein, zeaxanthin), polyphenols (e.g., dieckol, phlorotannins), and sterols (e.g., β-sitosterol). These compounds consistently demonstrate significant efficacy across various in vitro and in vivo models, primarily through multifaceted actions encompassing anti-excitotoxic, antioxidant, anti-inflammatory, and anti-apoptotic effects, as well as the modulation of crucial signaling pathways and preservation of blood–brain barrier integrity. While the existing preclinical evidence is highly promising, successful clinical translation necessitates further rigorous research to overcome challenges related to precise molecular understanding, translational relevance, pharmacokinetics, and safety. Beyond their pharmacological significance, the sustainable utilization of marine by-products as renewable sources of bioactive agents further highlights their dual value, offering not only novel therapeutic avenues for cerebral I/R injury but also contributing to marine resource valorization. Full article

Cerebral ischemia/reperfusion (I/R) injury remains a significant contributor to adult neurological morbidity, primarily due to exacerbated neuroinflammation and cell apoptosis. These processes amplify brain damage through the release of various pro-inflammatory cytokines and pro-apoptotic mediators. Although long non-coding RNAs (lncRNAs) are increasingly recognized for their involvement in regulating diverse biological pathways, their precise role in cerebral I/R injury has not been fully elucidated. In the current study, transcriptomic profiling was conducted using a rat model of focal cerebral I/R, leading to the identification of lncRNA-1810026B05Rik—also referred to as CHASERR—as a novel lncRNA responsive to ischemic conditions. The elevated expression of this lncRNA was observed in mouse brain tissues subjected to middle cerebral artery occlusion followed by reperfusion (MCAO/R), as well as in primary cortical neurons derived from rats exposed to oxygen-glucose deprivation and subsequent reoxygenation (OGD/R). The results suggested that lncRNA-1810026B05RiK mediates the activation of the nuclear factor-kappaB (NF-κB) signaling pathway by physically binding to NF-kappa-B inhibitor alpha (IκBα) and promoting its phosphorylation, thus leading to neuroinflammation and neuronal apoptosis during cerebral ischemia/reperfusion. In addition, lncRNA-1810026B05Rik knockdown acts as an NF-κB inhibitor in the OGD/R and MCAO/R pathological processes, suggesting that lncRNA-1810026B05Rik downregulation exerts a protective effect on cerebral I/R injury. In summary, the lncRNA-1810026B05Rik has been identified as a critical regulator of neuronal apoptosis and inflammation through the activation of the NF-κB signaling cascade. This discovery uncovers a previously unrecognized role of 1810026B05Rik in the molecular mechanisms underlying ischemic stroke, offering valuable insights into disease pathology. Moreover, its involvement highlights its potential as a novel therapeutic target, paving the way for innovative treatment strategies for stroke patients. Full article

Reperfusion therapy uses thrombolysis and clot removal to restore blood flow in the brain after stroke; however, three months after reperfusion therapy, roughly 46% of stroke patients become independent again. MiRNAs (micro RNA) regulate cerebral ischemia/reperfusion injury, and their transfer between cells via exosomes may differentially affect recipient cells. We examined serum exosomal miRNA levels, stroke treatments, and functional outcomes in stroke patients, and we explored the potential role of estimated differentially expressed miRNA (DEmiRNA) target genes in the brain’s reaction to reperfusion after ischemia. The patients in the study received aspirin or reperfusion therapy with either intravenous thrombolysis (rt-PA), mechanical thrombectomy (MT), or a combination of both (rt-PA/MT). Serum samples were collected from stroke patients on days 1 and 10 post-stroke. Serum exosomes’ miRNA was analyzed using qRT-PCR. We identified DEmiRNAs, estimated their targets, and performed enrichment analysis. Functional outcomes were assessed using the modified Rankin Scale (mRS) on days 10 and 90 post-stroke. Among studied treatments, only rt-PA/MT lowered DEmiRNA by day 10 vs. other groups. Specifically, patients with unfavorable mRS score exhibited decreased levels of miR-17, miR-20, miR-186 and miR-222 after combined stroke therapy. Functional analysis identified target genes and pathways associated with cytoskeleton remodeling, cell death, autophagy, inflammation, and dementia. In conclusion, unfavorable stroke outcomes following poor rt-PA/MT response could result from lower miRNA expression levels, thus activating cell death and neurodegenerative processes in brain. Full article

Cerebral ischemia/reperfusion (I/R) injury is a devastating neurological disorder with limited treatment options. Emerging evidence suggests that the N6-methyladenosine (m6A) modification and its regulatory factors play pivotal roles in the pathophysiology of I/R. This study aimed to elucidate the function of METTL3-mediated m6A modification of the long non-coding RNA (lncRNA) AU020206 in ferroptosis during cerebral I/R injury and to identify potential molecular targets for neuroprotection. A murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) and N2a cells subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) were established to assess m6A levels and ferroptosis-related changes. Effects of METTL3 overexpression and lncRNA-AU020206 silencing on neuronal apoptosis, inflammation, and ferroptosis were investigated in vitro and in vivo. The interaction between lncRNA-AU020206 and YTHDC2 and the resulting regulation of SLC7A11 mRNA stability and GPX4 expression were evaluated using molecular and biochemical assays. Both MCAO/R mice and OGD/R-treated N2a cells exhibited decreased m6A levels and upregulation of lncRNA-AU020206 accompanied by enhanced ferroptosis. METTL3 overexpression increased the m6A modification of AU020206, promoting its degradation and attenuating neuronal injury, whereas silencing AU020206 or overexpressing YTHDC2 decreased SLC7A11 mRNA stability and enhanced ferroptosis. Restoring the expression of SLC7A11/GPX4 can enhance cell viability, alleviate neuronal apoptosis, and reduce Fe²⁺ overload. Disruption of the METTL3–AU020206–YTHDC2 axis abolished these neuroprotective effects. METTL3-mediated m6A modification of lncRNA-AU020206 restrained ferroptosis and neuronal injury in cerebral I/R by maintaining the stability of the SLC7A11/GPX4 axis via interactions with YTHDC2. Targeting this epitranscriptomic signalling pathway may represent a promising therapeutic strategy for the treatment of ischemic stroke and related neurological disorders. Full article

Ischemic stroke is a neurological disorder resulting from localized brain injury due to focal cerebral ischemia, typically caused by the blockage of one or, in some cases, a few cerebral arteries. This arterial obstruction leads to hypoxia and energy failure, culminating in primary brain damage. Although reperfusion is critical to salvage viable tissue, it often intensifies injury through oxidative stress, inflammation, and cell death—a phenomenon called ischemia–reperfusion (I/R) injury. Milk fat globule-EGF factor 8 (MFG-E8), a multifunctional glycoprotein secreted by stem and immune cells, is a key regulator of inflammation and tissue repair. By modulating microglial activation, attenuating proinflammatory cytokine releases, and preserving neuronal integrity, MFG-E8 mitigates ischemia–reperfusion injury and emerges as a novel therapeutic target for ischemic stroke. Full article

Cerebral ischemia–reperfusion injury (CIRI) is a complex pathological process that arises when blood flow is restored to the brain after ischemia, often resulting in significant neuronal damage and triggering secondary inflammatory responses. This review explores the immune mechanisms underlying CIRI, focusing on the activation and polarization of resident central nervous system (CNS) cells—particularly microglia and astrocytes—and the infiltration of peripheral immune cells such as neutrophils, monocytes/macrophages, and T lymphocytes. We discuss the central role of microglia in the neuroinflammatory cascade, their polarization between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, and how this process influences neuronal damage and tissue repair. This review highlights the roles of the complement system, inflammasome activation, and blood–brain barrier disruption as key drivers of inflammation and neuronal injury. Additionally, we elaborate on the dynamic interactions between resident and infiltrating immune cells, which amplify inflammation and impede post-ischemic recovery. Finally, we discuss emerging therapeutic strategies targeting immune modulation, including cytokine regulation, microglial reprogramming, and targeted drug delivery systems, which offer promising avenues for improving outcomes in ischemic stroke. Full article