The blood-brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation. It tightly modulates the ion transport and nutrient influx, while restricting the entry of harmful factors, and selectively limiting the migration of immune cells, thereby maintaining brain homeostasis. Despite the well-established association between blood-brain barrier disruption and most neurodegenerative/neuroinflammatory diseases, much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown. Moreover, the role of blood-brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood. This review aims to revisit this concept of "blood-brain barrier breakdown," delving into the most controversial aspects, prevalent challenges, and knowledge gaps concerning the lack of blood-brain barrier integrity. By moving beyond the oversimplistic dichotomy of an "open"/"bad" or a "closed"/"good" barrier, our objective is to provide a more comprehensive insight into blood-brain barrier dynamics, to identify novel targets and/or therapeutic approaches aimed at mitigating blood-brain barrier dysfunction. Furthermore, in this review, we advocate for considering the diverse time- and location-dependent alterations in the blood-brain barrier, which go beyond tight-junction disruption or brain endothelial cell breakdown, illustrated through the dynamics of ischemic stroke as a case study. Through this exploration, we seek to underscore the complexity of blood-brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases.

Previous investigations have established a notable correlation between depressive symptoms and stroke incidence, as well as the link between stroke occurrence and the ratio of family income-to-poverty ratio (PIR). The intricate dynamics between depressive states and the incidence of stroke mediated by PIR, however, remains inadequately understood.

The objective of this research is to scrutinize the link between depressive states and stroke, assessing how PIR functions as a mediator in this dynamic. Through an analysis of the economic status of individuals exhibiting depressive symptoms, this study explores their potential influence on the susceptibility to stroke. Such analysis aims to uncover the intricate interactions among depression, the PIR, and stroke occurrence.

Data from 2015 to 2018 NHANES assessed adults' depressive symptoms using PHQ-9 scores. Participants reporting a stroke diagnosis by medical professionals were identified as the stroke cohort. The income levels were assessed using the PIR. To examine the relationship between depressive symptoms and stroke, weighted multivariate linear regression models, curve-fitting analyses, and subgroup assessments were employed, alongside mediation analyses to determine the role of PIR as a mediator.

In the analysis of 7204 participants, the data revealed a robust positive association between depressive symptoms and stroke risk within the comprehensively adjusted model. Additionally, the mediation analysis demonstrated that the PIR contributed to 10.3188 % of the explained variability in the link between depressive symptoms and stroke incidence, serving as a specific mediator of this association.

The findings of this research indicate that there is a significant positive link between depressive symptoms and the incidence of stroke, with the PIR serving as a notable mediator.

Stroke remains a leading cause of global mortality, with neuroinflammation significantly exacerbating clinical outcomes. Microglia serve as key mediators of post-stroke neuroinflammation, though the mechanisms driving their migration to injury sites remain poorly understood. In this study, using publicly available single-cell sequencing data (GSE234052), we identified a migration-associated microglial subtype in a murine model of distal middle cerebral artery occlusion (dMCAO). Additionally, ribosome-bound mRNA sequencing data (GSE225110) from microglia isolated from peri-infarct cortical tissue uncovered dMCAO-induced alterations in microglial mRNA translation. By integrating these datasets, we identified A Disintegrin And Metalloproteinase 8 (Adam8) as a key gene upregulated at both the transcriptional and translational levels post-dMCAO. Protein analysis revealed that both the precursor and active forms of Adam8 were predominantly expressed in microglia and significantly upregulated in peri-infarct regions following dMCAO. Notably, Adam8 inhibition with BK-1361 significantly reduced Adam8 cleavage, M1 microglial migration, inflammation, infarct size, and improved neurological outcomes. Bioinformatics analysis further identified Myo1e as a potential interacting partner of Adam8, a finding validated through immunofluorescence co-localization. These findings highlight Adam8 as a promising therapeutic target for mitigating post-stroke neuroinflammation and offer new insights into the mechanisms of microglial migration.

Experimental stroke models in rodents are essential for mechanistic studies and therapeutic development. However, these models have several limitations negatively impacting their translational relevance. Here we aimed to develop a minimally invasive thrombotic stroke model through magnetic particle delivery that does not require craniotomy, is amenable to reperfusion therapy, can be combined with in vivo imaging modalities, and can be performed in awake mice. We found that the model results in reproducible cortical infarcts within the middle cerebral artery (MCA) territory with cytologic and immune changes similar to that observed with more invasive distal MCA occlusion models. Importantly, the injury produced by the model was ameliorated by tissue plasminogen activator (tPA) administration. We also show that MCA occlusion in awake animals results in bigger ischemic lesions independent of day/night cycle. Magnetic particle delivery had no overt effects on physiologic parameters and systemic immune biomarkers. In conclusion, we developed a novel stroke model in mice that fulfills many requirements for modeling human stroke.

Hypoxic-ischemic brain damage (HIBD) is a significant cause of neonatal death and neurological dysfunction. Following this injury, activated microglia can lead to a series of inflammatory responses. Gastrodin (GAS), a polyphenol extracted from the Chinese herbal medicine Gastrodia elata Blume, has demonstrated antioxidant and anti-inflammatory effects. This study investigated the neuroprotective impact of GAS in HIBD mice model and in BV2 cells subjected to oxygen-glucose deprivation (OGD) treatment. Expression of various members of the Ccr2/Akt/Gsk-3β, including Ccl2, Ccr2, Akt, p-Akt, Gsk-3β, p-Gsk-3β and inflammatory factors TNF-α and IL-1β in activated microglia was assessed by Western blotting, immunofluorescence, and qRT-PCR in HIBD in postnatal mice, and in OGD-induced BV2 microglia in vitro with or without GAS treatment. The present results showed that GAS effectively reduces the expression of Ccl2 and Ccr2, increases the phosphorylation levels of Akt and Gsk-3β, and decreases the expression of the TNF-α and IL-1β. Additionally, we have shown that inhibition of Ccr2 by RS102895 increased the expression of p-Akt and p-Gsk-3β, and attenuate production of proinflammatory mediators in activated microglia. Of note, the expression of p-Akt, p-Gsk-3β, TNF-α and IL-1β remained unchanged after the combination of gastrodin and RS102895. Taken together, we conclude that GAS can play a protective role in reducing the neuroinflammatory response after HIBD. It is suggested that this is mainly through up-regulating the Akt/Gsk-3β signaling pathway via the Ccr2 receptor in the present experimental paradigm.

Ischemic stroke represents one of the leading cerebrovascular diseases with a high rate of mortality and disability globally. To date, there are no effective clinical drugs available to improve long-term outcomes for post-stroke patients. A novel nucleic acid agent circSCMH1 which can promote sensorimotor function recovery in rodent and nonhuman primate animal stroke models has been found. However, there are still delivery challenges to overcome for its clinical implementation. Besides, its effects on post-stroke cognitive functions remain unexplored. Herein, lipid nanoparticle circSCMH1@LNP1 is established to deliver circSCMH1 and explore its therapeutic efficacy comprehensively. Distribution experiments demonstrate that intranasal administration of circSCMH1@LNP1 significantly increases circSCMH1 distribution in the peri-infarct region and reduces its non-specific accumulation in other organs compared to intravenous injection. Therapeutic results indicate that circSCMH1@LNP1 promotes synaptic plasticity, vascular repair, neuroinflammation relief, and myelin sheath formation, thereby achieving enhanced sensorimotor and cognitive function recovery in post-stroke mice. In conclusion, this research presents a simple and effective LNP system for efficient delivery of circSCMH1 via intranasal administration to repair post-stroke brain injury. It is envisioned that this study may bridge a crucial gap between basic research and translational application, paving the way for clinical implementation of novel circSCMH1 in post-stroke patient management.

Stroke significantly impacts global health, being a primary cause of disability, dementia, and mortality. The interplay of nutritional deficiency and systemic inflammation plays a pivotal role in determining stroke outcomes. While the Prognostic Nutritional Index (PNI) and the Advanced Lung Cancer Inflammation Index (ALI) have been recognized for their prognostic value in various diseases, their relevance in stroke prognosis necessitates further exploration.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018, analyzing 908 stroke survivors to examine the associations between PNI, ALI, and mortality outcomes. Weighted Cox proportional hazards models were applied to assess the associations, controlling for demographic and health-related variables. Kaplan-Meier curves and restricted cubic splines were used to evaluate survival differences and non-linear relationships, respectively. Additionally, subgroup and sensitivity analyses were conducted to verify the robustness of the associations.

In our cohort, elevated PNI was associated with significantly lower risks of all-cause mortality (Hazard Ratio [HR]: 0.53, 95 % Confidence Interval [CI]: 0.37-0.75, p < 0.001) and cardiovascular mortality (HR: 0.60, 95 % CI: 0.38-0.94, p = 0.028). Similarly, higher ALI levels correlated with a reduced risk of all-cause mortality (HR: 0.53, 95 % CI: 0.37-0.72, p < 0.001), though its impact on cardiovascular mortality did not reach statistical significance after adjustment. Subgroup analysis revealed that gender, age, and diabetes status modulated the relationship between PNI/ALI and mortality outcomes, with significant interactions observed especially in diabetic patients (PNI: P for interaction = 0.025 and ALI: P for interaction = 0.007).

This study confirms that higher PNI and ALI are associated with lower all-cause mortality in stroke survivors. Elevated PNI also reduces cardiovascular mortality risk. Gender, age, and diabetes status influence these associations. These findings highlight the importance of monitoring nutritional and inflammatory status in stroke recovery.

To investigate the predictive value of Neutrophil to lymphocyte ratio (NLR) and Lymphocyte to monocyte ratio (LMR) on unfavorable outcomes of acute anterior circulation large vessel occlusion stroke (ALVOS) in patients who underwent mechanical thrombectomy (MT).

We retrospectively recruited 96 cases with ALVOS who underwent MT. These cases were divided into two groups including the favorable outcome group (3-month modified Rankin Scale scores (mRS) of 0-2) and the unfavorable outcome group (3-month mRS of 3-6). Logistic regression analysis was used to examine the independent risk factors of the 3-month unfavorable outcome of ALVOS. Moreover, we conducted a receiver operating characteristic curve (ROC) to estimate the valuable predictor of NLR, LMR, and the combination of NLR and LMR on unfavorable outcomes of ALVOS after MT.

46.9 % (45/96) cases had an unfavorable outcome and 53.1 % (51/96) cases had a favorable outcome. In the univariate regression analysis, baseline NIHSS score, symptomatic intracranial hemorrhage, and fasting glucose were included in the multi-factor binary logistic regression, and this revealed that NLR (OR 3.776, 95 %CI 1.067-13.363, p = 0.039) and LMR (OR 0.092, 95 %CI 0.017-0.0506, p = 0.006) were independent predictors of unfavorable outcomes (mRS score 3-6) at 3-month. Higher NLR (> 2.984) and lower LMR (< 3.775) were independently associated with unfavorable outcomes, and the combined predictive levels of both NLR and LMR (AUC = 0.941) were higher than single indicators (NLR, AUC = 0.876; LMR, AUC = 0.934).

The combination of NLR and LMR was a more powerful predictor of unfavorable outcomes of ALVOS after MT than NLR alone.

Inflammation is a critical factor in the pathogenesis of acute ischemic stroke (AIS). The systemic inflammation response index (SIRI), which combines three inflammatory markers, serves as a comprehensive, accessible, and cost-effective tool for assessing inflammation. However, the potential of SIRI to predict the 3-month outcomes of AIS patients following intravenous thrombolysis (IVT) has not been fully explored. Given the urgency of improving patient prognostication and treatment strategies, this study aims to assess the predictive value of SIRI for AIS prognosis at the 3-month mark, providing insights that could enhance clinical decision-making and guide future therapeutic approaches.

AIS patients who received IVT from December 2020 to June 2024 were enrolled. The Modified Rankin Scale (mRS) was utilized to evaluate clinical outcomes. Propensity score matching (PSM) and logistic regression analysis were performed to investigate the association between SIRI and the 3-month prognosis in AIS patients.

A total of 559 AIS patients were enrolled in the study, with 433 (77.5 %) experiencing poor outcome. Among the 83 matched patient pairs following propensity score matching (PSM), a significant association was observed between the SIRI and clinical outcomes (OR, 2.27; 95 % CI, 1.42-3.65; p < 0.001). The optimal cutoff value for predicting outcomes was identified as a SIRI level of 0.856, achieving sensitivity and specificity of 84.1 % and 51.7 %, respectively.

Elevated SIRI levels are indicative of an increased likelihood of poor outcomes following IVT in AIS patients, suggesting that SIRI could serve as a valuable prognostic biomarker for patient recovery.

Ischemic stroke (IS) has remained the main cause of mortality and neurological disabilities worldwide. Anti-CD20 treatments have a potent anti-inflammatory effect. Here, we investigated the effect of anti-CD20 on IS-induced inflammation and histopathologic changes in the rat model. Male Sprague-Dawley rats were divided into three groups: control, sham, and stroke. Rats in the stroke groups underwent photothrombosis-induced IS in the sensorimotor cortex area. They were divided into the following subgroups: treated with anti-CD20 after ischemia and killed after 5 and/or 10 days of IS. Histological changes were assessed by hematoxylin and eosin staining. mRNA levels of inflammation markers (VIM, ANXA3, SLC22 A4, and ADM), and also levels of transcription factors for Th1, Th2, and Th17 subsets (Tbet, GATA3, and ROR-γ, respectively), and also Foxp3 were detected in the peripheral blood mononuclear cells by quantitative real-time PCR. The levels of ADM and SLC22 A4 increased following IS on the 5th and 10th days, while treatment with anti-CD20 reversed their levels. Anti-CD20 therapy attenuated inflammation through down-regulation of VIM and ANXA3 after 10 days. This therapeutic effect was mainly mediated by the downregulation of Th1-Th17-driven inflammatory responses (Tbet and RORγt) and the upregulation of Th2 activities (GATA- 3). In addition, anti-CD20 increased the expression of Foxp3. Anti-CD20 treatment can also reduce brain tissue damage after 10 days. Our data showed that inflammation and histopathological alterations are associated with the photothrombotic model of IS, while treatment with anti-CD20 could reduce inflammation and alleviate histopathological changes.

Ischemic stroke is one of the leading causes of deaths and disability, which is linked to inflammation. In this study, we aimed to identify inflammation-related lncRNAs as diagnostic biomarkers of acute ischemic stroke (AIS). A competing endogenous RNAs (ceRNA) network was established through whole transcriptome analysis. Gene expression datasets from the GEO database were analyzed to identify differentially expressed genes (DEGs), miRNAs and lncRNAs. Inflammation-related DEGs were determined through the intersection of the DEGs of the inflammation-related gene set from Genecards. Multiple databases like lncBase and Targetscan were analyzed to establish a ceRNA network. Several hub genes and sub-networks were obtained from a protein to protein (PPI) network. In addition, the candidate lncRNAs derived from the subnetwork were validated using mice MCAO model and clinical samples. Finally, a network comprising 20 lncRNAs, 26 miRNAs, and 43 inflammatory genes was analyzed, leading to the identification of MALAT1, SNHG8, and GAS5 as potential diagnostic biomarkers. Knockdown of MALAT1 and GAS5 resulted in decreased neurological severity score and inflammation response in mice MCAO model, indicating that these genes were significant diagnostic biomarkers for distinguishing AIS from healthy controls. These findings show that circulating MALAT1 and GAS5 have the potential to serve as clinical diagnostic biomarkers of AIS associated with inflammation.

Cerebral ischaemia-reperfusion injury (CIRI) is a major contributor to global morbidity and mortality, although its underlying mechanisms remain only partly understood. Emerging evidence indicates that inhibiting microglia-mediated neuroinflammation would be an effective therapeutic approach for CIRI, and pharmacological interventions targeting this pathway hold significant therapeutic promise. This study aimed to identify a potent anti-inflammatory drug from a natural compound library as a potential treatment for CIRI.

We used oxygen-glucose deprivation/reperfusion (OGD/R) and middle cerebral artery occlusion in male C57BL/6 mice to evaluate the efficacy of DHA in neurological deficits and the anti-inflammatory effects. Using BV2 cells and murine brain tissue, liquid chromatography-tandem mass spectrometry was used to identify potential molecular targets of DHA, followed by bio-layer interferometry, molecular docking, molecular dynamics simulations and cellular thermal shift assays to validate DHA's binding interactions with protein kinase C delta (PKCδ).

DHA decreased production of pro-inflammatory cytokines following OGD/R, thereby inhibiting microglia-mediated neuroinflammation to protect neurons and reducing brain infarct size and improving neurological outcomes. Mechanistically, DHA directly bound to PKCδ, inhibiting its phosphorylation and downstream NF-κB signalling. This binding interaction involved TRP55 and LEU106 on PKCδ, as confirmed by molecular docking and other biophysical techniques.

DHA specifically interacts with PKCδ, preventing its phosphorylation induced by ischaemia-reperfusion injury. These results suggest that DHA is a novel inhibitor of PKCδ and provide solid experimental foundations for using DHA in treating neuroinflammation-related conditions, such as CIRI.

Ischemic stroke disrupts protein homeostasis in brain cells, causes endoplasmic reticulum (ER) stress, and consequently activates the unfolded protein response (UPR). The primary function of UPR activation is to help cells restore ER function, thereby promoting cell survival. A major adaptive UPR branch is mediated by activating transcription factor 6 (ATF6). We previously provided experimental evidence that activation of ATF6 signaling in neurons improves short-term outcome after both transient and permanent stroke. However, the effect of ATF6 activation in astrocytes on stroke outcome remains undetermined, and critically, the long-term therapeutic potential of targeting this UPR branch in permanent stroke has not been evaluated. The current study aimed to address these two critical unknowns. First, using conditional knock-in mice in which functional short-form ATF6 (sATF6) is specifically expressed in astrocytes, we demonstrated that astrocytic ATF6 activation modestly improved outcome after permanent stroke. Then, our pharmacokinetic analysis indicated that compound AA147, an ATF6-specific activator, can cross the blood-brain barrier. Lastly, we found that post-stroke treatment with AA147 had no significant beneficial effect on short-term outcome, but improved long-term functional recovery in both young and aged mice after permanent stroke. Together with previous findings, our data support the notion that the ATF6 pathway is a promising target for stroke therapy.

Ischemic stroke is a leading cause of mortality and disability worldwide, yet the interplay between peripheral and central immune responses is still only partially understood. Emerging evidence suggests that myeloid cells, when activated in the periphery, infiltrate the ischemic brain and contribute to the disruption of the blood-brain barrier (BBB) through both inflammatory and metabolic mechanisms.

In this study, we integrated bulk RNA-sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and flow cytometry data from human and mouse models of ischemic stroke. Mouse stroke models were induced by transient middle cerebral artery occlusion (tMCAO), and brain tissues were later collected at specified time points for analysis. We examined time-dependent transcriptional changes in the peripheral blood, delineated cell-type-specific responses by single-cell profiling, and validated myeloid infiltration into the ischemic brain. We also investigated endothelial metabolic reprogramming and oxidative stress by combining scMetabolism analyses (a computational R package for inferring metabolic pathway activity at the single-cell level) with in vitro oxygen-glucose deprivation/reperfusion (OGD/R) experiments.

Cross-species bulk RNA-seq revealed a modest early immune shift at 3 h post-stroke, escalating significantly by 24 h, with robust myeloid-centric gene signatures conserved in humans and mice. Single-cell analyses confirmed a pronounced expansion of neutrophils, monocytes, and megakaryocytes in peripheral blood, coupled with a decrease in T and B lymphocytes. Spatial transcriptomics and flow cytometry demonstrated substantial infiltration of CD11b+ myeloid cells into the infarct core, which showed extensive interaction with endothelial cells. Endothelial scRNA-seq data showed reductions in the oxidative phosphorylation, glutathione, and nicotinate metabolic pathways, together with elevated pentose phosphate pathway activity, suggestive of oxidative stress and compromised antioxidant capacity. Functional scoring further indicated diminished endothelial inflammation/repair potential, while in vitro OGD/R experiments revealed morphological disruption, CD31 downregulation, and increased 4-hydroxynonenal (4-HNE), underscoring the importance of endothelial oxidative damage in BBB breakdown.

These multi-omics findings highlight the existence of a coordinated peripheral-central immune axis in ischemic stroke, wherein myeloid cell recruitment and endothelial metabolic vulnerability jointly exacerbate inflammation and oxidative stress. The targeting of endothelial oxidative injury and myeloid-endothelial crosstalk may represent a promising strategy to mitigate secondary brain injury in ischemic stroke.

The impact of acute heart failure following acute ischemic stroke on short-term cardiovascular outcomes remains unclear. This study investigated the association between acute heart failure and cardiovascular outcomes within 90 days after acute ischemic stroke.

We retrospectively analyzed 1658 patients with acute ischemic stroke. In-hospital heart failure was defined as heart failure diagnosed on admission or within seven days of hospitalization. The primary outcome was a composite of major adverse cardiovascular events within 90 days of acute ischemic stroke. Secondary outcomes included a composite of fatal or nonfatal heart failure and all-cause mortality. Logistic regression analyses were used to identify predictors of these outcomes. Eighty-two patients with acute ischemic stroke (4.9 %) developed acute heart failure. Major adverse cardiovascular events occurred in 120 patients (7 %) within 90 days. In-hospital heart failure was an independent predictor of major adverse cardiovascular events (odds ratio [OR] 2.25, 95 % confidence interval [CI] 1.11-4.53, p = 0.023) and fatal or nonfatal heart failure (OR 4.72, 95 % CI 1.96-11.35, p = 0.001) within 90 days. However, it was not a significant predictor of all-cause mortality (OR 1.90, 95 % CI 0.94-3.84, p = 0.075).

In-hospital heart failure was a significant predictor of major adverse cardiovascular events and fatal or nonfatal heart failure within 90 days after acute ischemic stroke.

Pediatric stroke is a significant cause of childhood mortality and morbidity. The clinical research in this field bears certain limitations that do not exist in the pre-clinical setting. Experimental models of ischemic stroke show differences in lesion evolution and blood-brain barrier (BBB) permeability between adult and neonatal rats. However, little is known about these factors in the juvenile stage. Here, we characterize the evolution of the lesion, penumbra and degree of BBB permeability in a photothrombotic ring model of juvenile stroke using a mixed longitudinal and cross-sectional study. Fourteen Sprague Dawley juvenile rats (weight 130-189 g), lesion, penumbra volume and blood-brain barrier (BBB) leakage were measured longitudinally on days 0, 2, and 7 following photothrombotic stroke. Magnetic resonance imaging (MRI) techniques were used to measure lesion and penumbra volumes (T2-weighted imaging [T2]), water restriction (diffusion-weighted imaging [DWI]) and BBB leakage (with dynamic contrast-enhanced imaging [DCE]). To confirm stroke, histology was performed (n = 9) with Triphenyltetrazolium chloride staining (TTC) (n=9), (Haemotoxylin and Eosin (H&E) staining (n=3); andn Evans Blue (EB) staining to assess BBB permeability (n=9). We found the volume of the penumbra to be larger and better delineated on MRI and histology in the acute compared to the subacute and chronic stages. The lesion was smaller in volume and increased over time following same time trajectory. The BBB was most compromised at the hyperacute stage (day 0) and decreasingly, yet persistently, disrupted to day 7. Our in vivo and ex vivo findings provide insight into the evolution of stroke and could serve as a study model to test blood-brain barrier stabilization agents in the pediatric setting.

This study aimed to explore the relationship between the systemic immune-inflammatory index (SII) and the probability of in-hospital mortality among acute ischemic stroke (AIS) with atrial fibrillation (AF) patients undergoing intravenous thrombolysis.

This single-center, retrospective observational study included individuals among AIS with AF who received intravenous thrombolysis. The SII is determined by taking the product of the platelet and neutrophil counts, followed by dividing this result by the lymphocyte count. In-hospital mortality was defined as a Modified Rankin Scale (mRS) score of 6 point. The investigation applied logistic regression models, along with subgroup, sensitivity, and receiver operating characteristic (ROC) curve analyses assessments, to explore the relationship between the SII and in-hospital mortality.

541 patients were included in this study, 50 (9.24%) of whom died during their hospital stay. Multifactorial logistic regression analyses using fully adjusted models, demonstrated that the SII is independently associated with the risk of in-hospital death. Patients with elevated SII levels experienced a significantly increased risk of in-hospital mortality, which was found to be 2.557 (95% CI: 1.154-5.665, P = 0.021) times greater compared to those with lower SII levels. Through multivariate logistic regression analyses, a notable correlation between the SII and the probability of death during hospitalization was observed across various subgroups, including individuals aged ≤75 and >75years, women, patients with persistent AF, those receiving thrombolytic therapy, diabetic and nondiabetic patients, individuals with BMI ≥24 kg/m2, and those with an admission National Institutes of Health Stroke Scale score ≤20 (P < 0.05). Two sensitivity analyses confirmed the robustness of this association from multiple perspectives (P < 0.05). ROC analysis demonstrated that the SII, the baseline model, and their combined model all showed strong predictive power for in-hospital mortality. Notably, the combined model outperformed the SII alone (P < 0.05). In addition, the predictive value of SII for in-hospital death was significantly higher than that of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).

A significant association has been observed between the risk of in-hospital death among AIS with AF individual undergoing intravenous thrombolysis and the SII.

The activation of microglia and the resulting neuroinflammation play crucial regulatory roles in the pathogenesis and progression of neurological diseases, although the specific mechanisms remain incompletely understood. Cytidine monophosphate kinase 2 (CMPK2) is a key mitochondrial nucleotide kinase involved in cellular energy metabolism and nucleotide synthesis. Recent studies suggest that CMPK2 plays a role in microglial-mediated neuroinflammation; however, its specific impact on microglial activation remains unclear. In this study, we hypothesize that CMPK2 promotes microglial-mediated neuroinflammation by activating the cGAS-STING signaling pathway. To investigate this mechanism, we employed lipopolysaccharide (LPS)-treated microglial cells to investigate the detailed mechanisms by which CMPK2 regulates neuroinflammation. Our experimental results indicate that in the BV2 and mouse primary microglial neuroinflammation model, both CMPK2 protein and transcript levels were significantly elevated, accompanied by microglial activation phenotypes such as increased cell size, shortened processes, transformation to round or rod-like shapes, and elevated CD40 expression. Concurrently, there was an increase in pro-inflammatory cytokine levels and a decrease in anti-inflammatory cytokine levels. Further investigation revealed that in the microglial, the expression of cGAS and STING was elevated, along with an increase in oxidative products and inflammatory responses. CMA stimulation further intensified these changes, while cGAS knockdown mitigated them. Finally, we demonstrated that cGAS knockdown inhibited the oxidative stress, cell activation-related changes, and neuroinflammatory responses induced by CMPK2 overexpression in the BV2 neuroinflammation model. Molecular docking experiments showed that CMPK2 stably binds to cGAS at the protein level. These findings suggest that the cGAS-STING pathway mediates CMPK2-induced microglial activation. In summary, our study demonstrates that LPS-induced CMPK2 overactivity promotes microglial activation and neuroinflammatory through the cGAS-STING pathway.

Mitochondria play a critical role in oxidative stress (OS)-induced neuronal injury during ischemic stroke (IS), making them promising therapeutic targets. Mounting evidence underscores the extraordinary therapeutic promise of exosomes derived from human neural stem cells (hNSCs) in the management of central nervous system (CNS) diseases. Nonetheless, the precise mechanisms by which these exosomes target mitochondria to ameliorate the effects of IS remain only partially elucidated. This study investigates the protective effects of hNSC derived exosomes (hNSC-Exos) on neuronal damage.

Using a rat model of middle cerebral artery occlusion (MCAO) in vivo and OS-induced HT22 cells in vitro. Firstly, our research group independently isolated human neural stem cells (hNSCs) and subsequently prepared hNSC-Exos. In vivo, MCAO rats were restored to blood flow perfusion to simulate ischemia-reperfusion injury, and hNSC-Exos were injected through stereotaxic injection into the brain. Subsequently, the protective effects of hNSC-Exos on MCAO rats were evaluated, including histological studies, behavioral assessments. In vivo, H2O2 was used in HT22 cells to simulate the OS environment in MCAO, and then its protective effects on HT22 were evaluated by co-culturing with hNSC-Exos, including immunofluorescence staining, western blotting (WB), quantitative real time PCR (qRT-PCR). In the process of exploring specific mechanisms, we utilized RNA sequencing (RNA-seq) to detect the potential induction of mitophagy in OS-induced HT22 cells. Afterwards, we employed a series of mitochondrial function assessments and autophagy related detection techniques, including measuring mitochondrial membrane potential, reactive oxygen species (ROS) levels, transmission electron microscopy (TEM) imaging, monodansylcadaverine (MDC) staining, and mCherry-GFP-LC3B staining. In addition, we further investigated the regulatory pathway of hNSC-Exos by using autophagy inhibitor mdivi-1 and knocking out PTEN induced kinase 1 (PINK1) in HT22 cells.

Administration of hNSC-Exos significantly ameliorated brain tissue damage and enhanced behavioral outcomes in MCAO rats. This treatment led to a reduction in brain tissue apoptosis and facilitated the normalization of impaired neurogenesis and neuroplasticity. Notably, the application of hNSC-Exos in vitro resulted in an upregulation of mitophagy in HT22 cells, thereby remedying mitochondrial dysfunction. We demonstrate that hNSC-Exos activate mitophagy via the PINK1/Parkin pathway, improving mitochondrial function and reducing neuronal apoptosis.

These findings suggest that hNSC-Exos alleviate OS-induced neuronal damage by regulating the PINK1/Parkin pathway. These reveals a novel role of stem cell-derived mitochondrial therapy in promoting neuroprotection and suggest their potential as a therapeutic approach for OS-associated CNS diseases, including IS.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe neurological disorder caused by impaired cerebral blood flow and brain hypoxia, resulting in high morbidity and mortality rates. While therapeutic hypothermia remains the standard treatment and has been shown to reduce mortality to some extent, its therapeutic efficacy is limited, and it applies only to a select group of neonates who meet stringent inclusion criteria. Advances in our understanding of the pathophysiology of HIE have led to the identification of several promising neuroprotective strategies designed to mitigate or prevent the neurological damage induced by hypoxia-ischemia. Among these, preconditioning has emerged as a potent neuroprotective approach, enhancing cellular resilience to subsequent injury and potentially reducing treatment complexity and healthcare costs. Preconditioning/pretreatment and posttreatment offer significant promise in attenuating the neurological damage associated with HIE. Thus, exploring early intervention strategies for neonatal HIE, focusing on the comparative mechanisms and therapeutic targets of preconditioning and postconditioning, is critical to developing more effective treatment modalities. This review summarizes the current understanding of the pathophysiological mechanisms underlying neonatal HIE and its prevention and treatment strategies, providing new perspectives and a theoretical foundation for future neuroprotective interventions.

It has been validated that folic acid deficiency (FD) is associated with an increased risk of stroke and a worse prognosis. However, the specific mechanisms by which FD exerts its detrimental effects on ischemic stroke (IS) have not been fully understood. The results of this case-control study indicated that patients with IS had a decreased serum folate level, along with up-regulated long non-coding RNA H19 (lncRNA H19) and enhanced inflammatory responses. Meanwhile, it was corroborated that the serum folate level was negatively correlated with H19 expression and the systemic immune-inflammation index (SII). Similarly, FD was demonstrated to exacerbate neurological injury in the middle cerebral artery occlusion/reperfusion (MCAO/R) rats by up-regulating the expression of inflammatory cytokines and H19 in both peripheral blood and brain tissue. Notably, the alterations in the expression of these factors in peripheral blood were consistent with those observed in brain tissue. Additionally, in a co-culture of N2a neurons and BV2 microglia, FD promoted the transition of BV2 cells towards a pro-inflammatory state by up-regulating the expression of H19, which aggravated neuronal injury. Moreover, blocking H19 in BV2 cells mitigated inflammation and partially reversed the injury in N2a cells exacerbated by FD after the treatment with oxygen-glucose deprivation and reperfusion (OGD/R). These findings provide a more in-depth insight into the regulatory role of H19-mediated systemic inflammatory responses in the context of FD, suggesting the potential clinical utility of folic acid in managing ischemic brain injury.

Stroke is closely linked to inflammation, with the neutrophil-to-lymphocyte ratio (NLR) emerging as a promising inflammatory marker. This study aims to investigate the association between NLR and both morbidity and mortality in stroke patients.

Data from the National Health and Nutrition Examination Survey (NHANES) 1999-2020 were analyzed, including adults with complete neutrophil and lymphocyte count records. Multivariate logistic regression was used to examine the relationship between NLR and both stroke morbidity and all-cause mortality. Restricted cubic spline regression was employed to assess potential nonlinearity in these associations. Subgroup analyses were performed to identify influencing factors.

After adjusting for confounders, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for stroke in the higher NLR quartiles, compared to the lowest quartile, were 1.28 (1.07-1.52) and 1.36 (1.12-1.65), respectively. The restricted cubic spline curve indicated a nonlinear positive association between NLR and stroke risk. Additionally, an elevated NLR was positively associated with an increased risk of all-cause mortality.

The findings underscore the potential use of NLR in stratifying and predicting mortality risk in stroke patients, suggesting its relevance in clinical practice.

Neonatal hypoxic-ischemic brain injury (HIBI) can lead to white matter damage, which significantly contributes to cognitive dysfunction, emotional disorders, and sensorimotor impairments. Although dexmedetomidine enhances neurobehavioral outcomes, its impact on oligodendrocyte genesis and myelination following hypoxic-ischemic events, as well as the underlying mechanisms, remain poorly understood. Dexmedetomidine was administered 15 min post-HIBI. We assessed neurobehavioral deficits using various tests: surface righting, negative geotaxis, forelimb grip strength, cliff avoidance, sensory reflexes, novel object recognition, T-maze, and three-chamber social interaction. We also investigated the relationship between myelination and neurobehavioral outcomes. Measurements included oligodendrocyte precursor cell (OPC) proliferation and survival 24 h post-injury, early myelination, and oligodendrocyte differentiation by postnatal day 14. Furthermore, we evaluated microglial activation towards the M2 phenotype and the extent of neuroinflammation during the acute phase. Dexmedetomidine significantly ameliorated long-term neurological deficits caused by HIBI. Pearson linear regression analysis revealed a strong correlation between long-term neurological outcomes and myelin maturity. The treatment notably mitigated the long-term deterioration of myelin formation and maturation following HIBI. This protective effect was primarily due to enhanced OPC proliferation and survival post-HIBI during the acute phase and, to a lesser extent, to the modulation of microglial activity towards the M2 phenotype and a reduction in neuroinflammation. Dexmedetomidine offers substantial protection against long-term neurobehavioral disabilities induced by HIBI, primarily by revitalizing the impaired survival and maturation of oligodendrocyte progenitor cells and promoting myelination.

Mitochondrial dysfunction is a known contributor to subarachnoid haemorrhage (SAH) induced early brain damage (EBI), leading to poor neurological outcomes. An experimental SAH model was induced in adult male Wistar rats using endovascular perforation. Donepezil, an acetylcholinesterase (AChE) inhibitor (1 or 2 mg/kg body weight), was administered intraperitoneally 4 h after SAH. The severity of cerebral cortex injury was assessed using blood clot grading, behavioral tests and H and E staining. We carried out an assessment of neuroinflammatory markers using western blotting and immunofluorescence. Additionally, we examined neuronal architecture using H and E staining, measured mitochondrial redox imbalance or ROS and membrane potential (Δѱm) and analyzed mitochondrial morphology using transmission electron microscopy (TEM). Apoptotic markers and mitochondrial respiratory complexes were assessed by western blotting. Our results indicated that donepezil treatment significantly upregulated PSD95, α7-AChR, CaMKII, BDNF, CREB, and PI3K expression in cerebral cortical neurons in response to SAH. This was accompanied by improved neurological function, reduced brain edema, decreased neuronal degeneration, and increased levels of OXPHOS and ATP. In the cerebral cortex, donepezil inhibited mitochondria-associated neuronal apoptosis after SAH as revealed by increased membrane potential integrity of mitochondria, reducing the ratio of Bax to Bcl-2 and inhibiting caspase-3 activity. Additionally, donepezil upregulated synaptic proteins (PSD95), strengthening synaptic connections and supporting spatial working memory circuits via the neurotrophic factor BDNF in post-SAH rats. Our research concludes that donepezil has neuroprotective benefits by inhibiting SAH-induced mitochondrial-mediated cell death through the regulation of Drp1-mediated mitochondrial morphology changes.

Flap transplantation is a critical part of the recovery process for patients who have undergone tumor resection. However, the process of ischemia-reperfusion injury during flap transplantation and the resulting high-risk thrombotic microenvironment are unavoidable. In this study, based on an in-depth investigation of the ischemia time and prognosis of transplanted flaps, we propose a treatment strategy using sequential thrombolysis and ischemia-reperfusion injury prevention tailored to the ischemia time. This approach is designed to minimize the likelihood of thrombus formation and to clear the intravascular inflammatory microenvironment, with the aim of preventing and salvaging ischemic flaps. Specifically, we have successfully constructed a clinical-grade bionic vesicle, UK-PBNZ@PM, a system that cleverly incorporates drug components that have been widely used in clinical applications, thereby demonstrating a high degree of clinical translational potential. Prussian blue nano-enzymes (PBNZ) are the core component and demonstrate remarkable efficacy against ischemia-reperfusion injury due to their excellent biocompatibility, robust reactive oxygen species (ROS) scavenging capacity and anti-inflammatory properties. At the same time, urokinase (UK), a key pharmaceutical agent in antithrombotic therapy, has been effectively incorporated into the system, enhancing its ability to prevent and treat thrombosis. In addition, the integration of a platelet membrane (PM) has endowed the bionic vesicles with precise targeting and delivery capabilities, ensuring that the drugs can reach the lesion directly and facilitate efficient and precise release. The experimental results demonstrated that an ischemia-timed strategy can not only efficiently promote thrombolysis, but also effectively remove harmful elements in the microenvironment of ischemia-reperfusion injury. This discovery represents a new and promising approach to the treatment of thrombosis.

Ischemic stroke is a complex disease with high mortality and disability rates. Ischemia-reperfusion injury is a common aftermath. There have been significant advancements in understanding ischemia-reperfusion injury in ischemic stroke over the past two decades. This study aims to evaluate the current state of ischemia-reperfusion injury in ischemic stroke through bibliometric analysis, identifying key research areas and emerging trends.

Relevant documents in the Web of Science Core Collection, SCI-Expanded from January 1, 2003, to December 31, 2023, were downloaded on July 10, 2024. Bibliometric analysis was performed using HistCite, VOSviewer, CiteSpace, and Bibliometrics online analysis platform.

A total of 2179 research papers from 611 journals in 66 countries were included in this study. Among these papers, China emerged as the leading contributor of ischemia-reperfusion injury in ischemic stroke publications, with Capital Medical University standing out as the institution with the highest number of publications in this area. Y. Zhang was identified as the author with the most publications during the study period. Brain Research was found to be the most prolific journal for this research. The keywords "ferroptosis", "circular RNA", "polarization", and "fatty acid binding protein" represent the current hot spots of ischemia-reperfusion injury in ischemic stroke research.

This bibliometric analysis offers the first thorough overview of hot spots and research trends in ischemia-reperfusion injury in ischemic stroke over the previous 21 years, providing researchers with new ideas in the field. "ferroptosis", "circular RNA", "polarization", and "fatty acid binding protein" may be the focus of future studies.

Within the last decade, several studies have explored whether there might be a genetic component in hypoxic-ischaemic encephalopathy (HIE) that influences susceptibility to or outcomes following hypoxic-ischaemic injury. This review provides a comprehensive overview of the findings to date from published studies investigating the genetics of HIE. It also highlights some of the challenges faced by researchers, as well as recommendations for future research.

The systemic immune-inflammation index (SII) has been proven to predict the outcome in cancerous and non-cancerous diseases. We aimed to investigate the relationship between SII and other inflammatory markers and the prognosis in patients receiving intravenous thrombolysis (IVT).

Acute ischemic stroke patients treated with IVT were collected retrospectively. SII, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were constructed based on admission blood testing. Favorable outcome was defined as modified Rankin Scale of less than or equal to 2 at 90 days. In addition to outcome, cerebral edema was analyzed. The severity of brain edema was graded into three levels according to Thrombolysis in Stroke-Monitoring Study. Malignant cerebral edema (MCE) was defined as brain edema with midline shift.

278 patients were included. 140 (50.4%) achieved favorable outcome, 35 (12.6%) developed MCE. In patients with favorable outcomes, the levels of SII, NLR and PLR were lower compared to those with unfavorable outcomes [422.33 (258.69-624.68) vs 1269.83 (750.82-2497.22), p < 0.001; 2.73 (1.68-4.40) vs 4.76 (2.59-7.72), p < 0.001; 92.98 (62.35-126.24) vs 115.64 (85.51-179.04), p < 0.001]. The area under the Receiver Operating Characteristic curve was 0.698 for SII (95% CI = 0.637-0.760, p < 0.001), 0.694 for NLR (95% CI = 0.632-0.756, p < 0.001), 0.643 for PLR (95% CI = 0.579-0.707, p < 0.001). The optimal cut-off values were 652.73 for SII (sensitivity 0.572, specificity 0.786), 3.57 for NLR (sensitivity 0.659, specificity 0.693), 127.01 for PLR (sensitivity 0.457, specificity 0.757).

An early increase in SII levels was related to 3 months of unfavorable outcomes in AIS patients after IVT. However, it is not associated with malignant edema.

This article reviews the research progress on the direct regulation of the immune system by the central nervous system (CNS). The traditional "neuro-endocrine-immune" network model has confirmed the close connection between the CNS and the immune system. However, due to the complex mediating role of the endocrine system, its application in clinical treatment is limited. In recent years, the direct regulation of the peripheral immune system through the CNS has provided new methods for the clinical treatment of neuroimmune-related diseases. This article analyzes the changes in the peripheral immune system after CNS injury and summarizes the effects of various stimulation methods, including transcranial magnetic stimulation, transcranial electrical stimulation, deep brain stimulation, spinal cord stimulation, and vagus nerve stimulation, on the peripheral immune system. Additionally, it explores the clinical research progress and future development directions of these stimulation methods. It is proposed that these neural regulation techniques exhibit positive effects in reducing peripheral inflammation, protecting immune cells and organ functions, and improving immunosuppressive states, providing new perspectives and therapeutic potential for the treatment of immune-related diseases.

Acute brain injuries (ABI) caused by various emergencies can lead to structural and functional damage to brain tissue. Common causes include traumatic brain injury, cerebral hemorrhage, ischemic stroke, and heat stroke. Globally, ABI represent a significant portion of neurosurgical cases. Previous studies have emphasized the significant therapeutic potential of stem cell-derived extracellular vesicles (EVs). Recent research indicates that EVs extracted from resident cells in the central nervous system (CNS) also show therapeutic potential following brain injury. Microglia, as innate immune cells of the CNS, respond to changes in the internal environment by altering their phenotype and secreting EVs that impact various CNS cells, including neurons, astrocytes, oligodendrocytes, endothelial cells, neural stem cells (NSCs), and microglia themselves. Notably, under different external stimuli, microglia can either promote neuronal survival, angiogenesis, and myelin regeneration while reducing glial scarring and inflammation, or they can exert opposite effects. This review summarizes and evaluates the current research findings on how microglia-derived EVs influence various CNS cells after ABI under different external stimuli. It analyzes the interaction mechanisms between EVs and resident CNS cells and discusses potential future research directions and clinical applications.

Background: Predicting mortality in patients with acute ischemic stroke who need endovascular treatment (EVT) has previously been shown to be related to inflammation. In this study, we aimed to examine the effects of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and hypersensitive C-reactive protein-to-albumin ratio (CAR) values on mortality and hemorrhagic transformation. Methods: A total of 225 adult patients who underwent EVT between 2022 and 2024 were retrospectively analyzed. The presence of intracranial hemorrhage (ICH) after the procedure; good and poor clinical outcomes according to modified Rankin Scores; mortality status; and NLR, PLR, and CAR values were collected. Results: The average age of the patients was 66.95 ± 12.74 years, and 133 (59.1%) patients were male. Thirty-eight (30.4%) patients had symptomatic ICH. While 164 (72.9%) patients had a poor outcome, 80 (35.6%) patients died. There was a correlation between the NLR and PLR values and symptomatic ICH (p = 0.013, 0.009, respectively) in the univariate analysis, but this relationship was not found in the multivariate analyses (p: 0.212 and p: 0.459). No statistically significant relationship was observed between the CAR and symptomatic ICH and mortality (p = 0.784, 0.079, respectively). When the laboratory data were compared according to the mortality status, the NLR and PLR were observed to be statistically significantly higher in the patients with mortality (p < 0.001, 0.005, respectively) in univariate analyses. But, as a result, the NLR, PLR, and CAR were not associated with ICH and mortality according to the multivariable logistic regression analysis. Conclusions: Our findings highlight the need to better understand the post-stroke immune response. Our study demonstrated that the NLR, PLR, and CAR were not associated with ICH and mortality according to the multivariable logistic regression analysis.

Neutrophil extracellular traps (NETs) are increasingly recognized for their involvement in ischemic stroke (IS), yet their precise contribution to IS outcomes is not fully understood. This study aims to elucidate the role of NETs in IS progression and identify potential biomarkers and therapeutic targets. In this study, mice were subjected to middle cerebral artery occlusion (MCAO). RNA sequencing was conducted on brain tissue samples to identify differentially expressed genes (DEGs) using the "limma" package. The diagnostic potential of these biomarkers was assessed using receiver operating characteristic (ROC) curve analysis. Additionally, single-cell RNA sequencing data were analyzed with the Seurat package to further investigate the cellular dynamics. We identified DEGs, and NETs-related genes associated with IS progression. Specifically, Ceacam3, Tnf, Selp, and Fcgr4 were found to be upregulated in MCAO samples, exhibiting diagnostic value as biomarkers for IS. Immune infiltration analysis indicated associations between these genes and various immune cell types. Gene Set Enrichment Analysis (GSEA) revealed their involvement in IS-related pathways, including ferroptosis, IL-17 signaling, leukocyte transendothelial migration, necroptosis, and NETs formation. Single-cell data confirmed the expression of Tnf, Selp, and Fcgr4 in neutrophils. CellChat analysis uncovered key cell-cell interactions in IS, emphasizing the role of neutrophils in communicating with microglia and T cells via the JAM pathway, with Thbs1 and Cd47 as key mediators. The findings provide insights into the cellular and molecular mechanisms underlying IS and may pave the way for novel therapeutic strategies targeting NETs in IS patients.

Oxidative damage induced by glutamate triggers neuronal death in cerebral ischemic/reperfusion injury. BTB and CNC homology 1 (BACH1) is a major link between the cellular heme level, the redox state and the transcriptional response. p-Coumaric acid (p-CA) is a natural antioxidant that has been shown to ameliorate ischemic/reperfusion injury. In this study, we investigated whether and how p-CA regulated BACH1 in ischemic/reperfusion injury from the perspective of BACH1 subcellular localization and function. Middle cerebral artery occlusion (MCAO) model was established in male mice. MCAO mice were treated with p-CA (50, 100 mg/kg, ip) twice 5 min after MCAO and 5 h after reperfusion operation, respectively. We showed that p-CA treatment exerted dramatic neuroprotective effects, which were associated with the inhibition of BACH1. In HT22 cells, treatment with p-CA (20 μM) ameliorated OGD/R or glutamate-induced oxidative damage and mitochondrial dysfunction through decreasing the protein level of BACH1, the beneficial effect of p-CA was blocked by BACH1 overexpression. We demonstrated that BACH1 level was markedly elevated in the nucleus of HT22 cells under glutamate stimulation, and transcriptionally regulated NADPH oxidase 4 (NOX4) expression, thus mediating ROS outbreak. p-CA treatment activated the activated Cdc42-associated kinase 1 (ACK1)/protein kinase B (AKT) cascade to facilitate the phosphorylation of BACH1, augmented its interaction with chromosome region maintenance 1 (CRM1), thereby leading to the export of BACH1 from the nucleus and degradation mediated by heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1). In accord with this, administration of ACK1 inhibitor AIM-100 (20 mg/kg, ip) 5 min after MCAO significantly attenuated the neuroprotective effects of p-CA in MCAO mice. We concluded that ACK1/AKT/BACH1 axis may serve as a promising therapeutic approach for the management of ischemic stroke, thereby broadening the clinical utility of p-CA.Keywords: ischemic/reperfusion injury; p-Coumaric acid; BACH1; NOX4; ACK1/AKT; AIM-100.

Glucagon-like peptide-1 (GLP-1) receptor is widely distributed in the digestive system, cardiovascular system, adipose tissue and central nervous system. Numerous GLP-1 receptor-targeting drugs have been investigated in clinical studies for various indications, including type 2 diabetes and obesity (accounts for 70% of the total studies), non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease. This review presented fundamental information regarding two categories of GLP-1 receptor agonists (GLP-1RAs): peptide-based and small molecule compounds, and elaborated their potential neuroprotective effects by inhibiting neuroinflammation, reducing neuronal apoptosis, and ultimately improving cognitive function in various neurodegenerative diseases. As a new hypoglycemic drug, GLP-1RA has a unique role in reducing the concurrent risk of stroke in T2D patients. Given the infiltration of various peripheral immune cells into brain tissue, particularly in the areas surrounding the infarct lesion, we further investigated the potential immune regulatory mechanisms. GLP-1RA could not only facilitate the M2 polarization of microglia through both direct and indirect pathways, but also modulate the quantity and function of T cell subtypes, including CD4, CD8, and regulatory T cells, resulting into the inhibition of inflammatory responses and the promotion of neuronal regeneration through interleukin-10 secretion. Therefore, we believe that the "Tregs-microglia-neuron/neural precursor cells" axis is instrumental in mediating immune suppression and neuroprotection in the context of ischemic stroke. Given the benefits of rapid diffusion, favorable blood-brain barrier permeability and versatile administration routes, these small molecule compounds will be one of the important candidates of GLP-1RA. We look forward to the further clinical evidence of small molecule GLP-1RA intervention in ischemic stroke or T2D complicated by ischemic stroke.

The inflammatory response plays a central role in the clinical outcomes of cerebrovascular disease. The aim of this study was to investigate the clinical significance of pan-immune-inflammation value (PIV) in patients with acute ischemic stroke after mechanical thrombectomy (MT).

The study included 201 patients who underwent MT. Blood samples taken from the patients before the procedure were evaluated and inflammation markers were calculated. Severity of stroke was assessed using the National Institute of Health Stroke Scale (NIHSS) scores on admission. Poor 3-month functional outcome was defined as Modified Rankin Scale (mRS) scores of >2. Ischemic stroke types were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification RESULTS: In the logistic regression analysis, we observed that PIV was associated with a poor outcome. Post hoc multiple comparison tests revealed statistically significant differences in PIV between the stroke of other determined etiology and small-vessel occlusion (178.00 vs. 74.89, p = 0.015 and p < 0.05, respectively), large artery atherosclerosis (178.00 vs. 95.51, p = 0.032 and p < 0.05, respectively), and cardioembolism (178.00 vs.107.97, p = 0.043 and p < 0.05) subtypes. There was a moderate positive statistically significant relationship at the 95% confidence level between NIHSS score and PIV (r = 0.696, p < 0.05).

Our study revealed that PIV predicts a poor 3-month prognosis in acute ischemic cerebrovascular disease after MT with a significantly better performance than the widely known systemic immune-inflammation index, systemic inflammation response index, platelet/lymphocyte ratio, and neutrophil/lymphocyte ratio. PIV can be a novel prognostic marker indicating poor prognosis in patients treated with MT.

Ischemic stroke is a prevalent clinical condition that poses a significant global challenge. Developing innovative strategies to address this issue is crucial. Annexin A1 (ANXA1), a key member of the annexin superfamily, performs various functions, such as inhibiting inflammatory factor release, promoting phagocytosis, and blocking leukocyte migration. Evidence indicates that ANXA1 plays a pivotal role in the pathogenesis of ischemic stroke. The present article reviews involvement of ANXA1 in anti‑atherosclerosis, inflammatory processes, blood‑brain barrier protection, platelet aggregation and anti‑apoptotic mechanisms. The potential applications of ANXA1 in treating ischemic stroke are also explored.

The relationship between ischemic stroke (IS) and pyroptosis centers on the inflammatory response elicited by cerebral tissue damage during an ischemic stroke event. However, an in-depth mechanistic understanding of their connection remains limited. This study aims to comprehensively analyze the gene expression patterns of pyroptosis-related differentially expressed genes (PRDEGs) by employing integrated IS datasets and machine learning techniques. The primary objective was to develop classification models to identify crucial PRDEGs integral to the ischemic stroke process. Leveraging three distinct machine learning algorithms (LASSO, Random Forest, and Support Vector Machine), models were developed to differentiate between the Control and the IS patient samples. Through this approach, a core set of 10 PRDEGs consistently emerged as significant across all three machine learning models. Subsequent analysis of these genes yielded significant insights into their functional relevance and potential therapeutic approaches. In conclusion, this investigation underscores the pivotal role of pyroptosis pathways in ischemic stroke and identifies pertinent targets for therapeutic development and drug repurposing.

Ischemic stroke is a prevalent global condition and its associated brain damage poses a significant threat to patient survival and outcomes. The underlying mechanisms of ischemic stroke-induced brain injury remain elusive, necessitating further investigation.

Ischemic stroke models were established using middle cerebral artery occlusion (MCAO) in animals and oxygen-glucose deprivation and reperfusion (OGD-R) in cells. Phospholipase B domain-containing protein 1 (PLBD1) expression in these models was assessed via western blotting analysis, reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), and cell immunofluorescence. A comprehensive evaluation, incorporating cellular lactate dehydrogenase (LDH) release assays, glycolysis metabolism kits, RT-qPCR, western blotting, triphenyl tetrazolium chloride (TTC) staining, neurological scoring, brain tissue water content measurement, and creatine kinase-MB (CK-MB) analysis, was conducted to determine the impact of PLBD1 on brain injury. Potential lactylation sites in PLBD1 were predicted using the DeepKla database, with western blotting and co-immunoprecipitation (Co-IP) confirming the lactylation site.

PLBD1 was significantly upregulated in the brain tissue of MCAO animal models and OGD-R-treated cells. PLBD1 knockdown markedly mitigated OGD-R-induced cellular injury, suppressed glycolysis in vitro, and reversed MCAO-induced brain damage in vivo. Furthermore, lactylation at the K155 site of PLBD1 enhanced its expression in response to elevated lactate levels following OGD-R treatment. These results indicated that the upregulation of PLBD1 via K155 site lactylation plays a pivotal role in exacerbating ischemic stroke-induced brain damage.

Targeting the lactate/PLBD1 axis presents a promising therapeutic strategy for ischemic stroke management.

Background/Objectives: Cerebrovascular events (CVEs) are a leading cause of intensive care unit (ICU) admissions from the emergency department, often associated with high morbidity and mortality rates. Identifying reliable, non-invasive predictors of mortality in these patients is critical for improving prognostic accuracy and guiding therapeutic strategies. This retrospective cohort study evaluates the predictive value of the optic nerve sheath diameter (ONSD), measured using magnetic resonance imaging (MRI), in determining mortality among ICU patients with CVEs. Methods: This single-center, retrospective observational study included 102 patients diagnosed with CVEs and admitted to the ICU at Gaziantep City Hospital between October 2023 and March 2024. This study adhered to the Declaration of Helsinki. Ethics approval was obtained from Gaziantep Islam Science and Technology University (Decision No. 394.36.08), and the requirement for informed consent was waived due to the retrospective design. The sample size was determined using G-Power 3.1.9.4. Results: A statistically significant positive correlation was observed between the ONSD and mortality (p = 0.002). Patients with higher ONSD values demonstrated an increased mortality risk, underscoring the potential prognostic value of ONSD measurements in this population. Conclusions: MRI-based ONSD measurement offers a non-invasive method for predicting mortality in ICU patients with CVEs. Its integration into routine diagnostic protocols could enhance clinical decision-making and patient outcomes. Further multicenter studies are warranted to validate these findings and standardize ONSD measurement techniques.