Modulating the RPS27A/PSMD12/NF-κB pathway to control immune response in mouse brain ischemia-reperfusion injury.

BACKGROUND: Investigating immune cell infiltration in the brain post-ischemia-reperfusion (I/R) injury is crucial for understanding and managing the resultant inflammatory responses. This study aims to unravel the role of the RPS27A-mediated PSMD12/NF-κB axis in controlling immune cell infiltration in the context of cerebral I/R injury. METHODS: To identify genes associated with cerebral I/R injury, high-throughput sequencing was employed. The potential downstream genes were further analyzed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) analyses. For experimental models, primary microglia and neurons were extracted from the cortical tissues of mouse brains. An in vitro cerebral I/R injury model was established in microglia using the oxygen-glucose deprivation/reoxygenation (OGD/R) technique. In vivo models involved inducing cerebral I/R injury in mice through the middle cerebral artery occlusion (MCAO) method. These models were used to assess neurological function, immune cell infiltration, and inflammatory factor release. RESULTS: The study identified RPS27A as a key player in cerebral I/R injury, with PSMD12 likely acting as its downstream regulator. Silencing RPS27A in OGD/R-induced microglia decreased the release of inflammatory factors and reduced neuron apoptosis. Additionally, RPS27A silencing in cerebral cortex tissues mediated the PSMD12/NF-κB axis, resulting in decreased inflammatory factor release, reduced neutrophil infiltration, and improved cerebral injury outcomes in I/R-injured mice. CONCLUSION: RPS27A regulates the expression of the PSMD12/NF-κB signaling axis, leading to the induction of inflammatory factors in microglial cells, promoting immune cell infiltration in brain tissue, and exacerbating brain damage in I/R mice. This study introduces novel insights and theoretical foundations for the treatment of nerve damage caused by I/R, suggesting that targeting the RPS27A and downstream PSMD12/NF-κB signaling axis for drug development could represent a new direction in I/R therapy.

Neutrophil migration participates in the side effect of recombinant human tissue plasminogen activator.

AIMS: Ischemic stroke remains a challenge in medical research because of the limited treatment options. Recombinant human tissue plasminogen activator (rtPA) is the primary treatment for recanalization. However, nearly 50% of the patients experience complications that result in ineffective reperfusion. The precise factors contributing to ineffective reperfusion remain unclear; however, recent studies have suggested that immune cells, notably neutrophils, may influence the outcome of rtPA thrombolysis via mechanisms such as the formation of neutrophil extracellular traps. This study aimed to explore the nonthrombolytic effects of rtPA on neutrophils and highlight their contribution to ineffective reperfusion. METHODS: We evaluated the effects of rtPA treatment on middle cerebral artery occlusion in rats. We also assessed neutrophil infiltration and activation after rtPA treatment in vitro and in vivo in a small cohort of patients with massive cerebral ischemia (MCI). RESULTS: rtPA increased neutrophil infiltration into the brain microvessels and worsened blood-brain barrier damage during ischemia. It also increased the neutrophil counts of the patients with MCI. CONCLUSION: Neutrophils play a crucial role in promoting ischemic injury and blood-brain barrier disruption, making them potential therapeutic targets.

Identification of key genes and immune infiltration in peripheral blood biomarker analysis of delayed cerebral ischemia: Valproic acid as a potential therapeutic drug.

BACKGROUND: Delayed cerebral ischemia (DCI) is a common and serious complication of subarachnoid hemorrhage (SAH). Its pathogenesis is not fully understood. Here, we developed a predictive model based on peripheral blood biomarkers and validated the model using several bioinformatic multi-analysis methods. METHODS: Six datasets were obtained from the GEO database. Characteristic genes were screened using weighted correlation network analysis (WGCNA) and differentially expressed genes. Three machine learning algorithms, elastic networks-LASSO, support vector machines (SVM-RFE) and random forests (RF), were also used to construct diagnostic prediction models for key genes. To further evaluate the performance and predictive value of the diagnostic models, nomogram model were constructed, and the clinical value of the models was assessed using Decision Curve Analysis (DCA), Area Under the Check Curve (AUC), Clinical Impact Curve (CIC), and validated in the mouse single-cell RNA-seq dataset. Mendelian randomization(MR) analysis explored the causal relationship between SAH and stroke, and the intermediate influencing factors. We validated this by retrospectively analyzing the qPCR levels of the most relevant genes in SAH and SAH-DCI patients. This experiment demonstrated a statistically significant difference between SAH and SAH-DCI and normal group controls. Finally, potential small molecule compounds interacting with the selected features were screened from the Comparative Toxicogenomics Database (CTD). RESULTS: The fGSEA results showed that activation of Toll-like receptor signaling and leukocyte transendothelial cell migration pathways were positively correlated with the DCI phenotype, whereas cytokine signaling pathways and natural killer cell-mediated cytotoxicity were negatively correlated. Consensus feature selection of DEG genes using WGCNA and three machine learning algorithms resulted in the identification of six genes (SPOCK2, TRRAP, CIB1, BCL11B, PDZD8 and LAT), which were used to predict DCI diagnosis with high accuracy. Three external datasets and the mouse single-cell dataset showed high accuracy of the diagnostic model, in addition to high performance and predictive value of the diagnostic model in DCA and CIC. MR analysis looked at stroke after SAH independent of SAH, but associated with multiple intermediate factors including Hypertensive diseases, Total triglycerides levels in medium HDL and Platelet count. qPCR confirmed that significant differences in DCI signature genes were observed between the SAH and SAH-DCI groups. Finally, valproic acid became a potential therapeutic agent for DCI based on the results of target prediction and molecular docking of the characterized genes. CONCLUSION: This diagnostic model can identify SAH patients at high risk for DCI and may provide potential mechanisms and therapeutic targets for DCI. Valproic acid may be an important future drug for the treatment of DCI.

Research progress on immune-related therapeutic targets of brain injury caused by cerebral ischemia.

Stroke is the second leading cause of death worldwide and a leading cause of disability. The innate immune response occurs immediately after cerebral ischemia, resulting in adaptive immunity. More and more experimental evidence has proved that the immune response caused by cerebral ischemia plays an important role in early brain injury and later the recovery of brain injury. Innate immune cells and adaptive cells promote the occurrence of cerebral ischemic injury but also protect brain cells. A large number of studies have shown that cytokines and immune-related substances also have dual functions of promoting injury, reducing injury, or promoting injury recovery in the later stage of cerebral ischemia. They can be an important target for treating cerebral ischemic recovery. Therefore, this study discussed the immune cells, cytokines, and immune-related substances with dual roles in cerebral ischemia and summarized the therapeutic targets of cerebral ischemia. To explore more effective methods to treat cerebral ischemia, promote the recovery of brain function, and improve the prognosis of patients.

Minimally invasive vagus nerve stimulation modulates mast cell degranulation via the microbiota-gut-brain axis to ameliorate blood-brain barrier and intestinal barrier damage following ischemic stroke.

Mast cells (MCs) play a significant role in various diseases, and their activation and degranulation can trigger inflammatory responses and barrier damage. Several studies have indicated that vagus nerve stimulation (VNS) exerts ameliorates neurological injury, and regulates gut MC degranulation. However, there is limited research on the modulatory effect of VNS on MCs in both the gut and brain in brain ischemia-reperfusion (I/R) injury in this process. We aim to develop a minimally invasive, targeted and convenient VNS approach to assess the impact of VNS and to clarify the relationship between VNS and MCs on the prognosis of acute ischemic stroke. We utilized middle cerebral artery occlusion/reperfusion (MCAO/r) to induce brain I/R injury. After the experiment, the motor function and neurofunctional impairments of the rats were detected, and the gastrointestinal function, blood-brain barrier (BBB) and intestinal barrier damage, and systemic and local inflammation were evaluated by Nissl, TTC staining, Evans blue, immunofluorescence staining, transmission electron microscopy, western blot assays, ELISA, and fecal 16S rRNA sequencing methods. Our research confirmed that our minimally invasive VNS method is a novel approach for stimulating the vagus nerve. VNS alleviated motor deficits and gastrointestinal dysfunction while also suppressing intestinal and neuroinflammation. Additionally, VNS ameliorated gut microbiota dysbiosis in rats. Furthermore, our analysis indicated that VNS reduces chymase secretion by modulating MCs degranulation and improves intestinal and BBB damage. Our results showed that VNS treatment can alleviate the damage of BBB and colonic barrier after cerebral I/R by modulating mast cell degranulation, and alleviates systemic inflammatory responses.

Impact of inflammatory preconditioning on murine microglial proteome response induced by focal ischemic brain injury.

Preconditioning with lipopolysaccharide (LPS) induces neuroprotection against subsequent cerebral ischemic injury, mainly involving innate immune pathways. Microglia are resident immune cells of the central nervous system (CNS) that respond early to danger signals through memory-like differential reprogramming. However, the cell-specific molecular mechanisms underlying preconditioning are not fully understood. To elucidate the distinct molecular mechanisms of preconditioning on microglia, we compared these cell-specific proteomic profiles in response to LPS preconditioning and without preconditioning and subsequent transient focal brain ischemia and reperfusion, - using an established mouse model of transient focal brain ischemia and reperfusion. A proteomic workflow, based on isolated microglia obtained from mouse brains by cell sorting and coupled to mass spectrometry for identification and quantification, was applied. Our data confirm that LPS preconditioning induces marked neuroprotection, as indicated by a significant reduction in brain infarct volume. The established brain cell separation method was suitable for obtaining an enriched microglial cell fraction for valid proteomic analysis. The results show a significant impact of LPS preconditioning on microglial proteome patterns by type I interferons, presumably driven by the interferon cluster regulator proteins signal transducer and activator of transcription1/2 (STAT1/2).

Systemic immune-inflammation index is associated with cardiac complications following acute ischemic stroke: A retrospective single-center study.

BACKGROUND: Stroke-induced heart syndrome is a feared complication of ischemic stroke, that is commonly encountered and has a strong association with unfavorable prognosis. More research is needed to explore underlying mechanisms and inform clinical decision making. This study aims to explore the relationship between the early systemic immune-inflammation (SII) index and the cardiac complications after acute ischemic stroke. METHODS: Consecutive patients with acute ischemic stroke were prospectively collected from January 2020 to August 2022 and retrospectively analyzed. We included subjects who presented within 24 hours after symptom onset and were free of detectable infections or cancer on admission. SII index [(neutrophils × platelets/ lymphocytes)/1000] was calculated from laboratory data at admission. RESULTS: A total of 121 patients were included in our study, of which 24 (19.8 %) developed cardiac complications within 14 days following acute ischemic stroke. The SII level was found higher in patients with stroke-heart syndrome (p<.001), which was an independent predictor of stroke-heart syndrome (adjusted odds ratio 5.089, p=.002). CONCLUSION: New-onset cardiovascular complications diagnosed following a stroke are very common and are associated with early SII index.

MiR-24-3p enhances the Treg/Th17 balance to improve cerebral ischemic injury by suppressing acetyl-CoA carboxylase 1 expression.

BACKGROUND: Targeting ACC1 (acetyl coenzyme A carboxylase 1) to restore the balance between T-helper 17 (Th17) cells and regulatory T cells (Tregs) through metabolic reprogramming has emerged as a promising strategy for reducing neuroinflammation following stroke. We examined the roles of potential miRNAs in regulating ACC1 expression in Tregs and treating ischemic stroke. METHODS: The expression of miR-24-3p in CD4+T cells of mice was confirmed. Then the protective effects of Ago-24-3p in a mouse model of prolonged occlusion of the distal middle cerebral artery (dMCAO) were examined. We analyzed the infiltration of Tregs and CD3+T cells into the brain and evaluated the improvement of neurological deficits induced by Ago-24-3p using the Modified Garcia Score and foot fault testing. RESULTS: Our investigation revealed that miR-24-3p specifically targets ACC1. Elevated levels of miR-24-3p have been demonstrated to increase the population of Tregs and enhance their proliferation and suppressive capabilities. Conversely, targeted reduction of ACC1 in CD4+T cells has been shown to counteract the improved functionality of Tregs induced by miR-24-3p. In a murine model of dMCAO, administration of Ago-24-3p resulted in a substantial reduction in the size of the infarct within the ischemic brain area. This effect was accompanied by an upregulation of Tregs and a downregulation of CD3+T cells in the ischemic brain region. In ACC1 conditional knockout mice, the ability of Ago-24-3p to enhance infiltrating Treg cells and diminish CD3+T cells in the ischemic brain area has been negated. Furthermore, its capacity to reduce infarct volume has been reversed. Furthermore, we demonstrated that Ago-24-3p sustained improvement in post-stroke neurological deficits for up to 4 weeks after the MCAO procedure. CONCLUSIONS: MiR-24-3p shows promise in the potential to reduce ACC1 expression, enhance the immunosuppressive activity of Tregs, and alleviate injuries caused by ischemic stroke. These discoveries imply that miR-24-3p could be a valuable therapeutic option for treating ischemic stroke.

Hyperacute immune responses associate with immediate neuropathology and motor dysfunction in large vessel occlusions.

OBJECTIVE: Despite successful endovascular therapy, a proportion of stroke patients exhibit long-term functional decline, regardless of the cortical reperfusion. Our objective was to evaluate the early activation of the adaptive immune response and its impact on neurological recovery in patients with large vessel occlusion (LVO). METHODS: Nineteen (13 females, 6 males) patients with acute LVO were enrolled in a single-arm prospective cohort study. During endovascular therapy (EVT), blood samples were collected from pre and post-occlusion, distal femoral artery, and median cubital vein (controls). Cytokines, chemokines, cellular and functional profiles were evaluated with immediate and follow-up clinical and radiographic parameters, including cognitive performance and functional recovery. RESULTS: In the hyperacute phase (within hours), adaptive immune activation was observed in the post-occlusion intra-arterial environment (post). Ischemic vascular tissue had a significant increase in T-cell-related cytokines, including IFN-γ and MMP-9, while GM-CSF, IL-17, TNF-α, IL-6, MIP-1a, and MIP-1b were decreased. Cellularity analysis revealed an increase in inflammatory IL-17+ and GM-CSF+ helper T-cells, while natural killer (NK), monocytes and B-cells were decreased. A correlation was observed between hypoperfused tissue, infarct volume, inflammatory helper, and cytotoxic T-cells. Moreover, helper and cytotoxic T-cells were also significantly increased in patients with improved motor function at 3 months. INTERPRETATION: We provide evidence of the activation of the inflammatory adaptive immune response during the hyperacute phase and the association of pro-inflammatory cytokines with greater ischemic tissue and worsening recovery after successful reperfusion. Further characterization of these immune pathways is warranted to test selective immunomodulators during the early stages of stroke rehabilitation.

Brain-associated innate leukocytes display diverse inflammatory states following experimental stroke.

Previous studies investigating innate leukocyte recruitment into the brain after cerebral ischemia have shown conflicting results. Using distinct cell surface and intracellular markers, the current study evaluated the contributions of innate immune cells to the poststroke brain following 1-h middle cerebral artery occlusion (tMCAO) or permanent MCAO (pMCAO), and assessed whether these cells ascribed to an inflammatory state. Moreover, we examined whether there is evidence for leukocyte infiltration into the contralateral (CL) hemisphere despite the absence of stroke infarct. We observed the recruitment of peripheral neutrophils, monocytes and macrophages into the hemisphere ipsilateral (IL) to the ischemic brain infarct at 24 and 96 h following both tMCAO and pMCAO. In addition, we found evidence of increased leukocyte recruitment to the CL hemisphere but to a lesser extent than the IL hemisphere after stroke. Robust production of intracellular cytokines in the innate immune cell types examined was most evident at 24 h after pMCAO. Specifically, brain-associated neutrophils, monocytes and macrophages demonstrated stroke-induced production of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1ß, while only monocytes and macrophages exhibit a significant expression of arginase 1 (Arg1) after stroke. At 96 h after stroke, brain-resident microglia demonstrated production of TNF-α and IL-1ß following both tMCAO and pMCAO. At this later timepoint, neutrophils displayed TNF-α production and brain-associated macrophages exhibited elevation of IL-1ß and Arg1 after tMCAO. Further, pMCAO induced significant expression of Arg1 and IL-1ß in monocytes and macrophages at 96 h, respectively. These results revealed that brain-associated innate immune cells display various stroke-induced inflammatory states that are dependent on the experimental stroke setting.

Differential Regulation of Microglial Activation in Response to Different Degree of Ischemia.

Microglia are primary immune cells within the brain and are rapidly activated after cerebral ischemia. The degree of microglial activation is closely associated with the severity of ischemia. However, it remains largely unclear how microglial activation is differentially regulated in response to a different degree of ischemia. In this study, we used a bilateral common carotid artery ligation (BCAL) model and induced different degrees of ischemia by varying the duration of ligation to investigate the microglial response in CX3CR1GFP/+ mice. Confocal microscopy, immunofluorescence staining, RNA sequencing, and qRT-PCR were used to evaluate the de-ramification, proliferation, and differential gene expression associated with microglial activation. Our results showed that 30 min of ischemia induced rapid de-ramification of microglia but did not have significant influence on the microglial density. In contrast, 60 min of ischemia led to a significant decrease in microglial density and more pronounced de-ramification of microglial processes. Importantly, 30 min of ischemia did not induce proliferation of microglia, but 60 min of ischemia led to a marked increase in the density of proliferative microglia. Further analysis utilized transcriptome sequencing showed that microglial activation is differentially regulated in response to different degrees of ischemia. A total of 1,097 genes were differentially regulated after 60 min of ischemia, but only 68 genes were differentially regulated after 30 min of ischemia. Pathway enrichment analysis showed that apoptosis, cell mitosis, immune receptor activity and inflammatory-related pathways were highly regulated after 60 min of ischemia compared to 30 min of ischemia. Multiple microglia-related genes such as Cxcl10, Tlr7, Cd86, Tnfrsf1a, Nfkbia, Tgfb1, Ccl2 and Il-6, were upregulated with prolonged ischemia. Pharmacological inhibition of CSF1 receptor demonstrated that CSF1R signaling pathway contributed to microglial proliferation. Together, these results suggest that the proliferation of microglia is gated by the duration of ischemia and microglia were differentially activated in responding to different degrees of ischemia.

Neutrophils predominate the immune signature of cerebral thrombi in COVID-19 stroke patients.

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis.

Varenicline improves cognitive impairment in a mouse model of mPFC ischemia: The possible roles of inflammation, apoptosis, and synaptic factors.

Ischemia in the medial prefrontal cortex (mPFC) causes cognitive impairment in stroke cases. This study aimed to examine the effects of varenicline as α7 and α4ß2 nicotine acetylcholine receptors (nAChRs) agonist, on cognitive impairment, inflammation, apoptosis, and synaptic dysfunction in mPFC ischemia. Mice were divided to three groups of control, sham, or photothrombotic mPFC ischemia model. The control and sham groups received 2 ml/kg of normal saline for a 14-day period. As well, the animals in the ischemia groups received normal saline (2 ml/kg) or varenicline at 0.1, 1, and 3 mg/kg doses for a 14-day period. Anxiety-like behaviors were then assessed by open field (OFT) and elevated plus-maze (EPM) tests. Memory was also evaluated using Morris water maze (MWM) and novel object recognition (NOR) tests. The levels of inflammatory (IL-1ß, TNF-α), apoptotic (Bax, caspase3, BCL-2), and synaptic (SYP, PSD-95, and GAP-43) proteins were examined using the western blot method. In addition, the histological evaluation was performed to assess tissue damage. The administration of Varenicline at the dose of 3 mg/kg reduced the IL-1ß, TNF-α, Bax, and caspase3 levels. Moreover, it increased BCL-2, SYP, PSD-95, and GAP-43 levels at the same dose and ameliorated memory impairment and anxiety-like behaviors in mPFC ischemic mice. Varenicline improved cognitive impairment by blocking inflammation and apoptosis, improving synaptic factors, and diminishing tissue damage in the mPFC ischemic mice.

Neuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment (Review).

Stroke is the leading cause of disabilities and cognitive deficits, accounting for 5.2% of all mortalities worldwide. Transient or permanent occlusion of cerebral vessels leads to ischemic strokes, which constitutes the majority of strokes. Ischemic strokes induce brain infarcts, along with cerebral tissue death and focal neuronal damage. The infarct size and neurological severity after ischemic stroke episodes depends on the time period since occurrence, the severity of ischemia, systemic blood pressure, vein systems and location of infarcts, amongst others. Ischemic stroke is a complex disease, and neuronal injuries after ischemic strokes have been the focus of current studies. The present review will provide a basic pathological background of ischemic stroke and cerebral infarcts. Moreover, the major mechanisms underlying ischemic stroke and neuronal injuries are summarized. This review will also briefly summarize some representative clinical trials and up­to­date treatments that have been applied to stroke and brain infarcts.

Hydrogen sulphide protects mice against the mutual aggravation of cerebral ischaemia/reperfusion injury and colitis.

This study was undertaken to determine whether ischaemia/reperfusion (I/R)-induced brain injury and dextran sulfate sodium (DSS)-induced colitis in mice are related. A cerebral I/R model of mice was established by blocking the bilateral common carotid arteries; 3% DSS in drinking water was administered to mice for 7 days to induce colitis; mice with cerebral I/R and colitis were administered DSS for 7 days from the third day onwards after acute cerebral I/R. Brain damage and intestinal inflammation were also tested. The results revealed that cerebral I/R induced brain damage and a marked increase in glial fibrillary acidic protein (GFAP) expression and upregulation of Rho-associated coiled coil-forming protein kinase (RhoA/ROCK) pathway in mouse hippocampal tissues. However, in the colon tissues of mice with colitis, we found a reduction in GFAP. In addition, the expression of endogenous hydrogen sulphide (H2S) synthase reduced in mice brain tissues with cerebral I/R injury, as well. as in mouse colon tissues with colitis. Interestingly, the cerebral I/R-induced pathological changes in mouse brain tissues were aggravated by colitis, colitis mediated colon inflammation, and pathological changes in intestinal tissues had deteriorated when the mice suffered cerebral I/R 2 days before DSS administration. However, brain injury and colon inflammation in mice suffering from both cerebral I/R and colitis were ameliorated by NaHS, an exogenous H2S donor. Furthermore, we found that NaHS promoted the transformation of astrocytes from "A1" to "A2" type. These findings reveal that cerebral I/R injury and colitis are related, the mechanism is correlated with endogenous H2S deficiency.

Predictive effects of admission white blood cell counts and hounsfield unit values on delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Neuroinflammatory response is deemed the primary pathogenesis of delayed cerebral ischemia (DCI) caused by aneurysmal subarachnoid hemorrhage (aSAH). Both white blood cell (WBC) count and Hounsfield Unit (HU) are gradually considered can reflect inflammation in DCI. This study aims to identify the relationship between WBC count and HU value and investigate the effects of both indicators in predicting DCI after aSAH. METHODS: We enrolled 109 patients with aSAH admitted within 24 h of onset in our study. A multivariate logistic regression analysis was used to evaluate the admission WBC count, HU value, and combined WBC-HU associated with DCI. The receiver operating characteristic curve and area under the curve (AUC) were used to determine thresholds and detect the predictive ability of these predictors. These indicators were also compared with the established inflammation markers. RESULTS: Thirty-six (33%) patients developed DCI. Both WBC count and HU value were strongly associated with the admission glucose level (ρ = .303, p = .001; ρ = .273, p = .004), World Federation of Neurosurgical Societies grade (ρ = .452, p < .001; ρ = .578; p < .001), Hunt-Hess grade (ρ = .450, p < .001; ρ = .510, p < .001), and modified Fisher scale score (ρ = .357, p < .001; ρ = .330, p < .001). After controlling these public variables, WBC count (ρ = .300, p = .002) positively correlated with HU value. An early elevated WBC (odds ratio [OR] 1.449, 95% confidence interval [CI]: 1.183-1.774, p < .001) count and HU value (OR 1.304, 95%CI: 1.149-1.479, p < .001) could independently predict the occurrence of DCI. However, only these patients with both WBC count and HU value exceeding the cut-off points (OR 36.89, 95%CI: 5.606-242.78, p < .001) were strongly correlated with DCI. Compared with a single WBC count (AUC 0.811, 95%CI: 0.729-0.892, p < .001) or HU value (AUC 0.869, 95%CI: 0.803-0.936, p < .001), the combined WBC-HU (AUC 0.898, 95%CI: 0.839-0.957, p < .001) demonstrated a better ability to predict the occurrence of DCI. Inspiringly, the prediction performance of these indicators outperformed the established inflammatory markers. CONCLUSION: An early elevated WBC count and HU value could independently predict DCI occurrence between 4 and 30 days after aSAH. Furthermore, WBC count was positively correlated with HU value, and the combined WBC-HU demonstrated a superior prediction ability for DCI development compared with the individual indicator.

Xi-Xian-Tong-Shuan capsule alleviates vascular cognitive impairment in chronic cerebral hypoperfusion rats by promoting white matter repair, reducing neuronal loss, and inhibiting the expression of pro-inflammatory factors.

BACKGROUND: While the number of cases of vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) has been increasing every year, there are currently no clinically effective treatment methods. At present, Xi-Xian-Tong-Shuan capsule is predominantly used in patients with acute cerebral ischemia; however, its protective effect on CCH has rarely been reported. OBJECTIVE: To explore the underlying mechanisms by which Xi-Xian-Tong-Shuan capsule alleviates cognitive impairment caused by CCH. METHODS: A model of CCH was established in specific-pathogen-free (SPF)-grade male Sprague-Dawley (SD) rats using bilateral common carotid artery occlusion (BCCAO). Xi-Xian-Tong-Shuan capsules were intragastrically administered for 42 days after the BCCAO surgery. We then assessed for changes in cognitive function, expression levels of pro-inflammatory factors, and coagulation function as well as for the presence of white matter lesions and neuronal loss. One-way ANOVA and Tukey's test were used to analyze the experimental data. RESULTS: The rats showed significant cognitive dysfunction after the BCCAO surgery along with white matter lesions, a loss of neurons, and elevated levels of inflammatory factors, all of which were significantly reversed after intervention with Xi-Xian-Tong-Shuan capsules. CONCLUSION: Xi-Xian-Tong-Shuan capsules can ameliorate vascular cognitive impairment in CCH rats by preventing damage of white matter, reducing neuronal loss, and inhibiting the expression of pro-inflammatory factors. Our study provides a new reference for the clinical treatment of chronic cerebral ischemia with Xi-Xian-Tong-Shuan capsules.

Regulatory T cells in ischemic stroke.

Recent evidence shows that when ischemic stroke (IS) occurs, the BBB would be destructed, thereby promoting the immune cells to migrate into the brain, suggesting that the immune responses can play a vital role in the pathology of IS. As an essential subpopulation of immunosuppressive T cells, regulatory T (Treg) cells are involved in maintaining immune homeostasis and suppressing immune responses in the pathophysiological conditions of IS. During the past decades, the regulatory role of Treg cells has attracted the interest of numerous researchers. However, whether they are beneficial or detrimental to the outcomes of IS remains controversial. Moreover, Treg cells exert distinctive effects in the different stages of IS. Therefore, it is urgent to elucidate how Treg cells modulate the immune responses induced by IS. In this review, we describe how Treg cells fluctuate and play a role in the regulation of immune responses after IS in both experimental animals and humans, and summarize their biological functions and mechanisms in both CNS and periphery. We also discuss how Treg cells participate in poststroke inflammation and immunodepression and the potential of Treg cells as a novel therapeutic approach.

Microglia and Macrophages in Neuroprotection, Neurogenesis, and Emerging Therapies for Stroke.

Stroke remains the number one cause of morbidity in the United States. Within weeks to months after an ischemic event, there is a resolution of inflammation and evidence of neurogenesis; however, years following a stroke, there is evidence of chronic inflammation in the central nervous system, possibly by the persistence of an autoimmune response to brain antigens as a result of ischemia. The mechanisms underlying the involvement of macrophage and microglial activation after stroke are widely acknowledged as having a role in ischemic stroke pathology; thus, modulating inflammation and neurological recovery is a hopeful strategy for treating the long-term outcomes after ischemic injury. Current treatments fail to provide neuroprotective or neurorestorative benefits after stroke; therefore, to ameliorate brain injury-induced deficits, therapies must alter both the initial response to injury and the subsequent inflammatory process. This review will address differences in macrophage and microglia nomenclature and summarize recent work in elucidating the mechanisms of macrophage and microglial participation in antigen presentation, neuroprotection, angiogenesis, neurogenesis, synaptic remodeling, and immune modulating strategies for treating the long-term outcomes after ischemic injury.