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Glycyrrhizin (GL) has been reported to protect against ischemia and reperfusion (I/R)-induced injury by inhibiting the cytokine activity of high mobility group box 1 (HMGB1). In the present study, the protective effects of GL against I/R injury, as well as the related molecular mechanisms, were investigated in rat brains. Focal cerebral I/R injury was induced by intraluminal filamentous occlusion of the middle cerebral artery (MCA) in Male Sprague-Dawley rats. GL alone or GL and rHMGB1 were administered intravenously at the time of reperfusion. Serum levels of HMGB1 and inflammatory mediators were quantified via enzyme-linked immunosorbent assay (ELISA). Histopathological examination, immunofluorescence, RT-PCR and western blotting analyses were performed to investigate the protective and anti-apoptotic effects and related molecular mechanisms of GL against I/R injury in rat brains. Pre-treatment with GL significantly reduced infarct volume and improved the accompanying neurological deficits in locomotor function. The release of HMGB1 from the cerebral cortex into the serum was inhibited by GL administration. Moreover, pre-treatment with GL alleviated apoptotic injury resulting from cerebral I/R through the inhibition of cytochrome C release and caspase 3 activity. The expression levels of inflammation- and oxidative stress-related molecules including TNF-α, iNOS, IL-1β, and IL-6, which were over-expressed in I/R, were decreased by GL. P38 and P-JNK signalling were involved in this process. All of the protective effects of GL could be reversed by rHMGB1 administration. GL has a protective effect on ischemia-reperfusion injury in rat brains through the inhibition of inflammation, oxidative stress and apoptotic injury by antagonising the cytokine activity of HMGB1.

AbstractAcute cerebral infarction (ACI) possesses high mortality. Exosomes present in serum have potential application value in ACI diagnosis. This study investigated the mechanism of serum exosomes in ACI. Serum exosomes isolated from ACI patients and normal people were identified and then injected into the established middle cerebral artery occlusion (MCAO) rat model to evaluate cerebral injury and inflammation. Exosomal microRNA (miR)-27-3p expression was detected and interfered to analyze rat cerebral inflammation. The binding relationship between miR-27-3p and PPARγ was predicted and verified. The lipopolysaccharide (LPS)-treated microglia model was established and intervened with miR-27-3p to detect PPARγ, Iba-1, and inflammation-related factor expressions. After overexpressing PPARγ, rat cerebral inflammation was evaluated. The clinical significance of serum exosomal miR-27-3p in ACI was evaluated. Serum exosomes from ACI patients caused exacerbated MCAO rat cerebral injury and poor behavior recovery, as well as promoted cerebral inflammation. Serum exosomal miR-27-3p deepened rat brain inflammation. miR-27-3p targeted PPARγ to promote microglia activation and inflammation-related factor expressions in MCAO rats, and overexpressing PPARγ attenuated MCAO rat cerebral inflammation. Serum exosomal miR-27-3p promised to be a biomarker for ACI. We proved that serum exosomes from ACI patients aggravated ACI patient cerebral inflammation via the miR-27-3p/PPARγ axis.

Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. In mice, these poorer functional outcomes are associated with decreased brain activity of AMP-activated protein kinase (AMPK), a molecule that recently emerged as a potential therapeutic target for ischemic stroke. The antidiabetic drug metformin, a well-known activator of AMPK, has improved stroke outcomes in diabetic patients with normal renal function. We investigated whether chronic metformin pre-conditioning can rescue AMPK activity and prevent stroke damage in non-diabetic mice with CKD. Eight-week-old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery, followed by left total nephrectomy. Mice were then allocated to receive metformin (200 mg/kg/day) or vehicle for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). The infarct volumes were lower in CKD mice exposed to metformin than in vehicle-treated CKD mice 24 h after tMCAO. Metformin pre-conditioning of CKD mice improved their neurological score, grip strength, and prehensile abilities. It also enhanced AMPK activation, reduced apoptosis, increased neuron survival and decreased microglia/macrophage M 1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice.

In patients with cerebral infarction (CI), elevated serum uric acid (UA) level may exacerbate the occurrence and development of carotid atherosclerosis (AS). Our study intended to explore the underlying mechanism. We enrolled 86 patients with CI, and divided them into four groups: Non-AS, AS-mild, AS-moderate, and AS-severe groups; the levels of UA and oxidative stress-related factors in serum were detected. The middle cerebral artery occlusion (MCAO) model was used to stimulate CI in rats, and different doses of UA were administrated. The levels of oxidative stress-related factors in serum were detected. Hematoxylin & eosin (H&E) staining was used to observe the morphological alterations, and the apoptotic cell death detection kit was used to detect apoptotic cells. Increased UA concentration and enhanced oxidative stress were found in AS patients. H&E staining results showed that UA treatment exacerbated morphological damage in rats with MCAO, promoted oxidative stress, and enhanced vascular endothelial cell apoptosis in rats with MCAO.

There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes. Vehicle or an established protective dose (30 mg/kg, p.o.) of GSK360A was administered to male Sprague-Dawley rats. Initially, GSK360A pharmacokinetics and organ distribution were determined, and then PHD-HIF pharmacodynamic markers were measured (i.e., to validate the pharmacological effects of the GSK360A administration regimen). Results obtained using this validated PHD dose-regimen indicated significant improvement by GSK360A (30mg/kg); administered at 18 and 5 hours prior to transient middle cerebral artery occlusion (stroke). GSK360A exposure and plasma, kidney and brain HIF-PHD pharmacodynamics endpoints (e.g., erythropoietin; EPO and Vascular Endothelial Growth Factor; VEGF) were measured. GSK360A provided rapid exposure in plasma (7734 ng/ml), kidney (45-52% of plasma level) and brain (1-4% of plasma level), and increased kidney EPO mRNA (80-fold) and brain VEGF mRNA (2-fold). We also observed that GSK360A increased plasma EPO (300-fold) and VEGF (2-fold). Further assessments indicated that GSK360A reduced post-stroke surgery neurological deficits (47-64%), cognitive dysfunction (60-75%) and brain infarction (30%) 4 weeks later. Thus, PHD inhibition using GSK360A pretreatment produced long-term post-stroke brain protection and improved behavioral functioning. These data support PHD inhibition, specifically by GSK360A, as a potential strategy for pre-surgical use to reduce brain injury and functional decline due to surgery-related cerebral injury.

Leukotriene B (LTB ) has been implicated in ischemic stroke pathology. We examined the prognostic significance of LTB levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infarction, plasma LTB levels were found to increase rapidly, roughly doubling within 24 h when compared to initial post-stroke levels. Further analyses indicate that poor functional recovery is associated with early and more sustained increase in LTB rather than the peak levels. Results from studies using a rat embolic stroke model showed increased 5-lipoxygenase (5-LOX) expression in the ipsilateral infarcted cortex compared with sham control or respective contralateral regions at 24 h post-stroke with a concomitant increase in LTB levels. In addition, neutrophil influx was also observed in the infarcted cortex. Double immunostaining indicated that neutrophils express 5-LOX and leukotriene A hydrolase (LTA H), highlighting the pivotal contributions of neutrophils as a source of LTB . Importantly, rise in plasma LTB levels corresponded with an increase in LTB amount in the infarcted cortex, thereby supporting the use of plasma as a surrogate for brain LTB levels. Pre-stroke LTB loading increased brain infarct volume in tMCAO rats. Conversely, administration of the 5-LOX-activating protein (FLAP) inhibitor BAY-X1005 or B-leukotriene receptor (BLTR) antagonist LY255283 decreased the infarct volume by a similar extent. To conclude, targeted interruption of the LTB pathway might be a viable treatment strategy for acute ischemic stroke.

Gut microbiome and plasma metabolome serve a role in the pathogenesis of ischemic stroke (IS). However, the relationship between the microbiota and metabolites remains unclear. This study aimed to reveal the specific asso-ciation between the microbiota and the metabolites in IS using integrated 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) analysis. Male Sprague Dawley (SD) rats were divided into three groups: normal group (n = 8, Normal), model group (n = 9, IS), and sham-operated group (n = 8, Sham). Rats in the IS group were induced by middle cerebral artery occlusion (MCAO), and rats in the Sham group received an initial anesthesia and neck incision only. A neurological function test and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used to assess the IS rat model. Then, the plasma samples were analyzed using untargeted LC-MS. The cecum samples were collected and analyzed using 16S rRNA sequencing. Pearson correlation analysis was performed to explore the association between the gut microbiota and the plasma metabolites. The 16S rRNA sequencing showed that the composition and diversity of the microbiota in the IS and control rats were significantly different. Compared with the Sham group, the abundance of the Firmicutes phylum was decreased, whereas Proteobacteria and Deferribacteres were increased in the IS group. Ruminococcus_sp_15975 and Lachnospiraceae_UCG_001 might be considered as biomarkers for the IS and Sham groups, respectively. LC-MS analysis revealed that many metabolites, such as L-leucine, L-valine, and L-phenylalanine, displayed different patterns between the IS and Sham groups. Pathway analysis indicated that these metabolites were mainly involved in mineral absorption and cholinergic synapse. Furthermore, integrated analysis correlated IS-related microbes with metabolites. For example, Proteobacteria were positively correlated with L-phenylalanine, while they were negatively correlated with eicosapentaenoic acid (EPA). Our results provided evidence of the relationship between the gut microbiome and plasma metabolome in IS, suggesting that these microflora-related metabolites might serve as potential diagnostic and therapeutic markers.

Transient ischaemic attack (TIA) and cerebral infarction are difficult to identify within the thrombolytic time window. Blood markers are efficient, economical and noninvasive and can be beneficial in the diagnosis of many diseases. Plasma exosomal biomarkers are rarely reported in TIA. Exosomal microRNAs (miRNAs) were extracted from plasma and cerebrospinal fluid after middle cerebral artery occlusion (MCAo) in rats (0 min, 5 min, 10 min, 2 h). Deep sequencing was used to detect exosomal miRNAs in rat plasma and confirm significant differentially expressed miRNAs. Polymerase chain reaction (PCR) was used to detect the differentially expressed miRNAs in plasma and cerebrospinal fluid. Exosomal miRNAs with the same expression trends in plasma and cerebrospinal fluid were selected, and bioinformatics analysis was then carried out. Finally, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was determined to assess the diagnostic accuracy of miRNAs for TIA in rats. First, high-throughput sequencing was used to detect the expression level of plasma exosome miRNA, and rno-miR-450b-5p with a decreasing expression level was screened. Second, the expression levels of exosomal miRNAs were verified in cerebrospinal fluid and plasma samples by PCR, and the results indicated that exosomal rno-miR-450b-5p was similarly expressed in cerebrospinal fluid and plasma. ROC analysis showed high AUC values for rno-miR-450b-5p (0.880) in the 10 min ischaemia rats compared with the control rats. Finally, bioinformatic analysis indicated that exosomal rno-miR-450b-5p may be involved in cerebral ischaemia. Plasma exosomal rno-miR-450b-5p has a high diagnostic value and may become a therapeutic target for rat TIA.

Leptomeningeal collaterals (LMCs) carry important prognostic value for patients with Acute ischemic stroke (AIS). Insulin resistance (IR) is associated with cardiovascular disease, but its impact on stroke outcomes is less clear. The triglyceride-glucose (TyG) index is a novel, accessible biomarker for IR. This study aims to evaluate the association between TyG index and LMCs. In this cross-sectional study, we included patients with internal carotid artery or middle cerebral artery occlusion and having CTA within 24 h of symptoms onset. TyG index formula was: ln [triglyceride (mg/dl) × glucose (mg/dl)]/2. CTA collaterals were classified into symmetrical, malignant, and other. Hypoperfusion Intensity Ratio (HIR) calculated from CT perfusion (CTP) was used as secondary marker. We did a multivariate ordinal logistic regression analysis for collaterals and multi linear regression analysis for HIR. Of 265 patients, 54.1 % were males, and 45.9 % were females, with a mean BMI of 28. A total of 219 (82 %) patients received reperfusion therapy, with 40 % and 74 % patients receiving tPA and EVT, respectively. 39.2 % and 27.2 % of patients had symmetrical and malignant CTA collateral scores, respectively. TyG index was a significant predictor of malignant CTA collaterals (β = 2.2, 95 % CI: 1.7 – 2.7) and CTP HIR (β = 0.1, 95 % CI: 0.03–0.14). TyG > 8.7 had diagnostic accuracy of 0.76 for malignant CTA collaterals. IR, as measured by TyG index, is predictive of worse LMCs. TyG is a promising biomarker with a potential value in predicting stroke outcomes after reperfusion therapy.1.Insulin resistance, assessed by the TyG index is associated with elevated stroke risk, early stroke deterioration and stroke recurrence.2.TyG index was a significant predictor of malignant CTA collaterals3.Future studies should look at TYG index biomarker to risk-stratify stroke patients undergoing reperfusion therapy

The hemoglobin, albumin, lymphocyte, and platelet (HALP) score, easily calculated parameter, indicating systemic inflammation and nutritional status In this study, we used the HALP score in patients with acute ischemic stroke (AIS) undergoing mechanical thrombectomy (MT) to predict 90-day mortality. 122 patients with AIS who underwent either MT or MT and tissue plasminogen activator (tPA) for middle cerebral artery (MCA) M1 occlusion. The HALP score was calculated, demographic data, modified Rankin Scale (mRS) score, and mortality status in retrospectively reviewed. The effectiveness of the HALP score in predicting mortality within 90 days was assessed using the receiver operating characteristic ( ROC) curves. The optimal cutoff value for HALP was 13.10. A HALP score <13.10 increased the risk of death within 90 days and was associated with a higher incidence of large artery thrombosis. Cardioembolism and hyperlipidemia were more common in patients with high (>13) HALP scores. In addition to the HALP score, the length of hospital stay, 24-h National Institutes of Health Stroke Scale score (NIHSS), number of days of intubation, acute physiologic assessment and chronic health evaluation (APACHE) II score, and symptom-to-groin time were statistically significant risk factors for mortality within 90 days. The HALP score is an easily calculated, inexpensive, and noninvasive parameter that can be used to predict mortality in patients with MCA M1 occlusion undergoing reperfusion therapy. Low HALP scores indicate a poor prognosis. Thus, there is a relationship between the HALP score and survival. •Inflammation is related to prognosis in acute ischemic stroke.•Albumin is an indicator of nutritional status. Nutrition affects the prognosis in acute ischemic stroke.•HALP score can be used to predict prognosis in patients undergoing thrombectomy.