S100B promotes microglia M1 polarization and migration to aggravate cerebral ischemia.

AIM AND OBJECTIVE: S100B has been found abundantly expressed in microglia during cerebral ischemia. However, S100B effects on phenotype changes and migration of microglia are unclear. METHODS: Real-time PCR of S100B, M1 and M2 markers were tested to characterize phenotypic changes in microglia in mice middle cerebral artery occlusion (MCAO) model. Migration assay and additional mechanism studies were performed to elucidate the role of NF-κB in S100B-mediated microglia M1/M2 phenotype change and migration. Finally, S100B treatment on MCAO models was performed to show the in vivo evidence. RESULTS: S100B was identified as an induced gene with its pattern in accordance with M1 markers in mice MCAO model. That S100B was promoted by M1 stimuli whereas inhibited by M2 stimuli further confirmed S100B a M1 marker. Moreover, S100B promotes microglia M1 polarization with enhanced migration ability and inhibits M2 polarization. Additionally, NF-κB is essential in S100B control in microglia M1/M2 polarization and migration. Furthermore, S100B aggravated cerebral ischemia in murine MCAO model and exacerbated the microglia M1 polarization and migration. CONCLUSIONS: Our findings demonstrate that S100B promotes microglia M1 polarization to aggravate cerebral ischemia, and provide a better understanding on the therapeutic effects of S100B and/or its antagonist/neutralization antibody in stroke.

Molecular Mechanism Exploration of Ischemic Stroke by Integrating mRNA and miRNA Expression Profiles.

BACKGROUND: Stroke is one of the leading causes of death worldwide, and ischemic stroke accounts for about 80 percent of all cases. Ischemic stroke is usually caused by a blockage in an artery to the brain. However, its molecular mechanisms remain largely unclear. The integration of mRNA and miRNA expression patterns is an effective strategy to investigate the potential molecular mechanisms of ischemic stroke in posttranscriptional regulation level. METHODS: The mRNA and miRNA expression data were downloaded from the GEO database. The genes and miRNAs with fold change ≥ 1.5 and p-value ≤ 0.05 were considered differential expressions. GO and KEGG pathway annotations of differentially expressed genes were performed to investigate the potential biology function. The constructed mRNA-miRNA interaction networks were used to identify new genes and molecular mechanism of ischemic stroke. RESULTS: Three hundred thirty-eight DEGs (differentially expressed genes) in mRNA expression data were collected from blood samples of 23 patients with ischemic stroke and 23 vascular risk factor controls, and 8 miRNAs from peripheral blood cells of 48 patients with ischemic stroke and vascular risk factor controls. By analyzing the mRNA-miRNA regulation network, 6 miRNAs are responsible for the differential expression of 63 DEGs. Among these miRNAs, 4 screened miRNAs were shown to regulate oxidative stress, apoptosis, and thrombus formation of ischemic stroke in previous reports. In addition, the predicted target genes, such as BCL2A1 and TPM2, showed a crucial or potential role in the pathogenic mechanism of ischemic stroke. CONCLUSIONS: These results deciphered posttranscriptional regulation of the molecular mechanism of ischemic stroke and identified valuable genes in the development process of ischemic stroke.

Tacrolimus in the treatment of myasthenia gravis in patients with an inadequate response to glucocorticoid therapy: randomized, double-blind, placebo-controlled study conducted in China.

BACKGROUND: To determine the efficacy of low-dose, immediate-release tacrolimus in patients with myasthenia gravis (MG) with inadequate response to glucocorticoid therapy in a randomized, double-blind, placebo-controlled study. METHODS: Eligible patients had inadequate response to glucocorticoids (GCs) after ⩾6 weeks of treatment with prednisone ⩾0.75 mg/kg/day or 60-100 mg/day. Patients were randomized to receive 3 mg tacrolimus or placebo daily (orally) for 24 weeks. Concomitant glucocorticoids and pyridostigmine were allowed. Patients continued GC therapy from weeks 1-4; from week 5, the dose was decreased at the discretion of the investigator. The primary efficacy outcome measure was a reduction, relative to baseline, in quantitative myasthenia gravis (QMG) score assessed using a generalized linear model; supportive analyses used alternative models. RESULTS: Of 138 patients screened, 83 [tacrolimus (n = 45); placebo (n = 38)] were enrolled and treated. The change in adjusted mean QMG score from baseline to week 24 was -4.9 for tacrolimus and -3.3 for placebo (least squares mean difference: -1.7, 95% confidence interval: -3.5, -0.1; p = 0.067). A post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group (68.2%) versus the placebo group (44.7%; p = 0.044). Adverse event profiles were similar between treatment groups. CONCLUSIONS: Tacrolimus 3 mg treatment for patients with MG and inadequate response to GCs did not demonstrate a statistically significant improvement in the primary endpoint versus placebo over 24 weeks; however, a post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group versus the placebo group. This study was limited by the low number of patients, the absence of testing for acetylcholine receptor antibody and the absence of stratification by disease duration (which led to a disparity between the two groups). ClinicalTrials.gov identifier: NCT01325571.

Low T3 levels as a predictor marker predict the prognosis of patients with acute ischemic stroke.

BACKGROUND: Early and accurate prediction of outcome in acute stroke is important. The aim of this prospective study was to explore the correlation between serum triiodothyronine level and prognosis in acute ischemic stroke patients. METHODS: A prospective observational study which included 359 consecutive patients with acute ischemic stroke from December 2014 to November 2015 was interrogated. Serum triiodothyronine (T3) concentrations were measured on admission to understand their value in predicting functional outcome within 90 d using multivariable models adjusted for confounding factors. Receiver operating characteristic (ROC) curves were calculated to define the best cut-off value of triiodothyronine to predict outcome. The accuracy of the test was assessed measuring the area under the ROC curve (AUROC). RESULTS: Triiodothyronine was significantly decreased in patients with an unfavorable functional outcome as compared to patients with a favorable functional outcome within 90 d (p = 0.01). Binary logistic regression analyses revealed that lower triiodothyronine concentrations on admission were associated with a risk for poor outcomes (OR 0.05, 95% CI 0.01-0.25; p < 0.01). In addition, in ROC curve analysis, triiodothyronine may improve the National Institutes of Health Stroke Scale (NIHSS) score in predicting functional outcome. The combined model AUROC was 0.84 for 30 d and 0.91 for 90 d, which were both significantly higher than the AUROCs of original NIHSS (0.83 and 0.87), triiodothyronine (0.64 and 0.69) and age (0.57 and 0.68) (all p < 0.05). CONCLUSIONS: Low serum triiodothyronine levels can be a predictive marker of short-term outcome after ischemic stroke. A combined model (triiodothyronine, age and NIHSS score) can add significant additional predictive information to the clinical score of the NIHSS.

S100ß as a biomarker for differential diagnosis of intracerebral hemorrhage and ischemic stroke.

OBJECTIVE: To explore the efficacy of S100 calcium-binding protein B (S100ß) in differentiating between intracerebral hemorrhage (ICH) and ischemic stroke (IS). METHODS: From June 2014 to July 2015, 46 ICH and 71 IS patients who had undergone computed tomography (CT) scans were enrolled. Patients' neurological deficits were evaluated by the National Institutes of Health stroke scale (NIHSS), and the modified Rankin scale (mRS) was used to assess functional disability 90 days after discharge. Plasma S100ß was measured from a blood sample drawn upon arrival at the emergency department. RESULTS: The plasma S100ß concentration in the ICH group was significantly higher than in the IS group (p < 0.001). There were only significant correlations between S100ß and hemorrhage volume (r = 0.820, p < 0.001), NIHSS score (r = 0.389, p = 0.008), and mRS (r = 0.732, p < 0.001) in the ICH group. Furthermore, receiver-operating characteristic (ROC) curve analysis revealed that an S100ß concentration of 67 pg/ml yielded an area under the curve (AUC) of 0.903 with 95.7% sensitivity and 70.4% specificity in differentiating between ICH and IS. In the ICH group, the plasma S100ß concentration was significantly elevated in patients with poor functional outcome vs. those with favorable functional outcome (p < 0.001). ROC curve analysis showed that an S100ß concentration of 133 pg/ml yielded an AUC of 0.924 with 100% sensitivity and 76.2% specificity in identifying ICH patients with poor functional outcome. CONCLUSION: S100ß could serve as a potential biomarker for differentiating between ICH and IS and predicting short-term functional outcome after ICH.

CXCR7 suppression modulates microglial chemotaxis to ameliorate experimentally-induced autoimmune encephalomyelitis.

Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE), widely used as an animal model of MS, classically manifests as an ascending paralysis that is characterized by extensive infiltration of the CNS by inflammatory cells. Although several studies uncover the significant role of microglia in the development of EAE, the cellular mechanisms of microglia that govern EAE pathogenesis remain unknown. In the current study, we report that CXCR7 expression is dynamic regulated in activated microglia during CNS autoimmunity and positively correlates with the clinical severity of EAE. In addition, microglial chemotaxis is mediated by CXCR7 during CNS autoimmunity, signaling through extracellular signal-regulated kinase (ERK)1/2 activation, whereas p38 mitogen-activated protein kinase (MAPK) and (c-Jun N-terminal kinase) JNK are not involved. Most importantly, CXCR7 neutralizing treatment ameliorates the clinical severity of EAE along with ERK1/2 phosphorylation reduction. Collectively, our data demonstrate that CXCR7 suppression modulates microglial chemotaxis to ameliorate EAE.