RIPK1 inhibition contributes to lysosomal membrane stabilization in ischemic astrocytes via a lysosomal Hsp70.1B-dependent mechanism.

Receptor-interacting protein kinase 1 (RIPK1) contributes to necroptosis. Our previous study showed that pharmacological or genetic inhibition of RIPK1 protects against ischemic stroke-induced astrocyte injury. In this study, we investigated the molecular mechanisms underlying RIPK1-mediated astrocyte injury in vitro and in vivo. Primary cultured astrocytes were transfected with lentiviruses and then subjected to oxygen and glucose deprivation (OGD). In a rat model of permanent middle cerebral artery occlusion (pMCAO), lentiviruses carrying shRNA targeting RIPK1 or shRNA targeting heat shock protein 70.1B (Hsp70.1B) were injected into the lateral ventricles 5 days before pMCAO was established. We showed that RIPK1 knockdown protected against OGD-induced astrocyte damage, blocked the OGD-mediated increase in lysosomal membrane permeability in astrocytes, and inhibited the pMCAO-induced increase in astrocyte lysosome numbers in the ischemic cerebral cortex; these results suggested that RIPK1 contributed to the lysosomal injury in ischemic astrocytes. We revealed that RIPK1 knockdown upregulated the protein levels of Hsp70.1B and increased the colocalization of Lamp1 and Hsp70.1B in ischemic astrocytes. Hsp70.1B knockdown exacerbated pMCAO-induced brain injury, decreased lysosomal membrane integrity and blocked the protective effects of the RIPK1-specific inhibitor necrostatin-1 on lysosomal membranes. On the other hand, RIPK1 knockdown further exacerbated the pMCAO- or OGD-induced decreases in the levels of Hsp90 and the binding of Hsp90 to heat shock transcription factor-1 (Hsf1) in the cytoplasm, and RIPK1 knockdown promoted the nuclear translocation of Hsf1 in ischemic astrocytes, resulting in increased Hsp70.1B mRNA expression. These results suggest that inhibition of RIPK1 protects ischemic astrocytes by stabilizing lysosomal membranes via the upregulation of lysosomal Hsp70.1B; the mechanism underlying these effects involves decreased Hsp90 protein levels, increased Hsf1 nuclear translocation and increased Hsp70.1B mRNA expression.

Triglyceride-glucose index and short-term functional outcome and in-hospital mortality in patients with ischemic stroke.

BACKGROUND AND AIMS: The triglyceride-glucose (TyG) index has been demonstrated as an independent marker of ischemic stroke. Whether TyG index predicts short-term outcomes in patients with ischemic stroke remains uncertain. The aim of the study was to investigate the early prognosis value of TyG index in ischemic stroke patients. METHODS AND RESULTS: A total of 3216 acute ischemic stroke patients from 22 hospitals were included in this analysis. The TyG index was calculated as ln (fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2). Logistic regression model was performed to estimate the relationship between TyG index and unfavorable functional outcome of death or disability (modified Rankin Scale score of 4-6) at discharge. Risk reclassification with TyG index to predict unfavorable functional outcome was analyzed. During hospitalization, 748 patients (23.3%) experienced poor functional outcome and 105 patients (3.3%) died from all causes. The multivariable adjusted odds ratios for the highest versus lowest quartile of TyG index was 1.62 (95% CI 1.15-2.29) for unfavorable functional outcome at discharge. The addition of TyG index to the conventional model improved the risk reclassification (net reclassification improvement 10.37%; integrated discrimination improvement 0.27%; both p < 0.05) for poor functional outcome. Moreover, TyG index was associated with an odds ratio (95% CI) of 1.26 (1.02-1.55) for an ordinal shift in mRS score and 2.49 (1.21-5.12) for in-hospital mortality. CONCLUSIONS: Higher TyG index was associated with higher risk of unfavorable functional outcome at discharge and in-hospital mortality, implicating the significant short-term prognostic effect of TyG index in patients with ischemic stroke.

Prognostic significance of international normalised ratio and prothrombin time in Chinese acute ischaemic stroke patients.

BACKGROUND: We investigated the association between international normalised ratio (INR) and prothrombin time (PT) levels on hospital admission and in-hospital outcomes in acute ischaemic stroke (AIS) patients. METHODS: A total of 3175 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included. We divided patients into four groups according to their level of admission INR: (<0.92), Q2 (0.92-0.98), Q3 (0.98-1.04) and Q4 (≥1.04) and PT. Logistic regression models were used to estimate the effect of INR and PT on death or major disability (modified Rankin Scale score (mRS)>3), death and major disability (mRS scores 4-5) separately on discharge in AIS patients. RESULTS: Having an INR level in the highest quartile (Q4) was associated with an increased risk of death or major disability (OR 1.69; 95% CI 1.23 to 2.31; P-trend = 0.001), death (OR, 2.64; 95% CI 1.12 to 6.19; P-trend = 0.002) and major disability on discharge (OR, 1.56; 95% CI 1.13 to 2.15; P-trend = 0.008) in comparison to Q1 after adjusting for potential covariates. Moreover, in multivariable logistic regression models, having a PT level in the highest quartile also significantly increased the risk of death (OR, 2.38; 95% CI 1.06 to 5.32; P-trend = 0.006) but not death or major disability (P-trend = 0.240), major disability (P-trend = 0.606) on discharge. CONCLUSIONS: High INR at admission was independently associated with death or major disability, death and major disability at hospital discharge in AIS patients and increased PT was also associated with death at hospital discharge.

Prognostic significance of serum globulin in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: We investigated the association between serum globulin levels upon hospital admission and in-hospital short-term outcomes in acute ischemic stroke (AIS) patients. METHODS: A total of 3,127 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included in the present study. We divided patients into 4 groups according to their level of admission serum globulin: Q1 (<23.5 g/L), Q2 (23.5-26.4 g/L), Q3 (26.4-29.9 g/L), and Q4 (≥29.9 g/L). Logistic regression models were used to estimate the effect of serum globulin on the short-term outcomes, including all cause in-hospital mortality, poor outcome upon discharge (modified Rankin Scale score ≥3) and in-hospital pneumonia in AIS patients. RESULTS: The median National Institutes of Health Stroke Scale (NIHSS) score was 4.0 (IQR, 2.0-7.0). The risk of in-hospital mortality was significantly higher in patients with highest serum globulin level (Q4) compared to those with lowest (Q1) (adjusted odds ratio [OR] 2.30; 95% confidence interval [CI], 1.12-4.70; P-trend =0.026). The highest serum globulin level (Q4) was associated with a 1.32-fold and 1.62-fold increase in the risk of poor outcome upon discharge (adjusted OR 1.32; 95% CI, 1.00-1.75; P-trend = 0.070) and in-hospital pneumonia (adjusted OR 1.62; 95% CI, 1.18-2.23; P-trend = 0.001) in comparison to Q1 after adjustment for potential covariates. CONCLUSIONS: A high level of serum globulin upon hospital admission was independently associated with all cause in-hospital mortality, poor outcome upon discharge and in-hospital pneumonia in relative mild AIS patients.

Triglyceride-glucose index and common carotid artery intima-media thickness in patients with ischemic stroke.

BACKGROUND: Triglyceride glucose (TyG) index was recently reported to be associated with an increased risk of the development and recurrence of cardiovascular events, and atherosclerosis is a main speculative mechanism. However, data on the relationship between TyG index and atherosclerosis, especially in the setting of ischemic stroke, is rare. We aimed to explore the association between TyG index and carotid atherosclerosis in patients with ischemic stroke. METHODS: A total of 1523 ischemic stroke patients with TyG index and carotid artery imaging data were enrolled in this analysis. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Carotid atherosclerosis was measured by common carotid artery intima-media thickness (cIMT), and abnormal cIMT was defined as a mean cIMT and maximum cIMT value ≥ 1 mm. Multivariable logistic regression models and restricted cubic spline models were used to assess the relationships between TyG index and abnormal cIMT. Risk reclassification and calibration of models with TyG index were analyzed. RESULTS: The multivariable-adjusted odds ratios (95% CIs) in quartile 4 versus quartile 1 of TyG index were 1.56 (1.06-2.28) for abnormal mean cIMT and 1.46 (1.02-2.08) for abnormal maximum cIMT, respectively. There were linear relationships between TyG index and abnormal mean cIMT (P for linearity = 0.005) and abnormal maximum cIMT (P for linearity = 0.027). In addition, the TyG index provided incremental predictive capacity beyond established risk factors, shown by an increase in net reclassification improvement and integrated discrimination improvement (all P < 0.05). CONCLUSIONS: A higher TyG index was associated with carotid atherosclerosis measured by cIMT in patients with ischemic stroke, suggesting that TyG could be a promising atherosclerotic marker.

Prognostic significance of international normalised ratio and prothrombin time in Chinese acute ischaemic stroke patients.

BACKGROUND: We investigated the association between international normalised ratio (INR) and prothrombin time (PT) levels on hospital admission and in-hospital outcomes in acute ischaemic stroke (AIS) patients. METHODS: A total of 3175 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included. We divided patients into four groups according to their level of admission INR: (<0.92), Q2 (0.92-0.98), Q3 (0.98-1.04) and Q4 (≥1.04) and PT. Logistic regression models were used to estimate the effect of INR and PT on death or major disability (modified Rankin Scale score (mRS)>3), death and major disability (mRS scores 4-5) separately on discharge in AIS patients. RESULTS: Having an INR level in the highest quartile (Q4) was associated with an increased risk of death or major disability (OR 1.69; 95% CI 1.23 to 2.31; P-trend = 0.001), death (OR, 2.64; 95% CI 1.12 to 6.19; P-trend = 0.002) and major disability on discharge (OR, 1.56; 95% CI 1.13 to 2.15; P-trend = 0.008) in comparison to Q1 after adjusting for potential covariates. Moreover, in multivariable logistic regression models, having a PT level in the highest quartile also significantly increased the risk of death (OR, 2.38; 95% CI 1.06 to 5.32; P-trend = 0.006) but not death or major disability (P-trend = 0.240), major disability (P-trend = 0.606) on discharge. CONCLUSIONS: High INR at admission was independently associated with death or major disability, death and major disability at hospital discharge in AIS patients and increased PT was also associated with death at hospital discharge.

LINK-A lncRNA Promotes Proliferation and Inhibits Apoptosis of Mantle Cell Lymphoma Cell by Upregulating Survivin.

BACKGROUND LINK-A lncRNA acts as an oncogene in triple-negative breast cancer, but its involvement in other diseases is unknown. The present study was performed to investigate the involvement of LINK-A lncRNA in mantle cell lymphoma. MATERIAL AND METHODS Expressions of LINK-A lncRNA and survivin in plasma of patients with mantle cell lymphoma and healthy controls were detected by qRT-PCR and ELISA, respectively. ROC curve analysis was performed to investigate the diagnostic value of LINK-A lncRNA for mantle cell lymphoma. Correlations between plasma level of LINK-A lncRNA and survivin were analyzed by Pearson correlation coefficient. LINK-A lncRNA shRNA and expression vector were transfected into cells of human mantle cell lymphoma cell lines, followed by detection of cell proliferation, cell apoptosis, and survivin expression by cell proliferation assay, cell apoptosis assay, and Western blot analysis, respectively. RESULTS We found that, compared with healthy controls, plasma levels of LINK-A lncRNA and survivin were significantly increased in patients with mantle cell lymphoma. Upregulation of LINK-A lncRNA sensitively distinguished patients with mantle cell lymphoma from healthy controls. Plasma levels of LINK-A lncRNA and survivin were positively correlated in mantle cell lymphoma patients but not in healthy controls. CONCLUSIONS LINK-A lncRNA overexpression promoted cell proliferation, inhibited cell apoptosis, and upregulated survivin expression, while LINK-A lncRNA knockdown had the opposite effect.

Serum Alkaline Phosphatase, Phosphate, and In-Hospital Mortality in Acute Ischemic Stroke Patients.

BACKGROUND: The clinical impacts of serum alkaline phosphatase (ALP) and phosphate on early death are not fully understood in patients with acute ischemic stroke. We examined the associations between serum ALP, phosphate, and in-hospital mortality after ischemic stroke. METHODS: Serum ALP and phosphate were measured in 2944 ischemic stroke patients from 22 hospitals in Suzhou City from December 2013 to May 2014. Cox proportional hazard models and restricted cubic splines were used to estimate the relationships between serum ALP and phosphate (both as categorical and continuous variables) and risk of in-hospital mortality. RESULTS: During hospitalization, 111 patients (3.7%) died from all causes. After multivariable adjustment, the hazard ratio (HR) of the highest quartile compared with the lowest quartile of ALP was 2.19 (95% confidence interval [CI], 1.20-4.00) for early death. Restricted cubic spline analysis indicated a significant linear association between ALP and death (P-linearity = .017). A U-shaped association of phosphate with in-hospital mortality was observed (P-nonlinearity = .011). Compared with the third quartile of phosphate (1.08-1.21 mmol/L), HRs of the lowest and highest quartiles for early death were 2.17 (1.15-4.08) and 1.70 (.88-3.30), respectively. Sensitivity analyses further confirmed our findings. CONCLUSIONS: We observed a graded relationship between serum ALP levels and risk of early death in patients with acute ischemic stroke. There was a U-shaped association between phosphate and all-cause mortality with significantly increased risk among patients with lower phosphate levels.

Admission Low Magnesium Level Is Associated with In-Hospital Mortality in Acute Ischemic Stroke Patients.

BACKGROUND: Low magnesium levels are associated with an elevated risk of stroke. In this study, we investigated the association between magnesium levels on hospital admission and in-hospital mortality in acute ischemic stroke (AIS) patients. METHODS: A total of 2,485 AIS patients, enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city, were included in this study. The patients were divided into 4 groups according to their level of admission magnesium: Q1 (<0.82 mmol/L), Q2 (0.82-0.89 mmol/L), Q3 (0.89-0.98 mmol/L), and Q4 (≥0.98 mmol/L). Cox proportional hazard model was used to estimate the effect of magnesium on all-cause in-hospital mortality in AIS patients. RESULTS: During hospitalization, 92 patients (3.7%) died from all causes. The lowest serum magnesium level (Q1) was associated with a 2.66-fold increase in the risk of in-hospital mortality in comparison to Q4 (hazard ratio [HR] 2.66; 95% CI 1.55-4.56; p-trend < 0.001). After adjusting for age, sex, time from onset to hospital admission, baseline National Institutes of Health Stroke Scale score, and other potential covariates, HR for Q1 was 2.03 (95% CI 1.11-3.70; p-trend = 0.014). Sensitivity and subgroup analyses further confirmed a significant association between lower magnesium levels and a high risk of in-hospital mortality. CONCLUSIONS: Decreased serum magnesium levels at admission were independently associated with in-hospital mortality in AIS patients.

DNA methylation in cystathionine-γ-lyase (CSE) gene promoter induced by ox-LDL in macrophages and in apoE knockout mice.

Recent studies suggest that epigenetic alterations such as DNA methylation control many aspects of monocytes/macrophages and participate in the pathogenesis of atherosclerosis, a lipid-driven inflammatory disorder. Our and other groups demonstrated that dysregulation of cystathionine γ-lyase (CSE) -hydrogen sulfide (H2S) pathway was involved in monocyte/macrophages-mediated inflammation and atherosclerosis. However, it remains unknown whether altered cse methylation in macrophages may play a role in linking CSE-H2S dysregulation and atherosclerosis. In the present study, we showed that plasma H2S and H2S production in the peritoneal macrophages of apolipoprotein knockout (apoE(-/-)) mice gradually decreased with ages, and were also lower than that in control mice at 12 weeks older. Moreover, CSE mRNA expressions decreased while DNA methyltransferase (DNMT) expressions increased in the peritoneal macrophages isolated from apoE(-/-) mice, compared to age-matched wildtype mice. Similar observations were obtained in an in vitro study. In oxidized low-density lipoprotein (ox-LDL)-treated raw264.7 macrophages, cse transcription was down-regulated while the expression and activity of DNMT was up-regulated, associated with enhanced DNA methylation in cse promoter. Suppression of DNMT with its inhibitor or siRNA reversed the decrease of CSE mRNA. Therefore, our data suggest that DNA hypermethylation of CpG rich region in cse promoter might contribute to the decrease of cse transcription and H2S production in macrophages, and thus contribute to atherosclerosis development.

Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter.

Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H2S), which is formed via the transsulfuration pathway catalyzed by cystathionine ß-synthase and cystathionine γ-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF-α and IL-1ß in the plasma and reductions of plasma H2S level and CSE expression in the peritoneal macrophages. H2S-releasing compound GYY4137 attenuated the increases of TNF-α and IL-1ß in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H2S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.

Hydrogen sulfide protects blood-brain barrier integrity following cerebral ischemia.

By using two structurally unrelated hydrogen sulfide (H2 S) donors 5-(4-methoxyphenyl) -3H-1, 2-dithiole-3-thione (ADT) and sodium hydrosulfide (NaHS), this study investigated if H2 S protected blood-brain barrier (BBB) integrity following middle cerebral artery occlusion (MCAO). ICR mice underwent MCAO and received H2 S donors at 3 h after reperfusion. Infarction, neurological scores, brain edema, Evans blue (EB) extravasation, and tight junction protein expression were examined at 48 h after MCAO. We also investigated if ADT protected BBB integrity by suppressing post-ischemic inflammation-induced Matrix Metalloproteimase-9 (MMP9) and Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). ADT increased blood H2 S concentrations, decreased infarction, and improved neurological deficits. Particularly, ADT reduced EB extravasation, brain edema and preserved expression of tight junction proteins in the ischemic brain. NaHS also increased blood H2 S levels and reduced EB extravasation following MCAO. Moreover, ADT inhibited expression of pro-inflammatory markers induced Nitric Oxide Synthase (iNOS) and IL-1ß while enhanced expression of anti-inflammatory markers arginase 1 and IL-10 in the ischemic brain. Accordingly, ADT attenuated ischemia-induced expression and activity of MMP9. Moreover, ADT reduced NOX-4 mRNA expression, NOX activity, and inhibited nuclear translocation of Nuclear Factor Kappa-B (NF-κB) in the ischemic brain. In conclusion, H2 S donors protected BBB integrity following experimental stroke possibly by acting through NF-κB inhibition to suppress neuroinflammation induction of MMP9 and NOX4-derived free radicals. To determine H2 S effects on blood-brain barrier (BBB) disruption following stroke, we used two structurally unrelated H2 S donors ADT and NaHS. Both ADT and NaHS remarkably protected BBB integrity following experimental stroke. The slow-releasing donor ADT also reduced post-ischemic inflammation-induced expression and activity of MMP9 and NOX4 in the ischemic brain possibly by inhibiting NF-κB activation.

Statins upregulate cystathionine γ-lyase transcription and H2S generation via activating Akt signaling in macrophage.

Hydrogen sulfide (H2S), the third gaseous transmitter, is implicated in various pathophysiologic processes. In the cardiovascular system, H2S exerts effects of cardioprotection, vascular tone regulation, and atherogenesis inhibition. Recent studies demonstrated that atorvastatin, the inhibitor of 3-hydroxyl-3-methyl coenzyme A reductase, affected H2S formation in kidney and other organs. However, the underlying mechanisms are not fully understood. In this study, we examined the effects of three different statins (fluvastatin, atorvastatin and pravastatin) on H2S formation in raw264.7 macrophages. There was a remarkable rise in H2S level in fluvastatin- and atorvastatin-stimulated macrophages, while pravastatin failed to show any significant effect on it. Moreover, fluvastatin and atorvastatin enhanced the mRNA and protein expression of cystathionine γ-lyase (CSE) in dose- and time-dependent manners. Fluvastatin also markedly enhanced the CSE activity. However, fluvastatin did not alter the mRNA or protein expression of another H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase. Blockade of CSE with its inhibitor dl-propargylglycine (PAG) or siRNA markedly reduced the H2S level in fluvastatin-stimulated macrophages. In addition, fluvastatin elevated Akt phosphorylation, which occurred as early as 15 min after treatment, peaked at 1h, and lasted at least 3h. Both PI3K inhibitor LY294002 (10 µM) and Akt inhibitor perifosine (10µM) were able to reverse the increases of CSE mRNA and H2S production in fluvastatin-stimulated macrophages. Last, we showed that fluvastatin reduced the mRNA levels of pro-inflammatory molecules such as IL-1ß and MCP-1 in LPS-treated macrophages, which were completely reversed by CSE inhibitor PAG. Taken together, the findings demonstrate that statins may up-regulate CSE expression/activity and subsequently elevate H2S generation by activating Akt signaling pathway and also imply that CSE-H2S pathway plays a critical role in the anti-inflammation elicited by statins.

Expression of the immune checkpoint molecules PD­L1 and PD­1 in EBV­associated lymphoproliferative disorders: A meta­analysis.

Epstein-Barr virus (EBV) has been implicated in the development of a wide range of lymphoproliferative disorders. In this process, the role of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) has remained to be clarified. A meta-analysis of 20 studies was performed and risk ratios (RRs) with 95% confidence intervals (CIs) were used to evaluate the association between PD-L1/PD-1 expression and the status of EBV infection. The results showed that the expression level of PD-L1 in tumor cells was significantly higher in EBV+ cases with a pooled RR of 2.26 (95% CI, 1.63-3.14; P<0.01), particularly in subtypes of diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma. Similarly, EBV infection increased the expression of PD-L1 in immune cells with a pooled RR of 2.20 (95% CI, 1.55-3.12; P<0.01). In subtypes of DLBCL and post-transplant lymphoproliferative disorder, the expression of PD-L1 in immune cells is increased in EBV+ cases. Regarding the expression level of PD-1 in tumor-infiltrating lymphocytes (TILs), no significance was found between EBV infection and PD-1 expression, with a pooled RR of 1.10 (95% CI, 0.81-1.48; P>0.05). The present meta-analysis demonstrated that in EBV-associated lymphoproliferative disorders, EBV infection was associated with the expression level of PD-L1 in tumor cells and immune cells but was not associated with the expression of PD-1 in TILs.

Predictive Value of the Neutrophil-to-Lymphocyte Ratio and C-Reactive Protein in Patients with Idiopathic Facial Nerve Palsy.

Objective: This study aims to investigate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) in patients with idiopathic facial nerve palsy. Methods: The clinical data of patients with idiopathic facial nerve palsy were retrospectively analyzed. After three months of follow-up, patients were divided into good prognosis and poor prognosis, and the correlation between NLR, CRP and idiopathic facial nerve palsy was analyzed. Results: Negative correlation of NLR with Portmann score in idiopathic facial nerve palsy (r=-0.788, P<0.05); In contrast to the group with poor prognosis, patients in good prognosis group had low levels of body mass index (BMI), NLR, and C-reactive protein (CRP), and high Portmann score (P<0.05); Multivariate logistic regression analysis showed Portmann score (OR=1.268, 95% CI (1.005-1.616)), NLR (OR=0.262, 95% CI (0.128-0.533)) and CRP levels (OR=0.949, 95% CI (0.895-0.989)) were risk factors of poor prognosis for patients with idiopathic facial nerve palsy. The area under the receiver operator characteristic (ROC) curve of NLR and CRP levels in predicting poor facial nerve function was 0.764 and 0.697, the specificity was 85.5% and 75.0%, and the sensitivity was 74. 0% and 76.0%, respectively. The ROC curve of the combined diagnosis was 0.829, the specificity was 80.7%, and the sensitivity was 82.0%. Conclusion: Elevated NLR and CRP are associated with a poor prognosis of idiopathic facial nerve palsy and can serve as an indicator for clinical prognosis, and can be widely used in clinical.

Matrilin-3 supports neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation.

In the brain, the role of matrilin-3, an extracellular matrix component in cartilage, is unknown. Here, we identify that matrilin-3 decreased in reactive astrocytes but was unchanged in neurons after ischemic stroke in animals. Importantly, it declined in serum of patients with acute ischemic stroke. Genetic or pharmacological inhibition or supplementation of matrilin-3 aggravates or reduces brain injury, astrocytic cell death, and glial scar, respectively, but has no direct effect on neuronal cell death. RNA sequencing demonstrates that Matn3-/- mice display an increased inflammatory response profile in the ischemic brain, including the nuclear factor κB (NF-κB) signaling pathway. Both endogenous and exogenous matrilin-3 reduce inflammatory mediators. Mechanistically, extracellular matrilin-3 enters astrocytes via caveolin-1-mediated endocytosis. Cytoplasmic matrilin-3 translocates into the nucleus by binding to NF-κB p65, suppressing inflammatory cytokine transcription. Extracellular matrilin-3 binds to BMP-2, blocking the BMP-2/Smads pathway. Thus, matrilin-3 is required for astrocytes to exert neuroprotection, at least partially, by suppressing astrocyte-mediated neuroinflammation.

The association between serum phosphorus and common carotid artery intima-media thickness in ischemic stroke patients.

Purpose: An elevated concentration of phosphorus is associated with an increased risk of atherosclerosis and cardiovascular diseases. Common carotid artery intima-media thickness (cIMT) is an imaging marker of atherosclerosis. However, data on the relationship between phosphorus and cIMT in ischemic stroke are scarce. We aimed to evaluate the association between serum phosphorus levels and cIMT in patients who had experienced ischemic stroke. Patients and methods: A total of 1,450 ischemic stroke patients were enrolled. Participants were divided into four groups (quartiles) according to baseline serum phosphorus level. Carotid atherosclerosis was identified by measurement of cIMT; abnormal cIMT was defined as a maximum cIMT or mean cIMT ≥ 1 mm. Multivariable logistic regression models were used to assess the association between serum phosphorus level and the presence of abnormal cIMT. Results: In the multivariable adjusted analysis, falling into the highest quartile for serum phosphorus (Q4) was associated with a 2.00-fold increased risk of having abnormal maximum cIMT [adjusted odds ratio (OR) 2.00; 95% confidence interval (CI) 1.44-2.79] and a 1.76-fold increased risk of having abnormal mean cIMT (adjusted OR 1.76; 95% CI 1.22-2.53) in comparison to Q1. Furthermore, the association between serum phosphorus and abnormal cIMT was confirmed in analyses treating serum phosphorus as a continuous variable and in subgroup analyses. Conclusion: In acute ischemic stroke patients, baseline elevated serum phosphorus level was found to be independently associated with carotid atherosclerosis, as measured by cIMT.

Albumin-Globulin Ratio and Common Carotid Artery Intima-Media Thickness in Patients with Ischemic Stroke.

BACKGROUND: The relationships between serum albumin, albumin-globulin (A/G) ratio, globulin and atherosclerosis in acute ischemic stroke (AIS) remain uncertain. We investigated the associations between serum albumin, A/G ratio, globulin levels and carotid atherosclerosis in patients with AIS. METHODS: A total of 1,339 AIS patients were enrolled. Admission A/G ratio was divided into quartiles, and serum albumin and globulin levels were also categorized. Carotid atherosclerosis was detected through the assessment of common carotid artery intima-media thickness (cIMT), and abnormal cIMT was characterized by mean and maximum cIMT values of ≥1 mm. We evaluated the relationships between A/G ratio, albumin, globulin and abnormal cIMT, using multivariable logistic regression models. RESULTS: In the multivariable-adjusted analysis, the highest A/G ratio quartile (Q4) was linked to a 59% decreased risk of abnormal mean cIMT (OR 0.41; 95% CI 0.29-0.60) and a 58% decreased risk of abnormal maximum cIMT (OR 0.42; 95% CI 0.30-0.60) when compared to the lowest quartile (Q1), respectively. Moreover, decreased albumin and elevated globulin levels were also associated with abnormal mean cIMT and maximum cIMT. In addition, the A/G ratio provided supplementary predictive capability beyond the already established risk factors, and the C-statistic of the A/G ratio for abnormal cIMT is larger than globulin (P <0.01). CONCLUSION: Decreased serum A/G ratio, albumin and elevated serum globulin were independently associated with abnormal cIMT in AIS patients. Moreover, the A/G ratio appeared to be a better predictor of abnormal cIMT.

Role of Semaphorins in Ischemic Stroke.

Ischemic stroke is one of the major causes of neurological morbidity and mortality in the world. Although the management of ischemic stroke has been improved significantly, it still imposes a huge burden on the health and property. The integrity of the neurovascular unit (NVU) is closely related with the prognosis of ischemic stroke. Growing evidence has shown that semaphorins, a family of axon guidance cues, play a pivotal role in multiple pathophysiological processes in NVU after ischemia, such as regulating the immune system, angiogenesis, and neuroprotection. Modulating the NVU function via semaphorin signaling has a potential to develop a novel therapeutic strategy for ischemic stroke. We, therefore, review recent progresses on the role of semphorin family members in neurons, glial cells and vasculature after ischemic stroke.

Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Patients with Chronic Internal Carotid Artery Occlusion Complicated by Cerebral Infarction.

Purpose: This study aims to investigate the prognostic value of the peripheral neutrophil-to-lymphocyte ratio (NLR) in patients with chronic internal carotid artery occlusion (CICAO) complicated by cerebral infarction. Patients and Methods: The clinical data of 99 CICAO patients complicated by cerebral infarction were retrospectively analyzed. The modified Rankin Scale (mRS) was used to assess their 3-month prognosis, and a multivariate logistic regression model was established to explore risk factors for poor prognosis. Results: Multivariate logistic regression analysis demonstrated that NLR (OR=2.114; 95% CI: 1.129-3.959) and baseline National Institute of Health Stroke Scale (NIHSS; OR=1.288, 95% CI: 1.053-1.574) score were risk factors of poor prognosis. The area under the receiver operator characteristic (ROC) curve of NLR in predicting the 3-month outcome after onset was 0.717 (95% CI: 0.606-0.828, P<0.000). The optimal cut-off value was 3.22, with a sensitivity of 0.743 and a specificity of 0.791. Conclusion: NLR is an independent risk factor for the poor prognosis of CICAO patients complicated by cerebral infarction and can serve as an indicator for clinical prognosis.