Phenotype Shifting in Astrocytes Account for Benefits of Intra-Arterial Selective Cooling Infusion in Hypertensive Rats of Ischemic Stroke.

The translational failure of neuroprotective therapies in stroke may be influenced by the mismatch of existing comorbidities between animal models and patients. Previous studies found that single-target neuroprotective agents reduced infarction in Sprague-Dawley but not in spontaneously hypertensive rats. It is of great interest to explore whether multi-target neuroprotectants and stroke models with comorbidities should be used in further translational researches. Ischemic stroke was induced in normotensive or hypertensive rats by 90- or 120-min middle cerebral artery occlusion (MCAO) and reperfusion. Intra-Arterial Selective Cooling Infusion (IA-SCI) was started at the onset of reperfusion for 30 minutes. Acute neurological deficits, infarct volumes, gene expression and markers of A1-like and A2-like astrocytes were evaluated. In further analysis, TNFα and IL-1α were administrated intracerebroventricularly, phenotype shifting of astrocytes and infarct volumes were assessed. Normobaric oxygen treatment, as a negative control, was also assessed in hypertensive rats. IA-SCI led to similar benefits in normotensive rats with 120-min MCAO and hypertensive rats with both 90-min and 120-min MCAO, including mitigated functional deficit and reduced infarct volumes. IA-SCI shifted astrocyte phenotypes partly by downregulating A1-like astrocytes and upregulating A2-like astrocytes in both RNA and protein levels. Upregulated A1-type astrocyte markers levels, induced by intracerebroventricular injection of TNFα and IL-1α, were closely related to increased infarct volumes in hypertensive rats, despite receiving IA-SCI treatment. In addition, infarct volumes and A1/A2-like genes were not affected by normobaric oxygen treatment. IA-SCI reduced infarction in both normotensive and hypertensive rats. Our results demonstrated the neuroprotective effects of IA-SCI in hypertensive rats may be related with phenotype shifting of astrocytes.

Polymorphisms and plasma soluble levels of E-selectin in patients with chronic hepatitis B virus infection.

BACKGROUND: Infections with hepatitis B virus (HBV) may lead to a distinct clinical outcome which is partially related to host genetic variability. Our aim was to investigate the relationships between the polymorphisms of the E-selectin gene and disease progression in a HBV-infected Chinese Han population, and also to determine the plasma soluble E-selectin (sE-selectin) levels in this population. METHODS: Genomic DNA was extracted from the peripheral blood of 367 HBV carriers and 281 healthy controls. Two polymorphisms (PstI for A561C and HphI for G98T) of the E-selectin gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Circulating sE-selectin levels were measured by specific enzyme-linked immunosorbent assay (ELISA). RESULTS: The frequency of the C allele (AC or CC) of the A561C polymorphism was significantly higher in patients with liver cirrhosis (LC) compared to controls (p=0.002). There was no difference in allele distribution of the G98T polymorphism. But in patients with LC, classified according to the Child-Pugh classification, the frequency of the T carrier (GT and TT) was significantly different between Child-Pugh class A and class B plus C (p=0.009). Levels of plasma soluble E-selectin (sE-selectin) were significantly increased in HBV carriers with chronic hepatitis (CH) and LC (mean+/-SD 68.94+/-34.09 and 43.39+/-18.00 ng/mL) compared to controls (13.96+/-7.50 ng/mL) (p<0.01). In the LC subgroup, levels of sE-selectin were significantly decreased from Child-Pugh class A to class C (p<0.05). In each group, individuals with the C allele showed higher sE-selectin levels than those with the A allele (p<0.05). CONCLUSIONS: This is the first report describing the association between E-selectin polymorphisms and HBV-related chronic liver diseases. Our data suggest that the A561C polymorphism of the E-selectin gene may be associated with disease progression in patients with chronic HBV infection and control the expression of plasma soluble levels, while the G98T polymorphism may be related to fibrotic severity in the Chinese population.