NLRP6 Inflammasome Ameliorates Brain Injury after Intracerebral Hemorrhage.

NLRP6 inflammasome, one of the important intracellular innate immune sensors, has been shown to regulate immune responses. However, its roles in the intracerebral hemorrhage (ICH) are completely not clear. In the present study, we investigated the expression profile and biological roles of NLRP6 inflammasome in perihematomal brain tissues of mice subjected to ICH. In this study, we investigated the expression profile of NLRP6 inflammasome in the perihematomal brain tissues and explored the biological role of NLRP6 inflammasome upon acute brain injury in mice subjected to ICH. Increased expression of NLRP6 inflammasome was found in perihematomal brain tissues ranging from 6 h to 3 days, with a peak level at 1 day after ICH. Immunohistochemistry staining also showed that NLRP6 inflammasome was significantly increased in the perihematomal brain tissues at 1 day after ICH. Moreover, immunofluorescence staining showed that NLRP6 inflammasome was mainly colocalized in glial fibrillary acidic protein (GFAP)-positive astrocytes, while with little colocalized expression in NeuN-positive neurons and without expression in CD11b-positive microglia and CD31-positive endothelial cell in the perihematomal brain tissue of mice after ICH. Furthermore, NLRP6-/- ICH mice exhibited significantly higher brain water contents (BMCs), proinflammatory cytokines, NF-κB activity and neurological deficit scores when compared with the wild type (WT) ICH mice. In addition, we found that Toll-like receptor 4 (TLR4)-/- mice, as well as the TAK242 treated mice, had markedly lower expression of NLRP6 inflammasome expression in the perihematomal brain tissue at 1 day after ICH. Our data suggest that the upregulated NLRP6 inflammasome in perihematomal brain tissues attenuates ICH-induced brain injury.

Associations between biomarkers of renal function with cerebral microbleeds in hypertensive patients.

BACKGROUND: Cerebral microbleeds (CMBs) have been observed in the elderly and have been regarded as a manifestation of small vessel disease (SVD). Cerebral and glomerular SVD may have a common source of pathogenesis because these organs are closely connected through anatomic and hemodynamic similarities. The purpose of this study was to clarify the associations between kidney biomarker levels and CMBs in hypertensive patients. METHODS: The presence and number of CMBs were assessed on susceptibility-weighted imaging. We calculated the urinary albumin/creatinine ratio (UACR) from morning spot urine and the estimated glomerular filtration rate (eGFR) in serum samples. Serum cystatin C (CysC) was measured with an automated particle-enhanced turbidimetric immunoassay. RESULTS: UACR and CysC levels were higher in the patients with CMBs than those without, and the eGFR was lower in the patients with CMBs than those without. A logistic regression analysis indicates that eGFR and UACR were independently associated with the prevalence of deep or infratentorial CMBs. The odds ratio (OR) (95% confidence interval (CI)) of eGFR and UACR was 1.95 (1.37-3.27) and 2.25 (1.66-4.46), respectively. CysC was independently associated with CMBs in both deep or infratentorial and lobar locations. The ORs (95% CI) were 2.59 (1.57-6.22) and 1.57 (1.15-4.85), respectively. Furthermore, CysC exhibited fair diagnostic value for CMBs, with an area under the curve of 0.80. CONCLUSIONS: Kidney biomarker levels are associated with the presence of CMB in hypertensive patients without a history of transient ischemic attack (TIA) or stroke, independent of conventional risk factors, and CysC was a better marker for CMBs than eGFR and UACR.

Serum cystatin C and cerebral microbleeds in patients with acute cerebral stroke.

Recent studies have shown that kidney dysfunction is associated with cerebral microbleeds (CMB). Cystatin C is a more useful measurement than creatinine-based estimating equations for evaluating kidney function. The purpose of this study was to clarify the relationship between cystatin C levels and CMB in patients with acute cerebral stroke. This cross-sectional study included a total of 485 patients with acute ischemic stroke and 129 patients with cerebral hemorrhage. The serum levels of cystatin C were significantly higher in acute cerebral stroke patients with CMB than in those without (p<0.001). Multivariate logistic regression analyses showed that for each single standard deviation increase of cystatin C levels, there was a significant increase in the presence of CMB after adjusting for age and sex, and after additional adjustment for cardiovascular risk factors, silent lacunar infarction, and white matter hyperintensity in patients with acute stroke. The odds ratio (95% confidence interval) in patients with acute cerebral infarction and cerebral hemorrhage were 2.92 (1.81-6.93) and 2.98 (1.76-6.97), respectively. The present study suggests that elevated levels of cystatin C are associated with the presence of CMB in acute stroke patients, independent of conventional risk factors.

Effects of ethanol on liver sinusoidal endothelial cells-fenestrae of rats.

BACKGROUND: Important advances have been made in research into the mechanism of alcoholic liver disease (ALD) over the past few years, but the role of liver sinusoidal endothelial cell (LSEC) in ALD has not been elucidated adequately. This study was undertaken to investigate the effect of ethanol on fenestrae of LSECs in rats. METHODS: A rat model of alcoholic liver disease was established by means of direct intragastric instillation of ethanol. Fifty-five rats of experimental (35 rats) and control (20) groups were sacrificed at the end of 4, 8, 12 weeks respectively, and also at the end of 12-week abstinence. After heart perfusion, the liver tissue was fixed and stained with hematoxylin and eosin for observation of serial changes of LSEC-fenestrae under a transmission electron microscope. RESULTS: Normal LESC was flat with a nucleus and organelles arranged regularly. The distal cytoplasm displayed as a lamina with many fenestrae, lacking the basement membrane(BM) underneath the endothelium. At the end of 4-week alcohol feeding, the number of fenestrae decreased at the distal cytoplasm in some LSECs, without the formation of the BM underneath the endothelium. At the end of 8 weeks, the number of fenestrae decreased significantly or even disappeared. The BM began to develop incompletely underneath the endothelium, while the active fibroblast appeared. At the end of 12 weeks, the number of fenestrae decreased more significantly and the complete BM could even be seen. But the changes were mostly limited in the single or adjoining sinus, and fibrosis was scarcely formed. At the end of 12-week abstinence, defenestration and formation of the endothelial BM lightened significantly. CONCLUSIONS: Defenestration and formation of the BM in LSECs develop gradually with the chronic stimulation of ethanol. Hepatic sinusoidal capillarization and fibrosis will be seen if their state is more serious. These early changes, i.e., limited and regional defenestration and capillarization may be the basis of alcoholic peri-fibrosis. This kind of hepatic fibrosis is reversible after removal of etiological factors.

[The influence of alcohol on the liver sinusoids endothelial cell fenestrae of rats].

OBJECTIVE: To study the influence of alcohol on the liver sinusoids endothelial cell (LSEC) fenestrae of rats. METHODS: Setting up the rat model of alcoholic liver disease by orogastric administration of alcohol, then kill the experimental and control groups of rats at the end of 4 weeks, 8 weeks and 12 weeks after alcohol feeding, and also at the end of another 12 weeks after balance foods feeding succeeding with alcohol feeding for 12 weeks. Staining the liver tissue by means of HE method and observing the successive change of LSEC fenestrae by transmission electron microscope. RESULTS: The normal LSEC was flat with nucleus and organelle arranged regularly. The distal cytoplasm displayed as lamina with many fenestrae, not accompanied by basement membrane (BM) formation under the endothelial cell. At the end of 4 weeks of alcohol feeding, fenestrae decreased at the partial distal LSEC cytoplasm, but no BM developed. At the end of 8 weeks, fenestrae decreased significantly, even disappeared, with the BM developed incompletely under the endothelial cell. Concomitantly, fibroblast with active function developed. At the end of 12 weeks, the changes became more obvious; the complete BM could even be seen. However, this kind of changes was mostly limited in the single or adjoining sinusoids, as well as with little widespread formation of fibrosis. At the end of 12 weeks of stopping alcohol feeding, defenestrae and development of BM attenuated obviously. CONCLUSION: The defenestrae and BM of LSEC develop gradually with the chronic alcohol stimulation. Sinusoid capillarization and liver fibrosis even form when significant changes happen. The early change of the limited defenestrae and capillarization may be the basis of alcohol periportal fibrosis formation. This kind of liver fibrosis can be reversible after stopping alcohol feeding.