Angiotensin and Cerebral Blood Flow

1.General properties of the cerebral circulation.2.Cerebral blood flow autoregulation in hypertension, in stroke, and during the aging process.3.The Angiotensin system.4.Angiotensin receptor subtypes.5.Angiotensin receptors and actions of Angiotensin II in the brain: interactions between the brain and circulating Angiotensin II.6.The cerebrovascular Angiotensin system.7.Effects of Angiotensin II on cerebrovascular reactivity.8.Angiotensin and cerebrovascular flow.9.Effects of therapeutic modulation of the Angiotensin II system on cerebrovascular regulation in health and disease.10.Conclusions.     

A panel of two miRNAs correlated to systolic blood pressure is a good diagnostic indicator for stroke

Background: We aimed to develop a diagnostic indicator of stroke based on serum miRNAs correlated to systolic blood pressure.Methods: Using miRNA expression profiles in {"type":"entrez-geo","attrs":{"text":"GSE117604","term_id":"117604"}}GSE117604 from the Gene Expression Omnibus (GEO), we utilized the WGCNA to identify hub miRNAs correlated to systolic blood pressure (SBP). Differential analysis was applied to highlight hub differentially expressed miRNAs (DE-miRNAs), whereby we built a miRNA-based diagnostic indicator for stroke using bootstrap ranking Least Absolute Shrinkage and Selection Operator (LASSO) regression with 10-fold cross-validation. The classification value of the indicator was validated with receiver operating characteristic (ROC) analysis in both the training set and test set, as well as quantitative real-time PCR (qRT-PCR) for the feature miRNAs. Further, target genes of hub miRNAs and hub DE-miRNAs were retrieved for functional enrichment.Results: A total of 447 hub miRNAs in the blue modules were significantly correlated with systolic blood pressure (r = 0.32, false discovery rate = 10⁻⁶). Target genes predicted with the hub miRNAs were mostly implicated in the Kyoto Encyclopedia of Genes and Genomes (KEGG) terms including mitogen-activated protein kinase (MAPK) pathway, senescence, and TGF-β signaling pathway. The diagnostic indicator with miR-4420 and miR-6793-5p showed remarkable performance in the training set (area under curve [AUC]= 0.953), as well as in the test set (AUC = 0.894). Results of qRT-PCR validated the diagnostic value of the two miRNAs embedded in the proposed indicator.Conclusions: We developed a panel of two miRNAs, which is a good diagnostic indicator for stroke. These results require further investigation.     

No association of moon phase with stroke occurrence

Stroke occurrence shows strong correlations with sleep disorders and even subtle sleep disturbances have been shown to affect ischemic stroke (IS) occurrence. Chronobiology also exerts effects, like the morning surge in IS occurrence. Lunar cycles have also been shown to affect sleep and other physiological processes, but studies on moon phases and its possible association with occurrence of stroke are rare and nonconclusive. Therefore, we studied the effects of moon phases on stroke hospitalizations and in-hospital mortality nationwide in Finland in 2004–2014. All patients aged ≥18 years with IS or intracerebral hemorrhage (ICH) as primary discharge diagnosis were included. Daily number of admissions was treated as a response variable while moon phase, year and astronomical season were independent variables in Poisson regression modeling. We found no association between moon phases and stroke occurrence. The overall occurrence rates did not vary between different moon phases for IS or ICH (p = 0.61 or higher). There were no differences between moon phases in daily admission rates among men, women, young and old patients for any of the stroke subtypes. There was no difference in in-hospital mortality with regard to moon phase for IS or ICH overall (p = 0.19 or higher), nor in subgroup analyses. There were no significant interactions between moon phase and astronomical season for stroke occurrence or in-hospital mortality. To conclude, in this over a decade-long nationwide study including a total of 46 million person years of follow-up, we found no association between moon phases and occurrence or in-hospital mortality rates of IS or intracerebral hemorrhage.     

Mechanism of mesenchymal stem cell–induced neuron recovery and anti-inflammation

Background aimsAfter ischemic or hemorrhagic stroke, neurons in the penumbra surrounding regions of irreversible injury are vulnerable to delayed but progressive damage as a result of ischemia and hemin-induced neurotoxicity. There is no effective treatment to rescue such dying neurons. Mesenchymal stem cells (MSCs) hold promise for rescue of these damaged neurons. In this study, we evaluated the efficacy and mechanism of MSC-induced neuro-regeneration and immune modulation.MethodsOxygen-glucose deprivation (OGD) was used in our study. M17 neuronal cells were subjected to OGD stress then followed by co-culture with MSCs. Rescue effects were evaluated using proliferation and apoptosis assays. Cytokine assay and quantitative polymerase chain reaction were used to explore the underlying mechanism. Antibody and small molecule blocking experiments were also performed to further understand the mechanism.ResultsWe showed that M17 proliferation was significantly decreased and the rate of apoptosis increased after exposure to OGD. These effects could be alleviated via co-culture with MSCs. Tumor necrosis factor-α was found elevated after OGD stress and was back to normal levels after co-culture with MSCs. We believe these effects involve interleukin-6 and vascular endothelial growth factor signaling pathways.DiscussionOur studies have shown that MSCs have anti-inflammatory properties and the capacity to rescue injured neurons.     

Amelioration of Stroke-Induced Neurological Deficiency by Lyophilized Powder of Catapol and Puerarin

Catalpol and puerarin are active ingredients isolated from Rehmannia glutinosa Libosch and Radix Puerariae, respectively. They are popular in research for their poly-pharmacological effects. This research focused on effect of anti-stroke by lyophilized powder of catalpol and puerarin (C-P) and potential mechanisms. At the beginning of research, C-P was identified and analyzed by HPLC. Neurological function was evaluated by Longa score, neurological complex function score and beam balance score after permanent middle cerebral artery occlusion (PMCAO) in mice. Infarct volume and water content were evaluated after treatment of C-P. Anti-oxidative stress, anti-apoptosis, angiogenesis and neurogenesis were investigated by ELISA, WB and immunohistochemical stain respectively. With treatment of C-P, neurological deficiency of PMCAO mice was ameliorated. Morphologically, infarct volume and water content in ischemic hemisphere were significantly reduced by C-P. In vivo and in vitro, oxidative stress injury was extenuated by C-P. Meanwhile, Caspase-3 was down-regulated and Bxl-2 was up-regulated by C-P in vivo. In addition, C-P enhanced angiogenesis around the infarct of cortex and neurogenesis in the Hippocampal Dentate Gyrus (DG). Hence, C-P ameliorated stroke-induced neurological deficiency through its multiple neuroprotections. What''s more, this article provides us a novel formula of active ingredients for stroke.     

Development of a flow cytometry–based pulse-width assay for detection of aggregates in cellular therapeutics to be infused by catheter

Background aimsDelivery of cell-based therapies through the carotid artery with the use of an intra-arterial catheter could introduce aggregates and cause focal ischemia in the brain. We developed a pulse-width flow cytometry method for aggregate detection and quantification. The assay was designed to be used as a cell product release assay in a clinical trial seeking to treat ischemic stroke with sorted cells brightly expressing aldehyde dehydrogenase (ALDH^br cells) delivered through intra-arterial catheters.MethodsThe forward light scatter pulse-width axis of a flow cytometer was calibrated for particle diameter measurements through the use of traceable standard microspheres and linear regression. As a positive control, Concanavalin A–aggregated cells were counted manually and sorted onto slides to compare with pulse width–determined values. Known numbers of aggregates were spiked into purified singlet cells for quantification. A clinical standard for aggregate count and diameter was determined. The assay was used to qualify catheters with the use of ALDH^br cells.ResultsThe pulse-width axis was highly linear for microsphere diameter (r² > 0.99), which allowed for size calibration. Microscopically determined counts and diameters corresponded to pulse width-determined values. Known aggregate counts were linear with pulse width–determined aggregate counts (r² = 0.98). The limit of detection was determined to be 0.004%. Flow of ALDH^br cells through catheters did not generate aggregates. The final method to be used as a release assay for the stroke clinical trial was tested successfully on samples from volunteer donors.ConclusionsThe pulse-width aggregate detection assay provides a reliable, reproducible, accurate and rapid means of detection, classification and quantification of aggregates in cell therapy products.     

Increase of atrial ANP release by 2,3-butanedione monoxime in beating rabbit atria

2,3-Butanedione monoxime (BDM) is a chemical phosphatase and has been known to dissociate mechanical contraction in the excitation–contraction coupling via inhibition of myofibrillar ATPase. BDM has also been found to decrease sarcolemmal L-type Ca²⁺ channel activity and intracellular Ca²⁺ in cardiac myocytes. It has been shown that Ca²⁺ entry via L-type Ca²⁺ channels decreased atrial myocyte atrial natriuretic peptide (ANP) release. The purpose of the present study was to address the effects of BDM in the regulation of ANP release. Experiments were performed in perfused beating rabbit atria. BDM accentuated atrial myocyte ANP release concomitantly with a decrease in atrial stroke volume and pulse pressure in a concentration-dependent manner. The BDM-induced activation of ANP release was attenuated by the treatment with nifedipine, an inhibitor of L-type Ca²⁺ channels. BDM further decreased atrial stroke volume and pulse pressure in the presence of nifedipine. Blockade of function of the sarcoplasmic reticulum with thapsigargin plus ryanodine slightly but not significantly attenuated the BDM-induced activation of ANP release. These data show that BDM is a potent stimulator for the ANP release and also suggest that the mechanism by which BDM activates atrial myocyte ANP release is related to inhibition of the L-type Ca²⁺ channel activity. The present finding also suggests that the effects of ANP released may be considered in an occasion of uncoupling by BDM of the excitation–contraction coupling of cardiomyocytes.     

The importance of voltage-dependent sodium channels in cerebral ischaemia

Summary Strategies for the treatment of thromboembolic stroke are based on restoring the blood flow as soon as possible and protecting the neurons from the deleterious consequences of cerebral ischaemia. Interest has focused on blockers of voltage-dependent Na⁺ channels as potential neuroprotective agents because they prevent neuronal death in various experimental models of cerebral ischaemia and act cytoprotectively in models of white matter damage. Although several Na⁺ blockers are currently being tested in various phases of clinical development, most of these agents are relatively weak and unspecific. I therefore consider it worthwhile to search for molecules which specifically block voltage-dependent Na⁺ channels for the treatment of cerebral ischaemia.