Role In Cerebrovascular Disease Research Articles

Use of CALLY index to predict aneurysmal subarachnoid hemorrhage patient outcome

Background & Objective: Aneurysmal subarachnoid hemorrhage (aSAH) is a condition linked to elevated mortality and morbidity rates. Despite limited knowledge of the exact mechanism in aSAH patients, systemic inflammation is thought to have a significant role in cerebrovascular disease. The CALLY index is a prognostic marker utilized in many diseases, derived from parameters such as CRP, albumin, and lymphocytes. Nevertheless, there is limited research on its implementation in aSAH patients. This study aimed to investigate the CALLY index’s prognostic usefulness in aSAH patients. Methods: The research cohort comprises patients who attended a tertiary teaching and research hospital’s emergency department between January 1st, 2021, and January 1st, 2022, with a confirmed diagnosis of aneurysmal rupture. Basic demographic data and associated comorbidities of the cohort, in addition to the CALLY index derived from CRP, albumin, and lymphocyte levels, were documented. A comparison of the effects of investigations and data on in-patient mortality between the groups was conducted. Results: A total of 190 patients who met the inclusion criteria participated in the study. Patients with mortality were observed to have significantly lower CALLY Index scores than those in the other group (1.940 vs. 8.805). Regression analysis showed that mortality could be predicted based on the CALLY index (OR 0.393, 95% CI 0.1511-1.058, p=0.058). An AUC of 0.752, sensitivity of 78.2, specificity of 59.8 [p<0.001] was achieved by the optimal value for CALLY index. Conclusion: Based on the findings of this study, it can be inferred that CALLY index is a simple marker which can serve as an indicator of mortality in aSAH patients.

Association between serum osteocalcin and atherosclerosis in Type-2 diabetes mellitus: a cross-sectional study

BackgroundThe past few decades have seen a marked increase in the macrovascular complications of Type-2 diabetes mellitus (T2DM) such as coronary heart disease, peripheral arterial disease, and cerebrovascular disease. This has been predominantly attributed to the increased atherosclerosis in these patients. Atherosclerosis usually remains an asymptomatic condition and this poses a significant challenge in its early diagnosis and timely intervention. Hence, there is an immediate need for exploring novel tools to aid in the early detection of atherosclerosis, especially in T2DM patients. Osteocalcin (OC), synthesized by osteoblasts, is a protein hormone found in the skeletal system. This protein is considered as a marker for bone density and in recent times has been gaining interest due to its protective role in cerebrovascular diseases(CVD).MethodsWe conducted a cross-sectional study and evaluated the association between serum OC levels and atherosclerosis in 113 T2DM patients. Carotid intima-media thickness (CC-IMT) was used as an estimate of atherosclerosis and patients were divided into two groups (CC-IMT < 0.9 and ≥ 0.9). Correlation of serum OC levels and glycemic parameters and lipid profiles were studied and compared between both groups.ResultsThere is a significant negative correlation between the CC-IMT estimates and serum OC levels. CC-IMT also has a significant association with other biochemical parameters such as fasting blood sugar, glycated hemoglobin and high-density lipoprotein.ConclusionAlthough the independent association of serum OC could not be established in the T2DM patient population, overall, the results favor low serum OC as a prognostic marker for atherosclerosis.

Lipidomic Approaches in Common and Rare Cerebrovascular Diseases: The Discovery of Unconventional Lipids as Novel Biomarkers.

Stroke remains a major cause of death and disability worldwide. Identifying new circulating biomarkers able to distinguish and monitor common and rare cerebrovascular diseases that lead to stroke is of great importance. Biomarkers provide complementary information that may improve diagnosis, prognosis and prediction of progression as well. Furthermore, biomarkers can contribute to filling the gap in knowledge concerning the underlying disease mechanisms by pointing out novel potential therapeutic targets for personalized medicine. If many "conventional" lipid biomarkers are already known to exert a relevant role in cerebrovascular diseases, the aim of our study is to review novel "unconventional" lipid biomarkers that have been recently identified in common and rare cerebrovascular disorders using novel, cutting-edge lipidomic approaches.

RDW-to-ALB Ratio Is an Independent Predictor for 30-Day All-Cause Mortality in Patients with Acute Ischemic Stroke: A Retrospective Analysis from the MIMIC-IV Database.

Previous studies have shown that the peripheral red blood cell distribution width (RDW) and human serum albumin (ALB) were both predictors of the risk and mortality of cerebrovascular diseases, and the ratio of RDW to ALB (RAR) was a combined new index that can predict the prognosis of the cardiovascular and respiration systemic diseases, but its role in cerebrovascular diseases had not been effectively evaluated. This study is aimed at exploring whether RAR can effectively predict the 30-day all-cause mortality of acute ischemic stroke (AIS) patients. This retrospective cohort study was conducted on AIS patients (age > 18 years) in the intensive care database MIMIC-IV. The RAR was measured based on the red blood cell distribution width and albumin. The main result was 30-day all-cause mortality, and the secondary results were ICU mortality and hospital mortality. Obtain the odds ratio (OR) estimate from the logistic regression model of log-transformed RAR values and mortality. We had used another database for external validation. A total of 1412 patients were enrolled, with an average age of 68.8 ± 15.9, including 708 (50.1%) males. When log-transformed RAR values were used as a continuous variable, as the values increases, the risk of death increases (30-day all-cause mortality OR = 4.02 (2.21, 7.32) P < 0.0001, ICU mortality OR = 3.81 (1.92, 7.54) P = 0.0001, and hospital mortality OR = 3.31 (1.83, 6.00) P < 0.0001), when the values were used as three-category variables and as a trend variable was also positively correlated with each mortality rate. Especially as the categorical variables, a dose-response relationship was clearly observed, that was, as the category of RAR increased (Q1 to Q3), the HR value of the risk of death gradually steadily increased. Such a relationship can also be observed in the external validation database. In the subgroup analysis, we observed an increased risk of death in the patient with hyperlipidemia and low HAS-BLED scores; however, no significant interaction was found in other subgroup analyses (including the diagnostic sequence of AIS). RAR was a predictor of mortality in AIS patients. However, more in-depth research is needed to further analyze and confirm the role of RAR in AIS patients.

Inhibition of miR-423-5p Exerts Neuroprotective Effects in an Experimental Rat Model of Cerebral Ischemia/Reperfusion Injury

MicroRNAs (miRNAs) are widely acknowledged to play a unique role in cerebrovascular disease. This research investigates the function of microRNAs in ischemic stroke via a middle cerebral artery occlusion (MCAO) model. Four differentially expressed microRNAs in rat brains were identified by bioinformatics analysis, and qRT-PCR showed that miR-423-5p exhibited the highest expression in cerebral ischemia/reperfusion injury in rats, with peak levels observed at 24 hours. After microRNA inhibitors and mimics were administrated in the rat model of MCAO, the neurological scores and brain water content were detected, and triphenyltetrazolium chloride (TTC), Hematoxylin and Eosin (H&E), and Nissl staining were conducted to explore the influence of miR-423-5p on ischemic stroke. Subsequently, western blot, ELISA, MPO, TUNEL and commercial assay kits were applied to assess the influence of miR-423-5p on NLRP3 inflammasome, apoptosis, and oxidative stress levels in ischemic penumbra tissue. The results showed that miR-423-5p knockdown could effectively improve neurological indicators, such as cerebral infarct volume, brain water content, neurological scores, and nerve tissue damage, and inhibit the NLRP3 inflammasome, apoptosis, and oxidative stress. In contrast, the miR-423-5p mimic yielded opposite results. In conclusion, inhibition of miR-423-5p expression could effectively attenuate ischemic stroke and might be considered a promising target for stroke.

Forkhead Box 1(FoxO1) mediates psychological stress-induced neuroinflammation

ABSTRACT Objectives Neuroinflammation plays a key role in cerebrovascular disease (CVD). Neuropsychiatric disorders appear to share an epidemiological association with inflammation, but the mechanisms are unclear. Forkhead box 1 (FoxO1) regulates inflammatory signaling in diabetes and cardiovascular diseases, but its role in psychological stress-induced neuroinflammation remains unknown. Therefore, we investigated the potential involvement of FoxO1 in repeated social defeat stress (RSDS)-induced neuroinflammation. Methods 6-week-old male C57BL/6 J mice were randomly divided into RSDS or control groups. In the RSDS group, mice (18–22 g) were individually subjected to social defeat by an 8-week-old CD-1 mouse (28–32 g) for 10 min daily for 10 consecutive days. At 24 h after this 10-day process, corticosterone (CORT), epinephrine (EPI), hydrogen peroxide, and inflammatory factors (TNF-α, IL-6, IL-1β, and VCAM-1) from serum and brain tissues were assayed using ELISA, real-time PCR, and Western blot. Iba-1 was determined by immunofluorescence (IF), and FoxO1 siRNA was transfected into BV2 cells to further analyze the expression of inflammatory factors. Results RSDS significantly increased the levels of TNF-α, IL-6, IL-1β, and VCAM-1 in the serum; it also increased both mRNA and protein expression of these in the brain. FoxO1 was significantly increased after stress, while its knockdown significantly suppressed stress-induced inflammation. Immunofluorescence demonstrated the activation of microglia in the setting of RSDS. Conclusion RSDS induced a measurable inflammatory response in the blood and brain, and FoxO1 was demonstrated in vitro to aggravate stress-induced inflammation.

Intracranial Flow Velocity Quantification Using Non-Contrast Four-Dimensional Flow MRI: A Prospective Comparative Study with Transcranial Doppler Ultrasound.

Four-dimensional (4D) flow magnetic resonance imaging (MRI) allows three-dimensional velocity encoding to measure blood flow in a single scan, regardless of the intracranial artery direction. We compared blood flow velocity quantification by non-contrast 4D flow MRI and by transcranial Doppler ultrasound (TCD), the most widely used modality for measuring velocity. Twenty-two patients underwent both TCD and non-contrast 4D flow MRI. The mean time interval between TCD and non-contrast 4D flow MRI was 0.7 days. Subsegmental velocities were measured bilaterally in the middle cerebral and basilar arteries using TCD and non-contrast 4D flow MRI. Intracranial velocity measurements using TCD and non-contrast 4D flow MRI demonstrated a strong correlation in the bilateral M1, especially at the proximal segment (right r = 0.74, left r = 0.78; all p < 0.001). Mean velocities acquired with 4D flow MRI were approximately 8 to 10% lower than those acquired with TCD according to the location of M1. Intracranial arterial flow measurements estimated using non-contrast 4D flow MRI and TCD showed strong correlation. 4D flow MRI enables simultaneous assessment of vascular morphology and quantitative hemodynamic measurement, providing three-dimensional blood flow visualization. 4D flow MRI is a clinically useful sequence with a promising role in cerebrovascular disease.

Frailty and cerebrovascular disease: Concepts and clinical implications for stroke medicine.

Frailty is a distinctive health state in which the ability of older people to cope with acute stressors is compromised by an increased vulnerability brought by age-associated declines in physiological reserve and function across multiple organ systems. Although closely associated with age, multimorbidity, and disability, frailty is a discrete syndrome that is associated with poorer outcomes across a range of medical conditions. However, its role in cerebrovascular disease and stroke has received limited attention. The estimated rise in the prevalence of frailty associated with changing demographics over the coming decades makes it an important issue for stroke practitioners, cerebrovascular research, clinical service provision, and stroke survivors alike. This review will consider the concept and models of frailty, how frailty is common in cerebrovascular disease, the impact of frailty on stroke risk factors, acute treatments, and rehabilitation, and considerations for future applications in both cerebrovascular clinical and research settings.

Serum neopterin levels and their role in the prognosis of patients with ischemic stroke: A systematic review and meta-analysis

BackgroundNeopterin is an inflammatory marker that is found to have prognostic value in cardiovascular diseases but its prognostic role in cerebrovascular diseases is not as clear. This study evaluates the prognostic role of neopterin in patients with ischemic stroke. MethodStudies were identified after a literature search in electronic databases (Ovid, PubMed, Science Direct, and Wiley) and were selected based on precise eligibility criteria. Random-effects meta-analyses were performed to estimate mean difference in blood neopterin levels between ischemic stroke patients and healthy individuals or between severe and low/moderate ischemic stroke. Prognostic information contained in research articles of included studies was synthesized. ResultsFourteen studies (1823 ischemic stroke patients and 2189 healthy individuals) were included. Serum neopterin levels were 4.22 ng/ml [95% confidence interval (CI): 3.66, 4.77] in ischemic stroke patients and 1.80 ng/ml [95% CI: 1.13, 2.46] in normal individuals (mean difference 2.14 ng/ml [95% CI: 1.41, 2.87]; p < 0.00001). Neopterin levels were significantly higher in patients with severe than in low/moderate ischemic stroke (mean difference 1.36 ng/ml [95% CI: 0.58, 2.13]; p = 0.0006). In individual studies, higher serum neopterin levels were found to be predictive of secondary stroke, adverse clinical or functional outcomes, depression, and mortality. Neopterin levels correlated positively with high-sensitivity c reactive protein (hsCRP), National Institutes of Health Stroke Scale score, and infarct volume. ConclusionBlood neopterin levels are found significantly higher in ischemic stroke patients and correlated positively with hsCRP, disease severity, and infarct volume. Higher neopterin levels are associated with a worse prognosis of ischemic stroke.

The Role of NLRP3 Inflammasome in Cerebrovascular Diseases Pathology and Possible Therapeutic Targets.

Cerebrovascular diseases are pathological conditions involving impaired blood flow in the brain, primarily including ischaemic stroke, intracranial haemorrhage, and subarachnoid haemorrhage. The nucleotide-binding and oligomerisation (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome is a protein complex and a vital component of the immune system. Emerging evidence has indicated that the NLRP3 inflammasome plays an important role in cerebrovascular diseases. The function of the NLRP3 inflammasome in the pathogenesis of cerebrovascular diseases remains an interesting field of research. In this review, we first summarised the pathological mechanism of cerebrovascular diseases and the pathological mechanism of the NLRP3 inflammasome in aggravating atherosclerosis and cerebrovascular diseases. Second, we outlined signalling pathways through which the NLRP3 inflammasome participates in aggravating or mitigating cerebrovascular diseases. Reactive oxygen species (ROS)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ROS/thioredoxin-interacting protein (TXNIP) and purinergic receptor-7 (P2X7R) signalling pathways can activate the NLRP3 inflammasome; activation of the NLRP3 inflammasome can aggravate cerebrovascular diseases by mediating apoptosis and pyroptosis. Autophagy/mitochondrial autophagy, nuclear factor E2-related factor-2 (Nrf2), interferon (IFN)-β, sirtuin (SIRT), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) reportedly alleviate cerebrovascular diseases by inhibiting NLRP3 inflammasome activation. Finally, we explored specific inhibitors of the NLRP3 inflammasome based on the two-step activation of the NLRP3 inflammasome, which can be developed as new drugs to treat cerebrovascular diseases.

Arterial Remodeling of the Intracranial Arteries in Patients With Hypertension and Controls: A Postmortem Study.

The intracranial arteries play a major role in cerebrovascular disease, but arterial remodeling due to hypertension has not been well described in humans. We aimed to quantify this remodeling for: the basilar artery, the vertebral, internal carotid, middle/anterior (inferior)/posterior cerebral, posterior communicating, and superior cerebellar arteries of the circle of Willis. Ex vivo circle of Willis specimens, selected from individuals with (n=24) and without (n=25) a history of hypertension, were imaged at 7T magnetic resonance imaging using a 3-dimensional gradient-echo sequence. Subsequently, histological analysis was performed. We validated the vessel wall thickness and area measurements from magnetic resonance imaging against histology. Next, we investigated potential differences in vessel wall thickness and area between both groups using both techniques. Finally, using histological analysis, we investigated potential differences in arterial wall stiffness and atherosclerotic plaque severity and load. All analyses were unadjusted. Magnetic resonance imaging and histology showed comparable vessel wall thickness (mean difference: 0.04 mm (limits of agreement:-0.12 to 0.19 mm) and area (0.43 mm2 [-0.97 to 1.8 mm2]) measurements. We observed no statistically significant differences in vessel wall thickness and area between both groups using either technique. Histological analysis showed early and advanced atherosclerotic plaques in almost all arteries for both groups. The arterial wall stiffness was significantly higher for the internal carotid artery in the hypertensive group. Concluding, we did not observe vessel wall thickening in the circle of Willis arteries in individuals with a history of hypertension using either technique. Using histological analysis, we observed a difference in vessel wall composition for the internal carotid artery.

Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice.

Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.

Antiphospholipid syndrome and its role in pediatric cerebrovascular diseases: A literature review.

Antiphospholipid syndrome (APS) or Hughes syndrome is an acquired thromboinflammatory disorder. Clinical criteria of APS diagnosis are large- and small-vessel thrombosis as well as obstetric problems; laboratory criteria are the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies and anti-β2-glycoprotein-1). The presence of at least 1 clinical and 1 laboratory criterion allows definitive diagnosis of APS. Primary APS is diagnosed in patients without features of connective tissue disease; secondary APS is diagnosed in patients with clinical signs of autoimmune disease. A high frequency of catastrophic APS as well as a high tendency to evolve from primary APS to secondary syndrome during the course of lupus and lupus-like disease is a feature of pediatric APS. The most characteristic clinical presentation of APS in the pediatric population is venous thrombosis, mainly in the lower limbs, and arterial thrombosis causing ischemic brain stroke. Currently, no diagnostic criteria for pediatric APS exist, which probably results in an underestimation of the problem. Similarly, no therapeutic procedures for APS specific for children have yet been established. In the present literature review, we discussed data concerning APS in children and its role in cerebrovascular diseases, including pediatric arterial ischemic stroke, migraine and cerebral venous thrombosis.

Long non-coding RNA Gas5 potentiates the effects of microRNA-21 downregulation in response to ischaemic brain injury

Brain ischaemia, which can cause severe nerve injury, is a global health challenge. Long non-coding RNA (lncRNA) growth-arrest specific 5 (Gas5) has been documented to exert tumour suppressive effects in several cancers. However, its role in cerebrovascular disease still requires further investigation. Therefore, in this study, we focused on the role of lncRNA regulatory signalling related to lncRNA Gas5 in ischaemic brain injury. Middle cerebral artery occlusion (MCAO) was employed as a model of ischaemic brain injury in rats. The expression of lncRNA Gas5 and microRNA-21 (miR-21) was altered in neurons to elucidate their effects in ischaemic brain injury and to identify the interactions among lncRNA Gas5, miR-21 and Pten. The neuronal survival rate, apoptosis and the expression of phosphatidyl inositol 3-kinase (PI3K)/Akt signalling pathway-related genes were also evaluated in vitro to determine the effects of lncRNA Gas5. In the brains of rats subjected to MCAO, the expression of lncRNA Gas5 and Pten was upregulated, while miR-21 was downregulated. LncRNA Gas5 inhibited miR-21 expression, leading to elevated levels of Pten. In vitro experiments revealed that lncRNA Gas5 depletion and miR-21 elevation resulted in the suppression of neuronal apoptosis, thus promoting neuronal survival via the PI3K/Akt signalling pathway. These findings demonstrate that lncRNA Gas5 increases miR-21 and activates Pten, contributing to the development of ischaemic brain injury, supporting the silencing of lncRNA Gas5 as a possible therapeutic target for the treatment of ischaemic brain injury.

Endothelial Immune Activation by Medin: Potential Role in Cerebrovascular Disease and Reversal by Monosialoganglioside-Containing Nanoliposomes.

BackgroundThe function of medin, one of the most common human amyloid proteins that accumulates in the vasculature with aging, remains unknown. We aim to probe medin's role in cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients and studying its effects on endothelial cell (EC) immune activation and neuroinflammation. We also tested whether monosialoganglioside‐containing nanoliposomes could reverse medin's adverse effects.Methods and ResultsCerebral artery medin and astrocyte activation were measured and compared between VaD and cognitively normal elderly brain donors. ECs were exposed to physiologic dose of medin (5 μmol/L), and viability and immune activation (interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) were measured without or with monosialoganglioside‐containing nanoliposomes (300 μg/mL). Astrocytes were exposed to vehicle, medin, medin‐treated ECs, or their conditioned media, and interleukin‐8 production was compared. Cerebral collateral arterial and parenchymal arteriole medin, white matter lesion scores, and astrocyte activation were higher in VaD versus cognitively normal donors. Medin induced EC immune activation (increased interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) and reduced EC viability, which were reversed by monosialoganglioside‐containing nanoliposomes. Interleukin‐8 production was augmented when astrocytes were exposed to medin‐treated ECs or their conditioned media.ConclusionsCerebral arterial medin is higher in VaD compared with cognitively normal patients. Medin induces EC immune activation that modulates astrocyte activation, and its effects are reversed by monosialoganglioside‐containing nanoliposomes. Medin is a candidate novel risk factor for aging‐related cerebrovascular disease and VaD.

Abstract TP557: Endothelial Cell Proinflammatory Priming by Amyloidogenic Medin via NFκB and Inflammasome Pathways and Reversal by Monosialoganglioside Nanoliposomes

Medin is a common amyloid protein that accumulates in cerebral vessels with aging and cause endothelial dysfunction in human cerebral arterioles. Studying its role in cerebrovascular disease could provide insights on cerebrovascular aging. We aim to test whether medin induces pro-inflammatory priming of endothelial cells (ECs) and probe mechanistic bases, and determine whether monosialoganglioside-containing nanoliposomes (NLGM1), previously shown to protect against AL amyloid vascular dysfunction, would abrogate this response. Methods: Human umbilical vein ECs were treated (20 hours) with physiologic dose of medin (5 μM) or vehicle, and proinflammatory markers IL-1β, caspase-1, IL-8, IL-6, ICAM-1, phospho-NFκB and pro-thrombotic marker plasminogen activator inhibitor-1 (PAI-1) gene and/or protein expressions were measured. In some replicates, medin was co-treated with either specific NFκB small molecule inhibitor RO106-9920 100 μM or NLGM1 (70:20:5% phosphatidylcholine, cholesterol, monosialoganglioside, 1:10 medin:NLGM1 mass ratio). Results: Medin increased gene expression of IL-1β (104.0±30.2x vs. control, p=0.002), IL-8 (5560±1864x, p&lt;0.001), IL-6 (80.4±48x, p&lt;0.001), ICAM-1 (72.0±8.5x, p&lt;0.001) and PAI-1 (5.4±1x, p&lt;0.001) (n=13-44). There were corresponding increases in protein expression as well as increased phospho-NFκB and caspase-1 (Figure). RO106-9920 co-treatment reduced gene expressions of IL-8, IL-6, ICAM-1 and PAI-1 but not IL-1β (versus medin treatment) whereas NLGM1 normalized gene expressions of all cytokines including IL-1β. Conclusions: Medin induced profound proinflammatory and prothrombotic responses in endothelial cells. Both NFκB and inflammasome-mediated mechanisms mediate medin’s vascular priming effects. Medin-induced pathology is a potential new mechanism of aging-related cerebrovascular inflammation. NLGM1 protects against medin’s effects and may represent a new therapeutic approach.

Long non-coding RNA GAS5 aggravates hypoxia injury in PC-12 cells via down-regulating miR-124.

One important feature of cerebral ischemia is hypoxia injury in nerve cells. Growth arrest-specific transcript 5 (GAS5) is widely reported as a tumor suppressor gene; however, the investigations about its role in cerebrovascular disease are relatively rare. This study was aimed to explore the impact of GAS5 on hypoxia response in nervous cells. PC-12 cells were incubated under anoxic condition to induce hypoxia injury. Regulatory effects of GAS5 on miR-124 and miR-124 on ICAM-1 expression were assessed by qRT-PCR and/or Western blot. Targeting effect of miR-124 on ICAM-1 3'-untranslated regions (UTR) was evaluated through dual luciferase activity assay. The potential regulatory mechanism on hypoxia injury in PC-12 cells was assessed by detecting key elements of NF-κB and Notch signaling pathways using Western blot. GAS5 ectopic expression accentuated hypoxia injury in PC-12 cells. miR-124 expression was negatively regulated by GAS5 expression. Cells with overexpressions of GAS5 and miR-124 alleviated hypoxia injury as in compassion with cells only with GAS5 overexpression. ICAM-1 expression was negatively regulated by miR-124 expression. ICAM-1 was a functional target of miR-124. ICAM-1 overexpression aggravated hypoxia injury, but inversely, ICAM-1 silence diminished hypoxia damage. Besides, ICAM-1 expression was negatively related with activation of NF-κB and Notch pathways. GAS5-miR-124-ICAM-1 axis could regulate hypoxia injury in PC-12 cells. GAS5 might aggravate hypoxia injury via down-regulating miR-124, then up-regulating ICAM-1, and further enhancing activations of NF-κB and Notch pathways.

Exendin-4 attenuates neuronal death via GLP-1R/PI3K/Akt pathway in early brain injury after subarachnoid hemorrhage in rats

Neuronal apoptosis is considered to be a crucial therapeutic target against early brain injury (EBI) after subarachnoid hemorrhage (SAH). Emerging evidence indicates that Exendin-4 (Ex-4), a glucagon-like peptide 1 receptor (GLP-1R) agonist, plays a neuroprotective role in cerebrovascular disease. This study was conducted in order to verify the neuroprotective role of EX-4 in EBI after SAH in rats. The endovascular perforation model of SAH was performed in Sprague-Dawley rats (n = 153). Ex-4 was intraperitoneally injected 1 h after SAH induction in the rats (SAH + Ex-4). To elucidate the underlying molecular mechanism, small interfering ribonucleic acid (siRNA) for GLP-1R and a specific inhibitor of PI3K, LY294002, were injected intracerebroventricularly into SAH + Ex-4 rats before induction of SAH (n = 6 per group). SAH grading evaluation, immunohistochemistry, Western blots, neurobehavioral assessment, and Fluoro-Jade C (FJC) staining experiments were performed. Expression of GLP-1R was significantly increased and mainly expressed in neurons at 24 h after SAH induction. Administration of Ex-4 significantly improved both short- and long-term neurobehavior in SAH + Ex-4 group compared to SAH + Vehicle group after SAH. Ex-4 treatment significantly increased the expression of GLP-1R, PI3K, p-Akt, Bcl-xl, and Bcl-2, while at the same time was found to decrease expression of Bax in the brain. Effects of Ex-4 were reversed by the intervention of GLP-1R siRNA and LY294002 in SAH + Ex-4+GLP-1R siRNA and SAH + Ex-4+LY294002 groups, respectively. In conclusion, the neuroprotective effect of Ex-4 in EBI after SAH was mediated by attenuation of neuronal apoptosis via GLP-1R/PI3K/Akt signaling pathway, therefore EX-4 should be further investigated as a potential therapeutic agent in stroke patients.

Assessment and Imaging of the Cerebrovascular Glycocalyx.

The glycocalyx is a gel-like layer lining the luminal surface of the endothelium. The glycocalyx exerts an important barrier role because it prevents exposure of plasma components to the endothelial surface. Disruption of the glycocalyx by local inflammation or ischemia results in decreased glycocalyx thickness which is associated with a number of vascular diseases. The cerebrovascular glycocalyx has sparsely been studied, but is of great interest because of its potential role in cerebrovascular disease. In this review, we describe all existing techniques to visualize the glycocalyx and designate techniques that may be suitable for studying the cerebrovascular glycocalyx. A total of seven imaging techniques are discussed thoroughly, including transmission electron microscopy, intravital microscopy, micro-particle image velocimetry, confocal laser scanning microscopy, two-photon laser scanning microscopy, orthogonal polarization spectral imaging and sidestream dark field/oblique imaging. Measurement of serum concentrations of glycocalyx-specific constituents is another method for glycocalyx analysis. Also, we have reviewed the methods of glycocalyx analysis by using these imaging techniques. So far, the cerebrovascular glycocalyx has only been studied in vitro. However, other cerebral microcirculatory properties have been studied in vivo. This suggests that the cerebrovascular glycocalyx can be studied in vivo by using some of the described techniques, when specific software is subjoined to the analysis. In conclusion, we have summarized techniques available for glycocalyx assessment, and explained the significance and technical possibilities regarding cerebrovascular glycocalyx visualization. Cerebrovascular glycocalyx assessment would add valuable information to our understanding of the pathophysiology of cerebrovascular disease. Moreover, as a part of the blood-brain barrier, more knowledge on the cerebrovascular glycocalyx may lead to better understanding of neurodegenerative conditions that are caused by a compromised blood-brain barrier including Alzheimer`s disease, vascular dementia, multiple sclerosis and epilepsy.

Vasorelaxant effects of Shunaoxin pill are mediated by NO/cGMP pathway, HO/CO pathway and calcium channel blockade in isolated rat thoracic aorta

Ethnopharmacological relevanceShunaoxin pill (SNX), one of the famous classical recipes in traditional Chinese medicine, is developed from the “Decoction of Xionggui”. It has been used for treatment of cerebrovascular related diseases. It is well known that vasodilatation plays a very important role in cerebrovascular diseases. The effect of SNX on vasorelaxant activity has not yet been explored. Therefore, we aimed to investigate the vasorelaxant effects of SNX on isolated rat thoracic aorta so as to assess some of the possible mechanisms. We also investigate the gasotransmitter signaling pathway involved which has been rarely reported in isolated rat thoracic aorta before. Aim of the studyThe present study was performed to examine the vasodilative activity of SNX and its mechanisms in isolated rat thoracic aorta. Materials and methodsSNX was studied on isolated rat thoracic aorta in vitro, including endothelium-intact and endothelium-denuded aortic rings. In present study, specific inhibitors including soluble guanylate cyclase (sGC) inhibitor 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), cyclooxygenase (COX) inhibitor indomethacin (INDO), NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME), heme oxygenase-1 (HO-1) inhibitor zinc-protoporphyrin (ZnPP), cystathionine γ-lyase (CSE) inhibitor DL-Propargylglycine (PAG), non-selective K+ channel inhibitor tetraethylammonium chloride (TEA), KV channel inhibitor 4-Aminopyridine (4-AP), and KATP channel inhibitor Glibenclamide (Gli) were used, they were added 20min before NE contraction and then added SNX to induce vasodilation. ResultsRemoval of endothelium or pretreatment of aortic rings (intact endothelium) with L-NAME, ODQ or ZnPP significantly blocked SNX-induced relaxation. Pretreatment with the non-selective K+ channel inhibitor TEA, KV channel inhibitor 4-AP or the KATP channel inhibitor Gli, none of them had influences on the SNX-induced response (p>0.05). Besides, SNX inhibited the contraction triggered by NE in endothelium-denuded rings in Ca2+-free medium. SNX also produced rightward parallel displacement of CaCl2 curves. ConclusionsThese results suggest that SNX can induce less endothelium-dependent and more endothelium-independent vascular relaxation. The NO/cGMP and HO/CO pathways, blockade of Ca2+ channels are inhibition of IP3R mediated Ca2+ mobilization from intracellular stores, are likely involved in this relaxation. Furthermore, the underlying mechanisms of combined compositions in SNX await further investigations.