CircTLK1: A novel regulator involved in VSMC phenotypic switching and the developmental process of atherosclerosis.

Phenotypic switching of vascular smooth muscle cells (VSMCs) is essential for atherosclerosis development. Circular RNA (circRNA) is a specific non-coding RNA that is produced as a closed-loop structure in mammals, and its specific expression pattern is closely related to its cell type and tissue. To clarify the roles of circTLK1 in VSMC phenotypic switching, we performed qRT-PCR, immunoblotting, and immunostaining. qRT-PCR revealed that circTLK1 was upregulated in both mouse models of atherosclerosis in vivo and PDGF (platelet-derived growth factor)-BB-induced VSMCs in vitro. Furthermore, the overexpression of circTLK1 promoted PDGF-BB-induced VSMC phenotypic switching. Conversely, experiments performed in vivo demonstrate that the knockdown of SMC-specific circTLK1 led to a reduction in the development of atherosclerosis. The relationship between circTLK1 and miR-513a-3p and Krüppel-like factor 4 (KLF4) was detected by RNA immunoprecipitation (RIP), luciferase reporter assay, RNA pull-down, and RNA fluorescence in situ hybridization (RNA FISH). Mechanistically, circTLK1 acted as a sponge for miR-513a-3p, leading to the upregulation of KLF4, a key transcription factor for phenotypic switching. Targeting the circTLK1/miR-513a-3p/KLF4 axis may provide a potential therapeutic strategy for atherosclerosis.

The Role of Lipid Subcomponents in the Development of Atherosclerotic Plaques.

Atherosclerosis (AS) is a long-standing cardiovascular and cerebrovascular disease. Its occurrence and development are related to the pathophysiology of lipids including cholesteryl ester (CE), cholesterol, triacylglycerol (TG), and phospholipid (PL). In this review, we focus on the roles and possible mechanisms of different lipid subcomponents in the process of AS, and provide new ideas for the prevention, diagnosis and treatment of AS.

Cytotoxin-associated gene A (CagA) promotes aortic endothelial inflammation and accelerates atherosclerosis through the NLRP3/caspase-1/IL-1ß axis.

Atherosclerosis is a chronic inflammatory disease. Pathophysiological similarities between chronic infections and atherosclerosis triggered interests between these conditions. The seroepidemiological study showed that Helicobacter pylori strains that express cytotoxin-associated gene A (CagA), an oncoprotein and a major virulence factor, was positively correlated with atherosclerosis and related clinical events. Nevertheless, the underlying mechanism is poorly understood. In this study, the seroprevalence of infection by H. pylori and by strains express CagA assessed by enzyme-linked immunosorbent assay (ELISA) showed that the prevalence of CagA strains rather than H. pylori in patients was positively correlated with atherogenesis. Correspondingly, we found that CagA augmented the growth of plaque of ApoE-/- mice in the early stage of atherosclerosis and promoted the expression of adhesion molecules and inflammatory cytokines in mouse aortic endothelial cells (MAECs). Mechanistically, both si-NLRP3 and si-IL-1ß mitigated the promoting effect of CagA on the inflammatory activation of HAECs. In vivo, the inhibition of NLRP3 by MCC950 significantly attenuated the promoting effect of CagA on plaque growth of ApoE-/- mice. We also propose NLRP3 as a potential therapeutic target for CagA-positive H. pylori infection-related atherosclerosis and emphasize the importance of inflammation in atherosclerosis pathology.

An update on the phenotypic switching of vascular smooth muscle cells in the pathogenesis of atherosclerosis.

Vascular smooth muscle cells (VSMCs) are involved in phenotypic switching in atherosclerosis. This switching is characterized by VSMC dedifferentiation, migration, and transdifferentiation into other cell types. VSMC phenotypic transitions have historically been considered bidirectional processes. Cells can adopt a physiological contraction phenotype or an alternative "synthetic" phenotype in response to injury. However, recent studies, including lineage tracing and single-cell sequencing studies, have shown that VSMCs downregulate contraction markers during atherosclerosis while adopting other phenotypes, including macrophage-like, foam cell, mesenchymal stem-like, myofibroblast-like, and osteochondral-like phenotypes. However, the molecular mechanism and processes regulating the switching of VSMCs at the onset of atherosclerosis are still unclear. This systematic review aims to review the critical outstanding challenges and issues that need further investigation and summarize the current knowledge in this field.

sLRP1 (Soluble Low-Density Lipoprotein Receptor-Related Protein 1): A Novel Biomarker for P2Y12 (P2Y Purinoceptor 12) Receptor Expression in Atherosclerotic Plaques.

OBJECTIVE: Recent studies suggest that the P2Y12 (P2Y purinoceptor 12) receptor of vascular smooth muscle cells in atherosclerotic plaques aggravates atherosclerosis, and P2Y12 receptor inhibitors such as CDL (clopidogrel) may effectively treat atherosclerosis. It is imperative to identify an effective biomarker for reflecting the P2Y12 receptor expression on vascular smooth muscle cells in plaques. Approach and Results: We found that there was a positive correlation between the level of circulating sLRP1 (soluble low-density lipoprotein receptor-related protein 1) and the number of LRP1+ α-SMA+ (α-smooth muscle actin), P2Y12+, or P2Y12+ LRP1+ cells in plaques from apoE-/- mice fed a high-fat diet. Furthermore, activation of the P2Y12 receptor increased the expression and shedding of LRP1 in vascular smooth muscle cells by inhibiting cAMP (3'-5'-cyclic adenosine monophosphate)/PKA (protein kinase A)/SREBP-2 (sterol regulatory element binding transcription factor 2). Conversely, genetic knockdown or pharmacological inhibition of the P2Y12 receptor had the opposite effects. Additionally, CDL decreased the number of lesional LRP1+ α-SMA+ cells and the levels of circulating sLRP1 by activating cAMP/PKA/SREBP-2 in apoE-/- mice fed a high-fat diet. CONCLUSIONS: Our study suggests that sLRP1 may be a biomarker that reflects the P2Y12 receptor level in plaques and has the potential to be an indicator for administering P2Y12 receptor inhibitors for patients with atherosclerosis.

Infection and atherosclerosis: TLR-dependent pathways.

Atherosclerotic vascular disease (ASVD) is a chronic process, with a progressive course over many years, but it can cause acute clinical events, including acute coronary syndromes (ACS), myocardial infarction (MI) and stroke. In addition to a series of typical risk factors for atherosclerosis, like hyperlipidemia, hypertension, smoking and obesity, emerging evidence suggests that atherosclerosis is a chronic inflammatory disease, suggesting that chronic infection plays an important role in the development of atherosclerosis. Toll-like receptors (TLRs) are the most characteristic members of pattern recognition receptors (PRRs), which play an important role in innate immune mechanism. TLRs play different roles in different stages of infection of atherosclerosis-related pathogens such as Chlamydia pneumoniae (C. pneumoniae), periodontal pathogens including Porphyromonas gingivalis (P. gingivalis), Helicobacter pylori (H. pylori) and human immunodeficiency virus (HIV). Overall, activation of TLR2 and 4 seems to have a profound impact on infection-related atherosclerosis. This article reviews the role of TLRs in the process of atherosclerosis after C. pneumoniae and other infections and the current status of treatment, with a view to providing a new direction and potential therapeutic targets for the study of ASVD.

Neurologists' attitudes and options for anticoagulation therapy in central China.

AIMS: We aim to find out the factors affecting the use of anticoagulants and the intensity of their choices, and to establish a basis for improving neurologists' effective implementation of the guidelines. METHODS: A cross-sectional study is conducted in Hubei province in central China. Each neurologist completes a standard-structured anonymous questionnaire through face-to-face interviews. The problems include the attitude and options about anticoagulant therapy. RESULTS: A total of 611 neurologists from 38 hospitals respond to this survey. For the best treatment of atrial fibrillation, more than 80% of physicians choose anticoagulant therapy. For patients with atrial fibrillation and cerebral infarction, physicians think that Warfarin is the preferred drug as high as 93.8%. Among the anticoagulant drugs ever used by clinicians, the use rate of Warfarin is 93.8%, but the use rate of direct oral anticoagulants is insufficient. The use of direct oral anticoagulants is related to the educational level and the geographical location of the hospital. Bleeding risk is the first reason influencing clinicians' choice of Warfarin, accounts for 88.9%. 97.7% of the clinicians recommend patients with Warfarin to regularly monitor the INR, but the frequency of monitoring is inconsistent. Clinicians have a high willingness to learn about AF, but the proportion of hospitals that carry out appropriate training is low. CONCLUSIONS: There are still some gaps with the guidelines on the choice of anticoagulant drugs. Neurologists have positive attitude towards anticoagulant therapy and a strong willingness to learn, but the corresponding training is lacking. Continuous professional training is necessary.

Sema3E/PlexinD1 signaling inhibits postischemic angiogenesis by regulating endothelial DLL4 and filopodia formation in a rat model of ischemic stroke.

Angiogenesis is a crucial defense response to hypoxia that regulates the process of raising the promise of long-term neurologic recovery during the management of stroke. A high expression of antiangiogenic factors leads to the loss of neovascularization capacity in pathologic conditions. We have previously documented an impairment of the cerebral vessel perfusion and neovascularization in the cortex neighboring the stroke-induced lesion, which was accompanied by an activation of semaphorin 3E (Sema3E)/PlexinD1 after ischemic stroke. In this study, we employed micro-optical sectioning tomography to fully investigate the details of the vascular pattern, including the capillaries. We found that after transient middle cerebral artery occlusion, inhibiting PlexinD1 signaling led to an organized recovery of the vascular network in the ischemic area. We then further explored the possible mechanisms. In vivo, Sema3E substantially decreased dynamic delta-like 4 (DLL4) expression. In cultured brain microvascular endothelial cells, Sema3E down-regulated DLL4 expression via inhibiting Ras-related C3 botulinum toxin substrate 1-induced JNK phosphorylation. At the microcosmic level, Sema3E/PlexinD1 signaling promoted F-actin disassembly and focal adhesion reduction by activating the small guanosine triphosphatase Ras homolog family member J by releasing RhoGEF Tuba from direct binding to PlexinD1, thus mediating endothelial cell motility and filopodia retraction. Our study reveals that Sema3E/PlexinD1 signaling, which suppressed endothelial DLL4 expression, cell motility, and filopodia formation, is expected to be a novel druggable target for angiogenesis during poststroke progression.-Zhou, Y.-F., Chen, A.-Q., Wu, J.-H., Mao, L., Xia, Y.-P., Jin, H.-J., He, Q.-W., Miao, Q. R., Yue, Z.-Y., Liu, X.-L., Huang, M., Li, Y.-N., Hu, B. Sema3E/PlexinD1 signaling inhibits postischemic angiogenesis by regulating endothelial DLL4 and filopodia formation in a rat model of ischemic stroke.

Exosomal CagA derived from Helicobacter pylori-infected gastric epithelial cells induces macrophage foam cell formation and promotes atherosclerosis.

BACKGROUND: Seroepidemiological studies have highlighted a positive relation between CagA-positive Helicobacter pylori (H. pylori), atherosclerosis and related clinic events. However, this link has not been well validated. The present study was designed to explore the role of H. pylori PMSS1 (a CagA-positive strain that can translocate CagA into host cells) and exosomal CagA in the progression of atherosclerosis. METHODS: To evaluate whether H. pylori accelerates or even induces atherosclerosis, H. pylori-infected C57/BL6 mice and ApoE-/- mice were maintained under different dietary conditions. To identify the role of H. pylori-infected gastric epithelial cells-derived exosomes (Hp-GES-EVs) and exosomal CagA in atherosclerosis, ApoE-/- mice were given intravenous or intraperitoneal injections of saline, GES-EVs, Hp-GES-EVs, and recombinant CagA protein (rCagA). FINDINGS: CagA-positive H. pylori PMSS1 infection does not induce but promotes macrophage-derived foam cell formation and augments atherosclerotic plaque growth and instability in two animal models. Meanwhile, circulating Hp-GES-EVs are taken up in aortic plaque, and CagA is secreted in Hp-GES-EVs. Furthermore, the CagA-containing EVs and rCagA exacerbates macrophage-derived foam cell formation and lesion development in vitro and in vivo, recapitulating the pro-atherogenic effects of CagA-positive H. pylori. Mechanistically, CagA suppresses the transcription of cholesterol efflux transporters by downregulating the expression of transcriptional factors PPARγ and LXRα and thus enhances foam cell formation. INTERPRETATION: These results may provide new insights into the role of exosomal CagA in the pathogenesis of CagA-positive H. pylori infection-related atherosclerosis. It is suggested that preventing and eradicating CagA-positive H. pylori infection could reduce the incidence of atherosclerosis and related events.

MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5.

Blood-brain barrier (BBB) disruption plays a critical role in brain injury induced by cerebral ischemia, and preserving BBB integrity during ischemia could alleviate cerebral injury. We examined the role of miR-130a in ischemic BBB disruption by using models of rat middle cerebral artery occlusion and cell oxygen-glucose deprivation. We found that ischemia significantly increased microRNA-130a (miR-130a) level and that miR-130a was predominantly from brain microvascular endothelial cells. Antagomir-130a, an antagonist of miR-130a, could attenuate brain edema, lower BBB permeability, reduce infarct volume, and improve neurologic function. MiR-130a overexpression induced by miR-130a mimic increased monolayer permeability, and intercellular inhibition of miR-130a by a miR-130a inhibitor suppressed oxygen-glucose deprivation-induced increase in monolayer permeability. Moreover, dual luciferase reporter system showed that Homeobox A5 was the direct target of miR-130a. MiR-130a, by inhibiting Homeobox A5 expression, could down-regulate occludin, thereby increasing BBB permeability. Our results suggested that miR-130a might be implicated in ischemia-induced BBB dysfunction and serve as a target for the treatment of ischemic stroke.-Wang, Y., Wang, M.-D., Xia, Y.-P., Gao, Y., Zhu, Y.-Y., Chen, S.-C., Mao, L., He, Q.-W., Yue, Z.-Y., Hu, B. MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5.

MicroRNA-149-5p regulates blood-brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes.

Blood-brain barrier (BBB) disruption caused by reperfusion injury after ischemic stroke is an intractable event conducive to further injury. Brain pericytes play a vital role in maintaining BBB integrity by interacting with other components of the BBB. In this study, we found that sphingosine-1-phosphate receptor (S1PR)2 expressed in pericytes was significantly up-regulated after ischemia in vivo and in vitro. By using a S1PR2 antagonist (JTE-013), we showed that S1PR2 plays a critical role in the induction of BBB permeability of transient middle cerebral artery occlusion (tMCAO) rats and the in vitro BBB model. Furthermore, we discovered that S1PR2 may decrease N-cadherin expression and increase pericyte migration via NF-κB p65 signal and found that S1PR2 could be regulated by miR-149-5p negatively, which was decreased in the ischemic boundary zone and cultured pericytes after ischemia. Overexpression of miR-149-5p in cultured pericytes substantially increased N-cadherin expression and decreased pericyte migration, which decreased BBB leakage in the in vitro model. Up-regulating miR-149-5p by intracerebroventricular injection of agomir-149-5p attenuated BBB permeability and improved the outcomes of tMCAO rats significantly. Thus, our data suggest that miR-149-5p may serve as a potential target for treatment of BBB disruption after ischemic stroke.-Wan, Y., Jin, H.-J., Zhu, Y.-Y., Fang, Z., Mao, L., He, Q., Xia, Y.-P., Li, M., Li, Y., Chen, X., Hu, B. MicroRNA-149-5p regulates blood-brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes.

MicroRNA-23a-5p promotes atherosclerotic plaque progression and vulnerability by repressing ATP-binding cassette transporter A1/G1 in macrophages.

Disruption of carotid vulnerable atherosclerotic plaque is responsible for acute ischemic stroke (AIS) and the early detection and intervention approach are greatly limited. Undertaking a microarray of microRNAs (miRNAs) in the plasma of AIS patients with carotid vulnerable plaques, miR-23a-5p was markedly elevated and was positively correlated with the plaque progression and vulnerability. Correspondingly, we found that miR-23a-5p expression was significantly increased in both plasma and macrophages from atherosclerosis mice. Bioinformatics analysis and in vitro knockdown experiments identified that ATP-binding cassette transporter A1/G1 as a novel target of miR-23a-5p. Luciferase reporter assays showed that miR-23a-5p repressed the 3' untranslated regions (UTR) activity of ABCA1/G1. Moreover, functional analyses demonstrated that transfection of miR-23a-5p inhibitor enhanced cholesterol efflux and decreased foam cell formation through upregulating ABCA1/G1 expression levels. Furthermore, long term in vivo systemically delivered miR-23a-5p antagomir significantly increased ABCA1/G1 expression in the aorta of ApoE-/- mice. Importantly, the miR-23a-5p antagomir therapy significantly reduced atherosclerosis progression and promoted plaque stability. Our observations indicate that miR-23a-5p promotes macrophage-derived foam cell formation and might be a key regulator contributing to atherosclerotic plaque progression and vulnerability.

Acute stroke patients' knowledge of stroke at discharge in China: a cross-sectional study.

OBJECTIVES: A good mastery of stroke-related knowledge can be of great benefit in developing healthy behaviours. This study surveyed the knowledge about stroke and influencing factors among patients with acute ischaemic stroke (AIS) at discharge in a Chinese province. METHODS: A cross-section study was conducted from November 1, 2014 to January 31, 2015. A total of 1531 AIS patients in Hubei Province completed a questionnaire at discharge. Multivariate linear regression was used to identify the influencing factors of their knowledge of stroke. RESULTS: About 31.2% of the respondents did not know that stroke is caused by blockage or rupture of cerebral blood vessels and 20.3% did not realise they need immediate medical attention after onset. Approximately 50% did not know that sudden blurred vision, dizziness, headache and unconsciousness are the warning signs of stroke. Over 40% were not aware of the risk factors of the condition, such as hypertension, hyperlipidaemia, diabetes mellitus, smoking and obesity. Over 20% had no idea that they need long-term medication and strict control of blood pressure, blood lipids and blood sugar. Their knowledge levels were correlated with regions of residence (P < 0.0001), socioeconomic status (P < 0.05), physical condition (P < 0.01), previous stroke (P < 0.0001) and family members and friends having had a stroke (P < 0.01). CONCLUSIONS: Most AIS patients in Hubei Province, China, had little knowledge of stroke at discharge. Further efforts should be devoted to strengthening the in-hospital education of stroke patients, especially those with a low income and those from rural areas.

P2Y12 Promotes Migration of Vascular Smooth Muscle Cells Through Cofilin Dephosphorylation During Atherogenesis.

OBJECTIVE: P2Y12 is a well-recognized receptor expressed on platelets and the target of thienopyridine-type antiplatelet drugs. However, recent evidence suggests that P2Y12 expressed in vessel wall plays a role in atherogenesis, but the mechanisms remain elusive. In this study, we examined the molecular mechanisms of how vessel wall P2Y12 mediates vascular smooth muscle cells (VSMCs) migration and promotes the progression of atherosclerosis. APPROACH AND RESULTS: Using a high-fat diet-fed apolipoprotein E-deficient mice model, we found that the expression of P2Y12 in VSMCs increased in a time-dependent manner and had a linear relationship with the plaque area. Moreover, administration of P2Y12 receptor antagonist for 12 weeks caused significant reduction in atheroma and decreased the abundance of VSMCs in plaque. In cultured VSMCs, we found that activation of P2Y12 receptor inhibited cAMP/protein kinase A signaling pathway, which induced cofilin dephosphorylation and filamentous actin disassembly, thereby enhancing VSMCs motility and migration. In addition, the number of P2Y12-positive VSMCs was decreased in the carotid artery plaque from patients receiving clopidogrel. CONCLUSIONS: Vessel wall P2Y12 receptor, which promotes VSMCs migration through cofilin dephosphorylation, plays a critical role in the development of atherosclerotic lesion and may be used as a therapeutic target for atherosclerosis.

Identification of novel compound heterozygous SPG7 mutations-related hereditary spastic paraplegia in a Chinese family: a case report.

BACKGROUND: Autosomal recessive hereditary spastic paraplegias (ARHSPs) are a group of clinically and genetically heterogeneous neurodegenerative diseases with progressive spasticity and weakness in the lower limbs. Mutations in the Spastic Paraplegia gene 7 (SPG7) account for about 5-21% of ARHSP cases. However, in Asians, few reports about the mutations exist. In this study, we firstly report a novel finding from a Chinese family with compound heterozygous SPG7 mutations, in which three siblings were affected with a complicated form of ARHSP. CASE PRESENTATION: A 56-year-old man presented with progressive stiffness, weakness and ataxia in the lower limbs. Two sisters of him had similar symptoms and dysarthria. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy in each of the patients. Genetic analysis, which exerted a targeted next generation sequencing (NGS) panel covering 917 comprehensive ataxia genes to the proband, followed by Sanger sequencing of candidate genes in other eight family members, was used to find the etiology of the disease. Ultimately, we identified compound heterozygous SPG7 mutations with two mutations: (c.1150_1150-1insCTAC and c.2062C > T, p.Arg688Trp) and one single nucleotide polymorphism (c.2063G > A, p.Arg688Gln). CONCLUSIONS: The four bases insertion mutation (4bIM) was predicted to cause frameshift mutation or affect the splicing, and the last two variants were led to a stop codon mutation (p.Arg688Ter). As located in highly conserved positions and encoded paraplegin, the mutations were speculated to result in a truncated or defective protein and would be pathogenic factors of the disease. This paper proves to be the first case report of SPG7 mutation in ARHSP reported in Chinese population. Our findings widen the spectrum of SPG7 mutations of ARHSP and indicate that the SPG7 mutation is an important cause of adult-onset undiagnosed ataxia.

LncRNA TUG1 sponges microRNA-9 to promote neurons apoptosis by up-regulated Bcl2l11 under ischemia.

Emerging studies have illustrated that LncRNAs TUG1 play critical roles in multiple biologic processes. However, the LncRNA TUG1 expression and function in ischemic stroke have not been reported yet. In this study, we found that LncRNA TUG1 expression was significantly up-regulated in brain ischemic penumbra from rat middle carotid artery occlusion (MCAO) model, while similar results were also observed in cultured neurons under oxygen-glucose deprivation (OGD) insult. Knockdown of TUG1 decreased the ratio of apoptotic cells and promoted cells survival in vitro, which may be regulated by the elevated miRNA-9 expression and decreased Bcl2l11 protein. Furthermore, TUG1 could directly interact with miR-9 and down-regulating miR-9 could efficiently reverse the function of TUG1 on the Bcl2l11 expression. In summary, our result sheds light on the role of LncRNA TUG1 as a miRNA sponge for ischemic stroke, possibly providing a new therapeutic target in stroke.

MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats.

The mechanism of blood-brain barrier (BBB) disruption, involved in poststroke edema and hemorrhagic transformation, is important but elusive. We investigated microRNA-150 (miR-150)-mediated mechanism in the disruption of BBB after stroke in rats. We found that up-regulation of miR-150 increased permeability of BBB as detected by MRI after permanent middle cerebral artery occlusion in vivo as well as increased permeability of brain microvascular endothelial cells after oxygen-glucose deprivation in vitro. The expression of claudin-5, a key tight junction protein, was decreased in the ischemic boundary zone after up-regulation of miR-150. We found in brain microvascular endothelial cells that overexpression of miR-150 decreased not only cell survival rate but also the expression levels of claudin-5 after oxygen-glucose deprivation. With dual-luciferase assay, we confirmed that miR-150 could directly regulate the angiopoietin receptor Tie-2. Moreover, silencing Tie-2 with lentivirus-delivered small interfering RNA reversed the effect of miR-150 on endothelial permeability, cell survival, and claudin-5 expression. Furthermore, poststroke treatment with antagomir-150, a specific miR-150 antagonist, contributed to BBB protection, infarct volume reduction, and amelioration of neurologic deficits. Collectively, our findings suggested that miR-150 could regulate claudin-5 expression and endothelial cell survival by targeting Tie-2, thus affecting the permeability of BBB after permanent middle cerebral artery occlusion in rats, and that miR-150 might be a potential alternative target for the treatment of stroke.-Fang, Z., He, Q.-W., Li, Q., Chen, X.-L., Baral, S., Jin, H.-J., Zhu, Y.-Y., Li, M., Xia, Y.-P., Mao, L., Hu, B. MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats.

Effect of retinoic acid on expression of LINGO-1 and neural regeneration after cerebral ischemia.

The purpose of this study was to observe the expression of LINGO-1 after cerebral ischemia, investigate the effects of retinoic acid (RA) on the expression of LINGO-1 and GAP-43, and the number of synapses, and to emplore the repressive effect of LINGO-1 on neural regeneration after cerebral ischemia. The model of permanent focal cerebral ischemia was established by the modified suture method of middle cerebral artery occlusion (MCAO) in Sprague-Dawley (SD) rats. The expression of LINGO-1 was detected by Western blotting and that of GAP-43 by immunohistochemistry. The number of synapses was observed by transmission electron microscopy. The SD rats were divided into three groups: sham operation (sham) group, cerebral ischemia (CI) group and RA treatment (RA) group. The results showed that the expression level of LINGO-1 at 7th day after MCAO in sham, CI and RA groups was 0.266 ± 0.019, 1.215 ± 0.063 and 0.702 ± 0.081, respectively (P<0.01). The number of Gap-43-positive nerve cells at 7th day after MCAO in sham, CI and RA group was 0, 59.08 ± 1.76 and 76.20 ± 3.12 per high power field, respectively (P<0.05). The number of synapses at 7th day after MCAO was 8.42 ± 0.13, 1.74 ± 0.37 and 5.39 ± 0.26 per µm², respectively (P<0.05). It is concluded that LINGO-1 expression is up-regulated after cerebral ischemia, and RA inhibits the expression of LINGO-1, promotes the expression of GAP-43 and increases the number of synapses. It suggests that LINGO-1 may be involved in the pathogenesis of cerebral ischemia, which may provide an experimenal basis for LINGO-1 antogonist, RA, for the treatment of cerebral ischemia.

CYP2C19 polymorphism and clinical outcomes among patients of different races treated with clopidogrel: A systematic review and meta-analysis.

Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.