MSC 2021 Virtual E-Abstract

Aim. Stroke is the second significant cause for death, with ischemic stroke (IS) being the main type threatening human being’s health. Acorus tatarinowii (AT) is widely used in the treatment of Alzheimer disease, epilepsy, depression, and stroke, which leads to disorders of consciousness disease. However, the systemic mechanism of AT treating IS is unexplicit. This article is supposed to explain why AT has an effect on the treatment of IS in a comprehensive and systematic way by network pharmacology. Methods and Materials. ADME (absorbed, distributed, metabolized, and excreted) is an important property for screening-related compounds in AT, which were screening out of TCMSP, TCMID, Chemistry Database, and literature from CNKI. Then, these targets related to screened compounds were predicted via Swiss Targets, when AT-related targets database was established. The gene targets related to IS were collected from DisGeNET and GeneCards. IS-AT is a common protein interactive network established by STRING Database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analysed by IS-AT common target genes. Cytoscape software was used to establish a visualized network for active compounds-core targets and core target proteins-proteins interactive network. Furthermore, we drew a signal pathway picture about its effect to reveal the basic mechanism of AT against IS systematically. Results. There were 53 active compounds screened from AT, inferring the main therapeutic substances as follows: bisasaricin, 3-cyclohexene-1-methanol-α,α,4-trimethyl,acetate, cis,cis,cis-7,10,13-hexadecatrienal, hydroxyacoronene, nerolidol, galgravin, veraguensin, 2′-o-methyl isoliquiritigenin, gamma-asarone, and alpha-asarone. We obtained 398 related targets, 63 of which were the same as the IS-related genes from targets prediction. Except for GRM2, remaining 62 target genes have an interactive relation, respectively. The top 10 degree core target genes were IL6, TNF, IL1B, TLR4, NOS3, MAPK1, PTGS2, VEGFA, JUN, and MMP9. There were more than 20 terms of biological process, 7 terms of cellular components, and 14 terms of molecular function through GO enrichment analysis and 13 terms of signal pathway from KEGG enrichment analysis based on P < 0.05 . Conclusion. AT had a therapeutic effect for ischemic via multicomponent, multitarget, and multisignal pathway, which provided a novel research aspect for AT against IS.

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Disorder Genes Regulate the Progression of Ischemic Stroke through the NF-κB Signaling Pathway

BioMed Research International ◽

10.1155/2021/2464269 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Wei Wei ◽

Wenqiang Xin ◽

Yufeng Tang ◽

Zhonglun Chen ◽

Yue Heng ◽

...

Keyword(s):

Ischemic Stroke ◽

Signaling Pathway ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Target Genes ◽

Enrichment Analysis ◽

Differential Gene ◽

Coexpression Network Analysis ◽

Geo Database ◽

Differential Genes

Stroke is an acute cerebrovascular disease, including ischemic and hemorrhagic stroke. Stroke is the second leading cause of death after ischemic heart disease, which accounts for 9% of the global death toll. To explore the molecular mechanisms of the effects of the dysregulated factors, in the GEO database, we obtained transcriptome data from 24 h/72 h of mice with ischemic stroke and 24 h/72 h of normal mice. We then performed differential gene analysis, coexpression analysis, enrichment analysis, and regulator prediction bioinformatics analysis to identify the potential genes. We made a comparison between the ischemic stroke 72 h and the ischemic stroke for 24 h, and 5103 differential genes were obtained ( p < 0.05 ). Four functional barrier modules were obtained by weighted gene coexpression network analysis. The critical genes of each module were ASTL, Zfp472, Fmr1 gene, and Nap1l1. The results of the enrichment analysis showed ncRNA metabolism, microRNAs in cancer, and biosynthesis of amino acids. These three functions and pathways have the most considerable count value. The regulators of the regulatory dysfunction module were predicted by pivotal analysis of TF and noncoding RNA, and critical regulators including NFKB1 (NF-κB1), NFKBIA, CTNNB1, and SP1 were obtained. Finally, the pivotal target gene found that CTNNB1, NFKB1, NFKBia, and Sp1 are involved in 18, 32, 2, and 60 target genes, respectively. Therefore, we believe that NFKB1 and Sp1 have a potential role in the progression of ischemic stroke. The NFKB signaling pathway promotes inflammatory cytokines and regulates the progression of ischemic stroke.

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Isolation and identification of serum exosomes and correlation of its contents with acute ischemic stroke

10.21203/rs.3.rs-108426/v1 ◽

2020 ◽

Author(s):

Pei Yu ◽

Wencheng Chen

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Roc Curve ◽

Target Genes ◽

Quantitative Polymerase Chain Reaction ◽

Disease Diagnosis ◽

Control Group ◽

Isolation And Identification ◽

Diagnostic Potential ◽

Serum Exosomes

Abstract Background Erythrocyte deformability is one of the pathophysiological changes of high-risk factors such as smoking, hypertension and atherosclerosis in stroke. It mainly affects blood viscosity and fluidity in the occurrence, development and outcome of the disease. Exosomes are a new type of biological activity test target, and it mainly contents miRNA, but its effect on stroke is still not clear. Objective To detect the serum exosome-derived miR-150-5p expression in patients with acute ischemic stroke and explore its diagnostic potential for acute ischemic stroke. Methods A total of 84 samples were collected with matched age and gender, collecting relevant laboratory indicators and general clinical data of the research subjects. The kit was used to extract serum exosomes, real-time fluorescent quantitative polymerase chain reaction was used to determine the expression of serum exosomal miR-150-5p, evaluate its value as a diagnostic marker through the ROC curve. Through Randa, Target Scan and other online databases, bioinformatics methods predict the target genes of miR-150, the results are drawn Venny to take intersection analysis, literature screening and ischemic stroke related target genes. Results The exosomes showed elliptical or round membranous vesicles with a diameter between 30–200 nm and fusion phenomenon and detected the exosomal marker proteins CD63 and HSP70; Compared with the control group, the relative expression of exosomal miR-150-5p in patients with acute ischemic stroke was increased (T = 8, P < 0.001). The expression of serum exosomal miR-150-5p in the disease group at different time points after stroke, the difference was not statistically significant(Chi-square = 2.925, P = 0.232); the area under the ROC curve was 0.883. bioinformatics prediction analysis of miR-150 target genes, which may be involved in the development of stroke disease through EGR2 and PLP2, as well as erythrocyte membrane protein-related genes SLC4A1 and SPTB also belong to the miR-150 prediction targets. Conclusion The expression of exosome-derived miR-150-5p is relatively high in patients with acute stroke, and it has a certain potential for early disease diagnosis.

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Integrated analysis of ischemic stroke datasets revealed sex and age difference in anti-stroke targets

PeerJ ◽

10.7717/peerj.2470 ◽

2016 ◽

Vol 4 ◽

pp. e2470 ◽

Cited By ~ 13

Author(s):

Wen-Xing Li ◽

Shao-Xing Dai ◽

Qian Wang ◽

Yi-Cheng Guo ◽

Yi Hong ◽

...

Keyword(s):

Ischemic Stroke ◽

Target Genes ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Integrated Analysis ◽

Age Difference ◽

Differential Expression Genes ◽

Males And Females ◽

Young Subjects ◽

Microarray Datasets

Ischemic stroke is a common neurological disorder and the burden in the world is growing. This study aims to explore the effect of sex and age difference on ischemic stroke using integrated microarray datasets. The results showed a dramatic difference in whole gene expression profiles and influenced pathways between males and females, and also in the old and young individuals. Furthermore, compared with old males, old female patients showed more serious biological function damage. However, females showed less affected pathways than males in young subjects. Functional interaction networks showed these differential expression genes were mostly related to immune and inflammation-related functions. In addition, we found ARG1 and MMP9 were up-regulated in total and all subgroups. Importantly, IL1A, ILAB, IL6 and TNF and other anti-stroke target genes were up-regulated in males. However, these anti-stroke target genes showed low expression in females. This study found huge sex and age differences in ischemic stroke especially the opposite expression of anti-stroke target genes. Future studies are needed to uncover these pathological mechanisms, and to take appropriate pre-prevention, treatment and rehabilitation measures.

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Systematic Investigation of the Effect of Powerful Tianma Eucommia Capsule on Ischemic Stroke Using Network Pharmacology

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/8897313 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Pengcheng Feng ◽

Guixia Li ◽

Yan Huang ◽

Jinhong Pei

Keyword(s):

Ischemic Stroke ◽

Amino Acid ◽

Molecular Mechanism ◽

Gene Network ◽

Target Gene ◽

Target Genes ◽

Enrichment Analysis ◽

Receptor Activity ◽

Signal Pathways ◽

Therapeutic Effects

Background. Ischemic stroke (IS) is a serious disease with a high rate of death and disability, and a growing number of people are becoming victims. Existing drugs not only have limited therapeutic effects but also have obvious side effects. Most importantly, drug resistance due to long-term or improper use of drugs is detrimental to patients. Therefore, it is urgent to find some alternative or supplementary medicines to alleviate the current embarrassment. Powerful Tianma Eucommia Capsule (PTEC) is mainly used to treat IS in China for thousands of years; however, the molecular mechanism is not clear. Methods. Pharmacology ingredients and target genes were filtered and downloaded from websites. A pharmacology ingredient-target gene network was constructed to predict the molecular interactions between ingredients and target genes. Enrichment analysis was performed to explore the possible signal pathways. LeDock was used to simulate the interaction form between proteins and main active ingredients and to deduce key amino acid positions. Results. Two hundred eighty-nine target genes and seventy-four pharmacological ingredients were obtained from public databases. Several key ingredients (quercetin, kaempferol, and stigmasterol) and primary core target genes (PTGS1, NCOA2, and PRSS1) were detected through ingredient-target gene network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrated that ingredients affect networks mainly in nuclear receptor activity and G protein-coupled amine receptor activity; besides, fluid shear stress and atherosclerosis, human cytomegalovirus infection, and hepatitis B signaling pathways might be the principal therapy ways. A series of presumed key amino acid sites (189ASP, 190SER, 192GLN, 57HIS, and 99TYE) were calculated in PRSS1. Six of the target genes were differentially expressed between male and female patients. Conclusions. Seven new putative target genes (ACHE, ADRA1A, AR, CHRM3, F7, GABRA1, and PRSS1) were observed in this work. Based on the result of GO and KEGG analysis, this work will be helpful to further demonstrate the molecular mechanism of PTEC treatment of IS.

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Abstract WP127: Intravenous Administration of Microrna-122 Mimic for Treatment of Ischemic and Hemorrhagic Strokes in Rats

Stroke ◽

10.1161/str.51.suppl_1.wp127 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

DaZhi Liu

Keyword(s):

Ischemic Stroke ◽

Drug Targets ◽

Target Genes ◽

Time Window ◽

Artery Occlusion ◽

Luciferase Reporter ◽

Mirna Expression Data ◽

Reporter Assays ◽

Target Binding

MicroRNAs(miRs)are very promising next generation drug targets due to their unique miR-target binding that is different from the traditional ligand-receptor. A single miR binds to complementary bases in the 3’ untranslated regions(3’UTR) of hundreds of target genes and down-regulates these genes. MiR therapeutics have been developed for treatment of various diseases, with several miR drugs(e.g., miR-122/miR-155 inhibitors, miR-16/29/34 mimics) being advanced into human trials in the last decade. Our previous studies showed that intravenous (i.v.) miR-122 mimic (2.4mg/kg, wrapped in PEG-liposomes) improves outcomes after suture middle cerebral artery occlusion(MCAO)-induced ischemic stroke (IS) with a 6 hour time window. In pilot whole genome miR expression studies, we demonstrated that microRNA-122 (miR-122) is the most significantly decreased miR in blood after intraventricularautologousfresh blood-induced intracerebral hemorrhage (ICH) in rats. As compared to sham controls, miR-122 decreased 28 fold at 3 hrs, 34 fold at 24 hrs, 31 fold at 7 days and 19 fold at 14 days in blood after ICH in rats. These miRNA expression data suggest that elevating miR-122 in blood has great potential to treat ICH in addition to IS. Therefore, we hypothesized that i.v. miR-122 mimic improves outcomes after ICH, in addition to IS. Our miR-122 targetome studies show that a set of miR-122 target genes (Pla2g2a, Vcam1, Nos2, Rhbdf1, Olig1, Nrep) are responsible for the therapeutic efficacy of miR-122 mimic on ischemic stroke, while another set of genes (Ywhaq, Klrk1, Tpst1, Vars2)account for efficacy in ICH. Using3’UTR luciferase reporter assays and anti-sense Morpholino Oligos (MOs), we show that miR-122 binds to 3’UTR of its target genes Pla2g2a and Vcam1, rather than Nos2. In addition, in vivo MO-miR-122-Pla2g2a blocks miR-122 mimic treatment-induced decrease of Pla2g2a in blood cells after ischemic stroke. In summary, our data suggest miR-122 mimic can treat IS and ICH. Therefore, the miR-122 mimic treatment for IS and ICH could likely be performed without brain imaging (e.g. in the ambulance, and/or emergency room) since it is broadly efficacious for both IS and ICH.

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Abstract WP424: Let7i Microrna Regulates Immune Response in Patients with Ischemic Stroke

Stroke ◽

10.1161/str.48.suppl_1.wp424 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Glen C Jickling ◽

Bradley P Ander ◽

Natasha Shroff ◽

Boryana Stamova ◽

Cheryl Dykstra-Aiello ◽

...

Keyword(s):

Immune Response ◽

Transcriptional Regulation ◽

Ischemic Stroke ◽

Brain Injury ◽

Acute Ischemic Stroke ◽

Target Genes ◽

Luciferase Assay ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Post Transcriptional Regulation

Background and Purpose: The immune system responds rapidly following ischemic brain injury and can contribute to the final extent of brain damage. microRNA are differentially expressed in leukocytes following ischemic stroke and may regulate the immune response to ischemic brain injury. In this study we evaluate microRNA let7i-5p in ischemic stroke and its regulation of leukocytes. Methods: A total of 212 patients were studied; 106 with acute ischemic stroke and 106 risk factor matched controls. . RNA from circulating leukocytes was isolated from blood collected in PaxGene tubes. Let7i-5p miRNA expression was assessed by Taqman qRT-PCR. Given microRNAs act to destabilize and degrade their target mRNA, mRNA that inversely correlated with let7i were identified. To demonstrate let7i post-transcriptional regulation of target genes, a 3’UTR luciferase assay was performed. Target protein expression was assessed by ELISA. Results: Let7i was decreased in patients with acute ischemic stroke (fold change -1.70, p<0.00001). A modest inverse correlation between let7i and NIH Stroke Scale at admission (r= -0.32, p=0.02), infarct volume (r= -0.21, p=0.04) and plasma MMP9 (r= -0.46, p=0.01) was identified. The decrease in let7i was associated with increased expression of several of its messenger RNA targets including CD86, CXCL8 and HMGB1. In vitro studies confirm let7i post-transcriptional regulation of target genes CD86, CXCL8 and HMGB1. Functional analysis predicted let7i regulates pathways involved in leukocyte activation, recruitment, and proliferation including canonical pathways CD86 signaling in T helper cells, HMGB1 signaling, and CXCL8 signaling. Conclusions: Let7i is decreased in circulating leukocytes of patients with acute ischemic stroke. Mechanisms by which let7i regulates inflammatory response post-stroke include targeting CD86, CXCL8 and HMGB1.

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Abstract WP329: The Role of miR-34b/c in Global Ischemic Stroke

Stroke ◽

10.1161/str.51.suppl_1.wp329 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Hyae-Ran Byun ◽

Morgan Porch ◽

Fabrizio Pontarelli ◽

Brenda L Court Vazquez ◽

R.Suzanne Zukin ◽

...

Keyword(s):

Ischemic Stroke ◽

Cognitive Deficits ◽

Neuronal Death ◽

Target Genes ◽

Pyramidal Neurons ◽

Unmet Need ◽

Global Ischemia ◽

Hippocampal Ca1

Transient global ischemia arising as a consequence of cardiac arrest in humans causes selective, delayed death of hippocampal CA1 pyramidal neurons and cognitive impairment. Effective treatments to ameliorate the neurodegeneration and cognitive dysfunction associated with global ischemia are an unmet need. Emerging evidence points to a widespread role for microRNAs (miRNAs) as key modulators of target gene expression in neurons. Accordingly, dysregulation of miRNAs are implicated in the pathophysiology of neurodegenerative disease and neurological disorders. Our findings, derived via miRNA-seq, indicate that expression of a subset of microRNAs are altered in postischemic CA1 including miR-34b/c, miR-21, miR-331, miR-181 and miR-29. Ingenuity pathway analysis reveals that miR-34b/c is the leading miR candidate implicated in cell death and survival. A role for miR-34 in the pathogenesis of global ischemia is, as yet, unclear. Here we show ischemia induces p53-dependent activation of miR-34b/c and downregulation of its target genes Bcl-2 and Sirt1, which together promote neuronal death in selectively vulnerable hippocampal CA1 in vivo . Consistent with this, inhibition of miR-34b/c affords neuroprotection, rescues impaired synaptic plasticity and reduces memory deficits in global ischemia. These findings document a causal role for p53-dependent activation of miR-34b/c in neuronal death and identify a novel therapeutic target for amelioration of the neurodegeneration and cognitive deficits associated with ischemic stroke.

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Bioinformatics method combined with logistic regression analysis reveal potentially important miRNAs in ischemic stroke

Bioscience Reports ◽

10.1042/bsr20201154 ◽

2020 ◽

Vol 40 (8) ◽

Author(s):

Zhiqiang Wei ◽

Xingdi Qi ◽

Yan Chen ◽

Xiaoshuang Xia ◽

Boyu Zheng ◽

...

Keyword(s):

Logistic Regression ◽

Regression Analysis ◽

Ischemic Stroke ◽

Logistic Regression Analysis ◽

Target Genes ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Bioconductor Package ◽

Diagnostic Signature

Abstract Purpose: The present study aimed to investigate the comprehensive differential expression profile of microRNAs (miRNAs) by screening for miRNA expression in ischemic stroke and normal samples. Methods: Differentially expressed miRNA (DEM) analysis was conducted using limma R Bioconductor package. Target genes of DEMs were identified from TargetScanHuman and miRTarBase databases. Functional enrichment analysis of the target genes was performed using clusterProfiler R Bioconductor package. The miRNA-based ischemic stroke diagnostic signature was constructed via logistic regression analysis. Results: Compared with the normal cohort, a total of 14 DEMs, including 5 up-regulated miRNAs and 9 down-regulated miRNAs, were identified in ischemic stroke patients. These DEMs have 1600 regulatory targets. Using a logistic regression model, the top five miRNAs were screened for constructing an miRNA-based ischemic stroke diagnostic signature. Using the miRNA–mRNA interaction pairs, two target genes (specificity protein 1 (SP1) and Argonaute 1 (AGO1)) were speculated to be the primary genes of ischemic stroke. Discussion and conclusion: Here, several potential miRNAs biomarkers were identified and an miRNA-based diagnostic signature for ischemic stroke was established, which can be a valuable reference for future clinical researches.

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Dysregulation of Principal Circulating miRNAs in Non-human Primates Following Ischemic Stroke

Frontiers in Neuroscience ◽

10.3389/fnins.2021.738576 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jian Chen ◽

Haiping Zhao ◽

Yuyou Huang ◽

Yuqian Li ◽

Junfen Fan ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Target Genes ◽

Coiled Coil ◽

Differentially Expressed ◽

Research Progress ◽

Protein Subunit ◽

Chemokine Signaling ◽

Plasma Microrna ◽

Pathway Analyses

Despite the recent interest in plasma microRNA (miRNA) biomarkers in acute ischemic stroke patients, there is limited knowledge about the miRNAs directly related to stroke itself due to the multiple complications in patients, which has hindered the research progress of biomarkers and therapeutic targets of ischemic stroke. Therefore, in this study, we compared the differentially expressed miRNA profiles in the plasma of three rhesus monkeys pre- and post-cerebral ischemia. After cerebral ischemia, Rfam sequence category revealed increased ribosomic RNA (rRNA) and decreased transfer RNAs (tRNAs) in plasma. Of the 2049 miRNAs detected after cerebral ischemia, 36 were upregulated, and 76 were downregulated (fold change ≥2.0, P < 0.05). For example, mml-miR-191-5p, miR-421, miR-409-5p, and let-7g-5p were found to be significantly overexpressed, whereas mml-miR-128a-5p_R − 2, miR-431_R − 1, and let-7g-3p_1ss22CT were significantly downregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed miRNAs were implicated in the regulation of ubiquitin-mediated proteolysis and signaling pathways in cancer, glioma, chronic myeloid leukemia, and chemokine signaling. miRNA clustering analysis showed that mml-let-7g-5p and let-7g-3p_1ss22CT, which share three target genes [RB1-inducible coiled-coil 1 (RB1CC1), G-protein subunit γ 5 (GNG5), and chemokine (C-X-C motif) receptor 4 (CXCR4)], belong to one cluster, were altered in opposite directions following ischemia. These data suggest that circulating mml-let-7g may serve as a therapeutic target for ischemic stroke.

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