Platelets as drivers of ischemia/reperfusion injury after stroke.

Ischemic stroke is a leading cause of morbidity and mortality worldwide and, despite reperfusion either via thrombolysis or thrombectomy, stroke patients often suffer from lifelong disabilities. These persistent neurological deficits may be improved by treating the ischemia/reperfusion (I/R) injury that occurs following ischemic stroke. There are currently no approved therapies to treat I/R injury, and thus it is imperative to find new targets to decrease the burden of ischemic stroke and related diseases. Platelets, cell fragments from megakaryocytes, are primarily known for their role in hemostasis. More recently, investigators have studied the nonhemostatic role of platelets in inflammatory pathologies, such as I/R injury after ischemic stroke. In this review, we seek to provide an overview of how I/R can lead to platelet activation and how activated platelets, in turn, can exacerbate I/R injury after stroke. We will also discuss potential mechanisms by which platelets may ameliorate I/R injury

Gender Parity in Authorship of Published Randomized Clinical Trials in Stroke Neurology From 2000 to 2021.

Gender parity is a crucial goal in clinical medicine so that women have equal access and representation. Although approximately half (46%) of US neurology residents and fellows are female, proportions of female assistant, associate, and full professors are 49%, 41%, and 23%, respectively. This has far-reaching effects, from clinical publications to invited speakerships.Although a study noted increasing trends in female authorship in high-impact neurology journals the current literature lacks evidence on a more informative benchmark—first and last authorship in randomized clinical trials (RCTs), which is typically considered for career advancement. This study assessed annual proportions and trends of female first and last authorship in neurovascular (stroke) RCTs from 2000 to 2021

The histone deacetylase inhibitor tubacin mitigates endothelial dysfunction by up-regulating the expression of endothelial nitric oxide synthase.

Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo.Wefound that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found that these effects were not mediated by tubacin\u27s inhibitory effect on HDAC6 activity, but rather were due to its ability to stabilize eNOS mRNA transcripts. Consistent with these findings, tubacin also inhibited proinflammatory cytokine-induced degradation of eNOS transcripts and impairment of endothelium-dependent relaxation in the mouse aorta. Furthermore, we found that tubacin-induced up-regulation in eNOS expression in vivo is associated with improved endothelial function in diabetic db/db mice and with a marked attenuation of ischemic brain injury in a murine stroke model. Our findings indicate that tubacin exhibits potent eNOS-inducing effects and suggest that this compound might be useful for the prevention or management of endothelial dysfunction-associated cardiovascular diseases. © 2019 Chen et al

The Role of Platelets in Remote Organ Injury and Infection After Stroke

Strokes are a leading cause of death globally, and the leading cause of preventable disability in the United States. The current clinical management of ischemic strokes is removing the occlusion to allow for reperfusion. However, the subsequent reperfusion can lead to increased tissue death and further pathologies such as remote organ injury (ROI) and infection. During the post-acute state of recovery, stroke victims most commonly die due to stroke-associated infection, predominantly pneumonia. Platelets get activated after ischemic stroke and can then circulate throughout the body, but whether platelets affect ROI after stroke has not been studied. Following transient Middle Cerebral Artery Occlusion (tMCAO) with 1h of ischemia, we found that stroke significantly increased platelet adhesion and P-selectin expression, suggesting that stroke/reperfusion increases platelet activity. To specifically investigate the role of platelets in ROI after stroke, we depleted platelets from mice 1 day after tMCAO, as cerebral infarct size does not increase after 1 day. Excitingly, platelet depletion significantly improved survival of mice after stroke, compared to vehicle-treated mice, along with preventing damage to the intestinal villi, attenuating intestinal epithelial and vascular permeability, and dramatically reducing bacteria in the liver, spleen, and the bronchoalveolar lavage fluid (BALF) after stroke. After rectally instilling Ampicillin-resistant, green fluorescent protein expressing E. coli into sham and stroke mice, we found that platelet depletion dramatically reduced bacterial translocation across all observed tissues. Lastly, we used DC101 (a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist) and various antiplatelet therapies, including aspirin and clopidogrel, to decrease platelet mediated ROI and infection after stroke. Promisingly, all of these treatments decreased the number of bacteria in the BALF of post-stroke mice, compared to vehicle treated mice. Thus, our studies show, for the first time, that platelets promote ROI and infection after stroke and, very excitingly, targeting platelet activity may be a promising therapeutic target to help in the recovery of stroke patients

Expression levels in lung adenocarcinoma and lung squamous cell carcinoma cells in compression to normal tissues from GEPIA2.

A) SREK1. B) IRAK2. C) DDX3Y. D) C1QTNF2. The signature score is calculated by mean value of log2 (TPM + 1). The |Log2FC| cutoff of the expression of proposed biomarker was 1. The p-value cutoff of the expression of proposed biomarker was 0.01. The red box indicates the tumor samples while the gray one represents the normal tissues. E. Pathological Stage Plot of SREK1, IRAK2, DDX3Y and C1QTNF2 genes in lung cancer.</p

DataSheet2_A comparative mRNA- and miRNA transcriptomics reveals novel molecular signatures associated with metastatic prostate cancers.docx

Background: Prostate cancer (PC) is a fatally aggressive urogenital cancer killing millions of men, globally. Thus, this study aims to identify key miRNAs, target genes, and drug targets associated with prostate cancer metastasis.Methods: The miRNA and mRNA expression datasets of 148 prostate tissue biopsies (39 tumours and 109 normal tissues), were analysed by differential gene expression analysis, protein interactome mapping, biological pathway analysis, miRNA-mRNA networking, drug target analysis, and survival curve analysis.Results: The dysregulated expression of 53 miRNAs and their 250 target genes involved in Hedgehog, ErbB, and cAMP signalling pathways connected to cell growth, migration, and proliferation of prostate cancer cells was detected. The subsequent miRNA-mRNA network and expression status analysis have helped us in narrowing down their number to 3 hub miRNAs (hsa-miR-455-3p, hsa-miR-548c-3p, and hsa-miR-582-5p) and 9 hub genes (NFIB, DICER1, GSK3B, DCAF7, FGFR1OP, ABHD2, NACC2, NR3C1, and FGF2). Further investigations with different systems biology methods have prioritized NR3C1, ABHD2, and GSK3B as potential genes involved in prostate cancer metastasis owing to their high mutation load and expression status. Interestingly, down regulation of NR3C1 seems to improve the prostate cancer patient survival rate beyond 150 months. The NR3C1, ABHD2, and GSK3B genes are predicted to be targeted by hsa-miR-582-5p, besides some antibodies, PROTACs and inhibitory molecules.Conclusion: This study identified key miRNAs (miR-548c-3p and miR-582-5p) and target genes (NR3C1, ABHD2, and GSK3B) as potential biomarkers for metastatic prostate cancers from large-scale gene expression data using systems biology approaches.</p

DataSheet1_A comparative mRNA- and miRNA transcriptomics reveals novel molecular signatures associated with metastatic prostate cancers.docx

Background: Prostate cancer (PC) is a fatally aggressive urogenital cancer killing millions of men, globally. Thus, this study aims to identify key miRNAs, target genes, and drug targets associated with prostate cancer metastasis.Methods: The miRNA and mRNA expression datasets of 148 prostate tissue biopsies (39 tumours and 109 normal tissues), were analysed by differential gene expression analysis, protein interactome mapping, biological pathway analysis, miRNA-mRNA networking, drug target analysis, and survival curve analysis.Results: The dysregulated expression of 53 miRNAs and their 250 target genes involved in Hedgehog, ErbB, and cAMP signalling pathways connected to cell growth, migration, and proliferation of prostate cancer cells was detected. The subsequent miRNA-mRNA network and expression status analysis have helped us in narrowing down their number to 3 hub miRNAs (hsa-miR-455-3p, hsa-miR-548c-3p, and hsa-miR-582-5p) and 9 hub genes (NFIB, DICER1, GSK3B, DCAF7, FGFR1OP, ABHD2, NACC2, NR3C1, and FGF2). Further investigations with different systems biology methods have prioritized NR3C1, ABHD2, and GSK3B as potential genes involved in prostate cancer metastasis owing to their high mutation load and expression status. Interestingly, down regulation of NR3C1 seems to improve the prostate cancer patient survival rate beyond 150 months. The NR3C1, ABHD2, and GSK3B genes are predicted to be targeted by hsa-miR-582-5p, besides some antibodies, PROTACs and inhibitory molecules.Conclusion: This study identified key miRNAs (miR-548c-3p and miR-582-5p) and target genes (NR3C1, ABHD2, and GSK3B) as potential biomarkers for metastatic prostate cancers from large-scale gene expression data using systems biology approaches.</p