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

Dynamic Changes in Yeast Phosphatase Families Allow for Specialization in Phosphate and Thiamine Starvation

Convergent evolution is often due to selective pressures generating a similar phenotype. We observe relatively recent duplications in a spectrum of Saccharomycetaceae yeast species resulting in multiple phosphatases that are regulated by different nutrient conditions – thiamine and phosphate starvation. This specialization is both transcriptional and at the level of phosphatase substrate specificity. In Candida glabrata, loss of the ancestral phosphatase family was compensated by the co-option of a different histidine phosphatase family with three paralogs. Using RNA-seq and functional assays, we identify one of these paralogs, CgPMU3, as a thiamine phosphatase. We further determine that the 81% identical paralog CgPMU2 does not encode thiamine phosphatase activity; however, both are capable of cleaving the phosphatase substrate, 1-napthyl-phosphate. We functionally demonstrate that members of this family evolved novel enzymatic functions for phosphate and thiamine starvation, and are regulated transcriptionally by either nutrient condition, and observe similar trends in other yeast species. This independent, parallel evolution involving two different families of histidine phosphatases suggests that there were likely similar selective pressures on multiple yeast species to recycle thiamine and phosphate. In this work, we focused on duplication and specialization, but there is also repeated loss of phosphatases, indicating that the expansion and contraction of the phosphatase family is dynamic in many Ascomycetes. The dynamic evolution of the phosphatase gene families is perhaps just one example of how gene duplication, co-option, and transcriptional and functional specialization together allow species to adapt to their environment with existing genetic resources

Association of two hub genes with the lung related traits and lung cancer from GWAS catalog database.

Association of two hub genes with the lung related traits and lung cancer from GWAS catalog database.</p

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

Fig 1 -

B Analysis of COPD differentially expressed genes (DEGs) in comparison to corresponding controls (A) Volcano plots of log fold changes in gene expression. (B) Identification of 63 common DEGs from blood and lung tissue datasets using VENNY. The overlapped area defines the shared DEGs of lung tissue and blood. (C) Heatmap of DEGs with a LogFC > 1.5. Red: up-regulation; green: down-regulation.</p

Development, optimization, and evaluation of luliconazole nanoemulgel for the treatment of fungal infection

The present study aimed to optimize luliconazole nanoemulsion using Box–Behnken statistical design, which was further incorporated into the polymeric gel of Carbopol 934. The formulation was characterized for its size, entrapment efficiency, ex vivo permeation, and mechanism of release. The size of the dispersed globules of the optimized drug-loaded nanoemulsion was found to be 17 ± 3.67 nm with a polydispersity index (PDI) less than 0.5. Although the surface charge was recorded at –9.53 ± 0.251, the stability was maintained by the polymeric matrix that prevented aggregation and coalescence of the dispersed globules. The luliconazole-nanoemulgel (LUL-NEG) was characterized for drug content analysis, viscosity, pH, and refractive index, where the results were found to be 99.06 ± 0.59%, 9.26 ± 0.08 Pa.s, 5.65 ± 0.17, and 1.31 ± 0.08, respectively. The permeation across the rat skin was found to be significantly higher with LUL-NEG when compared with LUL gel. Furthermore, the skin irritation test performed in experimental animals revealed that the blank NEG, as well as the LUL-NEG, did not produce any signs of erythema following 48 h exposure. In addition, the histopathological findings of the experimental skins reported no abnormal signs at the formulation application site. Finally, the NEG formulation was found to create a statistically significant zone of inhibition (P < 0.05) when compared to all other test groups. Overall, it could be summarized that the nanoemulgel approach of delivering luliconazole across the skin to treat skin fungal infections could be a promising strategy