Prognostic Significance and Gene Co-Expression Network of PLAU and PLAUR in Gliomas

The urokinase-type plasminogen activator(PLAU) and its receptor PLAUR participate in a series of cell physiological activities on the extracellular surface. Abnormal expression of PLAU and PLAUR is associated with tumorigenesis. This study aims to evaluate the prognostic value of PLAU/PLAUR transcription expression in glioma and to explore how they affect the generation and progression of glioma. In this study, online databases are applied, such as Oncomine, GEPIA, CGGA, cBioPortal, and LinkedOmics. Overexpression of PLAU/PLAUR was found to be significantly associated with clinical variables including age, tumor type, WHO grade, histology, IDH-1 mutation, and 1p19q status. PLAU and PLAUR had a high correlation in transcriptional expression levels. High expression of PLAU and PLAUR predicted a poor prognosis in primary glioma and recurrent glioma patients, especially in lower grade gliomas. Cox regression analysis indicated that high expression of PLAU and PLAUR were independent prognostic factors for shorter overall survival in glioma patients. In gene co-expression network analysis PLAU and PLAUR and their co-expression genes were found to be involved in inflammatory activities and tumor-related signaling pathways. In conclusion, PLAU and PLAUR could be promising prognostic biomarkers and potential therapeutic targets of glioma patients.

Tenecteplase use in the management of acute ischemic stroke: Literature review and clinical considerations

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Several research articles have been published within the last decade comparing the use of tenecteplase to alteplase in ischemic stroke management. Prior reporting on the comparative therapeutic efficacy and safety profiles of tenecteplase and alteplase is reviewed. Summary Tenecteplase is a variant of native tissue-type plasminogen activator, which rapidly promotes thrombolysis by catalyzing formation of the serine protease plasmin. Tenecteplase has theoretical advantages over alteplase as it has greater fibrin specificity and has a longer half-life than alteplase. This allows the administration of a single bolus over 5 to 10 seconds, as opposed to a bolus followed by a 1-hour infusion with alteplase. While currently approved by the Food and Drug Administration for the treatment of ST-segment elevation myocardial infarction, tenecteplase has also been studied in the treatment of acute ischemic stroke and has extensive data for this off-label indication. The most comprehensive trials to date evaluating the use of tenecteplase in acute ischemic stroke include the TNK-S2B, Australian TNK, ATTEST, Nor-Test, and EXTEND-IA TNK trials. Findings from these randomized controlled studies suggest that tenecteplase is at least as efficacious as alteplase in terms of neurological outcomes. The majority of these studies also reported a trend toward improved safety profiles with the use of tenecteplase. Conclusion Current clinical evidence shows that tenecteplase is not inferior to alteplase for the treatment of ischemic stroke and suggests that tenecteplase may have a superior safety profile. Furthermore, tenecteplase also has practical advantages in terms of its administration. This can potentially lead to a decrease in medication errors and improvement in door to thrombolytic time.

Pharmacophore Modeling, Docking, and Molecular Dynamics Simulation of Flavonoids as Inhibitors of Urokinase-type Plasminogen Activator

The urokinase-type plasminogen activator (uPA) system plays a significant role in the invasion and metastasis of cancer cells. The present study was conducted to investigate natural product compounds as inhibitors and hit molecules of uPA using in-silico analysis. A pharmacophore model was built to screen the Indonesian Herbal Database (HerbalDB) to obtain inhibitors of different scaffolds. Based on the molecular docking score, four ligands were selected as potential uPA inhibitors. Subsequently, the stability of the ligand-uPA complex was analyzed using molecular dynamics (MD) simulation. An RMSD graph of the backbone protein and the RMSF values of the amino acid residues were also determined. In addition, the MM-PBSA method was applied to calculate the free binding energy. According to the results, Model_3, characterized by aromatic rings 23 (F1 and F2), cationic H-bond donor (F3), and metal ligator (F4) features, had an adequate goodness-of-hit score (GH). The four top-ranked ligands, isorhamnetin, rhamnetin, quercetin, and kaempferol, showed higher docking scores compared to the others. This study confirmed that isorhamnetin, rhamnetin, and kaempferol build stable complexes with uPA with lower binding energy than quercetin.

Antithrombotic Activity of Heparinoid G2 and Its Derivatives from the Clam Coelomactra antiquata

Clam heparinoid G2 (60.25 kDa) and its depolymerized derivatives DG1 (24.48 kDa) and DG2 (6.75 kDa) prepared from Coelomactra antiquata have been documented to have excellent fibrinolytic and anticoagulant activity. In this study, to further explore the antithrombotic activity of G2, DG1 and DG2, azure A, sheep plasma, and clot lytic rate assays were used to determine their anticoagulant and thrombolytic activity in vitro. The results indicated that the anticoagulant titer of G2 was approximately 70% that of heparin and the thrombolytic activity of DG2 was greater than G2, DG1, and heparin activities. Moreover, in a carrageenan-induced venous thrombosis model, oral administration of G2 and DG1 each at 20 mg/kg and 40 mg/kg for 7 days significantly reduced blacktail thrombus formation, increased tissue-type plasminogen activator, fibrin degradation products, and D-dimer levels, decreased von Willebrand factor and thromboxane B2 levels, and restored phylum and genus abundance changes of intestinal bacteria. DG2 had no antithrombotic effect. At 20 mg/kg, G2, DG1, and heparin had comparable antithrombotic activities, and DG1 at 40 mg/kg had more muscular antithrombotic activity than G2. Thus, DG1 could be an antithrombotic oral agent owing to its more robust antithrombotic activity and lower molecular weight.

Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival

Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the recruitment of N-Methyl-D-Aspartate receptors (NMDARs) and to the endocytosis and proteasome-dependent degradation of NMDARs containing the GluN2B subunit. Accordingly, tc-tPA down-regulated GluN2B-NMDAR-driven signalling, a process prevented by blockers of HGFR/MET and mimicked by its agonists, leading to a modulation of neuronal death. Thus, our present study unmasks a new mechanism of action of tPA, with its two-chains form mediating a crosstalk between MET and the GluN2B subunit of NMDARs to control neuronal survival.

Nursing Skill and Responsibility in Administration of Injection Actilyse

Actilyse can break blood clots that form in the heart, blood arteries, or lungs during a heart attack. This medication is also given to stroke patients to improve recovery and reduce the likelihood of impairment. Recombinant DNA technology was used to create Activase, a tissue plasminogen activator. It is a sterile, purified glycoprotein of 527 amino acids. It is made by combining complementary DNA (cDNA) from a human melanoma cell line with the natural human tissue-type plasminogen activator. After reconstitution with Sterile Water for Injection, USP, Activase is a sterile, white to off-white lyophilized powder for intravenous injection.

Efficacy of ultrasound assisted catheter-directed thrombolysis compared to catheter-directed thrombolysis in vitro

Background Catheter-directed thrombolysis (CDT) is an effective and safe endovascular method used in critical limb ischemia and many other thromboembolic events. Ultrasound-assisted catheter-directed thrombolysis (US-CDT) is an emerging technique considered to accelerate thrombolysis and therefore is supposed to improve outcome. Purpose To evaluate the efficacy of US-CDT in comparison to standard CDT in vitro. Material and Methods A total of 69 sets of human venous blood were evaluated, each comprising a tube just treated with CDT, a tube treated with US-CDT, and a control tube. All tubes were kept under physiological conditions. Except for the controls, in all tubes 5 mg of tissue-type plasminogen activator was administered over the predetermined treatment interval. Thrombus mass was weighted at the end of the lysis intervals at 6 h or 24 h, respectively. Results CDT led to a mean thrombus reduction of 32% and ultrasound-assisted lysis led to a mean thrombus reduction of 41% ( P < 0.001 for both). Thrombus reduction was significantly higher after US-CDT compared to CDT ( P = 0.001). The better efficacy of US-CDT was mostly already apparent at early phases during thrombolysis and did further mildly increase over time (r = 0.24; P = 0.047). Conclusion In vitro US-CDT is significantly superior to standard CDT; this effect is apparent at an early timepoint of lysis and slightly further increases over time.

Tissue-type plasminogen activator induces TNF-α-mediated preconditioning of the blood-brain barrier

Ischemic tolerance is a phenomenon whereby transient exposure to a non-injurious preconditioning stimulus triggers resistance to a subsequent lethal ischemic insult. Despite the fact that not only neurons but also astrocytes and endothelial cells have a unique response to preconditioning stimuli, current research has been focused mostly on the effect of preconditioning on neuronal death. Thus, it is unclear if the blood-brain barrier (BBB) can be preconditioned independently of an effect on neuronal survival. The release of tissue-type plasminogen activator (tPA) from perivascular astrocytes in response to an ischemic insult increases the permeability of the BBB. In line with these observations, treatment with recombinant tPA increases the permeability of the BBB and genetic deficiency of tPA attenuates the development of post-ischemic edema. Here we show that tPA induces ischemic tolerance in the BBB independently of an effect on neuronal survival. We found that tPA renders the BBB resistant to an ischemic injury by inducing TNF-α-mediated astrocytic activation and increasing the abundance of aquaporin-4-immunoreactive astrocytic end-feet processes in the neurovascular unit. This is a new role for tPA, that does not require plasmin generation, and with potential therapeutic implications for patients with cerebrovascular disease.