Search results for "95"
showing 10 items of 2244 documents
Annexin A2-Mediated Plasminogen Activation in Endothelial Cells Contributes to the Proangiogenic Effect of Adenosine A2A Receptors
2021
Adenosine A2A receptor mediates the promotion of wound healing and revascularization of injured tissue, in healthy and animals with impaired wound healing, through a mechanism depending upon tissue plasminogen activator (tPA), a component of the fibrinolytic system. In order to evaluate the contribution of plasmin generation in the proangiogenic effect of adenosine A2A receptor activation, we determined the expression and secretion of t-PA, urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) and annexin A2 by human dermal microvascular endothelial cells stimulated by the selective agonist CGS-21680. The plasmin generation was assayed through an enzymatic assay a…
CNS Macrophages Control Neurovascular Development via CD95L.
2017
The development of neurons and vessels shares striking anatomical and molecular features, and it is presumably orchestrated by an overlapping repertoire of extracellular signals. CNS macrophages have been implicated in various developmental functions, including the morphogenesis of neurons and vessels. However, whether CNS macrophages can coordinately influence neurovascular development and the identity of the signals involved therein is unclear. Here, we demonstrate that activity of the cell surface receptor CD95 regulates neuronal and vascular morphogenesis in the post-natal brain and retina. Furthermore, we identify CNS macrophages as the main source of CD95L, and macrophage-specific del…
Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABAA Receptor γ2 Subunit in the …
2016
Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuro…
Artemisinin Derivatives Target Topoisomerase 1 and Cause DNA Damage in Silico and in Vitro
2017
DNA topoisomerases 1 and 2 are enzymes that maintain DNA topology and play important essential genome functions, including DNA replication and transcription. Aberrant topoisomerases cause genome instability and a wide range of diseases, cancer in particular. Both Topo 1 and 2 are the targets of valuable anticancer drugs, such as camptothecin. It has been previously shown that artemisinin, a sesquiterpene lactone from Artemisia annua L. also known as qinghaosu, possesses anti-cancer effects and one of its derivatives, artesunate inhibits Topo 2. In this study, we evaluated artemisinin and 40 derivatives as potential Topo 1 inhibitors at first by in silico molecular docking analyses. Five com…
Hepatoprotective Effect of Steroidal Glycosides From Dioscorea villosa on Hydrogen Peroxide-Induced Hepatotoxicity in HepG2 Cells
2018
Dioscorea villosa, commonly known as “Wild Yam” and native to North America, is well documented for its pharmacological properties due to the presence of steroidal glycosides. However, the hepatoprotective potential of these compounds has not been studied so far. The present investigation was aimed to study the hepatoprotective effect of the steroidal glycosides from D. villosa against H2O2, a known hepatotoxin, in human liver cell line (HepG2). Cytotoxicity assessment was carried out in cells exposed to various concentrations (10–50 μM) of compounds for 24 h using MTT assay and morphological changes. All tested compounds were known and among them, spirostans (zingiberensis saponin I, diosc…
DNA multigene characterization of Fasciola hepatica and Lymnaea neotropica and its fascioliasis transmission capacity in Uruguay, with historical cor…
2017
Background Fascioliasis is a pathogenic disease transmitted by lymnaeid snails and recently emerging in humans, in part due to effects of climate changes, anthropogenic environment modifications, import/export and movements of livestock. South America is the continent presenting more human fascioliasis hyperendemic areas and the highest prevalences and intensities known. These scenarios appear mainly linked to altitude areas in Andean countries, whereas lowland areas of non-Andean countries, such as Uruguay, only show sporadic human cases or outbreaks. A study including DNA marker sequencing of fasciolids and lymnaeids, an experimental study of the life cycle in Uruguay, and a review of hum…
Molecular docking-based virtual drug screening revealing an oxofluorenyl benzamide and a bromonaphthalene sulfonamido hydroxybenzoic acid as HDAC6 in…
2020
HDAC6 is a crucial epigenetic modifier that plays a vital role in tumor progression and carcinogenesis due to its multiple biological functions. It is a unique member of class-II HDAC enzymes. It possesses two catalytic domains, which function independently of the overall enzyme activity. Up to date, there are only a few selective HDAC6 inhibitors with anti-cancer activity. In this study, 175,204 ligands obtained from the ZINC15 and OTAVAchemical databases were used for virtual drug screening against HDAC6. Molecular docking studies were performed for 100 selected compounds. Furthermore, the top 10 compounds obtained from docking were tested for their efficacy to inhibit the function of HDA…
In Silico Insights towards the Identification of NLRP3 Druggable Hot Spots
2019
NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) activation has been linked to several chronic pathologies, including atherosclerosis, type-II diabetes, fibrosis, rheumatoid arthritis, and Alzheimer’s disease. Therefore, NLRP3 represents an appealing target for the development of innovative therapeutic approaches. A few companies are currently working on the discovery of selective modulators of NLRP3 inflammasome. Unfortunately, limited structural data are available for this target. To date, MCC950 represents one of the most promising noncovalent NLRP3 inhibitors. Recently, a possible region for the binding of MCC950 to the NLRP3 protein was described but no details were …
Considerations for an in vitro, cell-based testing platform for detection of adverse drug-induced inotropic effects in early drug development. Part 1…
2019
Drug-induced effects on cardiac contractility can be assessed through the measurement of the maximal rate of pressure increase in the left ventricle (LVdP/dtmax) in conscious animals, and such studies are often conducted at the late stage of preclinical drug development. Detection of such effects earlier in drug research using simpler, in vitro test systems would be a valuable addition to our strategies for identifying the best possible drug development candidates. Thus, testing platforms with reasonably high throughput, and affordable costs would be helpful for early screening purposes. There may also be utility for testing platforms that provide mechanistic information about how a given d…
Berberine Mediated Positive Inotropic Effects on Rat Hearts via a Ca2+-Dependent Mechanism
2020
Previous studies showed that berberine, an alkaloid from Coptis Chinensis Franch, might exert a positive inotropic effect on the heart. However, the underlying mechanisms were unclear. Here, we reported that berberine at 10-20 µM increased the left ventricular (LV) developed pressure and the maximal rate of the pressure rising, and it increased the maximal rate of the pressure descending at 20 µM in Langendorff-perfused isolated rat hearts. These effects diminished with the concentration of berberine increasing to 50 µM. In the concentration range of 50-300 µM, berberine increased the isometric tension of isolated left ventricular muscle (LVM) strips with or without electrical stimulations,…