Search results for "Purinergic"

Abacavir Increases Purinergic P2X7 Receptor Activation by ATP: Does a Pro-inflammatory Synergism Underlie Its Cardiovascular Toxicity?

2021

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Dopamine induces inhibitory effects on the circular muscle contractility of mouse distal colon via D1- and D2-like receptors

2016

Dopamine (DA) acts as gut motility modulator, via D1- and D2-like receptors, but its effective role is far from being clear. Since alterations of the dopaminergic system could lead to gastrointestinal dysfunctions, a characterization of the enteric dopaminergic system is mandatory. In this study, we investigated the role of DA and D1- and D2-like receptors in the contractility of the circular muscle of mouse distal colon by organ-bath technique. DA caused relaxation in carbachol-precontracted circular muscle strips, sensitive to domperidone, D2-like receptor antagonist, and mimicked by bromocriptine, D2-like receptor agonist. 7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz…

Abacavir induces platelet-endothelium interactions by interfering with purinergic signalling: A step from inflammation to thrombosis.

2017

The controversy connecting Abacavir (ABC) with cardiovascular disease has been fuelled by the lack of a credible mechanism of action. ABC shares structural similarities with endogenous purines, signalling molecules capable of triggering prothrombotic/proinflammatory programmes. Platelets are leading actors in the process of thrombosis. Our study addresses the effects of ABC on interactions between platelets and other vascular cells, while exploring the adhesion molecules implicated and the potential interference with the purinergic signalling pathway. The effects of ABC on platelet aggregation and platelet-endothelium interactions were evaluated, respectively, with an aggregometer and a flo…

Staphylococcus aureus α-toxin: small pore, large consequences

2018

Abstract The small β-pore-forming α-toxin, also termed α-hemolysin or Hla is considered to be an important virulence factor of Staphylococcus aureus. Perforation of the plasma membrane (PM) by Hla leads to uncontrolled flux of ions and water. Already a small number of toxin pores seems to be sufficient to induce complex cellular responses, many of which depend on the efflux of potassium. In this article, we discuss the implications of secondary membrane lesions, for example, by endogenous channels, for Hla-mediated toxicity, for calcium-influx and membrane repair. Activation of purinergic receptors has been proposed to be a major contributor to the lytic effects of various pore forming prot…

The Guanine-Based Purinergic System: The Tale of An Orphan Neuromodulation.

2016

Guanine-based purines (GBPs) have been recently proposed to be not only metabolic agents but also extracellular signaling molecules that regulate important functions in the central nervous system. In such way, GBPs-mediated neuroprotection, behavioral responses and neuronal plasticity have been broadly described in the literature. However, while a number of these functions (i.e., GBPs neurothophic effects) have been well-established, the molecular mechanisms behind these GBPs-dependent effects are still unknown. Furthermore, no plasma membrane receptors for GBPs have been described so far, thus GBPs are still considered orphan neuromodulators. Interestingly, an intricate and controversial f…

Abacavir Induces Arterial Thrombosis in a Murine Model.

2018

Background The purinergic system is known to underlie prothrombotic and proinflammatory vascular programs, making the profile of experimental actions demonstrated by abacavir compatible with thrombogenesis. However, direct evidence of a prothrombotic effect by the drug has been lacking. Methods The present study appraised the effects of abacavir in a well-validated animal model of arterial thrombosis. The role of ATP-P2X7 receptors in the actions of the drug was also assessed, and the actions of recognized vascular-damaging agents and other nucleoside reverse-transcriptase inhibitors (NRTIs) were evaluated and compared to those of abacavir. Results Abacavir dose-dependently promoted thrombu…

Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells

2017

Epithelial to mesenchymal transition (EMT) occurs during embryogenesis or under pathological conditions such as hypoxia, injury, chronic inflammation, or tissue fibrosis. In renal tubular epithelial cells (MDCK), TGF-β1 induces EMT by reducing or increasing epithelial or mesenchymal marker expression, respectively. In this study, we confirmed that the cAMP analogues, 8-CPT-cAMP or N6-Ph-cAMP, inhibited the TGF-β1-driven overexpression of the mesenchymal markers ZEB-1, Slug, Fibronectin, and α-SMA. Furthermore, we showed that A1, A2A, P2Y1, P2Y11, and P2X7 purine receptor agonists modulated the TGF-β1-induced EMT through the involvement of PKA and/or MAPK/ERK signaling. The stimulation o…

Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression

2017

The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated.Methods and results: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibito…

2017

The pore forming hemolysin A, Hla, is a major virulence factor of Staphylococcus aureus. Apparently, 1-2 pore(s) per cell suffice(s) to cause cell death. Accumulated experimental evidence points towards a major role of ATP-gated purinergic receptors (P2XR) for hemolysis caused by Hla, complement and other pore forming proteins, presumably by increasing membrane permeability. Indeed, in experiments employing rabbit erythrocytes, inhibitory concentrations of frequently employed P2XR-antagonists were in a similar range as previously reported for erythrocytes of other species and other toxins. However, Hla-dependent hemolysis was not enhanced by extracellular ATP, and oxidized adenosinetriphosp…

Tissue factor prothrombotic activity is regulated by integrin-arf6 trafficking

2017

Objective— Coagulation initiation by tissue factor (TF) is regulated by cellular inhibitors, cell surface availability of procoagulant phosphatidylserine, and thiol-disulfide exchange. How these mechanisms contribute to keeping TF in a noncoagulant state and to generating prothrombotic TF remain incompletely understood. Approach and Results— Here, we study the activation of TF in primary macrophages by a combination of pharmacological, genetic, and biochemical approaches. We demonstrate that primed macrophages effectively control TF cell surface activity by receptor internalization. After cell injury, ATP signals through the purinergic receptor P2rx7 induce release of TF + microvesicles. T…