scholarly journals Performance of P2x7 and P2Y Purinergic Receptors as an Inhibiting Factor in the Progression of Pulmonary Neoplastic Cells

2020 ◽  
pp. 56-62
Author(s):  
Matheus Ribeiro Bizuti ◽  
Laura Nyland Jostl ◽  
Emanuely Scramim ◽  
Keroli Eloiza Tessaro da Silva ◽  
Luana Paula Schio ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Adenosine Receptors ◽  
Purinergic Receptors ◽  
Cell Permeability ◽  
Lung Cells ◽  
Nucleotide Receptors ◽  
Toxic Substances ◽  
P2x7 Receptors ◽  
Specific Targeting ◽  
Inhibiting Factor

Different pathological processes are considered in lung cancer, such as nicotine deposition, oxidative stress, deregulation of metal ions and chronic inflammation. Purine signaling is involved in all processes, suggesting the importance of nucleotide receptors (P2X7 and P2Y) and adenosine receptors present in lung cells. The accumulation of toxic substances promotes chronic inflammation and cellular alteration, which induces the release of Adenosine Triphosphate (ATP) in the extracellular space, thus stimulating P2X7 receptors. The activation of P2X7 promotes an increase in the synthesis and release of some pro-inflammatory mediators. P2Y works by promoting the increase of intracellular calcium levels and, P2X7, changing cell permeability. Thus, drugs can be developed with a specific targeting for such recipients, thus provid additional therapeutic options to those existing.

scholarly journals Sulfated Glycosides from the Sea Cucumbers Block Ca2+ Flow in Murine Neuroblastoma Cells

2018 ◽  
Vol 13 (8) ◽  
pp. 1934578X1801300 ◽  
Author(s):  
Evgeny A. Pislyagin ◽  
Ekaterina S. Menchinskaya ◽  
Dmitry L. Aminin ◽  
Sergey A. Avilov ◽  
Alexandra S. Silchenko
Keyword(s):  
Cytotoxic Activity ◽  
Cellular Immunity ◽  
Immune Cells ◽  
Purinergic Receptors ◽  
Neuroblastoma Cells ◽  
Triterpene Glycosides ◽  
P2x7 Receptors ◽  
Sea Cucumbers ◽  
Scientific Task

Recently the ability of triterpene glycosides from sea cucumbers to interact with purinergic receptors of P2X family on the membranes of immune cells enhancing the reversible ATP-dependent Ca2+ intake and therefore modulating (stimulating) the receptor's activity was discovered. As a result the activation of cellular immunity on the organism level was observed. Purinergic receptors are associated with a series of important functions in normal and pathophysiology, thus the searching of its new modulators (both stimulants and blockers) seems to be very important medical and scientific task. The cytotoxic activity of four triterpene glycosides isolated from different species of sea cucumbers: liouvilloside A (1) from Pseudocolochirus violaceus, fallaxoside D1 (2) from Cucumaria fallax and magnumosides C3 (3) and C4 (4) from Massinium (=Neothynidium) magnum against neuroblastoma Neuro 2A cells was tested. The glycosides 1 and 4 were the most cytotoxic in the series (EC50 5.0 μM and 21.5 μM, correspondingly). Moreover, non-cytotoxic concentration (1 μM) of these compounds inhibited ATP-dependent Ca2+ intake into the Neuro 2A cells, containing P2X7 receptors on the surface, by 53 and 47%, correspondingly. The ability of sea cucumbers triterpene glycosides to block the purinergic receptors in vitro is first discovered.

scholarly journals Role of A2a Extracellular Adenosine Receptor-Mediated Signaling in Adenosine-Mediated Inhibition of T-Cell Activation and Expansion

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1600-1610 ◽  
Author(s):  
Steve Huang ◽  
Sergey Apasov ◽  
Masahiro Koshiba ◽  
Michail Sitkovsky
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Adenosine Receptors ◽  
Purinergic Receptors ◽  
Interleukin 2 ◽  
Strong Inhibition ◽  
Extracellular Adenosine ◽  
A2a Receptor ◽  
Adenosine Deaminase Activity

Abstract Accumulation of adenosine and of deoxyadenosine in the absence of adenosine deaminase activity (ADA) activity results in lymphocyte depletion and in severe combined immunodeficiency (ADA SCID), which is currently explained by direct cell death-causing effects of intracellular products of adenosine metabolism. We explored the alternative mechanisms of peripheral T-cell depletion as due to inhibition of T-cell expansion by extracellular adenosine-mediated signaling through purinergic receptors. The strong inhibition of the T-cell receptor (TCR)-triggered proliferation and of upregulation of interleukin-2 receptor α chain (CD25) molecules, but not the direct lymphotoxicity, were observed at low concentrations of extracellular adenosine. These effects of extracellular adenosine (Ado) are likely to be mediated by A2a receptor-mediated signaling rather than by intracellular toxicity of adenosine catabolites, because (1) poorly metabolized adenosine analogs cause the accumulation of cAMP and strong inhibition of TCR-triggered CD25 upregulation; (2) the A2a, but not the A1 or A3, receptors are the major expressed and functionally coupled adenosine receptors in mouse peripheral T and B lymphocytes, and the adenosine-induced cAMP accumulation in lymphocytes correlates with the expression of A2a receptors; (3) the specific agonist of A2a receptor, CGS21680, induces increases in [cAMP]i in lymphocytes, whereas the specific antagonist of A2a receptor, CSC, inhibits the effects of Ado and CGS21680; and (4) the increases in [cAMP]i mimic the adenosine-induced inhibition of TCR-triggered CD25 upregulation and splenocyte proliferation. These studies suggest the possible role of adenosine receptors in the regulation of lymphocyte expansion and point to the downregulation of A2a purinergic receptors on T cells as a potentially attractive pharmacologic target.

scholarly journals Purinergic Signaling in Endometriosis-Associated Pain

2020 ◽  
Vol 21 (22) ◽  
pp. 8512
Author(s):  
Carla Trapero ◽  
Mireia Martín-Satué
Keyword(s):  
Atp Hydrolysis ◽  
Current Knowledge ◽  
Purinergic Signaling ◽  
Uterine Cavity ◽  
Nucleotide Receptors ◽  
P2x3 Receptor ◽  
P2x7 Receptors ◽  
Pharmacological Management ◽  
Predominant Symptom ◽  
Therapeutic Tools

Endometriosis is an estrogen-dependent gynecological disease, with an associated chronic inflammatory component, characterized by the presence of endometrial tissue outside the uterine cavity. Its predominant symptom is pain, a condition notably altering the quality of life of women with the disease. This review is intended to exhaustively gather current knowledge on purinergic signaling in endometriosis-associated pain. Altered extracellular ATP hydrolysis, due to changes in ectonucleotidase activity, has been reported in endometriosis; the resulting accumulation of ATP in the endometriotic microenvironment points to sustained activation of nucleotide receptors (P2 receptors) capable of generating a persistent pain message. P2X3 receptor, expressed in sensory neurons, mediates nociceptive, neuropathic, and inflammatory pain, and is enrolled in endometriosis-related pain. Pharmacological inhibition of P2X3 receptor is under evaluation as a pain relief treatment for women with endometriosis. The role of other ATP receptors is also discussed here, e.g., P2X4 and P2X7 receptors, which are involved in inflammatory cell–nerve and microglia–nerve crosstalk, and therefore in inflammatory and neuropathic pain. Adenosine receptors (P1 receptors), by contrast, mainly play antinociceptive and anti-inflammatory roles. Purinome-targeted drugs, including nucleotide receptors and metabolizing enzymes, are potential non-hormonal therapeutic tools for the pharmacological management of endometriosis-related pain.

scholarly journals Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

2004 ◽  
Vol 1 (1) ◽  
pp. 23-34 ◽  
Author(s):  
BETH STEVENS ◽  
TOMOKO ISHIBASHI ◽  
JIANG-FAN CHEN ◽  
R. DOUGLAS FIELDS
Keyword(s):  
Schwann Cells ◽  
Adenosine Receptors ◽  
Intracellular Signaling ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Intracellular Signaling Pathways ◽  
Molecular Approaches ◽  
Myelinating Glia ◽  
Activity Dependent ◽  
Stimulation Of

Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron–glia communication are not known. Recent research shows that adenosine is a neuron–glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2A adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.

scholarly journals P2X7 receptor activates extracellular signal-regulated kinases ERK1 and ERK2 independently of Ca2+ influx

2003 ◽  
Vol 374 (1) ◽  
pp. 51-61 ◽  
Author(s):  
Jan AMSTRUP ◽  
Ivana NOVAK
Keyword(s):  
P2x7 Receptor ◽  
Fluorescent Protein ◽  
Expression System ◽  
Receptor Expression ◽  
Nucleotide Receptors ◽  
P2x7 Receptors ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
293 Cells ◽  
Extracellular Signal

P2X7 nucleotide receptors modulate a spectrum of cellular events in various cells including epithelia, such as exocrine pancreas. Although the pharmacology and channel properties of the P2X7 receptors have been studied intensively, signal transduction pathways are relatively unknown. In this study we applied a heterologous expression system of rat P2X7 receptors in HEK-293 cells. We followed the receptor expression and function using the enhanced green fluorescent protein (EGFP) tag, activation of intracellular proteins and increases in cellular Ca2+. EGFP-P2X7 receptors localized to the plasma membrane, clusters within the membrane and intracellularly. Stimulation of P2X7 receptors in HEK-293 cells led to an activation of extracellular signal-regulated kinases ERK1 and ERK2 and this activation was seen after just 1 min of stimulation with ATP. Using C- and N-terminal P2X7-receptor mutants we show that the N-terminus is important in activation of ERKs, whereas deletion of the last 230 amino acids in the C-terminus did not effect ERK activation. On the other hand, Ca2+ entry was impaired in C-terminal but not in N-terminal mutants. In cell suspensions prepared from rat pancreas we show that P2X7 receptors also activate ERK1 and ERK2, indicating that these signalling pathways are also turned on in native epithelium.

scholarly journals Role of A2a Extracellular Adenosine Receptor-Mediated Signaling in Adenosine-Mediated Inhibition of T-Cell Activation and Expansion

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1600-1610 ◽  
Author(s):  
Steve Huang ◽  
Sergey Apasov ◽  
Masahiro Koshiba ◽  
Michail Sitkovsky
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Adenosine Receptors ◽  
Purinergic Receptors ◽  
Interleukin 2 ◽  
Strong Inhibition ◽  
Extracellular Adenosine ◽  
A2a Receptor ◽  
Adenosine Deaminase Activity

Accumulation of adenosine and of deoxyadenosine in the absence of adenosine deaminase activity (ADA) activity results in lymphocyte depletion and in severe combined immunodeficiency (ADA SCID), which is currently explained by direct cell death-causing effects of intracellular products of adenosine metabolism. We explored the alternative mechanisms of peripheral T-cell depletion as due to inhibition of T-cell expansion by extracellular adenosine-mediated signaling through purinergic receptors. The strong inhibition of the T-cell receptor (TCR)-triggered proliferation and of upregulation of interleukin-2 receptor α chain (CD25) molecules, but not the direct lymphotoxicity, were observed at low concentrations of extracellular adenosine. These effects of extracellular adenosine (Ado) are likely to be mediated by A2a receptor-mediated signaling rather than by intracellular toxicity of adenosine catabolites, because (1) poorly metabolized adenosine analogs cause the accumulation of cAMP and strong inhibition of TCR-triggered CD25 upregulation; (2) the A2a, but not the A1 or A3, receptors are the major expressed and functionally coupled adenosine receptors in mouse peripheral T and B lymphocytes, and the adenosine-induced cAMP accumulation in lymphocytes correlates with the expression of A2a receptors; (3) the specific agonist of A2a receptor, CGS21680, induces increases in [cAMP]i in lymphocytes, whereas the specific antagonist of A2a receptor, CSC, inhibits the effects of Ado and CGS21680; and (4) the increases in [cAMP]i mimic the adenosine-induced inhibition of TCR-triggered CD25 upregulation and splenocyte proliferation. These studies suggest the possible role of adenosine receptors in the regulation of lymphocyte expansion and point to the downregulation of A2a purinergic receptors on T cells as a potentially attractive pharmacologic target.

ATP Released From Astrocytes During Swelling Activates Chloride Channels

2003 ◽  
Vol 89 (4) ◽  
pp. 1870-1877 ◽  
Author(s):  
Mark Darby ◽  
J. Brent Kuzmiski ◽  
William Panenka ◽  
Denise Feighan ◽  
Brian A. MacVicar
Keyword(s):  
Chloride Channels ◽  
Purinergic Receptors ◽  
Neuronal Excitability ◽  
Regulatory Volume Decrease ◽  
Atp Release ◽  
Cell Swelling ◽  
Disulfonic Acid ◽  
P2x7 Receptors ◽  
Whole Cell Patch Clamp ◽  
Cultured Astrocytes

ATP release from astrocytes contributes to calcium ([Ca2+]) wave propagation and may modulate neuronal excitability. In epithelial cells and hepatocytes, cell swelling causes ATP release, which leads to the activation of a volume-sensitive Cl− current ( I Cl,swell) through an autocrine pathway involving purinergic receptors. Astrocyte swelling is counterbalanced by a regulatory volume decrease, involving efflux of metabolites and activation of I Cl,swell and K+currents. We used whole cell patch-clamp recordings in cultured astrocytes to investigate the autocrine role of ATP in the activation of I Cl,swell by hypo-osmotic solution (HOS). Apyrase, an ATP/ADP nucleotidase, inhibited HOS-activated I Cl,swell, whereas ATP and the P2Y agonists, ADPβS and ADP, induced Cl− currents similar to I Cl,swell. Neither the P2U agonist, UTP nor the P2X agonist, α,β-methylene ATP, were effective. BzATP was less effective than ATP, suggesting that P2X7 receptors were not involved. P2 purinergic antagonists, suramin, RB2, and pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) reversibly inhibited activation of I Cl,swell, suggesting that ATP-activated P2Y1 receptors. Thus ATP release mediates I Cl,swell in astrocytes through the activation of P2Y1-like receptors. The multidrug resistance protein (MRP) transport inhibitors probenicid, indomethacin, and MK-571 all potently inhibited I Cl.swell. ATP release from astrocytes in HOS was observed directly using luciferin-luciferase and MK-571 reversibly depressed this HOS-induced ATP efflux. We conclude that ATP release via MRP and subsequent autocrine activation of purinergic receptors contributes to the activation of I Cl,swell in astrocytes by HOS-induced swelling.

scholarly journals Function of TREM1 and TREM2 in Liver-Related Diseases

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2626
Author(s):  
Huifang Sun ◽  
Jianguo Feng ◽  
Liling Tang
Keyword(s):  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Acute Inflammation ◽  
Immunoglobulin Superfamily ◽  
Toxic Substances ◽  
Main Function ◽  
Toll Like Receptor ◽  
Liver Sinusoidal Endothelial Cells ◽  
Toll Like Receptor 4 ◽  
Parenchymal Cells

TREM1 and TREM2 are members of the triggering receptors expressed on myeloid cells (TREM) family. Both TREM1 and TREM2 are immunoglobulin superfamily receptors. Their main function is to identify foreign antigens and toxic substances, thereby adjusting the inflammatory response. In the liver, TREM1 and TREM2 are expressed on non-parenchymal cells, such as liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, and cells which infiltrate the liver in response to injury including monocyte-derived macrophages and neutrophils. The function of TREM1 and TREM2 in inflammatory response depends on Toll-like receptor 4. TREM1 mainly augments inflammation during acute inflammation, while TREM2 mainly inhibits chronic inflammation to protect the liver from pathological changes. Chronic inflammation often induces metabolic abnormalities, fibrosis, and tumorigenesis. The above physiological changes lead to liver-related diseases, such as liver injury, nonalcoholic steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma. Here, we review the function of TREM1 and TREM2 in different liver diseases based on inflammation, providing a more comprehensive perspective for the treatment of liver-related diseases.

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