Extracellular adenosine-induced apoptosis in mouse neuroblastoma cells studies on involvement of adenosine receptors and adenosine uptake11Abbreviations: NECA, 5′-(N-ethylcarboxamido)adenosine; AMDA, 5′-amino-5′-deoxyadenosine; CPA, N6-cyclopentyladenosine; NBI, nitrobenzylthioinosine; 2-Cl-IB-MECA, 2-chloro-N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide; AMV–RT, Avian myeloblastosis virus–reverse transcriptase; PCR, polymerase chain reaction; DEVD-AMC, N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin; D

Schrier, S.Mariette; Tilburg, Erica W. van; Meulen, H. van der; IJzerman, Adriaan P.; Mulder, G. J.; Nagelkerke, J. Fred

doi:10.1016/s0006-2952(00)00573-6

Cited by 55 publications

(10 citation statements)

References 33 publications

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“…Even though in physiological conditions it is difficult to increase Ade as high as several millimolar levels, the findings will help us to further understand the importance of Ade, both in experimental and clinical conditions. In low ATP states, cells lack energy to perform their biological activities, therefore it is reasonable to understand that addition of Ade can increase cell viability by increasing intracellular ATP concentrations; while in normal ATP states, Ade decreased cell viability, which is consistent with previous reports [1]–[4].…”

Section: Discussionsupporting

confidence: 90%

“…Cells of the immune system express Ade receptors and are responsive to the modulatory effects of Ade in an inflammatory environment. The role of Ade in the control of immune and inflammatory systems has generated the potential use of Ade-receptor-based therapies in the treatment of infection, autoimmunity, ischemia, and degenerative diseases [1], [28], [32]. Despite a large body of literature, the role of A 2A and A 3 in apoptosis and cell death induction remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Extracellular adenosine (Ade) interacts with cells by two pathways: by activating cell surface receptors at nanomolar/micromolar concentrations; and by interfering with the homeostasis of the intracellular nucleotide pool at millimolar concentrations [1]. Studies have reported that Ade shows contradictory effects: on the one hand, Ade impairs cell proliferation [2]–[4], and induces apoptosis and cell death [5], [6]; on the other hand, Ade provides cytoprotective functions in the heart and brain during ischemia, hypoxia, or ischemia-reperfusion [7]–[9].…”

Section: Introductionmentioning

confidence: 99%

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Intracellular ATP Concentration Contributes to the Cytotoxic and Cytoprotective Effects of Adenosine

Guo

et al. 2013

PLoS ONE

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Extracellular adenosine (Ade) interacts with cells by two pathways: by activating cell surface receptors at nanomolar/micromolar concentrations; and by interfering with the homeostasis of the intracellular nucleotide pool at millimolar concentrations. Ade shows both cytotoxic and cytoprotective effects; however, the underlying mechanisms remain unclear. In the present study, the effects of adenosine-mediated ATP on cell viability were investigated. Adenosine treatment was found to be cytoprotective in the low intracellular ATP state, but cytotoxic under the normal ATP state. Adenosine-mediated cytotoxicity and cytoprotection rely on adenosine-derived ATP formation, but not via the adenosine receptor pathway. Ade enhanced proteasome inhibition-induced cell death mediated by ATP generation. These data provide a new pathway by which adenosine exerts dual biological effects on cell viability, suggesting an important role for adenosine as an ATP precursor besides the adenosine receptor pathway.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intracellular ATP Concentration Contributes to the Cytotoxic and Cytoprotective Effects of Adenosine

Guo

et al. 2013

PLoS ONE

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“…Such inhibitors have two advantages over ATP-competitive inhibitors: (i) they often show greater target selectivity, since they do not bind to the active form of the kinase, evading the ATP-binding pocket that is largely conserved across the kinases; and (ii) they do not compete for binding with ATP at the ATP binding site on the active form of the kinase. ATP is an abundant molecule with intracellular concentrations of 0.1‒10 mM 38 , which has very high affinity for the ATP-binding sites of kinases in their active conformations.…”

Section: Discussionmentioning

confidence: 99%

Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs

Balasubramaniam

Mainali

Kuarm

et al. 2020

Sci Rep

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Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer’s and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3β protect against Alzheimer’s disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3β with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3β, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3β. Our model predicts that phosphorylation of GSK3β Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3β to be inactive, and are consistent with biochemical evidence for the TDZD-8–interacting residues of GSK3β. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3β as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3β can facilitate the identification of novel GSK3β inhibitors of high potency and specificity.

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“…Adenosine has an important physiological signaling role in the peripheral and central nervous systems and it is known to take part in several different metabolic pathways by activating cell surface G protein-coupled receptors [56]. However, abnormal levels of adenosine may be bad for health [57, 58]. A degradative pathway converts adenosine to inosine which is mediated by adenosine deaminase (ADA).…”

Section: Adenosine Signalingmentioning

confidence: 99%

The Signaling Pathways Involved in Chondrocyte Differentiation and Hypertrophic Differentiation

Dong

2016

Stem Cells International

124

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Chondrocytes communicate with each other mainly via diffusible signals rather than direct cell-to-cell contact. The chondrogenic differentiation of mesenchymal stem cells (MSCs) is well regulated by the interactions of varieties of growth factors, cytokines, and signaling molecules. A number of critical signaling molecules have been identified to regulate the differentiation of chondrocyte from mesenchymal progenitor cells to their terminal maturation of hypertrophic chondrocytes, including bone morphogenetic proteins (BMPs), SRY-related high-mobility group-box gene 9 (Sox9), parathyroid hormone-related peptide (PTHrP), Indian hedgehog (Ihh), fibroblast growth factor receptor 3 (FGFR3), and β-catenin. Except for these molecules, other factors such as adenosine, O2 tension, and reactive oxygen species (ROS) also have a vital role in cartilage formation and chondrocyte maturation. Here, we outlined the complex transcriptional network and the function of key factors in this network that determine and regulate the genetic program of chondrogenesis and chondrocyte differentiation.

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Cited by 55 publications

References 33 publications

Intracellular ATP Concentration Contributes to the Cytotoxic and Cytoprotective Effects of Adenosine

Intracellular ATP Concentration Contributes to the Cytotoxic and Cytoprotective Effects of Adenosine

Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs

The Signaling Pathways Involved in Chondrocyte Differentiation and Hypertrophic Differentiation

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