Scan Science and Technology
Contact Leading Edge Experts & Companies
The Experts below are selected from a list of 3564 Experts worldwide ranked by ideXlab platform
Edwin K. Jackson – One of the best experts on this subject based on the ideXlab platform.
Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin DHypertension, 2015Co-Authors: Raghvendra K. Dubey, Jürgen Fingerle, Delbert G. Gillespie, Marinella Rosselli, Bruno Imthurn, Edwin K. JacksonAbstract:
The goal of this study was to determine whether and how adenosine affects the proliferation of human coronary artery smooth muscle cells (HCASMCs). In HCASMCs, 2–Chloroadenosine (stable adenosine analogue), but not N(6)-cyclopentyladenosine, CGS21680, or N(6)-(3-iodobenzyl)-adenosine-5′-N-methyluronamide, inhibited HCASMC proliferation (A2B receptor profile). 2–Chloroadenosine increased cAMP, reduced phosphorylation (activation) of ERK and Akt (protein kinases known to increase cyclin D expression and activity, respectively), and reduced levels of cyclin D1 (cyclin that promotes cell-cycle progression in G1). Moreover, 2–Chloroadenosine inhibited expression of S-phase kinase-associated protein-2 (Skp2; promotes proteolysis of p27(Kip1)) and upregulated levels of p27(Kip1) (cell-cycle regulator that impairs cyclin D function). 2–Chloroadenosine also inhibited signaling downstream of cyclin D, including hyperphosphorylation of retinoblastoma protein and expression of cyclin A (S phase cyclin). Knockdown of A2B receptors prevented the effects of 2–Chloroadenosine on ERK1/2, Akt, Skp2, p27(Kip1), cyclin D1, cyclin A, and proliferation. Likewise, inhibition of adenylyl cyclase and protein kinase A abrogated 2–Chloroadenosine‘s inhibitory effects on Skp2 and stimulatory effects on p27(Kip1) and rescued HCASMCs from 2–Chloroadenosine-mediated inhibition. Knockdown of p27(Kip1) also reversed the inhibitory effects of 2–Chloroadenosine on HCASMC proliferation. In vivo, peri-arterial (rat carotid artery) 2–Chloroadenosine (20 μmol/L for 7 days) downregulated vascular expression of Skp2, upregulated vascular expression of p27(Kip1), and reduced neointima hyperplasia by 71% (P
Assessment of the effect of 2–Chloroadenosine in normal rat brain using spin-labeled MRI measurement of perfusionMagnetic resonance in medicine, 2001Co-Authors: Patrick M. Kochanek, Courtney L. Robertson, Donald S. Williams, Kristy S. Hendrich, John A. Melick, Donald W. Marion, Edwin K. JacksonAbstract:
Adenosine analogs such as 2–Chloroadenosine are potent cerebrovasodilators. Spin-labeled MRI was used to investigate the spatial distribution, dose-response, and timing of the effect of 2–Chloroadenosine on cerebral blood flow (CBF) after intraparenchymal injection into rat brain. Sprague-Dawley rats (N = 10) were injected with 2–Chloroadenosine at doses of 0.3, 6.0, or 12 nmoles, or saline vehicle (2-4 microL). CBF was serially quantified in a slice through the injection site in a circular (3.6 mm diameter) region of interest (ROI) around the injection and in ipsilateral hemispheric ROIs at approximately 90 min and approximately 180 min. Marked 3.77- and 3.93-fold increases in CBF (vs. vehicle) were seen in the circular ROI at approximately 90 min and approximately 180 min after 12-nmol injection, respectively. Similarly, 2.92– and 2.78-fold increases in hemispheric CBF were observed at approximately 90 min and approximately 180 min, respectively, after injection of 12 nmoles. Linear dose-response relationships were observed at both times after injection in both ROIs (all P < 0.01). Spin-labeling MRI assessment revealed that parenchymal injection of 2–Chloroadenosine produces potent, dose-dependent, and sustained vasodilation over large areas of brain. This treatment and imaging paradigm should facilitate investigation of the effect of CBF promotion in models of traumatic and ischemic brain injury.
Assessment of 2–Chloroadenosine Treatment After Experimental Traumatic Brain Injury in the Rat Using Arterial Spin-Labeled MRI: A Preliminary ReportActa neurochirurgica. Supplement, 2000Co-Authors: Courtney L. Robertson, Edwin K. Jackson, Kristy S. Hendrich, Patrick M. Kochanek, John A. Melick, Steven H. Graham, Donald W. Marion, Donald S. WilliamsAbstract:
Adenosine is a putative endogenous neuroprotectant. Its action at Al receptors mitigates excitotoxicity while action at A2 receptors increases cerebral blood flow (CBF). We hypothesized that cerebral injection of the adenosine analog, 2–Chloroadenosine, would decrease swelling and increase CBF early after experimental traumatic brain injury (TBI). To test this hypothesis, rats were anesthetized and subjected to TBI using a controlled cortical impact (CCI) model (n = 5/group). Immediately after injury, 2–Chloroadenosine (0.3 nmole in 2 µl) or an equal volume of vehicle were stereotactically injected lateral to the area of contusion. Using magnetic resonance imaging (MRI), in vivo spin-lattice relaxation time of tissue water (Tlobs) and CBF (arterial spin labeling) were measured in a 2-mm thick slice in the injured and non-injured hemispheres at 3–4 h after CCI. In a separate, preliminary experiment, the effect of 2–Chloroadenosine injection in normal rat brain was studied. Rats (n = 2) were anesthetized and a burr hole was made for injection of 2–Chloroadenosine into the same site as in the TBI model. One rat received the standard dose of 0.3 nmole and one rat received a 6 nmole injection. Tlobs and CBF studies were obtained 1.5–3.5 h after injection, using the same MRI methods as in the TBI study. In rats subjected to TBI, treatment with 2–Chloroadenosine attenuated the increase in Tlobs after injury (p < 0.05 for treatment vs vehicle) in both hippocampus and cortex ipsilateral to injury. However, treatment with 2–Chloroadenosine did not improve post-traumatic hypoperfusion. In normal rats, injection of 0.3 nmole of 2–Chloroadenosine did not increase CBF, but the higher dosage of 6 nmole dramatically increased hemispheric CBF by 1.5–2.0-fold. The effect of local injection of 2–Chloroadenosine at a dose of 0.3 nmole after experimental TBI on Tlobs presumably represents a reduction in post-traumatic edema. This reduction in edema, along with the augmentation of CBF seen in normal rats at higher dosage (6 nmole), supports a role for adenosine in neuroprotection following TBI.
Zsuzsa Szondy – One of the best experts on this subject based on the ideXlab platform.
Methylprednisolone and 2–Chloroadenosine induce DNA fragmentation at different stages of human T-lymphocyte developmentImmunology letters, 1997Co-Authors: Zsuzsa SzondyAbstract:
Abstract Both methylprednisolone (MPS) and 2–Chloroadenosine (2-CA) were shown previously to induce DNA fragmentation and cell death in human thymocytes at an optimum concentration of 1 and 40 μ M, respectively. Though both compounds affected the CD4 + CD8 + population, 2-CA depleted primarily thymocytes expressing medium or high levels of CD3-T-cell receptor molecule, while the glucocorticoid treatment affected cells expressing a lower level of CD3-T-cell receptor. Their effect on thymocyte viability and DNA fragmentation was observed already at day 1 of culture and involved the bcl-2 negative thymocytes. Incubation of peripheral T-lymphocytes (which express bcl-2) with the same concentration of MPS did not affect the viability for up to 5 days, while 2-CA induced 100% cell death and DNA fragmentation by day 5. If T-cells were stimulated with concanavalin A in the presence of MPS or 2-CA the cell proliferation was inhibited and a decrease in cell viability with a concomittant increase in DNA fragmentation was observed. If MPS was added at 24 h or later after mitogenic stimulation, it was not able to induce apoptosis and the inhibition of proliferation was less pronounced. 2-CA, on the other hand, inhibited proliferation and induced cell death whenever it was added to the culture. The decreased sensitivity towards the apoptosis induction effects of glucocorticoids at later phases of mitogenic stimulation can not be explained by an increased bcl-2 expression, since its expression level remained constant up to 48 h after mitogenic stimulation. Our data presented in this paper suggest: (1) that T-cells may show different sensitivity towards the same apoptosis inducer signals at different stages of the T-cell development; (2) the apoptotic sensitivity towards various signals may be different at the same stage of T-cell differentiation; and (3) their apoptotic sensitivity does not always correlate with the bcl-2 expression alone.
The 2-chlorodeoxyadenosine-induced cell death signalling pathway in human thymocytes is different from that induced by 2–Chloroadenosine.Biochemical Journal, 1995Co-Authors: Zsuzsa SzondyAbstract:
2–Chloroadenosine induced DNA fragmentation and cell death in human thymocytes primarily by Ca(2+)-dependent mechanisms. Incubation of human thymocytes with 2-chlorodeoxyadenosine (5-1000 nM) also induced cell death (apoptosis) which was dependent on macromolecule synthesis and involved activation of an endonuclease which was inhibited by Zn2+. The effect of 2-chlorodeoxyadenosine was prevented by addition of dipyridamole, a strong nucleoside transport inhibitor, or of deoxycytidine, previously shown to compete for uptake by deoxycytidine kinase. 2-Chlorodeoxyadenosine-induced apoptosis did not involve increases in the cytosolic Ca2+ concentration, but required the presence of intracellular Ca2+. It was not inhibited by activators of protein kinase C previously shown to inhibit Ca(2+)-dependent cell death. Addition of 2-chlorodeoxyadenosine induced an increase in the amount of p53 in human thymocytes, while 2–Chloroadenosine had no effect. These data suggest that 2–Chloroadenosine and 2-chlorodeoxyadenosine induce cell death in human thymocytes via different signalling pathways.
David W. Hoskin – One of the best experts on this subject based on the ideXlab platform.
2–Chloroadenosine Stimulates Granule Exocytosis from Mouse Natural Killer Cells: Evidence for Signal Transduction through a Novel Extracellular ReceptorExperimental cell research, 1997Co-Authors: Brent A. Williams, Jonathan Blay, David W. HoskinAbstract:
Abstract The effect of 2–Chloroadenosine (2CA), an adenosine receptor agonist, on the activation status of mouse natural killer (NK) cells was determined. Splenic lymphocytes incubated with 2CA exocytosed an NK cell-associated granzyme withNα-CBZ-L-lysine thiobenzyl ester (BLT) esterase activity in a dose- and timedependent manner. Selective depletion of NK cells by anti-asialoGM1 antibody plus complement pretreatment confirmed that NK cells were the source of the BLT esterase activity. 2CA-induced granule exocytosis was not reduced in the presence of the nucleoside uptake blockers NBTI, dilazep, or dipyridamole, indicating the involvement of an extracellular receptor. However, adenosine or other A1, A2, or A3cell-surface adenosine receptor agonists failed to trigger the exocytotic process. Furthermore, the nonselective adenosine receptor antagonist theophylline, as well as the selective A1receptor antagonist DPCPX and the selective A2receptor antagonist DMPX, did not interfere with 2CA-induced BLT esterase secretion. These data suggest that 2CA acts on NK cells via a novel (non-A1/A2/A3) cell-surface receptor. Genistein, a protein tyrosine kinase inhibitor, and calphostin C, a protein kinase C inhibitor, both interfered with 2CA-induced granule exocytosis. Pertussis toxin, an ADP-ribosylating toxin to which certain GTP-binding proteins are sensitive, also inhibited 2CA-stimulated BLT esterase release. In addition, 2CA-induced granule exocytosis was reduced in the presence of cyclosporin A, an inhibitor of Ca2+-dependent signaling pathways, and the Ca2+-chelating agent EGTA . We conclude that 2CA, acting through a novel extracellular receptor on mouse NK cells, triggers granule exocytosis via a Ca2+-dependent signal transduction pathway that is coupled to GTP-binding proteins and involves protein tyrosine kinase and protein kinase C activation.
Cyclosporin A inhibits 2–Chloroadenosine-induced DNA cleavage in mouse thymocytes.International journal of immunopharmacology, 1994Co-Authors: Andrew P. Makrigiannis, Jonathan Blay, David W. HoskinAbstract:
Abstract Incubation of mouse thymocytes with the adenosine analogue 2–Chloroadenosine resulted in enhanced internucleosomal DNA fragmentation which could be inhibited by the immunosuppressive drug cyclosporin A. In order to be effective, cyclosporin A had to be added to thymocyte preparations at the same time as 2–Chloroadenosine. Since cyclosporin A is a selective inhibitor of calcineurin, our data suggest a possible role for calcineurin as a signaling intermediate in the apoptotic pathway activated in thymocytes through adenosine receptors. However, at the present time we cannot exclude the possibility that the inhibitory effect of cyclosporin A on 2–Chloroadenosine– induced apoptosis may be mediated through a calcineurin-independent process