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Adenosine receptors modulation of inflammatory cells: the foam cells history.
No full textAdenosine is an endogenous purine nucleoside that is constitutively present at low levels outside the
cells but might dramatically increase its concentrations following metabolic stress conditions like those
induced by hypoxia or ischaemia. After its release adenosine induces its biological effects through the
interaction with four cell surface receptors classified by molecular, biochemical and pharmacological
data into four subtypes: A1, A2A, A2B and A3. Adenosine through the interaction with A2 and A3
receptors plays a crucial role in inflammation and in the regulation of immune cells. A2A receptors,
proposed as “natural” brakes of inflammation, appear to represent a promising pharmacological target
to treat a wide variety of diseases characterized by a strong immunoinflammatory component. On the
other hand, it may be advantageous in some circumstances to enhance certain aspects of inflammation
in order to eliminate the causative agent, as in the case of cancer. In fact, it has to be remarked that
tumour defence mechanisms are akin to inflammatory processes. Solid tumours, due to their abnormal
vasculature, are often hypoxic and show increased levels of adenosine that may be an important
mediator of tumour-associated immunosuppression. It is likely that killer T cells that may be recruited
against cancer cells fail to act in an effective manner due to the high level of adenosine in the tumour
microenvironment. Because several of these immunosuppressive effects have been attributed to the
stimulation of A3 and A2A receptors, expressed on the surface of T cells, adenosine antagonists of these
subtypes may be potentially useful in the immunotherapy of cancer. The interest in the elucidation of
A3 adenosine receptor involvement in inflammation is evident from the large amount of experimental
work carried out in peripheral blood cells of the immune system and in a variety of inflammatory
conditions. A3 adenosine receptor subtype play a complex role as both pro and anti-inflammatory
effects depending not only on the cell types investigated but also on the model of inflammation used
and the species considered. In this study we discuss developments in our understanding of the role of
adenosine A3 receptor activation in the function of the different types of cells of the immune system
including neutrophils, eosinophils, lymphocytes, monocytes, macrophages and dendritic cells. Then we
focused our attention on the role of adenosine in atherosclerosis, a chronic inflammatory disease of the
arteries, characterized by an hypoxic region with an high concentration of adenosine and a large
number of foam cells. Foam cells formation by oxidized low-density lipoprotein (oxLDL)
accumulation in macrophages is crucial for development of atherosclerosis. Hypoxia has been
demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote
intraplaque angiogenesis and foam cells development. As hypoxia induces HIF-1α stabilization and
adenosine accumulation, we investigated whether this nucleoside regulates HIF-1α in FC. Adenosine,
under hypoxia, stimulates HIF-1α accumulation by activating all adenosine receptors, while it has only
a slight effect in normoxia. HIF-1α modulation involved extracellular signal-regulated kinase 1/2 (ERK
1/2), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase B (Akt) phosphorylation in
the case of A1, A2A, A2B and ERK 1/2 phosphorylation in the case of A3 receptors. Ado, through the
activation of A3 and A2B receptors, stimulates vascular endothelial growth factor (VEGF) secretion in a
HIF-1α dependent way. Furthermore ado, through the A2B subtype, induces an increase of Interleukin-8
(IL-8) secretion in a ERK 1/2, p38 and Akt kinases-dependent but not HIF-1α-mediated way. Finally,
adenosine stimulates FC formation and this effect is strongly reduced by A3 and A2B blockers and by
HIF-1α silencing. In conclusion this study provides the first evidence that A3, A2B or mixed A3/A2B
antagonists may be useful to block important steps in the atherosclerotic plaque development adoinduced
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Thermodynamics of A2B adenosine receptor binding discriminates agonistic from antagonistic behaviour
No full textThermodynamic parameters DeltaG degrees , DeltaH degrees and DeltaS degrees of the binding equilibrium of 12 ligands (six agonists and six antagonists) to the A(2B) adenosine receptor subtype have been determined by affinity measurements carried out on HEK 293 cells stably transfected with human A(2B) adenosine receptors at six different temperatures (4, 10, 15, 20, 25, 30 degrees C) and van't Hoff plot analysis have been performed. Affinity constants were obtained from saturation experiments of [(3)H]MRE 2029-F20 or by its displacement in inhibition assays for the other compounds. van't Hoff plots were essentially linear in the temperature range investigated, showing that the DeltaC(p) degrees of the binding equilibrium is nearly zero. Thermodynamic parameters are in the range 7</=DeltaH degrees </=23kJmol(-1)and 123</=DeltaS degrees </=219JK(-1)mol(-1) for agonists and -40</=DeltaH degrees </=-20kJmol(-1) and 10</=DeltaS degrees </=91JK(-1)mol(-1) for antagonists indicating that agonistic binding is always totally entropy-driven while antagonistic binding is enthalpy and entropy-driven. In the -TDeltaS degrees versus DeltaH degrees plot the thermodynamic data are clearly arranged in separate clusters for agonists and antagonists, which, therefore, turn out to be thermodynamically discriminated
Adenosine modulates HIF-1, VEGF, IL-8 and foam cells formation in a human model of hypoxic foam cells
No full textBackground: Foam cells formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and foam cells (FC) development. As hypoxia induces HIF-1α stabilization and adenosine (ado) accumulation, we investigated whether this nucleoside regulates HIF-1α in FC.
Methods: Evaluation of ado receptors expression through real-time RT-PCR, binding and western blot experiments. Evaluation of HIF-1alpha, VEGF, IL-8 and foam cells modulation by ado receptors through western blot analysis, ELISA studies and oil red O staining.
Results: Ado, under hypoxia, stimulates HIF-1α accumulation by activating all adenosine receptors (ARs). HIF-1α modulation involved extracellular signal-regulated kinase 1/2 (ERK 1/2), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase B (Akt) phosphorylation in the case of A1, A2A, A2B and ERK 1/2 phosphorylation in the case of A3 receptors. Ado, through the activation of A3 and A2B receptors, stimulates vascular endothelial growth factor (VEGF) secretion in a HIF-1α dependent way. Furthermore ado, through the A2B subtype, induces an increase of Interleukin-8 (IL-8) secretion in a ERK 1/2, p38 and Akt kinases-dependent but not HIF-1α-mediated way. Finally, ado stimulates FC formation and this effect is strongly reduced by A3 and A2B blockers and by HIF-1α silencing.
Conclusions: This study provides the first evidence that A3, A2B or mixed A3/A2B antagonists may be useful to block important steps in the atherosclerotic plaque development ado-induced
THERMODYNAMICS OF A2B ADENOSINE RECEPTOR BINDING DISCRIMINATES AGONISTIC FROM ANTAGONISTIC BEHAVIOUR
No full textThermodynamic parameters ΔG°, ΔH° and ΔS° of the binding equilibrium of six agonists and six antagonists to the A2B adenosine receptor subtype have been evaluated by affinity measurements carried out on HEK 293 cells stably transfected with human A2B adenosine receptors at six different temperatures (4, 10, 15, 20, 25, 30 °C) and van't Hoff plot analysis have been performed. Affinity constants were obtained from saturation experiments of [3H]MRE 2029-F20 or by its displacement in inhibition assays for the other compounds. van't Hoff plots were essentially linear in the temperature range investigated, showing that the ΔCp°of the binding equilibrium is nearly zero. Thermodynamic parameters are in the range 7≤ ΔH° ≤ 23 kJ mol-1 and 123≤ΔS°≤219 JK-1mol-1 for agonists and -40≤ΔH°≤-20 kJ mol-1 and 10≤ΔS°≤91 JK-1mol-1 for antagonists indicating that agonistic binding is always totally entropy-driven while antagonistic binding is enthalpy and entropy-driven. In the - TΔS°versus ΔH° degrees plot the thermodynamic data are clearly arranged in separate clusters for agonists and antagonists, which, therefore, turn out to be thermodynamically discriminated according to the behavior of A1,1 A2A2 and A33 adenosine receptors.
(1) Borea, P.A.; Varani, K.; Guerra, L.; Gilli, P.; Gilli, G. Binding thermodynamics of A1 adenosine receptor ligands. Mol. Neuropharmacol. 1992, 2, 273–81.
(2) Borea, P.A.; Dalpiaz, A.; Varani, K; Guerra, L; Gilli, G. Binding thermodynamics of adenosine A2A receptor ligands.Biochem. Pharmacol. 1995, 49, 461–9.
(3) Merighi, S.; Varani, K.; Gessi, S.; Klotz, K-N.; Leung, E; Baraldi, P.G.; Borea, P.A. Binding thermodynamics at the human A3 adenosine receptor. Biochem. Pharmacol. 2002, 63, 157–61
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