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1.
Cancer is a chronic disease and its pathogenesis is well correlated with infection and inflammation. Adenosine is a purine nucleoside, which is produced under metabolic stress like hypoxic conditions. Acute or chronic inflammatory conditions lead to the release of precursor adenine nucleotides (adenosine triphosphate (ATP), adenosien diphosphate (ADP) and adenosine monophosphate (AMP)) from cells, which are extracellularly catabolized into adenosine by extracellular ectonucleotidases, i.e., CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. It is now well-known that adenosine is secreted by cancer as well as immune cells during tumor pathogenesis under metabolic stress or hypoxia. Once adenosine is released into the extracellular environment, it exerts various immunomodulatory effects via adenosine receptors (A 1, A 2A, A 2B, and A 3) expressed on various immune cells (i.e., macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), T cells, regulatory T cell (T regs), etc.), which play very important roles in the pathogenesis of cancer. This review is intended to summarize the role of inflammation and adenosine in the immunopathogenesis of tumor along with regulation of tumor-specific immune response and its modulation as an adjunct approach to tumor immunotherapy. 相似文献
2.
There are four adenosine receptors, A 1, A 2A, A 2B and A 3, together forming a defined subgroup of G protein coupled receptors. They are well conserved and widely expressed. The endogenous agonist, adenosine, has a minimal concentration in body fluids (20-200 nM) that is sufficient to slightly activate the receptors where they are very highly expressed—as in the basal ganglia, on fat cells and in the kidney. Here adenosine can play a physiological role and here antagonists such as caffeine can have effects in healthy individuals. Adenosine levels rise in stress and distress (up to 30 μM in ischemia) and tend to minimize the risk for adverse outcomes by increasing energy supply and decreasing cellular work, by stimulating angiogenesis, mediating preconditioning and having multiple effects on immune competent cells. These pathophysiological roles of adenosine also offer some potential drug targets, but the fact that adenosine receptors are involved in so many processes does not simplify drug development. 相似文献
3.
Latest results on the action of adenosine A 2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia
possess high levels of adenosine A 2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus,
and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A 2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A 2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The
experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with
simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A 2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A 2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility
during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A 2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects.
In combination therapy, the adenosine A 2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration
of adenosine A 2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It
was demonstrated in various animal models that inhibition of adenosine A 2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or
stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor
of adenosine A 2A receptors, as an anti-Parkinson drug. 相似文献
4.
Evidence has accumulated in the last three decades to suggest tissue protection and regeneration by adenosine in multiple
different cell types. Adenosine produced in hypoxic or inflamed environments reduces tissue injury and promotes repair by
receptor-mediated mechanisms. Among other actions, regulation of cytokine production and secretion by immune cells, astrocytes
and microglia (the brain immunocytes) has emerged as a main mechanism at the basis of adenosine effects in diseases characterized
by a marked inflammatory component. Many recent studies have highlighted that signalling through A 1 and A 2A adenosine receptors can powerfully prevent the release of pro-inflammatory cytokines, thus inhibiting inflammation and reperfusion
injury. However, the activation of adenosine receptors is not invariably protective of tissues, as signalling through the
A 2B adenosine receptor has been linked to pro-inflammatory actions which are, at least in part, mediated by increased release
of pro-inflammatory cytokines from epithelial cells, astrocytes and fibroblasts. Here, we discuss the multiple actions of
P1 receptors on cytokine secretion, by analyzing, in particular, the role of the various adenosine receptor subtypes, the
complex reciprocal interplay between the adenosine and the cytokine systems, their pathophysiological significance and the
potential of adenosine receptor ligands as new anti-inflammatory agents. 相似文献
5.
Summary. Glutamate increases the extracellular adenosine levels, an important endogenous neuromodulator. The neurotoxicity induced
by glutamate increases the ecto-5′-nucleotidase activity in neurons, which produces adenosine from AMP. L- and D-aspartate
(Asp) mimic most of the actions of glutamate in the N-methyl-D-aspartate (NMDA) receptors. In the present study, both amino
acids stimulated the ecto-5′-nucleotidase activity in cerebellar granule cells. MK-801 and AP-5 prevented the L- and D-Asp-evoked
activation of ecto-5′-nucleotidase. Both NMDA receptor antagonists prevented completely the damage induced by L-Asp, but partially
the D-Asp-induced damage. The antagonist of adenosine A 2A receptors (ZM 241385) prevented totally the L- Asp-induced cellular death, but partially the neurotoxicity induced by D-Asp
and the antagonist of adenosine A 1 receptors (CPT) had no effect. The results indicated a different involvement of NMDA receptors on the L- or D-Asp-evoked
activation of ecto-5′-nucleotidase and on cellular damage. The adenosine formed from ecto-5′-nucleotidase stimulation preferentially
acted on adenosine A 2A receptor which is probably co-operating with the neurotoxicity induced by amino acids. 相似文献
6.
Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. Adenosine released from different
cells or generated through the activity of cell-surface ectoenzymes exerts its effects through the binding of four different
G-protein-coupled adenosine receptors. In platelets, binding of A 2 subtypes (A 2A or A 2B) leads to consequent elevation of intracellular cyclic adenosine monophosphate, an inhibitor of platelet activation. The
significance of this ligand and its receptors for platelet activation is addressed in this review, including how adenosine
metabolism and its A 2 subtype receptors impact the expression and activity of adenosine diphosphate receptors. The expression of A 2 adenosine receptors is induced by conditions such as oxidative stress, a hallmark of aging. The effect of adenosine receptors
on platelet activation during aging is also discussed, as well as potential therapeutic applications. 相似文献
7.
A series of 2-phenylethynyladenosine (PEAdo) derivatives substituted in the N 6- and 4′-position was synthesised and the new derivatives were tested at the four human adenosine receptors stably transfected into Chinese hamster ovary (CHO) cells, using radioligand binding studies (A 1, A 2A, A 3) or adenylyl cyclase activity assay (A 2B). Binding studies showed that the presence of a phenyl ethynyl group in the 2 position of adenosine favoured the interaction with A 3 receptors, resulting in compounds endowed with high affinity and selectivity for the A 3 subtype. Additional substitution of the N 6- and 4′-position increases both A 3 affinity and selectivity. The results showed that the new compounds have a good affinity for the A 3 receptor and in particular, the N 6-methoxy-2-phenylethynyl-5′-N-methylcarboxamidoadenosine, with a K i at A 3 of 1.9 nM and a selectivity A 1/A 3 and A 2A/A 3 of 4,800- and 8,600-fold, respectively. Therefore, it is one of the most potent and selective agonists at the human A 3 adenosine receptor subtype reported so far. Furthermore, functional assays of inhibition of 10 μM forskolin-stimulated cAMP production via the adenosine A 3 receptor revealed that the new trisubstituted adenosine derivatives behave as full agonist of this receptor subtype. Docking analysis of these compounds was performed at a homology model of the human A 3 receptor based on the bovine rhodopsin crystal structure as template, and the results are in accordance with the biological data.An erratum to this article can be found at 相似文献
8.
Adenosine modulates the proliferation, survival and apoptosis of many different cell types, ranging from epithelial, endothelial and smooth muscle cells, to cells of the immune and neural lineages. In this review, we critically discuss the available in vitro and in vivo data which support a role for adenosine in both development-associated apoptosis, and in diseases characterized by either pathologically increased cell death (e.g., ischemia, trauma and aging-associated neurodegeneration) or abnormally reduced spontaneous apoptosis (e.g., cancer). Particular emphasis is given to the possible role of extracellular adenosine receptors, since these may represent novel and attractive molecular targets for the pharmacological modulation of apoptosis. In some instances, adenosine-induced cell death has been demonstrated to require entry of the nucleoside inside cells; however, in many other cases, activation of specific adenosine extracellular receptors has been demonstrated. Of the four G protein-coupled adenosine receptors so far identified, the A 2A and the A 3 receptors have been specifically implicated in modulation of cell death. For the A 3 receptor, results obtained by exposing both cardiomyocytes and brain astrocytes to graded concentrations of selective agonists suggest induction of both cell protection and cell death. Such opposite effects, which likely depend on the degree of receptor activation, may have important therapeutic implications in the pharmacological modulation of cardiac and brain ischemia. For the A 2A receptor, recent intriguing data suggest a specific role in immune cell death and immunosuppression, which may be relevant to both adenosine-deaminase-immunodeficiency syndrome (a pathology characterized by accumulation of adenosine to toxic levels) and in tumors where induction of apoptosis via activation of specific extracellular receptors may be desirable. Finally, preliminary data suggest that, in a similar way to the adenosine-deaminase-immunodeficiency syndrome, the abnormal accumulation of adenosine in degenerative muscular diseases may contribute to muscle cell death. Although the role of adenosine receptors in this effect still remains to be determined, these data suggest that adenosine-induced apoptosis may also represent a novel pathogenic pathway in muscular dystrophies. 相似文献
9.
Adenosine receptors were classified into A 1- and A 2-receptors in the laboratory of Bernd Hamprecht more than 25 years ago. Adenosine receptors are instrumental to the neurotrophic
effects of glia cells. Both microglia and astrocytes release after stimulation via adenosine receptors factors that are important
for neuronal survival and growth. Neuronal resilience is now considered as of pivotal importance in the neurobiology of mood
disorders and their treatment. Both sleep deprivation and electroconvulsive therapy, two effective therapeutic measures in
mood disorders, are associated with an increase of adenosine and upregulation of adenosine A 1-receptors in the brain. Parameters closely related to adenosine receptor activation such as cerebral metabolic rate and delta
power in the sleep EEG provide indirect evidence that adenosinergic signaling may be associated with the therapeutic response
to these measures. Thus, neurotrophic effects evoked by adenosine receptors might be important in the mechanism of action
of ECT and perhaps also sleep deprivation. 相似文献
10.
BackgroundEssential hypertension is considered to be a multifactorial disorder and its aetiology has yet to be clearly identified. As the adenosine receptors have a significant role in mediating vasodilation, alterations in their structures or signalling pathways may be involved in the development of hypertension. This study aimed to measure the expression of adenosine A 3 receptors in a range of cardiovascular tissues and determine whether they could be altered with essential hypertension, and to functionally test responses to adenosine A 3 receptor agonists in coronary blood vessels using the isolated perfused heart preparation. MethodsmRNA samples from cardiovascular tissues and a range of blood vessels were collected from 10 week old male spontaneously hypertensive rats and age-gender matched Wistar rats (n = 8). The Langendorff heart perfusion preparation was used to characterise adenosine A 3 receptor mediated coronary vasodilation in the rat heart. ResultsAdenosine A 3 receptor agonists induced coronary vasodilation. The expression of adenosine A 3 receptors in cardiovascular tissues was altered in a tissue-specific pattern. Specifically, down-regulation of adenosine A 3 receptor expression occurred in hypertensive hearts, which might be associated with attenuated vasodilator responses observed in coronary vessels to adenosine A 3 receptor agonists. ConclusionsThis study demonstrated alterations in the expression of adenosine A 3 receptors occurred in a tissue specific mode, and reduced adenosine A 3 receptor mediated coronary vasodilation in hearts from spontaneously hypertensive rats. Our findings with regard to changes in the adenosine A 3 receptor in hypertensive hearts suggest that adenosine A 3 receptor might play a role in the physiopathology of essential hypertension and potentially open the way to pharmacologic manipulation of vasomotor activity by the use of adenosine A 3 receptor agonists. 相似文献
11.
Adenosine is an important mediator of inhibition of platelet activation. This metabolite is released from various cells, as well as generated via activity of ecto‐enzymes on the cell surface. Binding of adenosine to A 2 subtypes (A 2A or A 2B), G‐protein coupled adenosine receptors, results in increased levels of intracellular cyclic adenosine monophosphate (cAMP), a strong inhibitor of platelet activation. The role and importance of adenosine and its receptors in platelet physiology are addressed in this review, including recently identified roles for the A 2B adenosine receptor as a modulator of platelet activation through its newly described role in the control of expression of adenosine diphosphate (ADP) receptors. J. Cell. Physiol. 226: 46–51, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
12.
Prior studies demonstrate that adenosine, acting at one or more of its receptors, mediates the anti-inflammatory effects of
methotrexate in animal models of both acute and chronic inflammation. Both adenosine A 2A and A 3 receptors contribute to the anti-inflammatory effects of methotrexate treatment in the air pouch model of inflammation, and
the regulation of inflammation by these two receptors differs at the cellular level. Because different factors may regulate
inflammation at different sites we examined the effect of low-dose weekly methotrexate treatment (0.75 mg/kg/week) in a model
of acute peritoneal inflammation in adenosine A 2A receptor knockout mice and A 3 receptor knockout mice and their wild-type littermates. Following intraperitoneal injection of thioglycollate there was no
significant difference in the number or type of leukocytes, tumor necrosis factor alpha (TNF-α) and IL-10 levels that accumulated
in the thioglycollate-induced peritoneal exudates in adenosine A 2A knockout mice or wild-type control mice. In contrast, there were more leukocytes, TNF-α and IL-10 in the exudates of the
adenosine A 3 receptor-deficient mice. Low-dose, weekly methotrexate treatment increased the adenosine concentration in the peritoneal
exudates of all mice studied, and reduced the leukocyte accumulation in the wild-type mice and A 3 receptor knockout mice but not in the A 2A receptor knockout mice. Methotrexate reduced exudate levels of TNF-α in the wild-type mice and A 3 receptor knockout mice but not the A 2A receptor knockout mice. More strikingly, IL-10, a critical regulator of peritoneal inflammation, was increased in the methotrexate-treated
wild-type mice and A 3 knockout mice but decreased in the A 2A knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was similarly effective in
wild-type mice, A 2A mice and A 3 knockout mice. These findings provide further evidence that adenosine is a potent regulator of inflammation that mediates
the anti-inflammatory effects of methotrexate. Moreover, these data provide strong evidence that the anti-inflammatory effects
of methotrexate and adenosine are mediated by different receptors in different inflammatory loci, an observation that may
explain why inflammatory diseases of some organs but not of other organs respond to methotrexate therapy. 相似文献
13.
The early stages of diabetic retinopathy (DR) are characterized by alterations similar to neurodegenerative and inflammatory conditions such as increased neural apoptosis, microglial cell activation and amplified production of pro-inflammatory cytokines. Adenosine regulates several physiological functions by stimulating four subtypes of receptors, A 1AR, A 2AAR, A 2BAR, and A 3AR. Although the adenosinergic signaling system is affected by diabetes in several tissues, it is unknown whether diabetic conditions in the retina can also affect it. Adenosine delivers potent suppressive effects on virtually all cells of the immune system, but its potential role in the context of DR has yet to be studied in full. In this study, we used primary mixed cultures of rat retinal cells exposed to high glucose conditions, to mimic hyperglycemia, and a streptozotocin rat model of type 1 diabetes to determine the effect diabetes/hyperglycemia have on the expression and protein levels of adenosine receptors and of the enzymes adenosine deaminase and adenosine kinase. We found elevated mRNA and protein levels of A 1AR and A 2AAR, in retinal cell cultures under high glucose conditions and a transient increase in the levels of the same receptors in diabetic retinas. Adenosine deaminase and adenosine kinase expression and protein levels showed a significant decrease in diabetic retinas 30 days after diabetes induction. An enzymatic assay performed in retinal cell cultures revealed a marked decrease in the activity of adenosine deaminase under high glucose conditions. We also found an increase in extracellular adenosine levels accompanied by a decrease in intracellular levels when retinal cells were subjected to high glucose conditions. In conclusion, this study shows that several components of the retinal adenosinergic system are affected by diabetes and high glucose conditions, and the modulation observed may uncover a possible mechanism for the alleviation of the inflammatory and excitotoxic conditions observed in diabetic retinas. 相似文献
14.
From a collection containing more than 1500 academic compounds, in silico screening identified a hit for the human A 1 adenosine receptor containing a new purine scaffold. To study the structure activity relationships of this new chemical series for adenosine receptors, a library of 24 purines was synthesized and tested in radioligand binding assays at human A 1, A 2A, A 2B and A 3 adenosine receptor subtypes. Fourteen molecules showed potent antagonism at A 1, A 3 or dual A 1/A 3 adenosine receptors. This purine scaffold is an important source for novel biochemical tools and/or therapeutic drugs. 相似文献
15.
Amyotrophic lateral sclerosis (ALS) is a fatal progressing neurodegenerative disease; to date, despite the intense research effort, only two therapeutic options, with very limited effects, are available. The purinergic system has been indicated as a possible new therapeutic target for ALS, but the results are often contradictory and generally confused. The present study was designed to determine whether P1 adenosine receptor ligands affected disease progression in a transgenic model of ALS. SOD1G93A mice were chronically treated, from presymptomatic stage, with a selective adenosine A2A receptor agonist (CGS21680), antagonist (KW6002) or the A1 receptor antagonist DPCPX. Body weight, motor performance and survival time were evaluated. The results showed that neither the stimulation nor the blockade of adenosine A2A receptors modified the progressive loss of motor skills or survival of mSOD1G93A mice. Conversely, blockade of adenosine A1 receptors from the presymptomatic stage significantly attenuated motor disease progression and induced a non-significant increase of median survival in ALS mice. Our data confirm that the modulation of adenosine receptors can elicit very different (and even opposite) effects during the progression of ALS course, thus strengthens the importance of further studies to elucidated their real therapeutic potential in this pathology. 相似文献
16.
Allosteric modulators for adenosine receptors may have potential therapeutic advantage over orthosteric ligands. Allosteric enhancers at the adenosine A 1 receptor have been linked to antiarrhythmic and antilipolytic activity. They may also have therapeutic potential as analgesics and neuroprotective agents. A 3 allosteric enhancers are postulated to be useful against ischemic conditions or as antitumor agents. In this review, we address recent developments regarding the medicinal chemistry of such compounds. Most efforts have been and are directed toward adenosine A 1 and A 3 receptors, whereas limited or no information is available for A 2A and A 2B receptors. We also discuss some findings, mostly receptor mutation studies, regarding localization of the allosteric binding sites on the receptors. 相似文献
17.
Adenosine A 1 and A 2A receptors are attracting great interest as drug targets for their role in cognitive and motor deficits, respectively. Antagonism of both these adenosine receptors may offer therapeutic benefits in complex neurological diseases, such as Alzheimer’s and Parkinson’s disease. The aim of this study was to explore the affinity and selectivity of 2-benzylidene-1-tetralone derivatives as adenosine A 1 and A 2A receptor antagonists. Several 5-hydroxy substituted 2-benzylidene-1-tetralone analogues with substituents on ring B were synthesized and assessed as antagonists of the adenosine A 1 and A 2A receptors via radioligand binding assays. The results indicated that hydroxy substitution in the meta and para position of phenyl ring B, displayed the highest selectivity and affinity for the adenosine A 1 receptor with K i values in the low micromolar range. Replacement of ring B with a 2-amino-pyrimidine moiety led to compound 12 with an increase of affinity and selectivity for the adenosine A 2A receptor. These substitution patterns led to enhanced adenosine A 1 and A 2A receptor binding affinity. The para-substituted 5-hydroxy analogue 3 behaved as an adenosine A 1 receptor antagonists in a GTP shift assay performed with rat whole brain membranes expressing adenosine A 1 receptors. In conclusion, compounds 3 and 12, showed the best adenosine A 1 and A 2A receptor affinity respectively, and therefore represent novel adenosine receptor antagonists that may have potential with further structural modifications as drug candidates for neurological disorders. 相似文献
18.
A new series of 2,6,9-trisubstituted adenines ( 5–14) have been prepared and evaluated in radioligand binding studies for their affinity at the human A 1, A 2A and A 3 adenosine receptors and in adenylyl cyclase experiments for their potency at the human A 2B subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N
6 position of 9-propyladenine significantly increased binding affinity at the human A 1 and A 3 adenosine receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending
on the receptor subtype and/or on the substituent present in the N
6 position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A 2A subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human
A 2B subtype, adenine is a useful template for further development of simplified adenosine receptor antagonists with distinct
receptor selectivity profiles. 相似文献
19.
腺苷作为神经调质,调节多种神经生物学功能.随觉醒时间延长,动物脑内腺苷水平逐渐增高,在睡眠期显著降低.因此,腺苷被认为是调节睡眠的内稳态因子之一.腺苷受体(receptor,R)有A1R、A2AR、A2BR和A3R四种亚型,其中A1R和A2AR与诱导睡眠相关.激活A1R可抑制促觉醒神经元诱导睡眠,也可抑制促眠神经元导致... 相似文献
20.
Limonene is a major aromatic compound in essential oils extracted from citrus rind. The application of limonene, especially in aromatherapy, has expanded significantly, but its potential effects on cellular metabolism have been elusive. We found that limonene directly binds to the adenosine A 2A receptor, which may induce sedative effects. Results from an in vitro radioligand binding assay showed that limonene exhibits selective affinity to A 2A receptors. In addition, limonene increased cytosolic cAMP concentration and induced activation of protein kinase A and phosphorylation of cAMP-response element-binding protein in Chinese hamster ovary cells transfected with the human adenosine A 2A receptor gene. Limonene also increased cytosolic calcium concentration, which can be achieved by the activation of adenosine A 2A receptors. These findings suggest that limonene can act as a ligand and an agonist for adenosine A 2A receptors. 相似文献
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