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International Journal of Molecular... Jan 2021Increased vascular permeability is a hallmark of several cardiovascular anomalies, including ischaemia/reperfusion injury and inflammation. During both... (Review)
Review
Increased vascular permeability is a hallmark of several cardiovascular anomalies, including ischaemia/reperfusion injury and inflammation. During both ischaemia/reperfusion and inflammation, massive amounts of various nucleotides, particularly adenosine 5'-triphosphate (ATP) and adenosine, are released that can induce a plethora of signalling pathways via activation of several purinergic receptors and may affect endothelial barrier properties. The nature of the effects on endothelial barrier function may depend on the prevalence and type of purinergic receptors activated in a particular tissue. In this review, we discuss the influence of the activation of various purinergic receptors and downstream signalling pathways on vascular permeability during pathological conditions.
Topics: Adenosine; Animals; Biomarkers; Blood-Air Barrier; Blood-Brain Barrier; Capillary Permeability; Endothelium; Humans; Purines; Receptors, Purinergic; Receptors, Purinergic P2; Signal Transduction
PubMed: 33530557
DOI: 10.3390/ijms22031207 -
Journal of Neuroscience Research Sep 2016Until recently, analysis of the mechanisms underlying epilepsy was centered on neuron dysfunctions. Accordingly, most of the available pharmacological treatments aim at... (Review)
Review
Until recently, analysis of the mechanisms underlying epilepsy was centered on neuron dysfunctions. Accordingly, most of the available pharmacological treatments aim at reducing neuronal excitation or at potentiating neuronal inhibition. These therapeutic options can lead to obvious secondary effects, and, moreover, seizures cannot be controlled by any known medication in one-third of the patients. A purely neurocentric view of brain functions and dysfunctions has been seriously questioned during the past 2 decades because of the accumulation of experimental data showing the functional importance of reciprocal interactions between glial cells and neurons. In the case of epilepsy, our current knowledge of the human disease and analysis of animal models clearly favor the involvement of astrocytes and microglial cells during the progression of the disease, including at very early stages, opening the way to the identification of new therapeutic targets. Purinergic signaling is a fundamental feature of neuron-glia interactions, and increasing evidence indicates that modifications of this pathway contribute to the functional remodeling of the epileptic brain. This Review discusses the recent experimental results indicating the roles of astrocytic and microglial P2X and P2Y receptors in epilepsy. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Astrocytes; Epilepsy; Humans; Microglia; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 27302739
DOI: 10.1002/jnr.23770 -
Biochemical Pharmacology May 2021Maintenance of a healthy skeleton is highly dependent on an intricate regulation of bone metabolism, as changes in the balance between bone formation and bone resorption... (Review)
Review
Maintenance of a healthy skeleton is highly dependent on an intricate regulation of bone metabolism, as changes in the balance between bone formation and bone resorption leads to bone loss, bone fragility and ultimately bone fractures. During the last three decades it has become increasingly evident that physiological release of purines in the extracellular space is imperative for bone homeostasis and is orchestrated via the network of purinoceptors. Adenosine derivatives are released locally in the skeleton either by the bone forming osteoblasts or the bone degrading osteoclasts actioned directly by processes like mechanical loading and indirectly by systemic hormones. Adenosine derivatives directly affect the bone cells by their action on the membranal receptors or have co-stimulatory actions with bone active hormones such as parathyroid hormone or the gut hormones. Any deviations leading to increased levels of extracellular adenosine derivatives in the bone tissue such as in pathologic situations, trigger complex pathways with opposing effects on tissue health as presented by studies involving a range of model organisms. Pathological conditions where skeletal purinergic signaling is affected are following tissue injury like microdamage and macroscopic fractures; and during inflammatory processes where nucleotides and nucleosides play an important part in the pathophysiological skeletal response. Moreover, adenosine derivatives also play an important role in the interaction between malignant cells and bone cells in several types of cancers involving the skeleton, such as but not limited to multiple myeloma and bone osteolysis. Much knowledge has been gained over the last decades. The net- resulting phenotype of adenosine derivatives in bone (including the ratio of ATP to Adenosine) is highly dependent on CD39 and CD73 enzymes together with the expression and activity of the specific receptors. Thus, each component is important in the physiological and pathophysiological processes in bone. Promising perspectives await in the future in treating skeletal disorders with medications targeting the individual components of the purinergic signaling pathway.
Topics: Animals; Extracellular Fluid; Homeostasis; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Purines; Receptors, Purinergic
PubMed: 33482152
DOI: 10.1016/j.bcp.2021.114425 -
Neuroscience May 2019Microglia are the main resident immune-competent cell type of the central nervous system (CNS); these cells are highly sensitive to subtle changes in the chemical... (Review)
Review
Microglia are the main resident immune-competent cell type of the central nervous system (CNS); these cells are highly sensitive to subtle changes in the chemical environment of the brain. Microglia are activated during diverse conditions, such as apoptosis, trauma, inflammation, and infection. The specific activities of microglia result from the confluence of environmental stimuli and the cellular state. It is likely that several signaling systems with different biological functions operate in competition and/or synergy, thus regulating similar microglial behaviors. The purinergic system is one of the fundamental signaling systems that establish microglial behavior in a wide spectrum of conditions. Adenosine tri-phosphate (ATP) belongs to the purinergic signaling system, which includes P2X, P2Y, and P1 receptors, as well as other proteins participating in ATP secretion and extracellular ATP degradation, and molecules that recognize purines as a ligand. In this review, we focus on the latest pre-clinical and basic purinergic system and microglial research, with particular attention to data collected in vivo and ex vivo. This chapter is divided into sections related to microglial ATP release, ATP degradation, and ATP-related actions mediated by P2X and P2Y receptor activation.
Topics: Adenosine Triphosphate; Animals; Calcium; Humans; Microglia; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 30582977
DOI: 10.1016/j.neuroscience.2018.12.021 -
Trends in Molecular Medicine Mar 2015Cell surface expression of specific receptors and ecto-nucleotidases makes extracellular nucleotides such as ATP, ADP, UTP, and adenosine suitable as signaling molecules... (Review)
Review
Cell surface expression of specific receptors and ecto-nucleotidases makes extracellular nucleotides such as ATP, ADP, UTP, and adenosine suitable as signaling molecules for physiological and pathological events, including tissue stress and damage. Recent data have revealed the participation of purinergic signaling in atherosclerosis, depicting a scenario in which, in addition to some exceptions reflecting dual effects of individual receptor subtypes, adenosine and most P1 receptors, as well as ecto-nucleotidases, show a protective, anti-atherosclerotic function. By contrast, P2 receptors promote atherosclerosis. In consideration of these findings, modulation of purinergic signaling would represent an innovative and valuable tool to counteract atherosclerosis. We summarize recent developments on the participation of the purinergic network in atheroma formation and evolution.
Topics: Animals; Atherosclerosis; Clinical Trials as Topic; Disease Progression; Humans; Models, Biological; Receptors, Purinergic; Signal Transduction
PubMed: 25637413
DOI: 10.1016/j.molmed.2014.12.008 -
Purinergic Signalling Sep 2022P2 purinergic receptors are involved in the normal function of the kidney, bladder, and prostate via signaling that occurs in response to extracellular nucleotides.... (Review)
Review
P2 purinergic receptors are involved in the normal function of the kidney, bladder, and prostate via signaling that occurs in response to extracellular nucleotides. Dysregulation of these receptors is common in pathological states and often associated with disease initiation, progression, or aggressiveness. Indeed, P2 purinergic receptor expression is altered across multiple urologic disorders including chronic kidney disease, polycystic kidney disease, interstitial cystitis, urinary incontinence, overactive bladder syndrome, prostatitis, and benign prostatic hyperplasia. P2 purinergic receptors are likewise indirectly associated with these disorders via receptor-mediated inflammation and pain, a common characteristic across most urologic disorders. Furthermore, select P2 purinergic receptors are overexpressed in urologic cancer including renal cell carcinoma, urothelial carcinoma, and prostate adenocarcinoma, and pre-clinical studies depict P2 purinergic receptors as potential therapeutic targets. Herein, we highlight the compelling evidence for the exploration of P2 purinergic receptors as biomarkers and therapeutic targets in urologic cancers and other urologic disease. Likewise, there is currently optimism for P2 purinergic receptor-targeted therapeutics for the treatment of inflammation and pain associated with urologic diseases. Further exploration of the common pathways linking P2 purinergic receptor dysregulation to urologic disease might ultimately help in gaining new mechanistic insight into disease processes and therapeutic targeting.
Topics: Adenosine Triphosphate; Carcinoma, Transitional Cell; Humans; Inflammation; Male; Pain; Receptors, Purinergic P2; Urinary Bladder Neoplasms; Urologic Diseases
PubMed: 35687210
DOI: 10.1007/s11302-022-09875-1 -
Journal of the American Heart... Sep 2020Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which... (Review)
Review
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which result in an increase in afterload imposed onto the right ventricle, leading to right heart failure. Current therapies are incapable of reversing the disease progression. Thus, the identification of novel and potential therapeutic targets is urgently needed. An alteration of nucleotide- and nucleoside-activated purinergic signaling has been proposed as a potential contributor in the pathogenesis of PAH. Adenosine-mediated purinergic 1 receptor activation, particularly AR activation, reduces pulmonary vascular resistance and attenuates pulmonary vascular remodeling and right ventricle hypertrophy, thereby exerting a protective effect. Conversely, AR activation induces pulmonary vascular remodeling, and is therefore deleterious. ATP-mediated P2XR activation and ADP-mediated activation of P2YR and P2YR play a role in pulmonary vascular tone, vascular remodeling, and inflammation in PAH. Recent studies have revealed a role of ectonucleotidase nucleoside triphosphate diphosphohydrolase, that degrades ATP/ADP, in regulation of pulmonary vascular remodeling. Interestingly, existing evidence that adenosine activates erythrocyte AR signaling, counteracting hypoxia-induced pulmonary injury, and that ATP release is impaired in erythrocyte in PAH implies erythrocyte dysfunction as an important trigger to affect purinergic signaling for pathogenesis of PAH. The present review focuses on current knowledge on alteration of nucleot(s)ide-mediated purinergic signaling as a potential disease mechanism underlying the development of PAH.
Topics: Animals; Humans; Pulmonary Arterial Hypertension; Purinergic Agents; Receptors, Purinergic
PubMed: 32867554
DOI: 10.1161/JAHA.120.017404 -
Cells Jul 2020Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this... (Review)
Review
Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.
Topics: Adenosine Triphosphate; Animals; Humans; Neoplasms; Receptors, Purinergic; Signal Transduction; Tumor Microenvironment
PubMed: 32635260
DOI: 10.3390/cells9071612 -
Advances in Experimental Medicine and... 2020ATP is a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the brain. There is a widespread presence of both adenosine (P1) and P2... (Review)
Review
ATP is a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the brain. There is a widespread presence of both adenosine (P1) and P2 nucleotide receptors in the brain on both neurons and glial cells. Adenosine receptors play a major role in presynaptic neuromodulation, while P2X ionotropic receptors are involved in fast synaptic transmission and synaptic plasticity. P2Y G protein-coupled receptors are largely involved in presynaptic activities, as well as mediating long-term (trophic) signalling in cell proliferation, differentiation and death during development and regeneration. Both P1 and P2 receptors participate in neuron-glial interactions. Purinergic signalling is involved in control of cerebral vascular tone and remodelling and has been implicated in learning and memory, locomotor and feeding behaviour and sleep. There is increasing interest in the involvement of purinergic signalling in the pathophysiology of the CNS, including trauma, ischaemia, epilepsy, neurodegenerative diseases, neuropsychiatric and mood disorders, and cancer, including gliomas.
Topics: Adenosine Triphosphate; Animals; Brain; Humans; Receptors, Purinergic; Signal Transduction; Synaptic Transmission
PubMed: 32034706
DOI: 10.1007/978-3-030-30651-9_1 -
Neuropharmacology Oct 2023The purinergic system includes P1 and P2 receptors, which are activated by ATP and its metabolites. They are expressed in adult neuronal and glial cells and are crucial... (Review)
Review
The purinergic system includes P1 and P2 receptors, which are activated by ATP and its metabolites. They are expressed in adult neuronal and glial cells and are crucial in brain function, including neuromodulation and neuronal signaling. As P1 and P2 receptors are expressed throughout embryogenesis and development, purinergic signaling also has an important role in the development of the peripheral and central nervous system. In this review, we present the expression pattern and activity of purinergic receptors and of their signaling pathways during embryonic and postnatal development of the nervous system. In particular, we review the involvement of the purinergic signaling in all the crucial steps of brain development i.e. in neural stem cell proliferation, neuronal differentiation and migration as well as in astrogliogenesis and oligodendrogenesis. Then, we review data showing a crucial role of the ATP and adenosine signaling pathways in the formation of the peripheral neuromuscular junction and of central GABAergic and glutamatergic synapses. Finally, we examine the consequences of deregulation of the purinergic system during development and discuss the therapeutic potential of targeting it at adult stage in diseases with reactivation of the ATP and adenosine pathway. This article is part of the Special Issue on "Purinergic Signaling: 50 years".
Topics: Neurons; Receptors, Purinergic; Adenosine; Adenosine Triphosphate; Brain; Cell Proliferation
PubMed: 37348675
DOI: 10.1016/j.neuropharm.2023.109640