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British Journal of Pharmacology Mar 2023Senescent preadipocytes promote adipose tissue dysfunction by secreting pro-inflammatory factors, although little is known about the mechanisms regulating their...
BACKGROUND AND PURPOSE
Senescent preadipocytes promote adipose tissue dysfunction by secreting pro-inflammatory factors, although little is known about the mechanisms regulating their production. We investigated if up-regulated purinoceptor function sensitizes senescent preadipocytes to cognate agonists and how such sensitization regulates inflammation.
EXPERIMENTAL APPROACH
Etoposide was used to trigger senescence in 3T3-L1 preadipocytes. CRISPR/Cas9 technology or pharmacology allowed studies of transcription factor function. Fura-2 imaging was used for calcium measurements. Interleukin-6 levels were quantified using quantitative PCR and ELISA. Specific agonists and antagonists supported studies of purinoceptor coupling to interleukin-6 production. Experiments in MS1 VEGF angiosarcoma cells and adipose tissue samples from obese mice complemented preadipocyte experiments.
KEY RESULTS
DNA damage-induced senescence up-regulated purinoceptor expression levels in preadipocytes and MS1 VEGF angiosarcoma cells. ATP-evoked Ca release was potentiated in senescent preadipocytes. ATP enhanced interleukin-6 production, an effect mimicked by ADP but not UTP, in a calcium-independent manner. Senescence-associated up-regulation and activation of the adenosine A receptor also enhanced interleukin-6 production. However, nucleotide hydrolysis was not essential because exposure to ATPγS also enhanced interleukin-6 secretion. Pharmacological experiments suggested coupling of P2X ion channels and P2Y -P2Y receptors to downstream interleukin-6 production. Interleukin-6 signalling exacerbated inflammation during senescence and compromised adipogenesis.
CONCLUSIONS AND IMPLICATIONS
We report a previously uncharacterized link between cellular senescence and purinergic signalling in preadipocytes and endothelial cancer cells, raising the possibility that up-regulated purinoceptors play key modulatory roles in senescence-associated conditions like obesity and cancer. There is potential for exploitation of specific purinoceptor antagonists as therapeutics in inflammatory disorders.
Topics: Mice; Animals; Interleukin-6; Receptors, Purinergic P2; Calcium; Hemangiosarcoma; Vascular Endothelial Growth Factor A; Adenosine Triphosphate; Receptors, Purinergic; Cellular Senescence; Inflammation; STAT1 Transcription Factor
PubMed: 36321760
DOI: 10.1111/bph.15978 -
Purinergic Signalling Jun 2022The inner ear comprises the cochlea and vestibular system, which detect sound and acceleration stimulation, respectively. The function of the inner ear is regulated by... (Review)
Review
The inner ear comprises the cochlea and vestibular system, which detect sound and acceleration stimulation, respectively. The function of the inner ear is regulated by ion transport activity among sensory epithelial cells, neuronal cells, non-sensory epithelial cells, and luminal fluid with a unique ionic composition of high [K] and low [Na], which enables normal hearing and balance maintenance. One of the important mechanisms regulating ion transport in the inner ear is purinergic signaling. Various purinergic receptors are distributed throughout inner ear epithelial cells and neuronal cells. To date, most studies have focused on the role of purinergic receptors in the cochlea, and few studies have examined these receptors in the vestibular system. As purinergic receptors play an important role in the cochlea, they would likely do the same in the vestibular system, which is fairly similar to the cochlea in cellular structure and function. Based on available studies performed to date, purinergic signaling is postulated to be involved in the regulation of ion homeostasis, protection of hair cells, otoconia formation, and regulation of electrical signaling from the sensory epithelium to vestibular neurons. In this review, the distribution and roles of purinergic receptors in the peripheral vestibular system are summarized and discussed.
Topics: Cochlea; Ear, Inner; Receptors, Purinergic; Signal Transduction; Vestibular System
PubMed: 35344126
DOI: 10.1007/s11302-022-09855-5 -
British Journal of Pharmacology Jan 2006While there were early papers about the extracellular actions of purines, the role of ATP as a purinergic neurotransmitter in nonadrenergic, noncholinergic nerves in the...
While there were early papers about the extracellular actions of purines, the role of ATP as a purinergic neurotransmitter in nonadrenergic, noncholinergic nerves in the gut and bladder in 1972 was a landmark discovery, although it met considerable resistance for the next 20 years. In the early 1990s, receptors for purines were cloned: four P1 receptor subtypes and seven P2X ionotropic and eight P2Y metabotropic receptor subtypes are currently recognized and characterized. The mechanisms underlying ATP release and breakdown are discussed. Purines and pyrimidines have major roles in the activities of non-neuronal cells as well as neurons. This includes fast signalling roles in exocrine and endocrine secretion, platelet aggregation, vascular endothelial cell-mediated vasodilation and nociceptive mechanosensory transduction, as well as acting as a cotransmitter and neuromodulator in most, if not all, nerve types in the peripheral and central nervous systems. More recently, slow (trophic) purinergic signalling has been implicated in cell proliferation, migration, differentiation and death in embryological development, wound healing, restenosis, atherosclerosis, ischaemia, cell turnover of epithelial cells in skin and visceral organs, inflammation, neuroprotection and cancer.
Topics: Adenosine Triphosphate; Animals; History, 20th Century; History, 21st Century; Humans; Nervous System Physiological Phenomena; Neurotransmitter Agents; Receptors, Purinergic; Signal Transduction
PubMed: 16402102
DOI: 10.1038/sj.bjp.0706429 -
Biomedical Journal Oct 2016Human schistosomiasis is a chronic inflammatory disease caused by blood fluke worms belonging to the genus Schistosoma. Health metrics indicate that the disease is... (Review)
Review
Human schistosomiasis is a chronic inflammatory disease caused by blood fluke worms belonging to the genus Schistosoma. Health metrics indicate that the disease is related to an elevated number of years lost-to-disability and years lost-to-life. Schistosomiasis is an intravascular disease that is related to a Th1 and Th2 immune response polarization, and the degree of polarization affects the outcome of the disease. The purinergic system is composed of adenosine and nucleotides acting as key messenger molecules. Moreover, nucleotide-transforming enzymes and cell-surface purinergic receptors are obligatory partners of this purinergic signaling. In mammalian cells, purinergic signaling modulates innate immune responses and inflammation among other functions; conversely purinergic signaling may also be modulated by inflammatory mediators. Moreover, schistosomes also express some enzymes of the purinergic system, and it is possible that worms modulate host purinergic signaling. Current data obtained in murine models of schistosomiasis support the notion that the host purinergic system is altered by the disease. The dysfunction of adenosine receptors, metabotropic P2Y and ionotropic P2X receptors, and NTPDases likely contributes to disease morbidity.
Topics: Animals; Humans; Inflammation; Receptors, Purinergic; Signal Transduction
PubMed: 27884378
DOI: 10.1016/j.bj.2016.06.006 -
American Journal of Transplantation :... Mar 2014The purine nucleotide adenosine triphosphate (ATP) is a universal source of energy for any intracellular reaction. Under specific physiological or pathological... (Review)
Review
The purine nucleotide adenosine triphosphate (ATP) is a universal source of energy for any intracellular reaction. Under specific physiological or pathological conditions, ATP can be released into extracellular spaces, where it binds and activates the purinergic receptors system (i.e. P2X, P2Y and P1 receptors). Extracellular ATP (eATP) binds to P2X or P2Y receptors in immune cells, where it mediates proliferation, chemotaxis, cytokine release, antigen presentation and cytotoxicity. eATP is then hydrolyzed by ectonucleotidases into adenosine diphosphate (ADP), which activates P2Y receptors. Ectonucleotidases also hydrolyze ADP to adenosine monophosphate and adenosine, which binds P1 receptors. In contrast to P2X and P2Y receptors, P1 receptors exert mainly an inhibitory effect on the immune response. In transplantation, a prominent role has been demonstrated for the eATP/P2X7R axis; the targeting of this pathway in fact is associated with long-term graft function and reduced graft versus host disease severity in murine models. Novel P2X receptor inhibitors are available for clinical use and are under assessment as immunomodulatory agents. In this review, we will focus on the relevance of the purinergic system and on the potential benefits of targeting this system in allograft rejection and tolerance.
Topics: Animals; Graft Rejection; Humans; Organ Transplantation; Receptors, Purinergic; Transplantation Tolerance; Transplantation, Homologous
PubMed: 24433446
DOI: 10.1111/ajt.12567 -
International Journal of Molecular... Jun 2021Neurodegenerative-neuroinflammatory disorders of the retina seriously hamper human vision. In searching for key factors that contribute to the development of these... (Review)
Review
Neurodegenerative-neuroinflammatory disorders of the retina seriously hamper human vision. In searching for key factors that contribute to the development of these pathologies, we considered potential interactions among purinergic neuromodulation, glycinergic neurotransmission, and microglia activity in the retina. Energy deprivation at cellular levels is mainly due to impaired blood circulation leading to increased release of ATP and adenosine as well as glutamate and glycine. Interactions between these modulators and neurotransmitters are manifold. First, P2Y purinoceptor agonists facilitate reuptake of glycine by glycine transporter 1, while its inhibitors reduce reverse-mode operation; these events may lower extracellular glycine levels. The consequential changes in extracellular glycine concentration can lead to parallel changes in the activity of NR1/NR2B type NMDA receptors of which glycine is a mandatory agonist, and thereby may reduce neurodegenerative events in the retina. Second, P2Y purinoceptor agonists and glycine transporter 1 inhibitors may indirectly inhibit microglia activity by decreasing neuronal or glial glycine release in energy-compromised retina. These inhibitions may have a role in microglia activation, which is present during development and progression of neurodegenerative disorders such as glaucomatous and diabetic retinopathies and age-related macular degeneration or loss of retinal neurons caused by thromboembolic events. We have hypothesized that glycine transporter 1 inhibitors and P2Y purinoceptor agonists may have therapeutic importance in neurodegenerative-neuroinflammatory disorders of the retina by decreasing NR1/NR2B NMDA receptor activity and production and release of a series of proinflammatory cytokines from microglial cells.
Topics: Animals; Glycine Agents; Humans; Inflammation; Neurodegenerative Diseases; Neurons; Receptors, Purinergic; Retinal Diseases
PubMed: 34201404
DOI: 10.3390/ijms22126209 -
Purinergic Signalling Jun 2021
Topics: Periodicals as Topic; Purines; Receptors, Purinergic
PubMed: 33398640
DOI: 10.1007/s11302-020-09762-7 -
Biomedicine & Pharmacotherapy =... Feb 2023Different studies have confirmed that P2X purinergic receptors play a key role in inflammation. Activation of P2X purinergic receptors can release inflammatory cytokines... (Review)
Review
Different studies have confirmed that P2X purinergic receptors play a key role in inflammation. Activation of P2X purinergic receptors can release inflammatory cytokines and participate in the progression of inflammatory diseases. In an inflammatory microenvironment, cells can release a large amount of ATP to activate P2X receptors, open non-selective cation channels, activate multiple intracellular signaling, release multiple inflammatory cytokines, amplify inflammatory response. While P2X4 and P2X7 receptors play an important role in the process of inflammation. P2X4 receptor can mediate the activation of microglia involved in neuroinflammation, and P2X7 receptor can mediate different inflammatory cells to mediate the progression of tissue-wide inflammation. At present, the role of P2X receptors in inflammatory response has been widely recognized and affirmed. Therefore, in this paper, we discussed the role of P2X receptors-mediated inflammation. Moreover, we also described the effects of some antagonists (such as A-438079, 5-BDBD, A-804598, A-839977, and A-740003) on inflammation relief by antagonizing the activities of P2X receptors.
Topics: Humans; Cytokines; Ion Channels; Inflammation; Receptors, Purinergic P2X4; Receptors, Purinergic P2X7; Adenosine Triphosphate
PubMed: 36916431
DOI: 10.1016/j.biopha.2022.114205 -
Purinergic Signalling Jun 2018Obesity is a growing worldwide health problem, with an alarming increasing prevalence in developed countries, caused by a dysregulation of energy balance. Currently, no... (Review)
Review
Obesity is a growing worldwide health problem, with an alarming increasing prevalence in developed countries, caused by a dysregulation of energy balance. Currently, no wholly successful pharmacological treatments are available for obesity and related adverse consequences. In recent years, hints obtained from several experimental animal models support the notion that purinergic signalling, acting through ATP-gated ion channels (P2X), G protein-coupled receptors (P2Y) and adenosine receptors (P1), is involved in obesity, both at peripheral and central levels. This review has drawn together, for the first time, the evidence for a promising, much needed novel therapeutic purinergic signalling approach for the treatment of obesity with a 'proof of concept' that hopefully could lead to further investigations and clinical trials for the management of obesity.
Topics: Animals; Humans; Obesity; Receptors, Purinergic; Signal Transduction
PubMed: 29619754
DOI: 10.1007/s11302-018-9605-8 -
Brain Research Bulletin Sep 2019Retinal injuries and diseases are major causes of human disability involving vision impairment by the progressive and permanent loss of retinal neurons. During... (Review)
Review
Retinal injuries and diseases are major causes of human disability involving vision impairment by the progressive and permanent loss of retinal neurons. During development, assembly of this tissue entails a successive and overlapping, signal-regulated engagement of complex events that include proliferation of progenitors, neurogenesis, cell death, neurochemical differentiation and synaptogenesis. During retinal damage, several of these events are re-activated with both protective and detrimental consequences. Purines and pyrimidines, along with their metabolites are emerging as important molecules regulating both retinal development and the tissue's responses to damage. The present review provides an overview of the purinergic signaling in the developing and injured retina. Recent findings on the presence of vesicular and channel-mediated ATP release by retinal and retinal pigment epithelial cells, adenosine synthesis and release, expression of receptors and intracellular signaling pathways activated by purinergic signaling in retinal cells are reported. The pathways by which purinergic receptors modulate retinal cell proliferation, migration and death of retinal cells during development and injury are summarized. The contribution of nucleotides to the self-repair of the injured zebrafish retina is also discussed.
Topics: Adenosine; Adenosine Triphosphate; Animals; Cell Death; Cell Differentiation; Humans; Purines; Receptors, Purinergic; Receptors, Purinergic P2X; Receptors, Purinergic P2Y; Retina; Signal Transduction
PubMed: 30458250
DOI: 10.1016/j.brainresbull.2018.10.016