Purinergic Signalling最新文献

{"title":"The effect of P2RX7 functional SNPs on osteoblast cell phenotype, function and signalling- roles in bone homeostasis and osteogenesis.","authors":"Luke Tattersall, Qiguang Wang, Anna Lisa Giuliani, Elena Adinolfi, Alison Gartland","doi":"10.1007/s11302-026-10171-5","DOIUrl":"10.1007/s11302-026-10171-5","url":null,"abstract":"<p><p>Bone cells are known to express multiple purinergic receptors. These are involved in various aspects of bone physiology depending on the cell type and receptor involved, both in normal and disease states, with extracellular ATP being particularly abundant in the bone microenvironment. The P2X7R subtype has been the subject of in-depth research in bone homeostasis. Different splice isoforms and single nucleotide polymorphisms (SNPs) have been discovered in the P2RX7 gene, these have functional implications on the receptor, conferring both gain of function (GOF) and loss of function (LOF), with consequences for bone phenotype, turnover and mass. We examined the full length P2RX7A, truncated P2RX7B, their co-expression and different receptor SNPs. The SNPs included the c.489C > T variant (p.His155Tyr) GOF, c.946G > A (p.Arg307Gln) LOF and c.1513A > C (p.Glu496Ala) LOF. The effect of these isoforms and SNPs on the normal cellular behaviour of the TE85 osteoblastic cell line were measured for intracellular calcium uptake, pore formation, cell proliferation, Alkaline phosphatase (ALP) activity, mineralisation, and changes in osteogenic gene expression. The results demonstrate that transfection of P2RX7 isoforms and SNP variants influenced several important bone processes. Compared to TE85 cells all isoform variants had an increased calcium response with only the co-transfected P2RX7AB having pore formation. This variant also had the highest mineralisation and ALP activity but was the least proliferative. Of the co-transfected SNP variants only the TE85 + P2RX7B + 155Y GOF cell line had both pore formation and an increased calcium response. Mineralisation was lower in all SNP cell lines as was ALP activity, however, proliferation was increased. Mechanistically, gene expression arrays showed that Nuclear Factor of Activated T-cells 1 (NFATc1) increased in the highly proliferative cell variants. Osteogenic genes such as Bone morphogenetic protein 2 (BMP2), ALP and collagen type I alpha 1 chain (COL1A1) were increased in the cell variants that had high mineralisation and ALP activity, and were decreased in the highly proliferative variants, demonstrating multiple bone phenotypes depending on GOF or LOF. In conclusion, this study extends our knowledge into the role of the P2X7R in maintaining bone homeostasis and provides assessment of P2RX7 polymorphisms in osteoblasts. In future this could help to identify associations between specific variants and increased/reduced bone mineral density or accelerated bone loss/fracture risk in a number of bone related conditions.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13310211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Responsiveness to adenosine diphosphate on carotid arterial and platelet functions in type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats.","authors":"Hideaki Tagashira, Kumiko Taguchi, Takayuki Nagano, Tsuneo Kobayashi, Hiroaki Kimura, Naoko Tanaka-Totoribe, Takayuki Matsumoto","doi":"10.1007/s11302-026-10173-3","DOIUrl":"10.1007/s11302-026-10173-3","url":null,"abstract":"<p><p>Extracellular nucleotides, including adenosine diphosphate (ADP), are pivotal in regulating vascular and platelet function. Thus, their abnormal function contributes significantly to the initiation and progression of diabetic complications. This study investigated ADP-induced changes in carotid arterial responses and platelet aggregation in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. In the carotid arteries, ADP- and sodium nitroprusside (SNP)-induced relaxations were similar between OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats. However, acetylcholine (ACh)-induced relaxation was lower in OLETF rats than in LETO rats. The prostacyclin analog beraprost did not induce relaxation in both groups. Under nitric oxide synthase inhibition, both ADP- and ACh-induced relaxation were eliminated in both rat groups. Under cyclooxygenase inhibition, ADP-induced relaxation was comparable between the groups, whereas ACh-induced relaxation was lower in OLETF rats than in LETO rats. ADP-induced platelet aggregation was greater in OLETF rats than in LETO rats, whereas collagen-induced aggregations was similar between the two groups. Beraprost suppressed both ADP- and collagen-induced aggregation in each group, while diminishing group differences in ADP-induced platelet aggregation. SNP did not affect either ADP- or collagen-induced platelet aggregation in both groups. Overall, these results demonstrate that responsiveness to ADP was preserved in the carotid arteries but was augmented in platelets in OLETF rats. These different ADP-induced reactivities may provide important clues for elucidating the mechanisms of diabetes-associated complications.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective P2X3 versus dual P2X2/3 receptor antagonists in refractory chronic cough: a systematic review and dose-response meta-analysis of randomized controlled trials.","authors":"Jeevarathinam Thirumalai, Indra Sivakumar, Saravanan Sekaran","doi":"10.1007/s11302-026-10172-4","DOIUrl":"10.1007/s11302-026-10172-4","url":null,"abstract":"<p><p>Extracellular adenosine triphosphate (ATP)-mediated purinergic signalling via P2X3 and heteromeric P2X2/3 ion channel receptors underlies hypersensitisation of vagal airway afferents in refractory chronic cough (RCC), making this pathway a key therapeutic target. Two pharmacological strategies have emerged: dual P2X2/3 receptor antagonism and selective P2X3 inhibition. While dual antagonists (gefapixant) demonstrate robust antitussive efficacy, their clinical use is limited by taste disturbance resulting from P2X2/3 inhibition in gustatory pathways. We conducted a systematic review and dose-response meta-analysis of randomised controlled trials evaluating purinergic receptor antagonists in RCC, with nine RCTs (21 active arms; N = 1,934) identified from major databases. The primary outcome was percentage change in 24-h cough frequency (24-h CF) versus placebo. Dual P2X2/3 antagonists produced greater reductions in 24-h CF than selective P2X3 antagonists (- 38.12% vs - 19.93%; p = 0.016), consistent with broader receptor blockade. However, selective P2X3 antagonists demonstrated a markedly improved safety profile, with substantially lower dysgeusia incidence (8% vs 51%; p < 0.0001), reflecting sparing of P2X2/3-mediated gustatory signalling. Dose-response analysis indicated steeper efficacy gains with dual antagonists but disproportionately higher taste-related adverse effects. Among selective agents, camlipixant (≥ 50 mg BID) achieved clinically meaningful cough reduction (- 34%) with minimal dysgeusia (5-7%). These findings demonstrate a mechanistically defined benefit-risk trade-off in purinergic receptor targeting, supporting selective P2X3 antagonism as a more favourable strategy for modulating ATP-driven airway sensory signalling in RCC while preserving tolerability.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A tale of two ATPs: biased activation of the P2X3 receptor.","authors":"Paul-Pierre Boutet","doi":"10.1007/s11302-026-10170-6","DOIUrl":"10.1007/s11302-026-10170-6","url":null,"abstract":"<p><p>In a recent publication in Proceedings of the National Academy of Science, Wang et al. explore the structural and physiological outcomes of P2X3 receptor (P2X3R) activation by MgATP^2- and ATP^4-, two endogenous forms of ATP. The authors find that the P2X3R, which mediates pain and taste perception as well as cough responses, exhibits distinct conformational changes in response to the two forms of ATP. Such behavior parallels the \"biased agonism\" observed in G protein-coupled receptors and may have important pharmacological implications. To demonstrate the potential utility of this finding, the authors show that two P2X3R inhibitors differentially block the two forms of ATP, with one reducing pain sensitivity and cough response without impacting sweet taste perception. These findings will help inform new therapeutic approaches to targeting the P2X3R, and potentially the broader P2X receptor family.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13264640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenosine A2A receptor signaling in neuroinflammation, glial modulation, and mechanisms associated with chronic pain.","authors":"Clara Andressa Barros, Jéssica Gonçalves Rangel, Bruno de Oliveira Cruz, Leonardo Pereira De Araújo, Giovane Galdino","doi":"10.1007/s11302-026-10167-1","DOIUrl":"10.1007/s11302-026-10167-1","url":null,"abstract":"<p><p>Chronic pain is increasingly recognized as a complex and multidimensional condition that extends beyond peripheral nociceptive input, encompassing maladaptive central mechanisms such as persistent neuroinflammation, glial dysfunction, aberrant synaptic plasticity, and disturbances in affective-motivational circuits. Adenosine, an endogenous purine nucleoside, plays a pivotal role in central nervous system homeostasis through activation of four G protein-coupled receptors (A1, A2A, A2B, and A3). Among these, the adenosine A2A receptor (A2AR) has emerged as an important modulator of neuroimmune signaling, astrocyte-neuron communication, synaptic excitability, and behavior. Although adenosinergic signaling has been extensively investigated in the context of pain and neurological disorders, the specific contribution of A2AR to pain-related mechanisms is often addressed indirectly, as many studies focus on upstream neurobiological processes rather than nociception itself. In this narrative review, we integrate recent experimental, translational and observational evidence from in silico, in vitro, ex vivo, in vivo, and human studies to examine how A2AR-dependent signaling may influence mechanisms associated with pain modulation. The literature is organized according to conceptual and mechanistic criteria into four thematic axes: (i) neuroinflammation and central sensitization, (ii) astrocytic regulation and synaptic modulation, (iii) neurological disorders with pain-related components, and (iv) affective and emotional processes associated with the pain experience. Across these domains, convergent evidence suggests that A2AR signaling is involved in interactions between glial activation, inflammatory signaling, synaptic plasticity, and affective regulation. Together, these findings provide a framework for understanding how A2AR-related mechanisms contribute to process associated with chronic pain development and persistence, even in experimental contexts not explicitly designed to assess nociception. This integrative perspective supports further investigation of A2AR as a potential therapeutic target in chronic pain and related neuroinflammatory conditions.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13250032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148212179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: The analgesic effect of electroacupuncture in alleviating paclitaxel-induced peripheral neuropathic pain and its possible mechanism relates to TLR4/P2X7-NLRP3 signaling pathway.","authors":"Yuan-Xi Zhou, Man-Ni Wang, Juan-Juan Xin, Jing-Wei Tan, Xiao Sang, Yu-Xue Zhao","doi":"10.1007/s11302-026-10169-z","DOIUrl":"10.1007/s11302-026-10169-z","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13253908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzamide derivatives as allosteric ligands of the human and rat P2X7 receptor.","authors":"Andrea Spinaci, Aleksei Smirnov, Beatrice Francucci, Michela Buccioni, Catia Lambertucci, Gabriella Marucci, Elena Adinolfi, Diego Dal Ben, Rosaria Volpini","doi":"10.1007/s11302-026-10168-0","DOIUrl":"10.1007/s11302-026-10168-0","url":null,"abstract":"<p><p>The P2X7 receptor (P2X7R) is a key player of the purinergic signalling and is widely expressed throughout the body. The involvement of this protein in the regulation of physiological processes and the onset and progression of pathological conditions make the P2X7R a key target for the development of novel pharmacological tools for the treatment of inflammation-related conditions, cancer, and neurological diseases. Here we report the synthesis and biological evaluation of an array of 2-bromo-benzamide derivatives as novel allosteric ligands of the P2X7R. The compounds ability to bind and inhibit the receptor was evaluated with radioligand binding assay at both the human and rat proteins and functional studies at the human P2X7R, stably transfected in HEK293 cells. The affinity was analysed with the aid of molecular modelling studies performed at both receptors. All the compounds showed nanomolar to micromolar affinity for the human P2X7R and a lower ability to bind the rat protein. Inhibitory potency at the human P2X7R ranged from nanomolar to micromolar levels, with one compound showing sub-nanomolar inhibitory potency. These results confirm the 2-bromo-benzamide scaffold as a solid basis for the development of novel P2X7R allosteric ligands.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13237292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148157696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Turning failure into success: how artificial intelligence can help personalize therapies and re-use patient data.","authors":"Maria P Abbracchio, Ernesto Damiani","doi":"10.1007/s11302-026-10165-3","DOIUrl":"10.1007/s11302-026-10165-3","url":null,"abstract":"<p><p>Despite robust preclinical evidence, many clinical trials, including several that targeted the purinergic system, fail to demonstrate efficacy in humans. Failure may stem from inability to accurately identify patient subgroups responding similarly to treatments. Here, we explore the potential of artificial intelligence to revolutionize how we group and classify patients in clinical studies. We introduce a new framework using Large Language Models-generated embeddings of detailed patient data, to create a semantic-aware latent space, enabling us to identify truly meaningful patients' clusters. Large Language Models can provide explainable groupings, giving clear reasons why certain patients respond similarly to treatments. We present an example of successful application of this approach through the re-analysis of the AMARANTH clinical trial (NCT02245737, involving ~ 2200 patients and completed in 2018) testing Lanabecestat, a BACE1 inhibitor decreasing β-amyloid production in Alzheimer's disease, for which traditional analysis reported no efficacy. As in the original trial, our simulation showed no overall benefit. However, re-analysis per patients' clusters and subjects' re-stratification by semantic similarities (shared symptom profiles, progression patterns) identified a patients' subgroup in one of the clusters showing Lanabecestat-associated slower disease worsening, thus succeeding where the full trial had failed. By making a new therapy available to at least a subset of patients with a defined disease, this new approach may help maximize the return on drug development and reduce the burden on healthcare. Moreover, it will significantly improve the precision, efficiency and interpretability of clinical trials, paving the way for a new era of personalized medical treatments.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13221484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148056489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleotide signaling in neutrophils: a key player in cancer dynamics.","authors":"Jean Lucas Gutknecht da Silva, Jean Sévigny, Daniela Bitencourt Rosa Leal","doi":"10.1007/s11302-026-10166-2","DOIUrl":"10.1007/s11302-026-10166-2","url":null,"abstract":"<p><p>Neutrophils are key innate immune cells whose effector mechanisms are increasingly recognized as therapeutic targets in chronic inflammation and cancer. While highly heterogeneous and functionally versatile, they can also exacerbate inflammation and tissue damage, making precise modulation critical for homeostasis. Nucleotide signaling-including extracellular nucleotide-metabolizing enzymes and receptors for ATP, UTP, and adenosine-plays a central role in regulating neutrophil responses. Extracellular nucleotides influence adhesion, chemotaxis, and degranulation, with important implications in cancer. Neutrophil heterogeneity affects tumor progression through both pro- and antitumor mechanisms. This review summarizes these findings and highlights therapeutic strategies targeting nucleotide signaling to modulate neutrophil activity in cancer.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13201813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148016940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P2Y6 receptor in the superior cervical ganglion: a key mediator of post-myocardial ischemic sympathetic hyperexcitability via NF-κB mediated neuroinflammation.","authors":"Lifang Zou, Changyi Li, Mingshuo He, Chenxi Li, Chengxu Chen, Xuexuan Yang, Shuangmei Liu","doi":"10.1007/s11302-026-10164-4","DOIUrl":"10.1007/s11302-026-10164-4","url":null,"abstract":"<p><p>Myocardial ischemia (MI) often leads to sympathetic overexcitation, though the underlying mechanisms are not fully understood. This work was to elucidate the role of P2Y6 receptors in the superior cervical ganglion (SCG) in mediating sympathetic hyperactivity after MI. In vivo, a rat model of MI was established by mild ligation of the left anterior descending coronary artery. These rats exhibited ST-segment elevation, elevated blood pressure, increased heart rate, enhanced sympathetic nerve discharge, raised serum norepinephrine levels, and structural damage to myocardial tissue. These changes were accompanied by P2Y6 expression upregulation in the SCG and NF-κB signalling activation, as indicated by increased levels of p65, phospho-p65, IL-1β, and TNF-α. P2Y6 knockdown with shRNA significantly alleviated these pathological manifestations. In vitro, oxygen-glucose deprivation in PC12 cells similarly upregulated P2Y6 expression and activated NF-κB signalling. The P2Y6 agonist UDP further enhanced, while the antagonist MRS2578 suppressed, the expression of p65, phospho-p65, IL-1β, and TNF-α. Moreover, the NF-κB inhibitor PTD-P65-P1 abolished UDP-induced IL-1β release. In conclusion, P2Y6 receptors in the SCG contribute to MI-related sympathetic overactivity via NF-κB-mediated inflammatory signalling, highlighting P2Y6 as a potential therapeutic target for autonomic dysregulation after myocardial ischemia.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13201709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148016950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}