Purinergic Signalling最新文献

{"title":"Pharmacological melatonin induces mitochondrial dysfunction and alters extracellular nucleotide metabolism and CD39/CD73 expression in human melanoma cells.","authors":"Bruna Cristina Ozelame, Daiane Mânica, Gilnei Bruno da Silva, Andreia Machado Cardoso, Margarete Dulce Bagatini, Aline Mânica","doi":"10.1007/s11302-026-10193-z","DOIUrl":"https://doi.org/10.1007/s11302-026-10193-z","url":null,"abstract":"<p><p>Cutaneous melanoma remains an aggressive malignant neoplasm characterized by molecular heterogeneity and therapeutic resistance, highlighting the need to identify alternative pathways involved in tumor progression. Purinergic signaling, particularly the conversion of extracellular ATP to immunosuppressive adenosine mediated by ectonucleotidases CD39 (NTPDase1) and CD73 (ecto-5'-nucleotidase), has emerged as a critical determinant of melanoma biology, but its potential regulation by melatonin remains unexplored.Here, we investigated whether pharmacological melatonin (0.1-5 mM, 24 and 48 h) influences metabolic activity, mitochondrial homeostasis, and extracellular nucleotide metabolism in two human melanoma cell lines with distinct molecular profiles (SK-MEL-28 and A375). Melatonin reduced metabolic activity and induced mitochondrial depolarization in both cell lines, although A375 cells exhibited greater mitochondrial sensitivity than SK-MEL-28 cells. These mitochondrial alterations were accompanied by distinct apoptosis- and inflammation-related transcriptional responses, indicating lineage-dependent cellular response to pharmacological melatonin. In parallel, melatonin differentially altered extracellular nucleotide metabolism and CD39/CD73 gene expression, with distinct responses observed between the two melanoma cell lines. Collectively, these findings indicate that the biological effects of pharmacological melatonin extend beyond mitochondrial dysfunction and involve remodeling of extracellular nucleotide metabolism, providing new evidence for an interaction between melatonergic and purinergic signaling in melanoma.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 6","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian regulation of the S1PR1-P2X7 signalling axis in obesity-associated metabolic inflammation: molecular crosstalk and therapeutic perspectives.","authors":"Alka Patel, Parag Jain, Hina Sahu","doi":"10.1007/s11302-026-10194-y","DOIUrl":"https://doi.org/10.1007/s11302-026-10194-y","url":null,"abstract":"<p><p>Obesity is a chronic, low-grade inflammatory condition expressed by inflammation and immune damage that mediates component(s) of insulin resistance and cardiometabolic syndrome in the presence of disruption of circadian rhythms. Primary research data indicate that the interplay between biological timing and immunological signalling occurs in a synchronised manner to govern metabolic homeostasis, thereby leading us to coin the term Circadian regulation of metabolic inflammation. These signalling pathways directly affect immune cell trafficking and endothelial integrity in sphingosine-1-phosphate receptor 1 (S1PR1) or purinergic P2X7 receptor (P2X7)-mediated regulation, and inflammasome activation. This review highlights a new molecular link establishing the S1PR1-P2X7 axis between circadian rhythm and obesity-linked immunometabolic disorders. We discuss the interplay of lipid and purinergic signalling, focusing on their convergence at nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), signal transducer and activator of transcription 3 (STAT3), reactive oxygen species (ROS), and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) activation pathways that act in concert to exacerbate both fatty tissue inflammation and systemic insulin metabolic resistance. Altogether, we summarise the latest advances in receptor-based pharmacotherapy, chronotherapy, and nanomedicine-guided drug delivery aimed at restoring circadian homeostasis and metabolic balance. Understanding the circadian regulation of the S1PR1-P2X7 axis may inform new precision treatment strategies for obesity-linked metabolic diseases.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 6","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the P2X7 receptor in Alzheimer's disease: mechanistic insights and emerging therapeutic strategies.","authors":"Maida Engels Se, Anandhi Ramalingam","doi":"10.1007/s11302-026-10191-1","DOIUrl":"10.1007/s11302-026-10191-1","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common cause of dementia worldwide and is characterized by progressive cognitive decline, amyloid-β deposition, tau pathology, neuroinflammation, and neuronal loss. Current therapies provide only limited symptomatic benefit, and although anti-amyloid monoclonal antibodies have demonstrated disease-modifying potential in selected patients, additional disease-modifying targets are still needed. The purinergic P2X7 receptor (P2X7R), an ATP-gated ion channel predominantly expressed on microglia and astrocytes, has emerged as a key regulator of neuroinflammatory signalling and AD progression. This narrative review summarizes and critically discusses recent preclinical, translational, and clinical evidence published through 2026. Evidence from cellular and animal models, post-mortem human brain analyses, positron emission tomography (PET) imaging studies, and pharmacological investigations was evaluated to assess the role of P2X7R in AD pathogenesis and therapeutic intervention. Accumulating evidence demonstrates that extracellular ATP-mediated activation of P2X7R promotes NLRP3 inflammasome assembly, caspase-1 activation, and the release of pro-inflammatory cytokines, including interleukin-1β and interleukin-18, thereby sustaining chronic neuroinflammation. Genetic deletion or pharmacological inhibition of P2X7R reduced amyloid plaque burden, attenuated tau hyperphosphorylation, improved synaptic function, and ameliorated cognitive deficits in experimental AD models. Human studies further revealed elevated P2X7R expression and increased neuroinflammatory activity associated with AD pathology. Emerging therapeutic approaches include selective P2X7R antagonists, natural-product modulators, RNA-based interventions, nanotechnology-assisted drug delivery systems, and combination therapies targeting multiple pathogenic pathways. P2X7R represents a promising candidate target for disease-modifying therapeutic strategies in AD, based on convergent in vitro, animal-model, human post-mortem, and imaging/biomarker evidence linking ATP-mediated danger signalling to neuroinflammation, amyloid and tau pathology, and neurodegeneration. However, its clinical efficacy in AD remains to be established, as no clinical trial data for P2X7R-targeted therapies in this disease are yet available. Future clinical translation will require improved CNS-penetrant antagonists, enhanced receptor selectivity, biomarker-guided patient stratification, and precision medicine approaches.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184033","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":"Targeting P2Y₁₄R inhibits proliferation of cervical cancer cells and organoids and activates cAMP/PKA/CREB signaling pathway.","authors":"Rui Li, Hai-Yun Xiong, Shi-Yu Chen, Yong Tang, Wen-Bin Ma","doi":"10.1007/s11302-026-10192-0","DOIUrl":"10.1007/s11302-026-10192-0","url":null,"abstract":"<p><p>Purinergic signaling has been widely recognized as a critical regulator of tumor progression, yet the role of P2Y₁₄R in cervical cancer remains unclear. This study used the P2Y₁₄R antagonist PPTN in in vitro cell experiments; the results showed that it significantly inhibited cell proliferation and increased LDH release. The anti-tumor effect of P2Y₁₄R antagonism was further validated using a cervical cancer organoid model. Mechanistically, PPTN treatment elevated intracellular cAMP levels, enhanced the phosphorylation of PKA and CREB, and thereby activated the cAMP/PKA/CREB signaling axis. Moreover, PPTN intervention reduced Ki67 expression in cervical cancer organoids without affecting CK13 expression, suggesting that the anti-tumor effect of PPTN may not mediated through regulation of differentiation. Collectively, these findings identify P2Y₁₄R as a novel regulator of the cAMP/PKA/CREB signaling pathway in cervical cancer cells, providing a promising therapeutic target for cervical cancer.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184106","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":"P2X7 receptor gene polymorphisms in atherosclerosis patients classified based on angiographic stenosis grading.","authors":"Süleyman Ince, Ahu Soyocak, Funda Seher Özalp Ateş, Emrah Ermiş","doi":"10.1007/s11302-026-10190-2","DOIUrl":"10.1007/s11302-026-10190-2","url":null,"abstract":"<p><p>Atherosclerosis is a complex and progressive vascular disease characterized by lipid accumulation and inflammation. In recent years, the purinergic signaling system, particularly the P2X7 receptor, has been suggested to play a role in atherosclerosis pathogenesis through the regulation of inflammatory responses. The present study aimed to evaluate the association between P2RX7 rs1718119 (G > A) and rs2393799 (C > T) polymorphisms and the angiographic severity of coronary artery stenosis in a Turkish atherosclerosis population. Patients with angiographically confirmed atherosclerosis were enrolled and stratified according to the degree of coronary artery stenosis. Genotyping of the P2RX7 rs1718119 and rs2393799 polymorphisms was performed using real-time polymerase chain reaction-based fluorescence melting curve analysis (FMCA). No significant associations were observed between the genotype or allele distributions of either polymorphism and the angiographic severity of coronary artery stenosis. The investigated variants were not associated with angiographic stenosis severity. Associations with selected hematological and biochemical parameters should be regarded as exploratory and require further validation. These findings provide additional data on P2RX7 genetic variation in patients with atherosclerosis and highlight the need for further functional studies.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075762","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":"ATP is not always pro-inflammatory: rethinking purinergic signalling in cancer and autoimmunity.","authors":"Mohamed S Nafie, Mohamed K Diab","doi":"10.1007/s11302-026-10188-w","DOIUrl":"10.1007/s11302-026-10188-w","url":null,"abstract":"<p><p>Extracellular adenosine 5'-triphosphate (ATP) has been recognized for many years as a prototypical danger signal that promotes inflammation primarily through activation of purinergic receptors, particularly P2X7. This framework has had a massive influence on how immunology, cancer biology, and autoimmunity are now conceived. Nonetheless, increasing experimental and clinical observations do not support the simple, unidimensional model of ATP as a pro-inflammatory mediator; instead, they suggest that, depending on the concentration, timing, receptor context, and cellular status, ATP may have strong immunosuppressive/tolerogenic effects. Prolonged ATP signalling has increasingly been implicated in immune effector fatigue during chronic inflammation, cancer, and sustained infection, which dampens down immune stimulation rather than augmenting it. In this narrative review, we critically examine published evidence supporting the context-dependent effects of extracellular ATP and discuss how receptor expression, ATP concentration, exposure duration, nucleotide metabolism, and cellular state may shape immune responses in cancer and autoimmune disease.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040365","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":"PathSepsisNet: a pathway-aware temporal graph attention network integrating inflammatory crosstalk dynamics for early prediction of multi-organ dysfunction in sepsis.","authors":"Hilal Ustundag, Songul Doganay","doi":"10.1007/s11302-026-10185-z","DOIUrl":"10.1007/s11302-026-10185-z","url":null,"abstract":"<p><p>Sepsis-induced multi-organ dysfunction syndrome (MODS) remains a leading cause of intensive care unit (ICU) mortality worldwide. The complex interplay among inflammatory signaling pathways TLR4/NF-κB, NLRP3/P2X7 and Nrf2/HO-1 plays a critical role in determining organ damage trajectories, yet existing artificial intelligence (AI) models fail to capture these molecular dynamics. We propose PathSepsisNet, a pathway-aware temporal graph attention network that integrates biological pathway crosstalk knowledge into a deep learning architecture for early MODS prediction. We developed a biologically-informed graph neural network in which six nodes represent molecular pathway activation states (estimated from routine clinical biomarkers) and twelve directed edges encode established crosstalk relationships. A dual spatial-temporal attention mechanism with gated fusion captures inter-pathway crosstalk dynamics and within-pathway temporal evolution simultaneously. A novel Pathway Divergence Score (PDS) quantifies the imbalance between pro-inflammatory and cytoprotective pathways. The model was trained and validated on 29,765 adult patients with sepsis (Sepsis-3) from the Medical Information Mart for Intensive Care IV (MIMIC-IV) v3.1 using only the first 12 h of ICU data to predict MODS development at 12-36 h, with strict data leakage prevention (no SOFA sub-scores as inputs). PathSepsisNet achieved area under the receiver operating characteristic curve (AUROC) 0.895 and an area under the precision-recall curve (AUPRC) of 0.901 for MODS prediction, outperforming bidirectional long short term memory (BiLSTM) (0.886), Transformer (0.890) and logistic regression (0.876), while providing unique pathway-level interpretability. Gradient boosting methods (XGBoost: 0.906; LightGBM: 0.905) achieved marginally higher raw AUROC, but lack mechanistic insight. The PDS demonstrated remarkable standalone discriminative ability (MODS + : 0.596 ± 0.185 vs. MODS - : 0.299 ± 0.163; PDS AUROC: 0.872). Node importance analysis identified CytokineStorm (0.290), NLRP3/P2X7 (0.212) and mitochondrial dysfunction (0.211) as the most influential pathway modules. MODS + patients exhibited significantly higher lactate (2.34 vs. 1.63 mmol/L), CRP (123.5 vs. 97.2 mg/L), bilirubin (2.91 vs. 0.97 mg/dL) and lower albumin (2.82 vs. 3.04 g/dL) and platelets (160 vs. 207 K/μL), validating pathway-specific hypotheses. PathSepsisNet demonstrates that integrating biological pathway knowledge into graph neural network architectures yields predictive performance competitive with state-of-the-art methods, while uniquely providing pathway-level mechanistic insights. The PDS represents a novel computational biomarker bridging molecular pathway biology and clinical decision support. These findings support the paradigm that biologically informed AI can close the gap between predictive accuracy and clinical interpretability in sepsis management.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017865","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":"ATP-sensing DNA origami nanodevices for targeted modulation of purinergic signaling in inflammatory tissue injury.","authors":"Abdel-Aziz S Shatat","doi":"10.1007/s11302-026-10187-x","DOIUrl":"10.1007/s11302-026-10187-x","url":null,"abstract":"<p><p>The pathophysiology of inflammatory illnesses is significantly influenced by purinergic signaling dysregulation, e.g., excessive extracellular ATP (exATP), yet current medication development efforts to inhibit purinergic receptors are inadequate. In a recent publication in Nature Communications, Li et al. [1] found that design and characterization of ATP-sensing DNA origami nanotubes (NTs) provide a novel method for metabolite sensing, utilizing ATP sensors and catalytic units (ENPP1/CD73). The innovative design led to reliable ATP binding and conversion to adenosine (ADO), supporting purinergic signaling modulation. Nanodevices (NDs) demonstrated effectiveness in sensing pathological exATP levels, crucial for purinergic receptor activation, significantly reducing cytokine expression and mitochondrial damage in immune cells. Monocyte-targeted ND delivery enhanced anti-inflammatory effects in acute lung and kidney injury models, showcasing superior therapeutic potential compared to unmodified NDs. RNA sequencing highlighted gene expression changes linked to inflammation, while metabolomic analysis showed improvements in mitochondrial function. The findings underscore the significance of purinergic signaling in inflammation and propose the DNA nanodevice as a promising therapeutic strategy, although challenges regarding stability and measurement remain to be addressed.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008830","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: 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/s11302-026-10189-9","DOIUrl":"10.1007/s11302-026-10189-9","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991169","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":"The role of natural polyphenols in purinergic signaling: from molecular mechanisms to physiological implications.","authors":"Ujjawal Sharma, Simran Soni, Bunty Sharma, Deeksha Pal, Damandeep Kaur, Shafiul Haque, Hardeep SinghTuli, Ginpreet Kaur, Katrin Sak","doi":"10.1007/s11302-026-10183-1","DOIUrl":"10.1007/s11302-026-10183-1","url":null,"abstract":"<p><p>Purinergic signaling plays a pivotal role in regulating cellular functions involved in many pathogenic processes underlying the development of cardiovascular, neurological, and malignant disorders. Therefore, identifying novel, safe, and efficient inhibitors to regulate the actions of extracellular purines and pyrimidines via their wide array of P1 and P2 membrane receptors is crucial for better management of these diseases in the future. In recent years, numerous studies have demonstrated that natural polyphenolic compounds derived from various plant extracts can modulate purinergic receptor activity and thereby regulate downstream intracellular signaling pathways. In this review article, the current knowledge of these activities is compiled to provide a useful platform for advancing natural lead compounds as novel inhibitors of purinergic signaling.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991212","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}