Purinergic Signalling最新文献

{"title":"P2Y6 promoted pruning of FSTL1 nerves by cutaneous macrophages to reset pain threshold and cardiac function.","authors":"Yun Liu, Xiao Sun, Zhengxu Jia, Qun Hou, Mingqian Yuan, Tiancheng Xu, Jinhong Yuan, Bin Xu, Zhi Yu","doi":"10.1007/s11302-025-10088-5","DOIUrl":"10.1007/s11302-025-10088-5","url":null,"abstract":"<p><p>Hyperactivation of cutaneous macrophages promotes the development of chronic pain. Stimulation of nociceptive regions promotes neuroplasticity, which affects pain perception and related physiological responses. However, the specific mechanisms by which cutaneous macrophages sense and elicit nociceptive responses are unknown. Here, we exacerbated the reduction of systemic pain threshold after chronic heart failure (CHF) by silencing follistatin-like 1 (FSTL1), especially the abnormal cutaneous nociceptive sensation at PC6 acupoint, the site associated with cardiac involvement pain. The upregulation of P2Y6 and interleukin-27 expression is intimately linked to the activation of skin macrophages. Hyperactivation of P2Y6 receptor (P2Y6R) may be associated with MHC II M1⁺ macrophage polarization in PC6. Thus, P2Y6 is one of the key factors that modulate the functional polarization of skin macrophages, which may subsequently influence the expansion of the pain field. The supportive effect of CD206 M2⁺ macrophages on the cutaneous FSTL1⁺ nerves was significantly reduced. Meanwhile, FSTL1⁺ nerves in PC6 functionally interacted with calcitonin gene-related peptide (CGRP)⁺ nerves, and the overactivation of nerve growth factor (NGF) secreted by cutaneous macrophages induced CGRP⁺ neuropathological remodeling, which supported the enlargement of the pain sensory area. The activation of CGRP and P2X3 receptor (P2X3R), Na⁺/K⁺ ATPase (NKA), and P2X3R in the C8 DRG may be one of the molecular bases mediating cutaneous nociceptive transmission and affecting the function of the heart. Hyperactivation of NKA was consistent with decreased pain threshold and changes in cardiac dysfunction, and PC6 injection of an NKA inhibitor (digilanid C) was effective in ameliorating nociception and cardiac impairment. The beneficial effects of digilanid C were counteracted by FSTL1 silencing. These results indicated that P2Y6 mediates the remodeling of pain perception by skin macrophages via the action of FSTL1, while NKA inhibitors synergistically exert their therapeutic effects.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"621-635"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042202","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":"P2Y₆R together with CYSLTR2 serves as endogenous receptor for long-chain ceramides in atherosclerosis.","authors":"Qing Ye, Yong Tang","doi":"10.1007/s11302-025-10090-x","DOIUrl":"10.1007/s11302-025-10090-x","url":null,"abstract":"<p><p>In a recent article published in Nature, 2025 Zhang et al. identified the pyrimidinergic receptor P2Y₆ (P2Y₆R), together with the cysteinyl leukotriene receptor 2 (CYSLTR2), as key receptor mediating ceramide-induced atherosclerotic cardiovascular disease (ASCVD). High levels of plasma ceramides bind to P2Y₆R and CYSLTR2, activating the Gαq signaling pathway, which triggers NLRP3 inflammasome activation and the release of the pro-inflammatory cytokine IL-1β, thereby accelerating the progression of atherosclerosis. These findings provide credible evidence supporting the long-chain ceramides as clinical predictors for risks of ASCVD. Designing small-molecule drugs and antagonists that target the binding sites of ceramide-CYSLTR2/P2Y₆R complexes presents a potential clinical strategy beyond traditional lipid-lowering therapies.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"1001-1003"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014658","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":"Microbe-derived extracellular ATP via P2X7R signaling regulate macrophage heterogeneity in intestinal lymphoid tissue.","authors":"Yu-Lihan Tang, Yong Tang","doi":"10.1007/s11302-024-10001-6","DOIUrl":"10.1007/s11302-024-10001-6","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"991-992"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140050270","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":"Purinergic pathways and their clinical use in the treatment of acute myeloid leukemia.","authors":"Huijuan Wang, Yujie Wei, Na Wang","doi":"10.1007/s11302-024-09997-8","DOIUrl":"10.1007/s11302-024-09997-8","url":null,"abstract":"<p><p>Despite the use of various therapies such as hematopoietic stem cell transplantation and chimeric antigen receptor T cell therapy (CAR-T), the prognosis of patients with acute myeloid leukemia (AML) is still generally poor. However, immunotherapy is currently a hot topic in the treatment of hematological tumors. Extracellular adenosine triphosphate (ATP) can be converted to adenosine diphosphate (ADP) via CD39, and ADP can be converted to adenosine via CD73, which can bind to P1 and P2 receptors to exert immunomodulatory effects. Research on the mechanism of the purinergic signaling pathway can provide a new direction for the treatment of AML, and inhibitors of this signaling pathway have been discovered by several researchers and gradually applied in the clinic. In this paper, the mechanism of the purinergic signaling pathway and its clinical application are described, revealing a new target for the treatment of AML and subsequent improvement in patient prognosis.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"735-746"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140040235","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 functional role of P2 purinergic receptors in the progression of gastric cancer.","authors":"Fei-Long Zou, Ji-Peng Liu, Cheng Zuo, Peng-Fei He, Jin-Xiong Ye, Wen-Jun Zhang","doi":"10.1007/s11302-024-10000-7","DOIUrl":"10.1007/s11302-024-10000-7","url":null,"abstract":"<p><p>Studies have confirmed that P2 purinergic receptors (P2X receptors and P2Y receptors) expressed in gastric cancer (GC) cells and GC tissues and correlates with their function. Endogenous nucleotides including ATP, ADP, UTP, and UDP, as P2 purinergic receptors activators, participate in P2 purinergic signal transduction pathway. These activated P2 purinergic receptors regulate the progression of GC mainly by mediating ion channels and intracellular signal cascades. It is worth noting that there is a difference in the expression of P2 purinergic receptors in GC, which may play different roles in the progression of GC as a tumor promoting factor or a tumor suppressor factor. Among them, P2 × 7, P2Y2 and P2Y6 receptors have certain clinical significance in patients with GC and may be used as biological molecular markers for the prediction of patients with GC. Therefore, in this paper, we discuss the functional role of nucleotide / P2 purinergic receptors signal axis in regulating the progression of GC and that these P2 purinergic receptors may be used as potential molecular targets for the prevention and treatment of GC.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"781-790"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140111285","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":"Electroacupuncture may alleviate inflammatory pain by downregulating the expression of P2Y₁₄ receptor in the primary somatosensory cortex.","authors":"Shuai Hou, Cui-Yuan Chen, Rui-Zhu Zhou, Liu-Xuan He, Xiao-Xiao Zhao, Sha-Sha Chen, Sha Yang, Hai-Yan Yin, Shu-Guang Yu","doi":"10.1007/s11302-024-10058-3","DOIUrl":"10.1007/s11302-024-10058-3","url":null,"abstract":"<p><p>Increasing evidence indicated that purinergic signalling involved in electroacupuncture (EA)-induced analgesia. Whether purinergic P2Y₁₄ receptor contributes to EA-mediated analgesia remains unclear. Here, we report that the expression of P2Y₁₄ receptor in the hindlimb region of the primary somatosensory cortex (S1HL) was significantly upregulated on Complete Freund's Adjuvant (CFA)-induced pain model mice, while was downregulated after EA treatment (2 Hz frequency, 1 mA intensity, and 30 min duration) at \"Zusanli\" (also named ST36 acupoint). EA-mediated analgesia could be reversed by injection of P2RY₁₄ agonist uridine diphosphate glucose (UDPG) into the bilateral S1HL, while prolonged by injection of P2RY₁₄ antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPTN). It suggested that EA may alleviate inflammatory pain by downregulating the expression of P2RY₁₄ in the S1HL.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"515-521"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606151","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 exploration of active components of 701 Dieda Zhentong patch and analgesic properties on chronic constriction injury rats.","authors":"Jun Meng, Zhenglang Zhang, Yujie Wang, Lina Long, Anqi Luo, Zhenhui Luo, Kexin Cai, Xi Chen, Hong Nie","doi":"10.1007/s11302-024-10056-5","DOIUrl":"10.1007/s11302-024-10056-5","url":null,"abstract":"<p><p>An increasing number of traditional Chinese medicine(TCM) have been confirmed to possess analgesic bioactivity. 701 Dieda Zhentong patch(701-DZP) which includes 14 kinds of TCMs exhibited excellent efficacy in alleviating back or leg pain after a soft-tissue injury. In this study, UPLC/MS was used to construct the fingerprint of 701-DZP and excavate the potential bioactive ingredients of it. 21 compounds were detected and identified in the fingerprint including 12 compounds that pass through the skin and 6 compounds observed in the plasma. Then, the role of 701-DZP in neuropathic pain(NPP) was assessed by network pharmacology and CCI rats. 701-DZP inhibited pain sensitization(MWT and TWL) and the release of inflammation mediators(IL-1β and IL-6) in CCI rats which were in keeping with the core targets of the PPI network. The results of IHC and Western blot showed that the expression of the P2X3 receptor in the DRG and SC of CCI rats was significantly reduced after the treatment with 701-DZP. Moreover, the 701-DZP down-regulated the level of phosphorylation of ERK1/2 MAPK instead of P38 MAPK in the DRG of CCI rats. In conclusion, this study has clarified 6 potential analgesic active compounds of 701-DZP and explored the analgesic properties, which may inhibit the expression of the P2X3 receptor to reduce the release of inflammatory mediators based on the ERK1/2 MAPK pathway to alleviate the NPP.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"593-609"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569296","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":"Antagonism of the ATP-gated P2X7 receptor inhibits the proliferation of hepatocellular carcinoma cells.","authors":"Xinxing Tantai, Xin Yang, Xinyuan Liu, Xiao Yang","doi":"10.1007/s11302-024-10064-5","DOIUrl":"10.1007/s11302-024-10064-5","url":null,"abstract":"<p><p>The P2X7 receptor, an ATP-gated ion channel which belongs to the P2X receptor family, plays critical roles in recognizing extracellular adenosine 5'-triphosphate (ATP) and is widely expressed in most tumor cells as well as inflammatory cells. Previously, the P2X7 receptor has been demonstrated to modulate the progression of various malignancies, including glioblastoma, pancreatic cancer, lung cancer, leukemia, and lymphoma. However, the biological function and prognostic values of P2X7 receptor in hepatocellular carcinoma remain to be determined. Here, we investigated the expression level of P2X7 receptor in patients with hepatocellular carcinoma. Then MTS and EdU assays were carried out to study the role of P2X7 receptor blockade in the proliferation of hepatocellular carcinoma cells. In addition, the underlying mechanism was further elucidated by bulk RNAseq. Compared to the control group, the P2X7 receptor was significantly up-regulated in the hepatocellular carcinoma group. Interestingly, A740003 and A438079, two selective antagonists at P2X7 receptor, significantly blocked Ca²⁺ influx and decreased the proliferative rate of hepatocellular carcinoma cells. Furthermore, the expression level of chondroitin sulfate synthase 1 (CHSY1), an enzyme that mediates the polymerization step of chondroitin sulfate, was reduced by both A740003 and A438079. In conclusion, inhibition of the P2X7 receptor attenuated the proliferation of hepatocellular carcinoma cells, and this process was largely modulated by CHSY1. Thus, our findings reveal a previously unknown role for P2X7 receptor in the proliferation of hepatocellular carcinoma cells and imply that the P2X7 receptor may represent a new target for the treatment of hepatocellular carcinoma.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"721-733"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644663","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":"SCH58261 effectively prevents the reduction in excitability of striatal MSNs in mice following 20 h of sleep deprivation.","authors":"Jin Peng, Xinyu Huang, Peijie Liu, Yushi Hu, Liang Kang","doi":"10.1007/s11302-025-10072-z","DOIUrl":"10.1007/s11302-025-10072-z","url":null,"abstract":"<p><p>Adenosine, a sleep-associated neuromodulator, is crucial in various physiological and pathological processes. Previous studies have demonstrated that sleep deprivation (SD) alters striatal neuronal activity. In this study, we used in vitro electrophysiological recordings to investigate the effects of 20 h of SD on the neuronal excitability of mouse dorsal striatal medium spiny neurons (MSNs). Our findings revealed that SD resulted in altered action potential (AP) discharge properties and reduced neuronal excitability compared to the control group. Importantly, these changes were partially offset by the prophylactic injection of the A2A receptor (A2AR) antagonist SCH58261. Additionally, 20 h of SD caused a decrease in the amplitude and an increase in the interval of spontaneous excitatory postsynaptic currents (sEPSCs) compared to control. However, the prophylactic injection of the A2AR antagonism shortened the sEPSC interval, while the A1 receptor (A1R) antagonist DPCPX not only shortened the interval but also further reduced the amplitude of sEPSCs. Thus, it can be concluded that SCH58261 effectively prevents the reduction in excitability of striatal MSNs in mice following 20 h of sleep deprivation, whereas DPCPX does not.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"709-719"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449819","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":"Electroacupuncture may alleviate diabetic neuropathic pain by inhibiting the microglia P2X4R and neuroinflammation.","authors":"Si-Ying Qu, Han-Zhi Wang, Qun-Qi Hu, Yi-Qi Ma, Yu-Rong Kang, Li-Qian Ma, Xiang Li, Lu-Hang Chen, Bo-Yu Liu, Xiao-Mei Shao, Bo-Yi Liu, Jun-Ying Du, Yi Liang, Hong-Li Zhao, Yong-Liang Jiang, Jian-Qiao Fang, Xiao-Fen He","doi":"10.1007/s11302-023-09972-9","DOIUrl":"10.1007/s11302-023-09972-9","url":null,"abstract":"<p><p>Diabetic neuropathic pain (DNP) is a common and destructive complication of diabetes mellitus. The discovery of effective therapeutic methods for DNP is vitally imperative because of the lack of effective treatments. Although 2 Hz electroacupuncture (EA) was a successful approach for relieving DNP, the mechanism underlying the effect of EA on DNP is still poorly understood. Here, we established a rat model of DNP that was induced by streptozotocin (STZ) injection. P2X4R was upregulated in the spinal cord after STZ-injection. The upregulation of P2X4R was mainly expressed on activated microglia. Intrathecal injection of a P2X4R antagonist or microglia inhibitor attenuated STZ-induced nociceptive thermal hyperalgesia and reduced the overexpression of brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord. We also assessed the effects of EA treatment on the pain hypersensitivities of DNP rats, and further investigated the possible mechanism underlying the analgesic effect of EA. EA relieved the hyperalgesia of DNP. In terms of mechanism, EA reduced the upregulation of P2X4R on activated microglia and decreased BDNF, IL-1β and TNF-α in the spinal cord. Mechanistic research of EA's analgesic impact would be beneficial in ensuring its prospective therapeutic effect on DNP as well as in extending EA's applicability.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"533-547"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49692187","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}