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Purinergic Signalling最新文献

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Purinergic regulation of pulmonary vascular tone. 嘌呤能调节肺血管张力。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-12-01 Epub Date: 2024-05-07 DOI: 10.1007/s11302-024-10010-5
Marco Alveal, Andrea Méndez, Aline García, Mauricio Henríquez

Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This intricate signaling system encompasses two primary receptor classes: P1 and P2 receptors. P1 receptors selectively bind adenosine, while P2 receptors exhibit an affinity for ATP, ADP, UTP, and UDP. Functionally, P1 receptors are associated with vasodilation, while P2 receptors mediate vasoconstriction, particularly in basally relaxed vessels, through modulation of intracellular Ca2+ levels. The P2X subtype receptors facilitate extracellular Ca2+ influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca2+ release. Notably, the primary receptor responsible for ATP-induced vasoconstriction is P2X1, with α,β-meATP and UDP being identified as potent vasoconstrictor agonists. Interestingly, ATP has been shown to induce endothelium-dependent vasodilation in pre-constricted vessels, associated with nitric oxide (NO) release. In the context of P1 receptors, adenosine stimulation of pulmonary vessels has been unequivocally demonstrated to induce vasodilation, with a clear dependency on the A2B receptor, as evidenced in studies involving guinea pigs and rats. Importantly, evidence strongly suggests that this vasodilation occurs independently of endothelium-mediated mechanisms. Furthermore, studies have revealed variations in the expression of purinergic receptors across different vessel sizes, with reports indicating notably higher expression of P2Y1, P2Y2, and P2Y4 receptors in small pulmonary arteries. While the existing evidence in this area is still emerging, it underscores the urgent need for a comprehensive examination of the specific characteristics of purinergic signaling in the regulation of pulmonary vascular tone, particularly focusing on the disparities observed across different intrapulmonary vessel sizes. Consequently, this review aims to meticulously explore the current evidence regarding the role of purinergic signaling in pulmonary vascular tone regulation, with a specific emphasis on the variations observed in intrapulmonary vessel sizes. This endeavor is critical, as purinergic signaling holds substantial promise in the modulation of vascular tone and in the proactive prevention and treatment of pulmonary vascular diseases.

嘌呤能信号是调控肺血管生理机能的重要决定因素,也是治疗肺部疾病的有效途径。这一复杂的信号系统包括两个主要的受体类别:P1 和 P2 受体。P1 受体选择性地结合腺苷,而 P2 受体则对 ATP、ADP、UTP 和 UDP 具有亲和力。在功能上,P1 受体与血管扩张有关,而 P2 受体则通过调节细胞内 Ca2+ 水平介导血管收缩,尤其是在基础松弛的血管中。P2X 亚型受体促进细胞外 Ca2+ 的流入,而 P2Y 亚型受体则与内质网 Ca2+ 的释放有关。值得注意的是,P2X1 是 ATP 诱导血管收缩的主要受体,α,β-meATP 和 UDP 被认为是强效的血管收缩激动剂。有趣的是,在收缩前的血管中,ATP 可诱导内皮依赖性血管扩张,这与一氧化氮(NO)的释放有关。在 P1 受体方面,腺苷对肺血管的刺激已被明确证实可诱导血管舒张,并明显依赖于 A2B 受体,这在涉及豚鼠和大鼠的研究中得到了证明。重要的是,有证据有力地表明,这种血管扩张的发生与内皮介导的机制无关。此外,研究还发现不同大小的血管中嘌呤能受体的表达存在差异,有报告显示肺小动脉中 P2Y1、P2Y2 和 P2Y4 受体的表达明显较高。虽然这一领域的现有证据仍在不断涌现,但它强调了对嘌呤能信号调节肺血管张力的具体特征进行全面研究的迫切需要,尤其是重点研究在不同大小的肺内血管中观察到的差异。因此,本综述旨在仔细探讨有关嘌呤能信号在肺血管张力调节中的作用的现有证据,并特别强调在肺内血管大小中观察到的差异。这项工作至关重要,因为嘌呤能信号在调节血管张力以及积极预防和治疗肺血管疾病方面大有可为。
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引用次数: 0
Metastasis and angiogenesis in cervical cancer: key aspects of purinergic signaling in platelets and possible therapeutic targets. 宫颈癌的转移和血管生成:血小板中嘌呤能信号转导的关键环节和可能的治疗靶点。
IF 4.3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-12-01 Epub Date: 2024-05-16 DOI: 10.1007/s11302-024-10020-3
Paula C L Faria, Rackel S Resende, Andréia M Cardoso

Cervical cancer ranks as the fourth most common and fatal cancer among women worldwide. Studies have demonstrated a strong association between purinergic platelet signaling and tumor progression in this type of cancer. The literature shows that neoplastic cells, when in the bloodstream, secrete adenosine triphosphate (ATP) and adenosine nucleotide diphosphate (ADP) that act on their corresponding platelet P2Y and P2X receptors. The interaction of these nucleotides with their receptors results in platelet activation and degranulation, ensuing several consequences, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, ADP, and ATP. These molecules play essential roles in angiogenesis and tumor metastasis in cervical cancer. Several purinergic receptors are found in endothelial cells. Their activation, especially P2Y2, by the nucleotides released by platelets can induce relaxation of the endothelial barrier and consequent extravasation of tumor cells, promoting the development of metastases. Cancer cells that enter the bloodstream during the metastatic process are also subject to high shear stress and immune surveillance. In this context, activated platelets bind to circulating tumor cells and protect them against shear stress and the host's immune system, especially against natural killer cells, facilitating their spread throughout the body. Furthermore, activation of the P2Y12 receptor present on the platelet surface promotes the release of VEGF, the main inducer of angiogenesis in cervical cancer, in addition to increasing the concentration of several other pro-angiogenic molecules. Therefore, this review will address the role of platelet purinergic signaling in tumor progression of cervical cancer and propose possible therapeutic targets.

宫颈癌是全球妇女第四大最常见的致命癌症。研究表明,嘌呤能血小板信号传导与此类癌症的肿瘤进展密切相关。文献显示,瘤细胞在血液中会分泌三磷酸腺苷(ATP)和二磷酸腺苷核苷酸(ADP),作用于相应的血小板 P2Y 和 P2X 受体。这些核苷酸与其受体的相互作用会导致血小板活化和脱颗粒,从而产生多种后果,如血管内皮生长因子(VEGF)、血小板衍生生长因子、基质金属蛋白酶、ADP 和 ATP。这些分子在宫颈癌的血管生成和肿瘤转移中起着至关重要的作用。内皮细胞中存在多种嘌呤能受体。血小板释放的核苷酸会激活这些受体,尤其是 P2Y2,从而导致内皮屏障松弛,肿瘤细胞随之外渗,促进肿瘤转移。在转移过程中进入血液的癌细胞也会受到高剪切应力和免疫监视。在这种情况下,活化的血小板会与循环中的肿瘤细胞结合,保护它们免受剪切应力和宿主免疫系统(尤其是自然杀伤细胞)的侵袭,从而促进它们向全身扩散。此外,激活血小板表面的 P2Y12 受体可促进血管内皮生长因子的释放,而血管内皮生长因子是宫颈癌血管生成的主要诱导因子,此外还能增加其他几种促血管生成分子的浓度。因此,本综述将探讨血小板嘌呤能信号在宫颈癌肿瘤进展中的作用,并提出可能的治疗靶点。
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引用次数: 0
Pharmacological differences between human and mouse P2X4 receptor explored using old and new tools. 利用新旧工具探索人类和小鼠 P2X4 受体的药理差异。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-12-01 Epub Date: 2024-05-20 DOI: 10.1007/s11302-024-10018-x
Anna Fortuny-Gomez, Samuel J Fountain

There is growing interest in the P2X4 receptor as a therapeutic target for several cardiovascular, inflammatory and neurological conditions. Key to exploring the physiological and pathophysiological roles of P2X4 is access to selective compounds to probe function in cells, tissues and animal models. There has been a recent growth in selective antagonists for P2X4, though agonist selectivity is less well studied. As there are some known pharmacological differences between P2X receptors from different species, it is important to understand these differences when designing a pharmacological strategy to probe P2X4 function in human tissue and mouse models. Here, we provide a systematic comparison of agonist and antagonist pharmacology in 1321N1 cells expressing either human or mouse P2X4 orthologues. We identify a rank order of agonist potency of ATP > 2-MeSATP > αβmeATP = BzATP > CTP = γ-[(propargyl)-imido]-ATP for human P2X4 and ATP > 2-MeSATP = CTP > ATPγS = γ-[(propargyl)-imido]-ATP = BzATP for mouse. Human P2X4 is not activated by ATPγS but can be activated by αβmeATP. We identify a rank order of antagonist potency of BAY-1797 = PSB-12062 = BX-430 > 5-BDBD > TNP-ATP = PPADS for human P2X4 and BAY-1797 > PSB-12062 = PPADS > TNP-ATP for mouse. Mouse P2X4 is not antagonised by 5-BDBD or BX-430. The study reveals key pharmacological differences between human and mouse P2X4, highlighting caution when selecting tools for comparative studies between human and mouse and ascribing cellular responses of some commonly used agonists to P2X4.

人们对 P2X4 受体作为治疗多种心血管、炎症和神经疾病的靶点越来越感兴趣。探索 P2X4 生理和病理生理学作用的关键是获得选择性化合物,以探测细胞、组织和动物模型的功能。最近,P2X4 的选择性拮抗剂越来越多,但激动剂的选择性研究较少。由于不同物种的 P2X 受体之间存在一些已知的药理学差异,因此在设计药理学策略以探究 P2X4 在人体组织和小鼠模型中的功能时,了解这些差异非常重要。在这里,我们对表达人或小鼠 P2X4 同源物的 1321N1 细胞中的激动剂和拮抗剂药理学进行了系统比较。我们确定人 P2X4 的激动剂效力等级顺序为 ATP > 2-MeSATP > αβmeATP = BzATP > CTP = γ-[(丙炔基)-亚氨基]-ATP,小鼠为 ATP > 2-MeSATP = CTP > ATPγS = γ-[(丙炔基)-亚氨基]-ATP = BzATP。人的 P2X4 不被 ATPγS 激活,但能被 αβmeATP 激活。我们确定了人类 P2X4 的拮抗剂效力排序:BAY-1797 = PSB-12062 = BX-430 > 5-BDBD > TNP-ATP = PPADS;小鼠的拮抗剂效力排序:BAY-1797 > PSB-12062 = PPADS > TNP-ATP。小鼠 P2X4 不被 5-BDBD 或 BX-430 拮抗。该研究揭示了人和小鼠 P2X4 的主要药理差异,强调了在选择工具进行人鼠比较研究以及将一些常用激动剂的细胞反应归因于 P2X4 时应谨慎。
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引用次数: 0
Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist. 制备和初步评估氚标记的异源 P2X4 受体拮抗剂。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-12-01 Epub Date: 2024-05-25 DOI: 10.1007/s11302-024-10005-2
Jessica Nagel, Olli Törmäkangas, Katja Kuokkanen, Ali El-Tayeb, Josef Messinger, Aliaa Abdelrahman, Christiane Bous, Anke C Schiedel, Christa E Müller

P2X4 receptors are ATP-gated cation channels that were proposed as novel drug targets due to their role in inflammation and neuropathic pain. Only few potent and selective P2X4 receptor antagonists have been described to date. Labeled tool compounds suitable for P2X4 receptor binding studies are lacking. Here, we present a novel allosteric P2X4 receptor antagonist possessing high potency in the low nanomolar range. We describe its tritium-labeling resulting in the P2X4-selective radiotracer [3H]PSB-OR-2020 with high specific activity (45 Ci/mmol; 1.67 TBq/mmol). A radioligand binding assay was developed using human embryonic kidney (HEK293) cell membranes recombinantly expressing the human P2X4 receptor. Competition binding studies with structurally diverse P2X4 receptor antagonists revealed different allosteric binding sites indicating that the new class of P2X4 receptor antagonists, to which PSB-OR-2020 belongs, interacts with an unprecedented allosteric site. [3H]PSB-OR-2020 may become a useful tool for research on P2X4 receptors and for promoting drug development.

P2X4 受体是 ATP 门控阳离子通道,因其在炎症和神经性疼痛中的作用而被提出作为新型药物靶点。迄今为止,只有少数强效和选择性的 P2X4 受体拮抗剂被描述过。目前还缺乏适合于 P2X4 受体结合研究的标记工具化合物。在这里,我们介绍了一种新型异位 P2X4 受体拮抗剂,它在低纳摩尔范围内具有很高的效力。我们描述了对其进行氚标记后得到的 P2X4 选择性放射性示踪剂 [3H]PSB-OR-2020,它具有很高的特异性活性(45 Ci/mmol;1.67 TBq/mmol)。利用重组表达人类 P2X4 受体的人类胚胎肾脏(HEK293)细胞膜开发了一种放射性配体结合试验。与结构不同的 P2X4 受体拮抗剂的竞争结合研究发现了不同的异构结合位点,表明 PSB-OR-2020 所属的新型 P2X4 受体拮抗剂与一个前所未有的异构位点相互作用。[3H]PSB-OR-2020可能成为研究P2X4受体和促进药物开发的有用工具。
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引用次数: 0
Unexpected role of microglia and P2Y12 in the induction of and emergence from anesthesia. 小胶质细胞和 P2Y12 在麻醉诱导和唤醒中的意外作用。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-12-01 Epub Date: 2024-05-10 DOI: 10.1007/s11302-024-10014-1
Bijay Parajuli, Schuichi Koizumi
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引用次数: 0
Machine learning-aided search for ligands of P2Y6 and other P2Y receptors. 机器学习辅助搜索 P2Y6 和其他 P2Y 受体的配体。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-12-01 Epub Date: 2024-03-25 DOI: 10.1007/s11302-024-10003-4
Ana C Puhl, Sarah A Lewicki, Zhan-Guo Gao, Asmita Pramanik, Vadim Makarov, Sean Ekins, Kenneth A Jacobson

The P2Y6 receptor, activated by uridine diphosphate (UDP), is a target for antagonists in inflammatory, neurodegenerative, and metabolic disorders, yet few potent and selective antagonists are known to date. This prompted us to use machine learning as a novel approach to aid ligand discovery, with pharmacological evaluation at three P2YR subtypes: initially P2Y6 and subsequently P2Y1 and P2Y14. Relying on extensive published data for P2Y6R agonists, we generated and validated an array of classification machine learning model using the algorithms deep learning (DL), adaboost classifier (ada), Bernoulli NB (bnb), k-nearest neighbors (kNN) classifier, logistic regression (lreg), random forest classifier (rf), support vector classification (SVC), and XGBoost (XGB) classifier models, and the common consensus was applied to molecular selection of 21 diverse structures. Compounds were screened using human P2Y6R-induced functional calcium transients in transfected 1321N1 astrocytoma cells and fluorescent binding inhibition at closely related hP2Y14R expressed in CHO cells. The hit compound ABBV-744, an experimental anticancer drug with a 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine scaffold, had multifaceted interactions with the P2YR family: hP2Y6R inhibition in a non-surmountable fashion, suggesting that noncompetitive antagonism, and hP2Y1R enhancement, but not hP2Y14R binding inhibition. Other machine learning-selected compounds were either weak (experimental anti-asthmatic drug AZD5423 with a phenyl-1H-indazole scaffold) or inactive in inhibiting the hP2Y6R. Experimental drugs TAK-593 and GSK1070916 (100 µM) inhibited P2Y14R fluorescent binding by 50% and 38%, respectively, and all other compounds by < 20%. Thus, machine learning has led the way toward revealing previously unknown modulators of several P2YR subtypes that have varied effects.

P2Y6 受体由二磷酸尿苷(UDP)激活,是炎症、神经退行性疾病和代谢性疾病的拮抗剂靶点,但目前已知的强效选择性拮抗剂很少。这促使我们使用机器学习这种新方法来帮助发现配体,并对三种 P2YR 亚型进行药理学评估:最初是 P2Y6,随后是 P2Y1 和 P2Y14。根据已发表的 P2Y6R 激动剂的大量数据,我们使用深度学习 (DL)、adaboost 分类器 (ada)、Bernoulli NB (bnb)、k-近邻 (kNN) 分类器、逻辑回归 (lreg)、随机森林分类器 (rf)、支持向量分类器 (SVC) 和 XGBoost (XGB) 分类器模型等算法生成并验证了一系列分类机器学习模型,并将共识应用于 21 种不同结构的分子筛选。利用转染 1321N1 星形细胞瘤细胞中人 P2Y6R 诱导的功能性钙离子瞬态和在 CHO 细胞中表达的密切相关的 hP2Y14R 的荧光结合抑制作用筛选化合物。命中化合物ABBV-744是一种具有6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶支架的实验性抗癌药物,它与P2YR家族具有多方面的相互作用:以不可逾越的方式抑制hP2Y6R,表明其具有非竞争性拮抗作用;增强hP2Y1R,但不抑制hP2Y14R的结合。其他机器学习筛选出的化合物对 hP2Y6R 的抑制要么很弱(具有苯基-1H-吲唑支架的实验性抗哮喘药物 AZD5423),要么没有活性。实验药物 TAK-593 和 GSK1070916(100 µM)对 P2Y14R 荧光结合的抑制率分别为 50%和 38%,而所有其他化合物对 P2Y14R 荧光结合的抑制率均为 40%。
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引用次数: 0
Molecular mechanisms of extracellular-ATP-mediated colorectal cancer progression: Implication of purinergic receptors-mediated nucleocytoplasmic shuttling of HuR. 细胞外-ATP 介导的结直肠癌进展的分子机制:嘌呤能受体介导的 HuR 核胞质穿梭的影响
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-12-01 Epub Date: 2024-05-27 DOI: 10.1007/s11302-024-10021-2
Abdel-Aziz S Shatat, Elsayed M Mahgoup, Mohammed H Rashed, Ibrahim G Saleh, El-Sayed Akool

One of the leading causes of cancer-related deaths worldwide is colorectal cancer (CRC). Extracellular ATP (e-ATP) and purinergic receptors (P2R) play a central role in CRC proliferation and progression. Human antigen R (HuR) is becoming more and more understood to be essential for the expression of genes linked to cancer. The current study demonstrates that ATP can mediate CRC (Caco-2 cells) progression via induction of HuR nucleocytoplasmic shuttling and subsequent expression of cancer-related genes, a consequence mostly mediated via the P2R receptor. It was also noted that suppression of HuR activity by using dihydrotanshinone I (DHTS) prevents cancer-related gene expression and subsequent CRC (Caco-2 cells) progression induced by ATP. The expression of cyclin A2/cyclin-dependent kinase 2 (CDK2), Bcl-2, ProT-α, hypoxia-inducible factor1-α (HIF1-α), vascular endothelial growth factor A (VEGF-A), transforming growth factor-β (TGF-β) and matrix metallopeptidase 9 (MMP-9) induced by ATP were highly reduced in the presence of either PPADS (non-selective P2R antagonist) or DHTS. In addition, e-ATP-induced Caco-2 cell proliferation as well as cell survival were highly reduced in the presence of either PPADS or DHTS or selective CDK-2 inhibitor (Roscovitine) or selective Bcl-2 inhibitor (ABT-263). Furthermore, it was found that MMP-9 is critical for Caco-2 cells migration induced by e-ATP as demonstrated by a clear reduction in cells migration in the presence of a selective MMP-9 inhibitor (Marimastat). Collectively, these data demonstrate that ATP through P2R activation can induce HuR nucleocytoplasmic shuttling that could be translated into an increase in cancer-related genes expression and subsequent, cell proliferation and progression.

结直肠癌(CRC)是全球癌症相关死亡的主要原因之一。细胞外 ATP(e-ATP)和嘌呤能受体(P2R)在 CRC 的增殖和发展中起着核心作用。人类抗原 R(HuR)对于癌症相关基因的表达至关重要,这一点已被越来越多的人所认识。目前的研究表明,ATP 可通过诱导 HuR 核胞质穿梭和随后的癌症相关基因表达来介导 CRC(Caco-2 细胞)的进展,而这主要是通过 P2R 受体介导的结果。研究还注意到,使用二氢丹参酮 I(DHTS)抑制 HuR 活性可防止 ATP 诱导的癌症相关基因表达和随后的 CRC(Caco-2 细胞)进展。在 PPADS(非选择性 P2R 拮抗剂)或 DHTS 的作用下,ATP 诱导的细胞周期蛋白 A2/细胞周期蛋白依赖性激酶 2 (CDK2)、Bcl-2、ProT-α、低氧诱导因子 1-α (HIF1-α)、血管内皮生长因子 A (VEGF-A)、转化生长因子-β (TGF-β) 和基质金属肽酶 9 (MMP-9) 的表达均显著降低。此外,在 PPADS 或 DHTS 或选择性 CDK-2 抑制剂(Roscovitine)或选择性 Bcl-2 抑制剂(ABT-263)存在的情况下,e-ATP 诱导的 Caco-2 细胞增殖和细胞存活率均显著降低。此外,研究还发现,MMP-9 对 e-ATP 诱导的 Caco-2 细胞迁移至关重要,这表现在有选择性 MMP-9 抑制剂(Marimastat)存在时细胞迁移明显减少。总之,这些数据表明,ATP 通过 P2R 激活可诱导 HuR 核胞质穿梭,从而转化为癌症相关基因表达的增加,进而导致细胞增殖和进展。
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引用次数: 0
Role of ecto-5'-nucleotidase in bladder function activity and smooth muscle contractility. 外-5'-核苷酸酶在膀胱功能活动和平滑肌收缩中的作用
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-12-01 Epub Date: 2024-05-08 DOI: 10.1007/s11302-024-10015-0
Basu Chakrabarty, Bahareh Vahabi
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引用次数: 0
Antagonism of the ATP-gated P2X7 receptor inhibits the proliferation of hepatocellular carcinoma cells. 拮抗 ATP 门控 P2X7 受体可抑制肝癌细胞的增殖。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-11-16 DOI: 10.1007/s11302-024-10064-5
Xinxing Tantai, Xin Yang, Xinyuan Liu, Xiao Yang

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.

P2X7受体是一种ATP门控离子通道,属于P2X受体家族,在识别细胞外5'-三磷酸腺苷(ATP)方面起着关键作用,广泛表达于大多数肿瘤细胞和炎症细胞中。在此之前,P2X7 受体已被证实能调节各种恶性肿瘤的进展,包括胶质母细胞瘤、胰腺癌、肺癌、白血病和淋巴瘤。然而,P2X7 受体在肝细胞癌中的生物学功能和预后价值仍有待确定。在此,我们研究了肝细胞癌患者体内 P2X7 受体的表达水平。然后通过 MTS 和 EdU 试验研究 P2X7 受体阻断对肝癌细胞增殖的作用。此外,还通过大量 RNAseq 进一步阐明了其潜在机制。与对照组相比,肝癌组的 P2X7 受体明显上调。有趣的是,P2X7 受体的两种选择性拮抗剂 A740003 和 A438079 能明显阻断 Ca2+ 的流入,降低肝癌细胞的增殖率。此外,A740003 和 A438079 还降低了硫酸软骨素合成酶 1(CHSY1)的表达水平,而 CHSY1 是一种介导硫酸软骨素聚合步骤的酶。总之,抑制 P2X7 受体可减轻肝癌细胞的增殖,而这一过程在很大程度上受 CHSY1 的调节。因此,我们的研究结果揭示了 P2X7 受体在肝癌细胞增殖过程中的未知作用,并暗示 P2X7 受体可能是治疗肝癌的新靶点。
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引用次数: 0
CD39 activities in the treated acupoints contributed to the analgesic mechanism of acupuncture on arthritis rats. 治疗穴位中的 CD39 活性有助于针灸对关节炎大鼠的镇痛机制。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-11-15 DOI: 10.1007/s11302-024-10065-4
Yu-Jia Li, Jie Lin, Si-Qi Tang, Wei-Min Zuo, Guang-Hong Ding, Xue-Yong Shen, Li-Na Wang

Our previous work had identified that at the acupuncture point (acupoint), acupuncture-induced ATP release was a pivotal event in the initiation of analgesia. We aimed to further elucidate the degradation of ATP by CD39. Acupuncture was administered at Zusanli acupoint on arthritis rats, and pain thresholds of the hindpaws were determined. Pharmacological tools or adeno-associated viruses were administered at the acupoints to interfere with targeting signals. Protein expression was determined with qRT-PCR, WB, or immunofluorescent labeling. Cultured keratinocytes, HaCaT line, were subjected to hypotonic shock to simulate needling stimulation. Extracellular ATP and adenosine levels were quantified using luciferase-luciferin assay and ELISA, respectively. Acupuncture-induced prompt analgesia was impaired by inhibiting CD39 activities to prevent the degradation of ATP to AMP but was mimicked by using CD39 agonists. Acupuncture-induced ATP accumulation exhibited synchronous changes. Similarly, acupuncture analgesia was hindered by suppressing CD73 to prevent the conversion of AMP to adenosine. Furthermore, the acupuncture effect was replicated by agonism at P2Y2Rs but inhibited by antagonism at them. Acupuncture upregulated CD73 and P2Y2Rs but not CD39. Immunofluorescent labeling demonstrated that keratinocytes were a primary site for these proteins. Shallow acupuncture also demonstrated antinociception. In vitro tests showed that hypotonic shock induced HaCaT cells to release ATP and adenosine, which was impaired by suppressing CD39 and CD73, respectively. Finally, agonism at P2Y2Rs promoted ATP release and [Ca2+]i rise. CD39 at the acupoints contributes to the analgesic mechanism of acupuncture. It may facilitate adenosine signaling in conjunction with CD73 or provide an appropriate ATP milieu for P2Y2Rs. Skin tissue may be one of the scenes for these signalings.

我们之前的研究发现,在穴位处,针刺诱导的 ATP 释放是启动镇痛的关键事件。我们的目的是进一步阐明 CD39 对 ATP 的降解作用。我们针刺了关节炎大鼠的足三里穴,并测定了大鼠后爪的痛阈。在穴位处注射药理工具或腺相关病毒以干扰靶向信号。通过 qRT-PCR、WB 或免疫荧光标记测定蛋白质表达。对培养的 HaCaT 系角质细胞进行低渗休克,以模拟针刺刺激。细胞外 ATP 和腺苷水平分别用荧光素酶-荧光素测定法和酶联免疫吸附法进行量化。通过抑制CD39活性以阻止ATP降解为AMP,针刺诱导的快速镇痛受到影响,但使用CD39激动剂可模拟针刺诱导的快速镇痛。针刺诱导的 ATP 积累呈现同步变化。同样,抑制 CD73 以阻止 AMP 转化为腺苷,也会阻碍针刺镇痛。此外,P2Y2Rs的激动作用可复制针刺镇痛效果,但拮抗作用则可抑制针刺镇痛效果。针灸能上调 CD73 和 P2Y2Rs,但不能上调 CD39。免疫荧光标记表明,角朊细胞是这些蛋白的主要存在部位。浅针刺也显示出抗痛作用。体外测试表明,低渗休克会诱导 HaCaT 细胞释放 ATP 和腺苷,而抑制 CD39 和 CD73 会分别削弱这种作用。最后,激动 P2Y2Rs 可促进 ATP 释放和[Ca2+]i 上升。穴位上的 CD39 有助于针灸的镇痛机制。它可能与 CD73 一起促进腺苷信号转导,或为 P2Y2Rs 提供适当的 ATP 环境。皮肤组织可能是这些信号传递的场景之一。
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Purinergic Signalling
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