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P2X7 receptor is essential for ST36-attenuated cardiac fibrosis upon beta-adrenergic insult P2X7受体对ST36减轻β-肾上腺素能损伤时的心脏纤维化至关重要
IF 3.5 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-27 DOI: 10.1007/s11302-024-10009-y
Ting Zhang, Jing Lv, Zhong-yue Liu, Qiu-lian Lei, Ze-fei Jiang, Xiao-xiang Sun, Xing Yue, Xuan Li, Ke-li Zhu, Yun-kuan Yang, Ling Luo, Xin Cao

P2X7 receptor (P2X7R) plays an important role in modulating inflammation and fibrosis, but information is limited whether Zusanli (ST36) can inhibit inflammation and fibrosis by regulating P2X7R. Isoprenaline at 5 mg/kg was subcutaneously injected to wild-type and P2X7R knockout mice for 7 days, while treatment groups received electroacupuncture (EA) stimulation at ST36 for 7 sessions. Following 7-session treatment, Masson’s trichrome staining was performed to assess the fibrosis. Morphology, electrocardiogram, and echocardiography were carried out to evaluate the cardiac function and structure. Western blotting, hematoxylin and eosin staining, immunohistochemistry, and biochemical analysis of inflammatory cytokine and transmission electron microscopy were carried out to characterize the effect of ST36 on inflammation. P2X7R was overexpressed in ISO-treated mice. EA at ST36, but not at non-points, reduced ISO-induced cardiac fibrosis, increases in HW/BW, R+S wave relative to mice in ISO groups. In addition, EA at ST36 downregulated ISO-upregulated P2X7R and NLRP3 in ventricle. Moreover, EA reduced cytokines of IL-1β, IL-6, and IL-18 in serum, and inhibited foam cell gathering, inflammatory cell infiltration, and autophagy. However, EA at ST36 failed to attenuate the cardiac fibrosis and hypertrophy in P2X7R knockout mice. In conclusion, EA at ST36 attenuated ISO-induced fibrosis possibly via P2X7R.

P2X7受体(P2X7R)在炎症和纤维化过程中起着重要的调节作用,但祖传三针(ST36)是否能通过调节P2X7R抑制炎症和纤维化的研究还很有限。给野生型小鼠和 P2X7R 基因敲除小鼠皮下注射异丙肾上腺素 5 毫克/千克,连续 7 天;治疗组在 ST36 处接受电针刺激(EA),连续 7 个疗程。治疗 7 个疗程后,对小鼠进行马森氏三色染色以评估纤维化情况。通过形态学、心电图和超声心动图评估心脏功能和结构。为了描述 ST36 对炎症的影响,研究人员进行了 Western 印迹、苏木精和伊红染色、免疫组化、炎症细胞因子生化分析和透射电子显微镜检查。P2X7R 在 ISO 处理的小鼠中过表达。与 ISO 组的小鼠相比,ST36 点的 EA(而非非点的 EA)可减少 ISO 诱导的心脏纤维化、HW/BW 和 R+S 波的增加。此外,ST36 点的 EA 还能降低 ISO 在心室中上调的 P2X7R 和 NLRP3。此外,EA还降低了血清中的细胞因子IL-1β、IL-6和IL-18,抑制了泡沫细胞聚集、炎症细胞浸润和自噬。然而,ST36 EA 未能减轻 P2X7R 基因敲除小鼠的心脏纤维化和肥大。总之,ST36 位置的 EA 可通过 P2X7R 减轻 ISO 诱导的纤维化。
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引用次数: 0
P2X7 receptor: a potential target for treating comorbid anxiety and depression P2X7 受体:治疗合并焦虑症和抑郁症的潜在靶点
IF 3.5 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-20 DOI: 10.1007/s11302-024-10007-0
Jun Liu, Ting-Ting Liu, Lan Mou, Yuwen Zhang, Xiang Chen, Qi Wang, Bin-Lu Deng, Jie Liu

In clinical practice, depression and anxiety frequently coexist, and they are both comorbid with somatic diseases. The P2X7R is an adenosine 5’-triphosphate (ATP)-gated non-selective cation channel that is widely expressed in immune-related cells. Under conditions of stress, chronic pain, and comorbid chronic physical illness, P2X7R activation in glial cells leads to neuroinflammation. This could contribute to the development of anxiety and depression-related emotional disturbances. Previous studies have shown that the P2X7 receptor (P2X7R) plays an important role in the pathogenesis of both anxiety and depression. Thus, the P2X7R may play a role in the comorbidity of anxiety and depression. Positron emission tomography can be used to assess the degree and location of neuroinflammation by monitoring functional and expression-related changes in P2X7R, which can facilitate clinical diagnoses and guide the treatment of patients with anxiety and depression. Moreover, single nucleotide polymorphisms (SNPs) in the P2X7R gene are associated with susceptibility to different types of psychiatric disorders. Thus, evaluating the SNPs of the P2X7R gene could enable personalized mood disorder diagnoses and treatments. If the P2X7R were set as a therapeutic target, selective P2X7R antagonists may modulate P2X7R function, thereby altering the balance of intra- and extra-cellular ATP. This could have therapeutic implications for treating anxiety and depression, as well as for pain management. According to in vitro and in vivo studies, the P2X7R plays an important role in anxiety and depression. In this review, we consider the potential of the P2X7R as a therapeutic target for comorbid anxiety and depression, and discuss the potential diagnostic and therapeutic value of this receptor.

在临床实践中,抑郁和焦虑经常同时存在,而且它们都与躯体疾病并发。P2X7R 是一种腺苷-5'-三磷酸(ATP)门控的非选择性阳离子通道,在免疫相关细胞中广泛表达。在压力、慢性疼痛和合并慢性身体疾病的情况下,神经胶质细胞中的 P2X7R 激活会导致神经炎症。这可能会导致焦虑和抑郁相关的情绪紊乱。以往的研究表明,P2X7 受体(P2X7R)在焦虑症和抑郁症的发病机制中发挥着重要作用。因此,P2X7R 可能在焦虑症和抑郁症的并发症中发挥作用。正电子发射断层扫描可通过监测 P2X7R 的功能和表达相关变化来评估神经炎症的程度和位置,从而有助于焦虑症和抑郁症患者的临床诊断和指导治疗。此外,P2X7R 基因的单核苷酸多态性(SNPs)与不同类型精神疾病的易感性有关。因此,评估 P2X7R 基因的 SNPs 可以实现情绪障碍的个性化诊断和治疗。如果将 P2X7R 设为治疗靶点,选择性 P2X7R 拮抗剂可能会调节 P2X7R 的功能,从而改变细胞内外 ATP 的平衡。这可能对治疗焦虑症和抑郁症以及疼痛有治疗意义。根据体外和体内研究,P2X7R 在焦虑和抑郁中发挥着重要作用。在这篇综述中,我们探讨了 P2X7R 作为合并焦虑症和抑郁症治疗靶点的潜力,并讨论了该受体的潜在诊断和治疗价值。
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引用次数: 0
The P2Y2 receptor as a sensor of nucleotides and cell recruitment during inflammatory processes of the liver. P2Y2 受体是肝脏炎症过程中核苷酸和细胞招募的传感器。
IF 3.5 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-17 DOI: 10.1007/s11302-024-10008-z
V. S. Alves, Fabiana Cristina-Rodrigues, R. Coutinho-Silva
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引用次数: 0
Gene expression alterations of purinergic signaling components in obesity-associated intestinal low-grade inflammation in type 2 diabetes 肥胖引发的 2 型糖尿病肠道低度炎症中嘌呤能信号成分的基因表达变化
IF 3.5 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-08 DOI: 10.1007/s11302-024-10006-1
José R. Cruz-Muñoz, Eduardo E. Valdez-Morales, Alma Barajas-Espinosa, Tonatiuh Barrios-García, Andrómeda Liñán-Rico, Raquel Guerrero-Alba

Intestinal low-grade inflammation induced by a high-fat diet has been found to detonate chronic systemic inflammation, which is a hallmark of obesity, and precede the apparition of insulin resistance, a key factor for developing type 2 diabetes (T2D). Aberrant purinergic signaling pathways have been implicated in the pathogenesis of inflammatory bowel disease and other gastrointestinal diseases. However, their role in the gut inflammation associated with obesity and T2D remains unexplored. C57BL/6 J mice were fed a cafeteria diet for 21 weeks and received one injection of streptozotocin in their sixth week into the diet. The gene expression profile of purinergic signaling components in colon tissue was assessed by RT-qPCR. Compared to control mice, the treated group had a significant reduction in colonic length and mucosal and muscular layer thickness accompanied by increased NF-κB and IL-1β mRNA expression. Furthermore, colonic P2X2, P2X7, and A3R gene expression levels were lower, while the P2Y2, NT5E, and ADA expression levels increased. In conclusion, these data suggest that these purinergic signaling components possibly play a role in intestinal low-grade inflammation associated with obesity and T2D and thus could represent a novel therapeutic target for the treatment of the metabolic complications related to these diseases.

研究发现,高脂饮食诱发的肠道低度炎症会引发慢性全身性炎症,这是肥胖症的特征之一,并且会先于胰岛素抵抗的出现,而胰岛素抵抗是引发 2 型糖尿病(T2D)的关键因素。嘌呤能信号通路的异常与炎症性肠病和其他胃肠道疾病的发病机制有关。然而,它们在与肥胖和 T2D 相关的肠道炎症中的作用仍有待探索。C57BL/6 J小鼠以食堂饮食喂养21周,并在第六周接受一次链脲佐菌素注射。通过 RT-qPCR 评估了结肠组织中嘌呤能信号成分的基因表达谱。与对照组相比,治疗组小鼠的结肠长度、粘膜和肌层厚度显著减少,同时NF-κB和IL-1β mRNA表达增加。此外,结肠 P2X2、P2X7 和 A3R 基因表达水平降低,而 P2Y2、NT5E 和 ADA 表达水平升高。总之,这些数据表明,这些嘌呤能信号成分可能在与肥胖和 T2D 相关的肠道低度炎症中发挥作用,因此可能成为治疗与这些疾病相关的代谢并发症的新型治疗靶点。
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引用次数: 0
María Teresa Miras Portugal: a pioneer in the study of purinoceptors in chromaffin cells. 玛丽亚-特雷莎-米拉斯-葡萄牙:研究嗜铬细胞嘌呤受体的先驱。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-04-01 Epub Date: 2023-03-21 DOI: 10.1007/s11302-023-09934-1
Antonio R Artalejo, Marina Arribas-Blázquez, María Victoria Barahona, Celia Llorente-Sáez, Luis Alcides Olivos-Oré

María Teresa Miras Portugal devoted most of her scientific life to the study of purinergic signalling. In an important part of her work, she used a model system: the chromaffin cells of the adrenal medulla. It was in these cells that she identified diadenosine polyphosphates, from which she proceeded to the study of adrenomedullary purinome: nucleotide synthesis and degradation, adenosine transport, nucleotide uptake into chromaffin granules, exocytotic release of nucleotides and autocrine regulation of chromaffin cell function via purinoceptors. This short review will focus on the current state of knowledge of the purinoceptors of adrenal chromaffin cells, a subject to which María Teresa made seminal contributions and which she continued to study until the end of her scientific life.

玛丽亚-特雷莎-米拉斯-葡萄牙毕生致力于嘌呤能信号的研究。在她工作的重要部分,她使用了一个模型系统:肾上腺髓质的绒毛膜细胞。正是在这些细胞中,她发现了二腺苷多磷酸盐,并由此开始了对肾上腺髓质嘌呤基因组的研究:核苷酸的合成和降解、腺苷转运、核苷酸摄入嗜铬细胞颗粒、核苷酸的外排释放以及通过嘌呤受体对嗜铬细胞功能的自分泌调节。玛丽亚-特雷莎对这一课题做出了开创性的贡献,并一直研究到其科学生涯的最后一刻。
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引用次数: 0
María Teresa Miras Portugal: a pioneer for vesicular nucleotide storage. 玛丽亚-特雷莎-米拉斯-葡萄牙:囊泡核苷酸储存的先驱。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-04-01 Epub Date: 2022-12-16 DOI: 10.1007/s11302-022-09912-z
Yoshinori Moriyama, Nao Hasuzawa, Masatoshi Nomura

Chromaffin granules are secretory granules present in adrenal medulla chromaffin cells. They contain high contents of catecholamines and nucleotides and have been regarded as a model system for the study of vesicular transmitter uptake and release. In 1988, Dr. María Teresa Miras Portugal, when studying catecholamine biosynthesis, detected a novel group of nucleotides, the diadenosine polyphosphates, in the adrenal chromaffin granules. Based on this finding, she unraveled the existence of diadenosine polyphosphate-mediated chemical transmission, leading to a paradigm shift in the field of purinergic signaling. She is also a pioneer in the studies on vesicular nucleotide storage. First, María Teresa and her group characterized nucleotide transport in chromaffin granules and synaptic vesicles using fluorescent nucleotide derivatives such as 1, N6-ethenoadenosine triphosphates. Then, they revealed the presence of a hypothetical vesicular nucleotide transporter with unique properties in terms of substrate specificity. In this article, we will describe her contributions to vesicular nucleotide storage and the foundations she laid for future studies.

色素颗粒是存在于肾上腺髓质绒毛细胞中的分泌颗粒。它们含有大量儿茶酚胺和核苷酸,一直被视为研究囊泡递质摄取和释放的模型系统。1988 年,玛丽亚-特雷莎-米拉斯-葡萄牙博士在研究儿茶酚胺的生物合成时,在肾上腺绒毛膜颗粒中发现了一组新的核苷酸--二腺苷多磷酸盐。基于这一发现,她揭示了由多磷酸二腺苷介导的化学传递的存在,导致了嘌呤能信号领域的范式转变。她还是研究囊泡核苷酸储存的先驱。首先,玛丽亚-特雷莎和她的研究小组利用荧光核苷酸衍生物(如 1,N6-乙烯腺苷三磷酸酯)鉴定了嗜铬细胞颗粒和突触小泡中核苷酸的运输。随后,他们发现了一种假定的囊泡核苷酸转运体,这种转运体在底物特异性方面具有独特的特性。在本文中,我们将介绍她对囊泡核苷酸储存的贡献以及她为未来研究奠定的基础。
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引用次数: 0
Differently expression of the metabotropic P2Y receptor family after hypoxia-induced seizures in neonates and seizure suppression via P2Y1 receptor agonism. 新生儿缺氧诱发癫痫发作后代谢性 P2Y 受体家族的不同表达以及通过 P2Y1 受体激动抑制癫痫发作。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-04-01 Epub Date: 2023-02-16 DOI: 10.1007/s11302-023-09923-4
Jonathon Smith, Beatriz Gil Lopez-Avila, Tobias Engel, Eva M Jimenez Mateos, Mariana Alves
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引用次数: 0
Preface to special issue "A tribute to Maria Teresa Miras-Portugal". 向玛丽亚-特雷莎-米拉斯-葡萄牙致敬 "特刊序言。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-04-01 DOI: 10.1007/s11302-024-09990-1
Esmerilda Garcia Delicado, Herbert Zimmermann
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引用次数: 0
Crosstalk between P2Y receptors and cyclooxygenase activity in inflammation and tissue repair. P2Y 受体与环氧化酶活性在炎症和组织修复中的相互影响。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-04-01 Epub Date: 2023-04-13 DOI: 10.1007/s11302-023-09938-x
Adrián Povo-Retana, Sergio Sánchez-García, Carlota Alvarez-Lucena, Rodrigo Landauro-Vera, Patricia Prieto, Carmen Delgado, Paloma Martín-Sanz, Lisardo Boscá

The role of extracellular nucleotides as modulators of inflammation and cell stress is well established. One of the main actions of these molecules is mediated by the activation of purinergic receptors (P2) of the plasma membrane. P2 receptors can be classified according to two different structural families: P2X ionotropic ion channel receptors, and P2Y metabotropic G protein-coupled receptors. During inflammation, damaged cells release nucleotides and purinergic signaling occurs along the temporal pattern of the synthesis of pro-inflammatory and pro-resolving mediators by myeloid and lymphoid cells. In macrophages under pro-inflammatory conditions, the expression and activity of cyclooxygenase 2 significantly increases and enhances the circulating levels of prostaglandin E2 (PGE2), which exerts its effects both through specific plasma membrane receptors (EP1-EP4) and by activation of intracellular targets. Here we review the mechanisms involved in the crosstalk between PGE2 and P2Y receptors on macrophages, which is dependent on several isoforms of protein kinase C and protein kinase D1. Due to this crosstalk, a P2Y-dependent increase in calcium is blunted by PGE2 whereas, under these conditions, macrophages exhibit reduced migratory capacity along with enhanced phagocytosis, which contributes to the modulation of the inflammatory response and tissue repair.

细胞外核苷酸作为炎症和细胞压力调节剂的作用已得到公认。这些分子的主要作用之一是激活质膜上的嘌呤能受体(P2)。P2 受体可按两个不同的结构家族进行分类:P2X ionotropic 离子通道受体和 P2Y metabotropic G 蛋白偶联受体。在炎症过程中,受损细胞释放核苷酸,髓系细胞和淋巴细胞合成促炎症和促消炎介质的时间模式会产生嘌呤能信号。在促炎条件下的巨噬细胞中,环氧化酶 2 的表达和活性显著增加,并提高了前列腺素 E2(PGE2)的循环水平,PGE2 通过特定的质膜受体(EP1-EP4)和激活细胞内靶点发挥其作用。在此,我们回顾了 PGE2 与巨噬细胞上 P2Y 受体之间的串扰机制,这种串扰依赖于蛋白激酶 C 和蛋白激酶 D1 的几种同工形式。由于这种串扰,P2Y 依赖性钙增加被 PGE2 削弱,而在这种情况下,巨噬细胞表现出迁移能力下降,同时吞噬作用增强,这有助于炎症反应的调节和组织修复。
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引用次数: 0
DUSP1/MKP-1 represents another piece in the P2X7R intracellular signaling puzzle in cerebellar cells: our last journey with Mª Teresa along the purinergic pathways of Eden. DUSP1/MKP-1代表了小脑细胞P2X7R细胞内信号传导难题中的另一块:我们与MªTeresa沿着伊甸园嘌呤能通路的最后一次旅程。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-04-01 Epub Date: 2023-09-30 DOI: 10.1007/s11302-023-09970-x
Juan Carlos Gil-Redondo, María José Queipo, Yaiza Trueba, Celia Llorente-Sáez, Julia Serrano, Felipe Ortega, Rosa Gómez-Villafuertes, Raquel Pérez-Sen, Esmerilda G Delicado

The P2X7 receptor (P2X7R) stands out within the purinergic family as it has exclusive pharmacological and regulatory features, and it fulfills distinct roles depending on the type of stimulation and cellular environment. Tonic activation of P2X7R promotes cell proliferation, whereas sustained activation is associated with cell death. Yet strikingly, prolonged P2X7R activation in rat cerebellar granule neurons and astrocytes does not affect cell survival. The intracellular pathways activated by P2X7Rs involve proteins like MAPKs, ERK1/2 and p38, and interactions with growth factor receptors could explain their behavior in populations of rat cerebellar cells. In this study, we set out to characterize the intracellular mechanisms through which P2X7Rs and Trk receptors, EGFR (epidermal growth factor receptor) and BDNFR (brain-derived neurotrophic factor receptor), regulate the dual-specificity phosphatase DUSP1. In cerebellar astrocytes, the regulation of DUSP1 expression by P2X7R depends on ERK and p38 activation. EGFR stimulation can also induce DUSP1 expression, albeit less strongly than P2X7R. Conversely, EGF was virtually ineffective in regulating DUSP1 in granule neurons, a cell type in which BDNF is the main regulator of DUSP1 expression and P2X7R only induces a mild response. Indeed, the regulation of DUSP1 elicited by BDNF reflects the balance between both transcriptional and post-transcriptional mechanisms. Importantly, when the regulation of DUSP1 expression is compromised, the viability of both astrocytes and neurons is impaired, suggesting this phosphatase is essential to maintain proper cell cytoarchitecture and functioning.

P2X7受体(P2X7R)在嘌呤能家族中脱颖而出,因为它具有独特的药理学和调节特征,并且根据刺激类型和细胞环境发挥不同的作用。P2X7R的强化激活促进细胞增殖,而持续激活与细胞死亡有关。然而,令人惊讶的是,大鼠小脑颗粒神经元和星形胶质细胞中P2X7R的长期激活并不影响细胞存活。P2X7Rs激活的细胞内通路涉及MAPKs、ERK1/2和p38等蛋白质,与生长因子受体的相互作用可以解释它们在大鼠小脑细胞群中的行为。在本研究中,我们着手表征P2X7Rs和Trk受体EGFR(表皮生长因子受体)和BDNFR(脑源性神经营养因子受体)调节双特异性磷酸酶DUSP1的细胞内机制。在小脑星形胶质细胞中,P2X7R对DUSP1表达的调节依赖于ERK和p38的激活。EGFR刺激也可以诱导DUSP1表达,尽管不如P2X7R强烈。相反,EGF在调节颗粒神经元中的DUSP1方面几乎无效,在颗粒神经元中,BDNF是DUSP1表达的主要调节因子,P2X7R仅诱导轻度反应。事实上,BDNF引发的DUSP1的调节反映了转录和转录后机制之间的平衡。重要的是,当DUSP1表达的调节受损时,星形胶质细胞和神经元的生存能力都会受损,这表明这种磷酸酶对维持适当的细胞结构和功能至关重要。
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引用次数: 0
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Purinergic Signalling
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