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CD73 polymorphisms are associated with schizophrenia. CD73 多态性与精神分裂症有关。
IF 3.5 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-05-17 DOI: 10.1007/s11302-024-10004-3
He-Xia Peng, Li-Li Zhang, Dan Jiang, Na Jian, Ting-Mei Zhang, Jia-Guo Luo, Hai-Yan Yin

Ecto-5'-nucleotidase/CD73 enzyme plays a key role in the regulation of extracellular adenosine levels, thereby exerting influence on adenosine homeostasis. Emerging evidence suggests that perturbations in purines and ecto-5'-nucleotidase activity are associated with an augmented susceptibility to schizophrenia. However, the precise impact of genetic variations in CD73 on individuals with schizophrenia remains poorly understood. Here, our study demonstrated that rs3734442 allele and rs4431401 heterozygote were conferred a significant risk of schizophrenia disease (rs3734442: odds ratio, 0.556; 95% CI, 0.375 to 0.825; p = 0.004; rs4431401: odds ratio, 1.881, 95% CI, 1.117 to 3.166; p = 0.020). Comparing different genders, we observed a significant association between rs3734442 genotypes and male cases (rs3734442: odds ratio, 0.452; 95% CI, 0.257 to 0.796; p = 0.007). Likewise, there was a significant association between rs4431401 genotypes and male patients (rs4431401: odds ratio, 2.570; 95% CI, 1.196 to 5.522; p = 0.015). Based on family history and antipsychotics medication usage, our data reveals that the rs9444348 allele exhibits the most significant association with familial susceptibility to schizophrenia (odds ratio, 1.541; 95% CI, 1.009 to 2.353; p = 0.048 for A vs G). Moreover, individuals carrying variants of rs6922, rs2229523, and rs2065114 while being treated with clozapine demonstrate a higher frequency proportion compared to those receiving risperidone treatment (p = 0.035; p = 0.049; p = 0.027 respectively). Additionally, our results indicate that patients with GG genotype of rs9444348 had significantly higher likelihood of using clozapine instead of sulpiride (p = 0.048). Overall, our data strongly suggest that genetic variations in CD73 are significantly associated with schizophrenia risk and may serve as valuable resources for identifying therapeutic targets.

外向-5'-核苷酸酶/CD73酶在调节细胞外腺苷水平方面发挥着关键作用,从而对腺苷平衡产生影响。新的证据表明,嘌呤和外-5'-核苷酸酶活性的紊乱与精神分裂症易感性的增加有关。然而,人们对 CD73 基因变异对精神分裂症患者的确切影响仍知之甚少。在此,我们的研究表明,rs3734442 等位基因和 rs4431401 杂合子具有显著的精神分裂症患病风险(rs3734442:几率比,0.556;95% CI,0.375 至 0.825;p = 0.004;rs4431401:几率比,1.881,95% CI,1.117 至 3.166;p = 0.020)。比较不同性别,我们观察到 rs3734442 基因型与男性病例之间存在显著关联(rs3734442:几率比,0.452;95% CI,0.257 至 0.796;p = 0.007)。同样,rs4431401 基因型与男性患者之间也存在显著关联(rs4431401:几率比,2.570;95% CI,1.196 至 5.522;p = 0.015)。根据家族史和抗精神病药物的使用情况,我们的数据显示,rs9444348 等位基因与精神分裂症家族易感性的关系最为显著(几率比为 1.541;95% CI 为 1.009 至 2.353;A 与 G 相比,p = 0.048)。此外,与接受利培酮治疗的患者相比,携带 rs6922、rs2229523 和 rs2065114 变异的患者接受氯氮平治疗的频率比例更高(分别为 p = 0.035;p = 0.049;p = 0.027)。此外,我们的研究结果表明,rs9444348 基因型为 GG 的患者使用氯氮平而不是舒必利的可能性明显更高(p = 0.048)。总之,我们的数据有力地表明,CD73 的基因变异与精神分裂症的风险密切相关,可作为确定治疗靶点的宝贵资源。
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引用次数: 0
How selective antagonists and genetic modification have helped characterise the expression and functions of vascular P2Y receptors. 选择性拮抗剂和基因改造如何帮助确定血管 P2Y 受体的表达和功能特征。
IF 3.5 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-05-13 DOI: 10.1007/s11302-024-10016-z
Markie O Dales, Robert M Drummond, Charles Kennedy

Vascular P2Y receptors mediate many effects, but the role of individual subtypes is often unclear. Here we discuss how subtype-selective antagonists and receptor knockout/knockdown have helped identify these roles in numerous species and vessels. P2Y1 receptor-mediated vasoconstriction and endothelium-dependent vasodilation have been characterised using the selective antagonists, MRS2179 and MRS2216, whilst AR-C118925XX, a P2Y2 receptor antagonist, reduced endothelium-dependent relaxation, and signalling evoked by UTP or fluid shear stress. P2Y2 receptor knockdown reduced endothelial signalling and endothelial P2Y2 receptor knockout produced hypertensive mice and abolished vasodilation elicited by an increase in flow. UTP-evoked vasoconstriction was also blocked by AR-C118925XX, but the effects of P2Y2 receptor knockout were complex. No P2Y4 receptor antagonists are available and P2Y4 knockout did not affect the vascular actions of UTP and UDP. The P2Y6 receptor antagonist, MRS2578, identified endothelial P2Y6 receptors mediating vasodilation, but receptor knockout had complex effects. MRS2578 also inhibited, and P2Y6 knockout abolished, contractions evoked by UDP. P2Y6 receptors contribute to the myogenic tone induced by a stepped increase in vascular perfusion pressure and possibly to the development of atherosclerosis. The P2Y11 receptor antagonists, NF157 and NF340, inhibited ATP-evoked signalling in human endothelial cells. Vasoconstriction mediated by P2Y12/P2Y13 and P2Y14 receptors was characterised using the antagonists, cangrelor, ticagrelor, AR-C67085 and MRS2211 or PPTN respectively. This has yet to be backed up by receptor knockout experiments. Thus, subtype-selective antagonists and receptor knockout/knockdown have helped identify which P2Y subtypes are functionally expressed in vascular smooth muscle and endothelial cells and the effects that they mediate.

血管 P2Y 受体介导多种效应,但各个亚型的作用往往不明确。在此,我们将讨论亚型选择性拮抗剂和受体敲除/敲减如何帮助确定这些受体在许多物种和血管中的作用。P2Y1受体介导的血管收缩和内皮依赖性血管舒张已通过选择性拮抗剂MRS2179和MRS2216进行了表征,而P2Y2受体拮抗剂AR-C118925XX可减少内皮依赖性松弛以及UTP或流体剪切应力诱发的信号传导。P2Y2 受体敲除可减少内皮信号传导,内皮 P2Y2 受体敲除可产生高血压小鼠,并消除血流增加引起的血管舒张。AR-C118925XX 也能阻断UTP 诱导的血管收缩,但 P2Y2 受体敲除的影响是复杂的。目前还没有 P2Y4 受体拮抗剂,P2Y4 基因敲除并不影响UTP 和 UDP 对血管的作用。P2Y6 受体拮抗剂 MRS2578 发现了介导血管扩张的内皮 P2Y6 受体,但受体敲除的影响很复杂。MRS2578 还能抑制 UDP 诱导的收缩,而 P2Y6 受体敲除则能消除这种收缩。P2Y6 受体有助于血管灌注压阶梯式增加所诱导的肌张力,也可能有助于动脉粥样硬化的发展。P2Y11 受体拮抗剂 NF157 和 NF340 可抑制人内皮细胞中 ATP 诱导的信号传导。分别使用坎格雷罗、替卡格雷罗、AR-C67085 和 MRS2211 或 PPTN 等拮抗剂对 P2Y12/P2Y13 和 P2Y14 受体介导的血管收缩进行了表征。这还需要受体敲除实验的支持。因此,亚型选择性拮抗剂和受体剔除/敲除有助于确定哪些 P2Y 亚型在血管平滑肌和内皮细胞中有功能表达,以及它们介导的效应。
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引用次数: 0
P2Y14 receptors: a new target for treating ulcerative colitis. P2Y14 受体:治疗溃疡性结肠炎的新靶点。
IF 3.5 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-05-09 DOI: 10.1007/s11302-024-10017-y
Yan-Qin Zuo, Yong Tang
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引用次数: 0
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 Q2 NEUROSCIENCES 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 Q2 NEUROSCIENCES 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
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 Q2 NEUROSCIENCES 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
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Purinergic Signalling
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