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Pharmacology of pannexin channels 血管紧张素通道的药理学
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102359
Michael Koval , Wyatt J. Schug , Brant E. Isakson

Pannexin channels play fundamental roles in regulating inflammation and have been implicated in many diseases including hypertension, stroke, and neuropathic pain. Thus, the ability to pharmacologically block these channels is a vital component of several therapeutic approaches. Pharmacologic interrogation of model systems also provides a means to discover new roles for pannexins in cell physiology. Here, we review the state of the art for agents that can be used to block pannexin channels, with a focus on chemical pharmaceuticals and peptide mimetics that act on pannexin 1. Guidance on interpreting results obtained with pannexin pharmacologics in experimental systems is discussed, as well as strengths and caveats of different agents, including specificity and feasibility of clinical application.

Pannexin通道在调节炎症中发挥着基本作用,并与许多疾病有关,包括高血压、中风和神经性疼痛。因此,在药理学上阻断这些通道的能力是几种治疗方法的重要组成部分。对模型系统的药理学询问也为发现血管内皮素在细胞生理学中的新作用提供了一种手段。在这里,我们回顾了可用于阻断pannexin通道的药物的现状,重点是作用于pannexin1的化学药物和肽模拟物。讨论了在实验系统中解释pannexin药理学结果的指导,以及不同药物的优势和注意事项,包括临床应用的特异性和可行性。
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引用次数: 10
The role of extracellular ATP and P2X receptors in the pathogenesis of HIV-1 细胞外ATP和P2X受体在HIV-1发病机制中的作用
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102358
Natalia R. Rodriguez, Trinisia Fortune, Thien Vuong, Talia H. Swartz

Human Immunodeficiency Virus Type 1 (HIV-1) causes a chronic, incurable infection associated with chronic inflammation despite virologic suppression on antiretroviral therapy (ART). This chronic inflammation underlies significant comorbidities, including cardiovascular disease, neurocognition decline, and malignancies. The mechanisms of chronic inflammation have been attributed, in part, to the role of extracellular ATP and P2X-type purinergic receptors that sense damaged or dying cells and undergo signaling responses to activate inflammation and immunomodulation. This review describes the current literature on the role of extracellular ATP and P2X receptors in HIV-1 pathogenesis, describing the known intersection with the HIV-1 life cycle in mediating immunopathogenesis and neuronal disease. The literature supports key roles for this signaling mechanism in cell-to-cell communication and in activating transcriptional changes that impact the inflammatory state leading to disease progression. Future studies must characterize the numerous functions of ATP and P2X receptors in HIV-1 pathogenesis to inform future therapeutic targeting.

人类免疫缺陷病毒1型(HIV-1)会导致与慢性炎症相关的慢性、不可治愈的感染,尽管抗病毒治疗(ART)受到病毒抑制。这种慢性炎症是严重合并症的基础,包括心血管疾病、神经认知能力下降和恶性肿瘤。慢性炎症的机制在一定程度上归因于细胞外ATP和P2X型嘌呤能受体的作用,这些受体感知受损或垂死的细胞,并经历激活炎症和免疫调节的信号反应。这篇综述描述了目前关于细胞外ATP和P2X受体在HIV-1发病机制中的作用的文献,描述了已知的与HIV-1生命周期在介导免疫发病和神经元疾病中的交叉点。文献支持这种信号机制在细胞间通讯和激活影响炎症状态导致疾病进展的转录变化中的关键作用。未来的研究必须表征ATP和P2X受体在HIV-1发病机制中的多种功能,为未来的治疗靶向提供信息。
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引用次数: 0
The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: A mini-review of the potential mechanisms 胰高血糖素样肽-1受体激动剂的降压作用:潜在机制的初步综述
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102355
Joao Carlos Ribeiro-Silva , Caio A.M. Tavares , Adriana C.C. Girardi

The incretin hormone glucagon-like peptide 1 (GLP-1) is a key component of the signaling mechanisms promoting glucose homeostasis. Clinical and experimental studies demonstrated that GLP-1 receptor agonists, including GLP-1 itself, have favorable effects on blood pressure and reduce the risk of major cardiovascular events, independently of their effect on glycemic control. GLP-1 receptors are present in the hypothalamus and brainstem, the carotid body, the vasculature, and the kidneys. These organs are involved in blood pressure regulation, have their function altered in hypertension, and are positively benefited by the treatment with GLP-1 receptor agonists. Here, we discuss the potential mechanisms whereby activation of GLP-1R signaling exerts blood pressure-lowering effects beyond glycemic control.

肠促生长素-胰高血糖素样肽1(GLP-1)是促进葡萄糖稳态的信号机制的关键组成部分。临床和实验研究表明,GLP-1受体激动剂,包括GLP-1本身,对血压有良好影响,并降低重大心血管事件的风险,与它们对血糖控制的影响无关。GLP-1受体存在于下丘脑和脑干、颈动脉体、血管系统和肾脏中。这些器官参与血压调节,在高血压中其功能发生改变,并且通过GLP-1受体激动剂的治疗而积极受益。在这里,我们讨论了GLP-1R信号的激活发挥血糖控制之外的降压作用的潜在机制。
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引用次数: 1
Editorial overview: Immune regulation and cancers 编辑综述:免疫调节与癌症
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102360
Carlotta Giorgi, Shafi Kuchay
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引用次数: 0
How organoids can improve personalized treatment in patients with gastro-esophageal tumors 类器官如何改善胃食管肿瘤患者的个性化治疗
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102348
Manuel Cabeza-Segura , Blanca Garcia-Micò , Marcella La Noce , Giovanni Francesco Nicoletti , Valeria Conti , Amelia Filippelli , Tania Fleitas , Andrés Cervantes , Josefa Castillo , Federica Papaccio

Gastro-esophageal tumors constitute a big health problem. Treatment options still mainly rely on chemotherapy, and apart from human epidermal growth factor receptor 2 positive and microsatellite instable/Epstein–Barr Virus disease, there are no molecularly guided options. Therefore, despite the large number of identified molecular alterations, precision medicine is still far from the clinic. In this context, the recently developed technology of patient-derived organoids (PDOs) could offer the chance to accelerate drug development and biomarker discovery. Indeed, PDOs are 3D primary cultures that were shown to reproduce patient's tumor characteristics. Moreover, several reports indicated that PDOs can replicate patient's response to a given drug; therefore, they are one of the most promising tools for functional precision medicine.

胃食管肿瘤是一个巨大的健康问题。治疗选择仍然主要依赖于化疗,除了人类表皮生长因子受体2阳性和微卫星不稳定/EB病毒病外,没有分子指导的选择。因此,尽管有大量已鉴定的分子改变,但精准医学离临床还很远。在这种情况下,最近开发的患者衍生类器官(PDO)技术可能为加速药物开发和生物标志物发现提供机会。事实上,PDO是3D原代培养物,可以重现患者的肿瘤特征。此外,一些报告表明,PDO可以复制患者对给定药物的反应;因此,它们是功能性精准医学最有前景的工具之一。
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引用次数: 3
The P2X7 purinoceptor in pathogenesis and treatment of dystrophino- and sarcoglycanopathies P2X7嘌呤受体在肌营养不良和肌多糖病的发病机制和治疗中的作用
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102357
Dariusz C. Gόrecki, Robin M.H. Rumney

Dystrophinopathy and sarcoglycanopathies are incurable diseases caused by mutations in the genes encoding dystrophin or members of the dystrophin associated protein complex (DAPC). Restoration of the missing dystrophin or sarcoglycans via genetic approaches is complicated by the downsides of personalised medicines and immune responses against re-expressed proteins. Thus, the targeting of disease mechanisms downstream from the mutant protein has a strong translational potential. Acute muscle damage causes release of large quantities of ATP, which activates P2X7 purinoceptors, resulting in inflammation that clears dead tissues and triggers regeneration. However, in dystrophic muscles, loss of α-sarcoglycan ecto-ATPase activity further elevates extracellular ATP (eATP) levels, exacerbating the pathology. Moreover, seemingly compensatory P2X7 upregulation in dystrophic muscle cells, combined with high eATP leads to further damage. Accordingly, P2X7 blockade alleviated dystrophic damage in mouse models of both dystrophinopathy and sarcoglycanopathy. Existing P2X7 blockers could be re-purposed for the treatment of these highly debilitating diseases.

肌萎缩蛋白病和肌聚糖病是由编码肌萎缩蛋白或肌萎缩蛋白相关蛋白复合体(DAPC)成员的基因突变引起的不治之症。通过遗传方法恢复缺失的肌营养不良蛋白或肌聚糖由于个性化药物和针对重新表达的蛋白质的免疫反应的不利影响而变得复杂。因此,靶向突变蛋白下游的疾病机制具有很强的翻译潜力。急性肌肉损伤会导致大量ATP的释放,从而激活P2X7嘌呤受体,导致炎症,清除死亡组织并引发再生。然而,在营养不良肌肉中,α-肌聚糖胞外ATP酶活性的丧失进一步升高了细胞外ATP(eATP)水平,加剧了病理。此外,营养不良肌肉细胞中看似补偿性的P2X7上调,与高eATP相结合,会导致进一步的损伤。因此,P2X7阻断减轻了肌营养不良蛋白病和肌聚糖病小鼠模型中的肌营养不良损伤。现有的P2X7阻断剂可以重新用于治疗这些高度衰弱的疾病。
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引用次数: 0
Purinergic signalling in graft-versus-host disease 移植物抗宿主病中的嘌呤能信号传导
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102346
Ronald Sluyter , Peter Cuthbertson , Amal Elhage , Chloe Sligar , Debbie Watson

Allogeneic hematopoietic stem cell transplantation is used to treat blood cancers, but often results in lethal graft-versus-host disease (GVHD). GVHD is an inflammatory disorder mediated by donor leukocytes that damage host tissues. Purinergic signalling plays important roles in GVHD development in mice but studies of these pathways in human GVHD remain limited. P2X7 receptor activation by ATP on host antigen presenting cells contributes to the induction of GVHD, while activation of this receptor on regulatory T cells, myeloid-derived suppressor cells and possibly type 3 innate lymphoid cells results in their loss to promote GVHD progression. In contrast, A2A receptor activation by adenosine on donor T cells serves to restrict GVHD development. These and other purinergic signalling molecules remain potential biomarkers and therapeutic targets in GVHD.

异基因造血干细胞移植用于治疗血癌,但通常会导致致命的移植物抗宿主病(GVHD)。GVHD是一种由供体白细胞介导的炎症性疾病,可损伤宿主组织。嘌呤能信号传导在小鼠移植物抗宿主病的发展中起着重要作用,但对人类移植物抗逆转录病毒途径的研究仍然有限。宿主抗原呈递细胞上ATP激活P2X7受体有助于GVHD的诱导,而调节性T细胞、髓源性抑制细胞和可能的3型先天性淋巴细胞上该受体的激活导致其丢失以促进GVHD的进展。相反,供体T细胞上腺苷激活的A2A受体可限制移植物抗宿主病的发展。这些和其他嘌呤能信号分子仍然是移植物抗宿主病的潜在生物标志物和治疗靶点。
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引用次数: 2
The use of hormone stimulation in male infertility 激素刺激在男性不育中的应用
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102333
Daniel Foran , Runzhi Chen , Channa N. Jayasena , Suks Minhas , Tharu Tharakan

Infertility affects 15% of couples worldwide and in approximately 50% of cases the cause is secondary to an abnormality of the sperm. However, treatment options for male infertility are limited and empirical use of hormone stimulation has been utilised. We review the contemporary data regarding the application of hormone stimulation to treat male infertility. There is strong evidence supporting the use of hormone stimulation in hypogonadotropic hypogonadism but there is inadequate evidence for all other indications.

不孕影响着全世界15%的夫妇,在大约50%的情况下,原因是精子异常。然而,男性不育的治疗选择是有限的,并且已经使用了激素刺激的经验使用。我们回顾了关于激素刺激治疗男性不育的当代数据。有强有力的证据支持在促性腺功能减退症中使用激素刺激,但没有足够的证据支持所有其他适应症。
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引用次数: 0
The role of extracellular ATP in homeostatic immune cell migration 细胞外ATP在稳态免疫细胞迁移中的作用
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102331
Daichi Kobayashi , Eiji Umemoto , Masayuki Miyasaka

Antigen stimulation induces adenosine triphosphate (ATP) release from naïve lymphocytes in lymphoid tissues. However, previous studies indicated that the non-lytic release of ATP also occurs in most tissues and cell types under physiological conditions. Here, we show that extracellular ATP (eATP) is indeed constitutively produced by naïve T cells in response to lymphoid chemokines in uninflamed lymph nodes and is involved in the regulation of immune cell migration. In this review, we briefly summarize the homeostatic role of extracellular ATP in immune cell migration in vivo.

抗原刺激诱导淋巴组织中幼稚淋巴细胞释放三磷酸腺苷(ATP)。然而,先前的研究表明,在生理条件下,ATP的非溶解性释放也发生在大多数组织和细胞类型中。在这里,我们发现细胞外ATP(eATP)确实是由幼稚的T细胞组成性地产生的,以响应未炎症淋巴结中的淋巴趋化因子,并参与免疫细胞迁移的调节。在这篇综述中,我们简要总结了细胞外ATP在体内免疫细胞迁移中的稳态作用。
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引用次数: 1
Non-hereditary early onset gastric cancer: An unmet medical need 非遗传性早发癌症:未满足的医疗需求
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102344
Angelica Petrillo , Piera Federico , Gianpaolo Marte , Carlo Liguori , Andreas Seeber , Margaret Ottaviano , Andrea Tufo , Bruno Daniele

Gastric cancer (GC) is a lethal disease and the diagnosis in the young population is a major challenge from both individual and social point of views. Early-onset GC accounts for ∼5% of GC; among them, 3% are part of a hereditary syndrome and the majority are sporadic. However, even if the early-onset forms were less frequent in the past, the increasing number in the last decades has improved the interest and awareness of them in the society and in the scientific community. In particular, the different behaviour and characteristics of early-onset GC suggest that it is a completely different entity, which requires a tailored and personalized management. Here we provide an updated overview about non-hereditary early-onset GC, which is an unmet clinical need today, along with future perspectives in this field.

癌症是一种致命的疾病,从个人和社会角度来看,年轻人群的诊断是一个重大挑战。早期发作的GC占GC的~5%;其中,3%属于遗传性综合征,大多数为散发性综合征。然而,即使早发性形式在过去不那么常见,但在过去几十年中数量的增加提高了社会和科学界对它们的兴趣和认识。特别是,早发性GC的不同行为和特征表明,它是一个完全不同的实体,需要量身定制和个性化的管理。在这里,我们提供了关于非遗传性早发性GC的最新概述,这是当今尚未满足的临床需求,以及该领域的未来前景。
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引用次数: 0
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Current Opinion in Pharmacology
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