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Generation of Comprehensive GPCR-Transducer-Deficient Cell Lines to Dissect the Complexity of GPCR Signaling. 生成全面的 GPCR 转换器缺陷细胞系,以剖析 GPCR 信号的复杂性。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-14 DOI: 10.1124/pharmrev.124.001186
Ayaki Saito, Ryoji Kise, Asuka Inoue

G-protein-coupled receptors (GPCRs) compose the largest family of transmembrane receptors and are targets of approximately one-third of Food and Drug Administration-approved drugs owing to their involvement in almost all physiologic processes. GPCR signaling occurs through the activation of heterotrimeric G-protein complexes and β-arrestins, both of which serve as transducers, resulting in distinct cellular responses. Despite seeming simple at first glance, accumulating evidence indicates that activation of either transducer is not a straightforward process as a stimulation of a single molecule has the potential to activate multiple signaling branches. The complexity of GPCR signaling arises from the aspects of G-protein-coupling selectivity, biased signaling, interpathway crosstalk, and variable molecular modifications generating these diverse signaling patterns. Numerous questions relative to these aspects of signaling remained unanswered until the recent development of CRISPR genome-editing technology. Such genome editing technology presents opportunities to chronically eliminate the expression of G-protein subunits, β-arrestins, G-protein-coupled receptor kinases (GRKs), and many other signaling nodes in the GPCR pathways at one's convenience. Here, we review the practicality of using CRISPR-derived knockout (KO) cells in the experimental contexts of unraveling the molecular details of GPCR signaling mechanisms. To mention a few, KO cells have revealed the contribution of β-arrestins in ERK activation, Gα protein selectivity, GRK-based regulation of GPCRs, and many more, hence validating its broad applicability in GPCR studies. SIGNIFICANCE STATEMENT: This review emphasizes the practical application of G-protein-coupled receptor (GPCR) transducer knockout (KO) cells in dissecting the intricate regulatory mechanisms of the GPCR signaling network. Currently available cell lines, along with accumulating KO cell lines in diverse cell types, offer valuable resources for systematically elucidating GPCR signaling regulation. Given the association of GPCR signaling with numerous diseases, uncovering the system-based signaling map is crucial for advancing the development of novel drugs targeting specific diseases.

G 蛋白偶联受体(GPCR)是跨膜受体中最大的家族,由于其参与几乎所有生理过程,因此成为美国食品药物管理局批准的约三分之一药物的靶点。GPCR 信号传导是通过激活异三聚 G 蛋白复合物和 β-阻遏蛋白来实现的,这两种蛋白都是传导因子,会导致不同的细胞反应。尽管乍看起来很简单,但越来越多的证据表明,激活其中任何一种转导因子都不是一个简单的过程,因为刺激单个分子有可能激活多个信号分支。GPCR 信号转导的复杂性来自 G 蛋白偶联选择性、偏向信号转导、通路间串扰以及产生这些不同信号转导模式的可变分子修饰等方面。在最近开发出 CRISPR-Cas9 基因组编辑技术之前,与信号转导的这些方面有关的许多问题仍然没有答案。这种基因组编辑技术为长期消除 G 蛋白亚基、β-阻遏蛋白、GRK 和 GPCR 通路中的许多其他信号节点的表达提供了机会。在此,我们回顾了在揭示 GPCR 信号转导机制分子细节的实验中使用 CRISPR-Cas9 衍生的基因敲除(KO)细胞的实用性。KO 细胞揭示了 β-restins 在 ERK 激活、Gα 蛋白选择性、基于 GRK 的 GPCR 调控等方面的贡献,从而验证了它在 GPCR 研究中的广泛适用性。意义声明 本综述强调了 GPCR 效应 KO 细胞在剖析 GPCR 信号网络复杂调控机制中的实际应用。目前可用的细胞系以及在不同细胞类型中积累的 KO 细胞系为系统阐明 GPCR 信号调控提供了宝贵的资源。鉴于 GPCR 信号与多种疾病的关联,揭示基于系统的信号图谱对于推进针对特定疾病的新型药物的开发至关重要。
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引用次数: 0
Novel and Emerging Treatments to Target Pathophysiological Mechanisms in Various Phenotypes of Multiple Sclerosis. 针对多发性硬化症各种表型的病理生理机制的新疗法和新兴疗法。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-14 DOI: 10.1124/pharmrev.124.001073
Gabriel Bsteh, Assunta Dal Bianco, Tobias Zrzavy, Thomas Berger

The objective is to comprehensively review novel pharmacotherapies used in multiple sclerosis (MS) and the possibilities they may carry for therapeutic improvement. Specifically, we discuss pathophysiological mechanisms worth targeting in MS, ranging from well known targets, such as autoinflammation and demyelination, to more novel and advanced targets, such as neuroaxonal damage and repair. To set the stage, a brief overview of clinical MS phenotypes is provided, followed by a comprehensive recapitulation of both clinical and paraclinical outcomes available to assess the effectiveness of treatments in achieving these targets. Finally, we discuss various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials. SIGNIFICANCE STATEMENT: This comprehensive review discusses pathophysiological mechanisms worth targeting in multiple sclerosis. Various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials, are reviewed.

本文旨在全面综述用于多发性硬化症(MS)的新型药物疗法及其在改善治疗方面的可能性。具体而言,我们将讨论多发性硬化症值得关注的病理生理机制,包括众所周知的靶点,如自身炎症和脱髓鞘,以及更新颖、更先进的靶点,如神经轴损伤和修复。为了做好铺垫,我们首先简要介绍了多发性硬化症的临床表型,然后全面回顾了临床和准临床结果,以评估实现这些靶点的治疗效果。最后,我们讨论了各种有前景的新型疗法和新兴疗法,包括它们各自的假设作用模式和目前临床试验中可用的证据。意义声明 本综述讨论了多发性硬化症值得关注的病理生理机制。综述了各种有前景的新型治疗方法和新兴治疗方法,包括其各自假设的作用模式以及目前临床试验中获得的证据。
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引用次数: 0
Pharmacology and Precision Medicine-Preparing for the Next Era in Clinical Medicine-Editorial. 药理学与精准医学--为下一个临床医学时代做准备--社论。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-14 DOI: 10.1124/pharmrev.124.001017
Rhian M Touyz
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引用次数: 0
A Chance to Grow and Excel as an Associate Editor of Pharmacological Reviews-Editorial. 作为《药理学评论》(Pharmacological Reviews)的副主编,您有机会成长并取得优异成绩。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-02 DOI: 10.1124/pharmrev.124.001101
Ali H Eid
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引用次数: 0
A 25-Year Journey as Author and Associate Editor of Pharmacological Reviews-Editorial. 作为《药理学评论》(Pharmacological Reviews)的作者和副主编的 25 年历程。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-13 DOI: 10.1124/pharmrev.123.000990
Martin C Michel
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引用次数: 0
The Role of G Protein-Coupled Receptors and Receptor Kinases in Pancreatic β-Cell Function and Diabetes. G蛋白偶联受体和受体激酶在胰腺β细胞功能和糖尿病中的作用
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-13 DOI: 10.1124/pharmrev.123.001015
Matthew J Varney, Jeffrey L Benovic

Type 2 diabetes (T2D) mellitus has emerged as a major global health concern that has accelerated in recent years due to poor diet and lifestyle. Afflicted individuals have high blood glucose levels that stem from the inability of the pancreas to make enough insulin to meet demand. Although medication can help to maintain normal blood glucose levels in individuals with chronic disease, many of these medicines are outdated, have severe side effects, and often become less efficacious over time, necessitating the need for insulin therapy. G protein-coupled receptors (GPCRs) regulate many physiologic processes, including blood glucose levels. In pancreatic β cells, GPCRs regulate β-cell growth, apoptosis, and insulin secretion, which are all critical in maintaining sufficient β-cell mass and insulin output to ensure euglycemia. In recent years, new insights into the signaling of incretin receptors and other GPCRs have underscored the potential of these receptors as desirable targets in the treatment of diabetes. The signaling of these receptors is modulated by GPCR kinases (GRKs) that phosphorylate agonist-activated GPCRs, marking the receptor for arrestin binding and internalization. Interestingly, genome-wide association studies using diabetic patient cohorts link the GRKs and arrestins with T2D. Moreover, recent reports show that GRKs and arrestins expressed in the β cell serve a critical role in the regulation of β-cell function, including β-cell growth and insulin secretion in both GPCR-dependent and -independent pathways. In this review, we describe recent insights into GPCR signaling and the importance of GRK function in modulating β-cell physiology. SIGNIFICANCE STATEMENT: Pancreatic β cells contain a diverse array of G protein-coupled receptors (GPCRs) that have been shown to improve β-cell function and survival, yet only a handful have been successfully targeted in the treatment of diabetes. This review discusses recent advances in our understanding of β-cell GPCR pharmacology and regulation by GPCR kinases while also highlighting the necessity of investigating islet-enriched GPCRs that have largely been unexplored to unveil novel treatment strategies.

2 型糖尿病(T2D)已成为全球关注的主要健康问题,近年来,由于不良的饮食和生活方式,该病的发病率加速上升。由于胰腺无法制造足够的胰岛素来满足需求,患者的血糖水平很高。虽然药物可以帮助慢性病患者维持正常的血糖水平,但许多药物已经过时,有严重的副作用,而且随着时间的推移,疗效往往会降低,因此必须使用胰岛素治疗。G 蛋白偶联受体(GPCR)调节许多生理过程,包括血糖水平。在胰腺β细胞中,GPCRs调节β细胞的生长、凋亡和胰岛素分泌,这对于维持足够的β细胞质量和胰岛素输出以确保优生至关重要。近年来,对增量素受体和其他 GPCR 信号传导的新认识凸显了这些受体作为治疗糖尿病理想靶点的潜力。这些受体的信号传导受 GPCR 激酶(GRKs)的调节,GRKs 可使激动剂激活的 GPCRs 磷酸化,从而使受体与抑制素结合并内化。有趣的是,利用糖尿病患者队列进行的全基因组关联研究将 GRKs 和 arrestin 与 T2D 联系起来。此外,最近的报告显示,β 细胞中表达的 GRKs 和 arrestins 在调控 β 细胞功能方面起着关键作用,包括在依赖 GPCR 和不依赖 GPCR 的途径中调控 β 细胞生长和胰岛素分泌。在这篇综述中,我们将介绍有关 GPCR 信号传导的最新见解以及 GRK 功能在调节 β 细胞生理机能方面的重要性。意义声明:胰腺 β 细胞含有多种多样的 G 蛋白偶联受体(GPCR),这些受体已被证明可改善 β 细胞的功能和存活率,但只有少数几种 GPCR 已成功地成为治疗糖尿病的靶点。这篇综述讨论了我们对β细胞GPCR药理学和GPCR激酶调控的最新理解进展,同时还强调了研究大部分尚未开发的富含β细胞的GPCR以揭示新型治疗策略的必要性。
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引用次数: 0
Pharmacological Reviews’75th Year Anniversary: Past and Future—Editorial 药理综述》75 周年纪念:过去与未来--社论
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 DOI: 10.1124/pharmrev.123.000989
Lynette C. Daws
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引用次数: 0
Emergence of extracellular vesicles as 'liquid biopsy' for neurological disorders: Boom or Bust 细胞外囊泡作为治疗神经系统疾病的 "液体活检 "出现:繁荣还是萧条
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-12-19 DOI: 10.1124/pharmrev.122.000788
Ashish Kumar, Michael A. Nader, Gagan Deep
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引用次数: 0
Regulation of Pain Perception by Microbiota in Parkinson Disease. 帕金森病中微生物群对疼痛感知的调节。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-12-15 DOI: 10.1124/pharmrev.122.000674
Zulmary Manjarres, Margarita Calvo, Rodrigo Pacheco

Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons, affecting their excitability, or indirectly on non-neuronal cells, inducing changes in the production of proinflammatory or anti-inflammatory mediators. Importantly, Parkinson disease, a neurodegenerative and inflammatory disorder that affects mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also nonmotor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson disease involves a dysbiosis in the composition of the gut microbiota. In this review, we first summarize, integrate, and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Second, we analyze the changes on the commensal microbiota associated to Parkinson disease and propose how these changes affect the development of chronic pain in this pathology. SIGNIFICANCE STATEMENT: The microbiota regulates chronic pain through the action of bacterial signals into two main locations: the peripheral nociceptors and the postsynaptic excitatory neurons in the spinal cord. The dysbiosis associated to Parkinson disease reveals increased representation of commensals that potentially exacerbate chronic pain and reduced levels of bacteria with beneficial effects on pain. This review encourages further research to better understand the signals involved in bacteria-bacteria and bacteria-host communication to get the clues for the development of probiotics with therapeutic potential.

疼痛感知涉及外周伤害性神经的电流刺激和随后脊髓突触后兴奋性神经元的刺激。重要的是,在慢性疼痛中,中枢神经系统中外周伤害感受器和突触后神经元的神经活动都受到免疫系统产生的几种炎症介质的影响。越来越多的证据表明,共生微生物群通过直接作用于伤害感受器或间接调节免疫细胞的炎症活性,在调节疼痛感知方面发挥着积极作用。这种共生关系是由可溶性细菌介质或作用于真核细胞的细菌固有结构成分介导的,包括神经元、小胶质细胞、星形胶质细胞、巨噬细胞、T细胞、肠嗜铬细胞和肠神经胶质细胞。分子机制涉及细菌分子,它们直接作用于影响其兴奋性的神经元,或间接作用于非神经元细胞,诱导促炎或抗炎介质产生的变化。重要的是,帕金森病是一种神经退行性和炎症性疾病,主要影响与控制自主运动有关的多巴胺能神经元,它不仅涉及运动能力下降,还涉及非运动症状,包括慢性疼痛。值得注意的是,最近的几项研究表明,帕金森病涉及肠道微生物群组成的失调。在这篇综述中,首先,我们总结、整合和分类了微生物群介导的慢性疼痛调节的分子机制。其次,我们分析了与帕金森病相关的共生微生物群的变化,并提出了这些变化如何影响这种病理中慢性疼痛的发展。意义陈述微生物群通过细菌信号作用于两个主要位置来调节慢性疼痛:脊髓中的外周伤害感受器和突触后兴奋性神经元。与帕金森氏症相关的微生态失调显示,可能加剧慢性疼痛的共生现象增加,对疼痛有益的细菌水平降低。这篇综述鼓励进一步研究,以更好地了解细菌-细菌和细菌-宿主通讯中涉及的信号,从而为开发具有治疗潜力的益生菌提供线索。
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引用次数: 0
Halogenated Antimicrobial Agents to Combat Drug-Resistant Pathogens. 卤代抗菌剂对抗耐药病原体。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-12-15 DOI: 10.1124/pharmrev.123.000863
Olajide Sunday Faleye, Bharath Reddy Boya, Jin-Hyung Lee, Inho Choi, Jintae Lee

Antimicrobial resistance presents us with a potential global crisis as it undermines the abilities of conventional antibiotics to combat pathogenic microbes. The history of antimicrobial agents is replete with examples of scaffolds containing halogens. In this review, we discuss the impacts of halogen atoms in various antibiotic types and antimicrobial scaffolds and their modes of action, structure-activity relationships, and the contributions of halogen atoms in antimicrobial activity and drug resistance. Other halogenated molecules, including carbohydrates, peptides, lipids, and polymeric complexes, are also reviewed, and the effects of halogenated scaffolds on pharmacokinetics, pharmacodynamics, and factors affecting antimicrobial and antivirulence activities are presented. Furthermore, the potential of halogenation to circumvent antimicrobial resistance and rejuvenate impotent antibiotics is addressed. This review provides an overview of the significance of halogenation, the abilities of halogens to interact in biomolecular settings and enhance pharmacological properties, and their potential therapeutic usages in preventing a postantibiotic era. SIGNIFICANCE STATEMENT: Antimicrobial resistance and the increasing impotence of antibiotics are critical threats to global health. The roles and importance of halogen atoms in antimicrobial drug scaffolds have been established, but comparatively little is known of their pharmacological impacts on drug resistance and antivirulence activities. This review is the first to extensively evaluate the roles of halogen atoms in various antibiotic classes and pharmacological scaffolds and to provide an overview of their ability to overcome antimicrobial resistance.

抗微生物耐药性给我们带来了潜在的全球危机,因为它破坏了传统抗生素对抗病原微生物的能力。抗微生物剂的历史充满了含有卤素的支架的例子。在这篇综述中,我们讨论了卤素原子在各种抗生素类型和抗菌支架中的影响及其作用模式、构效关系,以及卤素原子在抗菌活性和耐药性中的贡献。综述了其他卤代分子,包括碳水化合物、肽、脂质和聚合物复合物,并介绍了卤代支架对药代动力学、药效学的影响,以及影响抗菌和抗病毒活性的因素。此外,还讨论了卤化以规避抗微生物耐药性和恢复无效抗生素活力的潜力。这篇综述概述了卤化的意义、卤素在生物分子环境中相互作用、增强药理学特性的能力及其在预防后抗生素时代中的潜在治疗用途。重要意义声明抗生素耐药性和日益严重的抗生素无能是对全球健康的严重威胁。卤素原子在抗菌药物支架中的作用和重要性已经确定,但对其对耐药性和抗毒力的药理学影响知之甚少。这篇综述首次广泛评估了卤素原子在各种抗生素类别和药理学支架中的作用,并概述了它们克服耐药性的能力。
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引用次数: 0
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Pharmacological Reviews
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