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Hepatic Bile Formation: Developing a New Paradigm. 肝胆汁形成:发展新范式。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-09-01 DOI: 10.1124/pharmrev.122.000799
Norman B Javitt

In 1959, Ivar Sperber contrasted bile formation with that of urine and proposed that water flow into the canalicular conduit is in response to an osmotic, not a hydrostatic, gradient. Early attempts to support the hypothesis using a bile acid, sodium taurocholate, and the hormone secretin to stimulate bile flow led to conflicting data and a moratorium on attempts to further develop the initial proposal. However, current data amplify the initial proposal and indicate both paracellular and transcellular water flow into hepatic ductules and the canalicular conduit in response to an osmotic gradient. Also, the need to further modify the initial proposal became apparent with the recognition that bile acid aggregates (micelles), which form in the canalicular conduit, generate lecithin-cholesterol vesicles that contain water unrelated to an osmotic gradient. As part of this development is the recent introduction of the fluorescent localization after photobleaching technique for direct determination of hepatic duct flow and clarification of the role of biomarkers such as mannitol and polyethylene glycol 900. With the new paradigm, these biomarkers may prove useful for quantifying paracellular and transcellular water flow, respectively. SIGNIFICANCE STATEMENT: It is essential to identify and characterize all the sites for water flow during hepatic bile formation to obtain more precision in evaluating the causes and possible therapeutic approaches to cholestatic syndromes. Updating the Sperber proposal provides a new paradigm that addresses the advances in knowledge that have occurred.

1959年,Ivar Sperber对比了胆汁和尿液的形成,并提出水流入小管是对渗透梯度的反应,而不是流体静力梯度。早期尝试使用胆汁酸、牛磺胆酸钠和激素分泌素来刺激胆汁流动,这导致了相互矛盾的数据,并暂停了进一步发展最初建议的尝试。然而,目前的数据强化了最初的建议,并表明细胞旁和细胞间的水都流入肝小管和小管,以响应渗透梯度。此外,随着胆汁酸聚集体(胶束)在小管导管中形成,产生卵磷脂-胆固醇囊泡,其中含有与渗透梯度无关的水,进一步修改最初建议的必要性变得明显。作为这一发展的一部分,最近引入了光漂白后荧光定位技术,用于直接测定肝管流量和澄清生物标志物(如甘露醇和聚乙二醇900)的作用。有了新的范例,这些生物标志物可能分别被证明对定量细胞旁和细胞间水流有用。意义声明:确定和表征肝胆汁形成过程中水流的所有部位对于更精确地评估胆汁淤积综合征的原因和可能的治疗方法至关重要。更新Sperber提案提供了一种新的范式,可以解决已经发生的知识进步。
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引用次数: 0
β-Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives. β-Arrestins:结构、功能、生理学和药理学展望。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-09-01 Epub Date: 2023-04-07 DOI: 10.1124/pharmrev.121.000302
Jürgen Wess, Antwi-Boasiako Oteng, Osvaldo Rivera-Gonzalez, Eugenia V Gurevich, Vsevolod V Gurevich

The two β-arrestins, β-arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiologic functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both β-arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, and biochemical studies have provided novel insights into how β-arrestins bind to activated GPCRs and downstream effector proteins. Studies with β-arrestin mutant mice have identified numerous physiologic and pathophysiological processes regulated by β-arrestin-1 and/or -2. Following a short summary of recent structural studies, this review primarily focuses on β-arrestin-regulated physiologic functions, with particular focus on the central nervous system and the roles of β-arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review also highlights potential therapeutic implications of these studies and discusses strategies that could prove useful for targeting specific β-arrestin-regulated signaling pathways for therapeutic purposes. SIGNIFICANCE STATEMENT: The two β-arrestins, structurally closely related intracellular proteins that are evolutionarily highly conserved, have emerged as multifunctional proteins able to regulate a vast array of cellular and physiological functions. The outcome of studies with β-arrestin mutant mice and cultured cells, complemented by novel insights into β-arrestin structure and function, should pave the way for the development of novel classes of therapeutically useful drugs capable of regulating specific β-arrestin functions.

两种β-抑制蛋白,β-抑制素-1和-2(系统名称分别为:抑制素-2和-3),是多功能细胞内蛋白,调节大量细胞信号通路的活性和生理功能。这两种蛋白质被发现具有通过与活化受体结合破坏G蛋白偶联受体(GPCR)信号传导的能力。然而,现在人们已经认识到,这两种β-抑制蛋白也可以通过GPCR依赖性或非依赖性机制作为许多细胞过程的直接调节剂。最近的结构、生物物理和生物化学研究为β-抑制蛋白如何与活化的GPCR和下游效应蛋白结合提供了新的见解。对β-抑制蛋白突变小鼠的研究已经确定了由β-抑制素-1和/或-2调节的许多生理和病理生理过程。在对最近的结构研究进行简短总结后,本综述主要关注β-抑制蛋白调节的生理功能,特别关注中枢神经系统以及β-抑制素在致癌和关键代谢过程中的作用,包括维持葡萄糖和能量稳态。这篇综述还强调了这些研究的潜在治疗意义,并讨论了可能被证明对靶向特定的β-抑制蛋白调节的信号通路用于治疗目的有用的策略。意义声明:这两种β-抑制蛋白是结构紧密相关的细胞内蛋白,在进化上高度保守,已成为能够调节大量细胞和生理功能的多功能蛋白。对β-arrestin突变小鼠和培养细胞的研究结果,加上对β-arrestin结构和功能的新见解,应该为开发能够调节特定β-arristin功能的新型治疗有用药物铺平道路。
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引用次数: 7
Review of Natural Language Processing in Pharmacology. 自然语言处理在药理学中的研究进展。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-07-01 DOI: 10.1124/pharmrev.122.000715
Dimitar Trajanov, Vangel Trajkovski, Makedonka Dimitrieva, Jovana Dobreva, Milos Jovanovik, Matej Klemen, Aleš Žagar, Marko Robnik-Šikonja

Natural language processing (NLP) is an area of artificial intelligence that applies information technologies to process the human language, understand it to a certain degree, and use it in various applications. This area has rapidly developed in the past few years and now employs modern variants of deep neural networks to extract relevant patterns from large text corpora. The main objective of this work is to survey the recent use of NLP in the field of pharmacology. As our work shows, NLP is a highly relevant information extraction and processing approach for pharmacology. It has been used extensively, from intelligent searches through thousands of medical documents to finding traces of adversarial drug interactions in social media. We split our coverage into five categories to survey modern NLP: methodology, commonly addressed tasks, relevant textual data, knowledge bases, and useful programming libraries. We split each of the five categories into appropriate subcategories, describe their main properties and ideas, and summarize them in a tabular form. The resulting survey presents a comprehensive overview of the area, useful to practitioners and interested observers. SIGNIFICANCE STATEMENT: The main objective of this work is to survey the recent use of NLP in the field of pharmacology in order to provide a comprehensive overview of the current state in the area after the rapid developments that occurred in the past few years. The resulting survey will be useful to practitioners and interested observers in the domain.

自然语言处理(NLP)是人工智能的一个领域,它应用信息技术来处理人类语言,并在一定程度上理解它,并将其用于各种应用。这一领域在过去几年中得到了迅速发展,现在使用现代的深度神经网络变体从大型文本语料库中提取相关模式。本工作的主要目的是调查NLP在药理学领域的最新应用。正如我们的工作所表明的,NLP是一种与药理学高度相关的信息提取和处理方法。它已经被广泛使用,从智能搜索成千上万的医疗文件到在社交媒体上寻找对抗性药物相互作用的痕迹。我们将我们的报道分为五类来调查现代NLP:方法论、通常处理的任务、相关的文本数据、知识库和有用的编程库。我们将这五个类别中的每一个划分为适当的子类别,描述它们的主要属性和思想,并以表格形式总结它们。由此产生的调查提出了该地区的全面概述,对从业者和感兴趣的观察者有用。意义声明:这项工作的主要目的是调查NLP在药理学领域的最新应用,以便在过去几年中发生的快速发展之后,对该领域的现状提供全面的概述。结果调查将对该领域的实践者和感兴趣的观察者有用。
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引用次数: 1
Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies. 细胞衰老:从机制到当前的生物标志物和衰老疗法。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-07-01 DOI: 10.1124/pharmrev.122.000622
Vasco Lucas, Cláudia Cavadas, Célia Alexandra Aveleira

An increase in life expectancy in developed countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided evidence of the prominent role of cellular senescence in many of these pathologies. Key traits of senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secretory phenotype resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senescence is a highly phenotypically heterogeneous process, hindering the discovery of totally specific and accurate biomarkers. Also, strategies to prevent the pathologic effect of senescent cell accumulation during aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies, and some are already in early stages of clinical translation. The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiologic functions. In this review, we explore the heterogeneous phenotype of senescent cells and its influence on the expression of biomarkers currently used for senescence detection. We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies. SIGNIFICANCE STATEMENT: This paper is an extensive review of what is currently known about the complex process of cellular senescence and explores its most defining features. The main body of the discussion focuses on how the multifeature fluctuation of the senescence phenotype and the physiological role of cellular senescence have both caused a limitation in the search for truly reliable senescence biomarkers and the progression in the development of senotherapies.

发达国家预期寿命的增加导致与衰老有关的慢性疾病激增。在过去的几十年里,一些研究已经提供了细胞衰老在许多这些病理中的突出作用的证据。衰老细胞的关键特征包括细胞周期阻滞、细胞凋亡抵抗和分泌组向衰老相关分泌表型的转变,导致各种对衰老病理生理重要的中间生物活性因子的分泌增加。然而,细胞衰老是一个高度表型异质性的过程,阻碍了完全特异性和准确的生物标志物的发现。此外,通过抑制衰老发生或促进衰老细胞清除来预防衰老过程中衰老细胞积累的病理效应的策略在体内研究中显示出了巨大的潜力,有些已经处于临床转化的早期阶段。由于缺乏适当的衰老靶向和衰老参与重要的生理功能,这些衰老治疗方法对人类应用的适应性受到质疑。在这篇综述中,我们探讨了衰老细胞的异质性表型及其对目前用于衰老检测的生物标志物表达的影响。我们还讨论了目前关于现有主要老年治疗策略的有效性、可靠性、发展阶段和人类适用性的证据。意义声明:本文对目前已知的细胞衰老的复杂过程进行了广泛的回顾,并探讨了其最明确的特征。讨论的主体集中在衰老表型的多特征波动和细胞衰老的生理作用如何导致寻找真正可靠的衰老生物标志物和衰老治疗发展的进展受到限制。
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引用次数: 7
Advances in Nanozymes as a Paradigm for Viral Diagnostics and Therapy. 纳米酶作为病毒诊断和治疗范例的研究进展。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-07-01 DOI: 10.1124/pharmrev.122.000719
Garima Sharma, Srijan Chatterjee, Chiranjib Chakraborty, Jin-Chul Kim

Over the past few decades, humankind has constantly encountered new viral species that create havoc in the socioeconomic balance worldwide. Among the method to combat these novel viral infections, fast and point-of-care diagnosis is of prime importance to contain the spreading of viral infections. However, most sensitive diagnostic systems for viral infections are time-consuming and require well-trained professionals, making it difficult for the patients. In recent years nanozymes emerged as promising therapeutic and fast diagnostic tools due to their multienzyme-like catalytic performance. Nanozymes can be designed using inorganic or organic components with tailorable physicochemical surface properties, enabling the attachment of various molecules and species on the surface of the nanozyme for specific recognition. In addition to the composition, the multienzyme-like catalytic performance can be modulated by the shape and size of the nanoparticles. Due to their multicatalytic abilities, nanozymes can be used for fast diagnosis and therapy for viral infections. Here we attempt to focus on the insights and recent explorations on the advances in designing various types of nanozymes as a theranostic tool for viral infections. Thus, this review intends to generate interest in the clinical translation of nanozymes as a theranostic tool for viral infections by providing knowledge about the multidisciplinary potential of nanozyme. SIGNIFICANCE STATEMENT: The multienzyme-like properties of nanozymes suggest their role in diagnosing and treating various diseases. Although the potential roles of nanozymes for various viral infections have been studied in the last few decades, no review provides recent explorations on designing various types of nanozymes for the detection and treatment of viral infections. This review provides insights into designing nanozymes to diagnose and treat viral infections, assisting future researchers in developing clinically translatable nanozymes to combat novel viral infections.

在过去的几十年里,人类不断遇到新的病毒物种,对全球社会经济平衡造成严重破坏。在对抗这些新型病毒感染的方法中,快速和即时诊断对于遏制病毒感染的传播至关重要。然而,大多数敏感的病毒感染诊断系统都很耗时,而且需要训练有素的专业人员,这对患者来说很困难。近年来,纳米酶因其多酶样催化性能而成为一种有前景的治疗和快速诊断工具。纳米酶可以使用具有可定制的物理化学表面性质的无机或有机成分来设计,使各种分子和物质附着在纳米酶的表面以进行特定识别。除了组合物外,多酶样催化性能还可以通过纳米颗粒的形状和大小来调节。由于其多催化能力,纳米酶可用于病毒感染的快速诊断和治疗。在这里,我们试图集中在见解和最近的探索在设计各种类型的纳米酶作为治疗工具的病毒感染的进展。因此,本综述旨在通过提供有关纳米酶的多学科潜力的知识,引起对纳米酶作为病毒感染治疗工具的临床翻译的兴趣。意义声明:纳米酶的多酶样特性提示其在诊断和治疗多种疾病中的作用。虽然在过去的几十年里,纳米酶在各种病毒感染中的潜在作用已经得到了研究,但目前还没有关于设计各种类型的纳米酶来检测和治疗病毒感染的综述。这篇综述为设计纳米酶来诊断和治疗病毒感染提供了见解,有助于未来的研究人员开发临床可翻译的纳米酶来对抗新型病毒感染。
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引用次数: 0
Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders. 当前和新出现的尿失禁及相关疾病的药理学靶点和治疗。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-07-01 DOI: 10.1124/pharmrev.121.000523
Martin C Michel, Linda Cardozo, Christopher J Chermansky, Francisco Cruz, Yasuhiko Igawa, Kyu-Sung Lee, Arun Sahai, Alan J Wein, Karl-Erik Andersson

Overactive bladder syndrome with and without urinary incontinence and related conditions, signs, and disorders such as detrusor overactivity, neurogenic lower urinary tract dysfunction, underactive bladder, stress urinary incontinence, and nocturia are common in the general population and have a major impact on the quality of life of the affected patients and their partners. Based on the deliberations of the subcommittee on pharmacological treatments of the 7th International Consultation on Incontinence, we present a comprehensive review of established drug targets in the treatment of overactive bladder syndrome and the aforementioned related conditions and the approved drugs used in its treatment. Investigational drug targets and compounds are also reviewed. We conclude that, despite a range of available medical treatment options, a considerable medical need continues to exist. This is largely because the existing treatments are symptomatic and have limited efficacy and/or tolerability, which leads to poor long-term adherence. SIGNIFICANCE STATEMENT: Urinary incontinence and related disorders are prevalent in the general population. While many treatments have been approved, few patients stay on long-term treatment despite none of them being curative. This paper provides a comprehensive discussion of existing and emerging treatment options for various types of incontinence and related disorders.

膀胱过动综合征伴或不伴尿失禁及相关病症、体征和障碍,如逼尿肌过度活动、神经源性下尿路功能障碍、膀胱过动、应激性尿失禁和夜尿症在普通人群中很常见,对患者及其伴侣的生活质量有重大影响。根据第七届国际尿失禁会议药理学治疗小组委员会的审议,我们对治疗膀胱过度活动综合征和上述相关疾病的既定药物靶点以及用于治疗该疾病的批准药物进行了全面回顾。研究药物靶点和化合物也进行了回顾。我们的结论是,尽管有一系列可用的医疗选择,但仍然存在相当大的医疗需求。这在很大程度上是因为现有的治疗方法是对症的,疗效和/或耐受性有限,这导致长期依从性差。意义声明:尿失禁和相关疾病在普通人群中普遍存在。虽然许多治疗方法已被批准,但很少有患者坚持长期治疗,尽管这些治疗方法都无法治愈。本文提供了一个全面的讨论现有的和新兴的治疗方案的各种类型的失禁和相关疾病。
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引用次数: 8
Pharmacogenomics: Driving Personalized Medicine. 药物基因组学:推动个性化医疗。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-07-01 Epub Date: 2023-03-16 DOI: 10.1124/pharmrev.122.000810
Wolfgang Sadee, Danxin Wang, Katherine Hartmann, Amanda Ewart Toland

Personalized medicine tailors therapies, disease prevention, and health maintenance to the individual, with pharmacogenomics serving as a key tool to improve outcomes and prevent adverse effects. Advances in genomics have transformed pharmacogenetics, traditionally focused on single gene-drug pairs, into pharmacogenomics, encompassing all "-omics" fields (e.g., proteomics, transcriptomics, metabolomics, and metagenomics). This review summarizes basic genomics principles relevant to translation into therapies, assessing pharmacogenomics' central role in converging diverse elements of personalized medicine. We discuss genetic variations in pharmacogenes (drug-metabolizing enzymes, drug transporters, and receptors), their clinical relevance as biomarkers, and the legacy of decades of research in pharmacogenetics. All types of therapies, including proteins, nucleic acids, viruses, cells, genes, and irradiation, can benefit from genomics, expanding the role of pharmacogenomics across medicine. Food and Drug Administration approvals of personalized therapeutics involving biomarkers increase rapidly, demonstrating the growing impact of pharmacogenomics. A beacon for all therapeutic approaches, molecularly targeted cancer therapies highlight trends in drug discovery and clinical applications. To account for human complexity, multicomponent biomarker panels encompassing genetic, personal, and environmental factors can guide diagnosis and therapies, increasingly involving artificial intelligence to cope with extreme data complexities. However, clinical application encounters substantial hurdles, such as unknown validity across ethnic groups, underlying bias in health care, and real-world validation. This review address the underlying science and technologies germane to pharmacogenomics and personalized medicine, integrated with economic, ethical, and regulatory issues, providing insights into the current status and future direction of health care. SIGNIFICANCE STATEMENT: Personalized medicine aims to optimize health care for the individual patients with use of predictive biomarkers to improve outcomes and prevent adverse effects. Pharmacogenomics drives biomarker discovery and guides the development of targeted therapeutics. This review addresses basic principles and current trends in pharmacogenomics, with large-scale data repositories accelerating medical advances. The impact of pharmacogenomics is discussed, along with hurdles impeding broad clinical implementation, in the context of clinical care, ethics, economics, and regulatory affairs.

个性化医疗为个人量身定制治疗、疾病预防和健康维护方案,而药物基因组学则是改善疗效和预防不良反应的重要工具。基因组学的进步将传统上侧重于单基因-药物配对的药物遗传学转变为药物基因组学,涵盖了所有"-组学 "领域(如蛋白质组学、转录物组学、代谢组学和元基因组学)。本综述总结了与转化为疗法相关的基因组学基本原理,评估了药物基因组学在融合个性化医疗的各种要素方面所起的核心作用。我们将讨论药物基因(药物代谢酶、药物转运体和受体)的遗传变异、它们作为生物标志物的临床意义以及数十年来药物基因学研究的成果。所有类型的疗法,包括蛋白质、核酸、病毒、细胞、基因和辐照,都能从基因组学中获益,从而扩大了药物基因组学在整个医学中的作用。美国食品药品管理局对涉及生物标记的个性化疗法的批准数量迅速增加,这表明药物基因组学的影响越来越大。作为所有治疗方法的灯塔,癌症分子靶向疗法凸显了药物发现和临床应用的趋势。为了考虑人类的复杂性,包含遗传、个人和环境因素的多组分生物标志物可以指导诊断和治疗,越来越多的人工智能参与其中,以应对极端复杂的数据。然而,临床应用遇到了巨大的障碍,如不同种族群体的有效性未知、医疗保健中的潜在偏见以及现实世界的验证。本综述探讨了与药物基因组学和个性化医疗相关的基础科学和技术,并结合了经济、伦理和监管问题,为医疗保健的现状和未来方向提供了见解。意义声明:个性化医疗旨在通过使用预测性生物标志物来改善疗效和预防不良反应,从而优化针对个体患者的医疗保健。药物基因组学推动了生物标志物的发现,并为靶向治疗药物的开发提供了指导。本综述探讨了药物基因组学的基本原理和当前趋势,大规模数据储存库加速了医学进步。文章从临床护理、伦理学、经济学和监管事务等方面讨论了药物基因组学的影响,以及阻碍广泛临床应用的障碍。
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引用次数: 0
Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment. 钾通道在帕金森病中的潜在作用:发病机制和创新的治疗分子靶点。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-07-01 DOI: 10.1124/pharmrev.122.000743
Xiaoyi Chen, Yunjiang Feng, Ronald J Quinn, Dean L Pountney, Des R Richardson, George D Mellick, Linlin Ma

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathologic progression of dopaminergic neurodegeneration. This unfortunate predicament is because of the current early stages in understanding the biologic targets and pathways involved in PD pathogenesis. Ion channels have become emerging targets for new therapeutic development for PD due to their essential roles in neuronal function and neuroinflammation. Potassium channels are the most prominent ion channel family and have been shown to be critically important in PD pathology because of their roles in modulating neuronal excitability, neurotransmitter release, synaptic transmission, and neuroinflammation. In this review, members of the subfamilies of voltage-gated K+ channels, inward rectifying K+ channels, and Ca2+-activated K+ channels are described. Evidence of the role of these channels in PD etiology is discussed together with the latest views on related pathologic mechanisms and their potential as biologic targets for developing neuroprotective drugs for PD. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, featuring progressive degeneration of dopaminergic neurons in the midbrain. It is a multifactorial disease involving multiple risk factors and complex pathobiological mechanisms. Mounting evidence suggests that ion channels play vital roles in the pathogenesis and progression of PD by regulating neuronal excitability and immune cell function. Therefore, they have become "hot" biological targets for PD, as demonstrated by multiple clinical trials of drug candidates targeting ion channels for PD therapy.

帕金森病(PD)是一种神经退行性疾病,其特征是中脑黑质致密部(SNpc)区域多巴胺能神经元的选择性丧失。神经元的丧失导致纹状体中多巴胺的减少,这是帕金森病核心运动症状的基础。到目前为止,还没有有效的治疗方法来阻止、减缓或逆转多巴胺能神经变性的病理进展。这种不幸的困境是由于目前对PD发病机制的生物学靶点和途径的了解尚处于早期阶段。离子通道因其在神经功能和神经炎症中的重要作用而成为PD治疗的新靶点。钾离子通道是最重要的离子通道家族,由于其在调节神经元兴奋性、神经递质释放、突触传递和神经炎症方面的作用,已被证明在PD病理中至关重要。在这篇综述中,描述了电压门控K+通道亚家族的成员,向内整流K+通道和Ca2+激活的K+通道。本文讨论了这些通道在PD病因学中作用的证据,以及相关病理机制的最新观点,以及它们作为PD神经保护药物开发的生物学靶点的潜力。意义声明:帕金森病(PD)是第二常见的神经退行性疾病,以中脑多巴胺能神经元进行性变性为特征。它是一种多因素疾病,涉及多种危险因素和复杂的病理生物学机制。越来越多的证据表明,离子通道通过调节神经元兴奋性和免疫细胞功能,在PD的发病和进展中发挥重要作用。因此,它们已成为PD的“热门”生物学靶点,多项针对PD治疗的候选药物的临床试验证明了这一点。
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引用次数: 8
Turn On, Tune In, Turnover! Target Biology Impacts In Vivo Potency, Efficacy, and Clearance. 打开,调谐,周转!目标生物学影响体内效力、功效和清除。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-05-01 DOI: 10.1124/pharmrev.121.000524
Johan Gabrielsson, Stephan Hjorth

Even though significant efforts have been spent in recent years to understand and define the determinants of in vivo potency and clearance, important pieces of information are still lacking. By introducing target turnover into the reasoning, we open up to further the understanding of central factors important to the optimization of translational dose-concentration-response predictions. We describe (i) new (open model) expressions of the in vivo potency and efficacy parameters, which embody target turnover, binding, and complex kinetics, also capturing full, partial, and inverse agonism and antagonism; (ii) a detailed examination of open models to show what potency and efficacy parameters have in common and how they differ; and (iii) a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease state, hormonal and nutritional state, and day-night cycle. The new open model expression, which integrates system and drug properties, shows the following. Fractional turnover rates rather than the absolute target or ligand-target complex expression determine necessary drug exposure via in vivo potency. Absolute ligand-target expression determines the need of a drug, based on the transduction ρ and in vivo efficacy parameters. The free enzyme concentration determines clearance and maximum metabolic rate. The fractional turnover rate determines time to equilibrium between substrate, free enzyme, and complex.The properties of substrate, target, and the complex demonstrate nonsaturable metabolic behavior at equilibrium. Nonlinear processes, previously referred to as capacity- and time-dependent kinetics, may occasionally have been disequilibria. Finally, the open model may pinpoint why some subjects differ in their demand of drug. SIGNIFICANCE STATEMENT: Understanding the target turnover is a central tenet in many translational dose-concentration-response predictions. New open model expressions of in vivo potency, efficacy parameter, and clearance are derived and anchored onto a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease, hormonal and nutritional state, day-night cycle, and more. Target turnover concepts will therefore significantly impact fundamental aspects of pharmacodynamics and pharmacokinetics, thereby also the basics of drug discovery, development, and optimization of clinical dosing.

尽管近年来已经付出了巨大的努力来理解和定义体内效力和清除的决定因素,但仍然缺乏重要的信息。通过将靶标转换引入推理,我们进一步打开了对优化平移剂量-浓度-反应预测的重要中心因素的理解。我们描述了(i)新的(开放模型)体内效力和功效参数的表达,这些参数体现了靶标转换、结合和复杂动力学,也捕获了完全、部分和反向的激动作用和拮抗作用;(ii)详细研究开放模型,以显示效力和功效参数的共同点和不同之处;(iii)综合文献综述显示靶细胞周转率随年龄、物种、组织/次区域、治疗、疾病状态、激素和营养状况以及昼夜周期而变化。新的开放模型表达式综合了系统和药物的性质,如下图所示。部分周转率而不是绝对靶标或配体-靶标复合物的表达,通过体内效价决定必要的药物暴露。配体-靶标的绝对表达决定了药物的需要,基于转导ρ和体内疗效参数。游离酶浓度决定清除率和最大代谢率。分数周转率决定了底物、游离酶和复合物之间达到平衡所需的时间。底物、靶物和配合物的性质在平衡状态下表现出不饱和代谢行为。非线性过程,以前被称为依赖于能力和时间的动力学,可能偶尔是不平衡的。最后,开放模型可以精确地解释为什么一些受试者对药物的需求不同。意义声明:了解靶标周转率是许多转译剂量-浓度-反应预测的中心原则。在全面的文献综述的基础上,导出了新的体内效价、疗效参数和清除率的开放模型表达式,表明靶周转率随年龄、物种、组织/次区域、治疗、疾病、激素和营养状态、昼夜周期等而变化。因此,靶标转换概念将显著影响药效学和药代动力学的基本方面,从而也是药物发现、开发和临床剂量优化的基础。
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引用次数: 2
Understanding the Neural Mechanisms of General Anesthesia from Interaction with Sleep-Wake State: A Decade of Discovery. 从睡眠-觉醒状态的相互作用来理解全身麻醉的神经机制:十年的发现。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-05-01 DOI: 10.1124/pharmrev.122.000717
Wei-Wei Bao, Shan Jiang, Wei-Min Qu, Wen-Xian Li, Chang-Hong Miao, Zhi-Li Huang

The development of cutting-edge techniques to study specific brain regions and neural circuits that regulate sleep-wake brain states and general anesthesia (GA), has increased our understanding of these states that exhibit similar neurophysiologic traits. This review summarizes current knowledge focusing on cell subtypes and neural circuits that control wakefulness, rapid eye movement (REM) sleep, non-REM sleep, and GA. We also review novel insights into their interactions and raise unresolved questions and challenges in this field. Comparisons of the overlapping neural substrates of sleep-wake and GA regulation will help us to understand sleep-wake transitions and how anesthetics cause reversible loss of consciousness. SIGNIFICANCE STATEMENT: General anesthesia (GA), sharing numerous neurophysiologic traits with the process of natural sleep, is administered to millions of surgical patients annually. In the past decade, studies exploring the neural mechanisms underlying sleep-wake and GA have advanced our understanding of their interactions and how anesthetics cause reversible loss of consciousness. Pharmacotherapies targeting the neural substrates associated with sleep-wake and GA regulations have significance for clinical practice in GA and sleep medicine.

研究调节睡眠-觉醒大脑状态和全身麻醉(GA)的特定大脑区域和神经回路的尖端技术的发展,增加了我们对这些表现出类似神经生理特征的状态的理解。本文综述了目前对控制觉醒、快速眼动(REM)睡眠、非快速眼动睡眠和GA的细胞亚型和神经回路的研究。我们还回顾了它们相互作用的新见解,并提出了该领域未解决的问题和挑战。比较睡眠-觉醒和GA调节的重叠神经基质将有助于我们理解睡眠-觉醒转换以及麻醉剂如何导致可逆的意识丧失。意义声明:全身麻醉(GA)与自然睡眠过程具有许多相同的神经生理特征,每年有数百万外科患者接受全身麻醉。在过去的十年中,探索睡眠-觉醒和GA背后的神经机制的研究提高了我们对它们之间相互作用的理解,以及麻醉剂如何导致可逆性意识丧失。针对与睡眠觉醒和GA调节相关的神经基质进行药物治疗对GA和睡眠医学的临床实践具有重要意义。
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引用次数: 7
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Pharmacological Reviews
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