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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
G Protein-Coupled Receptor Pharmacology-Insights from Mass Spectrometry. G蛋白偶联受体药理学-从质谱分析的见解。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-05-01 DOI: 10.1124/pharmrev.120.000237
Hsin-Yung Yen, Ali Jazayeri, Carol V Robinson

G protein-coupled receptors (GPCRs) are key drug targets due to their involvement in many physiological processes. The complexity of receptor pharmacology, however, is influenced by multiple interactions with various types of ligands and protein transducers representing significant challenges for drug discovery. The ability of mass spectrometry (MS) to observe both the binding of ligand molecules, such as lipids, ions, or drugs, and their impact on interaction with transducers provides an exciting opportunity to probe many aspects that are difficult to track directly in cell-based systems. From the early days, when hydrogen deuterium exchange (HDX) experiments were used to probe the different conformations of GPCRs, through to the most recent insights in which the intact receptor-G protein/arrestin complexes associated with small molecules can be preserved by MS, this review highlights the potential of MS techniques for in-depth investigations of GPCR biology. We describe the utility of MS, including HDX-MS and native-MS, in investigating GPCR pharmacology. Specifically, we include ligand-drug interactions and Gi/s protein coupling and illustrate how these techniques can lead to the discovery of endogenous allosteric ligands and thereby offer a new perspective for drug discovery of GPCRs. SIGNIFICANCE STATEMENT: GPCRs are the largest and most diverse group of membrane receptors in eukaryotes. To carry out signaling, GPCRs adopt a range of conformational states to elicit G-protein coupling or arrestin binding. Because of their conformational dynamics, GPCRs remain challenging to study, particular in the gas phase after release from their protective detergent micelles. Over the past decade great advances have been made, however, enabling direct measure of coupling and signaling across native membranes. In this review we highlight these advances and consider the future of this exciting and challenging area.

G蛋白偶联受体(gpcr)由于参与许多生理过程而成为关键的药物靶点。然而,受体药理学的复杂性受到与各种类型的配体和蛋白质转导的多重相互作用的影响,这对药物发现构成了重大挑战。质谱(MS)能够观察配体分子(如脂质、离子或药物)的结合,以及它们对换能器相互作用的影响,这为探测许多难以在细胞系统中直接跟踪的方面提供了令人兴奋的机会。从早期的氢氘交换(HDX)实验用于探测GPCR的不同构象,到最近的发现,完整的受体- g蛋白/与小分子相关的抑制蛋白复合物可以通过质谱保存,本综述强调了质谱技术在深入研究GPCR生物学方面的潜力。我们描述了质谱的效用,包括hdx -质谱和天然质谱,在研究GPCR药理学。具体来说,我们包括配体-药物相互作用和Gi/s蛋白偶联,并说明这些技术如何导致内源性变构配体的发现,从而为gpcr的药物发现提供了新的视角。意义声明:gpcr是真核生物中最大和最多样化的膜受体。为了进行信号传导,gpcr采用一系列构象状态来引发g蛋白偶联或抑制蛋白结合。由于其构象动力学,gpcr的研究仍然具有挑战性,特别是在从其保护性洗涤剂胶束释放后的气相中。然而,在过去的十年中,已经取得了巨大的进步,能够直接测量跨天然膜的偶联和信号。在这篇综述中,我们强调了这些进展,并考虑了这一令人兴奋和具有挑战性的领域的未来。
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引用次数: 3
Sulfotransferase 2B1b, Sterol Sulfonation, and Disease. 磺基转移酶 2B1b、甾醇磺化与疾病
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-05-01 Epub Date: 2022-12-22 DOI: 10.1124/pharmrev.122.000679
Ian Cook, Thomas S Leyh

The primary function of human sulfotransferase 2B1b (SULT2B1b) is to sulfonate cholesterol and closely related sterols. SULT2B1b sterols perform a number of essential cellular functions. Many are signaling molecules whose activities are redefined by sulfonation-allosteric properties are switched "on" or "off," agonists are transformed into antagonists, and vice versa. Sterol sulfonation is tightly coupled to cholesterol homeostasis, and sulfonation imbalances are causally linked to cholesterol-related diseases including certain cancers, Alzheimer disease, and recessive X-linked ichthyosis-an orphan skin disease. Numerous studies link SULT2B1b activity to disease-relevant molecular processes. Here, these multifaceted processes are integrated into metabolic maps that highlight their interdependence and how their actions are regulated and coordinated by SULT2B1b oxysterol sulfonation. The maps help explain why SULT2B1b inhibition arrests the growth of certain cancers and make the novel prediction that SULT2B1b inhibition will suppress production of amyloid β (Aβ) plaques and tau fibrils while simultaneously stimulating Aβ plaque phagocytosis. SULT2B1b harbors a sterol-selective allosteric site whose structure is discussed as a template for creating inhibitors to regulate SULT2B1b and its associated biology. SIGNIFICANCE STATEMENT: Human sulfotransferase 2B1b (SULT2B1b) produces sterol-sulfate signaling molecules that maintain the homeostasis of otherwise pro-disease processes in cancer, Alzheimer disease, and X-linked ichthyosis-an orphan skin disease. The functions of sterol sulfates in each disease are considered and codified into metabolic maps that explain the interdependencies of the sterol-regulated networks and their coordinate regulation by SULT2B1b. The structure of the SULT2B1b sterol-sensing allosteric site is discussed as a means of controlling sterol sulfate biology.

人类磺基转移酶 2B1b(SULT2B1b)的主要功能是磺化胆固醇和密切相关的固醇。SULT2B1b 固醇具有多种重要的细胞功能。许多固醇是信号分子,其活性通过磺化作用被重新定义--固醇特性被 "打开 "或 "关闭",激动剂被转化为拮抗剂,反之亦然。甾醇磺化与胆固醇平衡密切相关,磺化失衡与胆固醇相关疾病有因果关系,包括某些癌症、阿尔茨海默病和隐性 X 连锁鱼鳞病--一种孤儿皮肤病。许多研究将 SULT2B1b 的活性与疾病相关的分子过程联系起来。在这里,这些多方面的过程被整合到代谢图谱中,突出了它们之间的相互依存关系,以及它们的作用如何受到 SULT2B1b 氧甾醇磺化作用的调节和协调。这些图谱有助于解释为什么抑制 SULT2B1b 能阻止某些癌症的生长,并做出了新的预测:抑制 SULT2B1b 将抑制淀粉样β(Aβ)斑块和 tau 纤维的生成,同时刺激 Aβ 斑块的吞噬作用。SULT2B1b 含有一个固醇选择性异构位点,该位点的结构可作为创建抑制剂以调节 SULT2B1b 及其相关生物学的模板进行讨论。意义声明:人类磺基转移酶 2B1b(SULT2B1b)产生固醇硫酸盐信号分子,维持癌症、阿尔茨海默病和 X 连锁鱼鳞病(一种孤儿皮肤病)等疾病过程的平衡。研究考虑了固醇硫酸盐在每种疾病中的功能,并将其编入代谢图谱,解释了固醇调控网络的相互依存关系以及 SULT2B1b 对它们的协调调控。文章讨论了 SULT2B1b 固醇感应异构位点的结构,将其作为控制固醇硫酸盐生物学的一种手段。
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引用次数: 0
Time to Change: A Systems Pharmacology Approach to Disentangle Mechanisms of Drug-Induced Mitochondrial Toxicity. 改变的时间:一个系统药理学方法来解开药物诱导的线粒体毒性机制。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-05-01 DOI: 10.1124/pharmrev.122.000568
Charlotte A Hoogstraten, Jonathan J Lyon, Jan A M Smeitink, Frans G M Russel, Tom J J Schirris

An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, which is associated with almost half of all Food and Drug Administration black box warnings, a variety of drug withdrawals, and attrition of drug candidates. This can mainly be attributed to a historic lack of sensitive and specific assays to identify the mechanisms underlying mitochondrial toxicity during drug development. In the last decade, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based systems pharmacological approaches. Here, we propose the implementation of a tiered systems pharmacology approach to detect adverse mitochondrial drug effects during preclinical drug development, which is based on a toolset developed to study inherited mitochondrial disease. This includes phenotypic characterization, profiling of key metabolic alterations, mechanistic studies, and functional in vitro and in vivo studies. Combined with binding pocket similarity comparisons and bottom-up as well as top-down metabolic network modeling, this tiered approach enables identification of mechanisms underlying drug-induced mitochondrial dysfunction. After validation of these off-target mechanisms, drug candidates can be adjusted to minimize mitochondrial activity. Implementing such a tiered systems pharmacology approach could lead to a more efficient drug development trajectory due to lower drug attrition rates and ultimately contribute to the development of safer drugs. SIGNIFICANCE STATEMENT: Many commonly prescribed drugs adversely affect mitochondrial function, which can be detected using phenotypic assays. However, these methods provide only limited insight into the underlying mechanisms. In recent years, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based system pharmacological approaches. Their implementation in preclinical drug development could reduce the number of drug failures, contributing to safer drug design.

众所周知,越来越多的常用处方药会干扰线粒体功能,这与美国食品和药物管理局(Food and Drug Administration)几乎一半的黑框警告、各种药物停药和候选药物的损耗有关。这主要是由于历史上缺乏敏感和特异性的检测方法来确定药物开发过程中线粒体毒性的机制。在过去的十年中,通过基于网络和基于结构的系统药理学方法,对药物诱导的线粒体功能障碍有了更好的了解。在这里,我们建议实施分层系统药理学方法,在临床前药物开发过程中检测线粒体不良药物效应,该方法基于研究遗传性线粒体疾病的工具集。这包括表型特征、关键代谢改变的分析、机制研究以及体外和体内功能研究。结合结合口袋相似性比较以及自下而上和自上而下的代谢网络建模,这种分层方法能够识别药物诱导的线粒体功能障碍的机制。在验证这些脱靶机制后,可以调整候选药物以最小化线粒体活性。由于药物损耗率较低,实施这种分层系统药理学方法可能导致更有效的药物开发轨迹,并最终有助于开发更安全的药物。意义声明:许多常用处方药对线粒体功能有不良影响,这可以通过表型分析来检测。然而,这些方法只能提供有限的对底层机制的了解。近年来,通过基于网络和基于结构的系统药理学方法,对药物诱导的线粒体功能障碍有了更好的了解。它们在临床前药物开发中的应用可以减少药物失败的数量,有助于更安全的药物设计。
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引用次数: 2
Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interaction. NLRP3炎性小体的药理抑制:结构、分子活化和抑制剂-NLRP3相互作用。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-05-01 DOI: 10.1124/pharmrev.122.000629
Qiang Ma

The nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex that combines sensing, regulation, and effector functions to regulate inflammation in health and disease. NLRP3 is activated by a diverse range of inflammation-instigating signals known as pathogen associated molecular patterns and danger associated molecular patterns. Upon activation, NLRP3 oligomerizes and recruits partner proteins to form a supramolecular platform to process the maturation and release of interleukin (IL)-1β, IL-18, and gasdermin D, major mediators of inflammation and inflammatory cell death termed pyroptosis. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide range of disease conditions, including chronic inflammatory disease that are associated with lifestyle and dietary changes, aging, and environmental exposures, and have become the leading cause of death worldwide. Pharmacological targeting of NLRP3 and signaling demonstrated promising efficacy in ameliorating a list of disease conditions in animal models. These findings underscore the potential and importance of NLRP3 as a druggable target for treating a range of diseases. In this review, recent progress in understanding the structure and mechanism of action of the NLRP3 inflammasome is discussed with focus on pharmacological inhibition of NLRP3 by small molecule inhibitors. New structural and mechanistic insights into NLRP3 activation and inhibitor-NLRP3 interactions would aid in the rational design and pharmacological evaluation of NLRP3 inhibitors for treatment of human disease. SIGNIFICANCE STATEMENT: The NLRP3 inflammasome plays central role in innate immune sensing and control of inflammation. Pharmacological inhibition of NLRP3 demonstrated promising efficacy in a range of diseases in animal models. Recent elucidation of the structure and inhibitor binding of NLRP3 generated new insights into its mode of action and inhibitor-NLRP3 interaction at molecular levels, providing new framework for developing small chemical inhibitors of NLRP3 with improved efficacy and specificity against chronic disease that has become major health concerns worldwide.

核苷酸结合、寡聚化结构域样受体家族pyrin结构域3 (NLRP3)炎性小体是一种多蛋白复合物,结合传感、调节和效应功能,调节健康和疾病中的炎症。NLRP3被多种炎症诱导信号激活,这些信号被称为病原体相关分子模式和危险相关分子模式。激活后,NLRP3寡聚并招募伴侣蛋白,形成一个超分子平台,处理白细胞介素(IL)-1β、IL-18和gasdermin D的成熟和释放,这些物质是炎症和炎症细胞死亡(称为焦亡)的主要介质。NLRP3炎性小体与多种疾病的发病机制有关,包括与生活方式和饮食改变、衰老和环境暴露相关的慢性炎症性疾病,并已成为全球死亡的主要原因。在动物模型中,NLRP3的药理靶向和信号传导在改善一系列疾病状况方面显示出有希望的功效。这些发现强调了NLRP3作为治疗一系列疾病的可药物靶点的潜力和重要性。本文综述了近年来对NLRP3炎性小体结构和作用机制的研究进展,重点介绍了小分子抑制剂对NLRP3的药理抑制作用。关于NLRP3激活和抑制剂-NLRP3相互作用的结构和机制的新见解将有助于NLRP3抑制剂的合理设计和药理学评估,以治疗人类疾病。意义声明:NLRP3炎症小体在先天免疫感知和炎症控制中起核心作用。在动物模型中,NLRP3的药理抑制在一系列疾病中显示出有希望的功效。最近对NLRP3结构和抑制剂结合的阐明,在分子水平上对其作用模式和抑制剂-NLRP3相互作用有了新的认识,为开发具有提高慢性疾病疗效和特异性的NLRP3小化学抑制剂提供了新的框架。慢性疾病已成为世界范围内的主要健康问题。
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引用次数: 11
Sex/Gender Differences in the Time-Course for the Development of Substance Use Disorder: A Focus on the Telescoping Effect. 物质使用障碍发展时间过程中的性别差异:关注远程应对效应。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-03-01 Epub Date: 2022-12-12 DOI: 10.1124/pharmrev.121.000361
Eleanor Blair Towers, Ivy L Williams, Emaan I Qillawala, Emilie F Rissman, Wendy J Lynch

Sex/gender effects have been demonstrated for multiple aspects of addiction, with one of the most commonly cited examples being the "telescoping effect" where women meet criteria and/or seek treatment of substance use disorder (SUD) after fewer years of drug use as compared with men. This phenomenon has been reported for multiple drug classes including opioids, psychostimulants, alcohol, and cannabis, as well as nonpharmacological addictions, such as gambling. However, there are some inconsistent reports that show either no difference between men and women or opposite effects and a faster course to addiction in men than women. Thus, the goals of this review are to evaluate evidence for and against the telescoping effect in women and to determine the conditions/populations for which the telescoping effect is most relevant. We also discuss evidence from preclinical studies, which strongly support the validity of the telescoping effect and show that female animals develop addiction-like features (e.g., compulsive drug use, an enhanced motivation for the drug, and enhanced drug-craving/vulnerability to relapse) more readily than male animals. We also discuss biologic factors that may contribute to the telescoping effect, such as ovarian hormones, and its neurobiological basis focusing on the mesolimbic dopamine reward pathway and the corticomesolimbic glutamatergic pathway considering the critical roles these pathways play in the rewarding/reinforcing effects of addictive drugs and SUD. We conclude with future research directions, including intervention strategies to prevent the development of SUD in women. SIGNIFICANCE STATEMENT: One of the most widely cited gender/sex differences in substance use disorder (SUD) is the "telescoping effect," which reflects an accelerated course in women versus men for the development and/or seeking treatment for SUD. This review evaluates evidence for and against a telescoping effect drawing upon data from both clinical and preclinical studies. We also discuss the contribution of biological factors and underlying neurobiological mechanisms and highlight potential targets to prevent the development of SUD in women.

性/性别效应已被证明适用于成瘾的多个方面,其中最常被引用的例子之一是“伸缩效应”,即女性在与男性相比吸毒年限更短后达到标准和/或寻求药物使用障碍(SUD)的治疗。据报道,这种现象适用于多种药物类别,包括阿片类药物、精神刺激剂、酒精和大麻,以及赌博等非药物成瘾。然而,有一些不一致的报告显示,男性和女性之间没有差异,或者相反的影响,男性比女性成瘾更快。因此,本综述的目的是评估支持和反对女性伸缩效应的证据,并确定伸缩效应最相关的条件/人群。我们还讨论了临床前研究的证据,这些证据有力地支持了伸缩效应的有效性,并表明雌性动物比雄性动物更容易产生成瘾样特征(例如,强迫性药物使用、对药物的动机增强以及对药物的渴望/易复发性增强)。我们还讨论了可能导致伸缩效应的生物因素,如卵巢激素,及其神经生物学基础,重点是中边缘多巴胺奖励途径和皮质-中边缘谷氨酸能途径,考虑到这些途径在成瘾药物和SUD的奖励/增强作用中发挥的关键作用。我们总结了未来的研究方向,包括预防妇女SUD发展的干预策略。意义陈述:物质使用障碍(SUD)中被广泛引用的性别/性别差异之一是“伸缩效应”,它反映了女性与男性在SUD的发展和/或寻求治疗方面的加速过程。这篇综述根据临床和临床前研究的数据评估了支持和反对伸缩效应的证据。我们还讨论了生物学因素和潜在的神经生物学机制的作用,并强调了预防女性SUD发展的潜在靶点。
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引用次数: 0
Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications. 分子镊子:具有广谱生物应用的超分子宿主。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-03-01 Epub Date: 2022-12-22 DOI: 10.1124/pharmrev.122.000654
Hedieh Shahpasand-Kroner, Ibrar Siddique, Ravinder Malik, Gabriel R Linares, Magdalena I Ivanova, Justin Ichida, Tatjana Weil, Jan Münch, Elsa Sanchez-Garcia, Frank-Gerrit Klärner, Thomas Schrader, Gal Bitan

Lysine-selective molecular tweezers (MTs) are supramolecular host molecules displaying a remarkably broad spectrum of biologic activities. MTs act as inhibitors of the self-assembly and toxicity of amyloidogenic proteins using a unique mechanism. They destroy viral membranes and inhibit infection by enveloped viruses, such as HIV-1 and SARS-CoV-2, by mechanisms unrelated to their action on protein self-assembly. They also disrupt biofilm of Gram-positive bacteria. The efficacy and safety of MTs have been demonstrated in vitro, in cell culture, and in vivo, suggesting that these versatile compounds are attractive therapeutic candidates for various diseases, infections, and injuries. A lead compound called CLR01 has been shown to inhibit the aggregation of various amyloidogenic proteins, facilitate their clearance in vivo, prevent infection by multiple viruses, display potent anti-biofilm activity, and have a high safety margin in animal models. The inhibitory effect of CLR01 against amyloidogenic proteins is highly specific to abnormal self-assembly of amyloidogenic proteins with no disruption of normal mammalian biologic processes at the doses needed for inhibition. Therapeutic effects of CLR01 have been demonstrated in animal models of proteinopathies, lysosomal-storage diseases, and spinal-cord injury. Here we review the activity and mechanisms of action of these intriguing compounds and discuss future research directions. SIGNIFICANCE STATEMENT: Molecular tweezers are supramolecular host molecules with broad biological applications, including inhibition of abnormal protein aggregation, facilitation of lysosomal clearance of toxic aggregates, disruption of viral membranes, and interference of biofilm formation by Gram-positive bacteria. This review discusses the molecular and cellular mechanisms of action of the molecular tweezers, including the discovery of distinct mechanisms acting in vitro and in vivo, and the application of these compounds in multiple preclinical disease models.

赖氨酸选择性分子镊子(MTs)是一种超分子宿主分子,具有非常广泛的生物活性。MTs 以一种独特的机制抑制淀粉样蛋白的自组装和毒性。它们破坏病毒膜,抑制包膜病毒(如 HIV-1 和 SARS-CoV-2)的感染,其机制与其对蛋白质自组装的作用无关。它们还能破坏革兰氏阳性细菌的生物膜。MTs 的有效性和安全性已在体外、细胞培养和体内得到证实,这表明这些多用途化合物是治疗各种疾病、感染和损伤的极具吸引力的候选药物。一种名为 CLR01 的先导化合物已被证明能够抑制各种淀粉样蛋白的聚集,促进其在体内的清除,防止多种病毒的感染,显示出强大的抗生物膜活性,并且在动物模型中具有较高的安全系数。CLR01 对淀粉样蛋白生成蛋白的抑制作用对淀粉样蛋白生成蛋白的异常自组装具有高度特异性,在抑制所需的剂量下不会破坏哺乳动物的正常生物过程。CLR01 的治疗效果已在蛋白病、溶酶体储存疾病和脊髓损伤的动物模型中得到证实。在此,我们回顾了这些有趣化合物的活性和作用机制,并讨论了未来的研究方向。意义声明:分子镊子是一种超分子宿主分子,具有广泛的生物学应用,包括抑制异常蛋白质聚集、促进溶酶体清除有毒聚集体、破坏病毒膜以及干扰革兰氏阳性细菌形成生物膜。这篇综述讨论了分子镊的分子和细胞作用机制,包括发现体外和体内的不同作用机制,以及这些化合物在多种临床前疾病模型中的应用。
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引用次数: 0
Pharmacology of Heparin and Related Drugs: An Update. 肝素及相关药物的药理学进展。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-03-01 DOI: 10.1124/pharmrev.122.000684
John Hogwood, Barbara Mulloy, Rebeca Lever, Elaine Gray, Clive P Page

Heparin has been used extensively as an antithrombotic and anticoagulant for close to 100 years. This anticoagulant activity is attributed mainly to the pentasaccharide sequence, which potentiates the inhibitory action of antithrombin, a major inhibitor of the coagulation cascade. More recently it has been elucidated that heparin exhibits anti-inflammatory effect via interference of the formation of neutrophil extracellular traps and this may also contribute to heparin's antithrombotic activity. This illustrates that heparin interacts with a broad range of biomolecules, exerting both anticoagulant and nonanticoagulant actions. Since our previous review, there has been an increased interest in these nonanticoagulant effects of heparin, with the beneficial role in patients infected with SARS2-coronavirus a highly topical example. This article provides an update on our previous review with more recent developments and observations made for these novel uses of heparin and an overview of the development status of heparin-based drugs. SIGNIFICANCE STATEMENT: This state-of-the-art review covers recent developments in the use of heparin and heparin-like materials as anticoagulant, now including immunothrombosis observations, and as nonanticoagulant including a role in the treatment of SARS-coronavirus and inflammatory conditions.

肝素作为抗血栓和抗凝剂已被广泛使用近100年。这种抗凝活性主要归因于五糖序列,它增强了抗凝血酶的抑制作用,抗凝血酶是凝血级联的主要抑制剂。最近已经阐明,肝素通过干扰中性粒细胞胞外陷阱的形成而表现出抗炎作用,这也可能有助于肝素的抗血栓活性。这说明肝素与广泛的生物分子相互作用,发挥抗凝和非抗凝作用。自我们之前的综述以来,人们对肝素的这些非抗凝作用越来越感兴趣,其中对sars -冠状病毒感染患者的有益作用是一个备受关注的例子。这篇文章更新了我们之前的综述,包括肝素这些新用途的最新发展和观察结果,并概述了肝素类药物的发展现状。意义声明:这篇最新的综述涵盖了肝素和肝素样材料作为抗凝剂的最新进展,现在包括免疫血栓形成观察,以及作为非抗凝剂在治疗sars冠状病毒和炎症条件中的作用。
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引用次数: 5
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Pharmacological Reviews
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