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High-Throughput Screening to Advance In Vitro Toxicology: Accomplishments, Challenges, and Future Directions. 推进体外毒理学的高通量筛选:成就、挑战和未来方向》。
IF 11.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-07-28 DOI: 10.1146/annurev-pharmtox-112122-104310
Caitlin Lynch, Srilatha Sakamuru, Masato Ooka, Ruili Huang, Carleen Klumpp-Thomas, Paul Shinn, David Gerhold, Anna Rossoshek, Sam Michael, Warren Casey, Michael F Santillo, Suzanne Fitzpatrick, Russell S Thomas, Anton Simeonov, Menghang Xia

Traditionally, chemical toxicity is determined by in vivo animal studies, which are low throughput, expensive, and sometimes fail to predict compound toxicity in humans. Due to the increasing number of chemicals in use and the high rate of drug candidate failure due to toxicity, it is imperative to develop in vitro, high-throughput screening methods to determine toxicity. The Tox21 program, a unique research consortium of federal public health agencies, was established to address and identify toxicity concerns in a high-throughput, concentration-responsive manner using a battery of in vitro assays. In this article, we review the advancements in high-throughput robotic screening methodology and informatics processes to enable the generation of toxicological data, and their impact on the field; further, we discuss the future of assessing environmental toxicity utilizing efficient and scalable methods that better represent the corresponding biological and toxicodynamic processes in humans.

传统上,化学物质的毒性是通过体内动物实验来确定的,这种实验通量低、成本高,有时还无法预测化合物对人体的毒性。由于正在使用的化学品数量不断增加,而候选药物因毒性而失败的比例很高,因此开发体外高通量筛选方法来确定毒性势在必行。Tox21 计划是一个由联邦公共卫生机构组成的独特研究联盟,其成立的目的是利用一系列体外检测方法,以高通量、浓度响应的方式解决和确定毒性问题。在这篇文章中,我们回顾了高通量机器人筛选方法和信息学流程在生成毒理学数据方面取得的进步及其对该领域的影响;此外,我们还讨论了利用高效、可扩展的方法评估环境毒性的未来,这些方法能更好地代表人类相应的生物和毒效学过程。
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引用次数: 0
Addressing Ancestry and Sex Bias in Pharmacogenomics. 解决药物基因组学中的血统和性别偏见。
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-07-14 DOI: 10.1146/annurev-pharmtox-030823-111731
Manuel Corpas, Moneeza K Siddiqui, Opeyemi Soremekun, Rohini Mathur, Dipender Gill, Segun Fatumo

The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic variants and drug efficacy or toxicity, we are able to optimize pharmacological therapy according to an individual's genotype. Pharmacogenomics research has historically suffered from bias and underrepresentation of people from certain ancestry groups and of the female sex. These biases can arise from factors such as drugs and indications studied, selection of study participants, and methods used to collect and analyze data. To examine the representation of biogeographical populations in pharmacogenomic data sets, we describe individuals involved in gene-drug response studies from PharmGKB, a leading repository of drug-gene annotations, and showcaseCYP2D6, a gene that metabolizes approximately 25% of all prescribed drugs. We also show how the historical underrepresentation of females in clinical trials has led to significantly more adverse drug reactions in females than in males.

个人基因构成与其对药物反应的关联被称为药物基因组学。通过了解基因变异与药物疗效或毒性之间的关系,我们能够根据个人的基因型优化药物治疗。药物基因组学研究历来存在偏见,某些血统群体和女性的代表性不足。这些偏见可能源于所研究的药物和适应症、研究参与者的选择以及收集和分析数据的方法等因素。为了考察生物地理人群在药物基因组学数据集中的代表性,我们描述了参与药物基因组学研究的个体,这些个体来自药物基因注释的主要资源库 PharmGKB,并展示了代谢约 25% 处方药的基因 CYP2D6。我们还展示了历史上女性在临床试验中代表性不足是如何导致女性的药物不良反应明显多于男性的。
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引用次数: 0
Targeting Efferocytosis in Inflammaging. 在炎症过程中以吞噬细胞为目标
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-08-16 DOI: 10.1146/annurev-pharmtox-032723-110507
Ivan K H Poon, Kodi S Ravichandran

Rapid removal of apoptotic cells by phagocytes, a process known as efferocytosis, is key for the maintenance of tissue homeostasis, the resolution of inflammation, and tissue repair. However, impaired efferocytosis can result in the accumulation of apoptotic cells, subsequently triggering sterile inflammation through the release of endogenous factors such as DNA and nuclear proteins from membrane permeabilized dying cells. Here, we review the molecular basis of the three key phases of efferocytosis, that is, the detection, uptake, and degradation of apoptotic materials by phagocytes. We also discuss how defects in efferocytosis due to the alteration of phagocytes and dying cells can contribute to the low-grade chronic inflammation that occurs during aging, described as inflammaging. Lastly, we explore opportunities in targeting and harnessing the efferocytic machinery to limit aging-associated inflammatory diseases.

吞噬细胞快速清除凋亡细胞的过程被称为 "排出细胞",是维持组织平衡、消除炎症和组织修复的关键。然而,渗出功能受损会导致凋亡细胞堆积,随后通过从膜通透的凋亡细胞中释放 DNA 和核蛋白等内源性因子引发无菌性炎症。在此,我们回顾了流出吞噬三个关键阶段的分子基础,即吞噬细胞对凋亡物质的检测、摄取和降解。我们还讨论了由于吞噬细胞和凋亡细胞的改变而导致的渗出缺陷如何导致衰老过程中出现的低度慢性炎症,即炎症衰老。最后,我们探讨了针对和利用流出细胞机制限制衰老相关炎症疾病的机会。
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引用次数: 0
Gene-Environment Interactions: My Unique Journey. 基因与环境的相互作用:我独特的旅程。
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-10-03 DOI: 10.1146/annurev-pharmtox-022323-082311
Daniel W Nebert

I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored/coauthored more than 600 publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: (a) discovery and characterization of the AHR/CYP1 axis, (b) pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, (c) standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and (d) discovery and characterization of the SLC39A8 gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography.

我很荣幸能受邀撰写这本科学自传。作为一名医生、儿科医生、分子生物学家和遗传学家,我在临床医学、生物化学、生物物理学、药理学、药物代谢、毒理学、分子生物学、癌症、标准化基因命名法、发育毒理学和畸形发生、小鼠遗传学、人类遗传学和进化基因组学等领域撰写/合著了600多篇出版物。回顾过去,我认为我的职业生涯可以分为四个不同的研究领域,我在这篇文章中主要按时间顺序总结了这些领域:(a)AHR/CYP1轴的发现和表征,(b)药物基因组学和对药物和其他环境毒物反应的遗传预测,(c)基于进化差异的标准化药物代谢基因命名,和(d)编码ZIP8金属阳离子内流转运蛋白的SLC39A8基因的发现和表征。总的来说,这四个主题都包含了基因与环境的相互作用,因此我的自传命名为。《药理学与毒理学年度评论》第64卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
G Protein-Coupled Receptor Signaling: New Insights Define Cellular Nanodomains. G 蛋白偶联受体信号:定义细胞纳米域的新见解。
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-09-08 DOI: 10.1146/annurev-pharmtox-040623-115054
Martin J Lohse, Andreas Bock, Manuela Zaccolo

G protein-coupled receptors are the largest and pharmacologically most important receptor family and are involved in the regulation of most cell functions. Most of them reside exclusively at the cell surface, from where they signal via heterotrimeric G proteins to control the production of second messengers such as cAMP and IP3 as well as the activity of several ion channels. However, they may also internalize upon agonist stimulation or constitutively reside in various intracellular locations. Recent evidence indicates that their function differs depending on their precise cellular localization. This is because the signals they produce, notably cAMP and Ca2+, are mostly bound to cell proteins that significantly reduce their mobility, allowing the generation of steep concentration gradients. As a result, signals generated by the receptors remain confined to nanometer-sized domains. We propose that such nanometer-sized domains represent the basic signaling units in a cell and a new type of target for drug development.

G 蛋白偶联受体是最大的受体家族,也是药理学上最重要的受体家族,参与调节大多数细胞功能。它们中的大多数只存在于细胞表面,通过异三聚 G 蛋白发出信号,控制 cAMP 和 IP3 等第二信使的产生以及几种离子通道的活性。不过,它们也可能在激动剂刺激下内化或持续存在于细胞内的不同位置。最近的证据表明,它们的功能因其精确的细胞定位而有所不同。这是因为它们产生的信号,特别是 cAMP 和 Ca2+,大多与细胞蛋白结合,从而大大降低了它们的流动性,从而产生陡峭的浓度梯度。因此,受体产生的信号被限制在纳米级的区域内。我们认为,这种纳米级结构域是细胞中的基本信号传递单元,也是药物开发的新型靶点。
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引用次数: 0
Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders. 针对多巴胺系统上的毒蕈碱受体的作用:治疗神经精神疾病的新策略。
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-08-09 DOI: 10.1146/annurev-pharmtox-051921-023858
Eric J Nunes, Nii A Addy, P Jeffrey Conn, Daniel J Foster

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.

胆碱能对多巴胺(DA)信号传导的调节对精神分裂症、药物使用障碍和情绪相关障碍等多种疾病具有重要影响。中脑 DA 神经元的活动和末端区域的 DA 释放模式受到纹状体和后脑中胆碱能神经元的严格调控。这些胆碱能神经元可通过激活包括毒蕈碱乙酰胆碱受体(mAChR)亚型在内的多种受体来调节 DA 电路。本综述特别关注 M2、M4 和 M5 mAChR 亚型在调节 DA 神经元活动和 DA 释放中的复杂作用,以及靶向这些 mAChR 亚型的潜在临床意义。
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引用次数: 0
Direct K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance. 直接使用 K-Ras 抑制剂治疗癌症:治疗癌症的直接 K-Ras 抑制剂:进展、新见解和治疗耐药性的方法》(Progress, New Insights, and Approaches to Treat Resistance.
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-07-31 DOI: 10.1146/annurev-pharmtox-022823-113946
Ruth Nussinov, Hyunbum Jang

Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-RasG12C. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-RasG12C with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in cis, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.

在此,我们讨论 K-Ras 抑制方法和耐药性情况。针对 K-RasG12C 的共价药物是一个突破。随后的创新利用了相同基因的药物组合,以及将 K-RasG12C 与上游调节剂或下游激酶的辅助药物共同靶向。然而,原发性、适应性和获得性耐药性不可避免地会出现。预先存在的突变负荷可以解释,即使是无法观察到影响的极其罕见的突变也能促进耐药性、不敏感细胞克隆的生长和增殖。统计数据证实了大多数与耐药性相关的突变都是顺式突变的预期,这说明了同等位基因合作效应的可能性很高。除了靶向 Ras 抑制剂和药物组合外,针对 Ras 突变体的双功能分子和创新的三复合抑制剂也在开发之中。由于对已有突变和正在发生的突变的身份和潜在贡献尚不清楚,因此选择药物组合是一项艰巨的任务。我们的综述概述了各种考虑因素,并提供了药理学和耐药性方面的新见解。
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引用次数: 0
Novel Immunopharmacological Drugs for the Treatment of Allergic Diseases. 治疗过敏性疾病的新型免疫药理学药物。
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-09-18 DOI: 10.1146/annurev-pharmtox-051623-091038
Ekaterini Tiligada, Daria Gafarov, Maria Zaimi, Joana Vitte, Francesca Levi-Schaffer

The exponential rise in the prevalence of allergic diseases since the mid-twentieth century has led to a genuine public health emergency and has also fostered major progress in research on the underlying mechanisms and potential treatments. The management of allergic diseases benefits from the biological revolution, with an array of novel immunomodulatory therapeutic and investigational tools targeting players of allergic inflammation at distinct pathophysiological steps. Prominent examples include therapeutic monoclonal antibodies against cytokines, alarmins, and their receptors, as well as small-molecule modifiers of signal transduction mainly mediated by Janus kinases and Bruton's tyrosine kinases. However, the first-line therapeutic options have yet to switch from symptomatic to disease-modifying interventions. Here we present an overview of available drugs in the context of our current understanding of allergy pathophysiology, identify potential therapeutic targets, and conclude by providing a selection of candidate immunopharmacological molecules under investigation for potential future use in allergic diseases.

自二十世纪中叶以来,过敏性疾病的发病率呈指数级增长,导致了真正的公共卫生紧急状况,同时也促进了对其潜在机制和治疗方法的研究取得重大进展。过敏性疾病的治疗得益于生物学革命,一系列新型免疫调节治疗和研究工具针对不同病理生理阶段的过敏性炎症。突出的例子包括针对细胞因子、过敏素及其受体的治疗性单克隆抗体,以及主要由 Janus 激酶和布鲁顿酪氨酸激酶介导的信号转导小分子调节剂。然而,一线治疗方案尚未从对症治疗转变为改变疾病的干预措施。在此,我们将结合目前对过敏病理生理学的了解,概述现有的药物,确定潜在的治疗靶点,最后提供一些正在研究中的候选免疫药理分子,供将来在过敏性疾病中使用。
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引用次数: 0
Health Digital Twins in Life Science and Health Care Innovation. 生命科学和医疗保健创新中的健康数字双胞胎。
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-08-10 DOI: 10.1146/annurev-pharmtox-022123-022046
Kaushik P Venkatesh, Gabriel Brito, Maged N Kamel Boulos

Health digital twins (HDTs) are virtual representations of real individuals that can be used to simulate human physiology, disease, and drug effects. HDTs can be used to improve drug discovery and development by providing a data-driven approach to inform target selection, drug delivery, and design of clinical trials. HDTs also offer new applications into precision therapies and clinical decision making. The deployment of HDTs at scale could bring a precision approach to public health monitoring and intervention. Next steps include challenges such as addressing socioeconomic barriers and ensuring the representativeness of the technology based on the training and validation data sets. Governance and regulation of HDT technology are still in the early stages.

健康数字双胞胎(HDTs)是真实个体的虚拟代表,可用于模拟人体生理、疾病和药物作用。HDT 可用于改进药物的发现和开发,提供一种数据驱动的方法,为靶点选择、给药和临床试验设计提供信息。HDT 还为精准治疗和临床决策提供了新的应用。大规模部署 HDT 可以为公共卫生监测和干预提供一种精准方法。接下来的步骤包括应对社会经济障碍和确保基于训练和验证数据集的技术代表性等挑战。人类发展数据技术的治理和监管仍处于早期阶段。
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引用次数: 0
Translational In Vivo Assays in Behavioral Biology. 行为生物学的体内转化试验。
IF 12.5 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-23 Epub Date: 2023-09-14 DOI: 10.1146/annurev-pharmtox-051921-093711
Sarah L Withey, Diego A Pizzagalli, Jack Bergman

The failure of preclinical research to advance successful candidate medications in psychiatry has created a paradigmatic crisis in psychiatry. The Research Domain Criteria (RDoC) initiative was designed to remedy this situation with a neuroscience-based approach that employs multimodal and cross-species in vivo methodology to increase the probability of translational findings and, consequently, drug discovery. The present review underscores the feasibility of this methodological approach by briefly reviewing, first, the use of multidimensional and cross-species methodologies in traditional behavioral pharmacology and, subsequently, the utility of this approach in contemporary neuroimaging and electrophysiology research-with a focus on the value of functionally homologous studies in nonhuman and human subjects. The final section provides a brief review of the RDoC, with a focus on the potential strengths and weaknesses of its domain-based underpinnings. Optimistically, this mechanistic and multidimensional approach in neuropsychiatric research will lead to novel therapeutics for the management of neuropsychiatric disorders.

临床前研究未能成功推动精神病学候选药物的开发,这给精神病学带来了典型危机。研究领域标准(RDoC)计划旨在通过一种以神经科学为基础的方法来纠正这种状况,该方法采用多模式和跨物种活体方法来提高转化研究结果的概率,从而提高药物发现的概率。本综述强调了这种方法的可行性,首先简要回顾了多维和跨物种方法在传统行为药理学中的应用,随后介绍了这种方法在当代神经影像学和电生理学研究中的实用性--重点是在非人类和人类受试者中进行功能同源研究的价值。最后一节简要回顾了 RDoC,重点介绍了其基于领域的基础的潜在优势和不足。乐观地说,神经精神疾病研究中的这种机理和多维方法将为治疗神经精神疾病带来新的疗法。
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引用次数: 0
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Annual review of pharmacology and toxicology
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