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What Structural Biology Tells Us About the Mode of Action and Detection of Toxicants. 结构生物学告诉我们毒物的作用方式和检测方法。
IF 11.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-06 DOI: 10.1146/annurev-pharmtox-061724-080642
Albane le Maire, William Bourguet

The study of the adverse effects of chemical substances on living organisms is an old and intense field of research. However, toxicological and environmental health sciences have long been dominated by descriptive approaches that enable associations or correlations but relatively few robust causal links and molecular mechanisms. Recent achievements have shown that structural biology approaches can bring this added value to the field. By providing atomic-level information, structural biology is a powerful tool to decipher the mechanisms by which toxicants bind to and alter the normal function of essential cell components, causing adverse effects. Here, using endocrine-disrupting chemicals as illustrative examples, we describe recent advances in the structure-based understanding of their modes of action and how this knowledge can be exploited to develop computational tools aimed at predicting properties of large collections of compounds.

研究化学物质对生物体的不良影响是一个古老而又紧张的研究领域。然而,长期以来,毒理学和环境健康科学一直以描述性方法为主,这些方法能够提供关联或相关性,但相对较少提供可靠的因果联系和分子机制。最近的成就表明,结构生物学方法可以为这一领域带来附加值。通过提供原子级别的信息,结构生物学是一种强大的工具,可用于破译毒物与细胞基本成分结合并改变其正常功能从而造成不良影响的机制。在此,我们将以干扰内分泌的化学物质为例,介绍基于结构了解其作用模式的最新进展,以及如何利用这些知识开发旨在预测大量化合物特性的计算工具。
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引用次数: 0
Trichloroethylene: An Update on an Environmental Contaminant with Multiple Health Effects. 三氯乙烯:一种对健康有多重影响的环境污染物的最新情况。
IF 11.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-02 DOI: 10.1146/annurev-pharmtox-022724-120525
Lawrence H Lash

The halogenated solvent trichloroethylene (TCE) has had many uses in medicine, construction, consumer products, and the military. Many of these uses have been discontinued or restricted due to its toxicity, which affects multiple target organs and includes both acute, high-dose toxicity and chronic, low-dose toxicity that also encompass several cancers. US and international agencies have conducted risk and hazard assessments for TCE, with comprehensive publications coming out in the last 10-15 years. Accordingly, the focus of this article is to review recently published data since that time (i.e., 2014) that clarify unsettled questions or provide additional insights into the metabolism and mechanisms of toxicity of TCE in several target organs. Besides metabolism, the review focuses on the kidneys, liver, immune system, nervous system, cardiovascular and pulmonary systems, the search for biomarkers, and recent analyses of human cancer risk and incidence from TCE exposure.

卤代溶剂三氯乙烯(TCE)在医药、建筑、消费品和军事领域有许多用途。三氯乙烯的毒性影响多个靶器官,包括急性、高剂量毒性和慢性、低剂量毒性,其中慢性、低剂量毒性还包括多种癌症。美国和国际机构对三氯乙烷进行了风险和危害评估,并在过去 10-15 年间发表了全面的出版物。因此,本文的重点是回顾自那时(即 2014 年)以来最新发表的数据,这些数据澄清了一些悬而未决的问题,或提供了有关三氯乙烷在多个靶器官中的代谢和毒性机制的更多见解。除新陈代谢外,本文还重点关注肾脏、肝脏、免疫系统、神经系统、心血管和肺部系统、生物标志物的寻找,以及最近对接触三氯乙烯导致的人类癌症风险和发病率的分析。
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引用次数: 0
Progress and Challenges in the Field of Snakebite Envenoming Therapeutics. 蛇咬致病疗法领域的进展与挑战。
IF 11.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1146/annurev-pharmtox-022024-033544
José María Gutiérrez, Nicholas R Casewell, Andreas H Laustsen

Snakebite envenoming kills and maims hundreds of thousands of people every year, especially in the rural settings of tropical regions. Envenomings are still treated with animal-derived antivenoms, which have prevented many lives from being lost but which are also medicines in need of innovation. Strides are being made to improve envenoming therapies, with promising efforts made toward optimizing manufacturing and quality aspects of existing antivenoms, accelerating research and development of recombinant antivenoms based on monoclonal antibodies, and repurposing of small-molecule inhibitors that block key toxins. Here, we review the most recent advances in these fields and discuss therapeutic opportunities and limitations for different snakebite treatment modalities. Finally, we discuss challenges related to preclinical and clinical evaluation, regulatory pathways, large-scale manufacture, and distribution and access that need to be addressed to fulfill the goals of the World Health Organization's global strategy to prevent and control snakebite envenoming.

每年都有数十万人被蛇咬伤致死或致残,尤其是在热带地区的农村地区。目前仍在使用动物源性抗蛇毒血清治疗蛇毒中毒,这种抗蛇毒血清避免了许多生命的丧失,但也是需要创新的药物。目前,我们正在努力改进熏蒸疗法,在优化现有抗蛇毒血清的生产和质量、加快基于单克隆抗体的重组抗蛇毒血清的研究和开发,以及重新利用阻断关键毒素的小分子抑制剂等方面都取得了可喜的进展。在此,我们回顾了这些领域的最新进展,并讨论了不同蛇咬伤治疗方法的治疗机会和局限性。最后,我们讨论了为实现世界卫生组织预防和控制蛇咬伤全球战略的目标而需要应对的与临床前和临床评估、监管途径、大规模生产以及销售和获取有关的挑战。
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引用次数: 0
Prospects for Disease Slowing in Parkinson Disease. 帕金森病的疾病减缓前景。
IF 11.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1146/annurev-pharmtox-022124-033653
Elisa Menozzi, Anthony H V Schapira

The increasing prevalence of Parkinson disease (PD) highlights the need to develop interventions aimed at slowing or halting its progression. As a result of sophisticated disease modeling in preclinical studies, and refinement of specific clinical/genetic/pathological profiles, our understanding of PD pathogenesis has grown over the years, leading to the identification of several targets for disease modification. This has translated to the development of targeted therapies, many of which have entered clinical trials. Nonetheless, up until now, none of these treatments have satisfactorily shown disease-modifying effects in PD. In this review, we present the most up-to-date disease-modifying pharmacological interventions in the clinical trial pipeline for PD. We focus on agents that have reached more advanced stages of clinical trials testing, highlighting both positive and negative results, and critically reflect on strengths, weaknesses, and challenges of current disease-modifying therapeutic avenues in PD.

帕金森病(Parkinson disease,PD)的发病率越来越高,这凸显了开发旨在减缓或阻止其发展的干预措施的必要性。由于在临床前研究中进行了复杂的疾病建模,并对特定的临床/遗传/病理特征进行了改进,多年来我们对帕金森病发病机制的了解不断加深,从而确定了多个疾病调节靶点。这促进了靶向疗法的开发,其中许多疗法已进入临床试验阶段。然而,到目前为止,这些疗法都没有令人满意地显示出对帕金森病的疾病改变作用。在这篇综述中,我们介绍了目前正在进行临床试验的最新的帕金森病疾病调整药物干预措施。我们将重点关注已进入临床试验测试更高级阶段的药物,同时强调积极和消极的结果,并批判性地反思目前帕金森病疾病调节治疗途径的优势、劣势和挑战。
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引用次数: 0
Diffuse Pleural Mesothelioma: Advances in Molecular Pathogenesis, Diagnosis, and Treatment. 弥漫性胸膜间皮瘤:分子发病机制、诊断和治疗进展。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-24 Epub Date: 2023-09-18 DOI: 10.1146/annurev-pathol-042420-092719
Christopher A Febres-Aldana, Rachel Fanaroff, Michael Offin, Marjorie G Zauderer, Jennifer L Sauter, Soo-Ryum Yang, Marc Ladanyi

Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease.

弥漫性胸膜间皮瘤(DPM)是一种由胸膜表面间皮细胞引起的高度侵袭性恶性肿瘤。虽然DPM是一种公认的与石棉暴露有关的疾病,但最近的进展扩大了我们对分子发病机制的理解,并改变了我们的临床实践。这篇全面的综述探讨了DPM的当前概念和新趋势,包括风险因素、病理生物学、组织学分型和治疗管理,重点是对这种复杂疾病的多学科方法。《病理学年度评论:疾病机制》第19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
Dynamic Multiplex Tissue Imaging in Inflammation Research. 炎症研究中的动态多重组织成像。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-24 Epub Date: 2023-09-18 DOI: 10.1146/annurev-pathmechdis-070323-124158
Stefan Uderhardt, Georgiana Neag, Ronald N Germain

Inflammation is a highly dynamic process with immune cells that continuously interact with each other and parenchymal components as they migrate through tissue. The dynamic cellular responses and interaction patterns are a function of the complex tissue environment that cannot be fully reconstructed ex vivo, making it necessary to assess cell dynamics and changing spatial patterning in vivo. These dynamics often play out deep within tissues, requiring the optical focus to be placed far below the surface of an opaque organ. With the emergence of commercially available two-photon excitation lasers that can be combined with existing imaging systems, new avenues for imaging deep tissues over long periods of time have become available. We discuss a selected subset of studies illustrating how two-photon microscopy (2PM) has helped to relate the dynamics of immune cells to their in situ function and to understand the molecular patterns that govern their behavior in vivo. We also review some key practical aspects of 2PM methods and point out issues that can confound the results, so that readers can better evaluate the reliability of conclusions drawn using this technology.

炎症是一个高度动态的过程,免疫细胞在组织中迁移时不断相互作用,并与实质成分相互作用。动态细胞反应和相互作用模式是复杂组织环境的一种功能,无法在体外完全重建,因此有必要评估细胞动力学和体内不断变化的空间模式。这些动力学通常在组织深处发挥作用,需要将光学焦点放置在不透明器官表面的下方。随着可与现有成像系统相结合的商用双光子激发激光器的出现,长时间成像深层组织的新途径已经成为可能。我们讨论了一组选定的研究,说明双光子显微镜(2PM)如何帮助将免疫细胞的动力学与其原位功能联系起来,并了解控制其体内行为的分子模式。我们还回顾了2PM方法的一些关键实践方面,并指出了可能混淆结果的问题,以便读者能够更好地评估使用该技术得出的结论的可靠性。《病理学年度评论:疾病机制》第19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
The Nocebo Effect. 恐慌效应
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-08-16 DOI: 10.1146/annurev-pharmtox-022723-112425
Luana Colloca

Adverse nocebo responses can cause harm to patients and interfere with treatment adherence and effects in both clinic practice and clinical trials. Nocebo responses refer to negative outcomes to active medical treatments in clinical trials or practice that cannot be explained by the treatment's pharmacologic effects. Negative expectancies and nocebo effects are less known than placebo responses. Nocebo effects can be triggered by verbal suggestions, prior negative experiences, observation of others experiencing negative outcomes, and other contextual and environmental factors. As research advances over the years, mechanistic knowledge is accumulating on the neurobiological mechanisms of nocebo effects. This review summarizes studies on different facets of nocebo effects and responses and discusses clinical implications, ethical considerations, and future directions.

在临床实践和临床试验中,不良的前兆反应会对患者造成伤害,并影响治疗的依从性和效果。安慰剂反应是指在临床试验或实践中,积极的医学治疗产生了无法用治疗的药理作用来解释的负面结果。与安慰剂反应相比,消极预期和安慰剂效应鲜为人知。言语暗示、先前的负面经历、观察到他人经历负面结果以及其他背景和环境因素都可能引发安慰剂效应。随着多年来研究的进展,有关安慰剂效应神经生物学机制的知识也在不断积累。本综述总结了有关预兆效应和反应不同方面的研究,并讨论了其临床意义、伦理考虑和未来发展方向。
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引用次数: 0
Circulating Biomarkers Instead of Genotyping to Establish Metabolizer Phenotypes. 用循环生物标记物代替基因分型来确定代谢物表型。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-08-16 DOI: 10.1146/annurev-pharmtox-032023-121106
Roman Tremmel, Ute Hofmann, Mathias Haag, Elke Schaeffeler, Matthias Schwab

Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the genetic information of absorption, distribution, metabolism, and excretion (ADME) targets such as drug-metabolizing enzymes or transporters to predict differences in the patient's phenotype. However, there is evidence that the phenotype-genotype concordance is limited. Thus, we discuss different phenotyping strategies using exogenous xenobiotics (e.g., drug cocktails) or endogenous compounds for phenotype prediction. In particular, minimally invasive approaches focusing on liquid biopsies offer great potential to preemptively determine metabolic and transport capacities. Early studies indicate that ADME phenotyping using exosomes released from the liver is reliable. In addition, pharmacometric modeling and artificial intelligence improve phenotype prediction. However, further prospective studies are needed to demonstrate the clinical utility of individualized treatment based on phenotyping strategies, not only relying on genetics. The present review summarizes current knowledge and limitations.

药物基因组学(PGx)可实现个性化治疗,预测药物反应,避免药物不良反应。目前,药物基因组学主要依靠药物代谢酶或转运体等吸收、分布、代谢和排泄(ADME)靶点的遗传信息来预测患者的表型差异。然而,有证据表明,表型与基因型的一致性是有限的。因此,我们讨论了利用外源性异生物体(如药物鸡尾酒)或内源性化合物进行表型预测的不同表型分析策略。特别是以液体活检为重点的微创方法为预先确定代谢和转运能力提供了巨大的潜力。早期研究表明,利用肝脏释放的外泌体进行 ADME 表型分析是可靠的。此外,药效学建模和人工智能也改善了表型预测。然而,还需要进一步的前瞻性研究来证明基于表型策略的个体化治疗的临床效用,而不仅仅是依赖于遗传学。本综述总结了目前的知识和局限性。
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引用次数: 0
Mass Spectrometry-Based Proteogenomics: New Therapeutic Opportunities for Precision Medicine. 基于质谱的蛋白质组学:精准医学的新治疗机会。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-09-22 DOI: 10.1146/annurev-pharmtox-022723-113921
Sunil K Joshi, Paul Piehowski, Tao Liu, Sara J C Gosline, Jason E McDermott, Brian J Druker, Elie Traer, Jeffrey W Tyner, Anupriya Agarwal, Cristina E Tognon, Karin D Rodland

Proteogenomics refers to the integration of comprehensive genomic, transcriptomic, and proteomic measurements from the same samples with the goal of fully understanding the regulatory processes converting genotypes to phenotypes, often with an emphasis on gaining a deeper understanding of disease processes. Although specific genetic mutations have long been known to drive the development of multiple cancers, gene mutations alone do not always predict prognosis or response to targeted therapy. The benefit of proteogenomics research is that information obtained from proteins and their corresponding pathways provides insight into therapeutic targets that can complement genomic information by providing an additional dimension regarding the underlying mechanisms and pathophysiology of tumors. This review describes the novel insights into tumor biology and drug resistance derived from proteogenomic analysis while highlighting the clinical potential of proteogenomic observations and advances in technique and analysis tools.

蛋白质组学是指整合来自相同样本的全面基因组、转录组和蛋白质组学测量,目的是充分了解将基因型转化为表型的调控过程,通常强调对疾病过程有更深入的了解。尽管长期以来已知特定的基因突变会导致多种癌症的发展,但仅凭基因突变并不总能预测预后或对靶向治疗的反应。蛋白基因组学研究的好处是,从蛋白质及其相应途径获得的信息提供了对治疗靶点的深入了解,这些靶点可以通过提供关于肿瘤潜在机制和病理生理学的额外维度来补充基因组信息。这篇综述描述了蛋白基因组分析对肿瘤生物学和耐药性的新见解,同时强调了蛋白基因组观察的临床潜力以及技术和分析工具的进展。《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
Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy. 药物反应的昼夜节律调节:实现性别特异性和个性化的慢性疗法
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-09-18 DOI: 10.1146/annurev-pharmtox-051920-095416
Francis A Lévi, Alper Okyar, Eva Hadadi, Pasquale F Innominato, Annabelle Ballesta

Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock.

如今,精准医学面临的挑战包括整合分子钟对药物药代动力学、毒性和疗效的影响,以实现个性化的时间疗法。在过去的十年中,通过合理安排用药时间,药物的耐受性和/或疗效得到了显著改善,这一点已在免疫疗法和癌症化疗以及心血管、代谢、炎症和神经系统疾病的常用药物治疗中得到证实。最近的实验和人体研究发现,昼夜节律药物反应具有性别双态性。现在,专门的随机临床试验应着眼于为日常医疗实践提供个性化的昼夜节律时间建议,将昼夜节律指标的远程纵向监测、从单时间点活检中对分子钟功能的统计预测以及多尺度生物节律数学建模等创新技术结合起来。重要的是,需要确定昼夜节律功能健全的 "昼夜节律适宜 "患者,他们将从个性化的 "昼夜节律疗法 "中获益最多。相反,非昼夜节律失调患者则可以从针对昼夜节律的新兴药理类慢性生物制剂中获益。
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引用次数: 0
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