Annual Review of Pharmacology and Toxicology - Volume 65, 2025
Volume 65, 2025
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Treating Sickle Cell Disease: Gene Therapy Approaches
Vol. 65 (2025), pp. 397–413More LessSickle cell disease (SCD) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin molecules and thus distortion (sickling) of the red blood cells. SCD causes chronic pain and organ damage and shortens life expectancy. Gene therapy emerges as a potentially curative approach for people with SCD who lack a matched sibling donor for hematopoietic stem cell transplantation. Here, we review recent progress in gene therapy for SCD and focus on innovative technologies that target the genetic roots of the disease. We also review the challenges associated with gene therapy, including oncogenic risks, and the need for refined delivery methods. Despite these hurdles, the rapidly evolving landscape of gene therapy for SCD raises hope for a paradigm shift in the treatment of this debilitating disease. As research progresses, a deeper understanding of the molecular mechanisms involved and continuous improvements in gene-editing technologies promise to bring gene therapy for SCD closer to mainstream clinical application, offering a transformative, curative option for patients with this genetic disorder.
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Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics
Vol. 65 (2025), pp. 415–441More LessPhosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides. While the 11 PDE subfamilies share common features, key differences confer signaling specificity. The differences include substrate selectivity, enzymatic activity regulation, tissue expression, and subcellular localization. Selective inhibitors of each subfamily have elucidated the protean role of PDEs in normal cell function. PDEs are also linked to diseases, some of which affect the immune, cardiac, and vascular systems. Selective PDE inhibitors are clinically used to treat these specific disorders. Ongoing preclinical studies and clinical trials are likely to lead to the approval of additional PDE-targeting drugs for therapy in human disease. In this review, we discuss the structure and function of PDEs and examine current and evolving therapeutic uses of PDE inhibitors, highlighting their mechanisms and innovative applications that could further leverage this crucial family of enzymes in clinical settings.
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Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases
Vol. 65 (2025), pp. 443–463More LessRyanodine receptor type 2 (RyR2) is the principal intracellular calcium release channel in the cardiac sarcoplasmic reticulum (SR). Pathological RyR2 hyperactivity generates arrhythmia risk in genetic and structural heart diseases. RYR2 gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia. In structural heart diseases (i.e., heart failure), posttranslation modifications render RyR2 channels leaky, resulting in pathologic calcium release during diastole, contributing to arrhythmogenesis and contractile dysfunction. Hence, RyR2 represents a therapeutic target in arrhythmogenic heart diseases. We provide an overview of the structure and function of RyR2, and then review US Food and Drug Administration–approved and investigational RyR2 inhibitors. A therapeutic classification of RyR2 inhibitors is proposed based on their mechanism of action. Class I RyR2 inhibitors (e.g., flecainide) do not change SR calcium content and are primarily antiarrhythmic. Class II RyR2 inhibitors (e.g., dantrolene) increase SR calcium content, making them less effective as antiarrhythmics but preferable in conditions with reduced SR calcium content such as heart failure.
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Progress and Challenges in the Field of Snakebite Envenoming Therapeutics
Vol. 65 (2025), pp. 465–485More LessSnakebite 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.
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Toluene Toxicity in the Brain: From Cellular Targets to Molecular Mechanisms
Vol. 65 (2025), pp. 487–506More LessToluene intoxication constitutes a persistent public health problem worldwide. While most organs can be damaged, the brain is a primary target whether exposure is accidental, occupational, or recreational. Interventions to prevent/revert brain damage by toluene are curtailed by the scarce information on the molecular targets and mechanisms mediating toluene's brain toxicity and the common exposure to other neurotoxins and/or coexistence of neurological/psychiatric disorders. We examine (a) the physicochemical properties of toluene that allow this inhalant to primarily target the lipid-rich brain; (b) the cell types targeted by toluene (neurons, different types of glia), while considering a cerebrovascular component; and (c) putative molecular mechanisms by which toluene may modify receptor function while analyzing structural features that allow toluene to directly interact with membrane lipids or specific proteins. This information constitutes a stepping stone to design pharmacotherapies that counteract toluene brain intoxication.
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Trichloroethylene: An Update on an Environmental Contaminant with Multiple Health Effects
Vol. 65 (2025), pp. 507–527More LessThe 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.
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What Structural Biology Tells Us About the Mode of Action and Detection of Toxicants
Vol. 65 (2025), pp. 529–546More LessThe 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.
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Pollution of Soil by Pharmaceuticals: Implications for Metazoan and Environmental Health
Vol. 65 (2025), pp. 547–565More LessThe use of pharmaceuticals has grown substantially and their consequential release via wastewaters poses a potential threat to aquatic and terrestrial environments. While transportation prediction models for aquatic environments are well established, they cannot be universally extrapolated to terrestrial systems. Pharmaceuticals and their metabolites are, for example, readily detected in the excreta of terrestrial organisms (including humans). Furthermore, the trophic transfer of pharmaceuticals to and from food webs is often overlooked, which in turn highlights a public health concern and emphasizes the pressing need to elucidate how today's potpourri of pharmaceuticals affect the terrestrial system, their biophysical behaviors, and their interactions with soil metazoans. This review explores the existing knowledge base of pharmaceutical exposure sources, mobility, persistence, (bio)availability, (bio)accumulation, (bio)magnification, and trophic transfer of pharmaceuticals through the soil and terrestrial food chains.
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Advancements in Assays for Micro- and Nanoplastic Detection: Paving the Way for Biomonitoring and Exposomics Studies
Vol. 65 (2025), pp. 567–585More LessAlthough plastic pollution and exposure to plastic-related compounds have received worldwide attention, health risks associated with micro- and nanoplastics (MNPs) are largely unknown. Emerging evidence suggests MNPs are present in human biofluids and tissue, including blood, breast milk, stool, lung tissue, and placenta; however, exposure assessment is limited and the extent of human exposure to MNPs is not well known. While there is a critical need to establish robust and scalable biomonitoring strategies to assess human exposure to MNPs and plastic-related chemicals, over 10,000 chemicals have been linked to plastic manufacturing with no existing standardized approaches to account for even a fraction of these exposures. This review provides an overview of the status of methods for measuring MNPs and associated plastic-related chemicals in humans, with a focus on approaches that could be adapted for population-wide biomonitoring and integration with biological response measures to develop hypotheses on potential health effects of plastic exposures. We also examine the exposure risks associated with the widespread use of chemical additives in plastics. Despite advancements in analytical techniques, there remains a pressing need for standardized measurement protocols and untargeted, high-throughput analysis methods to enable comprehensive MNP biomonitoring to identify key MNP exposures in human populations. This review aims to merge insights into the toxicological effects of MNPs and plastic additives with an evaluation of analytical challenges, advocating for enhanced research methods to fully assess, understand, and mitigate the public health implications of MNPs.
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Previous Volumes
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Volume 65 (2025)
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Volume 64 (2024)
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Volume 63 (2023)
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Volume 62 (2022)
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Volume 61 (2021)
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Volume 60 (2020)
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Volume 59 (2019)
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Volume 58 (2018)
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Volume 57 (2017)
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Volume 56 (2016)
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Volume 55 (2015)
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Volume 54 (2014)
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Volume 53 (2013)
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Volume 52 (2012)
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Volume 51 (2011)
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Volume 50 (2010)
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Volume 49 (2009)
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Volume 48 (2008)
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Volume 47 (2007)
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Volume 46 (2006)
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Volume 45 (2005)
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Volume 44 (2004)
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Volume 43 (2003)
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Volume 42 (2002)
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Volume 41 (2001)
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Volume 40 (2000)
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Volume 39 (1999)
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Volume 38 (1998)
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Volume 37 (1997)
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Volume 36 (1996)
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Volume 35 (1995)
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Volume 34 (1994)
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Volume 33 (1993)
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Volume 32 (1992)
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Volume 31 (1991)
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Volume 30 (1990)
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Volume 29 (1989)
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Volume 28 (1988)
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Volume 27 (1987)
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Volume 26 (1986)
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Volume 25 (1985)
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Volume 24 (1984)
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Volume 23 (1983)
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Volume 22 (1982)
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Volume 21 (1981)
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Volume 20 (1980)
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Volume 19 (1979)
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Volume 18 (1978)
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Volume 17 (1977)
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Volume 16 (1976)
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Volume 15 (1975)
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Volume 14 (1974)
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Volume 13 (1973)
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Volume 12 (1972)
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Volume 11 (1971)
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Volume 10 (1970)
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Volume 9 (1969)
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Volume 8 (1968)
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Volume 7 (1967)
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Volume 6 (1966)
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Volume 5 (1965)
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Volume 4 (1964)
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Volume 3 (1963)
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Volume 2 (1962)
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Volume 1 (1961)
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Volume 0 (1932)