Annual review of pharmacology and toxicology最新文献

Alzheimer's disease (AD) is a complex neurodegenerative disease that leads to cognitive decline and dementia. Over the past two decades, many scientists have contributed to the discovery of therapeutics that target amyloid-beta (Aβ) to slow the progression of AD. These discoveries have led to the development of the first disease-modifying therapeutics in AD, though these come with the risk of side effects known as amyloid-related imaging abnormalities (ARIA). There are currently many exciting studies and trials working to mitigate ARIA risk that range from modifying antibodies to potential combination therapeutics. This review addresses some of the ongoing research areas for improving safety in Aβ targeting as well as clinical considerations for current patient treatment.

Giving old drugs new uses, a process known as drug repurposing, is an attractive strategy for finding therapeutic candidates for a wide number of diseases. In this context, data-driven approaches have emerged as a suitable framework to target this challenge. From molecular docking and network-based methods to omics data integration, computational techniques give invaluable insights into drug repurposing research. In the present review, we describe these methodologies and knowledge-based resources, also emphasizing the new horizons that artificial intelligence and large language models are revealing. A set of case studies illuminate the practical applications of these computational approaches to the identification of repurposing opportunities. By addressing a set of key challenges and proposing future directions, this review aims to be a resource for researchers navigating the multifaceted landscape of computational drug repurposing.

Volume 66 of the Annual Review of Pharmacology and Toxicology includes numerous articles that reveal evolving ideas and insights in pharmacology and toxicology. The major theme is new approaches, technology and techniques. New ideas include the use of systems biology, multiomics, and artificial intelligence to support wellness, prevention, early detection of disease, and precision medicine. Other reviews highlight new ideas and approaches to treat infectious diseases, including the repurposing of drugs approved for other indications and long-acting therapeutics. Related reviews emphasize aspects of global health. One review discusses psychedelics as therapeutics. Several reviews discuss advances in drug discovery modalities. Others relate to a variety of topics in toxicology, including aspects of mitochondrial biology, e-cigarettes, air pollution, microplastics, and nanoplastics. These reviews and others in this volume inform readers about recent advances in pharmacology and toxicology and show how both specialties continue to be vital for improving health and safety globally.

Long-acting (LA) therapeutics have emerged as a key component of infectious disease treatment and prevention strategies, their uptake fueled by the need to bridge notable gaps with short-acting drug formulations. In this review, we present the key drivers and summarize the enabling technologies. Focusing on infections with significant global disease burden (HIV, hepatitis B and C, tuberculosis, malaria, and COVID-19), the current state of knowledge on approved LA therapeutics and promising innovations currently in development are summarized. The potential role of LA therapeutics as countermeasures for diseases of pandemic potential and new approaches using computational modeling to accelerate their development for pediatric and perinatal health are discussed. Due to complexities in manufacturing, and the diversity of patent-protected technologies, barriers exist for global access to LA products and in upscaling intricate LA formulations. A multipronged strategic framework, including acceleration of equitable access through generic product manufacture, is proposed to realize the full potential of LA therapeutics for global health.

Atrial fibrillation (AF) is a common arrhythmia with a tremendous impact on quality of life and mortality. Its prevalence continues to rise alongside the increasing obesity and type 2 diabetes epidemics, raising a need for improved therapeutic strategies and a better understanding of the factors and mechanisms that drive metabolic disease-associated AF. To this end, the link between AF and metabolic disease is being increasingly explored in observational, clinical, and experimental studies. Chronic inflammation is a hallmark of metabolic disease, and multiple studies have also demonstrated a strong relationship between AF and inflammation. In this review, we discuss recent advances in our understanding of the mechanisms governing the development of AF in the context of metabolism and inflammation, related concepts in therapeutic development, and a novel role for calcitonin in AF.

Psychedelics show tremendous promise for treating psychiatric disorders and other illnesses, including pain and migraine. Despite decades of research, there is uncertainty which signaling mechanisms are necessary for rapid-acting and durable therapeutic effects of psychedelics. Although activation of the serotonin 5-HT_2A receptor is critical for their psychopharmacological effects, the precise signaling pathways and receptor conformations responsible are still under investigation. This review summarizes progress in studying 5-HT_2A signaling mechanisms and recent developments in the discovery of biased agonist tool compounds to disentangle therapeutic from adverse effects. Moreover, we review insights from structural studies regarding the design of psychedelic-derived compounds with tailored pharmacology and briefly discuss other 5-HT receptors that may be important for shaping therapeutic effects. Finally, by drawing parallels between 5-HT_2A biased signaling and the opioid field, we conclude with lessons learned and discuss the need for more rigor and reproducibility to facilitate the development of novel psychedelic-based pharmacotherapies.

Growing evidence points to mitochondria as not just the "powerhouse of the cell" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.

We explore three emerging molecular pathways driving neuroinflammation in chronic and acute brain diseases: the EP2 receptor for prostaglandin E2, the CCR2 receptor for chemokine CCL2, and JAK/STAT signaling. Inflammation is now recognized as a causative factor in neurodegenerative disorders, with neuroinflammation preceding symptom onset in Alzheimer's disease and likely heralding the onset of epilepsy and Parkinson's disease. The EP2 receptor modulates immune cell activation and exacerbates inflammatory responses, while CCR2 regulates peripheral immune cell recruitment to sites of brain inflammation. JAK/STAT pathways regulate neuronal and glial function across brain regions and can both amplify and resolve neuroinflammatory processes. These three signaling pathways converge at multiple nodes-immune cell recruitment, cytokine amplification, and transcriptional regulation-establishing feedforward loops that sustain pathology in chronic diseases. Understanding these mechanisms and their complex interactions provides opportunities for novel therapeutic interventions in neurological conditions characterized by inflammation, potentially leading to disease-modifying treatments.

African populations remain largely underrepresented in genomic studies despite their high genetic diversity. The significant variability in drug efficacy and toxicity across different ancestry populations should trigger more diversified and inclusive pharmacogenomic (PGx) studies. Non-European populations, especially Africans, remain largely underrepresented in GWASs and other genomic studies despite their high genetic diversity, which holds information critical for better understanding drug-related toxicity and enhancing the development of new drugs. Therefore, studies using population genetic clustering, polygenic risk scores, high-throughput organoid models, and multiomics analysis are urgently needed in African populations to enhance pharmacogenomics and drug development globally. For instance, studies of loss-of-function mutations in PCSK9, commonly found in populations of African descent, have led to the development of PCSK9 inhibitors, which are used globally to reduce hypercholesterolemia and cardiovascular disease risk. More studies on diverse African populations could elevate PGx, drug development, and therapeutics as illustrated by the PCSK9 example.

Biological neutralization refers to the process by which a biological agent, such as an antibody, enzyme, or therapeutic nanoparticle, renders a target molecule or pathogen harmless or inactive. Traditional approaches, such as antibody-based therapies, rely on precise molecular recognition, requiring customized development for each target. Recently, cell membrane-coated nanoparticles (cellular nanoparticles or CNPs), formulated by using natural cell membranes as drug substances, have emerged as a promising alternative. Acting as decoys, CNPs bind harmful agents based on membrane function rather than the molecular specificity, enabling broad-spectrum neutralization. This review examines how this fundamental pharmacological mechanism has guided CNP design to counteract pathological threats, including bacterial toxins, nerve agents, neurotoxins, inflammatory cytokines, autoantibodies, secretory enzymes, and viruses. Furthermore, we discuss strategies to enhance CNP performance through modifying the nanoparticle core or the membrane shell. By highlighting recent advancements, we aim to inspire further research into CNP-based approaches for tackling complex biological threats.