Pharmacological Reviews最新文献

Calorie restriction (CR) is a well known intervention associated with multifaceted anti-aging and pro-longevity health benefits. It induces complex physiological cellular and molecular adaptations, resulting in the fine-tuning of metabolic and immune responses in both homeostatic and diseased states. It has thus been extensively studied both preclinically and clinically, uncovering its therapeutic potential against inflammatory conditions, particularly autoimmune diseases. CR mimetics (CRMs), that is, molecules that mimic CR's effects, have also been widely investigated to counteract inflammatory states associated with numerous diseases, including autoimmunity. However, a comprehensive overview of how CR and CRMs modulate different aspects of immune responses, thereby potentially modifying autoimmunity, is still lacking. Here, we reviewed the latest progress on the impacts of CR and CRMs on the immune system and the current evidence on their potential translation in the clinical management of people with autoimmune diseases. First, we summarized different types of CR and CRMs and their main mechanisms of action. We next reviewed comprehensively how CR and CRMs modulate immune cells and discussed up-to-date preclinical and clinical advances in using CR and CRMs in the context of some of the most common autoimmune diseases. Finally, challenges faced in CR-related research and its translation into the clinic are discussed. SIGNIFICANCE STATEMENT: Calorie restriction (CR) encompasses various approaches for daily or intermittent reduction in calorie intake while maintaining adequate nutrient intake. It acts through cell-intrinsic and -extrinsic pathways to modulate immune cell functions. CR is emerging as a strategy for autoimmune disease management. CR's effects could be partially mimicked by molecules called CR mimetics, which are proposed to achieve CR's effects without reducing food intake. CR and CR mimetics have been tested as promising potential therapeutics in preclinical and clinical autoimmune disease studies.

The endocannabinoid system (eCB) is a complex signaling network discovered in mammals during the 1980s-1990s. It conventionally revolves around two arachidonic acid-derived mediators, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol; their main receptors, the cannabinoid receptors of type 1 (CB1) and type 2 (CB2), and the transient receptor potential vanilloid-1 channels; and the enzymes responsible for their biosynthesis and degradation. However, drawing on these discoveries, numerous eCB-like signaling lipids beyond the classical eCBs, have been unveiled, together with their receptors and metabolic enzymes, thus forming a more complex signaling network known as the endocannabinoidome (eCBome). This review explores the physiology, pharmacological complexity, and molecular targets of the mammalian eCBome, highlighting its versatility and redundancy in the context of global health. Emerging mediators, metabolic pathways and mechanisms, receptors, and their implications in human physiology and pathology are described, particularly concerning metabolic disorders, pain, inflammation, neurodegenerative diseases, and cancer. The importance of other "eCBomes" in nonmammalian forms of life that constitute the external and internal environments of mammals is also discussed for the first time in this context. The overarching objective of this article is to gain insights into the potential of eCBome-based therapeutic strategies aimed at enhancing both human and environmental well-being. SIGNIFICANCE STATEMENT: Lipid-based signaling molecules are ubiquitous in nature, yet their study remains challenging due to intricate regulatory mechanisms. Among lipid signaling pathways, the endocannabinoid (eCB) system and its extended version, the endocannabinoidome (eCBome), are particularly remarkable. Comprising hundreds of mediators, and dozens of receptors and metabolic enzymes, the eCBome regulates critical physiological processes not only in mammals but also across diverse organisms, including plants, fungi, and bacteria. This article examines the evolutionary and functional diversity of eCBomes and highlights their untapped potential as multikingdom therapeutic targets to address pressing challenges in global health.

Serotonin 5-HT_2A receptors were one of the first serotonin receptors to be pharmacologically characterized. In mammals, they are expressed throughout the body in nearly every cell and tissue type, with the highest density in cortical layer V of the brain. They are involved in several aspects of normal physiological processes and behaviors and have been implicated in the etiology of neuropsychiatric diseases such as schizophrenia. Atypical antipsychotics have targeted blockade of 5-HT_2A receptors as part of their therapeutic mechanism. More recently, 5-HT_2A receptors have come to prominence for their role as the primary target for psychedelic drugs, which activate this receptor subtype to produce their characteristic behavioral effects. 5-HT_2A receptor agonists like psilocybin, dimethyltryptamine, and lysergic acid diethylamide have each demonstrated long-lasting therapeutic efficacy in clinical trials for psychiatric disorders such as major depression and substance use disorders. There is a significant effort in both academia and industry to develop new agonists of 5-HT_2A receptors with therapeutic efficacy. There are 3 primary scaffolds for agonists: tryptamines, ergolines, and phenylalkylamines, each engaging different subsets of amino acid residues in the receptor binding pocket. Differences can lead to differential responses between ligands for functionally selective outcomes. Here, we provide a historical perspective on 5-HT_2A receptors, their key structural features and motifs involved in ligand-receptor interactions, and how these interactions can affect signaling pathways downstream of the receptor. Understanding how ligands interact with the 5-HT_2A receptor will fundamentally inform future drug discovery to optimize therapeutics for a variety of disorders. SIGNIFICANCE STATEMENT: Psychedelic drugs have demonstrated long-lasting therapeutic efficacy for several conditions in multiple clinical trials. Their target, serotonin 5-HT_2A receptors, are GPCRs with complex pharmacology. Having knowledge of how ligands interact with 5-HT_2A receptors in the orthosteric binding pocket at the structural level to induce specific signal transduction pathways will inform on efforts to design and develop functionally selective drugs to potentially treat a variety of diseases.

Chronic respiratory diseases are an enormous burden on healthcare and the third ranked cause of death globally. There is now compelling evidence that acceleration of lung aging and associated cellular senescence is a key driving mechanism of several chronic lung diseases, particularly chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Senescent cells, arising from oxidative stress and unrepaired damage, can accumulate in the lung and develop a senescence-associated secretory phenotype, spreading senescence and resulting in disease progression. In addition, there is a reduction in normally protective antiaging molecules, such as sirtuins, in the lungs. The role of cellular senescence in chronic lung disease has driven interest in senotherapy that targets senescent cells as a novel approach to treating respiratory diseases, and includes repurposing of existing drugs or developing new therapies. Senomorphics, which prevent the development of senescence and inhibit senescence-associated secretory phenotype mediators, include inhibitors of phosphoinositide-3-kinase-mechanistic target of rapamycin signaling, novel antioxidants, and sirtuin activators. Senolytics remove senescent cells by inducing apoptosis and include inhibitors of antiapoptotic proteins, such as B-cell lymphoma-extra large, inhibitors of forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. Senotherapies have been effective in animal models of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and several clinical trials are currently underway. The safety of these treatments after long-term administration requires further study, but this could potentially to be a promising approach to treating chronic lung diseases. SIGNIFICANCE STATEMENT: Cellular senescence induced by oxidative stress is a key driving mechanism in chronic lung diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and may account for disease progression. Senotherapies, including senomorphics that inhibit senescent cells and senolytics that eliminate them, are promising therapeutic approaches to these common diseases, either with repurposed drugs or several new drugs that are in development.

Asthma is a disease of airway inflammation and bronchial hyperresponsiveness affecting over 300 million individuals worldwide. Although described as early as 460 BC, the recognition of asthma as a disease, and the development and implementation of therapies to control it, emerged in the early 1900s. The subsequent century introduced the utilization of immunotherapy, inhaled medications, and anti-inflammatory corticosteroids for disease control. Since the beginning of the 21st century, however, the emergence of novel asthma pharmacotherapies has accelerated greatly. Our understanding of various asthma phenotypes and their underlying mechanisms (endotypes) has crystallized, leading to an era of precision medicine. Management strategies increasingly use targeted biologic medications aimed at interrupting key components of the inflammatory cascade. Monoclonal antibodies targeting the IgE, thymic stromal lymphopoietin, or interleukin-4, -5, and -13 pathways have revolutionized the care we provide our patients, resulting in a reduction in exacerbations and oral corticosteroid (OCS) dose, while improving lung function and asthma-related quality of life. Although they are able to provide relief for many sufferers of severe disease, and even remission in some, these biologic therapies are still in their infancy. Because their roles become further established, new therapeutic targets and modalities offer significant promise of an even greater personalized medicine approach. This review addresses historical standard-of-care strategies for asthma treatment, current recommendations, and a glimpse into future novel therapies that are likely to help millions worldwide. SIGNIFICANCE STATEMENT: Asthma affects hundreds of millions of individuals worldwide. In the last few decades, asthma treatment paradigms have transformed from recommendations to use anti-inflammatory and bronchodilatory inhalation-based therapies including corticosteroids and beta-agonists, to more precisely targeted add-on biologic therapies that employ monoclonal antibodies addressing specific mechanistic pathways associated with specific patient characteristics. Future therapies promise utilization of personalized medicine to a greater extent with novel therapeutic approaches to help improve the health and quality of life of those suffering from asthma.

Gene therapy has a pivotal role in treating new diseases. In addition to the recent mRNA-based COVID-19 vaccines produced by Pfizer-BioNTech and Moderna against severe acute respiratory syndrome corona virus 2, several new gene therapies have recently been approved as effective treatments for fatal genetic disorders such as Duchenne's muscular dystrophy, familial transthyretin amyloidosis, hemophilia A, hemophilia B, spinal muscle atrophy, early cerebral autoleukodystrophy, and β-thalassemia. This review provides novel insights into RNA therapeutics focusing on endogenous RNA species, RNA structure and function, and chemical modifications that improve the stability and distribution of RNAs. Furthermore, it includes updated knowledge on clinically approved gene therapies rendering a comprehensive understanding of the biochemical basis and clinical application of gene therapies. SIGNIFICANCE STATEMENT: There have recently been significant advances in clinical translation of RNA therapeutics. This review discusses the diverse types of RNA species, RNA structure and function, backbone and chemical modifications to RNAs, and every RNA therapeutic approved for clinical use at the time of writing.

The development of the first total-body positron emission tomography (PET) clinical scanner is a transformational moment in nuclear medicine, reigniting the field by tackling 2 long-standing and critical barriers to the widespread clinical use of PET: radiation dose and patient throughput. Total-body PET also provides several other unique research and clinical opportunities, including potential to streamline radiotracer discovery and development pipelines. PET does not exist without radiotracers. However, despite decades of radiotracer development programs, the number of successful PET radiotracers adopted and approved for human use is extremely low. In neurology, an important area for nuclear medicine, only approximately 4% of all novel radiotracers that survive the radiotracer translational "valley of death" are adopted clinically. The potential for total-body PET technology to reverse these low numbers of radiotracer development and adoption is high. This will require the PET community to come together with the regulators to chart new frameworks for radiotracer development and translational pipelines. This article will discuss which stages of the radiotracer discovery pipeline can benefit most from the recent development of total-body PET technology. It will review the latest key developments in radiochemistry modernization and describe how these could ameliorate regulatory hurdles and deliver the groundbreaking potential of total-body PET. Finally, this article will highlight emerging radiotracer discovery opportunities that could be rapidly facilitated by total-body PET. SIGNIFICANCE STATEMENT: In addition to creating new opportunities for clinical research and patient care, total-body positron emission tomography technology can also embolden radiochemistry modernization in the clinic and break long-standing translational barriers encountered during radiotracer discovery pipelines.

Recent advances in single-cell RNA sequencing have uncovered fibroblasts' heterogeneous and plastic nature across the cardiovascular system, highlighting their diverse roles beyond extracellular matrix production, including inflammatory signaling and phenotypic switching. This review synthesizes insights into fibroblast heterogeneity and modulation in healthy and diseased heart and vasculature states. It emphasizes the lack of a consensus nomenclature for fibroblast subtypes, attributing this gap to the need for large-scale meta-analyses and extensive validation studies. The emerging understanding of fibroblast subpopulations and their shared markers across cardiac and vascular tissues introduces therapeutic potential and safety concerns. Although preclinical studies targeting fibroblasts in the heart using gene silencing, editing, or epigenetic modulation show promise, comparable vascular interventions remain limited. Therapeutic strategies could benefit from improved fibroblast-specific markers to minimize off-target effects and enhance precision. Ultimately, the review advocates for refined characterization and nomenclature of fibroblast subsets to better exploit their therapeutic potential, while acknowledging the challenges posed by their overlapping phenotypes and diverse functionalities within the cardiovascular system. SIGNIFICANCE STATEMENT: Fibroblasts are a heterogeneous cell type with critical roles in cardiovascular homeostasis and disease. We explore advances in understanding fibroblast diversity and therapeutic potential. We underscore the importance of precision in cardiovascular disease through a consensus on nomenclature and marker specificity.

Chronic kidney disease (CKD) has become highly prevalent worldwide, with major implications for public health, including increased risk of progression to kidney failure, cardiovascular events, and mortality. Up to a decade ago, renin-angiotensin system inhibitors, that is angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, were the only available pharmacological interventions to slow kidney function loss and limit the associated cardiovascular morbidity and mortality in this context. More recently, landmark trials have demonstrated the ability of novel therapeutics to significantly ameliorate kidney and cardiovascular outcomes in patients with CKD, when added on top of optimized renin-angiotensin system blockade. These include sodium-glucose cotransporter-2 inhibitors in patients with diabetic and nondiabetic kidney disease, as well as the nonsteroidal mineralcorticoid receptor antagonist finerenone and the glucagon-like peptide-1 receptor agonist semaglutide in patients with diabetic kidney disease. We herein review the evolving scenario and the latest evidence for the treatment of CKD, mainly focusing on proteinuric CKD. We started with a presentation of established and more recently approved classes of kidney protective drugs, followed by a discussion of therapeutic interventions under clinical investigation to slow CKD progression. Finally, we underscore the added value of personalized and multidrug interventions, which are becoming increasingly more feasible with the availability of a growing number of kidney protective agents, and are likely to stand as the most powerful tools to safely slow, or even prevent, the progression of proteinuric CKD. SIGNIFICANCE STATEMENT: Chronic kidney disease (CKD) is highly prevalent globally, and is associated with substantial morbidity and mortality. This review provides a comprehensive overview of the currently approved and emerging therapeutic options for the treatment of proteinuric CKD. As novel kidney protective agents have recently become available, the outcomes of patients with CKD could hopefully improve over the few decades ahead.

γ-Hydroxybutyrate (GHB) is a multifaceted compound with an intriguing, yet undeciphered, pharmacology in the mammalian brain. As a metabolite of GABA it is tightly regulated in terms of synthesis and degradation, and is found in micromolar concentrations in the brain. When GHB is taken in high pharmacological doses, it causes euphoria, relaxation, hypothermia, and sedation, and regulates sleep. Through careful pharmacological and genetic studies, this profile has been convincingly matched to the metabotropic GABA_B receptor where GHB is a weak agonist. These effects explain the illicit substance use of GHB, but also its clinically useful effects as a drug in alcoholism and narcolepsy. Additionally, GHB binds with high affinity to a discrete binding site with high expression in the forebrain, and with very well defined anatomical, biochemical, and pharmacological characteristics. Despite this clear profile, the molecular identity of this binding protein or alleged "GHB receptor" has remained uncertain. However, recently, prompted by the development of GHB analogs with low nanomolar affinity and selectivity for the high-affinity site, the target was revealed to be the Ca²⁺/calmodulin (CaM)-dependent protein kinase II alpha subunit-a highly important brain kinase, mediating both physiological processes in synaptic plasticity, and detrimental Ca²⁺ signaling and cell death in cases of brain ischemia. The discovery of calmodulin-dependent protein kinase II alpha subunit as the high-affinity brain target for GHB represents a major leap forward in our understanding of GHB neurobiology, and dictates new times for GHB research, suggesting a potential role for GHB and GHB analogs as integrators of inhibitory and excitatory brain signaling. SIGNIFICANCE STATEMENT: γ-Hydroxybutyrate is a molecule with a multitude of actions in the mammalian brain, and with a rather complex molecular pharmacology. A low affinity at GABA_B receptors, located mainly at inhibitory synapses, and a high affinity at the Ca2+/CaM-dependent protein kinase II alpha subunit, located at excitatory synapses, makes GHB pharmacology especially intriguing.