Annual review of pharmacology and toxicology最新文献

As costs of next-generation sequencing decrease, identification of genetic variants has far outpaced our ability to understand their functional consequences. This lack of understanding is a central challenge to a key promise of pharmacogenomics: using genetic information to guide drug selection and dosing. Recently developed multiplexed assays of variant effect enable experimental measurement of the function of thousands of variants simultaneously. Here, we describe multiplexed assays that have been performed on nearly 25,000 variants in eight key pharmacogenes (ADRB2, CYP2C9, CYP2C19, NUDT15, SLCO1B1, TMPT, VKORC1, and the LDLR promoter), discuss advances in experimental design, and explore key challenges that must be overcome to maximize the utility of multiplexed functional data.

Imperfect medication adherence remains the biggest predictor of treatment failure for patients with tuberculosis. Missed doses during treatment lead to relapse, tuberculosis resistance, and further spread of disease. Understanding individual patient phenotypes, population pharmacokinetics, resistance development, drug distribution to tuberculosis lesions, and pharmacodynamics at the site of infection is necessary to fully measure the impact of adherence on patient outcomes. To decrease the impact of expected variabilityin drug intake on tuberculosis outcomes, an improvement in patient adherence and new forgiving regimens that protect against missed doses are needed. In this review, we summarize emerging technologies to improve medication adherence in clinical practice and provide suggestions on how digital adherence technologies can be incorporated in clinical trials and practice and the drug development pipeline that will lead to more forgiving regimens and benefit patients suffering from tuberculosis.

Chemogenetics refers to experimental systems that dynamically regulate the activity of a recombinant protein by providing or withholding the protein's specific biochemical stimulus. Chemogenetic tools permit precise dynamic control of specific signaling molecules to delineate the roles of those molecules in physiology and disease. Yeast d-amino acid oxidase (DAAO) enables chemogenetic manipulation of intracellular redox balance by generating hydrogen peroxide only in the presence of d-amino acids. Advances in biosensors have allowed the precise quantitation of these signaling molecules. The combination of chemogenetic approaches with biosensor methodologies has opened up new lines of investigation, allowing the analysis of intracellular redox pathways that modulate physiological and pathological cell responses. We anticipate that newly developed transgenic chemogenetic models will permit dynamic modulation of cellularredox balance in diverse cells and tissues and will facilitate the identification and validation of novel therapeutic targets involved in both physiological redox pathways and pathological oxidative stress.

Since prehistory, human species have depended on plants for both food and medicine. Even in countries with ready access to modern medicines, alternative treatments are still highly regarded and commonly used. Unlike modern pharmaceuticals, many botanical medicines are in widespread use despite a lack of safety and efficacy data derived from controlled clinical trials and often unclear mechanisms of action. Contributing to this are the complex and undefined composition and likely multifactorial mechanisms of action and multiple targets of many botanical medicines. Here, we review the newfound importance of the ubiquitous KCNQ subfamily of voltage-gated potassium channels as targets for botanical medicines, including basil, capers, cilantro, lavender, fennel, chamomile, ginger, and Camellia, Sophora, and Mallotus species. We discuss the implications for the traditional use of these plants for disorders such as seizures, hypertension, and diabetes and the molecular mechanisms of plant secondary metabolite effects on KCNQ channels.

The transcription factor NRF2 coordinates the expression of a vast array of cytoprotective and metabolic genes in response to various stress inputs to restore cellular homeostasis. Transient activation of NRF2 in healthy tissues has been long recognized as a cellular defense mechanism and is critical to prevent cancer initiation by carcinogens. However, cancer cells frequently hijack the protective capability of NRF2 to sustain the redox balance and meet their metabolic requirements for proliferation. Further, aberrant activation of NRF2 in cancer cells confers resistance to commonly used chemotherapeutic agents and radiotherapy. During the last decade, many research groups have attempted to block NRF2 activity in tumors to counteract the survival and proliferative advantage of cancer cells and reverse resistance to treatment. In this review, we highlight the role of NRF2 in cancer progression and discuss the past and current approaches to disable NRF2 signaling in tumors.

Transient receptor potential canonical (TRPC) proteins assemble to form homo- or heterotetrameric, nonselective cation channels permeable to K⁺, Na⁺, and Ca²⁺. TRPC channels are thought to act as complex integrators of physical and chemical environmental stimuli. Although the understanding of essential physiological roles of TRPC channels is incomplete, their implication in various pathological mechanisms and conditions of the nervous system, kidneys, and cardiovascular system in combination with the lack of major adverse effects of TRPC knockout or TRPC channel inhibition is driving the search of TRPC channel modulators as potential therapeutics. Here, we review the most promising small-molecule TRPC channel modulators, the understanding of their mode of action, and their potential in the study and treatment of cardiovascular and metabolic disease.

The aryl hydrocarbon receptor (AhR) is a transcriptional factor that regulates multiple functions following its activation by a variety of ligands, including xenobiotics, natural products, microbiome metabolites, and endogenous molecules. Because of this diversity, the AhR constitutes an exposome receptor. One of its main functions is to regulate several lines of defense against chemical insults and bacterial infections. Indeed, in addition to its well-established detoxication function, it has several functions at physiological barriers, and it plays a critical role in immunomodulation. The AhR is also involved in the development of several organs and their homeostatic maintenance. Its activity depends on the type of ligand and on the time frame of the receptor activation, which can be either sustained or transient, leading in some cases to opposite modes of regulations as illustrated in the regulation of different cancer pathways. The development of selective modulators and their pharmacological characterization are important areas of research.

Over the past 30 years there has been a surge of research on the placebo effect using a neuroscientific approach. The interesting aspects of this effort are related to the identification of several biological mechanisms of both the placebo and nocebo effects, the latter of which is defined as a negative placebo effect. Some important translational implications have emerged both in the setting of clinical trials and in routine medical practice. One of the principal contributions of neuroscience has been to draw the attention of the scientific and medical communities to the important role of psychobiological factors in therapeutic outcomes, be they drug related or not. Indeed, many biological mechanisms triggered by placebos and nocebos resemble those modulated by drugs, suggesting a possible interaction between psychological factors and drug action. Unfortunately, this new knowledge regarding placebos has the potential of being dangerously exploited by pseudoscience.

Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach.

The endocannabinoids are lipid-derived messengers that play a diversity of regulatory roles in mammalian physiology. Dysfunctions in their activity have been implicated in various disease conditions, attracting attention to the endocannabinoid system as a possible source of therapeutic drugs. This signaling complex has three components: the endogenous ligands, anandamide and 2-arachidonoyl-sn-glycerol (2-AG); a set of enzymes and transporters that generate, eliminate, or modify such ligands; and selective cell surface receptors that mediate their biological actions. We provide an overview of endocannabinoid formation, deactivation, and biotransformation and outline the properties and therapeutic potential of pharmacological agents that interfere with those processes. We describe small-molecule inhibitors that target endocannabinoid-producing enzymes, carrier proteins that transport the endocannabinoids into cells, and intracellular endocannabinoid-metabolizing enzymes. We briefly discuss selected agents that simultaneous-ly interfere with components of the endocannabinoid system and with other functionally related signaling pathways.