Annual review of pharmacology and toxicology最新文献

Synthetic cannabinoids (SCs) are a chemically diverse group of new psychoactive substances (NPSs) that target the endocannabinoid system, triggering a plethora of actions (e.g., elevated mood sensation, relaxation, appetite stimulation) that resemble, but are more intense than, those induced by cannabis. Although some of these effects have been explored for therapeutic applications, anticipated stronger psychoactive effects than cannabis and reduced risk perception have increased the recreational use of SCs, which have dominated the NPS market in the United States and Europe over the past decade. However, rising SC-related intoxications and deaths represent a major public health concern and embody a major challenge for policy makers. Here, we review the pharmacology and toxicology of SCs. A thorough characterization of SCs' pharmacodynamics and toxicodynamics is important to better understand the main mechanisms underlying acute and chronic effects of SCs, interpret the clinical/pathological findings related to SC use, and improve SC risk awareness.

Chronic diseases that affect our society are made more complex by comorbidities and are poorly managed by the current pharmacology. While all present inflammatory etiopathogeneses, there is an unmet need for better clinical management of these diseases and their multiple symptoms. We discuss here an innovative approach based on the biology of the resolution of inflammation. Studying endogenous pro-resolving peptide and lipid mediators, how they are formed, and which target they interact with, can offer innovative options through augmenting the expression or function of pro-resolving pathways or mimicking their actions with novel targeted molecules. In all cases, resolution offers innovation for the treatment of the primary cause of a given disease and/or for the management of its comorbidities, ultimately improving patient quality of life. By implementing resolution pharmacology, we harness the whole physiology of inflammation, with the potential to bring a marked change in the management of inflammatory conditions.

Pharmacology and toxicology are part of a much broader effort to understand the relationship between chemistry and biology. While biomedicine has necessarily focused on specific cases, typically of direct human relevance, there are real advantages in pursuing more systematic approaches to characterizing how health and disease are influenced by small molecules and other interventions. In this context, the zebrafish is now established as the representative screenable vertebrate and, through ongoing advances in the available scale of genome editing and automated phenotyping, is beginning to address systems-level solutions to some biomedical problems. The addition of broader efforts to integrate information content across preclinical model organisms and the incorporation of rigorous analytics, including closed-loop deep learning, will facilitate efforts to create systems pharmacology and toxicology with the ability to continuously optimize chemical biological interactions around societal needs. In this review, we outline progress toward this goal.

The coordinated movement of organic anions (e.g., drugs, metabolites, signaling molecules, nutrients, antioxidants, gut microbiome products) between tissues and body fluids depends, in large part, on organic anion transporters (OATs) [solute carrier 22 (SLC22)], organic anion transporting polypeptides (OATPs) [solute carrier organic (SLCO)], and multidrug resistance proteins (MRPs) [ATP-binding cassette, subfamily C (ABCC)]. Depending on the range of substrates, transporters in these families can be considered multispecific, oligospecific, or (relatively) monospecific. Systems biology analyses of these transporters in the context of expression patterns reveal they are hubs in networks involved in interorgan and interorganismal communication. The remote sensing and signaling theory explains how the coordinated functions of drug transporters, drug-metabolizing enzymes, and regulatory proteins play a role in optimizing systemic and local levels of important endogenous small molecules. We focus on the role of OATs, OATPs, and MRPs in endogenous metabolism and how their substrates (e.g., bile acids, short chain fatty acids, urate, uremic toxins) mediate interorgan and interorganismal communication and help maintain and restore homeostasis in healthy and disease states.

Air pollution is a complex mixture of gases and particulate matter, with adsorbed organic and inorganic contaminants, to which exposure is lifelong. Epidemiological studies increasingly associate air pollution with multiple neurodevelopmental disorders and neurodegenerative diseases, findings supported by experimental animal models. This breadth of neurotoxicity across these central nervous system diseases and disorders likely reflects shared vulnerability of their inflammatory and oxidative stress-based mechanisms and a corresponding ability to produce brain metal dyshomeo-stasis. Future research to define the responsible contaminants of air pollution underlying this neurotoxicity is critical to understanding mechanisms of these diseases and disorders and protecting public health.

Specialized pro-resolving mediators (SPMs), including resolvins, protectins, and maresins, are endogenous lipid mediators that are synthesized from omega-3 polyunsaturated fatty acids during the acute phase or resolution phase of inflammation. Synthetic SPMs possess broad safety profiles and exhibit potent actions in resolving inflammation in preclinical models. Accumulating evidence in the past decade has demonstrated powerful analgesia of exogenous SPMs in rodent models of inflammatory, neuropathic, and cancer pain. Furthermore, endogenous SPMs are produced by sham surgery and neuromodulation (e.g., vagus nerve stimulation). SPMs produce their beneficial actions through multiple G protein-coupled receptors, expressed by immune cells, glial cells, and neurons. Notably, loss of SPM receptors impairs the resolution of pain. I also highlight the emerging role of SPMs in the control of itch. Pharmacological targeting of SPMs or SPM receptors has the potential to lead to novel therapeutics for pain and itch as emerging approaches in resolution pharmacology.

Lysosomes play fundamental roles in material digestion, cellular clearance, recycling, exocytosis, wound repair, Ca²⁺ signaling, nutrient signaling, and gene expression regulation. The organelle also serves as a hub for important signaling networks involving the mTOR and AKT kinases. Electrophysiological recording and molecular and structural studies in the past decade have uncovered several unique lysosomal ion channels and transporters, including TPCs, TMEM175, TRPMLs, CLN7, and CLC-7. They underlie the organelle's permeability to major ions, including K⁺, Na⁺, H⁺, Ca²⁺, and Cl^-. The channels are regulated by numerous cellular factors, ranging from H⁺ in the lumen and voltage across the lysosomal membrane to ATP in the cytosol to growth factors outside the cell. Genetic variations in the channel/transporter genes are associated with diseases that include lysosomal storage diseases and neurodegenerative diseases. Recent studies with human genetics and channel activators suggest that lysosomal channels may be attractive targets for the development of therapeutics for the prevention of and intervention in human diseases.

Ubiquitously expressed throughout the body, ATP-sensitive potassium (K_ATP) channels couple cellular metabolism to electrical activity in multiple tissues; their unique assembly as four Kir6 pore-forming subunits and four sulfonylurea receptor (SUR) subunits has resulted in a large armory of selective channel opener and inhibitor drugs. The spectrum of monogenic pathologies that result from gain- or loss-of-function mutations in these channels, and the potential for therapeutic correction of these pathologies, is now clear. However, while available drugs can be effective treatments for specific pathologies, cross-reactivity with the other Kir6 or SUR subfamily members can result in drug-induced versions of each pathology and may limit therapeutic usefulness. This review discusses the background to K_ATP channel physiology, pathology, and pharmacology and considers the potential for more specific or effective therapeutic agents.

With the worldwide increase in life span, surgical patients are becoming older and have a greater propensity for postoperative cognitive impairment, either new onset or through deterioration of an existing condition; in both conditions, knowledge of the patient's preoperative cognitive function and postoperative cognitive trajectory is imperative. We describe the clinical utility of a tablet-based technique for rapid assessment of the memory and attentiveness domains required for executive function. The pathogenic mechanisms for perioperative neurocognitive disorders have been investigated in animal models in which excessive and/or prolonged postoperative neuroinflammation has emerged as a likely contender. The cellular and molecular species involved in postoperative neuroinflammation are the putative targets for future therapeutic interventions that are efficacious and do not interfere with the surgical patient's healing process.

Inflammation and its timely resolution are critical to ensure effective host defense and appropriate tissue repair after injury and or infection. Chronic, unresolved inflammation typifies many prevalent pathologies. The key mediators that initiate and drive the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. More recently, there is a growing appreciation that specific mediators, including arachidonate-derived lipoxins, are generated in self-limiting inflammatory responses to promote the resolution of inflammation and endogenous repair mechanisms without compromising host defense. We discuss the proresolving biological actions of lipoxins and recent efforts to harness their therapeutic potential through the development of novel, potent lipoxin mimetics generated via efficient, modular stereoselective synthetic pathways. We consider the evidence that lipoxin mimetics may have applications in limiting inflammation and reversing fibrosis and the underlying mechanisms.