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Annual Review of Pharmacology and Toxicology

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https://www.readbyqxmd.com/read/27860548/mitochondrial-dysfunction-and-myocardial-ischemia-reperfusion-implications-for-novel-therapies
#1
Edward J Lesnefsky, Qun Chen, Bernard Tandler, Charles L Hoppel
Mitochondria have emerged as key participants in and regulators of myocardial injury during ischemia and reperfusion. This review examines the sites of damage to cardiac mitochondria during ischemia and focuses on the impact of these defects. The concept that mitochondrial damage during ischemia leads to cardiac injury during reperfusion is addressed. The mechanisms that translate ischemic mitochondrial injury into cellular damage, during both ischemia and early reperfusion, are examined. Next, we discuss strategies that modulate and counteract these mechanisms of mitochondrial-driven injury...
November 17, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27860547/the-discovery-of-suvorexant-the-first-orexin-receptor-drug-for-insomnia
#2
Paul J Coleman, Anthony L Gotter, W Joseph Herring, Christopher J Winrow, John J Renger
Historically, pharmacological therapies have used mechanisms such as γ- aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal...
November 17, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27814025/stem-cell-extracellular-vesicles-extended-messages-of-regeneration
#3
Milad Riazifar, Egest J Pone, Jan Lötvall, Weian Zhao
Stem cells are critical to maintaining steady-state organ homeostasis and regenerating injured tissues. Recent intriguing reports implicate extracellular vesicles (EVs) as carriers for the distribution of morphogens and growth and differentiation factors from tissue parenchymal cells to stem cells, and conversely, stem cell-derived EVs carrying certain proteins and nucleic acids can support healing of injured tissues. We describe approaches to make use of engineered EVs as technology platforms in therapeutics and diagnostics in the context of stem cells...
October 28, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27814026/gper-gpr30-a-nongenomic-receptor-gpcr-for-steroid-hormones-with-implications-for-cardiovascular-disease-and-cancer
#4
Ross D Feldman, Lee E Limbird
Although the rapid effects of steroids, such as estrogen and aldosterone, were postulated originally to be nongenomic, it is now appreciated that activation of such signaling pathways via a steroid-acting G protein-coupled receptor, the G protein estrogen receptor (GPER), has important transcription-dependent outcomes in the regulation of cell growth and programmed cell death secondary to GPER-regulated second-messenger pathways. GPER is expressed ubiquitously and has diverse biological effects, including regulation of endocrine, immune, neuronal, and cardiovascular functions...
October 21, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27814027/harnessing-big-data-for-systems-pharmacology
#5
Lei Xie, Eli J Draizen, Philip E Bourne
Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets...
October 13, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732830/introduction-to-the-theme-new-methods-and-novel-therapeutic-approaches-in-pharmacology-and-toxicology
#6
Paul A Insel, Susan G Amara, Terrence F Blaschke, Urs A Meyer
Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e.g., nanobodies and techniques to explore proteinprotein interactions), new types of therapeutics (e...
October 12, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732799/critical-functions-of-the-lysosome-in-cancer-biology
#7
Shawn M Davidson, Matthew G Vander Heiden
Lysosomes (or lytic bodies) were so named because they contain high levels of hydrolytic enzymes. Lysosome function and dysfunction have been found to play important roles in human disease, including cancer; however, the ways in which lysosomes contribute to tumorigenesis and cancer progression are still being uncovered. Beyond serving as a cellular recycling center, recent evidence suggests that the lysosome is involved in energy homeostasis, generating building blocks for cell growth, mitogenic signaling, priming tissues for angiogenesis and metastasis formation, and activating transcriptional programs...
October 12, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732798/targeted-protein-degradation-by-small-molecules
#8
Daniel P Bondeson, Craig M Crews
Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to disrupt protein homeostasis, more recently identified techniques have been used to repurpose homeostatic networks to effect degradation of disease-relevant proteins. Here, we review recent advances in the use of small molecules to degrade proteins in a selective manner. First, we highlight all-small-molecule techniques with direct clinical application...
October 12, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732797/nanodomain-regulation-of-cardiac-cyclic-nucleotide-signaling-by-phosphodiesterases
#9
Kristen Kokkonen, David A Kass
Cyclic nucleotide phosphodiesterases (PDEs) form an 11-member superfamily comprising 100 different isoforms that regulate the second messengers cyclic adenosine or guanosine 3',5'-monophosphate (cAMP or cGMP). These PDE isoforms differ with respect to substrate selectivity and their localized control of cAMP and cGMP within nanodomains that target specific cellular pools and synthesis pathways for the cyclic nucleotides. Seven PDE family members are physiologically relevant to regulating cardiac function, disease remodeling of the heart, or both: PDE1 and PDE2, both dual-substrate (cAMP and cGMP) esterases; PDE3, PDE4, and PDE8, which principally hydrolyze cAMP; and PDE5A and PDE9A, which target cGMP...
October 12, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732801/adipose-vascular-coupling-and-potential-therapeutics
#10
Maik Gollasch
Excess visceral adipose tissue is associated with increased risk of high blood pressure, lipid disorders, type 2 diabetes, and cardiovascular disease. Adipose tissue is an endocrine organ with multiple humoral and metabolic roles in regulating whole-body physiology. However, perivascular adipose tissue (PVAT) also plays a functional role in regulating the contractile state of the underlying smooth muscle cell layer. Work during the past decade has shown that this adipose-vascular coupling is achieved by production of numerous substances released from PVAT...
October 10, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732800/pharmacology-of-antisense-drugs
#11
C Frank Bennett, Brenda F Baker, Nguyen Pham, Eric Swayze, Richard S Geary
Recent studies have led to a greater appreciation of the diverse roles RNAs play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides are the most direct means to target RNA in a selective manner and have become an established platform technology for drug discovery. There are multiple molecular mechanisms by which antisense oligonucleotides can be used to modulate RNAs in cells, including promoting the degradation of the targeted RNA or modulating RNA function without degradation...
October 10, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27648763/intestinal-and-hepatocellular-transporters-therapeutic-effects-and-drug-interactions-of-herbal-supplements
#12
Bruno Stieger, Zainab M Mahdi, Walter Jäger
Herbal supplements are generally considered safe; however, drug disposition is influenced by the interactions of herbal supplements and food constituents with transport and metabolic processes. Although the interference of herbal supplements with drug metabolism has been studied extensively, knowledge of how they interact with the drug transport processes is less advanced. Therefore, we describe here specific examples of experimental and human interaction studies of herbal supplement components with drug transporters addressing, for example, organic anion transporting polypeptides or P-glycoprotein, as such interactions may lead to severe side effects and altered drug efficacy...
September 14, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27618737/strategies-to-develop-inhibitors-of-motif-mediated-protein-protein-interactions-as-drug-leads
#13
Carles Corbi-Verge, Michael Garton, Satra Nim, Philip M Kim
Protein-protein interactions are fundamental for virtually all functions of the cell. A large fraction of these interactions involve short peptide motifs, and there has been increased interest in targeting them using peptide-based therapeutics. Peptides benefit from being specific, relatively safe, and easy to produce. They are also easy to modify using chemical synthesis and molecular biology techniques. However, significant challenges remain regarding the use of peptides as therapeutic agents. Identification of peptide motifs is difficult, and peptides typically display low cell permeability and sensitivity to enzymatic degradation...
September 8, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27618736/challenges-and-opportunities-in-protease-activated-receptor-drug-development
#14
Justin R Hamilton, JoAnn Trejo
Protease-activated receptors (PARs) are a unique class ofGprotein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging...
September 8, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27618738/changing-provider-behavior-in-the-context-of-chronic-disease-management-focus-on-clinical-inertia
#15
Kim L Lavoie, Joshua A Rash, Tavis S Campbell
Widespread acceptance of evidence-based medicine has led to the proliferation of clinical practice guidelines as the primary mode of communicating current best practices across a range of chronic diseases. Despite overwhelming evidence supporting the benefits of their use, there is a long history of poor uptake by providers. Nonadherence to clinical practice guidelines is referred to as clinical inertia and represents provider failure to initiate or intensify treatment despite a clear indication to do so. Here we review evidence for the ubiquity of clinical inertia across a variety of chronic health conditions, as well as the organizational and system, patient, and provider factors that serve to maintain it...
September 7, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27618739/don-t-worry-be-happy-endocannabinoids-and-cannabis-at-the-intersection-of-stress-and-reward
#16
Nora D Volkow, Aidan J Hampson, Ruben Baler
Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis...
September 2, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27575715/cns-target-identification-and-validation-avoiding-the-valley-of-death-or-naive-optimism
#17
P H Hutson, J A Clark, A J Cross
There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial. However, selecting the most biologically plausible molecular targets that are relevant to the disorder is a critical first step to improve the probability of success...
August 15, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27575716/pcsk9-regulation-and-target-for-drug-development-for-dyslipidemia
#18
Amy C Burke, Jacqueline S Dron, Robert A Hegele, Murray W Huff
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes...
August 8, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27483340/a-life-of-neurotransmitters
#19
Solomon H Snyder
Development of scientific creativity is often tied closely to mentorship. In my case, two years with Julius Axelrod, the sum total of my research training, was transformative. My mentoring generations of graduate students and postdoctoral fellows has been as nurturing for me as it has been for them. Work in our lab over fifty years has covered the breadth of neurotransmitters and related substances, focusing on the discovery and characterization of novel messenger molecules. I can't conceptualize a more rewarding professional life...
July 22, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27483339/accelerating-drug-development-antiviral-therapies-for-emerging-viruses-as-a-model
#20
Maaike Everts, Tomas Cihlar, J Robert Bostwick, Richard J Whitley
Drug discovery and development is a lengthy and expensive process. Although no one simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure...
July 22, 2016: Annual Review of Pharmacology and Toxicology
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