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Annual Review of Pharmacology and Toxicology

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https://www.readbyqxmd.com/read/28061690/organophosphorus-xenobiotic-toxicology
#1
John E Casida
Originally, organophosphorus (OP) toxicology consisted of acetylcholinesterase inhibition by insecticides and chemical threat agents acting as phosphorylating agents for serine in the catalytic triad, but this is no longer the case. Other serine hydrolases can be secondary OP targets, depending on the OP structure, and include neuropathy target esterase, lipases, and endocannabinoid hydrolases. The major OP herbicides are glyphosate and glufosinate, which act in plants but not animals to block aromatic amino acid and glutamine biosynthesis, respectively, with safety for crops conferred by their expression of herbicide-tolerant targets and detoxifying enzymes from bacteria...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28061689/mitochondrial-mechanisms-of-neuronal-cell-death-potential-therapeutics
#2
Ted M Dawson, Valina L Dawson
Mitochondria lie at the crossroads of neuronal survival and cell death. They play important roles in cellular bioenergetics, control intracellular Ca(2+) homeostasis, and participate in key metabolic pathways. Mutations in genes involved in mitochondrial quality control cause a myriad of neurodegenerative diseases. Mitochondria have evolved strategies to kill cells when they are not able to continue their vital functions. This review provides an overview of the role of mitochondria in neurologic disease and the cell death pathways that are mediated through mitochondria, including their role in accidental cell death, the regulated cell death pathways of apoptosis and parthanatos, and programmed cell death...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28061688/aptamers-as-therapeutics
#3
Shahid M Nimjee, Rebekah R White, Richard C Becker, Bruce A Sullenger
Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28061687/new-targets-for-drug-treatment-of-obesity
#4
Georgios Valsamakis, Panagiota Konstantakou, George Mastorakos
Antiobesity medical management has shown unsatisfactory results to date in terms of efficacy, safety, and long-term maintenance of weight loss. This poor performance could be attributed to the complexity of appetite regulation mechanisms; the serious drug side effects; and, crucially, the lack of profile-matching treatment strategies and individualized, multidisciplinary follow-up. Nevertheless, antiobesity pharmacotherapy remains a challenging, exciting field of intensive scientific interest. According to the latest studies, the future of bariatric medicine lies in developing drugs acting at multiple levels of the brain-gut axis...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28061686/autophagy-a-druggable-process
#5
Etienne Morel, Maryam Mehrpour, Joëlle Botti, Nicolas Dupont, Ahmed Hamaï, Anna Chiara Nascimbeni, Patrice Codogno
Macroautophagy (hereafter called autophagy) is a vacuolar, lysosomal pathway for catabolism of intracellular material that is conserved among eukaryotic cells. Autophagy plays a crucial role in tissue homeostasis, adaptation to stress situations, immune responses, and the regulation of the inflammatory response. Blockade or uncontrolled activation of autophagy is associated with cancer, diabetes, obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28061685/innovative-approaches-to-improve-anti-infective-vaccine-efficacy
#6
Michael R Yeaman, John P Hennessey
Safe and efficacious vaccines are arguably the most successful medical interventions of all time. Yet the ongoing discovery of new pathogens, along with emergence of antibiotic-resistant pathogens and a burgeoning population at risk of such infections, imposes unprecedented public health challenges. To meet these challenges, innovative strategies to discover and develop new or improved anti-infective vaccines are necessary. These approaches must intersect the most meaningful insights into protective immunity and advanced technologies with capabilities to deliver immunogens for optimal immune protection...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27959624/will-there-be-a-cure-for-ebola
#7
Anthony P Cardile, Travis K Warren, Karen A Martins, Ronald B Reisler, Sina Bavari
Despite the unprecedented Ebola virus outbreak response in West Africa, no Ebola medical countermeasures have been approved by the US Food and Drug Administration. However, multiple valuable lessons have been learned about the conduct of clinical research in a resource-poor, high risk-pathogen setting. Numerous therapeutics were explored or developed during the outbreak, including repurposed drugs, nucleoside and nucleotide analogues (BCX4430, brincidofovir, favipiravir, and GS-5734), nucleic acid-based drugs (TKM-Ebola and AVI-7537), and immunotherapeutics (convalescent plasma and ZMapp)...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27959623/nanobodies-to-study-g-protein-coupled-receptor-structure-and-function
#8
Aashish Manglik, Brian K Kobilka, Jan Steyaert
Ligand-induced activation of G protein-coupled receptors (GPCRs) is a key mechanism permitting communication between cells and organs. Enormous progress has recently elucidated the structural and dynamic features of GPCR transmembrane signaling. Nanobodies, the recombinant antigen-binding fragments of camelid heavy-chain-only antibodies, have emerged as important research tools to lock GPCRs in particular conformational states. Active-state stabilizing nanobodies have elucidated several agonist-bound structures of hormone-activated GPCRs and have provided insight into the dynamic character of receptors...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27860548/mitochondrial-dysfunction-and-myocardial-ischemia-reperfusion-implications-for-novel-therapies
#9
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27860547/the-discovery-of-suvorexant-the-first-orexin-receptor-drug-for-insomnia
#10
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27814027/harnessing-big-data-for-systems-pharmacology
#11
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...
January 6, 2017: 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
#12
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27814025/stem-cell-extracellular-vesicles-extended-messages-of-regeneration
#13
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...
January 6, 2017: 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
#14
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 protein-protein interactions), new types of therapeutics (e...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732801/adipose-vascular-coupling-and-potential-therapeutics
#15
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732800/pharmacology-of-antisense-drugs
#16
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732799/critical-functions-of-the-lysosome-in-cancer-biology
#17
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732798/targeted-protein-degradation-by-small-molecules
#18
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27732797/nanodomain-regulation-of-cardiac-cyclic-nucleotide-signaling-by-phosphodiesterases
#19
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27648763/intestinal-and-hepatocellular-transporters-therapeutic-effects-and-drug-interactions-of-herbal-supplements
#20
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...
January 6, 2017: Annual Review of Pharmacology and Toxicology
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