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Current Opinion in Pharmacology

Daniel Konstantinou, Nina Bertaux-Skeirik, Yana Zavros
The Hedgehog (Hh) signaling pathway not only plays a key part in controlling embryonic development, but in the adult stomach governs important cellular events such as epithelial cell differentiation, proliferation, gastric disease, and regeneration. In particular, Sonic Hedgehog (Shh) signaling has been well studied for its role in gastric physiology and pathophysiology. Shh is secreted from the gastric parietal cells and contributes to the regeneration of the epithelium in response to injury, or the development of gastritis during Helicobacter pylori infection...
October 14, 2016: Current Opinion in Pharmacology
Graham J Dockray, Andrea Varro
No abstract text is available yet for this article.
October 10, 2016: Current Opinion in Pharmacology
Malcolm Boyce, Katie A Lloyd, D Mark Pritchard
Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCK2R) binding and downstream signalling. Studies in animal models, healthy subjects and patients with gastric neuroendocrine tumours provide compelling evidence to justify developing a CCK2R antagonist (CCK2RA) for preventing or treating the trophic effects of hypergastrinaemia or conditions expressing CCK2R, and with or without a proton pump inhibitor, for treating gastric acid-related conditions...
October 3, 2016: Current Opinion in Pharmacology
Kyong-Mi Chang, Mengfei Liu
No abstract text is available yet for this article.
October 1, 2016: Current Opinion in Pharmacology
Min Gao, Donald R O'Boyle, Susan Roberts
The development of anti-HCV drugs is one of the most successful stories of antiviral therapy. In fact, for the first time in human history we have the potential to eradicate a chronic viral infection using only orally administered direct antiviral agents (DAAs). HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (DCV, BMS-790052, Daklinza®), are a new class of DAA. The astonishing in vitro potency of DCV (pM to low nM range) translated to remarkable efficacy in clinical trials, and 2nd generation NS5A inhibitors have become essential components of HCV combination therapies...
September 16, 2016: Current Opinion in Pharmacology
Arnau Cordomí, Daniel Fourmy, Irina G Tikhonova
Crystallization and determination of the high resolution three-dimensional structure of the β2-adrenergic receptor in 2007 was followed by structure elucidation of a number of other receptors, including those for neurotensin and glucagon. These major advances foster the understanding of structure-activity relationship of these receptors and structure-based rational design of new ligands having more predictable activity. At present, structure determination of gut hormone receptors in complex with their ligands (natural, synthetic) and interacting signalling proteins, for example, G-proteins, arrestins, represents a challenge which promises to revolutionize gut hormone endocrinonology...
September 16, 2016: Current Opinion in Pharmacology
Peter Revill, Stephen Locarnini
It has been over 50 years since the discovery of hepatitis B virus (HBV), yet 240 million people worldwide live with chronic HBV, resulting in up to 800000 deaths per year. A cure is yet to be achieved, due largely to a viral nuclear reservoir of transcriptionally active covalently closed circular DNA (cccDNA). While current antiviral therapies are effective at reducing viral replication, they have no impact on the existing cccDNA reservoir. Identifying mechanisms to either eliminate (complete cure) or inactivate (functional cure) HBV cccDNA are a major focus of HBV research worldwide...
September 15, 2016: Current Opinion in Pharmacology
Anthony P Cardile, Lydia G Downey, Perry D Wiseman, Travis K Warren, Sina Bavari
There have been significant developments in Ebola virus therapeutics. While the efficacy of several products was evaluated in the recent West Africa outbreak, a licensed treatment for EBOV disease remains elusive. Factors that negatively impacted the execution of clinical trials included an overall lack of world readiness to conduct clinical trials in an outbreak setting, ethical concerns limiting implementation of the randomized controlled trials in an outbreak setting, and a decline in case numbers by the time resources were mobilized to conduct clinical trials...
September 14, 2016: Current Opinion in Pharmacology
Andrew G Cole
The search for a cure for hepatitis B virus infection extends beyond interferon and the existing polymerase inhibitors, and targets different aspects of the virus life cycle to develop agents that operate by alternative mechanisms. Examples of small molecules that disrupt the encapsidation of pgRNA have been known for some time, but recent advances in the understanding of nucleocapsid formation, how compounds interact with core protein, and the development of drug-like molecules have recently progressed the study of capsid assembly modulators to proof of concept in the clinic with respect to reduction of viral load in chronic HBV patients...
September 13, 2016: Current Opinion in Pharmacology
Marcella Bassetto, Alberto Massarotti, Antonio Coluccia, Andrea Brancale
Structural biology has emerged during the last thirty years as a powerful tool for rational drug discovery. Crystal structures of biological targets alone and in complex with ligands and inhibitors provide essential insights into the mechanisms of actions of enzymes, their conformational changes upon ligand binding, the architectures and interactions of binding pockets. Structure-based methods such as crystallographic fragment screening represent nowadays invaluable instruments for the identification of new biologically active compounds...
September 6, 2016: Current Opinion in Pharmacology
Brian M Moran, Aine M McKillop, Finbarr Pm O'Harte
Incretin based glucagon-like peptide-1 receptor (GLP-1R) agonists which target a G-protein coupled receptor (GPCR) are currently used in the treatment of type 2 diabetes. This review focuses on GPCRs from pancreatic β-cells, including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon, somatostatin, pancreatic polypeptide (PP), cholecystokinin (CCK), peptide YY (PYY), oxyntomodulin (OXM) and ghrelin receptors. In addition, fatty acids GPCRs are thought to have an increasing role in regulating peptide secretions namely short fatty acids GPCR (GPR41, GPR43), medium chain fatty acid GPCR (GPR84), long chain fatty acid GPCR (GPR40, GPR120) and cannabinoid-like GPCR (GPR55, GPR119)...
September 5, 2016: Current Opinion in Pharmacology
Helen M Cox
Enteroendocrine cells (EECs) contain different combinations of hormones, which are released following stimulation of nutrient receptors that are selectively expressed by these cells. This chemosensation varies according to the intestinal area and species of interest, and responses to meals are rapidly modified following bariatric surgery. Such surgically-induced gastrointestinal (GI) changes highlight considerable enteroplasticity, however our understanding of even the acute physiological control and consequences of neuroendocrine peptide release is still under-developed...
September 3, 2016: Current Opinion in Pharmacology
Surya Panicker Rajeev, John Wilding
Glucagon-like peptide receptor agonists (GLP-1 RA) have multiple effects, including control of glycaemia via stimulation of insulin and suppression of glucagon secretion and reduction of adiposity by enhancing satiety, so are an attractive therapeutic option in type 2 diabetes management. Five GLP-1 RA are used currently and more are in development. The HbA1c reduction obtained varies from 1 to 2%; they reduce body weight by about 2-3kg when used to treat T2DM, while liraglutide results in greater weight loss at a higher dose and has recently been approved for the management of obesity...
September 1, 2016: Current Opinion in Pharmacology
Guillaume de Lartigue, Charlene Diepenbroek
Vagal afferent neurons (VANs) play an important role in the control of food intake by signaling nutrient type and quantity to the brain. Recent findings are broadening our view of how VANs impact not only food intake but also energy homeostasis. This review focuses exclusively on studies of the vagus nerve from the past 2 years that highlight major new advancements in the field. We firstly discuss evidence that VANs can directly sense nutrients, and we consider new insights into mechanisms affecting sensing of gastric distension and signaling by gastrointestinal hormones ghrelin and GLP1...
September 1, 2016: Current Opinion in Pharmacology
Yoku Hayakawa, Wenju Chang, Guangchun Jin, Timothy C Wang
Gastrin was initially identified as the hormone primarily responsible for gastric acid secretion, but was subsequently shown to be a growth factor for the proximal stomach, acting through the gastrin receptor CCK2R. Studies in the past several decades have explored the role of gastrin, along with its incompletely processed precursors, in cancer development. The growth in long-term PPI use has frequently led to elevations in serum gastrin levels in patients with upper GI disease, including GERD, peptic ulcers, and chronic gastritis...
August 31, 2016: Current Opinion in Pharmacology
Philip Prinz, Andreas Stengel
Nesfatin-1, an 82 amino acid peptide was discovered in 2006 in the rat hypothalamus and described as a centrally acting anorexigenic peptide. Besides its central expression and actions, NUCB2/nesfatin-1 has been subsequently described to be predominantly expressed in the periphery and to exert several peripheral effects. The current review focuses on the expression sites of NUCB2/nesfatin-1 in peripheral tissues of different species and its regulation by nutrition, body weight and various other parameters such as fetal development and sex...
August 30, 2016: Current Opinion in Pharmacology
Philip Prinz, Andreas Stengel
This review summarizes current data focusing on the peripheral effects of NUCB2/nesfatin-1 including the regulation of food intake, glucose homeostasis, lipid metabolism, cardiovascular effects and reproductive functions as well as its possible involvement in psychological disorders. Additionally, we will highlight gaps in knowledge in order to stimulate further research. Lastly, we will give an outlook on potential therapeutic implications of this pleiotropic peptide.
August 30, 2016: Current Opinion in Pharmacology
Kaori Austin, Melanie A Markovic, Patricia L Brubaker
Glucagon-like peptide-2 (GLP-2) is a gut hormone that promotes highly specific growth and function of the intestinal epithelium. Recent studies have begun to elucidate the complex mechanism of action of GLP-2, which is mediated indirectly through other intestinal factors. Although a long-acting GLP-2 analog has recently been approved for treatment of adult patients with short bowel syndrome, there remain numerous conditions characterized by intestinal insufficiency for which pre-clinical studies, as well as some limited clinical data, support further consideration of GLP-2 for expanded therapeutic use...
August 28, 2016: Current Opinion in Pharmacology
John T McLaughlin, Shane McKie
Functional mapping of human brain activation has made it possible to understand how different nutrients in the gut impact on homeostatic and appetitive brain responses. Current data are limited, but nutrient-specific effects are observed, with differential responses to lipid and sugars. Responses are not a simple function of calorie intake. Gut hormones such as CCK, PYY, GLP-1 and ghrelin are implicated in these responses, but may not exert effects directly on the brain. Research is now addressing how these homeostatic signalling states (fasting/fed) interact with hedonic responses, such as those evoked by images of appealing food...
August 27, 2016: Current Opinion in Pharmacology
Lieve Naesens, Annelies Stevaert, Evelien Vanderlinden
Adequate response to severe influenza infections or pandemic outbreaks requires two complementary strategies: preventive vaccination and antiviral therapy. The existing influenza drugs, M2 blockers and neuraminidase inhibitors, show modest clinical efficacy and established or potential resistance. In the past three years, several new agents have entered the clinical pipeline and already yielded some promising data from Phase 2 trials. For two main categories, that is, the broadly neutralizing anti-hemagglutinin antibodies and small-molecule inhibitors of the viral polymerase complex, crystallography was instrumental to guide drug development...
August 25, 2016: Current Opinion in Pharmacology
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