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Trends in Pharmacological Sciences

Vsevolod V Gurevich, Eugenia V Gurevich
Until the late 1990s, class A G protein-coupled receptors (GPCRs) were believed to function as monomers. Indirect evidence that they might internalize or even signal as dimers has emerged, along with proof that class C GPCRs are obligatory dimers. Crystal structures of GPCRs and their much larger binding partners were consistent with the idea that two receptors might engage a single G protein, GRK, or arrestin. However, recent biophysical, biochemical, and structural evidence invariably suggests that a single GPCR binds G proteins, GRKs, and arrestins...
May 5, 2018: Trends in Pharmacological Sciences
Theodora Vasilogiannakopoulou, Christina Piperi, Athanasios G Papavassiliou
High-grade gliomas are primary brain tumors with a highly aggressive, invasive phenotype and dismal outcome. Targeting cell metabolism and cancer bioenergetics has emerged as a potential effective therapeutic approach. Selective aldehyde dehydrogenase isoenzyme activity regulates glioma tumor growth, invasiveness, and resistance to current treatments, and has potential as a therapeutic target.
May 1, 2018: Trends in Pharmacological Sciences
Erwin Sigel, Margot Ernst
Everyday activity is based on a subtle equilibrium of excitatory and inhibitory neuronal systems. The most prominent players in neuronal inhibition are synaptic and extrasynaptic GABAA receptors. Benzodiazepines are popular drugs that act as positive allosteric modulators of a subset of these receptors. Benzodiazepines have sedative, hypnotic, muscle-relaxant, and anticonvulsive effects, and are of outstandingly low overdose risk. The discovery of a large number of subtypes of GABAA receptors has raised hopes for a clear separation of this spectrum of actions...
April 28, 2018: Trends in Pharmacological Sciences
Peter Rose, Philip Keith Moore, Yi-Zhun Zhu
Garlic (Allium sativum) and allied plant species are rich sources of sulfur compounds. Major roles for garlic and its sulfur constituents include the regulation of vascular homeostasis and the control of metabolic systems linked to nutrient metabolism. Recent studies have indicated that some of these sulfur compounds, such as diallyl trisulfide (DATS), alter the levels of gaseous signalling molecules including nitric oxide (NO), hydrogen sulfide (H2 S), and perhaps carbon monoxide (CO) in mammalian tissues...
April 26, 2018: Trends in Pharmacological Sciences
Marveh Rahmati, Mohammad Amin Moosavi, Michael F McDermott
Diverse physiological and pathological conditions that impact on protein folding of the endoplasmic reticulum (ER) cause ER stress. The unfolded protein response (UPR) and the ER-associated degradation (ERAD) pathway are activated to cope with ER stress. In rheumatoid arthritis (RA), inflammation and ER stress work in parallel by driving inflammatory cells to release cytokines that induce chronic ER stress pathways. This chronic ER stress may contribute to the pathogenesis of RA through synoviocyte proliferation and proinflammatory cytokine production...
April 22, 2018: Trends in Pharmacological Sciences
Lin-Cheng Ju, Zishuo Cheng, Walter Fast, Robert A Bonomo, Michael W Crowder
Metallo-β-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all β-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure-activity relationship interpretation...
April 18, 2018: Trends in Pharmacological Sciences
Bojun Wang, Tian Tian, Karl-Henning Kalland, Xisong Ke, Yi Qu
Despite the dramatic antitumor efficiency of certain immune checkpoint inhibitors, immunotherapy has met a bottleneck regarding the response rate and resistance in cancer patients. Increasing evidence indicates that Wnt/β-catenin signaling, one of the best-characterized cancer drivers, promotes cancer progression by regulating the tumor-immune cycle in most of the nodes, including dendritic cells, T cells, and tumor cells. Specifically, abnormal Wnt/β-catenin signaling directly alters a number of regulators critical for the antitumor activities of T cells, especially effector T cells, T helper cells, and regulatory T cells...
April 17, 2018: Trends in Pharmacological Sciences
Dante J Marciani
Numerous triterpenoid saponins are adjuvants that modify the activities of T cells and antigen-presenting cells, like dendritic cells (DCs). Saponins can induce either proinflammatory Th1/Th2 or sole anti-inflammatory Th2 immunities. Structure-activity relationships (SARs) have shown that imine-forming carbonyl groups are needed for T cell activation leading to induction of Th1/Th2 immunities. While saponins having different triterpenoid aglycons and oligosaccharide chains can activate DCs to induce Th1/Th2 immunoresponses, fucopyranosyl residues from their oligosaccharides by binding to the DC-SIGN receptor can bias DCs toward a sole Th2 immunity...
April 11, 2018: Trends in Pharmacological Sciences
Natalia V Ortiz Zacarías, Eelke B Lenselink, Adriaan P IJzerman, Tracy M Handel, Laura H Heitman
Recent crystal structures of multiple G protein-coupled receptors (GPCRs) have revealed a highly conserved intracellular pocket that can be used to modulate these receptors from the inside. This novel intracellular site partially overlaps with the G protein and β-arrestin binding site, providing a new manner of pharmacological intervention. Here we provide an update of the architecture and function of the intracellular region of GPCRs, until now portrayed as the signaling domain. We review the available evidence on the presence of intracellular binding sites among chemokine receptors and other class A GPCRs, as well as different strategies to target it, including small molecules, pepducins, and nanobodies...
April 10, 2018: Trends in Pharmacological Sciences
Susann Matthes, Michael Bader
The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed which cannot pass the blood-brain barrier to specifically block peripheral 5-HT synthesis...
April 5, 2018: Trends in Pharmacological Sciences
Kristin R Peterson, Matthew A Cottam, Arion J Kennedy, Alyssa H Hasty
Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages...
April 5, 2018: Trends in Pharmacological Sciences
Daniela Strobbe, Michelangelo Campanella
The complex biochemistry and dynamic structure of mitochondria have prevented them from being prominent pharmacological targets. New mechanistic understanding of cholesterol transport and associated neurosteroidogenesis is providing evidence on therapeutic outcomes in mental disorders that is achievable via mitochondrial pharmacology. This warrants general attention on mitochondrial pharmacology to inform therapies.
March 30, 2018: Trends in Pharmacological Sciences
Xavier Palomer, Javier Pizarro-Delgado, Manuel Vázquez-Carrera
The diabetic heart is characterized by metabolic disturbances that are often accompanied by local inflammation, oxidative stress, myocardial fibrosis, and cardiomyocyte apoptosis. Overall changes result in contractile dysfunction, concentric left ventricular (LV) hypertrophy, and dilated cardiomyopathy, that together affect cardiac output and eventually lead to heart failure, the foremost cause of death in diabetic patients. There are currently several validated biomarkers for the diagnosis and risk assessment of cardiac diseases, but none is capable of discriminating patients with diabetic cardiomyopathy (DCM)...
March 28, 2018: Trends in Pharmacological Sciences
Mireille Alhouayek, Julien Masquelier, Giulio G Muccioli
Lysophosphatidylinositols (LPIs) are membrane constituents that alter the properties of said membranes. However, recent data showing that the once orphan receptor, GPR55, can act as a receptor for LPIs has sparked a renewed interest in LPIs as bioactive lipids. As evidence supporting the importance of LPIs and/or GPR55 is continuously accumulating and because LPI levels are altered in a number of pathologies such as obesity and cancer, the coming years should bring new, exciting discoveries to this field. In this review, we discuss the recent work on LPIs and on their molecular target, the GPR55 receptor...
March 24, 2018: Trends in Pharmacological Sciences
Márton Vass, Albert J Kooistra, Dehua Yang, Raymond C Stevens, Ming-Wei Wang, Chris de Graaf
G protein-coupled receptors (GPCRs) are the largest family of cell signaling transmembrane proteins that can be modulated by a plethora of chemical compounds. Systematic cheminformatics analysis of structurally and pharmacologically characterized GPCR ligands shows that cocrystallized GPCR ligands cover a significant part of chemical ligand space, despite their limited number. Many GPCR ligands and substructures interact with multiple receptors, providing a basis for polypharmacological ligand design. Experimentally determined GPCR structures represent a variety of binding sites and receptor-ligand interactions that can be translated to chemically similar ligands for which structural data are lacking...
March 22, 2018: Trends in Pharmacological Sciences
Alba Di Pardo, Vittorio Maglione
Huntington's disease (HD) is a single-gene inheritable neurodegenerative disorder with an associated complex molecular pathogenic profile that renders it the most 'curable incurable' brain disorder. Continuous effort in the field has contributed to the recent discovery of novel potential pathogenic mechanisms. Findings in preclinical models of the disease as well as in human post-mortem brains from affected patients demonstrate that alteration of the sphingosine-1-phosphate (S1P) axis may represent a possible key player in the pathogenesis of the disease and may act as a potential actionable drug target for the development of more targeted and effective therapeutic approaches...
March 17, 2018: Trends in Pharmacological Sciences
Misty M Attwood, Mathias Rask-Andersen, Helgi B Schiöth
High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation...
June 2018: Trends in Pharmacological Sciences
Graeme Milligan, Asuka Inoue
Rapid developments in genome editing, based largely on CRISPR/Cas9 technologies, are offering unprecedented opportunities to eliminate the expression of single or multiple gene products in intact organisms and in model cell systems. Elimination of individual G protein-coupled receptors (GPCRs), both single and multiple G protein subunits, and arrestin adaptor proteins is providing new and sometimes unanticipated insights into molecular details of the regulation of cell signalling pathways and the behaviour of receptor ligands...
May 2018: Trends in Pharmacological Sciences
Sarah J Trenfield, Atheer Awad, Alvaro Goyanes, Simon Gaisford, Abdul W Basit
3D printing (3DP) is forecast to be a highly revolutionary technology within the pharmaceutical sector. In particular, the main benefits of 3DP lie in the production of small batches of medicines, each with tailored dosages, shapes, sizes and release characteristics. The manufacture of medicines in this way may finally lead to the concept of personalised medicines becoming a reality. In the shorter term, 3DP could be extended throughout the drug development process, ranging from preclinical development and clinical trials, through to frontline medical care...
May 2018: Trends in Pharmacological Sciences
Bindu D Paul, Juan I Sbodio, Solomon H Snyder
Besides its essential role in protein synthesis, cysteine plays vital roles in redox homeostasis, being a component of the major antioxidant glutathione (GSH) and a potent antioxidant by itself. In addition, cysteine undergoes a variety of post-translational modifications that modulate several physiological processes. It is becoming increasingly clear that redox-modulated events play important roles not only in peripheral tissues but also in the brain where cysteine disposition is central to these pathways...
May 2018: Trends in Pharmacological Sciences
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