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Trends in Pharmacological Sciences

Matthew Hearing, Nicholas Graziane, Yan Dong, Mark J Thomas
Commonalities in addictive behavior, such as craving, stimuli-driven drug seeking, and a high propensity for relapse following abstinence, have pushed for a unified theory of addiction that encompasses most abused substances. This unitary theory has recently been challenged - citing distinctions in structural neural plasticity, biochemical signaling, and neural circuitry to argue that addiction to opioids and psychostimulants is behaviorally and neurobiologically distinct. Recent more selective examination of drug-induced plasticity has highlighted that these two drug classes promote an overall reward circuitry signaling overlap through modifying excitatory synapses in the nucleus accumbens - a key constituent of the reward system...
January 12, 2018: Trends in Pharmacological Sciences
Rodney Rouse, Issam Zineh, David G Strauss
Translational science refers to translating basic scientific findings to practical application (i.e., 'bench-to-bedside'). An underappreciated aspect of translational science is regulatory science. Herein, we focus on the importance of regulatory science to facilitate development of innovative new drugs and optimize use of approved drugs, with a call for community participation.
January 9, 2018: Trends in Pharmacological Sciences
Feng Zhu, Xiao Xu Li, Sheng Yong Yang, Yu Zong Chen
The selection of the right drug targets is critically important for the successful and cost-effective development and clinical testing of drugs. A 2009 paper reported an in silico prospective prediction of the clinical potential of 156 targets of clinical trial drugs (all of these targets were without an approved drug at the time of the paper's publication). Eight years later, the assessment of the clinical status of these targets revealed impressive capability of the in silico method in prospectively predicting the clinical success of drug targets...
December 30, 2017: Trends in Pharmacological Sciences
Nshunge Musheshe, Martina Schmidt, Manuela Zaccolo
How cAMP generates hormone-specific effects has been debated for many decades. Fluorescence resonance energy transfer (FRET)-based sensors for cAMP allow real-time imaging of the second messenger in intact cells with high spatiotemporal resolution. This technology has made it possible to directly demonstrate that cAMP signals are compartmentalised. The details of such signal compartmentalisation are still being uncovered, and recent findings reveal a previously unsuspected submicroscopic heterogeneity of intracellular cAMP...
December 27, 2017: Trends in Pharmacological Sciences
Stephen J Briddon, Laura E Kilpatrick, Stephen J Hill
G protein-coupled receptors (GPCRs) are organised within the cell membrane into highly ordered macromolecular complexes along with other receptors and signalling proteins. Understanding how heterogeneity in these complexes affects the pharmacology and functional response of these receptors is crucial for developing new and more selective ligands. Fluorescence correlation spectroscopy (FCS) and related techniques such as photon counting histogram (PCH) analysis and image-based FCS can be used to interrogate the properties of GPCRs in these membrane microdomains, as well as their interaction with fluorescent ligands...
December 22, 2017: Trends in Pharmacological Sciences
Stephen J Hill, Stephen P Watson
No abstract text is available yet for this article.
December 21, 2017: Trends in Pharmacological Sciences
(no author information available yet)
No abstract text is available yet for this article.
December 16, 2017: Trends in Pharmacological Sciences
Jae Eun Cheong, Lijun Sun
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the commitment step of the kynurenine (KYN) metabolic pathway. Traditionally the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase general control nonderepressible 2 (GCN2). Emerging data have shed light on an unexpected role of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) in transducing the tumor immune escape function imparted by IDO1 and TDO2...
December 15, 2017: Trends in Pharmacological Sciences
Mark R Fielden, Lucas D Ward, Sheroy Minocherhomji, Paul Nioi, Herve Lebrec, David Jacobson-Kram
Cancer risk assessment of therapeutics is plagued by poor translatability of rodent models of carcinogenesis. In order to overcome this fundamental limitation, new approaches are needed that enable us to evaluate cancer risk directly in humans and human-based cellular models. Our enhanced understanding of the mechanisms of carcinogenesis and the influence of human genome sequence variation on cancer risk motivates us to re-evaluate how we assess the carcinogenic risk of therapeutics. This review will highlight new opportunities for applying this knowledge to the development of a battery of human-based in vitro models and biomarkers for assessing cancer risk of novel therapeutics...
December 11, 2017: Trends in Pharmacological Sciences
Ivana Vancurova, Mohammad M Uddin, Yue Zou, Ales Vancura
The rationale for developing histone deacetylase (HDAC) inhibitors (HDACi) as anticancer agents was based on their ability to induce apoptosis and cell cycle arrest in cancer cells. However, while HDACi have been remarkably effective in the treatment of hematological malignancies, clinical studies with HDACi as single agents in solid cancers have been disappointing. Recent studies have shown that, in addition to inducing apoptosis in cancer cells, class I HDACi induce IκB kinase (IKK)-dependent expression of proinflammatory chemokines, such as interleukin-8 (IL8; CXCL8), resulting in the increased proliferation of tumor cells, and limiting the effectiveness of HDACi in solid tumors...
December 9, 2017: Trends in Pharmacological Sciences
Hao Wang, Xiaoyu Mu, Hua He, Xiao-Dong Zhang
Radiotherapy (RT) is a mainstay treatment for many types of cancer, although it is still a large challenge to enhance radiation damage to tumor tissue and reduce side effects to healthy tissue. Radiosensitizers are promising agents that enhance injury to tumor tissue by accelerating DNA damage and producing free radicals. Several strategies have been exploited to develop highly effective and low-toxicity radiosensitizers. In this review, we highlight recent progress on radiosensitizers, including small molecules, macromolecules, and nanomaterials...
December 7, 2017: Trends in Pharmacological Sciences
Willem Jespers, Anke C Schiedel, Laura H Heitman, Robert M Cooke, Lisa Kleene, Gerard J P van Westen, David E Gloriam, Christa E Müller, Eddy Sotelo, Hugo Gutiérrez-de-Terán
The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A2A and inactive conformations of the A1 ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www...
December 1, 2017: Trends in Pharmacological Sciences
Ulrich Mrowietz, Peter John Morrison, Ina Suhrkamp, Margaret Kumanova, Bernd Clement
Fumaric acid ester-based drugs are used for the treatment of psoriasis and multiple sclerosis. All licensed fumaric acid ester drugs contain dimethylfumarate (DMF) as the main active component. Due to the expanding use of oral DMF there is growing scientific interest in determining its as-yet-unknown mechanism of action. However, the pharmacology and chemistry of DMF are often not fully considered in the design and interpretation of experiments; namely, that while DMF is plasma-membrane permeable and has strong effects on many cell types in vitro, it is rapidly metabolized into membrane-impermeable monomethylfumarate (MMF) in vivo...
November 25, 2017: Trends in Pharmacological Sciences
Michael Kauk, Carsten Hoffmann
Within the past decade, a large increase in structural knowledge from crystallographic studies has significantly fostered our understanding of the structural biology of G protein-coupled receptors (GPCRs). However, information on dynamic events upon receptor activation or deactivation is not yet readily accessed by these structural approaches. GPCR-based fluorescence resonance energy transfer or bioluminescence resonance energy transfer sensors or sensors for interacting proteins (e.g., G proteins or arrestins) can in part cover this gap...
November 24, 2017: Trends in Pharmacological Sciences
Davide Calebiro, Titiwat Sungkaworn
G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and are of great interest as pharmacological targets. Although the occurrence of GPCR signaling nanodomains has long been hypothesized based on indirect evidence, this and other fundamental aspects of GPCR signaling have been difficult to prove. The advent of single-molecule microscopy methods, which allow direct visualization of individual membrane proteins with unprecedented spatiotemporal resolution, provides unique opportunities to address several of these open questions...
November 17, 2017: Trends in Pharmacological Sciences
Qin Chen, Guangxuan Liu, Shuo Liu, Hongyan Su, Yue Wang, Jingyu Li, Cong Luo
The tumor microenvironment (TME) has profound impacts on cancer progression and remodeling of the TME has emerged as a strategy to facilitate cancer therapy. Recently, great progress in TME modulation has been made, especially with the rapid developments in nanomedicine. In this review we outline the latest advances in remodeling of the TME based on nanotherapeutics. First, novel strategies developed to modulate the tumor extracellular matrix (ECM) are discussed, including disruption, mimicking, and intervening in tumor ECM fabrication...
November 15, 2017: Trends in Pharmacological Sciences
Yoshinori Moriyama, Masatoshi Nomura
Clodronate is a first-generation bisphosphonate used worldwide for antiresorptive therapy for osteoporosis. Although clodronate is analgesic in nature, its mechanism and efficacy were unknown for some time. Recently, clodronate was identified as a selective and potent inhibitor for vesicular nucleotide transporter (VNUT), a transporter responsible for vesicular storage of ATP. Clodronate inhibits vesicular ATP release from neurons and reduces chronic neuropathic and inflammatory pain following blockade of purinergic chemical transmission...
November 13, 2017: Trends in Pharmacological Sciences
Leigh A Stoddart, Laura E Kilpatrick, Stephen J Hill
Recent advances in the development of fluorescent ligands for G-protein-coupled receptors (GPCRs) and receptor tyrosine kinase receptors (RTKs) have facilitated the study of these receptors in living cells. A limitation of these ligands is potential uptake into cells and increased nonspecific binding. However, this can largely be overcome by using proximity approaches, such as bioluminescence resonance energy transfer (BRET), which localise the signal (within 10nm) to the specific receptor target. The recent engineering of NanoLuc has resulted in a luciferase variant that is smaller and significantly brighter (up to tenfold) than existing variants...
November 10, 2017: Trends in Pharmacological Sciences
Igor V Kurochkin, Enrico Guarnera, Igor N Berezovsky
After decades of research and clinical trials there is still no cure for Alzheimer's disease (AD). While impaired clearance of amyloid beta (Aβ) peptides is considered as one of the major causes of AD, it was recently complemented by a potential role of other toxic amyloidogenic species. Insulin-degrading enzyme (IDE) is the proteolytic culprit of various β-forming peptides, both extracellular and intracellular. On the basis of demonstrated allosteric activation of IDE against Aβ, it is possible to propose a new strategy for the targeted IDE-based cleansing of different toxic aggregation-prone peptides...
November 10, 2017: Trends in Pharmacological Sciences
James H Felce, Simon J Davis, David Klenerman
How G protein-coupled receptors (GPCRs) are organized at the cell surface remains highly contentious. Single-molecule (SM) imaging is starting to inform this debate as receptor behavior can now be visualized directly, without the need for interpreting ensemble data. The limited number of SM studies of GPCRs undertaken to date have strongly suggested that dimerization is at most transient, and that most receptors are monomeric at any given time. However, even SM data has its caveats and needs to be interpreted carefully...
November 6, 2017: Trends in Pharmacological Sciences
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