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Trends in Pharmacological Sciences

Finn J Hawkins, Darrell N Kotton
Two recent studies have identified novel airway cells termed pulmonary ionocytes that express higher levels of CFTR than other airway cells express. These findings raise new questions in the evolving debate about the physiological role of CFTR in lung epithelia and its importance in the pathogenesis of cystic fibrosis (CF).
September 10, 2018: Trends in Pharmacological Sciences
Jagadeesh Bayry, Srini V Kaveri
Neonatal Fc receptors (FcRns) recycle IgGs by preventing their lysosome degradation. As this process also enhances half-life of pathogenic auto-IgG, inspired from the mechanisms of intravenous immunoglobulin, several inhibitors of IgG-FcRn interface have been conceived for treating autoimmune diseases. Among them, the high-affinity FcRn-binding engineered Fc molecule efgartigimod has recently completed phase I clinical trial.
September 7, 2018: Trends in Pharmacological Sciences
Glenn Hogan, Mark Tangney
Inquiry into declining pharmaceutical R&D efficiency has focussed on 'what' can be improved, with only brief thought given to 'who' can be improved. Here, we argue that enabling people in the idea-to-product chain to have a more holistic knowledge of the behaviours and incentives of each other can optimise R&D.
September 6, 2018: Trends in Pharmacological Sciences
Alex R B Thomsen, Dane D Jensen, Gareth A Hicks, Nigel W Bunnett
G-protein-coupled receptors (GPCRs) are conventionally considered to function at the plasma membrane, where they detect extracellular ligands and activate heterotrimeric G proteins that transmit intracellular signals. Consequently, drug discovery efforts have focused on identification of agonists and antagonists of cell surface GPCRs. However, β-arrestin (ARR)-dependent desensitization and endocytosis rapidly terminate G protein signaling at the plasma membrane. Emerging evidence indicates that GPCRs can continue to signal from endosomes by G-protein- and βARR-dependent processes...
September 1, 2018: Trends in Pharmacological Sciences
Ales Vancura, Pengli Bu, Madhura Bhagwat, Joey Zeng, Ivana Vancurova
Metformin has been a frontline therapy for type 2 diabetes (T2D) for many years. Its effectiveness in T2D treatment is mostly attributed to its suppression of hepatic gluconeogenesis; however, the mechanistic aspects of metformin action remain elusive. In addition to its glucose-lowering effect, metformin possesses other pleiotropic health-promoting effects that include reduced cancer risk and tumorigenesis. Metformin inhibits the electron transport chain (ETC) and ATP synthesis; however, recent data reveal that metformin regulates AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) by multiple, mutually nonexclusive mechanisms that do not necessarily depend on the inhibition of ETC and the cellular ATP level...
August 24, 2018: Trends in Pharmacological Sciences
Emanuele Canestrari, Zain Paroo
Across disease indications, there is immediate need for new drug targets. Target scarcity is reflected in a growing number of same-target drugs of marginal clinical value. Advances in RNA mechanisms of disease are revealing a windfall of targets for nucleic acids therapeutics. However, nucleic acids remain limited as pharmaceutical agents. Because enzymes are predominant drug targets, ribonucleases represent an established target class to capitalize on RNA mechanisms of disease. Analysis of the human proteome identified 122 ribonucleases...
August 22, 2018: Trends in Pharmacological Sciences
E Sally Ward, Raimund J Ober
The MHC class I-related receptor FcRn serves multiple roles ranging from the regulation of levels of IgG isotype antibodies and albumin throughout the body to the delivery of antigen into antigen loading compartments in specialized antigen-presenting cells. In parallel with studies directed towards understanding FcRn at the molecular and cellular levels, there has been an enormous expansion in the development of engineering strategies involving FcRn to modulate the dynamic behavior of antibodies, antigens, and albumin...
August 21, 2018: Trends in Pharmacological Sciences
Feng-Chi Chen
The manufacturing success in China has not yet radiated to the pharmaceutical sector. Recently, China released a policy guideline to foster its follow-on drug industry, revealing its ambition to become a great power in the field. Here, I briefly discuss how this guideline may change the industry landscape, and its associated challenges and opportunities.
August 8, 2018: Trends in Pharmacological Sciences
Gabriele Sulli, Emily N C Manoogian, Pam R Taub, Satchidananda Panda
Daily rhythms in behavior, physiology, and metabolism are an integral part of homeostasis. These rhythms emerge from interactions between endogenous circadian clocks and ambient light-dark cycles, sleep-activity cycles, and eating-fasting cycles. Nearly the entire primate genome shows daily rhythms in expression in tissue- and locus-specific manners. These molecular rhythms modulate several key aspects of cellular and tissue function with profound implications in public health, disease prevention, and disease management...
September 2018: Trends in Pharmacological Sciences
Tiantian Tang, Tao Gong, Wei Jiang, Rongbin Zhou
The NLRP3 inflammasome is an intracellular multimeric protein complex which plays an important role in the pathogenesis of various human inflammatory diseases, such as diabetes, Alzheimer's disease and atherosclerosis. Recently, various G protein-coupled receptors (GPCRs) have been reported to be involved in the activation and regulation of the NLRP3 inflammasome by sensing multiple ions, metabolites, and neurotransmitters, suggesting GPCR signaling is an important regulator for NLRP3 inflammasome. Here, we will review how various GPCRs promote or inhibit NLRP3 inflammasome activation and discuss the implications of GPCRs as drug targets for the therapy of NLRP3-driven diseases...
September 2018: Trends in Pharmacological Sciences
Gunnar Schulte, Shane C Wright
For more than 30 years, WNT/β-catenin and planar cell polarity signaling has formed the basis for what we understand to be the primary output of the interaction between WNTs and their cognate receptors known as Frizzleds (FZDs). In the shadow of these pathways, evidence for the involvement of heterotrimeric G proteins in WNT signaling has grown substantially over the years - redefining the complexity of the WNT signaling network. Moreover, the distinct characteristics of FZD paralogs are becoming better understood, and we can now apply concepts valid for classical GPCRs to grasp FZDs as molecular machines at the interface of ligand binding and intracellular effects...
September 2018: Trends in Pharmacological Sciences
Roland Seifert
Pharmacological nomenclature has been continuously developed over the last century and taught to generations of medical, pharmacy, and science students. Many pharmacological terms coined decades ago remain in textbooks and the scientific literature. With the advancement in the field and the identification of molecular drug targets, rethinking the pharmacological terms in the context of these new findings has become imperative. Some examples of such terms are antihistamine, beta blocker, calcium antagonist, disease-modifying antirheumatic drug (DMARD), and non-steroidal anti-inflammatory drug (NSAID)...
September 2018: Trends in Pharmacological Sciences
Dana Carroll
The efficacy of the powerful CRISPR-Cas9 genome-editing platform depends on DNA repair activities in the cells being targeted. Two new papers show that the low efficiency of targeting in some primary human cell lines is the result of p53-dependent cell arrest in response to the Cas9-induced break. This limitation must be overcome for some anticipated therapies.
September 2018: Trends in Pharmacological Sciences
Omar Al-Massadi, Timo Müller, Matthias Tschöp, Carlos Diéguez, Ruben Nogueiras
Liver-expressed antimicrobial peptide 2 (LEAP-2), the endogenous noncompetitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a), was recently identified as a key endocrine factor regulating systemic energy metabolism. This antagonist impairs the ability of ghrelin to activate GHSR1a and diminishes ghrelin-induced Ca2+ release in vitro. The physiological relevance of the molecular LEAP-2-GHSR1a interaction was subsequently demonstrated in vivo. LEAP-2 is therefore a promising therapeutic target in the treatment of obesity and other metabolic diseases...
August 2018: Trends in Pharmacological Sciences
Qing Yao, Longfa Kou, Ying Tu, Lin Zhu
Matrix metalloproteinases (MMPs) are major extracellular enzymes involved in cancer initiation, progression, and metastasis. MMPs are widely used as cancer biomarkers and therapeutic targets. Recently, MMPs have been investigated as robust tumor microenvironmental stimuli for 'smart' MMP-responsive drug delivery and tumor targeting and have shown great potential in cancer diagnosis and therapy. In this article, we review the newly emerging MMP-responsive strategies and major MMP-responsive nanomaterials and nanocarriers used for tumor-targeted delivery of drugs and imaging agents at the tissue, cellular, and intracellular levels...
August 2018: Trends in Pharmacological Sciences
Vasanth Sathiyakumar, Karan Kapoor, Steven R Jones, Maciej Banach, Seth S Martin, Peter P Toth
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in developed nations. Therapeutic modulation of dyslipidemia by inhibiting 3'-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is standard practice throughout the world. However, based on findings from Mendelian studies and genetic sequencing in prospective longitudinal cohorts from around the world, novel therapeutic targets regulating lipid and lipoprotein metabolism, such as apoprotein C3, angiopoietin-like proteins 3 and 4, and lipoprotein(a), have been identified...
August 2018: Trends in Pharmacological Sciences
Elif Engin, Rebecca S Benham, Uwe Rudolph
In the past 20 years we have learned a great deal about GABAA receptor (GABAA R) subtypes, and which behaviors are regulated or which drug effects are mediated by each subtype. However, the question of where GABAA Rs involved in specific drug effects and behaviors are located in the brain remains largely unanswered. We review here recent studies taking a circuit pharmacology approach to investigate the functions of GABAA R subtypes in specific brain circuits controlling fear, anxiety, learning, memory, reward, addiction, and stress-related behaviors...
August 2018: Trends in Pharmacological Sciences
Perla Pucci, Pasquale Rescigno, Semini Sumanasuriya, Johann de Bono, Francesco Crea
Taxanes are chemotherapeutic drugs employed in the clinic to treat a variety of malignancies. Despite their overall efficacy, cancer cells often display resistance to taxanes. Therefore, new strategies to increase the effectiveness of taxane-based chemotherapeutics are urgently needed. Multiple molecular players are linked to taxane resistance; these include efflux pumps, DNA repair mechanisms, and hypoxia-related pathways. In addition, emerging evidence indicates that both non-coding RNAs and epigenetic effectors might also be implicated in taxane resistance...
August 2018: Trends in Pharmacological Sciences
Terry Kenakin, Ryan T Strachan
Seven transmembrane receptor (7TMR) responses are modulated by orthosteric and allosteric ligands to great therapeutic advantage. Here we introduce a unique class of negative allosteric modulator (NAM) - the positive allosteric modulator (PAM)-antagonist - that increases the affinity of the receptor for the agonist but concomitantly decreases agonist efficacy when cobound. Notably, the reciprocation of allosteric energy causes the orthosteric agonist to increase the affinity of the receptor for the PAM-antagonist; thus, this modulator seeks out and destroys agonist-bound receptor complexes...
August 2018: 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...
July 2018: Trends in Pharmacological Sciences
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