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Trends in Pharmacological Sciences

Murugan Kalimutho, Katia Nones, Sriganesh Srihari, Pascal H G Duijf, Nicola Waddell, Kum Kum Khanna
Breast cancer is one of the most common cancers affecting women. Despite significant improvements in overall survival, it remains a significant cause of death worldwide. Genomic instability (GI) is a hallmark of cancer and plays a pivotal role in breast cancer development and progression. In the past decade, high-throughput technologies have provided a wealth of information that has facilitated the identification of a diverse repertoire of mutated genes and mutational processes operative across cancers. Here, we review recent findings on genomic alterations and mutational processes in breast cancer pathogenesis...
February 5, 2019: Trends in Pharmacological Sciences
Gabriele De Rubis, Sabna Rajeev Krishnan, Mary Bebawy
Liquid biopsies, comprising the noninvasive analysis of circulating tumor-derived material (the 'tumor circulome'), represent an innovative tool in precision oncology to overcome current limitations associated with tissue biopsies. Within the tumor circulome, circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the only components the clinical application of which is approved by the US Food and Drug Administration (FDA). Extracellular vesicles (EVs), circulating tumor RNA (ctRNA), and tumor-educated platelets (TEPs) are relatively new tumor circulome constituents with promising potential at each stage of cancer management...
February 5, 2019: Trends in Pharmacological Sciences
Matthew J Borrelli, Amer Youssef, Michael B Boffa, Marlys L Koschinsky
Interest in lipoprotein (a) [Lp(a)] has exploded over the past decade with the emergence of genetic and epidemiological studies pinpointing elevated levels of this unique lipoprotein as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). This review summarizes the most recent discoveries regarding therapeutic approaches to lower Lp(a) and presents these findings in the context of an emerging, although far from complete, understanding of the biosynthesis and catabolism of Lp(a)...
February 4, 2019: Trends in Pharmacological Sciences
Bin Zhou, David A Hall, Jesús Giraldo
Biased signaling, the differential activation of distinct signaling pathways, is currently at the center of pharmacology. Reliable characterization of biased ligands requires robust scales applicable to all ligand classes: agonists, neutral antagonists, and inverse agonists. To this end, constitutive receptor activity should be included in the models.
February 1, 2019: Trends in Pharmacological Sciences
Andrew C A Wan
At present, most drug screening efforts employ bulk cancer cell populations, which may lead to selection of the more drug-resistant cancer stem cells (CSCs). However, drug screening using CSCs has been limited, mainly owing to the difficulty of their isolation. This article discusses how methods of reprogramming cancer cells to primitive cancer cell states, such as transcription factor reprogramming, epithelial-mesenchymal transition (EMT), conditional reprogramming, and hypoxia, may approach the CSC state and thus be relevant for drug screening purposes...
January 29, 2019: Trends in Pharmacological Sciences
Anja Pfalzgraff, Günther Weindl
Lipopolysaccharide (LPS) sensing in the cytosol by the noncanonical inflammasome leads to pyroptosis and NLRP3 inflammasome activation. This mechanism may be more critical for sepsis development than recognition of LPS by Toll-like receptor 4. LPS is directly binding to its intracellular receptor caspase-4/5/11, mediated by outer membrane vesicles and guanylate-binding proteins that deliver LPS to the cytosol and mediate access of caspases to LPS. Caspase-11-dependent cleavage of gasdermin D is discussed as a link between LPS-induced activation of caspases and pyroptosis or NLRP3 inflammasome activation...
January 25, 2019: Trends in Pharmacological Sciences
Simoun Icho, Roman A Melnyk
Clostridium difficile (Clostridioides difficile) is a toxin-producing, multidrug-resistant bacterium. Inhibiting the effects of toxins, which are responsible for the symptoms of disease, is viewed as a promising non-antibiotic approach to treat C. difficile infection (CDI). By inducing premature activation of toxins, Ivarsson and colleagues (Cell Chemical Biology 2018; uncover a clever new strategy to block toxin action.
January 23, 2019: Trends in Pharmacological Sciences
M Gomaraschi, F Bonacina, G D Norata
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for metabolic purposes in the cell. The process also occurs in immune cells that adapt their metabolic machinery to cope with the different energetic requirements associated with cell activation, proliferation, and polarization. LAL deficiency (LALD) causes severe lipid accumulation and affects the immunometabolic signature in animal models. In humans, LAL deficiency is associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis...
January 18, 2019: Trends in Pharmacological Sciences
Yongde Luo, Sheng Ye, Xiaokun Li, Weiqin Lu
Endocrine fibroblast growth factors (eFGFs) control pathways that are crucial for maintaining metabolic homeostasis of lipids, glucose, energy, bile acids, and minerals. Unlike the heparin-binding paracrine FGFs, eFGFs require a unique Klotho family protein to form a productive triad complex, but the structural and mechanistical details of this complex have remained obscure since the beginning of the eFGF field. However, recent breakthroughs in resolving the 3D structures of eFGF signaling complexes have now unveiled the atomic details of multivalent interactions among eFGF, FGFR, and Klotho...
January 4, 2019: Trends in Pharmacological Sciences
Elizabeth Lemoine, Ravi Thadhani
Preeclampsia is one of the leading causes of maternal and perinatal morbidity and mortality, particularly in resource-limited settings. Treatment options for this devastating condition remain extremely limited. The successful application of RNAi technology to suppress the pathogenic protein soluble FMS-like tyrosine kinase-1 (sFLT1) in a baboon model of preeclampsia portends the development of effective therapies potentially accessible to areas with the greatest burden of disease.
January 1, 2019: Trends in Pharmacological Sciences
Dacquin M Kasumba, Nathalie Grandvaux
RIG-I and MDA5 receptors are key sensors of pathogen-associated molecular pattern (PAMP)-containing viral RNA and transduce downstream signals to activate an antiviral and immunomodulatory response. Fifteen years of research have put them at the center of an ongoing hunt for novel pharmacological pan-antivirals, vaccine adjuvants, and antitumor strategies. Current knowledge testifies to the redundant, but also distinct, functions mediated by RIG-I and MDA5, opening opportunities for the use of specific and potent nucleic acid agonists...
December 31, 2018: Trends in Pharmacological Sciences
Selena Mimmi, Domenico Maisano, Ileana Quinto, Enrico Iaccino
Peptides are emerging as a new reliable class of therapeutics and, thanks to their lower cost of production, they are becoming established as perfect drug aspirants. Here, we briefly review the phage display method and its contribution to the identification of peptides of interest for the therapeutic market.
December 31, 2018: Trends in Pharmacological Sciences
Zhichao Liu, Ruili Huang, Ruth Roberts, Weida Tong
Toxicogenomics (TGx) has contributed significantly to toxicology and now has great potential to support moves towards animal-free approaches in regulatory decision making. Here, we discuss in vitro TGx systems and their potential impact on risk assessment. We raise awareness of the rapid advancement of genomics technologies, which generates novel genomics features essential for enhanced risk assessment. We specifically emphasize the importance of reproducibility in utilizing TGx in the regulatory setting. We also highlight the role of machine learning (particularly deep learning) in developing TGx-based predictive models...
December 26, 2018: Trends in Pharmacological Sciences
Thomas Briston, David L Selwood, Gyorgy Szabadkai, Michael R Duchen
Mitochondrial permeability transition, as the consequence of opening of a mitochondrial permeability transition pore (mPTP), is a cellular catastrophe. Initiating bioenergetic collapse and cell death, it has been implicated in the pathophysiology of major human diseases, including neuromuscular diseases of childhood, ischaemia-reperfusion injury, and age-related neurodegenerative disease. Opening of the mPTP represents a major therapeutic target, as it can be mitigated by a number of compounds. However, clinical studies have so far been disappointing...
December 6, 2018: Trends in Pharmacological Sciences
Simone Brioschi, Marco Colonna
Ongoing research is revealing multiple, previously unappreciated, facets of immunity in the central nervous system, and the recent studies on the meningeal lymphatic system represent an emblematic example. In this context, a paper from Louveau and colleagues (Nat. Neurosci. 2018;21:1380-1391), which we discuss here, elucidates the importance of the meningeal lymphatics for the drainage of macromolecules and immune cells from the cerebrospinal fluid, and their delivery into the cervical lymph nodes, especially during neuroinflammatory diseases...
December 5, 2018: Trends in Pharmacological Sciences
Joseph J Gingell, Erica R Hendrikse, Debbie L Hay
The calcitonin gene-related peptide (CGRP) receptor system has emerged as an important drug target for migraine. This is highlighted by the recent regulatory approval of the first drug targeting the CGRP signalling pathway, the CGRP receptor antibody erenumab. The cellular compartments in which receptors are found affects drug access and whether they can exert their effects. G protein-coupled receptors (GPCRs) were thought to signal only at the cell surface, but it is now recognised that some GPCRs, including the CGRP receptor, undergo sustained signalling from endosomes, once internalised in response to ligand...
December 4, 2018: Trends in Pharmacological Sciences
Damien Gulliver, Eryn Werry, Tristan A Reekie, Timothy A Katte, William Jorgensen, Michael Kassiou
Deficits in social behavioral domains, such as interpersonal communication, emotion recognition, and empathy, are a characteristic symptom in several neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD). The neuropeptide oxytocin (OT) has emerged as a key regulator of diverse social behaviors in vertebrates and, thus, has been identified as a potential therapeutic target for improving social dysfunction. In recent years, the field of OT research has seen an explosion of scientific inquiry, producing a more comprehensive picture of oxytocinergic signaling and the pathways that regulate its release and degradation in the brain...
November 30, 2018: Trends in Pharmacological Sciences
Masataka Majima, Yoshiya Ito, Kanako Hosono, Hideki Amano
Migraine is a severe neurological disorder in which calcitonin gene-related peptide (CGRP) is a key molecule in pathophysiology. Neuronal system-derived CGRP enhances neovascularization in several important pathological conditions and sends a cue to the vascular system. In 2018, the FDA approved erenumab and fremanezumab, antibodies against CGRP receptor and CGRP, as the first new class of drugs for migraine. Treatment of migraine with these antibodies requires great care because neovascularization-related adverse effects may be induced in some patients...
November 28, 2018: Trends in Pharmacological Sciences
Reynold A Panettieri, Dedmer Schaafsma, Yassine Amrani, Cynthia Koziol-White, Rennolds Ostrom, Omar Tliba
Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs 'rapidly' enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma...
November 26, 2018: Trends in Pharmacological Sciences
Ariadna Recasens, Lenka Munoz
Cancer cell dormancy is a process whereby cells enter reversible cell cycle arrest, termed quiescence. Quiescence is essential for cancer cells to acquire additional mutations, to survive in a new environment and initiate metastasis, to become resistant to cancer therapy, and to evade immune destruction. Thus, dormant cancer cells are considered to be responsible for cancer progression. As we start to understand the mechanisms that enable quiescence, we can begin to develop pharmacological strategies to target dormant cancer cells...
February 2019: Trends in Pharmacological Sciences
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