Piezo Ion Channels in Cardiovascular Mechanobiology
Publication date: Available online 5 November 2019Source: Trends in Pharmacological SciencesAuthor(s): Dominique Douguet, Amanda Patel, Aimin Xu, Paul M. Vanhoutte, Eric HonoréMechanotransduction has a key role in vascular development, physiology, and disease states. Piezo1 is a mechanosensitive (MS) nonselective cationic channel that occurs in endothelial and vascular smooth muscle cells. It is activated by shear stress associated with increases in local blood flow, as well as by cell membrane stretch upon elevation of blood pressure. Here, we briefly review the pharmacological modulators of Piezo and discuss current und...
Source: Trends in Pharmacological Sciences - November 7, 2019 Category: Drugs & Pharmacology Source Type: research
Pharmacological and Molecular Mechanisms Behind the Sterilizing Activity of Pyrazinamide
Publication date: Available online 6 November 2019Source: Trends in Pharmacological SciencesAuthor(s): Pooja Gopal, Gerhard Grüber, Véronique Dartois, Thomas DickInclusion of pyrazinamide (PZA) in the tuberculosis (TB) drug regimen during the 1970s enabled a reduction in treatment duration from 12 to 6 months. PZA has this remarkable effect in patients despite displaying poor potency against Mycobacterium tuberculosis (Mtb) in vitro. The pharmacological basis for the in vivo sterilizing activity of the drug has remained obscure and its bacterial target controversial. Recently it was shown that PZA penetrates necrotic ...
Source: Trends in Pharmacological Sciences - November 7, 2019 Category: Drugs & Pharmacology Source Type: research
Dichotomous Sirtuins: Implications for Drug Discovery in Neurodegenerative and Cardiometabolic Diseases
Publication date: Available online 6 November 2019Source: Trends in Pharmacological SciencesAuthor(s): Pedro Gomes, Helena Leal, Alexandrina F. Mendes, Flávio Reis, Cláudia CavadasSirtuins (SIRT1–7), a class of NAD+-dependent deacylases, are central regulators of metabolic homeostasis and stress responses. While numerous salutary effects associated with sirtuin activation, especially SIRT1, are well documented, other reports show health benefits resulting from sirtuin inhibition. Furthermore, conflicting findings have been obtained regarding the pathophysiological role of specific sirtuin isoforms, suggesting that sirt...
Source: Trends in Pharmacological Sciences - November 7, 2019 Category: Drugs & Pharmacology Source Type: research
Why Are Some Driver Mutations Rare?
Publication date: Available online 5 November 2019Source: Trends in Pharmacological SciencesAuthor(s): Ruth Nussinov, Chung-Jung Tsai, Hyunbum JangUnderstanding why driver mutations that promote cancer are sometimes rare is important for precision medicine since it would help in their identification. Driver mutations are largely discovered through their frequencies. Thus, rare mutations often escape detection. Unlike high-frequency drivers, low-frequency drivers can be tissue specific; rare drivers have extremely low frequencies. Here, we discuss rare drivers and strategies to discover them. We suggest that allosteric driv...
Source: Trends in Pharmacological Sciences - November 5, 2019 Category: Drugs & Pharmacology Source Type: research
The Landscape of Atypical and Eukaryotic Protein Kinases
Publication date: Available online 31 October 2019Source: Trends in Pharmacological SciencesAuthor(s): Georgi K. Kanev, Chris de Graaf, Iwan J.P. de Esch, Rob Leurs, Thomas Würdinger, Bart A. Westerman, Albert J. KooistraKinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor intera...
Source: Trends in Pharmacological Sciences - November 2, 2019 Category: Drugs & Pharmacology Source Type: research
The B7x Immune Checkpoint Pathway: From Discovery to Clinical Trial
Publication date: Available online 31 October 2019Source: Trends in Pharmacological SciencesAuthor(s): Peter John, Yao Wei, Weifeng Liu, Meirong Du, Fangxia Guan, Xingxing ZangB7x (B7 homolog x, also known as B7-H4, B7S1, and VTCN1) was discovered by ourselves and others in 2003 as the seventh member of the B7 family. It is an inhibitory immune checkpoint of great significance to human disease. Tissue-expressed B7x minimizes autoimmune and inflammatory responses. It is overexpressed in a broad spectrum of human cancers, where it suppresses antitumor immunity. Further, B7x and PD-L1 tend to have mutually exclusive expressio...
Source: Trends in Pharmacological Sciences - November 2, 2019 Category: Drugs & Pharmacology Source Type: research
Combating Human Pathogens and Cancer by Targeting Phosphoinositides and Their Metabolism
Publication date: Available online 31 October 2019Source: Trends in Pharmacological SciencesAuthor(s): Thanh Kha Phan, Guneet K. Bindra, Scott A. Williams, Ivan K.H. Poon, Mark D. HulettPathogens and tumor cells have adopted various adept strategies to evade immunosurveillance and promote their growth and survival. There has been substantial evidence demonstrating phosphoinositide lipids and their modifying enzymes as essential host targets that are often hijacked by pathogens and tumor cells. The common dependence of pathogen virulence and tumor progression on phosphoinositides presents an exciting disease-combating poten...
Source: Trends in Pharmacological Sciences - November 2, 2019 Category: Drugs & Pharmacology Source Type: research
Pharmacogenomic Approach to Antimyopia Drug Development: Pathways Lead the Way
Publication date: Available online 30 October 2019Source: Trends in Pharmacological SciencesAuthor(s): Tatiana V. Tkatchenko, Andrei V. TkatchenkoMyopia is the most common eye disorder in the world which is caused by a mismatch between the optical power of the eye and its excessively long axial length. Recent studies revealed that the regulation of the axial length of the eye occurs via a complex signaling cascade, which originates in the retina and propagates across all ocular tissues to the sclera. The complexity of this regulatory cascade has made it particularly difficult to develop effective antimyopia drugs. The curr...
Source: Trends in Pharmacological Sciences - October 31, 2019 Category: Drugs & Pharmacology Source Type: research
miRNAs as Therapeutic Targets in Inflammatory Disease
Publication date: Available online 29 October 2019Source: Trends in Pharmacological SciencesAuthor(s): Qianjin Lu, Ruifang Wu, Ming Zhao, Antonio Garcia-Gomez, Esteban BallestarIn the past decade, we have witnessed considerable developments in understanding the roles and functions of miRNAs. In parallel, the identification of alterations in miRNA expression in inflammatory disease indicates their potential as therapeutic targets. Pharmacological treatments targeting abnormally expressed miRNAs for inflammatory diseases are not yet in clinical practice; however, some small compounds and nucleic acids targeting miRNAs have s...
Source: Trends in Pharmacological Sciences - October 30, 2019 Category: Drugs & Pharmacology Source Type: research
Comprehensive Analysis of ERK1/2 Substrates for Potential Combination Immunotherapies
Publication date: Available online 29 October 2019Source: Trends in Pharmacological SciencesAuthor(s): Lei Yang, Liangzhen Zheng, Wee Joo Chng, Jeak Ling DingRecent clinical and therapeutic success with RAF and MEK1/2 inhibitors has revolutionized the existing treatment schemes for previously incurable cancers like melanomas. However, the overall therapeutic efficacies are still largely compromised by the dose-limiting side effects and emerging drug resistance mechanisms. Accumulating evidence has revealed the intricate nature of the RAS-RAF-MEK1/2-ERK1/2 pathway, such as activation mechanisms, kinase–substrate relations...
Source: Trends in Pharmacological Sciences - October 30, 2019 Category: Drugs & Pharmacology Source Type: research
Has Drug Design Augmented by Artificial Intelligence Become a Reality?
Publication date: Available online 16 October 2019Source: Trends in Pharmacological SciencesAuthor(s): Hongming Chen, Ola EngkvistThe application of artificial intelligence (AI) to drug discovery has become a hot topic in recent years. Generative molecular design based on deep learning is a particular an area of attention. Zhavoronkov et al. recently published a novel approach in which de novo molecular design based on deep learning was used to discover novel potent DDR1 kinase inhibitors. It took 21 days from model building to compound design, and a total of six AI-designed compounds were synthesized and tested. The stu...
Source: Trends in Pharmacological Sciences - October 18, 2019 Category: Drugs & Pharmacology Source Type: research
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Publication date: October 2019Source: Trends in Pharmacological Sciences, Volume 40, Issue 10Author(s): (Source: Trends in Pharmacological Sciences)
Source: Trends in Pharmacological Sciences - October 15, 2019 Category: Drugs & Pharmacology Source Type: research
Advancing Drug Discovery via Artificial Intelligence
Publication date: October 2019Source: Trends in Pharmacological Sciences, Volume 40, Issue 10Author(s): H.C. Stephen Chan, Hanbin Shan, Thamani Dahoun, Horst Vogel, Shuguang Yuan (Source: Trends in Pharmacological Sciences)
Source: Trends in Pharmacological Sciences - October 15, 2019 Category: Drugs & Pharmacology Source Type: research
Editorial Board and Contents
Publication date: October 2019Source: Trends in Pharmacological Sciences, Volume 40, Issue 10Author(s): (Source: Trends in Pharmacological Sciences)
Source: Trends in Pharmacological Sciences - October 15, 2019 Category: Drugs & Pharmacology Source Type: research
Striving Towards the Perfect In Vitro Oral Drug Absorption Model
Publication date: October 2019Source: Trends in Pharmacological Sciences, Volume 40, Issue 10Author(s): John P. Gleeson, Fiona McCartneyOral drug delivery systems have multiple goals, assessing and enabling intestinal absorption at efficacious doses being one of them. Here we highlight the in vitro advances in modeling drug absorption, which more faithfully reflect human intestinal physiology and reduce the reliance on animal models. (Source: Trends in Pharmacological Sciences)
Source: Trends in Pharmacological Sciences - October 15, 2019 Category: Drugs & Pharmacology Source Type: research
