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Trends in Pharmacological Sciences

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https://www.readbyqxmd.com/read/28629580/folding-underlies-bidirectional-role-of-gpr37-pael-r-in-parkinson-disease
#1
REVIEW
Lina Leinartaité, Per Svenningsson
Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G-protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent role, particularly in relation to Parkinson disease (PD). GPR37 is a substrate for parkin and accumulates abnormally in autosomal recessive juvenile parkinsonism, contributing to endoplasmic reticulum stress and death of dopaminergic neurons...
June 16, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28625497/pitfalls-and-opportunities-for-epigenomic-analyses-focused-on-disease-diagnosis-prognosis-and-therapy
#2
REVIEW
Volker M Lauschke, Maxim Ivanov, Magnus Ingelman-Sundberg
No abstract text is available yet for this article.
June 15, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28606480/sphingosine-kinase-2-in-autoimmune-inflammatory-disease-and-the-development-of-sphingosine-kinase-2-inhibitors
#3
REVIEW
Nigel J Pyne, David R Adams, Susan Pyne
The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2(-/-) mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sphingosine kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation...
June 9, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28606479/therapeutic-potential-of-ranibizumab-in-corneal-neovascularization
#4
Marianne L Shahsuvaryan
Ranibizumab is a humanized, affinity-matured vascular endothelial growth factor (VEGF) antibody fragment that neutralizes all isoforms of VEGF and is FDA approved for use in ophthalmology. Recently it was suggested that ranibizumab may be useful in the treatment of corneal neovascularization, but in reality this therapy is not yet evidence based.
June 9, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28602395/reprogramming-of-the-tumor-in-the-hypoxic-niche-the-emerging-concept-and-associated-therapeutic-strategies
#5
REVIEW
Guan-Zhong Qiu, Ming-Zhu Jin, Jin-Xiang Dai, Wei Sun, Ji-Hong Feng, Wei-Lin Jin
Hypoxia exerts a profound impact on diverse aspects of cancer biology. Increasing evidence has revealed novel functions of hypoxia in cancer cell epigenomics, epitranscriptomics, metabolism, and intercellular communication, all hotspots of cancer research. Several drugs have been developed to target intratumoral hypoxia and have entered clinical trials to treat refractory tumors. However, direct targeting of hypoxia signaling still has limitations in the clinic with regard to cancer progression and resistance to therapy...
June 8, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28601256/aurora-a-kinase-is-a-priority-pharmaceutical-target-for-the-treatment-of-cancers
#6
REVIEW
Arun Prasath Damodaran, Lucie Vaufrey, Olivia Gavard, Claude Prigent
Aurora kinases control multiple events during cell cycle progression and are essential for mitotic and meiotic bipolar spindle assembly and function. There are three Aurora kinases in mammals, some of which have oncogenic properties and all of which are overexpressed in multiple cancers. Pharmaceutical companies quickly made these kinases priority targets for the development of inhibitors to be used as cancer treatments. In this review, we focus on Aurora A, against which several inhibiting compounds have been discovered and made available; however, even though some of these compounds underwent clinical trials, none have yet gone beyond Phase III trials...
June 7, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28558960/targeting-par1-now-what
#7
REVIEW
Robert Flaumenhaft, Karen De Ceunynck
Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited the clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market...
May 27, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28551355/roles-of-diacylglycerols-and-ceramides-in-hepatic-insulin-resistance
#8
REVIEW
Max C Petersen, Gerald I Shulman
Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and controversial. Diacylglycerols (DAGs) and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Both lipids were first associated with insulin resistance in skeletal muscle and were subsequently hypothesized to mediate insulin resistance in the liver. However, the putative roles for DAGs and ceramides in hepatic insulin resistance have proved more complex than originally imagined, with various genetic and pharmacologic manipulations yielding a vast and occasionally contradictory trove of data to sort...
May 24, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28551354/targeting-free-radicals-in-oxidative-stress-related-human-diseases
#9
REVIEW
Patrik Poprac, Klaudia Jomova, Miriama Simunkova, Vojtech Kollar, Christopher J Rhodes, Marian Valko
Cancer and Alzheimer's disease (AD) are characterized by (i) opposing biological mechanisms, (ii) an inverse correlation between their incidences, and (iii) oxidative stress being a common denominator of both diseases. Increased formation of reactive oxygen species (ROS) in cancer cells from oncogenic signaling and/or metabolic disturbances leads to upregulation of cellular antioxidant capacity to maintain ROS levels below a toxic threshold. Combining drugs that induce high levels of ROS with compounds that suppress cellular antioxidant capacity by depleting antioxidant systems [glutathione (GSH), superoxide dismutase (SOD), and thioredoxin (TRX)] and/or targeting glucose metabolism represents a potential anticancer strategy...
May 24, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28478994/emerging-paradigms-of-g-protein-coupled-receptor-dephosphorylation
#10
REVIEW
Andrea Kliewer, Rainer K Reinscheid, Stefan Schulz
Elucidation of the molecular mechanisms underlying G protein-coupled receptor (GPCR) dephosphorylation remains a major challenge. While specific GPCR phosphatases (GRPs) have eluded identification, prevailing models propose that receptors must first internalize into acidic endosomes to become dephosphorylated in a housekeeping-like process. Recently, phosphosite-specific antibodies, combined with siRNAs targeting specific phosphatase transcripts, have facilitated the identification of distinct protein phosphatase 1 (PP1) and PP2 catalytic subunits as bona fide GRPs...
May 4, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28473165/unpacking-artemisinin-resistance
#11
REVIEW
Jigang Wang, Chengchao Xu, Zhao-Rong Lun, Steven R Meshnick
Artemisinin and its derivatives, in combination with partner drugs, are currently the most effective treatments for malaria parasite infection. Even though artemisinin has been widely used for decades, its mechanism of action had remained controversial until recently. Artemisinin combination therapies (ACTs) have recently been found to be losing efficacy in Southeast Asia. This 'artemisinin resistance', defined by a delayed parasite clearance time, has been associated with several genetic mutations. As with any other drug resistance phenotype, resistance can best be understood based on its mechanism of action...
May 1, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28450072/contribution-of-clinical-neuroimaging-to-the-understanding-of-the-pharmacology-of-methylphenidate
#12
REVIEW
Luc Zimmer
Methylphenidate (MPH) is currently the most widely used molecule in the pharmacologic treatment of attention-deficit hyperactivity disorder (ADHD). Although experience of its application now extends over several decades, its psychotropic nature, prolonged use in children, and chemical relation to amphetamines still raise doubts in the minds of prescribers and the families of the patients. Brain imaging has shed considerable light on the neuropharmacology of MPH. The two main in vivo neuroimaging techniques are positron-emission tomography (PET) and magnetic resonance imaging (MRI), and these can be applied in both animal models and humans...
April 24, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28442167/tipping-points-and-endogenous-determinants-of-nigrostriatal-degeneration-by-mptp
#13
REVIEW
Stefan Schildknecht, Donato A Di Monte, Regina Pape, Kim Tieu, Marcel Leist
The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a Parkinson's disease (PD)-like syndrome by inducing degeneration of nigrostriatal dopaminergic neurons. Studies of the MPTP model have revealed the pathomechanisms underlying dopaminergic neurodegeneration and facilitated the development of drug treatments for PD. In this review, we provide an update on MPTP bioactivation and biodistribution, reconcile the distinct views on energetic failure versus reactive oxygen species (ROS) formation as main drivers of MPTP-induced neurodegeneration, and describe recently identified intrinsic features of the nigrostriatal system that make it particularly vulnerable to MPTP...
April 23, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28413098/therapeutic-inhibition-of-complement-well-worth-the-risk
#14
Scott R Barnum
Complement is an integral part of the immune system and protects against infection. Complement-mediated immunopathology in many autoimmune diseases and syndromes has led to the therapeutic targeting of complement and to questions around the safety of complement inhibition. Here; I examine and clarify the risks associated with complement therapeutics.
April 13, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28413097/mglu2-3-receptor-antagonists-as-novel-antidepressants
#15
REVIEW
Shigeyuki Chaki
Based on the discovery of the robust antidepressant effects of ketamine in patients with depression, including those with treatment-resistant depression, agents acting on the glutamatergic system have drawn much attention as potential novel antidepressants. Among the agents acting on the glutamatergic system, preclinical data have indicated that the group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3, are attractive targets for the development of novel antidepressants. The antidepressant effects of mGlu2/3 receptor antagonists have been demonstrated in rodent models, and the synaptic and neural mechanisms underlying the antidepressant effects of these compounds have been investigated...
April 13, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28412042/targeting-the-prostacyclin-pathway-beyond-pulmonary-arterial-hypertension
#16
REVIEW
Hélène Pluchart, Charles Khouri, Sophie Blaise, Matthieu Roustit, Jean-Luc Cracowski
Pioneering work demonstrated that an unstable substance isolated from rabbit and pig aortas could relax arterial smooth muscle and inhibit platelet aggregation. Since then, prostacyclin (prostaglandin I2, PGI2) and its analogs have raised much pharmacological interest. In this review we detail how the PGI2 signaling pathway is much more complex than was initially anticipated, involving peroxisome proliferator-activated receptors (PPARs), prostaglandin transporters (PGTs), and PGI2-thromboxane A2 (TXA2) receptor (IP TP) heterodimerization...
April 12, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28412041/targeting-tyrosine-phosphatases-time-to-end-the-stigma
#17
REVIEW
Stephanie M Stanford, Nunzio Bottini
Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, and several PTPs have been validated as therapeutic targets for human diseases. Historically, the development of drugs targeting PTPs has been highly challenging, leading to stigmatization of these enzymes as undruggable targets. Despite these difficulties, efforts to drug PTPs have persisted, and recent years have seen an influx of new probes providing opportunities for biological examination of old and new PTP targets...
April 12, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28389130/biological-evidence-for-paradoxical-improvement-of-psychiatric-disorder-symptoms-by-addictive-drugs
#18
Christian P Müller, Johannes Kornhuber
Addiction biology has focused on the mechanisms of the positive and negative reinforcing actions of addictive drugs but neglected potential benefits. Two new studies provide the first insights into a neurobiology of psychoactive drug instrumentalization. This may help us design better models for addiction neuroscience and opens a new dimension for the development of personalized pharmacotherapy of drug addiction.
April 4, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28372826/titrating-tipsy-targets-the-neurobiology-of-low-dose-alcohol
#19
REVIEW
Changhai Cui, George F Koob
Limited attention has been given to our understanding of how the brain responds to low-dose alcohol (ethanol) and what molecular and cellular targets mediate these effects. Even at concentrations lower than 10mM (0.046 g% blood alcohol concentration, BAC), below the legal driving limit in the USA (BAC 0.08 g%), alcohol impacts brain function and behavior. Understanding what molecular and cellular targets mediate the initial effects of alcohol and subsequent neuroplasticity could provide a better understanding of vulnerability or resilience to developing alcohol use disorders...
March 31, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28455089/a-brief-overview-of-tauopathy-causes-consequences-and-therapeutic-strategies
#20
REVIEW
Miranda E Orr, A Campbell Sullivan, Bess Frost
There are currently no disease-modifying therapies for the treatment of tauopathies, a group of progressive neurodegenerative disorders that are pathologically defined by the presence of tau protein aggregates in the brain. Current challenges for the treatment of tauopathies include the inability to diagnose early and to confidently discriminate between distinct tauopathies in patients, alongside an incomplete understanding of the cellular mechanisms involved in pathogenic tau-induced neuronal death and dysfunction...
July 2017: Trends in Pharmacological Sciences
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