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Trends in Pharmacological Sciences

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https://www.readbyqxmd.com/read/28442167/tipping-points-and-endogenous-determinants-of-nigrostriatal-degeneration-by-mptp
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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/28283199/drugs-and-driving-research-in-medicinal-drug-development
#8
J G Ramaekers
Medicinal drugs that cause drowsiness and inattentiveness may impair driving. The FDA recently emphasized that standardized procedures for measuring drug effects on driving are needed as part of drug registration. Here, I provide an overview of a standardized on-the-road driving test that offers maximal drug sensitivity and uses a real-life outcome measure of driver impairment that is strongly associated with crash risk.
March 7, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28209404/cell-penetrating-peptides-from-basic-research-to-clinics
#9
REVIEW
Giulia Guidotti, Liliana Brambilla, Daniela Rossi
The presence of cell and tissue barriers together with the low biomembrane permeability of various therapeutics often hampers systemic drug distribution; thus, most of the available molecules are of limited therapeutic value. Opportunities to increase medicament concentrations in areas that are difficult to access now exist with the advent of cell-penetrating peptides (CPPs), which can transport into the cell a wide variety of biologically active conjugates (cargoes). Numerous preclinical evaluations with CPP-derived therapeutics have provided promising results in various disease models that, in some cases, prompted clinical trials...
February 14, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28389129/sirtuin-inhibition-strategies-inhibitors-and-therapeutic-potential
#10
REVIEW
Yanhong Jiang, Jiajia Liu, Di Chen, Lingling Yan, Weiping Zheng
The β-NAD(+)-dependent N(ε)-acyl-lysine deacylation reaction catalyzed by sirtuin family members has been increasingly demonstrated to be important in regulating multiple crucial cellular processes and has also been proposed to be a therapeutic target for multiple human diseases. Accordingly, its inhibitors have been actively pursued over the past few years. In addition, we have also seen the pharmacological assessment of sirtuin inhibitory compounds, although to a lesser extent. In this review, we first discuss how sirtuin inhibitors were discovered with the use of various approaches...
May 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28377033/cannabidiol-claims-and-misconceptions-trends-in-pharmacological-sciences-38-198-201-2017
#11
Ethan B Russo
No abstract text is available yet for this article.
May 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28365093/cardiac-fibroblast-activation-post-myocardial-infarction-current-knowledge-gaps
#12
REVIEW
Yonggang Ma, Rugmani Padmanabhan Iyer, Mira Jung, Michael P Czubryt, Merry L Lindsey
In response to myocardial infarction (MI), the wound healing response of the left ventricle (LV) comprises overlapping inflammatory, proliferative, and maturation phases, and the cardiac fibroblast is a key cell type involved in each phase. It has recently been appreciated that, early post-MI, fibroblasts transform to a proinflammatory phenotype and secrete cytokines and chemokines as well as matrix metalloproteinases (MMPs). Later post-MI, fibroblasts are activated to anti-inflammatory and proreparative phenotypes and generate anti-inflammatory and proangiogenic factors and extracellular matrix (ECM) components that form the infarct scar...
May 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28363764/ferroptosis-inhibition-mechanisms-and-opportunities
#13
REVIEW
Jose Pedro Friedmann Angeli, Ron Shah, Derek A Pratt, Marcus Conrad
The past decade has yielded tremendous insights into how cells die. This has come with our understanding that several distinct forms of cell death are encompassed under the umbrella term necrosis. Among these distinct forms of regulated necrotic cell death, ferroptosis has attracted considerable attention owing to its putative involvement in diverse pathophysiological processes. A key feature of the ferroptosis process is the requirement of phospholipid peroxidation, a process that has been linked with several human pathologies...
May 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28343719/thromboprophylaxis-after-knee-arthroscopy-out-of-the-maze
#14
Giuseppe Lippi, Gianfranco Cervellin
The use of thromboprophylaxis after knee arthroplasty is heterogeneous among orthopedic surgeons. Two recent studies showed that low molecular weight heparin is not effective for preventing venous thromboembolism, whereas thrombotic episodes may be significantly reduced using direct oral anticoagulants, thus opening an interesting perspective for periprocedural management of knee arthroscopy.
May 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28283201/reversing-the-paradigm-protein-kinase-c-as-a-tumor-suppressor
#15
REVIEW
Alexandra C Newton, John Brognard
The discovery in the 1980s that protein kinase C (PKC) is a receptor for the tumor-promoting phorbol esters fueled the dogma that PKC is an oncoprotein. Yet 30+ years of clinical trials for cancer using PKC inhibitors not only failed, but in some instances worsened patient outcome. The recent analysis of cancer-associated mutations, from diverse cancers and throughout the PKC family, revealed that PKC isozymes are generally inactivated in cancer, supporting a tumor suppressive function. In keeping with a bona fide tumor suppressive role, germline causal loss-of-function (LOF) mutations in one isozyme have recently been identified in lymphoproliferative disorders...
May 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28283200/pharmacological-targeting-of-the-host-pathogen-interaction-alternatives-to-classical-antibiotics-to-combat-drug-resistant-superbugs
#16
REVIEW
Jason Munguia, Victor Nizet
The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance...
May 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28245913/a-new-view-of-pathway-driven-drug-resistance-in-tumor-proliferation
#17
REVIEW
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Defeating drug resistance in tumor cell proliferation is challenging. We propose that signaling in cell proliferation takes place via two core pathways, each embodying multiple alternative pathways. We consider drug resistance through an alternative proliferation pathway - within the same or within the other core pathway. Most drug combinations target only one core pathway; blocking both can restrain proliferation. We define core pathways as independent and acting similarly in cell-cycle control, which can explain why their products (e...
May 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28214012/the-endothelium-solves-problems-that-endothelial-cells-do-not-know-exist
#18
REVIEW
John G McCarron, Matthew D Lee, Calum Wilson
The endothelium is the single layer of cells that lines the entire cardiovascular system and regulates vascular tone and blood-tissue exchange, recruits blood cells, modulates blood clotting, and determines the formation of new blood vessels. To control each function, the endothelium uses a remarkable sensory capability to continuously monitor vanishingly small changes in the concentrations of many simultaneously arriving extracellular activators that each provides cues to the physiological state. Here we suggest that the extraordinary sensory capabilities of the endothelium do not come from single cells but from the combined activity of a large number of endothelial cells...
April 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28209403/small-molecules-that-sabotage-bacterial-virulence
#19
REVIEW
Benjamin K Johnson, Robert B Abramovitch
The continued rise of antibiotic-resistant bacterial infections has motivated alternative strategies for target discovery and treatment of infections. Antivirulence therapies function through inhibition of in vivo required virulence factors to disarm the pathogen instead of directly targeting viability or growth. This approach to treating bacteria-mediated diseases may have advantages over traditional antibiotics because it targets factors specific for pathogenesis, potentially reducing selection for resistance and limiting collateral damage to the resident microbiota...
April 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28188005/g-protein-gated-potassium-channels-a-link-to-drug-addiction
#20
REVIEW
Robert A Rifkin, Stephen J Moss, Paul A Slesinger
G protein-gated inwardly rectifying potassium (GIRK) channels are regulators of neuronal excitability in the brain. Knockout mice lacking GIRK channels display altered behavioral responses to multiple addictive drugs, implicating GIRK channels in addictive behaviors. Here, we review the effects of GIRK subunit deletions on the behavioral response to psychostimulants, such as cocaine and methamphetamine. Additionally, exposure of mice to psychostimulants produces alterations in the surface expression of GIRK channels in multiple types of neurons within the reward system of the brain...
April 2017: Trends in Pharmacological Sciences
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