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  • Designing Safer Analgesics via μ-Opioid Receptor Pathways
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-09-19
    H.C. Stephen Chan, Dillon McCarthy, Jianing Li, Krzysztof Palczewski, Shuguang Yuan

    Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects. In this review we outline recent progress towards the discovery of safer opioid analgesics.

    更新日期:2017-09-20
  • The Action Radius of Oxytocin Release in the Mammalian CNS: From Single Vesicles to Behavior
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-09-09
    Bice Chini, Matthijs Verhage, Valery Grinevich

    The hypothalamic neuropeptide oxytocin (OT) has attracted the attention both of the scientific community and a general audience because of its prosocial effects in mammals, and OT is now seen as a facilitator of mammalian species propagation. Furthermore, OT is a candidate for the treatment of social deficits in several neuropsychiatric and neurodevelopmental conditions. Despite such possibilities and a long history of studies on OT behavioral effects, the mechanisms of OT actions in the brain remain poorly understood. In the present review, based on anatomical, biochemical, electrophysiological, and behavioral studies, we propose a novel model of local OT actions in the central nervous system (CNS) via focused axonal release, which initiates intracellular signaling cascades in specific OT-sensitive neuronal populations and coordinated brain region-specific behaviors.

    更新日期:2017-09-10
  • Activating or Inhibiting Nrf2?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-09-05
    Xin-Yi Chu, Ye-Mao Liu, Hong-Yu Zhang

    Activating nuclear factor erythroid 2 (NF-E2)-related factor (Nrf2) is a widely recognized strategy for combating oxidative-stress-induced diseases. However, Nrf2 activation does not always bring advantageous effects. Therefore, before performing Nrf2-targeted therapy, we must pinpoint whether Nrf2 should be activated or inhibited.

    更新日期:2017-09-06
  • Genetically Engineered Bacteria for Treating Human Disease
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-28
    Buyun Ma, Qiuwei Pan, Maikel P. Peppelenbosch

    Bacteria have now been harnessed to combat human diseases, especially to meet the challenge of antimicrobial resistance. Modulating the microbiome, particularly by genetically engineering the bacteria, has provided proof-of-concept as potential pharmacotherapy, but those involved in this field should engage in discussion as how to move forward.

    更新日期:2017-09-06
  • An Overview of Novel Adjuvants Designed for Improving Vaccine Efficacy
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-28
    Srinivasa Reddy Bonam, Charalambos D. Partidos, Sampath Kumar M. Halmuthur, Sylviane Muller

    Adjuvants incorporated in prophylactic and/or therapeutic vaccine formulations impact vaccine efficacy by enhancing, modulating, and/or prolonging the immune response. In addition, they reduce antigen concentration and the number of immunizations required for protective efficacy, therefore contributing to making vaccines more cost effective. Our better understanding of the molecular mechanisms of immune recognition and protection has led research efforts to develop new adjuvants that are currently at various stages of development or clinical evaluation. In this review, we focus mainly on several of these promising adjuvants, and summarize recent work conducted in various laboratories to develop novel lipid-containing adjuvants

    更新日期:2017-09-06
  • Targeting the Thioredoxin System for Cancer Therapy
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-22
    Junmin Zhang, Xinming Li, Xiao Han, Ruijuan Liu, Jianguo Fang

    Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx.

    更新日期:2017-09-06
  • FFA4/GPR120: Pharmacology and Therapeutic Opportunities
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-19
    Graeme Milligan, Elisa Alvarez-Curto, Brian D. Hudson, Rudi Prihandoko, Andrew B. Tobin

    Free Fatty Acid receptor 4 (FFA4), also known as GPR120, is a G-protein-coupled receptor (GPCR) responsive to long-chain fatty acids that is attracting considerable attention as a potential novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Although no clinical studies have yet been initiated to assess efficacy in this indication, a significant number of primary publications and patents have highlighted the ability of agonists with potency at FFA4 to improve glucose disposition and enhance insulin sensitivity in animal models. However, the distribution pattern of the receptor suggests that targeting FFA4 may also be useful in other conditions, ranging from cancer to lung function. Here, we discuss and contextualise the basis for these ideas and the results to support these conclusions.

    更新日期:2017-09-06
  • Interstrand Crosslink Repair as a Target for HDAC Inhibition
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-04
    Teodora Nikolova, Nicole Kiweler, Oliver H. Krämer

    DNA interstrand crosslinks (ICLs) covalently connect complementary DNA strands. Consequently, DNA replication and transcription are hampered, DNA damage responses (DDR) are initiated, and cell death is triggered. Therefore, drugs inducing ICLs are effective against rapidly growing cancer cells. However, tumors engage a complicated enzymatic machinery to repair and survive ICLs. Several factors, including the post-translational acetylation/deacetylation of lysine residues within proteins, control this network. Histone deacetylases (HDACs) modulate the expression and functions of DNA repair proteins which remove ICLs and control the accessibility of chromatin. Accordingly, histone deacetylase inhibitors (HDACi) are small, pharmacologically and clinically relevant molecules that sensitize cancer cells to ICL inducers. We discuss the mechanism of ICL repair and targets of HDACi within this pathway.

    更新日期:2017-09-06
  • Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-22
    Miles Congreve, Christine Oswald, Fiona H. Marshall

    Structural insights have been revealed from X-ray co-complexes of a range of G protein-coupled receptors (GPCRs) and their allosteric ligands. The understanding of how small molecules can modulate the function of this important class of receptors by binding to a diverse range of pockets on and inside the proteins has had a profound impact on the structure-based drug design (SBDD) of new classes of therapeutic agents. The types of allosteric pockets and the mode of modulation as well as the advantages and disadvantages of targeting allosteric pockets (as opposed to the natural orthosteric site) are considered in the context of these new structural findings.

    更新日期:2017-09-06
  • Early and Late CNS Inflammation in Alzheimer’s Disease: Two Extremes of a Continuum?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-31
    A. Claudio Cuello

    In 1990 it was reported that individuals receiving NSAIDs (non-steroidal anti-inflammatory drugs) showed a markedly reduced prevalence of Alzheimer’s disease (AD) compared to the overall population. Large epidemiological studies corroborated this assertion and provoked numerous prospective AD clinical trials with a variety of NSAIDs, all of which demonstrated lack of efficacy. It is postulated that the explanation for the success of NSAIDS in preventing AD onset when given at preclinical stages, and for their failure when administered after AD clinical presentation, lies in the changing nature of central nervous system (CNS) inflammation in the decades-long continuum of AD pathology. Early disease-aggravating CNS inflammation might start decades before the presentation of severe cognitive impairments or dementia, and the nature of this process will co-evolve with the neuropathological progression from preclinical to clinical AD stages. This early CNS inflammation should be considered a promising therapeutic target as we continue searching for an unequivocal diagnosis of AD preclinical stages.

    更新日期:2017-09-06
  • Immunomodulatory Properties of Plants and Mushrooms
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-30
    Jan Martel, Yun-Fei Ko, David M. Ojcius, Chia-Chen Lu, Chih-Jung Chang, Chuan-Sheng Lin, Hsin-Chih Lai, John D. Young

    Plants and mushrooms are used for medicinal purposes and the screening of molecules possessing biological activities. A single plant or mushroom may produce both stimulatory and inhibitory effects on immune cells, depending on experimental conditions, but the reason behind this dichotomy remains obscure. We present here a large body of experimental data showing that water extracts of plants and mushrooms usually activate immune cells, whereas ethanol extracts inhibit immune cells. The mode of extraction of plants and mushrooms may thus determine the effects produced on immune cells, possibly due to differential solubility and potency of stimulatory and inhibitory compounds. We also examine the possibility of using such plant and mushroom extracts to treat immune system disorders.

    更新日期:2017-09-06
  • Targeting 12-Lipoxygenase As a Potential Novel Antiplatelet Therapy
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-29
    Benjamin E. Tourdot, Michael Holinstat

    Platelets are key contributors to the formation of occlusive thrombi; the major underlying cause of ischemic heart disease and stroke. Antiplatelet therapy has reduced the morbidity and mortality associated with thrombotic events; however, the utility of current antiplatelet therapies is limited by the concomitant risk of an adverse bleeding event. Novel antiplatelet therapies that are more efficacious at inhibiting thrombosis while minimally affecting hemostasis are required. Platelet-type 12-(S)-lipoxygenase (12-LOX), an oxygenase shown to potentiate platelet activation, represents a novel antiplatelet target. Recently, a selective 12-LOX inhibitor, ML355, was shown to decrease thrombosis without prolonging hemostasis. While published data suggests targeting 12-LOX is a viable approach, further work is required to determine the safety and effectiveness of 12-LOX inhibitors in humans.

    更新日期:2017-09-06
  • Amyloid in Alzheimer’s Disease: Guilty Beyond Reasonable Doubt?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-18
    Christian Behl

    Recently failed antiamyloidogenic trials call for an objective reassessment of the dominating amyloid cascade hypothesis of Alzheimer’s disease (AD). Ongoing efforts focusing on amyloid β protein (Aβ), its deposition, and its removal need to be complemented by more intensive research in new directions. Those may either integrate amyloid pathology or will propose pathogenetic routes independent of Aβ in the search for the causes of AD.

    更新日期:2017-09-06
  • Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-14
    Ruoji Zhou, An Xu, Julian Gingold, Louise C. Strong, Ruiying Zhao, Dung-Fang Lee

    Li–Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germline mutations in TP53, the gene encoding p53, are responsible for most cases of LFS. TP53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered to be a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as to screen potential compounds targeting oncogenic p53. In this review we briefly summarize the biology of LFS and current understanding of the oncogenic functions of mutant p53 in cancer development. We discuss the strengths and limitations of current LFS disease models, and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS induced pluripotent stem cell (iPSC) platform to develop precision cancer therapy.

    更新日期:2017-09-06
  • Targeting Mechanisms Linking COPD to Type 2 Diabetes Mellitus
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-07
    Mario Cazzola, Paola Rogliani, Luigino Calzetta, Davide Lauro, Clive Page, Maria Gabriella Matera

    Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) often coexist. The mechanistic links between these two diseases are complex, multifactorial, and not entirely understood, but they can influence the approach to treatment. Understanding whether COPD comes first followed by T2DM or vice versa, or whether the two diseases develop simultaneously due to common underlying mechanisms, is important for the development of novel therapeutic approaches to these two important diseases. In this review, we discuss the potential links between COPD and T2DM and pharmacological approaches that might target these links.

    更新日期:2017-09-06
  • Therapeutic Potential of Ranibizumab in Corneal Neovascularization
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-09
    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.

    更新日期:2017-09-06
  • Reprogramming of the Tumor in the Hypoxic Niche: The Emerging Concept and Associated Therapeutic Strategies
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-12
    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. Comprehensive understanding of the molecular mechanisms by which hypoxia reshapes tumors and their microenvironment, as well as how tumor cells adapt to and thrive in hypoxic conditions, will therefore continue to be a focus of cancer research and will provide new directions for hypoxic tumor treatment.

    更新日期:2017-09-06
  • Aurora A Kinase Is a Priority Pharmaceutical Target for the Treatment of Cancers
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-07
    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. The varying efficiencies and particularities of these drugs raise several questions that are explored in this review: is Aurora A even a good target? What biomarkers can we use to measure its activity in vivo? How can we improve the Aurora A-inhibiting drugs?

    更新日期:2017-09-06
  • Targeting PAR1: Now What?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-27
    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. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. In this review, we critically evaluate prospects for the next generation of PAR1-targeted therapeutics.

    更新日期:2017-09-06
  • Binding Kinetics and Pathways of Ligands to GPCRs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-20
    Andrea Strasser, Hans-Joachim Wittmann, Roland Seifert

    Previously, drugs were developed focusing on target affinity and selectivity. However, it is becoming evident that the drug–target residence time, related to the off-rate, is an important parameter for successful drug development. The residence time influences both the on-rate and overall effectiveness of drugs. Furthermore, ligand binding is now appreciated to be a multistep process because metastable and/or intermediate binding sites in the extracellular region have been identified. In this review, we summarize experimental ligand-binding data for G-protein-coupled receptors (GPCRs), and their binding pathways, analyzed by molecular dynamics (MD). The kinetics of drug binding to GPCRs are complex and depend on several factors, including charge distribution on the receptor surface, ligand–receptor interactions in the binding channel and the binding site, or solvation.

    更新日期:2017-09-06
  • The Cardiovascular Pharmacology of Nonsteroidal Anti-Inflammatory Drugs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-23
    Tilo Grosser, Emanuela Ricciotti, Garret A. FitzGerald

    The principal molecular mechanisms underlying the cardiovascular (CV) and renal adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs), such as myocardial infarction and hypertension, are understood in more detail than most side effects of drugs. Less is known, however, about differences in the CV safety profile between chemically distinct NSAIDs and their relative predisposition to complications. In review article, we discuss how heterogeneity in the pharmacokinetics and pharmacodynamics of distinct NSAIDs may be expected to affect their CV risk profile. We consider evidence afforded by studies in model systems, mechanistic clinical trials, a meta-analysis of randomized controlled trials, and two recent large clinical trials, Standard Care vs. Celecoxib Outcome Trial (SCOT) and Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION), designed specifically to compare the CV safety of the cyclooxygenase-2-selective NSAID, celecoxib, with traditional NSAIDs. We conclude that SCOT and PRECISION have apparently not compared equipotent doses and have other limitations that bias them toward underestimation of the relative risk of celecoxib.

    更新日期:2017-09-06
  • Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-16
    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. GPR37 also constitutes a core structure of Lewy bodies, demonstrating a more general involvement in PD pathology. However, if folded and matured properly, GPR37 seems to be neuroprotective. Moreover, GPR37 modulates functionality of the dopamine transporter and the dopamine D2 receptor and stimulates dopamine neurotransmission. Here we review the multiple roles of GPR37 with relevance to potential disease modification and symptomatic therapies of PD and highlight unsolved issues in this field.

    更新日期:2017-09-06
  • Structural Principles of Fluorescent RNA Aptamers
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-17
    Robert J. Trachman, Lynda Truong, Adrian R. Ferré-D'Amaré

    Several aptamer RNAs have been selected in vitro that bind to otherwise weakly fluorescent small molecules and enhance their fluorescence several thousand-fold. By genetically tagging cellular RNAs of interest with these aptamers and soaking cells in their cell-permeable cognate small-molecule fluorophores, it is possible to use them to study RNA localization and trafficking. These aptamers have also been fused to metabolite-binding RNAs to generate fluorescent biosensors. The 3D structures of three unrelated fluorogenic RNAs have been determined, and reveal a shared reliance on base quadruples (tetrads) to constrain the photo-excited chromophore. The structural diversity of fluorogenic RNAs and the chemical diversity of potential fluorophores to be activated are likely to yield a variety of future fluorogenic RNA tags that are optimized for different applications in RNA imaging and in the design of fluorescent RNA biosensors.

    更新日期:2017-09-06
  • Towards a Structural View of Drug Binding to hERG K+ Channels
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-12
    Jamie I. Vandenberg, Eduardo Perozo, Toby W. Allen

    The human ether-a-go-go-related gene (hERG) K+ channel is of great medical and pharmaceutical relevance. Inherited mutations in hERG result in congenital long-QT syndrome which is associated with a markedly increased risk of cardiac arrhythmia and sudden death. hERG K+ channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome and an increased risk of sudden death. The recent determination of the near-atomic resolution structure of the hERG K+ channel, using single-particle cryo-electron microscopy (cryo-EM), provides tremendous insights into how these channels work. It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding.

    更新日期:2017-09-06
  • Lessons Learned from Two Decades of Anticancer Drugs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-11
    Zhichao Liu, Brian Delavan, Ruth Roberts, Weida Tong

    Tremendous efforts have been made to elucidate the basis of cancer biology with the aim of promoting anticancer drug development. Especially over the past 20 years, anticancer drug development has developed from conventional cytotoxic agents to target-based and immune-related therapies. Consequently, more than 200 anticancer drugs are available on the market. However, anticancer drug development still suffers high attrition during the later phases of clinical development and is considered to be a difficult and risky therapeutic category within the drug development arena. The disappointing performance of investigational anticancer candidates implies that there are some shortcomings in the translation of preclinical in vitro and in vivo models to humans, and that heterogeneity in the patient population presents a significant challenge. Here, we summarize both successful and failed experiences in anticancer development during the past 20 years and help identify why the current paradigm may be suboptimal. We also offer potential strategies for improvement.

    更新日期:2017-09-06
  • Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-09
    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. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors.

    更新日期:2017-09-06
  • Targeting Free Radicals in Oxidative Stress-Related Human Diseases
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-24
    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. In AD, free metals and/or Aβ:metal complexes may cause damage to biomolecules in the brain (via Fenton reaction), including DNA. Metal chelation, based on the application of selective metal chelators or metal delivery, may induce neuroprotective signaling and represents a promising therapeutic strategy. This review examines therapeutic strategies based on the modulation of oxidative stress in cancer and AD.

    更新日期:2017-09-06
  • Contribution of Clinical Neuroimaging to the Understanding of the Pharmacology of Methylphenidate
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-24
    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. The present review seeks to show how human molecular and functional imaging has contributed to determining not only the molecular targets of MPH, and the action kinetics of the various pharmaceutical forms available, but also the connectivity and brain networks activated by treatment. We also discuss the perspectives opened up by new hybrid PET–MRI techniques that enable multimodal tracking of the impact of methylphenidate on neurotransmission.

    更新日期:2017-09-06
  • Emerging Paradigms of G Protein-Coupled Receptor Dephosphorylation
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-04
    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. Similar to phosphorylation, GPCR dephosphorylation is temporally and spatially regulated, starting immediately after receptor activation at the plasma membrane and continuing along the endocytic pathway. Dephosphorylation disrupts receptor–arrestin complexes, thus terminating arrestin-dependent signaling. Partially dephosphorylated GPCRs may remain membrane bound for renewed agonist activation while others undergo endocytosis. After internalization, further dephosphorylation facilitates the transition into the recycling pathway, leading to either plasma membrane repopulation or lysosomal degradation. These findings reveal unappreciated cellular sites and regulatory functions of receptor dephosphorylation and call for revised models of the GPCR activation/deactivation cycle.

    更新日期:2017-09-06
  • A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-25
    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. In this review, we describe current diagnostic and therapeutic strategies, known drivers of pathogenic tau formation, recent contributions to our current mechanistic understanding of how pathogenic tau induces neuronal death, and potential diagnostic and therapeutic approaches.

    更新日期:2017-09-06
  • Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-24
    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. In this review we examine the state of this field, turning a critical eye toward both DAGs and ceramides as putative mediators of lipid-induced hepatic insulin resistance.

    更新日期:2017-09-06
  • The Future of Cysteine Cathepsins in Disease Management
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-28
    Lovro Kramer, Dušan Turk, Boris Turk

    Since the discovery of the key role of cathepsin K in bone resorption, cysteine cathepsins have been investigated by pharmaceutical companies as drug targets. The first clinical results from targeting cathepsins by activity-based probes and substrates are paving the way for the next generation of molecular diagnostic imaging, whereas the majority of antibody–drug conjugates currently in clinical trials depend on activation by cathepsins. Finally, cathepsins have emerged as suitable vehicles for targeted drug delivery. It is therefore timely to review the future of cathepsins in drug discovery. We focus here on inflammation-associated diseases because dysregulation of the immune system accompanied by elevated cathepsin activity is a common feature of these conditions.

    更新日期:2017-09-06
  • Biological Evidence for Paradoxical Improvement of Psychiatric Disorder Symptoms by Addictive Drugs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-04
    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.

    更新日期:2017-09-06
  • Therapeutic Inhibition of Complement: Well Worth the Risk
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-14
    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.

    更新日期:2017-09-06
  • Unpacking ‘Artemisinin Resistance’
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-02
    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. Recently, it was demonstrated that artemisinin attacks multiple parasitic targets, suggesting that mutations in drug targets are unlikely to cause high-level artemisinin resistance. These findings will help us to better understand the mechanisms of artemisinin resistance and suggest protocol modifications that may improve the efficacy of ACTs.

    更新日期:2017-09-06
  • Targeting the Prostacyclin Pathway: Beyond Pulmonary Arterial Hypertension
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-12
    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. We discuss the distinct affinities of PGI2 analogs for prostanoid receptors. In addition, we introduce the new direct and indirect pharmacological approaches to targeting the PGI2 pathway within the systemic circulation, including non-prostanoid agonists of the prostacyclin receptor (IP) and PGT inhibitors, as well as transcutaneous pathways using iontophoresis and nanostructured lipid carriers.

    更新日期:2017-09-06
  • Targeting Tyrosine Phosphatases: Time to End the Stigma
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-12
    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. Here we discuss progress towards drugging PTPs with special emphasis on the development of selective probes with biological activity. We describe the development of new small-molecule orthosteric, allosteric, and oligomerization-inhibiting PTP inhibitors and discuss new studies targeting the receptor PTP (RPTP) subfamily with biologics.

    更新日期:2017-09-06
  • Tipping Points and Endogenous Determinants of Nigrostriatal Degeneration by MPTP
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-23
    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. We discuss these new perspectives on the endogenous tipping points of tissue homeostasis and the drivers responsible for vicious cycles in relation to their relevance for the development of novel intervention strategies for PD.

    更新日期:2017-09-06
  • Titrating Tipsy Targets: The Neurobiology of Low-Dose Alcohol
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-03-31
    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 10 mM (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. We review here what is known about the neurobiology of low-dose alcohol, provide insights into potential molecular targets, and discuss future directions and challenges in further defining targets of low-dose alcohol at the molecular, cellular, and circuitry levels.

    更新日期:2017-09-06
  • mGlu2/3 Receptor Antagonists as Novel Antidepressants
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-13
    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. Furthermore, these findings have indicated the similarities of the antidepressant effects and of the mechanisms underlying these effects between mGlu2/3 receptor antagonists and ketamine. Based on the results obtained hitherto, here I discuss the potential for mGlu2/3 receptor antagonists to be developed as next-generation antidepressants.

    更新日期:2017-09-06
  • Thromboprophylaxis after Knee Arthroscopy: Out of the Maze?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-03-23
    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.

    更新日期:2017-09-06
  • A New View of Pathway-Driven Drug Resistance in Tumor Proliferation
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-02-27
    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.g., ERK and YAP1) can substitute for each other in resistance. Core pathways can forecast possible resistance because acquired resistance frequently occurs through alternative proliferation pathways. This concept may help to predict the efficacy of drug combinations. The selection of distinct combinations for specific mutated pathways would be guided by clinical diagnosis.

    更新日期:2017-09-06
  • Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-03-08
    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. Thus, strategies in cancer treatment should focus on restoring rather than inhibiting PKC.

    更新日期:2017-09-06
  • Cardiac Fibroblast Activation Post-Myocardial Infarction: Current Knowledge Gaps
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-03-29
    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. Additional studies are needed to systematically examine how fibroblast activation shifts over the timeframe of the MI response and how modulation at different activation stages could alter wound healing and LV remodeling in distinct ways. This review summarizes current fibroblast knowledge as the foundation for a discussion of existing knowledge gaps.

    更新日期:2017-09-06
  • Sirtuin Inhibition: Strategies, Inhibitors, and Therapeutic Potential
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-05
    Yanhong Jiang, Jiajia Liu, Di Chen, Lingling Yan, Weiping Zheng

    The β-NAD+-dependent Nε-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. We then follow with a discussion of pharmacological studies using sirtuin inhibitors. Our aim here is to set a stage for developing future superior sirtuin inhibitors and for an expanded effort in exploiting inhibitors to explore and/or validate the therapeutic potential stemming from the inhibition of the sirtuin-catalyzed deacylation reaction.

    更新日期:2017-09-06
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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