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| Open AccessRepositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
Misfolding of transthyretin can cause amyloid aggregation disorders that can be treated by stabilizing the tetrameric form with tafamidis. Here the authors show that tolcapone, a drug already FDA-approved for Parkinson disease, has strong transthyretin stabilizing function and might be a superior therapeutic option for CNS amyloidosis as it can cross the blood brain barrier.
- Ricardo Sant'Anna
- , Pablo Gallego
- & Salvador Ventura
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Article
| Open AccessSelective labelling and eradication of antibiotic-tolerant bacterial populations in Pseudomonas aeruginosa biofilms
Pathogenic bacteria can aggregate to form biofilms and develop tolerance to antibiotics. Here, the authors use a proteomics approach to study the development of tolerance to the antibiotic colistin in Pseudomonas aeruginosabiofilms, and show that co-treatment with a second compound kills the tolerant cells.
- Song Lin Chua
- , Joey Kuok Hoong Yam
- & Liang Yang
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| Open AccessMechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain
Amphetamines are known to enhance extracellular dopamine levels, but the underlying mechanisms are unclear. Utilising a new pH biosensor for synaptic vesicles, the authors show that amphetamines diminish vesicle pH gradients, disrupting dopamine packaging and leading to increased neurotransmitter release.
- Zachary Freyberg
- , Mark S. Sonders
- & Jonathan A. Javitch
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Article
| Open AccessNetwork-based in silico drug efficacy screening
Attempts to predict novel use for existing drugs rarely consider information on the impact on the genes perturbed in a given disease. Here, the authors present a novel network-based drug-disease proximity measure that provides insight on gene specific therapeutic effect of drugs and may facilitate drug repurposing.
- Emre Guney
- , Jörg Menche
- & Albert-László Barábasi
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| Open AccessIn vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics
Directing nanomedicines to desired locations - such as tumour sites - is difficult to achieve selectively. Here, the authors develop a method to covalently crosslink peptide-modified upconversion nanocrystals into tumour sites for photodynamic therapy and show in vivotumour inhibition in mice.
- Xiangzhao Ai
- , Chris Jun Hui Ho
- & Bengang Xing
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Article
| Open AccessHaem-activated promiscuous targeting of artemisinin in Plasmodium falciparum
The mechanism of action of artemisinin, an antimalarial drug, is not well understood. Here, the authors use a labelled artemisinin analogue to show that the drug is mainly activated by haem and then binds covalently to over 120 proteins in the malaria parasite, affecting many of its cellular processes.
- Jigang Wang
- , Chong-Jing Zhang
- & Qingsong Lin
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| Open AccessTarget engagement and drug residence time can be observed in living cells with BRET
Drug molecules operate through physical interaction with specific cellular targets, and understanding this interaction is important for mechanisms and the potential therapeutic effect of drug candidates. Here, the authors show that bioluminescence resonance energy transfer can be used to monitor the intracellular engagement of a drug with its target.
- Matthew B. Robers
- , Melanie L. Dart
- & Keith V. Wood
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Article
| Open AccessTransformable liquid-metal nanomedicine
The use of inorganic carriers for drug delivery is often limited by toxicity and persistence of inorganic species in the body. Here, the authors report the use of nanocarriers with a liquid-phase eutectic gallium-indium core capable of delivering doxorubicin and subsequently fusing and degrading under mildly acidic conditions.
- Yue Lu
- , Quanyin Hu
- & Zhen Gu
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Article
| Open AccessPerfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy
Photodynamic therapy is used in cancer treatment and generates reactive oxygen species to kill tumour cells but is limited by the availability of oxygen. Here, the authors modify a photodynamic sensitiser so that it produces excess oxygen species and show enhanced tumour cell killing in vitro and in vivo.
- Yuhao Cheng
- , Hao Cheng
- & Yiqiao Hu
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Article
| Open AccessTumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug
Drug-loaded nanoparticles allow controlled release and enhanced delivery, yet understanding in vivobehavior has been difficult. Here, the authors develop a platinum prodrug coupled to a polymer platform, and use intravital imaging to show that the nanoparticle accumulates in macrophages, from the which drug redistributes to neighboring tumour cells.
- Miles A. Miller
- , Yao-Rong Zheng
- & Ralph Weissleder
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| Open AccessCardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice
Haem-free, NO-insensitive soluble guanylate cyclase (apo-sGC) generated during oxidative stress contributes to cardiovascular pathology. By generating and characterizing apo-sGC knock-in mice, Thoonen et al. provide a scientific ground for the therapeutic concept of sGC activators, and dissect the relevance of the NO-sGC axis.
- Robrecht Thoonen
- , Anje Cauwels
- & Peter Brouckaert
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Article
| Open AccessAtomic description of the immune complex involved in heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disease with limited treatment options. Here the authors present crystallographic data on the disease-causing immune complex, providing the structural basis for the development of new diagnostic and therapeutic approaches to HIT.
- Zheng Cai
- , Serge V. Yarovoi
- & Mark I. Greene
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Article
| Open AccessSynergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds
Endocrine-disrupting chemicals act on nuclear hormone receptors, such as PXR. Here, Delfosse et al. show how two such chemicals interact with each other in the PXR ligand-binding pocket, forming a so-called supramolecular ligand that is a more potent PXR activator than each of the two chemicals alone.
- Vanessa Delfosse
- , Béatrice Dendele
- & William Bourguet
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Article
| Open AccessStructural basis for drug-induced allosteric changes to human β-cardiac myosin motor activity
Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin in clinical trials for treatment of systolic heart failure. Here the authors determine the crystal structure of an OM-bound human β-cardiac myosin motor domain to provide molecular level insight into the mechanism of drug action.
- Donald A. Winkelmann
- , Eva Forgacs
- & Ann M. Stock
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Article
| Open AccessCarbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity
The inhibition of bacterial glycosyltransferase has the potential to be an effective therapeutic target against drug resistance bacteria. Here, the authors present a novel class of inhibitor compounds based on a monosaccharide scaffold, which are able to eliminate bacterial infections in mice.
- Johannes Zuegg
- , Craig Muldoon
- & Matthew A. Cooper
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Article
| Open AccessLansoprazole is an antituberculous prodrug targeting cytochrome bc1
Tuberculosis control is threatened by the continued emergence of drug-resistant strains. Here, Rybniker et al. screen a library of FDA-approved drugs and identify a gastric proton pump inhibitor that also has antituberculosis activity and targets the bacterial cytochrome bc1complex.
- Jan Rybniker
- , Anthony Vocat
- & Stewart T. Cole
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| Open AccessAneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells
CENP-E regulates chromosome alignment during mitosis to distribute chromosomes equally into daughter cells. Here, the authors show that CENP-E inhibition causes p53-mediated post-mitotic apoptosis in tumours where the spindle assembly checkpoint is compromised, suggesting that CENP-E is a therapeutic target for these cancers.
- Akihiro Ohashi
- , Momoko Ohori
- & Kentaro Iwata
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Pharmacological repression of PPARγ promotes osteogenesis
Central to the lineage commitment of multipotent mesenchymal stem cells is the nuclear receptor PPARγ, the master regulator of adipogenesis. Here the authors use a variety of structural approaches to rationally design PPARγ inverse agonist SR2595, and demonstrate its ability to promote osteogenesis.
- David P. Marciano
- , Dana S. Kuruvilla
- & Patrick R. Griffin
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| Open AccessPhotoswitchable fatty acids enable optical control of TRPV1
Fatty acids are ancient lipids with numerous functions, from metabolic processes as a source of energy to structural and signalling roles within cell membranes. Here, the authors present azobenzene-modified fatty acids and their application as photoswitchable agonists of the Vanilloid Receptor 1.
- James Allen Frank
- , Mirko Moroni
- & Dirk Trauner
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Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death
Cancer cells have elevated levels of reactive oxygen species. Here the authors show that cancer cells can be selectively killed in vitro and in vivoby an oxidative stress-activated drug, which amplifies the generation of reactive oxygen species while blocking the cells’ antioxidant defense.
- Joungyoun Noh
- , Byeongsu Kwon
- & Dongwon Lee
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| Open AccessAnalgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype
Benzodiazepines (BDZs) target GABAA receptors to alleviate pain but these also cause side effects. Here the authors use mice in which only one GABAA receptor is BDZ-sensitive at a time to identify α2GABAAas the receptor that provides maximal analgesic activity but minimal side-effects in response to BDZs.
- William T. Ralvenius
- , Dietmar Benke
- & Hanns Ulrich Zeilhofer
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Article
| Open AccessTriaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate
The emergence of resistant Plasmodiumstrains fuels the search for new antimalarials. Here, the authors present a new class of potent antimalarial compounds, the triaminopyrimidines, that display low toxicity and long half-life in animal models.
- Shahul Hameed P.
- , Suresh Solapure
- & Vasan K. Sambandamurthy
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| Open AccessStereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs
Therapeutic oligonucleotides can be made more stable by substituting their achiral phosphodiester groups for chiral phosphorothioate linkages. Here, the authors present a synthesis of phosphorothioated RNAs, where the activator controls strand stereochemistry, and also the activity of assembled siRNAs.
- Hartmut Jahns
- , Martina Roos
- & Jonathan Hall
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Article
| Open AccessBotulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity
It is unclear how ingested botulinum neurotoxin invades the host to cause illness. Here, the authors show that the toxin complex containing neurotoxin, hemagglutinin (HA), and NTNHA proteins traverses the epithelial barrier via HA-glycoprotein 2 interaction and endocytosis by Peyer’s patch microfold cells.
- Takuhiro Matsumura
- , Yo Sugawara
- & Yukako Fujinaga
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Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy
Tumour microenvironment affects the outcome of pharmacological anticancer treatments. Here, Kenny et al. show that organotypic cultures of ovarian cancer cells can recapitulate metastasis. They identify several new compounds that block cancer invasion and metastasis and improve survival in mouse models.
- Hilary A. Kenny
- , Madhu Lal-Nag
- & Ernst Lengyel
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| Open AccessThe ligand binding mechanism to purine nucleoside phosphorylase elucidated via molecular dynamics and machine learning
Understanding the dynamics of enzyme-substrate complexation provides an insight into potential drugs, but intermediate states are difficult to observe experimentally. Here, the authors use simulations and machine learning to analyse the binding of transition state inhibitors to purine nucleoside phosphorylase.
- Sergio Decherchi
- , Anna Berteotti
- & Andrea Cavalli
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Late-stage C–H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion
The ability to functionalize a C–H bond is useful in complex organic syntheses, but the scope of this approach is sometimes limited by its sensitivity to basic amines. Here, the authors achieve functionalization of amine-containing natural products by site-selective rhodium-carbene-mediated C–H insertion.
- Jing He
- , Lawrence G. Hamann
- & Rohan E. J. Beckwith
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Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin
Gephyrin is an adaptor molecule that binds to both GABAA receptors and glycine receptors. Here Maric et al. present the structure between gephyrin and a peptide from GABAAreceptor and identify key residues dictating the preference of gephyrin for glycine receptor.
- Hans Michael Maric
- , Vikram Babu Kasaragod
- & Hermann Schindelin
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Synthetic retinal analogues modify the spectral and kinetic characteristics of microbial rhodopsin optogenetic tools
Efforts to improve the performance of optogenetic tools for neuroscience research have mostly been focused on mutating the opsin backbones or mining-related algal genomes. Here the authors show that analogues of the chromophore, retinal, can be used for colour tuning of rhodopsins and altering their photocycle kinetics in several model organisms.
- N. AzimiHashemi
- , K. Erbguth
- & J. F. Liewald
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| Open AccessSteroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1
Use of aromatase inhibitors for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. Here the authors show that in mice, TRPA1 is a major mediator of the proinflammatory and proalgesic actions of aromatase inhibitors.
- Camilla Fusi
- , Serena Materazzi
- & Romina Nassini
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Article
| Open AccessPyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum
Novel antimalarial drugs are urgently needed to combat parasite drug resistance. Here, Vaidya et al. describe a new chemical class of potent antimalarial compounds that act by disrupting the parasite's sodium homeostasis.
- Akhil B. Vaidya
- , Joanne M. Morrisey
- & Lawrence W. Bergman
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Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors
Replication of the hepatitis C virus (HCV) requires a host RNA molecule, miR-122, whose transient inhibition is being explored as an antiviral therapy. Here, the authors study the interaction between miR-122 and HCV, and identify mutations in HCV strains that affect susceptibility to miR-122 inhibition.
- Benjamin Israelow
- , Gavriel Mullokandov
- & Matthew J. Evans
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| Open AccessPharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
- Iris Postmus
- , Stella Trompet
- & Chris C. A. Spencer
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| Open AccessCalcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts
The regulatory role of calcitonin in bone homeostasis is well studied, yet its molecular activity is poorly understood. The authors show that calcitonin regulates bone cells function by inhibiting the osteoclast secretion of sphingosine 1-phosphate, a lipid mediator of osteoclast–osteoblast crosstalk.
- Johannes Keller
- , Philip Catala-Lehnen
- & Michael Amling
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Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers
Cellular defects in autophagy contribute to the development of fatty liver in obesity. Here, Park et al.reveal that hepatic autophagy is impaired by chronically elevated cytosolic calcium levels, and show that a clinically approved calcium channel blocker can improve metabolic parameters of obese mice.
- Hwan-Woo Park
- , Haeli Park
- & Jun Hee Lee
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Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles
Clozapine-induced agranulocytosis/granulocytopenia, or CIAG, is characterised by a rare and potentially fatal reaction to antipsychotic drugs. Here, the authors identify genetic variants in two immune-related genes that may contribute to the pathophysiology of CIAG.
- Jacqueline I. Goldstein
- , L. Fredrik Jarskog
- & Patrick F. Sullivan
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Export of a single drug molecule in two transport cycles by a multidrug efflux pump
Secondary multidrug transporters use ion concentration gradients to power the removal of drug molecules from cells. Here, Fluman et al. demonstrate that the bacterial transporter MdfA can catalyse the efflux of divalent cations in two consecutive transport cycles where each charged moiety is transported as if it were a separate substrate.
- Nir Fluman
- , Julia Adler
- & Eitan Bibi
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Article
| Open AccessPyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators
Selective inhibitors of the L-type Ca2+ channel Cav1.3 are being developed as neuroprotective drugs. Here, Ortner et al. assess the pharmacological properties of a recently reported, selective Cav1.3 blocker and show that this agent is a Ca2+channel activator.
- Nadine J. Ortner
- , Gabriella Bock
- & Jörg Striessnig
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In vivo imaging of specific drug–target binding at subcellular resolution
The ability to image the action of drugs in cells in real time could yield valuable information on their efficacy and mode of action. Here, the authors use multiphoton fluorescence anisotropy microscopy to image drug distribution and target engagement in real time at the cellular level in vivo.
- J. M. Dubach
- , C. Vinegoni
- & R. Weissleder
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High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening
Current tools to test drug metabolism and toxicity in the liver are mainly based on time-consuming traditional cell culture methods. Here Kwon et al.report a high-throughput system employing cells cultured on micropillars that can be transfected with combinations of drug-metabolizing enzymes.
- Seok Joon Kwon
- , Dong Woo Lee
- & Moo-Yeal Lee
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Cellular protection using Flt3 and PI3Kα inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity
Cellular oxidative stress is implicated in neurodegeneration. Here, Kang et al.show that the receptor tyrosine kinase Flt3 and the signalling molecule PI3Kα play key roles in glutamate-mediated oxidative stress in neuronal cells, which can be prevented by Flt3- or PI3Kα-specific inhibitors.
- Yunyi Kang
- , Stefano Tiziani
- & Giovanni Paternostro
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An alternate binding site for PPARγ ligands
The nuclear receptor PPARγ regulates insulin sensitivity and is the molecular target of anti-diabetic drugs. Here, Hughes et al. show demonstrate binding of synthetic PPARγ agonists to a previously unknown binding site within PPARγ and show this affects structure and function of the receptor.
- Travis S. Hughes
- , Pankaj Kumar Giri
- & Douglas J. Kojetin
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Article
| Open AccessDelayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism
The delayed onset of bactericidal activity of the anti-tuberculosis antibiotic bedaquiline is puzzling. Here, Koul and colleagues show, using a multi-omics approach, that the drug triggers a metabolic remodelling in Mycobacterium tuberculosisthat enables the pathogen’s transient survival.
- Anil Koul
- , Luc Vranckx
- & Dirk Bald
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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a serious respiratory disease that is resistant to many forms of treatment. Tanake et al.screen compounds from a library of medicines and find that mepenzolate bromide reduces inflammatory responses and improves respiration in a mouse model of COPD.
- Ken-Ichiro Tanaka
- , Tomoaki Ishihara
- & Tohru Mizushima
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| Open AccessTetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies
Heparin-like oligosaccharides are implicated in various diseases. Hansen et al. report an efficient two-cycle [4+4+4] tetrasaccharide-iteration-based approach to synthesize a structurally defined heparin dodecasaccharide with a latent aldehyde tag for labelling and conjugation.
- Steen U. Hansen
- , Gavin J. Miller
- & John M. Gardiner
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The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism
The nuclear Farnesoid X receptor (FXR) regulates bile acid and cholesterol production. Here Jin et al. identify the clinically approved antiparasitic drug ivermectin as a novel FXR ligand and show that it has antidiabetic effects in mice.
- Lihua Jin
- , Xuhui Feng
- & Yong Li
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| Open AccessDrug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin
Anthracycline-based drugs can kill cancer cells by inhibiting topoisomerase II and promoting DNA double-strand breaks. Pang et al. show that anthracyclines also induce eviction of histones from open chromatin regions and, in doing so, modulate DNA repair and apoptosis in human cancer cells.
- Baoxu Pang
- , Xiaohang Qiao
- & Jacques Neefjes
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Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer
Androgen receptor signalling plays an important role in driving prostate cancer progression. Here the authors design a peptidomimetic that blocks the interaction between the androgen receptor and its coactivator PELP1, and show that the drug slows prostate cancer cell growth in a xenograft model.
- Preethi Ravindranathan
- , Tae-Kyung Lee
- & Ganesh V. Raj