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https://www.readbyqxmd.com/read/28326307/p75-neurotrophin-receptor-in-the-skin-beyond-its-neurotrophic-function
#1
REVIEW
Carlo Pincelli
p75 neurotrophin receptor (p75(NTR)), also known as CD271, is the low-affinity receptor that, together with the tyrosine kinase receptor tropomyosin-receptor kinase (Trk), mediate neurotrophin (NT) functions. Beside their classic role in skin innervation, NT and their receptors constitute a complex cutaneous network associated with a number of autocrine and paracrine activities. In this context, the role of p75(NTR) is becoming more and more important. This review will focus on the intriguing functions of p75(NTR) in healthy and diseased skin...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28319380/evaluation-and-characterization-of-trk-kinase-inhibitors-for-the-treatment-of-pain-reliable-binding-affinity-predictions-from-theory-and-computation
#2
Shunzhou Wan, Agastya P Bhati, Sarah Skerratt, Kiyoyuki Omoto, Veerabahu Shanmugasundaram, Sharan K Bagal, Peter Vivian Coveney
Optimisation of ligand binding affinity to the target protein of interest is a primary objective in small-molecule drug discovery. Until now, the prediction of binding affinities by computational methods has not been widely applied in the drug discovery process, mainly due to its lack of accuracy and reproducibility, as well as the long turnaround times required to obtain results. Herein, we report on a collaborative study that compares tropomyosin receptor kinase A (TrkA) binding affinity predictions using two recently formulated fast computational approaches - namely ESMACS (Enhanced Sampling of Molecular dynamics with Approximation of Continuum Solvent) and TIES (Thermodynamic Integration with Enhanced Sampling) - to experimentally derived TrkA binding affinities for a set of Pfizer pan-Trk compounds...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28315978/the-hallucinogen-2-5-dimethoxy-4-iodoamphetamine-hydrochloride-activates-neurotrophin-receptors-in-a-neuronal-cell-line-and-promotes-neurites-extension
#3
Zoya Marinova, Susanne Walitza, Edna Grünblatt
Decreased neurotrophic factors expression and neurotrophin receptors signalling have repeatedly been reported in association with stress, depression, and neurodegenerative disorders. We have previously identified the hallucinogen 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) as protective against trophic deprivation-induced cytotoxicity in human neuroblastoma SK-N-SH cells and established the dependence of this effect on the 5-HT2A receptor, tyrosine kinases activity, and the extracellular signal-regulated kinase pathway...
March 18, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28280935/crypt-cell-markers-in-the-olfactory-organ-of-poecilia-reticulata-analysis-and-comparison-with-the-fish-model-danio-rerio
#4
Simone Bettini, Liliana Milani, Maurizio Lazzari, Maria Gabriella Maurizii, Valeria Franceschini
Olfactory crypt neurons have been observed in several bony fishes and chondrichtyans. Although their morphology is uniform in all fish, very few is known about their antigenic properties, usually studied in zebrafish, but quite overlooked in other species. We tested in Poecilia reticulata (guppy) the two antibodies recognized to mark zebrafish crypt cells: while anti-S100 showed an immunohistochemical pattern comparable to what reported in zebrafish, anti-TrkA gave no signal. Western blot analysis revealed that S100-antiserum bound an antigen of expected weight, probably belonging to the S100 family...
March 9, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28270164/tropomyosin-receptor-antagonism-in-cylindromatosis-trac-an-early-phase-trial-of-a-topical-tropomyosin-kinase-inhibitor-as-a-treatment-for-inherited-cyld-defective-skin-tumours-study-protocol-for-a-randomised-controlled-trial
#5
Amy Cranston, Deborah D Stocken, Elaine Stamp, David Roblin, Julia Hamlin, James Langtry, Ruth Plummer, Alan Ashworth, John Burn, Neil Rajan
BACKGROUND: Patients with germline mutations in a tumour suppressor gene called CYLD develop multiple, disfiguring, hair follicle tumours on the head and neck. The prognosis is poor, with up to one in four mutation carriers requiring complete surgical removal of the scalp. There are no effective medical alternatives to treat this condition. Whole genome molecular profiling experiments led to the discovery of an attractive molecular target in these skin tumour cells, named tropomyosin receptor kinase (TRK), upon which these cells demonstrate an oncogenic dependency in preclinical studies...
March 7, 2017: Trials
https://www.readbyqxmd.com/read/28270021/tropomyosin-receptor-kinase-inhibitors-an-updated-patent-review-for-2010-2016-part-ii
#6
Justin J Bailey, Ralf Schirrmacher, Kristen Farrell, Vadim Bernard-Gauthier
TrkA/B/C receptor activation supports growth, survival, and differentiation of discrete neuronal populations during development, adult life, and ageing but also plays numerous roles in human disease onset and progression. Trk-specific inhibitors have therapeutic applications in cancer and pain and thus constitute a growing area of interest in oncology and neurology. There has been substantial growth in the number of structural classes of Trk inhibitors and the number of industrial entrants to the Trk inhibitor field over the past six years...
March 8, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28270010/tropomyosin-receptor-kinase-inhibitors-an-updated-patent-review-for-2010-2016-part-i
#7
Justin J Bailey, Ralf Schirrmacher, Kristen Farrell, Vadim Bernard-Gauthier
Tropomyosin receptor kinases (TrkA/B/C) play crucial roles in the development and maintenance of the nervous system, and aberrant expression of Trk has been implicated in neurological disorders as well as neural and non-neural neoplasms. Patent activity encompassing Trk inhibitors has grown substantially over the last 6 years, recognized by a rise in the number of pharmaceutical entrants to the field and the escalation of novel inhibitor chemotypes. Area covered: In Part I of this two part review, a biological and structural overview of Trk is provided in the context of Trk as a therapeutic target for cancer and pain, followed by the report of recent patent literature claiming small molecule inhibitors of Trk family kinases or which describe inhibitors developed for other kinase targets but include noteworthy Trk inhibition/application...
March 8, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28266869/pig-induced-pluripotent-stem-cell-derived-neural-rosettes-parallel-human-differentiation-into-sensory-neural-subtypes
#8
Robin L Webb, Amalia Gallegos-Cárdenas, Colette N Miller, Nicholas J Solomotis, Hong-Xiang Liu, Franklin D West, Steven L Stice
The pig is the large animal model of choice for study of nerve regeneration and wound repair. Availability of porcine sensory neural cells would conceptually allow for analogous cell-based peripheral nerve regeneration in porcine injuries of similar severity and size to those found in humans. After recently reporting that porcine (or pig) induced pluripotent stem cells (piPSCs) differentiate into neural rosette (NR) structures similar to human NRs, here we demonstrate that pig NR cells could differentiate into neural crest cells and other peripheral nervous system-relevant cell types...
March 7, 2017: Cellular Reprogramming
https://www.readbyqxmd.com/read/28266720/effects-of-p75ntr-deficiency-on-cholinergic-innervation-of-the-amygdala-and-anxiety-like-behavior
#9
R Busch, M Baldus, M Vogt, S Berger, D Bartsch, P Gass, O von Bohlen Und Halbach
The p75 neurotrophin receptor (p75NTR) is a low-affinity receptor that is capable of binding neurotrophins. Two different p75NTR knockout mouse lines are available either with a deletion in Exon III (p75NTR(E)(x)(III)(-/-) ) or in Exon IV (p75NTR(E)(x)(IV)(-/-) ). In p75NTR(E)(x)(III) knockout mice, only the full-length p75NTR is deleted, whereas in p75NTR(E)(x)(IV) knockout mice, the full-length as well as the truncated isoform of the receptor is deleted. Deletion of p75NTR has been shown to affect, among others, the septo-hippocampal cholinergic innervation pattern and neuronal plasticity within the hippocampus...
March 7, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28257759/blockade-of-trkb-receptors-in-the-nucleus-accumbens-prior-to-heterotypic-stress-alters-corticotropin-releasing-hormone-crh-vesicular-glutamate-transporter-2-vglut2-and-glucocorticoid-receptor-gr-within-the-mesolimbic-pathway
#10
Idu Azogu, Helene Plamondon
Inhibition of stress-induced elevations in brain-derived neurotrophic factor (BDNF) or its primary receptor tyrosine-related kinase B (TrkB) within the reward pathway may modulate vulnerability to anxiety and mood disorders. The current study examined the role of BDNF/TrkB signaling on biochemistry and behavior under basal conditions and following exposure to a 10-day heterotypic stress paradigm in male rats. Effects of intra-accumbal administration of TrkB antagonist ANA-12 (0.25μg/0.5μl/min) on anxiety, and expression of Trk-B, corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2) and glucocorticoid receptor (GR) within the mesolimbic pathway were determined...
March 14, 2017: Hormones and Behavior
https://www.readbyqxmd.com/read/28218045/the-significance-of-trk-receptors-in-pancreatic-cancer
#11
Matthew D Johnson, Brandon Stone, Bryan J Thibodeau, Andrew M Baschnagel, Sandra Galoforo, Laura E Fortier, Billie Ketelsen, Samreen Ahmed, Zakiya Kelley, Alaa Hana, Thomas G Wilson, John M Robertson, Robert P Jury, George D Wilson
This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity...
February 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28215304/neurotrophins-and-migraine
#12
L B Martins, A L Teixeira, R B Domingues
Neurotrophins (NTs) have been implicated in generation and modulation of nociceptive pathways. Change in NTs levels is associated with painful conditions and neurological diseases such as migraine. Currently, it is generally recognized that migraine headaches result from the activation and sensitization of trigeminal sensory afferent fibers leading to neuropeptides release such as calcitonin gene-related peptide (CGRP) and substance P (SP). This triggers an inflammatory cascade causing a neurogenic inflammation...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28215291/crystal-structures-of-neurotrophin-receptors-kinase-domain
#13
T Bertrand
Neurotrophins and their receptors (Trk) play key roles in the development of the nervous system and in cell survival. Trk receptors are therefore attractive pharmacological targets for brain disorders as well as for cancers. While the druggability of the extracellular domain of the receptors, that specifically binds neurotrophins, is yet to be proven, the intracellular kinase domains are attractive targets for small-molecule binding. The recent crystal structures of the three isoforms of the Trk family, TrkA, TrkB, and TrkC have been described in their apo forms and in complex with potent and selective pan-Trk inhibitors...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28213521/signalling-adaptor-shcd-suppresses-erk-phosphorylation-distal-to-the-ret-and-trk-neurotrophic-receptors
#14
Melanie K B Wills, Ava Keyvani Chahi, Hayley R Lau, Manali Tilak, Brianna Guild, Laura A New, Peihua Lu, Keévin Jacquet, Susan O Meakin, Nicolas Bisson, Nina Jones
Proteins of the Shc family are typically involved in signal transduction events involving Ras/MAPK and PI3K/Akt pathways. In the nervous system, they function proximal to the neurotrophic factors that regulate cell survival, differentiation, and neuron-specific characteristics. The least-characterized homolog, ShcD, is robustly expressed in the developing and mature nervous system, but its contributions to neural cell circuitry are largely uncharted. We now report that ShcD binds to active Ret, TrkA, and TrkB neurotrophic factor receptors predominantly via its phosphotyrosine binding (PTB) domain...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28197173/targeting-cell-surface-receptors-for-axon-regeneration-in-the-central-nervous-system
#15
REVIEW
Menghon Cheah, Melissa R Andrews
Axon regeneration in the CNS is largely unsuccessful due to excess inhibitory extrinsic factors within lesion sites together with an intrinsic inability of neurons to regrow following injury. Recent work demonstrates that forced expression of certain neuronal transmembrane receptors can recapitulate neuronal growth resulting in successful growth within and through inhibitory lesion environments. More specifically, neuronal expression of integrin receptors such as alpha9beta1 integrin which binds the extracellular matrix glycoprotein tenascin-C, trk receptors such as trkB which binds the neurotrophic factor BDNF, and receptor PTPσ which binds chondroitin sulphate proteoglycans, have all been show to significantly enhance regeneration of injured axons...
December 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/28183697/safety-and-antitumor-activity-of-the-multi-targeted-pan-trk-ros1-and-alk-inhibitor-entrectinib-rxdx-101-combined-results-from-two-phase-1-trials-alka-372-001-and-startrk-1
#16
Alexander Drilon, Salvatore Siena, Sai-Hong Ignatius Ou, Manish Patel, Myung Ju Ahn, Jeeyun Lee, Todd M Bauer, Anna F Farago, Jennifer J Wheler, Stephen V Liu, Robert Doebele, Laura Giannetta, Giulio Cerea, Giovanna Marrapese, Michele Schirru, Alessio Amatu, Katia Bencardino, Laura Palmeri, Andrea Sartore-Bianchi, Angelo Vanzulli, Sara Cresta, Silvia Damian, Matteo Duca, Elena Ardini, Gang Li, Jason Christiansen, Karey Kowalski, Ann Johnson, Rupal Patel, David Luo, Edna Chow-Maneval, Zachary Hornby, Pratik S Multani, Alice T Shaw, Filippo G De Braud
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two Phase 1 studies in patients with advanced or metastatic solid tumors, including patients with active CNS disease. Here we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the RP2D...
February 9, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28179120/novel-therapeutic-approaches-for-disease-modification-of-epileptogenesis-for-curing-epilepsy
#17
REVIEW
Bryan L Clossen, Doodipala Samba Reddy
This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982-2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition...
February 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28178969/neuroblastoma-treatment-in-the-post-genomic-era
#18
REVIEW
Maria Rosaria Esposito, Sanja Aveic, Anke Seydel, Gian Paolo Tonini
Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients.High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology...
February 8, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28174090/targeting-trk-family-proteins-in-cancer
#19
REVIEW
Yekaterina B Khotskaya, Vijaykumar R Holla, Anna F Farago, Kenna R Mills Shaw, Funda Meric-Bernstam, David S Hong
The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28167133/nmda-receptor-adjusted-co-administration-of-ecstasy-and-cannabinoid-receptor-1-agonist-in-the-amygdala-via-stimulation-of-bdnf-trk-b-creb-pathway-in-adult-male-rats
#20
Ghorbangol Ashabi, Mitra-Sadat Sadat-Shirazi, Solmaz Khalifeh, Laleh Elhampour, Mohammad-Reza Zarrindast
Consumption of cannabinoid receptor-1 (CB-1) agonist such as cannabis is widely taken in 3,4- methylenedioxymethamphetamine (MDMA) or ecstasy users; it has been hypothesized that co-consumption of CB-1 agonist might protect neurons against MDMA toxicity. N-methyl-d-aspartate (NMDA) receptors regulate neuronal plasticity and firing rate in the brain through Tyrosine-kinase B (Trk-B) activation. The molecular and electrophysiological association among NMDA and MDMA/Arachidonylcyclopropylamide (ACPA, a selective CB-1 receptor agonist) co-consumption was not well-known...
February 3, 2017: Brain Research Bulletin
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