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https://www.readbyqxmd.com/read/28515680/trk-receptors-and-neurotrophin-cross-interactions-new-perspectives-toward-manipulating-therapeutic-side-effects
#1
Yazan Haddad, Vojtěch Adam, Zbyněk Heger
Some therapeutic side-effects result from simultaneous activation of homolog receptors by the same ligand. Tropomyosin receptor kinases (TrkA, TrkB and TrkC) play a major role in the development and biology of neurons through neurotrophin signaling. The wide range of cross-interactions between Trk receptors and neurotrophins vary in selectivity, affinity and function. In this study, we discuss new perspectives to the manipulation of side-effects via a better understanding of the cross-interactions at the molecular level, derived by computational methods...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28476569/design-and-synthesis-of-a-fluorinated-quinazoline-based-type-ii-trk-inhibitor-as-a-scaffold-for-pet-radiotracer-development
#2
Vadim Bernard-Gauthier, Anne Mahringer, Matthew Vesnaver, Gert Fricker, Ralf Schirrmacher
NTRK1/2/3 fusions have recently been characterized as low incidence oncogenic alterations across various tumor histologies. Tyrosine kinase inhibitors (TKIs) of the tropomyosin receptor kinase family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in the clinic for the treatment of cancer patients whose diseases harbor NTRK tumor drivers. We describe herein the development of [(18)F]QMICF ([(18)F]-(R)-9), a quinazoline-based type-II pan-Trk radiotracer with nanomolar potencies for TrkA/B/C (IC50=85-650nM) and relevant TrkA fusions including TrkA-TPM3 (IC50=162nM)...
April 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28469194/kai-xin-san-series-formulae-alleviate-depressive-like-behaviors-on-chronic-mild-stressed-mice-via-regulating-neurotrophic-factor-system-on-hippocampus
#3
Yue Zhu, Cheng Chao, Xiuzhu Duan, Xiaoxuan Cheng, Pei Liu, Shulan Su, Jinao Duan, Tina Tingxia Dong, Karl Wah-Keung Tsim
Kai-xin-san (KXS) is a famous Chinese medicinal formula applied for treating stress-related psychiatric diseases with the symptoms such as depression, forgetfulness and dizziness. In clinic, the composition ratio of KXS is always varied and KXS series formulae are created. Here, we aim to compare the anti-depressive effect of different ratios of KXS and reveal its action mechanism on regulation of neurotrophic factor system. Firstly, daily intra-gastric administration of chemically standardized extracts of KXS series formulae for seven days significantly alleviated the depressive symptoms of chronic unpredictable mild stressed mice displayed by enhanced sucrose consumptions and decreased immobile time of forced swimming coupled with increased locomotor activities...
May 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28456118/dna-interaction-antimicrobial-anticancer-activities-and-molecular-docking-study-of-some-new-vo-ii-cr-iii-mn-ii-and-ni-ii-mononuclear-chelates-encompassing-quaridentate-imine-ligand
#4
Laila H Abdel-Rahman, Ahmed M Abu-Dief, Moustafa O Aboelez, Azza A Hassan Abdel-Mawgoud
The present study was conducted to synthesis of some new imine Cr(III), VO(II), Mn(II) and Ni(II) complexes derived from the condensation of 2-amino phenol with 2-hydroxynapthaldehyde were synthesized. The prepared HNPN imine ligand was analyzed by its melting point, IR, (1)H NMR and (13)C NMR spectroscopies. The investigated HNPN imine complexes were characterized by elemental analysis, FT IR, UV-vis and thermal analysis (TGA) under nitrogen atmosphere from ambient temperature to 750°C. The experimental results revealed that the investigated complexes contain hydrated water molecules...
April 9, 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/28444624/targeting-ntrk-fusion-in-non-small-cell-lung-cancer-rationale-and-clinical-evidence
#5
REVIEW
Biagio Ricciuti, Marta Brambilla, Giulio Metro, Sara Baglivo, Roberta Matocci, Matteo Pirro, Rita Chiari
In the era of personalized medicine, the identification of targetable genetic alterations represented a major step forward in anticancer therapy. NTRK rearrangements represent the molecular driver of a subset of solid tumors, including 3% of non-small-cell lung cancers (NSCLCs). Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies. The aim of this review is to describe the molecular biology of NTRK signaling pathway and to summarize the preclinical data on novel Trk inhibitors, touching upon the clinical development of these inhibitors for the treatment of advanced NSCLC, which have already shown encouraging anticancer activity and acceptable safety profile in early phase I clinical trials...
June 2017: Medical Oncology
https://www.readbyqxmd.com/read/28438600/neurotrophin-receptors-in-the-pathogenesis-diagnosis-and-therapy-of-neurodegenerative-diseases
#6
REVIEW
Jacopo Meldolesi
In the last few years, exciting properties have emerged regarding the activation, signaling, mechanisms of action, and therapeutic targeting of the two types of neurotrophin receptors: the p75(NTR) with its intracellular and extracellular peptides, the Trks, their precursors and their complexes. This review summarizes these new developments, with particular focus on neurodegenerative diseases. Based on the evolving knowledge, innovative concepts have been formulated regarding the pathogenesis of these diseases, especially the Alzheimer's and two other, the Parkinson's and Huntington's diseases...
April 21, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28433076/identification-of-ntrk3-fusions-in-childhood-melanocytic-neoplasms
#7
Lu Wang, Klaus J Busam, Ryma Benayed, Robert Cimera, Jiajing Wang, Ryan Denley, Mamta Rao, Ruth Aryeequaye, Kerry Mullaney, Long Cao, Marc Ladanyi, Meera Hameed
Spitzoid neoplasms are a distinct group of melanocytic tumors. Genetically, they lack mutations in common melanoma-associated oncogenes. Recent studies have shown that spitzoid tumors may contain a variety of kinase fusions, including ROS1, NTRK1, ALK, BRAF, and RET fusions. We report herein the discovery of recurrent NTRK3 gene rearrangements in childhood melanocytic neoplasms with spitzoid and/or atypical features, based on genome-wide copy number analysis by single-nucleotide polymorphism array, which showed intragenic copy number changes in NTRK3...
May 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28398601/antidepressant-imipramine-protects-bupivacaine-induced-neurotoxicity-in-dorsal-root-ganglion-neurons-through-co-activation-of-trka-and-trkb
#8
Jianrong Guo, Huan Wang, Qiang Tao, Shiyu Sun, Li Liu, Jianping Zhang, Dawei Yang
PURPOSE: In our work, we used an in vitro culture model to investigate whether antidepressant imipramine (Ip) may protect bupivacaine (Bv)-induced neurotoxicity in mouse dorsal root ganglion (DRG). METHODS: Adult mouse DRG was treated with 5 mM Bv in vitro to induce neurotoxicity. DRG was then pre-treated with Ip, prior to Bv, to examine its effects on protecting Bv-induced DRG apoptosis and neurite degeneration. Ip-induced dynamic changes in Trk receptors, including TrkA/B/C and phosphor (p-)TrkA/B/C, were examined by qPCR and western blot...
April 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28373203/three-tier-regulation-of-cell-number-plasticity-by-neurotrophins-and-tolls-in-drosophila
#9
Istvan Foldi, Niki Anthoney, Neale Harrison, Monique Gangloff, Brett Verstak, Mohanakarthik Ponnadai Nallasivan, Samaher AlAhmed, Bangfu Zhu, Mark Phizacklea, Maria Losada-Perez, Marta Moreira, Nicholas J Gay, Alicia Hidalgo
Cell number plasticity is coupled to circuitry in the nervous system, adjusting cell mass to functional requirements. In mammals, this is achieved by neurotrophin (NT) ligands, which promote cell survival via their Trk and p75(NTR) receptors and cell death via p75(NTR) and Sortilin. Drosophila NTs (DNTs) bind Toll receptors instead to promote neuronal survival, but whether they can also regulate cell death is unknown. In this study, we show that DNTs and Tolls can switch from promoting cell survival to death in the central nervous system (CNS) via a three-tier mechanism...
May 1, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28373196/development-of-a-novel-site-specific-pegylated-interferon-beta-for-antiviral-therapy-for-chronic-hepatitis-b
#10
Masataka Tsuge, Takuro Uchida, Nobuhiko Hiraga, Hiromi Kan, Grace Naswa Makokha, Hiromi Abe-Chayama, Daiki Miki, Michio Imamura, Hidenori Ochi, C Nelson Hayes, Rieko Shimozono, Tomokatsu Iwamura, Hideki Narumi, Tomohiko Suzuki, Mie Kainoh, Tadatsugu Taniguchi, Kazuaki Chayama
Although nucleot(s)ide analogues and pegylated-interferon-α2a (PEG-IFNα2a) can suppress hepatitis B virus (HBV) replication, it is difficult to achieve complete HBV elimination from hepatocytes. A novel site-specific pegylated recombinant human IFNβ (TRK-560) was recently developed. In the present study, we evaluated the antiviral effects of TRK-560 on HBV replication in vitro and in vivoIn vitro and in vivo HBV replication models were treated with antivirals including TRK-560, and changes in HBV markers were evaluated...
April 3, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28370021/roles-of-neurotrophins-in-skeletal-tissue-formation-and-healing
#11
REVIEW
Yu-Wen Su, Xin-Fu Zhou, Bruce K Foster, Brian L Grills, Jiake Xu, Cory J Xian
Neurotrophins and their receptors are key molecules that are known to be critical in regulating nervous system development and maintenance and have been recognized to be also involved in regulating tissue formation and healing in skeletal tissues. Studies have shown that neurotrophins and their receptors are widely expressed in skeletal tissues, implicated in chondrogenesis, osteoblastogenesis, and osteoclastogenesis, and are also involved in regulating tissue formation and healing events in skeletal tissue...
March 30, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28356268/neurotrophin-3-up-regulates-proliferation-and-collagen-production-in-human-aortic-valve-interstitial-cells-a-potential-role-in-aortic-valve-sclerosis
#12
Qingzhou Yao, Rui Song, Lihua Ao, Joseph C Cleveland, David A Fullerton, Xianzhong Meng
Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Diseased aortic valves are characterized by sclerosis (fibrosis) and nodular calcification. Sclerosis, an early pathological change, is caused by aortic valve interstitial cell (AVIC) proliferation and over-production of extracellular matrix (ECM) proteins. However, the mechanism of aortic valve sclerosis remains unclear. Recently, we observed that diseased human aortic valves over-express growth factor neurotrophin 3 (NT3)...
March 29, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28351971/trk-receptor-signaling-and-sensory-neuron-fate-are-perturbed-in-human-neuropathy-caused-by-gars-mutations
#13
James N Sleigh, John M Dawes, Steven J West, Na Wei, Emily L Spaulding, Adriana Gómez-Martín, Qian Zhang, Robert W Burgess, M Zameel Cader, Kevin Talbot, Xiang-Lei Yang, David L Bennett, Giampietro Schiavo
Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice...
April 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28347639/neurite-outgrowth-in-cultured-mouse-pelvic-ganglia-effects-of-neurotrophins-and-bladder-tissue
#14
Mari Ekman, Baoyi Zhu, Karl Swärd, Bengt Uvelius
Neurotrophic factors regulate survival and growth of neurons. The urinary bladder is innervated via both sympathetic and parasympathetic neurons located in the major pelvic ganglion. The aim of the present study was to characterize the effects of the neurotrophins nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) on the sprouting rate of sympathetic and parasympathetic neurites from the female mouse ganglion. The pelvic ganglion was dissected out and attached to a petri dish and cultured in vitro...
March 18, 2017: Autonomic Neuroscience: Basic & Clinical
https://www.readbyqxmd.com/read/28326307/p75-neurotrophin-receptor-in-the-skin-beyond-its-neurotrophic-function
#15
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
#16
Shunzhou Wan, Agastya P Bhati, Sarah Skerratt, Kiyoyuki Omoto, Veerabahu Shanmugasundaram, Sharan K Bagal, Peter V Coveney
Optimization 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 because of 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, Enhanced Sampling of Molecular dynamics with Approximation of Continuum Solvent (ESMACS) and Thermodynamic Integration with Enhanced Sampling (TIES), to experimentally derived TrkA binding affinities for a set of Pfizer pan-Trk compounds...
April 24, 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
#17
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
#18
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
#19
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
#20
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
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