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https://www.readbyqxmd.com/read/29617282/inhibiting-trk-proteins-in-clinical-cancer-therapy
#1
REVIEW
Allison M Lange, Hui-Wen Lo
Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways...
April 4, 2018: Cancers
https://www.readbyqxmd.com/read/29616344/novel-pharmacological-nonopioid-therapies-in-chronic-pain
#2
REVIEW
Alan David Kaye, Elyse M Cornett, Brendon Hart, Shilpadevi Patil, Andrew Pham, Matthew Spalitta, Kenneth F Mancuso
PURPOSE OF REVIEW: Opioid use and abuse has led to a worldwide opioid epidemic. And while opioids are clinically useful when appropriately indicated, they are associated with a wide range of dangerous side effects and whether they are effective at treating or eliminating chronic pain is controversial. There has long been a need for the development of nonopioid alternative treatments for patients that live in pain, and until recently, only a few effective treatments were available. Today, there are a wide range of nonopioid treatments available including NSAIDs, acetaminophen, corticosteroids, nerve blocks, SSRIs, neurostimulators, and anticonvulsants...
April 3, 2018: Current Pain and Headache Reports
https://www.readbyqxmd.com/read/29605512/a-novel-tropomyosin-related-kinase-a-inhibitor-kk5101-to-treat-pancreatic-cancer
#3
Zhenghuan Fang, Boreum Han, Kyung Hee Jung, Ju-Hyeon Lee, Ashraf Kareem El-Damasy, Changdev G Gadhe, Soo Jung Kim, Hong Hua Yan, Jung Hee Park, Ji Eun Lee, Yeo Wool Kang, Ae Nim Pae, Gyochang Keum, Soon-Sun Hong
Tropomyosin-related kinase A (TrkA) plays important roles in tumor cell growth and survival signaling and contributes to chemo-resistance in pancreatic cancer. Therefore, we developed KK5101, a novel TrkA target inhibitor and assessed its anti-cancer effects and investigated underlying mechanism of action in pancreatic cancer. KK5101 was characterized to inhibit TrkA selectively and potently by protein binding assay. It effectively inhibited the growth and proliferation of pancreatic cancer cells. Also, KK5101 increased apoptosis with loss of mitochondrial membrane potential, as evidenced by increases of cytochrome c releases...
March 29, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29589323/whole-tissue-3d-imaging-reveals-intra-adipose-sympathetic-plasticity-regulated-by-ngf-trka-signal-in-cold-induced-beiging
#4
Ying Cao, Huanhuan Wang, Wenwen Zeng
Sympathetic arborizations act as the essential efferent signals in regulating the metabolism of peripheral organs including white adipose tissues (WAT). However, whether these local neural structures would be of plastic nature, and how such plasticity might participate in specific metabolic events of WAT, remains largely uncharacterized. In this study, we exploit the new volume fluorescence-imaging technique to observe the significant, and also reversible, plasticity of intra-adipose sympathetic arborizations in mouse inguinal WAT in response to cold challenge...
March 27, 2018: Protein & Cell
https://www.readbyqxmd.com/read/29569362/temporally-restricted-death-and-the-role-of-p75ntr-as-a-survival-receptor-in-the-developing-sensory-nervous-system
#5
Irene Cheng, Lucy Jin, Lucy C Rose, Christopher D Deppmann
The peripheral somatosensory system overproduces neurons early in development followed by a period of cell death during final target innervation. The decision to survive or die in somatosensory neurons of the dorsal root ganglion (DRG) is mediated by target derived neurotrophic factors and their cognate receptors. Subsets of peripheral somatosensory neurons can be crudely defined by the neurotrophic receptors that they express: peptidergic nociceptors (TrkA+), non-peptidergic nociceptors (Ret+), mechanoreceptors (Ret+ or TrkB+), and proprioceptors (TrkC+)...
March 22, 2018: Developmental Neurobiology
https://www.readbyqxmd.com/read/29568869/therapeutic-effects-of-liver-soothing-pingchuan-formula-decoction-on-experimental-asthma-in-balb-c-mice-via-regulation-of-nerve-growth-factor-tyrosine-kinase-a-pathway
#6
Xin-Guang Zhang, Zheng Xue, Yi-Tao Zhao, Li Bai, Fei Liu, Li-Qing Li, Jie Wu, Jing-Dong Zhou, Jian-Er Yu
The present study was designed to investigate the effects of liver soothing pingchuan formula decoction (LSPF) on experimental asthma in BALB/c mice and explore its potential molecular mechanisms. An animal model of asthma was established in BALB/c mice through sensitization and activation with intraperitoneal injection of 10% ovalbumin (OVA)/Al(OH)3 solution in addition to inhalation of a 5% OVA solution. LSPF (300 and 600 mg/kg/day) was initially administered orally prior to activation. Following this, bronchoalveolar lavage fluid (BALF) and lung tissues were collected for histopathalogical examination...
March 14, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29563190/tropomyosin-receptor-kinase-a-novel-target-in-screened-neuroendocrine-tumors
#7
Elke Tatjana Aristizabal Prada, Vera Heinzle, Thomas Knösel, Svenja Nölting, Gerald Spoettl, Julian Maurer, Christine Spitzweg, Martin Angele, Nina Schmidt, Felix Beuschlein, Günter K Stalla, Rainer Blaser, Klaus A Kuhn, Christoph J Auernhammer
Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability...
March 21, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29553955/ntrk-fusions-define-a-novel-uterine-sarcoma-subtype-with-features-of-fibrosarcoma
#8
Sarah Chiang, Paolo Cotzia, David M Hyman, Alexander Drilon, William D Tap, Lei Zhang, Jaclyn F Hechtman, Denise Frosina, Achim A Jungbluth, Rajmohan Murali, Kay J Park, Robert A Soslow, Esther Oliva, A John Iafrate, Ryma Benayed, Marc Ladanyi, Cristina R Antonescu
Tropomyosin receptor kinase (Trk) inhibitors have shown high response rates in patients with tumors harboring NTRK fusions. We identified 4 NTRK fusion-positive uterine sarcomas that should be distinguished from leiomyosarcoma and undifferentiated uterine sarcoma. NTRK rearrangements were detected by fluorescence in situ hybridization (FISH) and/or targeted RNA or DNA sequencing in 4 undifferentiated uterine sarcomas with spindle cell morphology. Because of histologic overlap with leiomyosarcoma, TrkA and pan-Trk immunohistochemistry was performed in 97 uterine leiomyosarcomas...
March 16, 2018: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29550999/evaluation-of-the-immunoreactivity-of-nerve-growth-factor-and-tropomyosin-receptor-kinase-a-in-the-esophagus-of-noninfected-and-infected-individuals-with-trypanosoma-cruzi
#9
Jacqueline Garcia Duarte, Rodolfo Duarte Nascimento, Patrícia Rocha Martins, Débora d'Ávila Reis
Megaesophagus is one of the major manifestations of the chronic phase of Chagas disease. Its primary symptom is generally dysphagia due to disturbance in the lower esophageal sphincter. Microscopically, the affected organ presents denervation, which has been considered as consequence of an inflammatory process that begins at the acute phase and persists in the chronic phase. Inflammatory infiltrates are composed of lymphocytes, macrophages, natural killer cells, mast cells, and eosinophils. In this study, we evaluated the immunoreactivity of nerve growth factor (NGF), and of its receptor tropomyosin receptor kinase A (TrkA), molecules that are well known for having a relevant role in neuroimmune communication in the gastrointestinal tract...
March 17, 2018: Parasitology Research
https://www.readbyqxmd.com/read/29549340/transcytosis-of-trka-leads-to-diversification-of-dendritic-signaling-endosomes
#10
Kelly Barford, Austin Keeler, Lloyd McMahon, Kathryn McDaniel, Chan Choo Yap, Christopher D Deppmann, Bettina Winckler
The development of the peripheral nervous system relies on long-distance signaling from target organs back to the soma. In sympathetic neurons, this long-distance signaling is mediated by target derived Nerve Growth Factor (NGF) interacting with its axonal receptor, TrkA. This ligand receptor complex internalizes into what is commonly referred to as the signaling endosome which is transported retrogradely to the soma and dendrites to mediate survival signaling and synapse formation, respectively. The molecular identity of signaling endosomes in dendrites has not yet been determined...
March 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29535428/relapsed-acute-lymphoblastic-leukemia-specific-mutations-in-nt5c2-cluster-into-hotspots-driving-intersubunit-stimulation
#11
Aleš Hnízda, Milan Fábry, Takaya Moriyama, Petr Pachl, Michael Kugler, Vítězslav Brinsa, David B Ascher, William L Carroll, Petr Novák, Markéta Žaliová, Jan Trka, Pavlína Řezáčová, Jun J Yang, Václav Veverka
Activating mutations in NT5C2, a gene encoding cytosolic purine 5'-nucleotidase (cN-II), confer chemoresistance in relapsed acute lymphoblastic leukemia. Here we show that all mutants became independent of allosteric effects of ATP and thus constitutively active. Structural mapping of mutations described in patients demonstrates that 90% of leukemia-specific allelles directly affect two regulatory hotspots within the cN-II molecule-the helix A region: residues 355-365, and the intersubunit interface: helix B (232-242) and flexible interhelical loop L (400-418)...
February 25, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29518187/potent-and-rapid-activation-of-tropomyosin-receptor-kinase-a-in-endometrial-stromal-fibroblasts-by-seminal-plasma
#12
Jeremy W Martin, Joseph C Chen, Jason Neidleman, Keiji Tatsumi, James Hu, Linda C Giudice, Warner C Greene, Nadia R Roan
Seminal plasma (SP), the liquid fraction of semen, is not mandatory for conception, but clinical studies suggest that SP improves implantation rates. Prior in vitro studies examining the effects of SP on the endometrium, the site of implantation, surprisingly revealed that SP induces transcriptional profiles associated with neurogenesis. We investigated the presence and activity of neurogenesis pathways in the endometrium, focusing on TrkA, one of the canonical receptors associated with neurotrophic signaling...
March 6, 2018: Biology of Reproduction
https://www.readbyqxmd.com/read/29507419/ezh2-regulates-neuroblastoma-cell-differentiation-via-ntrk1-promoter-epigenetic-modifications
#13
Zhenghao Li, Hisanori Takenobu, Amallia Nuggetsiana Setyawati, Nobuhiro Akita, Masayuki Haruta, Shunpei Satoh, Yoshitaka Shinno, Koji Chikaraishi, Kyosuke Mukae, Jesmin Akter, Ryuichi P Sugino, Atsuko Nakazawa, Akira Nakagawara, Hiroyuki Aburatani, Miki Ohira, Takehiko Kamijo
The polycomb repressor complex 2 molecule EZH2 is now known to play a role in essential cellular processes, namely, cell fate decisions, cell cycle regulation, senescence, cell differentiation, and cancer development/progression. EZH2 inhibitors have recently been developed; however, their effectiveness and underlying molecular mechanisms in many malignancies have not yet been elucidated in detail. Although the functional role of EZH2 in tumorigenesis in neuroblastoma (NB) has been investigated, mutations of EZH2 have not been reported...
March 6, 2018: Oncogene
https://www.readbyqxmd.com/read/29483280/swedish-nerve-growth-factor-mutation-ngf-r100w-defines-a-role-for-trka-and-p75-ntr-in-nociception
#14
Kijung Sung, Luiz F Ferrari, Wanlin Yang, ChiHye Chung, Xiaobei Zhao, Yingli Gu, Suzhen Lin, Kai Zhang, Bianxiao Cui, Matthew L Pearn, Michael T Maloney, William C Mobley, Jon D Levine, Chengbiao Wu
Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFβ sequence (NGFR100W ) in patients with hereditary sensory and autonomic neuropathy, type V (HSAN V), made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular and live imaging experiments to examine the binding and signaling properties of NGFR100W Our results show that, similar to the wildtype NGF (wtNGF), the naturally occurring NGFR100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation...
February 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29473218/ngf-steers-microglia-toward-a-neuroprotective-phenotype
#15
Caterina Rizzi, Alexia Tiberi, Michela Giustizieri, Maria Cristina Marrone, Francesco Gobbo, Nicola Maria Carucci, Giovanni Meli, Ivan Arisi, Mara D'Onofrio, Silvia Marinelli, Simona Capsoni, Antonino Cattaneo
Microglia are the sentinels of the brain but a clear understanding of the factors that modulate their activation in physiological and pathological conditions is still lacking. Here we demonstrate that Nerve Growth Factor (NGF) acts on microglia by steering them toward a neuroprotective and anti-inflammatory phenotype. We show that microglial cells express functional NGF receptors in vitro and ex vivo. Our transcriptomic analysis reveals how, in primary microglia, NGF treatment leads to a modulation of motility, phagocytosis and degradation pathways...
February 23, 2018: Glia
https://www.readbyqxmd.com/read/29454290/ligand-based-computer-aided-drug-design-reveals-new-tropomycin-receptor-kinase-a-trka-inhibitors
#16
Rand Shahin, Iman Mansi, Lubna Swellmeen, Tahani Alwidyan, Nabil Al-Hashimi, Yaser Al-Qarar'h, Omar Shaheen
Targeting tropomycin kinase A (TrkA) by small molecule inhibitors is considered as a promising strategy for treating several human cancers. To achieve this goal, a ligand based QSAR model was applied using the Discovery studio 4.5 (DS 4.5). Hence, a total list of 161 TrkA inhibitors was investigated. The TrkA inhibitors were extensively explored to detect their optimal physicochemical properties and pharmacophoric binding modes, which were converted into numeric descriptors and allowed to compete within the context of the Genetic Function Algorithm (GFA) approximations to find the subset of terms that correlates best with the activity...
January 13, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29450621/ngf-protects-corneal-retinal-and-cutaneous-tissues-cells-from-phototoxic-effect-of-uv-exposure
#17
Maria Luisa Rocco, Bijorn Omar Balzamino, Luigi Aloe, Alessandra Micera
PURPOSE: Based on evidence that nerve growth factor (NGF) exerts healing action on damaged corneal, retinal, and cutaneous tissues, the present study sought to assess whether topical NGF application can prevent and/or protect epithelial cells from deleterious effects of ultraviolet (UV) radiation. METHODS: Eyes from 40 young-adult Sprague Dawley rats and cutaneous tissues from 36 adult nude mice were exposed to UVA/B lamp for 60 min, either alone or in the presence of murine NGF...
February 15, 2018: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/29438801/specific-activity-features-in-the-forced-swim-test-brain-neurotrophins-and-development-of-stress-induced-depressive-like-behavior-in-rats
#18
Mikhail Stepanichev, Anna Manolova, Danil Peregud, Mikhail Onufriev, Sofia Freiman, Viktor Aniol, Yulia Moiseeva, Margarita Novikova, Natalia Lazareva, Natalia Gulyaeva
Selective vulnerability or resilience to mood disorders is related to individual differences or personality. In the present study forced swim test (FST) was used as a tool for division of male rats according to their immobility behavior. The animals were subjected to a chronic unpredictable mild stress (CUS). Depressive-like behavior and modifications in brain neurotrophin system of were examined after CUS exposure. The low immobile (LI) and high immobile (HI) rats demonstrated elusive differences in expression of BDNF ExVI mRNA and TrkA mRNA which was higher in hippocampus and frontal cortex, respectively, of HI rats as compared to LI animals...
February 10, 2018: Neuroscience
https://www.readbyqxmd.com/read/29429227/-effect-of-nerve-growth-factor-on-osteogenic-potential-of-type-2-diabetic-mice-bone-marrow-stromal-cell-in-vitro
#19
G S Cui, J Y Zeng, J Zhang, R Lu
Objective: To study the effects of nerve growth factor (NGF) on the proliferation, osteogenic differentiation and mineralization of type 2 diabetic mice bone marrow stromal cell (BMSC), providing basis for clinical application of NGF. Methods: Three 8-week-old male db/db mice and two 8-week-old male C57BL/6J mice were used in the study. BMSC derived from femur were cultured though adherence method. BMSC of C57BL/6J mice and db/db mice was divided into normal group and diabetic group to conduct the osteogenic potential experiment, named experiment one...
February 9, 2018: Zhonghua Kou Qiang Yi Xue za Zhi, Zhonghua Kouqiang Yixue Zazhi, Chinese Journal of Stomatology
https://www.readbyqxmd.com/read/29420916/rutin-attenuates-cerebral-ischemia-reperfusion-injury-in-ovariectomized-rats-via-estrogen-receptor-mediated-bdnf-trkb-and-ngf-trka-signaling
#20
Hong Liu, Lili Zhong, Yuwei Zhang, Xuewei Liu, Ji Li
Rutin, a flavonoid glycoside, has been reported to exert neuroprotective effects. Loss of the endogenous estrogen and dysregulation of the estrogen receptor (ER) signaling pathway are associated with the increased risk of stroke in women after menopause. This study was performed to investigate whether rutin could protect against cerebral ischemia by modulating ER pathway. Ovariectomized (OVX) rats were given intraperitoneal injection of vehicle (DMSO), rutin (100 mg/kg) or 17β-estradiol (100 μg/kg) for 5 continuous days...
February 8, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
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