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https://www.readbyqxmd.com/read/27843590/ntrk-gene-fusions-as-novel-targets-of-cancer-therapy-across-multiple-tumour-types
#1
REVIEW
Alessio Amatu, Andrea Sartore-Bianchi, Salvatore Siena
The tropomyosin receptor kinase (Trk) receptor family comprises 3 transmembrane proteins referred to as Trk A, B and C (TrkA, TrkB and TrkC) receptors that are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and play an essential role in the physiology of development and function of the nervous system through activation by neurotrophins. Gene fusions involving NTRK genes lead to transcription of chimeric Trk proteins with constitutively activated or overexpressed kinase function conferring oncogenic potential...
2016: ESMO Open
https://www.readbyqxmd.com/read/27823570/neurotrophin-receptor-signaling-as-a-therapeutic-target-for-huntington-s-disease
#2
Danielle A Simmons, Frank M Longo, Stephen M Massa
Effective non-genetic disease modifying treatments for Huntington's disease (HD) will necessarily target multiple diverse neurodegenerative processes triggered by mutant huntingtin. Neurotrophin receptors are well-positioned for this task as they regulate signaling pathways that largely overlap with signaling networks contributing to HD-related synaptic dysfunction, glial activation, excitotoxicity, and other degenerative processes. This review will discuss the contributions of disrupted neurotrophin receptor-related signaling to primary HD neuropathologies, and prospects for harnessing this signaling to develop therapeutics to counteract HD degenerative mechanisms...
November 6, 2016: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/27815842/neurotrophin-signaling-and-stem-cells-implications-for-neurodegenerative-diseases-and-stem-cell-therapy
#3
REVIEW
Subrata Pramanik, Yanuar Alan Sulistio, Klaus Heese
Neurotrophins (NTs) are members of a neuronal growth factor protein family whose action is mediated by the tropomyosin receptor kinase (TRK) receptor family receptors and the p75 NT receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor family. Although NTs were first discovered in neurons, recent studies have suggested that NTs and their receptors are expressed in various types of stem cells mediating pivotal signaling events in stem cell biology. The concept of stem cell therapy has already attracted much attention as a potential strategy for the treatment of neurodegenerative diseases (NDs)...
November 5, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27813252/the-calcium-binding-protein-alg-2-promotes-er-exit-site-localization-and-polymerization-of-tfg
#4
Takashi Kanadome, Hideki Shibata, Keiko Kuwata, Terunao Takahara, Masatoshi Maki
ALG-2 (apoptosis-linked gene 2, a gene product of PDCD6) is a 22-kDa Ca(2+) -binding protein. Accumulating evidence points to a role for ALG-2 as a Ca(2+) -responsive adaptor protein. On binding to Ca(2+) , ALG-2 undergoes a conformational change that facilitates its interaction with various proteins. It also forms a homodimer and heterodimer with peflin, a paralog of ALG-2. However, the differences in cellular roles for the ALG-2 homodimer and ALG-2/peflin heterodimer are unclear. Here, we found that TFG (Trk-fused gene) interacted with the ALG-2 homodimer...
November 4, 2016: FEBS Journal
https://www.readbyqxmd.com/read/27812321/slitrk-missense-mutations-associated-with-neuropsychiatric-disorders-distinctively-impair-slitrk-trafficking-and-synapse-formation
#5
Hyeyeon Kang, Kyung Ah Han, Seoung Youn Won, Ho Min Kim, Young-Ho Lee, Jaewon Ko, Ji Won Um
Slit- and Trk-like (Slitrks) are a six-member family of synapse organizers that control excitatory and inhibitory synapse formation by forming trans-synaptic adhesions with LAR receptor protein tyrosine phosphatases (PTPs). Intriguingly, genetic mutations of Slitrks have been associated with a multitude of neuropsychiatric disorders. However, nothing is known about the neuronal and synaptic consequences of these mutations. Here, we report the structural and functional effects on synapses of various rare de novo mutations identified in patients with schizophrenia or Tourette syndrome...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27786317/neurotrophin-mimicking-peptides-at-the-biointerface-with-gold-respond-to-copper-ion-stimuli
#6
C Satriano, G Forte, A Magrì, P Di Pietro, A Travaglia, G Pandini, F Gianì, D La Mendola
The peptide fragments NGF1-14 and BDNF1-12, encompassing the N-terminal domains, respectively, of the proteins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were used in this study for the fabrication of a hybrid gold/peptide biointerface. These peptides mimic the Trk receptor activation of the respective whole protein - with a crucial role played by copper ions - and exhibit, in bulk solution, a pH-dependent capability to complex copper. We demonstrate here the maintenance of peptide-specific responses at different pH values as well as the copper binding also for the adlayers formed upon physisorption at the gold surface...
October 27, 2016: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/27766865/the-discovery-of-a-potent-selective-and-peripherally-restricted-pan-trk-inhibitor-pf-06273340-for-the-treatment-of-pain
#7
Sarah Elizabeth Skerratt, Mark D Andrews, Sharan K Bagal, James Bilsland, David Brown, Peter J Bungay, Susan Cole, Karl R Gibson, Russell Jones, Inaki Morao, Angus Nedderman, Kiyoyuki Omoto, Colin Robinson, Thomas Ryckmans, Kimberly Skinner, Paul Anthony Stupple, Gareth Waldron
The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention...
October 21, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27697534/emerging-roles-of-the-neurotrophin-receptor-trkc-in-synapse-organization
#8
Yusuke Naito, Alfred Kihoon Lee, Hideto Takahashi
Tropomyosin-receptor-kinase (Trk) receptors have been extensively studied for their roles in kinase-dependent signaling cascades in nervous system development. Synapse organization is coordinated by trans-synaptic interactions of various cell adhesion proteins, a representative example of which is the neurexin-neuroligin complex. Recently, a novel role for TrkC as a synapse organizing protein has been established. Post-synaptic TrkC binds to pre-synaptic type-IIa receptor-type protein tyrosine phosphatase sigma (PTPσ)...
September 30, 2016: Neuroscience Research
https://www.readbyqxmd.com/read/27693452/relative-expression-of-the-p75-neurotrophin-receptor-tyrosine-receptor-kinase-a-and-insulin-receptor-in-sh-sy5y-neuroblastoma-cells-and-hippocampi-from-alzheimer-s-disease-patients
#9
Shingo Ito, Michel Ménard, Trevor Atkinson, Leslie Brown, James Whitfield, Balu Chakravarthy
We have previously shown in SH-SY5Y human neuroblastoma cells that the expressions of basal (75 kDa) and high molecular weight (HMW; 85 kDa) isoforms of the p75 neurotrophic receptor (p75NTR) are stimulated by amyloid-β peptide1-42 oligomers (AβOs) via the insulin-like growth factor-1 receptor (IGF-1R). On the other hand, it is known that AβOs inhibit insulin receptor (IR) signaling. The purpose of the present study was to determine the involvement of IR signaling in the regulation of p75 neurotrophin receptor (p75NTR) protein isoform expression in cultured SH-SY5Y cells and in hippocampi from late-stage human Alzheimer's disease (AD) brains...
December 2016: Neurochemistry International
https://www.readbyqxmd.com/read/27683907/the-neurotrophic-factor-receptor-p75-in-the-rat-dorsolateral-striatum-drives-excessive-alcohol-drinking
#10
Emmanuel Darcq, Nadege Morisot, Khanhky Phamluong, Vincent Warnault, Jerome Jeanblanc, Frank M Longo, Stephen M Massa, Dorit Ron
UNLABELLED: Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) keeps alcohol intake in moderation. For example, activation of the BDNF receptor tropomyosin receptor kinase B (TrkB) in the DLS reduces intake in rats that consume moderate amounts of alcohol. Here, we tested whether long-term excessive consumption of alcohol produces neuroadaptations in BDNF signaling in the rat DLS. We found that BDNF was no longer able to gate alcohol self-administration after a history of repeated cycles of binge alcohol drinking and withdrawal...
September 28, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27681484/the-pharmacokinetics-of-beraprost-sodium-following-single-oral-administration-to-subjects-with-impaired-kidney-function
#11
Masahiro Shimamura, Jun Miyakawa, Masaaki Doi, Kiyonobu Okada, Hajimu Kurumatani, Yoshitaka Mori, Keiyu Oshida, Ikumi Nakajo, Keishi Oikawa, Fumihiko Ushigome, Aiji Miyashita, Masanao Isono, Yohei Miyamoto
The purpose of the present study was to evaluate the pharmacokinetics of beraprost sodium (BPS) and its active enantiomer, BPS-314d, in Japanese subjects with impaired kidney function. The plasma and urine concentrations of BPS and BPS-314d were measured following the single oral administration of 120 μg of BPS as the sustained-release tablet, TRK-100STP, under fasting conditions to 18 subjects with impaired kidney function (stage 2, 3, and 4 chronic kidney disease (CKD) (as categorized by the estimated glomerular filtration rate)) and to 6 age-, body weight-, and gender-matched subjects with normal kidney function (stage 1 CKD)...
September 28, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27639832/re-expression-of-cell-cycle-markers-in-aged-neurons-and-muscles-whether-cells-should-divide-or-die
#12
REVIEW
Renu Sharma, Dhiraj Kumar, Niraj Kumar Jha, Saurabh Kumar Jha, Rashmi K Ambasta, Pravir Kumar
Emerging evidence revealed that abrogated cell cycle entry into highly differentiated mature neurons and muscles is having detrimental consequences in response to cell cycle checkpoints disruption, altered signaling cascades, pathophysiological and external stimuli, for instance, Aβ, Parkin, p-tau, α-synuclein, impairment in TRK, Akt/GSK3β, MAPK/Hsp90, and oxidative stress. These factors, reinitiate undesired cell division by triggering new DNA synthesis, replication, and thus exquisitely forced mature cell to enter into a disturbed and vulnerable state that often leads to death as reported in many neuro- and myodegenerative disorders...
September 14, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27624843/reduced-neurotrophic-factor-level-is-the-early-event-before-the-functional-neuronal-deficiency-in-high-fat-diet-induced-obese-mice
#13
Huanhuan Wang, Bing Wang, Hongping Yin, Guoqing Zhang, Liping Yu, Xiangmin Kong, Haiying Yuan, Xingyue Fang, Qibing Liu, Cuiqing Liu, Liyun Shi
Neurodegeneration is considered one of the possible complications of high fat diet (HFD) induced obesity. Much evidence has shown the close relationship between HFD and dementia at comparatively later stage of neuronal injury. It is so far not clear that the initial events of neuronal injury resulting from HFD and obesity. In the present research, obese mouse model achieved by 3-month HFD was applied for the investigation of the possible neuronal deficiency before the obvious cognitive decline. We found that 3-month HFD has already increased the average level of body weight of mice...
September 13, 2016: Metabolic Brain Disease
https://www.readbyqxmd.com/read/27590859/down-regulation-of-brain-derived-neurotrophic-factor-and-its-signaling-components-in-the-brain-tissues-of-scrapie-experimental-animals
#14
Ting-Ting Wang, Chan Tian, Jing Sun, Hui Wang, Bao-Yun Zhang, Cao Chen, Jing Wang, Kang Xiao, Li-Na Chen, Yan Lv, Chen Gao, Qi Shi, Yan Xin, Xiao-Ping Dong
Prion is a unique nucleic acid-free pathogen that causes human and animal fatal neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is a prototypic neurotrophin that helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. There are two distinct classes of glycosylated receptors, neurotrophin receptor p75 (p75NTR) and tropomyosin-related kinase (Trk), that can bind to BDNF. To obtain insights into the possible alterations of brain BDNF and its signaling pathway in prion disease, the levels of BDNF and several molecules in the BDNF pathway in the brain tissues of scrapie agents 263K-infected hamsters were separately evaluated...
October 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27546056/neurotrophin-receptor-agonists-and-antagonists-as-therapeutic-agents-an-evolving-paradigm
#15
Sylvia Josephy-Hernandez, Sean Jmaeff, Iulia Pirvulescu, Tahar Aboulkassim, H Uri Saragovi
Neurodegenerative disorders are prevalent, complex and devastating conditions, with very limited treatment options currently available. While they manifest in many forms, there are commonalities that link them together. In this review, we will focus on neurotrophins - a family of related factors involved in neuronal development and maintenance. Neurodegenerative diseases often present with a neurotrophin imbalance, in which there may be decreases in trophic signaling through Trk receptors for example, and/or increases in pro-apoptotic activity through p75...
August 18, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27540475/recent-advances-in-understanding-neurotrophin-signaling
#16
REVIEW
Mark Bothwell
The nerve growth factor family of growth factors, collectively known as neurotrophins, are evolutionarily ancient regulators with an enormous range of biological functions. Reflecting this long history and functional diversity, mechanisms for cellular responses to neurotrophins are exceptionally complex. Neurotrophins signal through p75 (NTR), a member of the TNF receptor superfamily member, and through receptor tyrosine kinases (TrkA, TrkB, TrkC), often with opposite functional outcomes. The two classes of receptors are activated preferentially by proneurotrophins and mature processed neurotrophins, respectively...
2016: F1000Research
https://www.readbyqxmd.com/read/27528608/fty720-fingolimod-reduces-synucleinopathy-and-improves-gut-motility-in-a53t-mice-contributions-of-pro-brain-derived-neurotrophic-factor-pro-bdnf-and-mature-bdnf
#17
Guadalupe Vidal-Martínez, Javier Vargas-Medrano, Carolina Gil-Tommee, David Medina, Nathan T Garza, Barbara Yang, Ismael Segura-Ulate, Samantha J Dominguez, Ruth G Perez
Patients with Parkinson's disease (PD) often have aggregated α-synuclein (aSyn) in enteric nervous system (ENS) neurons, which may be associated with the development of constipation. This occurs well before the onset of classic PD motor symptoms. We previously found that aging A53T transgenic (Tg) mice closely model PD-like ENS aSyn pathology, making them appropriate for testing potential PD therapies. Here we show that Tg mice overexpressing mutant human aSyn develop ENS pathology by 4 months. We then evaluated the responses of Tg mice and their WT littermates to the Food and Drug Administration-approved drug FTY720 (fingolimod, Gilenya) or vehicle control solution from 5 months of age...
September 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27526999/developing-the-catecholamines-hypothesis-for-the-acute-exercise-cognition-interaction-in-humans-lessons-from-animal-studies
#18
REVIEW
Terry McMorris
The catecholamines hypothesis for the acute exercise-cognition interaction in humans fails to adequately explain the interaction between peripherally circulating catecholamines and brain concentrations; how different exercise intensities×durations affect different cognitive tasks; and how brain catecholamines, glucocorticoids, BDNF and 5-hydroxytryptamine interact. A review of the animal literature was able to clarify many of the issues. Rodent studies showed that facilitation of cognition during short to moderate duration (SMD), moderate exercise could be accounted for by activation of the locus coeruleus via feedback from stretch reflexes, baroreceptors and, post-catecholamines threshold, β-adrenoceptors on the vagus nerve...
October 15, 2016: Physiology & Behavior
https://www.readbyqxmd.com/read/27510267/neuroserpin-attenuates-h2o2-induced-oxidative-stress-in-hippocampal-neurons-via-akt-and-bcl-2-signaling-pathways
#19
Yong Cheng, Y Peng Loh, Nigel P Birch
Oxidative stress plays a critical role in neuronal injury and is associated with various neurological diseases. Here, we explored the potential protective effect of neuroserpin against oxidative stress in primary cultured hippocampal neurons. Our results show that neuroserpin inhibits H2O2-induced neurotoxicity in hippocampal cultures as measured by WST, LDH release, and TUNEL assays. We found that neuroserpin enhanced the activation of AKT in cultures subjected to oxidative stress and that the AKT inhibitor Ly294002 blocked this neuroprotective effect...
August 11, 2016: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/27498123/pharmacological-properties-of-microneurotrophin-drugs-developed-for-treatment-of-amyotrophic-lateral-sclerosis
#20
James P Bennett, Laura C O'Brien, David G Brohawn
Microneurotrophins (MNT's) are small molecule derivatives of dehydroepiandrosterone (DHEA) and do not have significant interactions with sex steroid receptors. MNT's retain high-affinity binding to protein tyrosine kinase (Trk) receptors and can mimic many pleiotropic actions of neurotrophin (NT) proteins on neurons. MNT's offer therapeutic potential for diseases such as amyotrophic lateral sclerosis (ALS) where motor neurons (MN) degenerate. MNT's cross artificial membranes mimicking the blood-brain barrier, are not major substrates for ABC (ATP-binding cassette) transporters and are metabolized rapidly by mouse but more slowly by human hepatocytes...
October 1, 2016: Biochemical Pharmacology
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