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https://www.readbyqxmd.com/read/28093646/mechanisms-of-inhibitory-action-of-trk-130-naltalimide-a-%C3%AE-opioid-receptor-partial-agonist-on-the-micturition-reflex
#1
Morihiro Fujimura, Naoki Izumimoto, Sayoko Kanie, Ryosuke Kobayashi, Satoru Yoshikawa, Shinobu Momen, Mikito Hirakata, Toshikazu Komagata, Satoshi Okanishi, Masashi Iwata, Tadatoshi Hashimoto, Takayuki Doi, Naoki Yoshimura, Koji Kawai
PURPOSE: To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex. METHODS: The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats...
January 16, 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28045258/concentration-dependent-self-assembly-of-trk-ngf-receptor-derived-tripeptide-new-insights-from-experiment-and-computer-simulations
#2
Parikshit Moitra, Yashonath Subramanian, Santanu Bhattacharya
Early research has shown that many neurodegenerative diseases are associated with the absence of a short and natural tripeptide sequence, Lys-Phe-Gly (KFG). Herein we report results of both experiments and extensive MD simulations of this tripeptide to understand the self-assembly and morphology as a function of its concentration. Morphologies of the aggregates formed by the tripeptide at low concentration (vesicles), and at high concentration (nanotubes) are studied by several independent 3 μs long Martini coarse-graining MD simulation runs...
January 3, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28044424/ocular-nerve-growth-factor-administration-modulates-brain-derived-neurotrophic-factor-signaling-in-prefrontal-cortex-of-healthy-and-diabetic-rats
#3
Pamela Rosso, Sara De Nicolò, Valentina Carito, Marco Fiore, Angela Iannitelli, Sandra Moreno, Paola Tirassa
AIMS: Nerve growth factor (NGF) eyedrops (ed-NGF) activate brain neurons, stimulate growth factors, including brain-derived neurotrophic factor (BDNF), and exert neuroprotection in the forebrain of streptozotocin-induced diabetic rats (STZ rats). In this study, the effects of ed-NGF on BDNF signaling in the prefrontal cortex (PFC) were explored in healthy and STZ-diabetic rats, in which cortical neuronal and axonal loss, and altered circulating BDNF associated with depressive phenotype are also described...
January 3, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28039433/structural-characterization-of-nonactive-site-trka-selective-kinase-inhibitors
#4
Hua-Poo Su, Keith Rickert, Christine Burlein, Kartik Narayan, Marina Bukhtiyarova, Danielle M Hurzy, Craig A Stump, Xufang Zhang, John Reid, Alicja Krasowska-Zoladek, Srivanya Tummala, Jennifer M Shipman, Maria Kornienko, Peter A Lemaire, Daniel Krosky, Amanda Heller, Abdelghani Achab, Chad Chamberlin, Peter Saradjian, Berengere Sauvagnat, Xianshu Yang, Michael R Ziebell, Elliott Nickbarg, John M Sanders, Mark T Bilodeau, Steven S Carroll, Kevin J Lumb, Stephen M Soisson, Darrell A Henze, Andrew J Cooke
Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28002846/unchanged-neurotrophic-factors-and-their-receptors-correlate-with-sparing-in-extraocular-muscles-in-amyotrophic-lateral-sclerosis
#5
Vahid M Harandi, Aida R N Gaied, Thomas Brännström, Fatima Pedrosa Domellöf, Jing-Xia Liu
Purpose: To investigate the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the distribution of neurotrophic factors (NTFs) and their receptors in EOMs and limb muscles from ALS transgenic mice. Methods: Muscle samples collected from transgenic mice overexpressing human superoxide dismutase type 1 mutations (SOD1G93A, the most widely used mouse model of ALS) at 50 and 150 days as well as age-matched controls were analyzed with immunohistochemistry using antibodies against brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and the neurotrophin receptors p75NTR, tyrosine kinase (Trk) receptor TrkB and TrkC, and GDNF family receptor alpha-1 (GFRα-1)...
December 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28002451/investigating-the-potential-signaling-pathways-that-regulate-activation-of-the-novel-pkc-downstream-of-serotonin-in-aplysia
#6
Carole A Farah, Bryan Rourke, Unkyung Shin, Larissa Ferguson, María José Luna, Wayne S Sossin
Activation of the novel PKC Apl II in sensory neurons by serotonin (5HT) underlies the ability of 5HT to reverse synaptic depression, but the pathway from 5HT to PKC Apl II activation remains unclear. Here we find no evidence for the Aplysia-specific B receptors, or for adenylate cyclase activation, to translocate fluorescently-tagged PKC Apl II. Using an anti-PKC Apl II antibody, we monitor translocation of endogenous PKC Apl II and determine the dose response for PKC Apl II translocation, both in isolated sensory neurons and sensory neurons coupled with motor neurons...
2016: PloS One
https://www.readbyqxmd.com/read/27989802/nerve-growth-factor-promotes-gastric-tumorigenesis-through-aberrant-cholinergic-signaling
#7
Yoku Hayakawa, Kosuke Sakitani, Mitsuru Konishi, Samuel Asfaha, Ryota Niikura, Hiroyuki Tomita, Bernhard W Renz, Yagnesh Tailor, Marina Macchini, Moritz Middelhoff, Zhengyu Jiang, Takayuki Tanaka, Zinaida A Dubeykovskaya, Woosook Kim, Xiaowei Chen, Aleksandra M Urbanska, Karan Nagar, Christoph B Westphalen, Michael Quante, Chyuan-Sheng Lin, Michael D Gershon, Akira Hara, Chun-Mei Zhao, Duan Chen, Daniel L Worthley, Kazuhiko Koike, Timothy C Wang
Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1(+) tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1(+) cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/27974047/fgfr1-and-ntrk3-actionable-alterations-in-wild-type-gastrointestinal-stromal-tumors
#8
Eileen Shi, Juliann Chmielecki, Chih-Min Tang, Kai Wang, Michael C Heinrich, Guhyun Kang, Christopher L Corless, David Hong, Katherine E Fero, James D Murphy, Paul T Fanta, Siraj M Ali, Martina De Siena, Adam M Burgoyne, Sujana Movva, Lisa Madlensky, Gregory M Heestand, Jonathan C Trent, Razelle Kurzrock, Deborah Morosini, Jeffrey S Ross, Olivier Harismendy, Jason K Sicklick
BACKGROUND: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies. METHODS: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations...
December 14, 2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27843590/ntrk-gene-fusions-as-novel-targets-of-cancer-therapy-across-multiple-tumour-types
#9
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
#10
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
#11
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-endoplasmic-reticulum-exit-site-localization-and-polymerization-of-trk-fused-gene-tfg-protein
#12
Takashi Kanadome, Hideki Shibata, Keiko Kuwata, Terunao Takahara, Masatoshi Maki
Apoptosis-linked gene 2 (ALG-2), which is 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. In the present study, we found that Trk-fused gene (TFG) protein 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
#13
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
#14
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
#15
Sarah E Skerratt, Mark 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 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...
November 23, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27697534/emerging-roles-of-the-neurotrophin-receptor-trkc-in-synapse-organization
#16
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
#17
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
#18
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
#19
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
#20
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...
January 2017: Biochimica et Biophysica Acta
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