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https://www.readbyqxmd.com/read/29139614/human-dental-stem-cell-derived-transgene-free-ipscs-generate-functional-neurons-via-embryoid-body-mediated-and-direct-induction-methods
#1
Ikbale El Ayachi, Jun Zhang, Xiao-Ying Zou, Zongdong Yu, Wei Wei, Kristen M S O'Connell, George T-J Huang
Induced pluripotent stem cells (iPSCs) give rise to neural stem/progenitor cells (NSCs), serving as a good source for neural regeneration. Here, we established transgene-free (TF) iPSCs from dental stem cells (DSCs) and determined their capacity to differentiate into functional neurons in vitro. Generated TF iPSCs from stem cells of apical papilla (SCAP) and dental pulp stem cells (DPSCs) underwent two methods -- embryoid body (EB)-mediated and direct induction, to guide TF-DSC iPSCs along with H9 or H9 Syn-GFP (human embryonic stem cells) into functional neurons in vitro...
November 15, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/29122010/expression-of-voltage-gated-sodium-channel-nav1-5-in-non-metastatic-colon-cancer-and-its-associations-with-estrogen-receptor-er-%C3%AE-expression-and-clinical-outcomes
#2
Jianhong Peng, Qingjian Ou, Xiaojun Wu, Rongxin Zhang, Qian Zhao, Wu Jiang, Zhenhai Lu, Desen Wan, Zhizhong Pan, Yujing Fang
BACKGROUND: Voltage-gated sodium channel 1.5 (Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β (ER-β) expression in non-metastatic colon cancer patients receiving radical resection. METHODS: A total of 269 consecutive patients with pathologically confirmed stages I-III colon cancer who underwent radical resection were selected...
November 9, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/29115943/membrane-protein-nav1-7-contributes-to-the-persistent-post-surgical-pain-regulated-by-p-p65-in-dorsal-root-ganglion-drg-of-smir-rats-model
#3
Zhisong Li, Yaru Li, Jing Cao, Xuemin Han, Weihua Cai, Weidong Zang, Jitian Xu, Wei Zhang
BACKGROUND: Persistent post-surgical pain is a difficult clinical problem. In this study, we intend to explore the mechanism underlying the persistent post-surgical pain in SMIR (skin/muscle incision and retraction) rats. METHODS: First of all, the expression of membrane protein Nav1.7 and p-p65 (Phosphorylation of p65) were detected in ipsilateral L4-6 DRGs of SMIR rats by western-blot and immunostaining. Then with ProTx-II (Nav1.7 blocker) or PDTC (p65 inhibitor) were intrathecally injected while the change of Nav1...
November 7, 2017: BMC Anesthesiology
https://www.readbyqxmd.com/read/29106681/common-missense-variant-of-scn9a-gene-is-associated-with-pain-intensity-in-patients-with-chronic-pain-from-disc-herniation
#4
Mateusz Kurzawski, Marcin Rut, Violetta Dziedziejko, Krzysztof Safranow, Anna Machoy-Mokrzynska, Marek Drozdzik, Monika Bialecka
Objective: Lumbar intervertebral disk herniation (LDH) is considered one of the major risk factors for lower back pain, mainly caused by irritation of a spinal nerve or its root. One of the genes related to pain perception is SCN9A, which encodes the voltage gated sodium channel NaV1.7, a key molecule involved in peripheral pain processing. It had been presented before that a common polymorphism within SCN9A (rs6746030: G > A, R1150W) might influence nociception in the general population...
November 2, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
https://www.readbyqxmd.com/read/29094728/enhancing-inactivation-rather-than-reducing-activation-of-nav1-7-channels-by-a-clinically-effective-analgesic-cnv1014802
#5
Yue-Ming Zheng, Wan-Fu Wang, Yan-Fen Li, Yong Yu, Zhao-Bing Gao
The Nav1.7 channel represents a promising target for pain relief. In the recent decades, a number of Nav1.7 channel inhibitors have been developed. According to the effects on channel kinetics, these inhibitors could be divided into two major classes: reducing activation or enhancing inactivation. To date, however, only several inhibitors have moved forward into phase 2 clinical trials and most of them display a less than ideal analgesic efficacy, thus intensifying the controversy regarding if an ideal candidate should preferentially affect the activation or inactivation state...
November 2, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29063143/the-nav1-7-blocker-protoxin-ii-reduces-burn-injury-induced-spinal-nociceptive-processing
#6
Jose Vicente Torres-Pérez, Pavel Adamek, Jiri Palecek, Marcela Vizcaychipi, Istvan Nagy, Angelika Varga
Controlling pain in burn-injured patients poses a major clinical challenge. Recent findings suggest that reducing the activity of the voltage-gated sodium channel Nav1.7 in primary sensory neurons could provide improved pain control in burn-injured patients. Here, we report that partial thickness scalding-type burn injury on the rat paw upregulates Nav1.7 expression in primary sensory neurons 3 h following injury. The injury also induces upregulation in phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), a marker for nociceptive activation in primary sensory neurons...
October 23, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29029933/highly-potent-and-selective-nav1-7-inhibitors-for-use-as-intravenous-agents-and-chemical-probes
#7
R Ian Storer, Andy Pike, Nigel A Swain, Aristos J Alexandrou, Bruce M Bechle, David C Blakemore, Alan D Brown, Neil A Castle, Matthew S Corbett, Neil J Flanagan, David Fengas, M Scott Johnson, Lyn H Jones, Brian E Marron, C Elizabeth Payne, David Printzenhoff, David J Rawson, Colin R Rose, Thomas Ryckmans, Jianmin Sun, Jonathan W Theile, Rubben Torella, Elaine Tseng, Joseph S Warmus
The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation...
November 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28990532/a-novel-scn9a-mutation-f826y-in-primary-erythromelalgia-alters-the-excitability-of-nav1-7
#8
B Wu, Y Zhang, H Tang, Mei Yang, Hai Long, Gaoxing Shi, Jianguang Tang, Xiaoliu Shi
Primary erythromelalgia (PE) is a dominant inherited disorder characterized by recurrent pain, redness, and warmth of the extremities that is caused by gain-of-function mutations in the voltage-gated sodium channel Nav1.7. We investigated a three-generation Chinese Han family with PE. The proband is a 15-year old girl presented with skin ulcers, recurrent burning pain, warmth, and redness of the lower extremities that are refractory to all kinds of reported medications. The other two patients presented with similar symptoms but with far less severity that naturally remitted near their forties...
October 9, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/28976422/antisense-oligonucleotides-selectively-suppress-target-rna-in-nociceptive-neurons-of-the-pain-system-and-can-ameliorate-mechanical-pain
#9
Apoorva Mohan, Bethany Fitzsimmons, Hien T Zhao, Yuhong Jiang, Curt Mazur, Eric E Swayze, Holly B Kordasiewicz
There is an urgent need for better treatments for chronic pain, which affects more than 1 billion people worldwide. Antisense oligonucleotides (ASOs) have proven successful in treating children with spinal muscular atrophy, a severe infantile neurological disorder, and several compounds based on ASOs are currently being tested in clinical trials for various neurological disorders. Here we characterize the pharmacodynamic activity of ASOs in spinal cord and dorsal root ganglia (DRG), key tissues for pain signaling...
September 30, 2017: Pain
https://www.readbyqxmd.com/read/28939386/investigation-into-the-role-of-an-extracellular-loop-in-mediating-proton-evoked-inhibition-of-voltage-gated-sodium-channels
#10
Elisa Harms, Carsten Stoetzer, Thomas Stueber, Andrias O O'Reilly, Andreas Leffler
Proton-evoked activation of sensory neurons is counteracted by inhibition of voltage-gated Na(+) channels, and the low acid-sensitivity of sensory neuron of the African naked mole-rat (ANMr) was reported to be due to a strong proton-evoked block of ANMrNav1.7. Here we aimed to reevaluate the role of the suggested negatively-charged motif in the ANMrNav1.7 domain IV P-loop for inhibition by protons. Patch clamp recordings were performed on the recombinant α-subunits Nav1.2-1.8. The insertion of the negatively charged motif (EKE) of ANMrNav1...
November 20, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28924048/a-mutant-of-the-buthus-martensii-karsch-antitumor-analgesic-peptide-exhibits-reduced-inhibition-to-hnav1-4-and-hnav1-5-channels-while-retaining-analgesic-activity
#11
Yijia Xu, Xiangxue Meng, Xue Hou, Jianfang Sun, Xiaohua Kong, Yuqi Sun, Zeyu Liu, Yuanyuan Ma, Ye Niu, Yongbo Song, Yong Cui, Mingyi Zhao, Jinghai Zhang
Scorpion toxins can kill other animals by inducing paralysis and arrhythmia, which limits the potential applications of these agents in the clinical management of diseases. Antitumor-analgesic peptide (AGAP), purified from Buthus martensii Karsch, has been proved to possess analgesic and antitumor activities. Trp(38), a conserved aromatic residue of AGAP, might play an important role in mediating AGAP activities according to the sequence and homology-modeling analyses. Therefore, an AGAP mutant, W38G, was generated, and effects of both AGAP and the mutant W38G were examined by whole-cell patch clamp techniques on the sodium channels hNav1...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28913981/age-dependent-expression-of-nav1-9-channels-in-medial-prefrontal-cortex-mpfc-pyramidal-neurons-in-rats
#12
Maciej Gawlak, Bartłomiej Szulczyk, Adam Berlowski, Katarzyna Grzelka, Anna Stachurska, Justyna Pelka, Katarzyna Czarzasta, Maciej Malecki, Przemyslaw Kurowski, Ewa Nurowska, Pawel Szulczyk
Developmental changes that occur in the prefrontal cortex during adolescence alter behavior. These behavioral alterations likely stem from changes in prefrontal cortex neuronal activity, which may depend on the properties and expression of ion channels. Nav1.9 sodium channels conduct a Na(+) current that is TTX resistant with a low threshold and noninactivating over time. The purpose of this study was to assess the presence of Nav1.9 channels in medial prefrontal cortex (mPFC) layer II and V pyramidal neurons in young (20-day-old), late adolescent (60-day-old) and adult (6-7-month-old) rats...
September 15, 2017: Developmental Neurobiology
https://www.readbyqxmd.com/read/28905186/antidepressants-inhibit-nav1-3-nav1-7-and-nav1-8-neuronal-voltage-gated-sodium-channels-more-potently-than-nav1-2-and-nav1-6-channels-expressed-in-xenopus-oocytes
#13
Takafumi Horishita, Nobuyuki Yanagihara, Susumu Ueno, Dan Okura, Reiko Horishita, Tomoko Minami, Yuichi Ogata, Yuka Sudo, Yasuhito Uezono, Takeyoshi Sata, Takashi Kawasaki
Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1...
December 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28898267/depolarization-of-the-conductance-voltage-relationship-in-the-nav1-5-mutant-e1784k-is-due-to-altered-fast-inactivation
#14
Colin H Peters, Alec Yu, Wandi Zhu, Jonathan R Silva, Peter C Ruben
E1784K is the most common mixed long QT syndrome/Brugada syndrome mutant in the cardiac voltage-gated sodium channel NaV1.5. E1784K shifts the midpoint of the channel conductance-voltage relationship to more depolarized membrane potentials and accelerates the rate of channel fast inactivation. The depolarizing shift in the midpoint of the conductance curve in E1784K is exacerbated by low extracellular pH. We tested whether the E1784K mutant shifts the channel conductance curve to more depolarized membrane potentials by affecting the channel voltage-sensors...
2017: PloS One
https://www.readbyqxmd.com/read/28880874/discovery-and-mode-of-action-of-a-novel-analgesic-%C3%AE-toxin-from-the-african-spider-ceratogyrus-darlingi
#15
Silmara R Sousa, Joshua S Wingerd, Andreas Brust, Christopher Bladen, Lotten Ragnarsson, Volker Herzig, Jennifer R Deuis, Sebastien Dutertre, Irina Vetter, Gerald W Zamponi, Glenn F King, Paul F Alewood, Richard J Lewis
Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 μM) but not Cav1.3 or Cav3.1 (IC50 > 30 μM) in fluorimetric assays...
2017: PloS One
https://www.readbyqxmd.com/read/28880078/the-role-of-disulfide-bond-replacements-in-analogues-of-the-tarantula-toxin-protx-ii-and-their-effects-on-inhibition-of-the-voltage-gated-sodium-ion-channel-nav1-7
#16
Zoë V F Wright, Stephen McCarthy, Rachael Dickman, Francis E Reyes, Silvia Sanchez-Martinez, Adam Cryar, Ian Kilford, Adrian Hall, Andrew K Takle, Maya Topf, Tamir Gonen, Konstantinos Thalassinos, Alethea B Tabor
Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues...
September 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28867800/ciguatoxins-evoke-potent-cgrp-release-by-activation-of-voltage-gated-sodium-channel-subtypes-nav1-9-nav1-7-and-nav1-1
#17
Filip Touska, Simon Sattler, Philipp Malsch, Richard J Lewis, Peter W Reeh, Katharina Zimmermann
Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals...
August 30, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28837387/crmp2-is-necessary-for-neurofibromatosis-type-1-related-pain
#18
Aubin Moutal, Song Cai, Shizhen Luo, Raphaëlle Voisin, Rajesh Khanna
Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases, affecting roughly 1 in 3000 individuals. As a multisystem disorder, it affects cognitive development, as well as bone, nerve and muscle constitution. Peripheral neuropathy in NF1 constitutes a potentially severe clinical complication and is associated with increased morbidity and mortality. The discovery of effective therapies for Neurofibromatosis type 1 (NF1) pain depends on mechanistic understanding that has been limited, in part, by the relative lack of availability of animal models relevant to NF1 pain...
August 24, 2017: Channels
https://www.readbyqxmd.com/read/28829200/pharmacological-treatment-of-trigeminal-neuralgia
#19
Giulia Di Stefano, Andrea Truini
Unique among the different neuropathic pain conditions, trigeminal neuralgia frequently has an excellent response to some selected drugs, which, on the other hand, often entail disabling side effects. Physicians should be therefore acquainted with the management of these drugs and the few alternative options. Areas covered: This article, based on a systematic literature review, describes the pharmacological options, and indicates the future perspectives for treating trigeminal neuralgia. The article therefore provides current, evidence-based knowledge about the pharmacological treatment of trigeminal neuralgia, and suggests a practical approach to the various drugs, including starting dose, titration and side effects...
October 2017: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/28818462/discovery-of-non-zwitterionic-aryl-sulfonamides-as-nav1-7-inhibitors-with-efficacy-in-preclinical-behavioral-models-and-translational-measures-of-nociceptive-neuron-activation
#20
Yong-Jin Wu, Jason Guernon, Andrea McClure, Guanglin Luo, Ramkumar Rajamani, Alicia Ng, Amy Easton, Amy Newton, Clotilde Bourin, Dawn Parker, Kathleen Mosure, Omar Barnaby, Matthew G Soars, Ronald J Knox, Michele Matchett, Rick Pieschl, James Herrington, Ping Chen, D V Sivarao, Linda J Bristow, Nicholas A Meanwell, Joanne Bronson, Richard Olson, Lorin A Thompson, Carolyn Dzierba
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons...
October 15, 2017: Bioorganic & Medicinal Chemistry
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