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https://www.readbyqxmd.com/read/29165759/transient-receptor-potential-melastatin-4-cation-channel-in-pediatric-heart-block
#1
J Tian, X-J An, M-Y Fu
Progressive cardiac conduction disease (PCCD) is a common pediatric heart conduction disorder. It is an autosomal inheritance of rare mutations, which leads to familial cases of PCCD. In these cases, the His-Purkinje system's conductive capacity is progressively deranged, involving either right or left bundle branch block. Also, QRS complexes display widening is an important characteristic that culminates in complete AV block, syncope, and sudden death. Mutations in TRPM4 gene that encodes for transient receptor potential melastatin 4 have recently been reported to cause familial cases of PCCD and heart block...
October 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29164451/the-potential-of-p2x7-receptors-as-a-therapeutic-target-including-inflammation-and-tumour-progression
#2
REVIEW
Geoffrey Burnstock, Gillian E Knight
Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases...
November 21, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/29164003/the-endocannabinoid-system-in-pain-and-inflammation-its-relevance-to-rheumatic-disease
#3
REVIEW
Nicola Barrie, Nicholas Manolios
Pain is the most common manifestation of both acute and chronic inflammation that often challenges patients with rheumatic disease. Simply, we attribute this to local joint changes of pH in joints, the formation of radicals, enhanced joint pressure, or cytokine release acting on local nerves to produce pain. However, there is a more complex interplay of interactions between cytokines, mediators of inflammation, and ion channels that influence the final immune response and our perception of pain. Endocannabinoids, a group of less well-known endogenous bioactive lipids, have such manifold immunomodulatory effects able to influence both inflammation and pain...
September 2017: European Journal of Rheumatology
https://www.readbyqxmd.com/read/29163198/ankyrins-and-spectrins-in-cardiovascular-biology-and-disease
#4
REVIEW
Mona M El Refaey, Peter J Mohler
Ankyrins are adaptor proteins critical for the expression and targeting of cardiac membrane proteins, signaling molecules, and cytoskeletal elements. Findings in humans and animal models have highlighted the in vivo roles for ankyrins in normal physiology and in cardiovascular disease, most notably in cardiac arrhythmia. For example, human ANK2 loss-of-function variants are associated with a complex array of electrical and structural phenotypes now termed "ankyrin-B syndrome," whereas alterations in the ankyrin-G pathway for Nav channel targeting are associated with human Brugada syndrome...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29163061/cyclodextrins-and-iatrogenic-hearing-loss-new-drugs-with-significant-risk
#5
REVIEW
Mark A Crumling, Kelly A King, R Keith Duncan
Cyclodextrins are a family of cyclic oligosaccharides with widespread usage in medicine, industry and basic sciences owing to their ability to solubilize and stabilize guest compounds. In medicine, cyclodextrins primarily act as a complexing vehicle and consequently serve as powerful drug delivery agents. Recently, uncomplexed cyclodextrins have emerged as potent therapeutic compounds in their own right, based on their ability to sequester and mobilize cellular lipids. In particular, 2-hydroxypropyl-β-cyclodextrin (HPβCD) has garnered attention because of its cholesterol chelating properties, which appear to treat a rare neurodegenerative disorder and to promote atherosclerosis regression related to stroke and heart disease...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29162479/mir-145-ameliorates-neuropathic-pain-via-inhibiting-inflammatory-responses-and-mtor-signaling-pathway-by-targeting-akt3-in-a-rat-model
#6
Jinshan Shi, Ke Jiang, Zhaoduan Li
Neuropathic pain perplexes a large population of patients with various diseases. Inflammation plays a key role in the physiopathology of neuropathic pain. Anti-inflammatory can be a promising strategy to treat neuropathic pain. We generated a chronic constriction injury rat model to mimic neuropathic pain by ligating the left ischiadic nerves of rats. Then we performed intrathecal injection of miR-145 mimics to treat these rats for seven consecutive days. Pain behavior tests including mechanical allodynia and thermal hyperalgesia, pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were analyzed...
November 18, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/29159026/highlights-for-the-6th-international-ion-channel-conference-ion-channel-structure-function-disease-and-therapeutics
#7
Limei Wang, Kewei Wang
To foster communication and interactions amongst international scholars and scientists in the field of ion channel research, the 6th International Ion Channel Conference (IICC-2017) was held between June 23-27, 2017 in the eastern coastal city of Qingdao, China. The meeting consisted of 450 attendees and 130 speakers and poster presenters. The program consisted of research progress, new findings and ongoing studies that were focused on (1) Ion channel structure and function; (2) Ion channel physiology and human diseases; (3) Ion channels as targets for drug discovery; (4) Technological advances in ion channel research...
November 2017: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/29159020/the-current-agonists-and-positive-allosteric-modulators-of-%C3%AE-7-nachr-for-cns-indications-in-clinical-trials
#8
REVIEW
Taoyi Yang, Ting Xiao, Qi Sun, Kewei Wang
The alpha-7 nicotinic acetylcholine receptor (α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca(2+)-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of α7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Currently, a number of α7 nAChR modulators have been reported and several of them have advanced into clinical trials...
November 2017: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/29155210/transition-from-androgenic-to-neurosteroidal-action-of-5%C3%AE-androstane-3%C3%AE-17%C3%AE-diol-through-the-type-a-%C3%AE-aminobutyric-acid-receptor-in-prostate-cancer-progression
#9
Ding Xia, Doan V Lai, Weijuan Wu, Zachary D Webb, Qing Yang, Lichao Zhao, Zhongxin Yu, Jessica E Thorpe, Bryan C Disch, Michael A Ihnat, Muralidharan Jayaraman, Danny N Dhanasekaran, Kelly L Stratton, Michael S Cookson, Kar-Ming Fung, Hsueh-Kung Lin
Androgen ablation is the standard of care prescribed to patients with advanced or metastatic prostate cancer (PCa) to slow down disease progression. Unfortunately, a majority of PCa patients under androgen ablation progress to castration-resistant prostate cancer (CRPC). Several mechanisms including alternative intra-prostatic androgen production and androgen-independent androgen receptor (AR) activation have been proposed for CRPC progression. Aldo-keto reductase family 1 member C3 (AKR1C3), a multi-functional steroid metabolizing enzyme, is specifically expressed in the cytoplasm of PCa cells; and positive immunoreactivity of the type A γ-aminobutyric acid receptor (GABAAR), an ionotropic receptor and ligand-gated ion channel, is detected on the membrane of PCa cells...
November 15, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29150520/dopaminergic-neurotoxins-induce-cell-death-by-attenuating-nf-%C3%AE%C2%BAb-mediated-regulation-of-trpc1-expression-and-autophagy
#10
Pramod Sukumaran, Yuyang Sun, Neil Antonson, Brij B Singh
Alterations in Ca(2+) homeostasis affect neuronal survival. However, the identity of Ca(2+) channels and the mechanisms underlying neurotoxin-induced neuronal degeneration are not well understood. In this study, the dopaminergic neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl -4-phenylpyridium ions (MPP(+)/MPTP), which mimic Parkinson's disease (PD), induced neuronal degeneration by decreasing store-mediated Ca(2+) entry. The function of the transient receptor potential canonical (TRPC)-1 channel was decreased upon exposure to the neurotoxins, followed by a decrease in TRPC1 expression...
November 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29134661/regulation-of-tmem16a-ano1-and-tmem16f-ano6-ion-currents-and-phospholipid-scrambling-by-ca-2-and-plasma-membrane-lipid
#11
Rainer Schreiber, Jiraporn Ousingsawat, Podchanart Wanitchakool, Lalida Sirianant, Roberta Benedetto, Karina Reiss, Karl Kunzelmann
TMEM16/anoctamin proteins form Ca(2+) activated ion channels or phospholipid scramblases. We found that both TMEM16A/ANO1 and TMEM16F/ANO6 produced Cl(-) currents when activated by intracellular Ca(2+) , but only TMEM16F was able to expose phosphatidylserine to the outer leaflet of the plasma membrane. Mutations within TMEM16F or TMEM16A/F chimeras similarly changed Cl(-) currents and phospholipid scrambling, suggesting the same intramolecular pathway for Cl(-) and phospholipids. When overexpressed, TMEM16A and TMEM16F produced spontaneous Cl(-) currents at 37°C even at resting intracellular Ca(2+) levels, which was abolished by inhibition of phospholipase A2 (PLA2 )...
November 14, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29131336/molecular-function-of-%C3%AE-7-nicotinic-receptors-as-drug-targets
#12
Cecilia Bouzat, Matías Lasala, Beatriz Elizabeth Nielsen, Jeremías Corradi, María Del Carmen Esandi
Nicotinic acetylcholine receptors (nAChR) are pentameric ligand-gated ion channels involved in many physiological and pathological processes. In vertebrates, there are seventeen different nAChR subunits that combine to yield a variety of receptors with different pharmacology, function, and localization. The homomeric α7 receptor is one of the most abundant nAChRs in the nervous system and it is also present in non-neuronal cells. It plays important roles in cognition, memory, pain, neuroprotection, and inflammation...
November 13, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29128504/biophysical-comparison-of-sodium-currents-in-native-cardiac-myocytes-and-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#13
Robert J Goodrow, Suveer Desai, Jacqueline A Treat, Brian K Panama, Mayurika Desai, Vladislav V Nesterenko, Jonathan M Cordeiro
INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for safety pharmacology and to investigate genetic diseases affecting cardiac ion channels. It is unclear whether adult myocytes or hiPSC-CMs are the better platform for cardiac safety pharmacology. We examined the biophysical and molecular properties of INa in adult myocytes and hiPSC-CMs. METHODS: hiPSC-CMs were plated at low density. Atrial and ventricular cells were obtained from dog hearts...
November 8, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29127487/towards-a-unified-understanding-of-lithium-action-in-basic-biology-and-its-significance-for-applied-biology
#14
REVIEW
Eric Jakobsson, Orlando Argüello-Miranda, See-Wing Chiu, Zeeshan Fazal, James Kruczek, Santiago Nunez-Corrales, Sagar Pandit, Laura Pritchet
Lithium has literally been everywhere forever, since it is one of the three elements created in the Big Bang. Lithium concentration in rocks, soil, and fresh water is highly variable from place to place, and has varied widely in specific regions over evolutionary and geologic time. The biological effects of lithium are many and varied. Based on experiments in which animals are deprived of lithium, lithium is an essential nutrient. At the other extreme, at lithium ingestion sufficient to raise blood concentration significantly over 1 mM/, lithium is acutely toxic...
November 10, 2017: Journal of Membrane Biology
https://www.readbyqxmd.com/read/29126066/formaldehyde-regulates-vascular-tensions-through-nitric-oxide-cgmp-signaling-pathway-and-ion-channels
#15
Quanxi Zhang, Peiru Tian, Miaomiao Zhai, Xiaodong Lei, Zhenhua Yang, Yan Liu, Mengting Liu, Hao Huang, Xiri Zhang, Xu Yang, Yun Zhao, Ziqiang Meng
Formaldehyde (FA) has been linked to the detrimental cardiovascular effects. Here, we explored the effects and mechanisms of FA on rat aortas both in vivo and in vitro. The results presented that FA evidently lowered the blood pressures of rats. The expression levels of BKCa subunits α and β1 and iNOS of the aortas were up-regulated by FA in vivo. However, FA markedly reduced the levels of Cav1.2 and Cav1.3, which are the subunits of L-Ca(2+) channel. Furthermore, the contents of NO, cGMP and iNOS in the aortas were augmented by FA...
November 4, 2017: Chemosphere
https://www.readbyqxmd.com/read/29125190/lambert-eaton-myasthenic-syndrome-mouse-passive-transfer-model-illuminates-disease-pathology-and-facilitates-testing-therapeutic-leads
#16
REVIEW
Stephen D Meriney, Tyler B Tarr, Kristine S Ojala, Man Wu, Yizhi Li, David Lacomis, Adolfo Garcia-Ocaña, Mary Liang, Guillermo Valdomir, Peter Wipf
Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the calcium ion flux that triggers acetylcholine release at the neuromuscular junction. To study the pathophysiology of LEMS and test candidate therapeutic strategies, a passive-transfer animal model has been developed in mice, which can be created by daily intraperitoneal injections of LEMS patient serum or IgG into mice for 2-4 weeks. Results from studies of the mouse neuromuscular junction have revealed that each synapse has hundreds of transmitter release sites but that the probability for release at each one is likely to be low...
November 10, 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29124309/gain-of-function-of-tmem16e-ano5-scrambling-activity-caused-by-a-mutation-associated-with-gnathodiaphyseal-dysplasia
#17
Eleonora Di Zanni, Antonella Gradogna, Joachim Scholz-Starke, Anna Boccaccio
Mutations in the human TMEM16E (ANO5) gene are associated both with the bone disease gnathodiaphyseal dysplasia (GDD; OMIM: 166260) and muscle dystrophies (OMIM: 611307, 613319). However, the physiological function of TMEM16E has remained unclear. We show here that human TMEM16E, when overexpressed in mammalian cell lines, displayed partial plasma membrane localization and gave rise to phospholipid scrambling (PLS) as well as non-selective ionic currents with slow time-dependent activation at highly depolarized membrane potentials...
November 9, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29122012/drug-target-ontology-to-classify-and-integrate-drug-discovery-data
#18
Yu Lin, Saurabh Mehta, Hande Küçük-McGinty, John Paul Turner, Dusica Vidovic, Michele Forlin, Amar Koleti, Dac-Trung Nguyen, Lars Juhl Jensen, Rajarshi Guha, Stephen L Mathias, Oleg Ursu, Vasileios Stathias, Jianbin Duan, Nooshin Nabizadeh, Caty Chung, Christopher Mader, Ubbo Visser, Jeremy J Yang, Cristian G Bologa, Tudor I Oprea, Stephan C Schürer
BACKGROUND: One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating the Druggable Genome (IDG) project develops resources to catalyze the development of likely targetable, yet currently understudied prospective drug targets. A central component of the IDG program is a comprehensive knowledge resource of the druggable genome...
November 9, 2017: Journal of Biomedical Semantics
https://www.readbyqxmd.com/read/29114033/na-leak-with-gating-pore-properties-in-hypokalemic-periodic-paralysis-v876e-mutant-muscle-ca-channel
#19
Clarisse Fuster, Jimmy Perrot, Christine Berthier, Vincent Jacquemond, Pierre Charnet, Bruno Allard
Type 1 hypokalemic periodic paralysis (HypoPP1) is a poorly understood genetic neuromuscular disease characterized by episodic attacks of paralysis associated with low blood K(+) The vast majority of HypoPP1 mutations involve the replacement of an arginine by a neutral residue in one of the S4 segments of the α1 subunit of the skeletal muscle voltage-gated Ca(2+) channel, which is thought to generate a pathogenic gating pore current. The V876E HypoPP1 mutation has the peculiarity of being located in the S3 segment of domain III, rather than an S4 segment, raising the question of whether such a mutation induces a gating pore current...
November 7, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/29113105/the-molecular-and-phenotypic-basis-of-the-glioma-invasive-perivascular-niche
#20
REVIEW
Mohammed Diksin, Stuart J Smith, Ruman Rahman
Gliomas are devastating brain cancers that have poor prognostic outcomes for their patients. Short overall patient survival is due to a lack of durable, efficacious treatment options. Such therapeutic difficulties exist, in part, due to several glioma survival adaptations and mechanisms, which allow glioma cells to repurpose paracrine signalling pathways and ion channels within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space or promote evasion from anti-cancer defence mechanisms...
November 6, 2017: International Journal of Molecular Sciences
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