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https://www.readbyqxmd.com/read/28333338/drug-discovery-for-male-subfertility-using-high-throughput-screening-a-new-approach-to-an-unsolved-problem
#1
Sarah J Martins da Silva, Sean G Brown, Keith Sutton, Louise V King, Halil Ruso, David W Gray, Paul G Wyatt, Mark C Kelly, Christopher L R Barratt, Anthony G Hope
STUDY QUESTION: Can pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility? SUMMARY ANSWER: High-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility. WHAT IS KNOWN ALREADY: There is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform...
March 16, 2017: Human Reproduction
https://www.readbyqxmd.com/read/28330959/predominantly-myalgic-phenotype-caused-by-the-c-3466g-a-p-a1156t-mutation-in-scn4a-gene
#2
Johanna Palmio, Satu Sandell, Michael G Hanna, Roope Männikkö, Sini Penttilä, Bjarne Udd
OBJECTIVE: To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation. METHODS: Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in the SCN4A gene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p...
March 22, 2017: Neurology
https://www.readbyqxmd.com/read/28327344/direct-activation-of-ca-2-and-voltage-gated-potassium-channels-of-large-conductance-by-anandamide-in-endothelial-cells-does-not-support-the-presence-of-endothelial-atypical-cannabinoid-receptor
#3
Alexander I Bondarenko, Olga Panasiuk, Iryna Okhai, Fabrizio Montecucco, Karim J Brandt, Francois Mach
Endocannabinoid anandamide induces endothelium-dependent relaxation commonly attributed to stimulation of the G-protein coupled endothelial anandamide receptor. The study addressed the receptor-independent effect of anandamide on large conductance Ca(2+)-dependent K(+) channels expressed in endothelial cell line EA.hy926. Under resting conditions, 10µM anandamide did not significantly influence the resting membrane potential. In a Ca(2+)-free solution the cells were depolarized by ~10 mV. Further administration of 10µM anandamide hyperpolarized the cells by ~8 mV...
March 19, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28326934/activations-of-muscarinic-m1-receptors-in-the-anterior-cingulate-cortex-contribute-to-the-antinociceptive-effect-via-gabaergic-transmission
#4
Kohei Koga, Yu Matsuzaki, Kenji Honda, Fumihiro Eto, Tomonori Furukawa, Keisuke Migita, Keiichi Irie, Kenichi Mishima, Shinya Ueno
Background Cholinergic systems regulate the synaptic transmission resulting in the contribution of the nociceptive behaviors. Anterior cingulate cortex is a key cortical area to play roles in nociception and chronic pain. However, the effect of the activation of cholinergic system for nociception is still unknown in the cortical area. Here, we tested whether the activation of cholinergic receptors can regulate nociceptive behaviors in adult rat anterior cingulate cortex by integrative methods including behavior, immunohistochemical, and electrophysiological methods...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28326931/overexpression-of-suppressor-of-cytokine-signaling-3-in-dorsal-root-ganglion-attenuates-cancer-induced-pain-in-rats
#5
Jinrong Wei, Meng Li, Dieyu Wang, Hongyan Zhu, Xiangpeng Kong, Shusheng Wang, You-Lang Zhou, Zhong Ju, Guang-Yin Xu, Guo-Qin Jiang
Background Cancer-induced pain (CIP) is one of the most severe types of chronic pain with which clinical treatment remains challenging and the involved mechanisms are largely unknown. Suppressor of cytokine signaling 3 (SOCS3) is an important intracellular protein and provides a classical negative feedback loop, thus involving in a wide variety of processes including inflammation and nociception. However, the role of SOCS3 pathway in CIP is poorly understood. The present study was designed to investigate the role of SOCS3 in dorsal root ganglion (DRG) in the development of CIP...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28322838/effect-of-antiarrhythmic-drugs-on-small-conductance-calcium-activated-potassium-channels
#6
Rafel Simó Vicens, Daniel R P Sauter, Morten Grunnet, Jonas G Diness, Bo H Bentzen
Atrial fibrillation (AF) is the most common type of arrhythmia. Current pharmacological treatment for AF is moderately effective and/or increases the risk of serious ventricular adverse effects. To avoid ventricular adverse effects, a new target has been considered, the small conductance calcium-activated K(+) channels (KCa2.X, SK channels). In the heart, KCa2.X channels are functionally more important in atria compared to ventricles, and pharmacological inhibition of the channel confers atrial selective prolongation of the cardiac action potential and converts AF to sinus rhythm in animal models of AF...
March 18, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28322832/dapoxetine-induces-neuroprotective-effects-against-glutamate-induced-neuronal-cell-death-by-inhibiting-calcium-signaling-and-mitochondrial-depolarization-in-cultured-rat-hippocampal-neurons
#7
Imju Jeong, Ji Seon Yang, Yi Jae Hong, Hee Jung Kim, Sang June Hahn, Shin Hee Yoon
Selective serotonin reuptake inhibitors (SSRIs) have an inhibitory effect on various ion channels including Ca(2+) channels. We used fluorescent dye-based digital imaging, whole-cell patch clamping and cytotoxicity assays to examine whether dapoxetine, a novel rapid-acting SSRI, affect glutamate-induced calcium signaling, mitochondrial depolarization and neuronal cell death in cultured rat hippocampal neurons. Pretreatment with dapoxetine for 10min inhibited glutamate-induced intracellular free Ca(2+) concentration ([Ca(2+)]i) increases in a concentration-dependent manner (Half maximal inhibitory concentration= 4...
March 16, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28320841/prefrontal-cortex-kca2-channels-regulate-mglu5-dependent-plasticity-and-extinction-of-alcohol-seeking-behavior
#8
Reginald Cannady, Justin T McGonigal, Ryan J Newsom, John J Woodward, Patrick J Mulholland, Justin T Gass
Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (KCa2) channels have also been implicated in extinction learning of fear memories, and mGlu5 receptor activation can reduce KCa2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined KCa2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats...
March 20, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28319196/h-channels-in-embryonic-biomphalaria-glabrata-cell-membranes-putative-roles-in-snail-host-schistosome-interactions
#9
Brandon J Wright, Utibe Bickham-Wright, Timothy P Yoshino, Meyer B Jackson
The human blood fluke Schistosoma mansoni causes intestinal schistosomiasis, a widespread neglected tropical disease. Infection of freshwater snails Biomphalaria spp. is an essential step in the transmission of S. mansoni to humans, although the physiological interactions between the parasite and its obligate snail host that determine success or failure are still poorly understood. In the present study, the B. glabrata embryonic (Bge) cell line, a widely used in vitro model for hemocyte-like activity, was used to investigate membrane properties, and assess the impact of larval transformation proteins (LTP) on identified ion channels...
March 20, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28306530/ascorbic-acid-does-not-modulate-potassium-currents-in-cultured-human-lymphocytes
#10
Saravanakumar Snekalatha, Praghalathan Kanthakumar
BACKGROUND: Ascorbic acid (AA) is known to modulate lymphocyte function, but the mechanism of action is not clearly understood. As voltage-gated potassium currents play an important role in lymphocyte function, the effect of AA on voltage-gated potassium currents was studied. METHODS: Peripheral blood mononuclear cells were cultured in the presence of increasing concentrations of AA (0, 0.125, 0.25, 0.5, and 1 mM). Potassium currents in resting lymphocytes were studied by whole cell patch clamp technique using a depolarizing protocol...
March 17, 2017: Journal of Basic and Clinical Physiology and Pharmacology
https://www.readbyqxmd.com/read/28303387/caveolar-remodeling-is-a-critical-mechanotransduction-mechanism-of-the-stretch-induced-l-type-ca-2-channel-activation-in-vascular-myocytes
#11
Sang Woong Park, Kyung Chul Shin, Hyun Ji Park, Soon-Kyu Yoou, Jin-Yeon Park, Young-Sun Kang, Dong Jun Sung, Jae Gon Kim, Seung Hwa Park, BoKyung Kim, Hana Cho, Young Min Bae
Activation of L-type voltage-dependent Ca(2+) channels (VDCCL) by membrane stretch contributes to many biological responses such as myogenic contraction of arteries. However, mechanism for the stretch-induced VDCCL activation is unclear. In this study, we examined the hypothesis that caveolar remodeling and its related signaling cascade contribute to the stretch-induced activation of VDCCL in rat mesenteric arterial smooth muscle cells. The VDCCL currents were recorded with nystatin-perforated or with conventional whole-cell patch-clamp technique...
March 16, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28300552/monoaminergic-modulation-of-gabaergic-transmission-onto-cerebellar-globular-cells
#12
Moritoshi Hirono, Soichi Nagao, Yuchio Yanagawa, Shiro Konishi
Cerebellar Purkinje cells (PCs) project their axon collaterals to underneath of the PC layer and make GABAergic synaptic contacts with globular cells, a subgroup of Lugaro cells. GABAergic transmission derived from the PC axon collaterals is so powerful that it could inhibit globular cells and regulate their firing patterns. However, the physiological properties and implications of the GABAergic synapses on globular cells remain unknown. Using whole-cell patch-clamp recordings from globular cells in the mouse cerebellum, we examined the monoaminergic modulation of GABAergic inputs to these cells...
March 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28299825/fingolimod-gilenya-%C3%A2-in-multiple-sclerosis-bradycardia-atrioventricular-blocks-and-mild-effect-on-the-qtc-interval-something-to-do-with-the-l-type-calcium-channel
#13
Sylvie Pilote, Chantale Simard, Benoit Drolet
Cardiac arrhythmias and ECG abnormalities including bradycardia, prolongation of the QT interval and atrioventricular (AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing-remitting form of multiple sclerosis. The present study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels; 1) in vitro, 2) ex vivo and 3) in vivo. 1) Patch-clamp experiments in whole cell configuration were performed on Cav 1...
March 16, 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28298303/ampa-receptor-mediated-rapid-epscs-in-vestibular-calyx-afferents
#14
Matthew Edward Kirk, Frances L Meredith, Tim A Benke, Katherine J Rennie
In the vestibular periphery neurotransmission between hair cells and primary afferent nerves occurs via specialized ribbon synapses. Type I vestibular hair cells (HCI) make synaptic contacts with calyx terminals, which enclose most of the HCI basolateral surface. To probe synaptic transmission, whole cell patch clamp recordings were made from calyx afferent terminals isolated together with their mature HCI from gerbil crista. Neurotransmitter release was measured as excitatory postsynaptic currents (EPSCs) in voltage clamp...
March 15, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28295315/a-comparative-analysis-of-the-physiological-properties-of-neurons-in-the-anterolateral-bed-nucleus-of-the-stria-terminalis-in-the-mus-musculus-rattus-norvegicus-and-macaca-mulatta
#15
Sarah E Daniel, Jidong Guo, Donald G Rainnie
The anterolateral group of the bed nucleus of the stria terminalis (BNSTALG ) is a critical modulator of a variety of rodent and primate behaviors spanning anxiety behavior and drug addiction. Three distinct neuronal cell types have been previously defined in the rat BNSTALG based on differences in the voltage-response to hyperpolarizing and depolarizing current injection. Differences in genetic expression profile between these three cell types suggest electrophysiological cell type may be an indicator for functional differences in the circuit of the rat BNSTALG ...
March 13, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28293175/two-photon-na-imaging-reports-somatically-evoked-action-potentials-in-rat-olfactory-bulb-mitral-and-granule-cell-neurites
#16
Tiffany Ona-Jodar, Niklas J Gerkau, S Sara Aghvami, Christine R Rose, Veronica Egger
Dendrodendritic synaptic interactions are a hallmark of neuronal processing in the vertebrate olfactory bulb. Many classes of olfactory bulb neurons including the principal mitral cells (MCs) and the axonless granule cells (GCs) dispose of highly efficient propagation of action potentials (AP) within their dendrites, from where they can release transmitter onto each other. So far, backpropagation in GC dendrites has been investigated indirectly via Ca(2+) imaging. Here, we used two-photon Na(+) imaging to directly report opening of voltage-gated sodium channels due to AP propagation in both cell types...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28290212/spirodela-polyrhiza-extract-modulates-the-activation-of-atopic-dermatitis-related-ion-channels-orai1-and-trpv3-and-inhibits-mast-cell-degranulation
#17
Joo Hyun Nam, Hyo Won Jung, Young-Won Chin, Won-Mo Yang, Hyo Sang Bae, Woo Kyung Kim
CONTEXT: Spirodela polyrhiza (L.) Schleid. (Lemnaceae), Spirodelae Herba (SH), has been known to relieve inflammation, urticaria and skin symptoms including pruritus, eczema and rash. OBJECTIVE: The effects of SH extract on two calcium ion channels, Orai1 and TRPV3, and their potential as novel therapeutics for atopic dermatitis (AD) were investigated. The regulatory role of Orai1 on mast cell degranulation was evaluated. MATERIALS AND METHODS: The dried leaves of SH were extracted by 70% methanol...
December 2017: Pharmaceutical Biology
https://www.readbyqxmd.com/read/28286482/restoration-of-epithelial-sodium-channel-function-by-synthetic-peptides-in-pseudohypoaldosteronism-type-1b-mutants
#18
Anita Willam, Mohammed Aufy, Susan Tzotzos, Heinrich Evanzin, Sabine Chytracek, Sabrina Geppert, Bernhard Fischer, Hendrik Fischer, Helmut Pietschmann, Istvan Czikora, Rudolf Lucas, Rosa Lemmens-Gruber, Waheed Shabbir
The synthetically produced cyclic peptides solnatide (a.k.a. TIP or AP301) and its congener AP318, whose molecular structures mimic the lectin-like domain of human tumor necrosis factor (TNF), have been shown to activate the epithelial sodium channel (ENaC) in various cell- and animal-based studies. Loss-of-ENaC-function leads to a rare, life-threatening, salt-wasting syndrome, pseudohypoaldosteronism type 1B (PHA1B), which presents with failure to thrive, dehydration, low blood pressure, anorexia and vomiting; hyperkalemia, hyponatremia and metabolic acidosis suggest hypoaldosteronism, but plasma aldosterone and renin activity are high...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28284823/activation-of-the-nmda-receptor-neuronal-nitric-oxide-synthase-pathway-within-the-ventral-bed-nucleus-of-the-stria-terminalis-mediates-the-negative-affective-component-of-pain
#19
Satoshi Deyama, Yaya Sugano, Sakura Mori, Taiju Amano, Mitsuhiro Yoshioka, Katsuyuki Kaneda, Masabumi Minami
Pain consists of sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been studied extensively, those underlying its affective component are only beginning to be elucidated. Previously, we showed the pivotal role of the ventral part of the bed nucleus of the stria terminalis (vBNST) in the negative affective component of pain. Here, we examined the role of glutamate-nitric oxide (NO) signaling in the affective component of pain in rats using a conditioned place aversion (CPA) test...
March 9, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28282785/peimine-inhibits-herg-potassium-channels-through-the-channel-inactivation-states
#20
Liandi Kan, Wei Zhao, Lanying Pan, Jianwei Xu, Qingmao Chen, Kai Xu, Liping Xiao, Yuan Chen
BACKGROUND AND OBJECTIVE: Fritillaria is a Chinese traditional herb. It has a long history and many medicinal usages including antitussive, anti-inflammatory and pain relieving actions. It is also used as food. However, its cardiac safety has not been tested. Peimine is one of the main active compounds of Fritillaria. To be listed as an herb in the Chinese Pharmacopoeia, a special minimal percentage of Peimine in the dry sample of Fritillaria is required. The main concern for cardiac safety determination is the possible inhibition of hERG ion channels...
March 6, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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