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https://www.readbyqxmd.com/read/29054436/in-vitro-and-ex-vivo-screening-of-candidate-therapeutics-to-restore-neurotransmission-in-nerve-terminals-intoxicated-by-botulinum-neurotoxin-serotype-a1
#1
Phillip H Beske, Aaron B Bradford, Katie M Hoffman, Sydney Mason, Patrick M McNutt
Botulinum neurotoxins (BoNTs) are exceedingly potent neurological poisons that block cholinergic release in the peripheral nervous system and cause death by asphyxiation. While post-exposure prophylaxis can effectively eliminate toxin in the bloodstream, there are no clinically effective treatments to prevent or reverse disease once BoNT has entered the neuron. To address the need for post-symptomatic countermeasures, we designed and developed an in vitro assay based on whole-cell, patch-clamp electrophysiological monitoring of miniature excitatory post-synaptic currents in synaptically active murine embryonic stem cell-derived neurons...
October 17, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29049116/basic-translational-development-of-forthcoming-opioid-and-nonopioid-targeted-pain-therapeutics
#2
Nebojsa Nick Knezevic, Ajay Yekkirala, Tony L Yaksh
Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state...
November 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/29044528/endomorphins-potentiate-asic-currents-and-enhance-the-lactic-acid-mediated-increase-in-arterial-blood-pressure-effects-amplified-in-hindlimb-ischemia
#3
Mohamed Farrag, Julie K Drobish, Henry L Puhl, Joyce S Kim, Paul B Herold, Marc P Kaufman, Victor Ruiz-Velasco
Chronic muscle ischemia leads to accumulation of lactic acid and other inflammatory mediators with a subsequent drop in interstitial pH. Acid-sensing ion channels (ASICs), expressed in thin muscle afferents, sense the decrease in pH and evoke a pressor reflex known to increase mean arterial pressure. The naturally occurring endomorphins are also released by primary afferents under ischemic conditions. We examined whether high affinity mu opioid receptor (MOR) agonists, endomorphin-1 (E-1) and -2 (E-2), modulate ASIC currents and the lactic acid-mediated pressor reflex...
October 16, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29042493/unraveling-the-self-assembly-of-the-pseudomonas-aeruginosa-xcpq-secretin-periplasmic-domain-provides-new-molecular-insights-into-type-ii-secretion-system-secreton-architecture-and-dynamics
#4
Badreddine Douzi, Nhung T T Trinh, Sandra Michel-Souzy, Aline Desmyter, Geneviève Ball, Pascale Barbier, Artemis Kosta, Eric Durand, Katrina T Forest, Christian Cambillau, Alain Roussel, Romé Voulhoux
The type II secretion system (T2SS) releases large folded exoproteins across the envelope of many Gram-negative pathogens. This secretion process therefore requires specific gating, interacting, and dynamics properties mainly operated by a bipartite outer membrane channel called secretin. We have a good understanding of the structure-function relationship of the pore-forming C-terminal domain of secretins. In contrast, the high flexibility of their periplasmic N-terminal domain has been an obstacle in obtaining the detailed structural information required to uncover its molecular function...
October 17, 2017: MBio
https://www.readbyqxmd.com/read/29039242/computational-elucidation-mutational-and-hot-spot-based-designing-of-potential-inhibitors-against-human-acid-sensing-ion-channels-hasic-1a-to-treatment-of-various-physiological-conditions
#5
Anurag Singh Chauhan, Md Yousuf Ansari, Rani Mansuri, Manas Ranjan Dikhit, Vahab Ali, Ganesh Chandra Sahoo, Pradeep Das
Acid-sensing ion channels (ASICs) are ligand/proton-gated ion channels belonging to the family of the degenerin/epithelial Na(+) channel (DEG/ENaC). They function as a sodium-selective pore for Ca(2+) entry into neuronal cells during pathological conditions. The blocking of this channel has therapeutic importance, because at basal physiological pH (7.2), it is in a closed state and under a more acidic condition, and the ASIC1a ion channel is activated. To investigate the different states of the hASIC1a channel based on mutational analysis, structure based virtual screening and molecular dynamics simulation studies...
October 17, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29033792/spontaneous-and-evoked-activity-from-murine-ventral-horn-cultures-on-microelectrode-arrays
#6
Bryan J Black, Rahul Atmaramani, Joseph J Pancrazio
Motor neurons are the site of action for several neurological disorders and paralytic toxins, with cell bodies located in the ventral horn (VH) of the spinal cord along with interneurons and support cells. Microelectrode arrays (MEAs) have emerged as a high content assay platform for mechanistic studies and drug discovery. Here, we explored the spontaneous and evoked electrical activity of VH cultures derived from embryonic mouse spinal cord on multi-well plates of MEAs. Primary VH cultures from embryonic day 15-16 mice were characterized by expression of choline acetyltransferase (ChAT) by immunocytochemistry...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29032346/fusion-of-anthopleurin-b-to-aav2-increases-specificity-of-cardiac-gene-transfer
#7
J Emanuel Finet, Xiaoping Wan, J Kevin Donahue
AAV-mediated gene therapy has become a promising therapeutic strategy for chronic diseases. Its clinical utilization, however, is limited by the potential risk of off-target effects. In this work we attempt to overcome this challenge, hypothesizing that cardiac ion channel-specific ligands could be fused onto the AAV capsid, and narrow its tropism to cardiac myocytes. We successfully fused the cardiac sodium channel (Nav1.5)-binding toxin Anthopleurin-B onto the AAV2 capsid without compromising virus integrity, and demonstrated increased specificity of cardiomyocyte attachment...
October 11, 2017: Virology
https://www.readbyqxmd.com/read/29027912/guanidinium-toxins-and-their-interactions-with-voltage-gated-sodium-ion-channels
#8
REVIEW
Lorena M Durán-Riveroll, Allan D Cembella
Guanidinium toxins, such as saxitoxin (STX), tetrodotoxin (TTX) and their analogs, are naturally occurring alkaloids with divergent evolutionary origins and biogeographical distribution, but which share the common chemical feature of guanidinium moieties. These guanidinium groups confer high biological activity with high affinity and ion flux blockage capacity for voltage-gated sodium channels (NaV). Members of the STX group, known collectively as paralytic shellfish toxins (PSTs), are produced among three genera of marine dinoflagellates and about a dozen genera of primarily freshwater or brackish water cyanobacteria...
October 13, 2017: Marine Drugs
https://www.readbyqxmd.com/read/29023421/helicobacter-pylori-vacuolating-toxin-and-gastric-cancer
#9
REVIEW
Mark S McClain, Amber C Beckett, Timothy L Cover
Helicobacter pylori VacA is a channel-forming toxin unrelated to other known bacterial toxins. Most H. pylori strains contain a vacA gene, but there is marked variation among strains in VacA toxin activity. This variation is attributable to strain-specific variations in VacA amino acid sequences, as well as variations in the levels of VacA transcription and secretion. In this review, we discuss epidemiologic studies showing an association between specific vacA allelic types and gastric cancer, as well as studies that have used animal models to investigate VacA activities relevant to gastric cancer...
October 12, 2017: Toxins
https://www.readbyqxmd.com/read/28993277/structure-folding-and-stability-of-a-minimal-homologue-from-anemonia-sulcata-of-the-sea-anemone-potassium-channel-blocker-shk
#10
Bankala Krishnarjuna, Christopher A MacRaild, Punnepalli Sunanda, Rodrigo A V Morales, Steve Peigneur, Jason Macrander, Heidi H Yu, Marymegan Daly, Srinivasarao Raghothama, Vikas Dhawan, Satendra Chauhan, Jan Tytgat, Michael W Pennington, Raymond S Norton
Peptide toxins elaborated by sea anemones target various ion-channel sub-types. Recent transcriptomic studies of sea anemones have identified several novel candidate peptides, some of which have cysteine frameworks identical to those of previously reported sequences. One such peptide is AsK132958, which was identified in a transcriptomic study of Anemonia sulcata and has a cysteine framework similar to that of ShK from Stichodactyla helianthus, but is six amino acid residues shorter. We have determined the solution structure of this novel peptide using NMR spectroscopy...
October 6, 2017: Peptides
https://www.readbyqxmd.com/read/28986244/expression-of-recombinant-%C3%AE-toxin-bmkm9-from-scorpion-buthus-martensii-karsch-and-its-functional-characterization-on-sodium-channels
#11
Fan Yang, Shuang Liu, Yaoyun Zhang, Chenhu Qin, Lingna Xu, Wenhua Li, Zhijian Cao, Wenxin Li, Yingliang Wu
Scorpion toxins are invaluable pharmacological tools for studying ion channels and potential drugs for channelopathies. The long-chain toxins from scorpion venom with four disulfide bridges exhibit their unusual bioactivity or biotoxicity by acting on the sodium channels. However, the functional properties of most toxins are still unclear due to their tiny amounts in crude venom and their challenging production by chemical and gene engineering techniques. Here, we expressed one of the long-chain α-toxins, BmKM9, found in the venom of the scorpion Buthus martensii Karsch and characterized its pharmacological properties on sodium channels...
October 3, 2017: Peptides
https://www.readbyqxmd.com/read/28976980/differential-toxicity-and-venom-gland-gene-expression-in-centruroides-vittatus
#12
Thomas McElroy, C Neal McReynolds, Alyssa Gulledge, Kelci R Knight, Whitney E Smith, Eric A Albrecht
Variation in venom toxicity and composition exists in many species. In this study, venom potency and venom gland gene expression was evaluated in Centruroides vittatus, size class I-II (immature) and size class IV (adults/penultimate instars) size classes. Venom toxicity was evaluated by probit analysis and returned ED50 values of 50.1 μg/g for class IV compared to 134.2 μg/g for class I-II 24 hours post injection, suggesting size class IV was 2.7 fold more potent. Next generation sequencing (NGS and qPCR were used to characterize venom gland gene expression...
2017: PloS One
https://www.readbyqxmd.com/read/28972668/wenxin-keli-diminishes-ca-2-overload-induced-by-hypoxia-reoxygenation-in-cardiomyocytes-through-inhibiting-inal-and-ical
#13
Antao Luo, Zhipei Liu, Zhenzhen Cao, Jie Hao, Lin Wu, Chen Fu, Mengliu Zeng, Wanzhen Jiang, Peihua Zhang, Buchang Zhao, Tao Zhao, Jing Zhao, Jihua Ma
BACKGROUND: An increase in the late sodium current (INaL ) causes intracellular Na(+) overload and subsequently intracellular Ca(2+) ([Ca(2+) ]i ) overload via the stimulated reverse Na(+) -Ca(2+) exchange (NCX). Wenxin Keli (WXKL) is an effective antiarrhythmic Chinese herb extract, but the underlying mechanisms are unclear. METHODS AND RESULTS: The INaL , NCX current (INCX ), L-type Ca(2+) current (ICaL ) and action potentials (APs) were recorded using the whole-cell patch-clamp technique in rabbit ventricular myocytes...
October 3, 2017: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/28970335/fusicoccin-activates-kat1-channels-by-stabilizing-their-interaction-with-14-3-3-proteins
#14
Andrea Saponaro, Alessandro Porro, Antonio Chaves-Sanjuan, Marco Nardini, Oliver Rauh, Gerhard Thiel, Anna Moroni
Plants acquire potassium (K+) ions for cell growth and movement via regulated diffusion through K+ channels. Here we present crystallographic and functional data showing that the K+ inward rectifier KAT1 channel is regulated by 14-3-3 proteins and further modulated by the phytotoxin fusicoccin, in analogy to the H+-ATPase. We identified a 14-3-3 mode III binding site at the very C-terminus of KAT1 and co-crystallized it with tobacco 14-3-3 proteins to describe the protein complex at atomic detail. Validation of this interaction by electrophysiology shows that 14-3-3 binding augments KAT1 conductance by increasing the maximal current and by positively shifting the voltage-dependency of gating...
September 29, 2017: Plant Cell
https://www.readbyqxmd.com/read/28967497/pulmonary-artery-hypertension-in-childhood-the-transforming-growth-factor-%C3%AE-superfamily-related-genes
#15
REVIEW
Shi-Min Yuan
Pulmonary artery hypertension (PAH) is very rare in childhood, and it can be divided into heritable, idiopathic drug- and toxin-induced and other disease (connective tissue disease, human immunodeficiency virus infection, portal hypertension, congenital heart disease, or schistosomiasis)-associated types. PAH could not be interpreted solely by pathophysiological theories. The impact of the transforming growth factor-β superfamily-related genes on the development of PAH in children remains to be clarified. Pertinent literature on the transforming growth factor-β superfamily-related genes in relation to PAH in children published after the year 2000 was reviewed and analyzed...
August 12, 2017: Pediatrics and Neonatology
https://www.readbyqxmd.com/read/28962160/effect-of-eicosapentaenoic-acid-and-pitavastatin-on-electrophysiology-and-anticoagulant-gene-expression-in-mice-with-rapid-atrial-pacing
#16
Maoqing Tong, Jiewen Wang, Yunxin Ji, Xiaomin Chen, Jieru Wang, Shuangshuang Wang, Liemin Ruan, Hanbin Cui, Ying Zhou, Qingyu Zhang, Eiichi Watanabe
Atrial remodeling is considered to be any persistent change in atrial structure or function, and is responsible for the development and perpetuation of atrial fibrillation (AF). Oxidative stress and intracellular pH regulation may also be linked to AF; however it remains unclear whether eicosapentaenoic acid (EPA) or statins have beneficial therapeutic effects. The aim of the present study was to investigate the effects of EPA and pitavastatin on the electrophysiology of and gene expressions in mice with rapidly-paced atria...
September 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28958150/synthesis-and-characterization-of-tethered-lipid-assemblies-for-membrane-protein-reconstitution-review
#17
Rémi Veneziano, Claire Rossi, Alexandre Chenal, Catherine Brenner, Daniel Ladant, Joël Chopineau
Biological membranes and their related molecular mechanisms are essential for all living organisms. Membranes host numerous proteins and are responsible for the exchange of molecules and ions, cell signaling, and cell compartmentation. Indeed, the plasma membrane delimits the intracellular compartment from the extracellular environment and intracellular membranes. Biological membranes also play a major role in metabolism regulation and cellular physiology (e.g., mitochondrial membranes). The elaboration of membrane based biomimetic systems allows us to reconstitute and investigate, in controlled conditions, biological events occurring at the membrane interface...
September 28, 2017: Biointerphases
https://www.readbyqxmd.com/read/28943336/the-origins-of-specificity-in-the-microcin-processing-protease-tldd-e
#18
Dmitry Ghilarov, Marina Serebryakova, Clare E M Stevenson, Stephen J Hearnshaw, Dmitry Volkov, Anthony Maxwell, David M Lawson, Konstantin Severinov
TldD and TldE proteins are involved in the biosynthesis of microcin B17 (MccB17), an Escherichia coli thiazole/oxazole-modified peptide toxin targeting DNA gyrase. Using a combination of biochemical and crystallographic methods we show that E. coli TldD and TldE interact to form a heterodimeric metalloprotease. TldD/E cleaves the N-terminal leader sequence from the modified MccB17 precursor peptide, to yield mature antibiotic, while it has no effect on the unmodified peptide. Both proteins are essential for the activity; however, only the TldD subunit forms a novel metal-containing active site within the hollow core of the heterodimer...
September 11, 2017: Structure
https://www.readbyqxmd.com/read/28941737/arthropod-toxins-acting-on-neuronal-potassium-channels
#19
REVIEW
Juana María Jiménez-Vargas, Lourival D Possani, Karen Luna-Ramírez
Arthropod venoms are a rich mixture of biologically active compounds exerting different physiological actions across diverse phyla and affecting multiple organ systems including the central nervous system. Venom compounds can inhibit or activate ion channels, receptors and transporters with high specificity and affinity providing essential insights into ion channel function. In this review, we focus on arthropod toxins (scorpions, spiders, bees and centipedes) acting on neuronal potassium channels. A brief description of the K(+) channels classification and structure is included and a compendium of neuronal K(+) channels and the arthropod toxins that modify them have been listed...
September 20, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28939608/the-type-ix-secretion-system-is-required-for-virulence-of-the-fish-pathogen-flavobacterium-columnare
#20
Nan Li, Yongtao Zhu, Benjamin R LaFrentz, Jason P Evenhuis, David W Hunnicutt, Rachel A Conrad, Paul Barbier, Connor W Gullstrand, Jack E Roets, Jonathan L Powers, Surashree S Kulkarni, Devon H Erbes, Julio C García, Pin Nie, Mark J McBride
Flavobacterium columnare, a member of the phylum Bacteroidetes, causes columnaris disease in wild and aquaculture-reared freshwater fish. The mechanisms responsible for columnaris disease are not known. Many members of the phylum Bacteroidetes use type IX secretion systems (T9SSs) to secrete enzymes, adhesins, and proteins involved in gliding motility. The F. columnare genome has all of the genes needed to encode a T9SS. gldN, which encodes a core component of the T9SS, was deleted in wild type strains of F...
September 22, 2017: Applied and Environmental Microbiology
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