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https://www.readbyqxmd.com/read/29216295/alpha-1-antichymotrypsin-is-involved-in-astrocyte-injury-in-concert-with-arginine-vasopressin-during-the-development-of-acute-hepatic-encephalopathy
#1
Jonghyuk Park, Takahiro Masaki, Yoshihiro Mezaki, Hiroshi Yokoyama, Mariko Nakamura, Haruka Maehashi, Takahiko J Fujimi, Sabine S Gouraud, Keisuke Nagatsuma, Madoka Nakagomi, Naofumi Kimura, Tomokazu Matsuura
BACKGROUND AND AIMS: We developed a bio-artificial liver (BAL) using a radial-flow bioreactor and rescued mini-pig models with lethal acute liver failure (ALF). The point of the rescue is the recovery from hepatic encephalopathy (HE). HE on ALF has sometimes resulted in brain death following brain edema with astrocyte swelling. Several factors, including ammonia and glutamine, have been reported to induce astrocyte swelling and injury. However, many clinicians believe that there are any other factors involved in the development of HE...
2017: PloS One
https://www.readbyqxmd.com/read/29196122/venoms-of-centruroides-and-tityus-species-from-panama-and-their-main-toxic-fractions
#2
Marcos H Salazar, Iván Arenas, Ligia L Corrales-García, Roberto Miranda, Sara Vélez, Jairo Sánchez, Karla Mendoza, John Cleghorn, Fernando Z Zamudio, Adolfo Castillo, Lourival D Possani, Gerardo Corzo, Hildaura Acosta
The scorpionism in Panama is notorious for the confluence and coexistence of buthid scorpions from the genera Centruroides and Tityus. This communication describes an overview of the larger representative toxic venom fractions from eight dangerous buthid scorpion species of Panama: Centruroides (C. granosus, C. bicolor, C. limbatus and C. panamensis) and Tityus (T. (A.) asthenes, T. (A.) festae, T. (T.) cerroazul and T. (A.) pachyurus). Their venoms were separated by HPLC and the corresponding sub-fractions were tested for lethality effects on mice and insects...
November 28, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29193176/using-voltage-sensor-toxins-and-their-molecular-targets-to-investigate-nav-1-8-gating
#3
John Gilchrist, Frank Bosmans
Voltage-gated sodium (NaV ) channel gating is a complex phenomenon which involves a distinct contribution of four integral voltage-sensing domains (VSDI, VSDII, VSDIII, and VSDIV). Utilizing accrued pharmacological and structural insights, we build on an established chimera approach to introduce animal toxin sensitivity in each VSD of an acceptor channel by transferring in portable S3b-S4 motifs from the four VSDs of a toxin-susceptible donor channel (NaV 1.2). By doing so, we observe that in NaV 1.8, a relatively unexplored channel subtype with distinctly slow gating kinetics, VSDI-III participate in channel opening whereas VSDIV can regulate opening as well as fast inactivation...
November 29, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29191747/peptide-fingerprinting-of-the-sea-anemone-heteractis-magnifica-mucus-revealed-neurotoxins-kunitz-type-proteinase-inhibitors-and-a-new-%C3%AE-defensin-%C3%AE-amylase-inhibitor
#4
Oksana Sintsova, Irina Gladkikh, Victoria Chausova, Margarita Monastyrnaya, Stanislav Anastyuk, Oleg Chernikov, Ekaterina Yurchenko, Dmitriy Aminin, Marina Isaeva, Elena Leychenko, Emma Kozlovskaya
Sea anemone mucus, due to its multiple and vital functions, is a valuable substance for investigation of new biologically active peptides. In this work, compounds of Heteractis magnifica mucus were separated by multistage liquid chromatography and resulting fractions were analyzed by MALDI-TOF MS. Peptide maps constructed according to the molecular masses and hydrophobicity showed presence of 326 both new and known peptides. Several major peptides from mucus were identified, including the sodium channel toxin RpII isolated earlier from H...
November 27, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/29186022/investigation-of-binding-modes-and-functional-surface-of-scorpion-toxins-anep-to-sodium-channels-1-7
#5
Yongbo Song, Zeyu Liu, Qi Zhang, Chunming Li, Wei Jin, Lili Liu, Jianye Zhang, Jinghai Zhang
The depressant β toxin anti-neuroexcitation peptide (ANEP) from the Chinese scorpion Buthus martensii Karsch has analgesic activity by interacting with receptor site 4 of the voltage-gated sodium channels (VGSCs). Here, with molecular dynamics simulations, we examined the binding modes between ANEP and the site 4 of mice sodium channel 1.7 (mNav1.7), a subtype of VGSCs related to peripheral pain. Homology modeling, molecular mechanics, and molecular dynamics in the biomembrane environment were adopted. The results suggested that ANEP bound to the resting site 4 mainly by amino acid residues in the β2-β3 loop and the 'NC' domains, and the activate site 4 mainly by amino acid residues in the hydrophobic domain of N-groove and residues in the 'pharmacophore'...
November 29, 2017: Toxins
https://www.readbyqxmd.com/read/29180755/nav-channel-binder-containing-a-specific-conjugation-site-based-on-a-low-toxicity-%C3%AE-scorpion-toxin
#6
Tomoya Kubota, Bobo Dang, Joao L Carvalho-de-Souza, Ana M Correa, Francisco Bezanilla
Voltage-gated sodium (Nav) channels play a key role in generating action potentials which leads to physiological signaling in excitable cells. The availability of probes for functional studies of mammalian Nav is limited. Here, by introducing two amino acid substitutions into the beta scorpion toxin Ts1, we have chemically synthesized a novel binder [S14R, W50Pra]Ts1 for Nav with high affinity, low dissociation rate and reduced toxicity while retaining the capability of conjugating Ts1 with molecules of interests for different applications...
November 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29180442/kca2-channel-localization-and-regulation-in-the-axon-initial-segment
#7
Krithika Abiraman, Anastasios V Tzingounis, George Lykotrafitis
Small conductance calcium-activated potassium (KCa2) channels are expressed throughout the CNS and play a critical role in synaptic and neuronal excitability. KCa2 channels have a somatodendritic distribution with their highest expression in distal dendrites. It is unclear whether KCa2 channels are specifically present on the axon initial segment (AIS), the site at which action potentials are initiated in neurons. Through a powerful combination of toxin pharmacology, single-molecule atomic force microscopy, and dual-color fluorescence microscopy, we report here that KCa2 channels-predominantly the KCa2...
November 27, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29179176/neurons-erythrocytes-and-beyond-the-diverse-functions-of-chorein
#8
Florian Lang, Lisann Pelzl, Ludger Schöls, Andreas Hermann, Michael Föller, Tilman E Schäffer, Christos Stournaras
Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases...
November 28, 2017: Neuro-Signals
https://www.readbyqxmd.com/read/29177188/%C3%AE-synuclein-dependent-calcium-entry-underlies-differential-sensitivity-of-cultured-sn-and-vta-dopaminergic-neurons-to-a-parkinsonian-neurotoxin
#9
Ori J Lieberman, Se Joon Choi, Ellen Kanter, Anastasia Saverchenko, Micah D Frier, Giulia M Fiore, Min Wu, Jyothisri Kondapalli, Enrico Zampese, D James Surmeier, David Sulzer, Eugene V Mosharov
Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra (SN). Although mitochondrial dysfunction and dysregulated α-synuclein (aSyn) expression are postulated to play a role in PD pathogenesis, it is still debated why neurons of the SN are targeted while neighboring dopaminergic neurons of the ventral tegmental area (VTA) are spared. Using electrochemical and imaging approaches, we investigated metabolic changes in cultured primary mouse midbrain dopaminergic neurons exposed to a parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+)...
November 2017: ENeuro
https://www.readbyqxmd.com/read/29162701/glycosylation-stabilizes-herg-channels-on-the-plasma-membrane-by-decreasing-proteolytic-susceptibility
#10
Shawn M Lamothe, Maggie Hulbert, Jun Guo, Wentao Li, Tonghua Yang, Shetuan Zhang
The human ether-a-go-go related gene (hERG)-encoded channel hERG undergoes N-linked glycosylation at position 598, which is located in the unusually long S5-pore linker of the channel. In other work we have demonstrated that hERG is uniquely susceptible to proteolytic cleavage at the S5-pore linker by proteinase K (PK) and calpain (CAPN). The scorpion toxin BeKm-1, which binds to the S5-pore linker of hERG, protects hERG from such cleavage. In the present study, our data revealed that, compared with normal glycosylated hERG channels, nonglycosylated hERG channels were significantly more susceptible to cleavage by extracellular PK...
November 21, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29161016/selective-voltage-gated-sodium-channel-peptide-toxins-from-animal-venom-pharmacological-probes-and-analgesic-drug-development
#11
Ying Wu, Hui Ma, Fan Zhang, Chun-Lei Zhang, Xiaohan Zou, Zhengyu Cao
Voltage-gated sodium channels (Navs) play critical roles in action potential generation and propagation. Nav channelopathy as well as pathological sensitization contribute to allodynia and hyperalgesia. Recent evidence has demonstrated the significant roles of Nav subtypes (Nav1.3, 1.7, 1.8 and 1.9) in nociceptive transduction and therefore these Navs may represent attractive targets for analgesic drug discovery. Animal toxins are structurally diverse peptides that are highly potent yet selective on ion channel subtypes and therefore representing valuable probes to elucidate the structures, gating properties and cellular functions of ion channels...
November 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29158500/use-dependent-potentiation-of-voltage-gated-calcium-channels-rescues-neurotransmission-in-nerve-terminals-intoxicated-by-botulinum-neurotoxin-serotype-a
#12
Phillip H Beske, Katie M Hoffman, James B Machamer, Margaret R Eisen, Patrick M McNutt
Botulinum neurotoxins (BoNTs) are highly potent toxins that cleave neuronal SNARE proteins required for neurotransmission, causing flaccid paralysis and death by asphyxiation. Currently, there are no clinical treatments to delay or reverse BoNT-induced blockade of neuromuscular transmission. While aminopyridines have demonstrated varying efficacy in transiently reducing paralysis following BoNT poisoning, the precise mechanisms by which aminopyridines symptomatically treat botulism are not understood. Here we found that activity-dependent potentiation of presynaptic voltage-gated calcium channels (VGCCs) underlies 3,4-diaminopyridine (3,4-DAP)-mediated rescue of neurotransmission in central nervous system synapses and mouse diaphragm neuromuscular junctions fully intoxicated by BoNT serotype A...
November 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29156586/in-depth-glyco-peptidomics-approach-reveals-unexpected-diversity-of-glycosylated-peptides-and-atypical-post-translational-modifications-in-dendroaspis-angusticeps-snake-venom
#13
Michel Degueldre, Julien Echterbille, Nicolas Smargiasso, Christian Damblon, Charlotte Gouin, Gilles Mourier, Nicolas Gilles, Edwin De Pauw, Loïc Quinton
Animal venoms represent a valuable source of bioactive peptides that can be derived into useful pharmacological tools, or even innovative drugs. In this way, the venom of Dendroaspis angusticeps (DA), the Eastern Green Mamba, has been intensively studied during recent years. It mainly contains hundreds of large toxins from 6 to 9 kDa, each displaying several disulfide bridges. These toxins are the main target of venom-based studies due to their valuable activities obtained by selectively targeting membrane receptors, such as ion channels or G-protein coupled receptors...
November 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29146176/neosaxitoxin-a-paralytic-shellfish-poison-toxin-effectively-manages-bucked-shins-pain-as-a-local-long-acting-pain-blocker-in-an-equine-model
#14
Gricel Riquelme, Joaquín M Sepúlveda, Zaki Al Ghumgham, Miguel Del Campo, Cecilia Montero, Nestor Lagos
Local anesthesia is an effective method to control pain. Neosaxitoxin is a phycotoxin whose molecular mechanism includes a reversible inhibition of voltage-gated sodium channels at the axonal level, impeding nerve impulse propagation. The present study was designed to evaluate the clinical efficacy of Neosaxitoxin as a local long-acting pain blocker in horse bucked shins, and it was found to effectively control pain. While Neosaxitoxin and Gonyautoxin, another Paralytic Shellfish Poison (PSP) toxin, have been successfully used in humans as long-lasting pain blockers, this finding marks the first time a PSP has been shown to have an established effect in veterinary medicine...
November 13, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29142737/cloning-expression-and-identification-of-ktx-sp4-a-selective-kv1-3-peptidic-blocker-from-scorpiops-pococki
#15
Yan Zou, Feng Zhang, Yaxian Li, Yuanfang Wang, Yi Li, Zhengtao Long, Shujuan Shi, Li Shuai, Jiukai Liu, Zhiyong Di, Shijin Yin
Background: Specific and selective peptidic blockers of Kv1.3 channels can serve as a valuable drug lead for treating T cell-mediated autoimmune diseases, and scorpion venom is an important source of kv1.3 channel inhibitors. Through conducting transcriptomic sequencing for the venom gland of Scorpiops pococki from Xizang province of China, this research aims to discover a novel functional gene encoding peptidic blocker of Kv1.3, and identify its function. Results: We screened out a new peptide toxin KTX-Sp4 which had 43 amino acids including six cysteine residues...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/29138759/identification-of-persistent-and-resurgent-sodium-currents-in-spiral-ganglion-neurons-cultured-from-the-mouse-cochlea
#16
Lorcan Browne, Katie E Smith, Daniel J Jagger
In spiral ganglion neurons (SGNs), the afferent single units of the auditory nerve, high spontaneous and evoked firing rates ensure preservation of the temporal code describing the key features of incoming sound. During postnatal development, the spatiotemporal distribution of ion channel subtypes contributes to the maturation of action potential generation in SGNs, and to their ability to generate spike patterns that follow rapidly changing inputs. Here we describe tetrodotoxin (TTX)-sensitive Na+ currents in SGNs cultured from mice, whose properties may support this fast spiking behavior...
November 2017: ENeuro
https://www.readbyqxmd.com/read/29138410/pla2-like-proteins-myotoxic-mechanism-a-dynamic-model-description
#17
Rafael J Borges, Ney Lemke, Marcos R M Fontes
Phospholipase A2-like (PLA2-like) proteins contribute to the development of muscle necrosis in Viperidae snake bites and are not efficiently neutralized by current antivenom treatments. The toxic mechanisms of PLA2-like proteins are devoid of catalytic activity and not yet fully understood, although structural and functional experiments suggest a dimeric assembly and that the C-terminal residues are essential to myotoxicity. Herein, we characterized the functional mechanism of bothropic PLA2-like structures related to global and local measurements using the available models in the Protein Data Bank and normal mode molecular dynamics (NM-MD)...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29136290/the-role-of-ca-2-dependent-k-channels-at-the-rat-corticostriatal-synapses-revealed-by-paired-pulse-stimulation
#18
Angel A Robles G, Ana V Vega, Carolina Gonzalez-Sandoval, Jaime Barral
Potassium channels play an important role in modulating synaptic activity both at presynaptic and postsynaptic levels. We have shown before that presynaptically located KV and KIR channels modulate the strength of corticostriatal synapses in rat brain, but the role of other types of potassium channels at these synapses remains largely unknown. Here we show that calcium-dependent potassium channels BK-type but not SK-type channels are located presynaptically in corticostriatal synapses. We stimulated cortical neurons in rat brain slices and recorded postsynaptic excitatory potentials (EPSP) in medium spiny neurons (MSN) in dorsal neostriatum...
November 14, 2017: Synapse
https://www.readbyqxmd.com/read/29128272/cytoprotection-of-lipoic-acid-against-toxicity-induced-by-saxitoxin-in-hippocampal-cell-line-ht-22-through-in-silico-modeling-and-in-vitro-assays
#19
Patrícia Ramos, Marcos Schmitz, Sibele Gama, Aline Portantiolo, Michael Gonzalez Durruthy, Ana Paula de Souza Votto, Luisa Rodrigues Cornetet, Karina Dos Santos Machado, Adriano Wehrli, Mariana Zancan Tonel, Solange Binotto Fagan, João Sarkis Yunes, José Maria Monserrat
Saxitoxins (STXs) are potent neurotoxins that block voltage-gated channels in neurons and induce cytotoxicity. These toxins not only can generate reactive oxygen species but also can alter antioxidant levels, promoting oxidative stress. Under this pro-oxidant situation, the use of the antioxidant lipoic acid (LA) can represent a chemoprotective alternative to minimize the deleterious effects induced by neurotoxins as STXs. P-glycoprotein (P-gp) is a well-known ATP-binding cassette (ABC) transporter that plays a crucial role in the extrusion of toxic substances, decreasing their accumulation and potential intracellular effects in virtue of its broad substrate specificity, its expression in many excretory tissues and its large efflux capacity...
November 8, 2017: Toxicology
https://www.readbyqxmd.com/read/29120948/parvalbumin-containing-gaba-cells-and-schizophrenia-experimental-model-based-on-targeted-gene-delivery-through-adeno-associated-viruses
#20
Marta U Woloszynowska-Fraser, Peer Wulff, Gernot Riedel
Understanding the contribution of transmitter systems in behavioural pharmacology has a long tradition. Multiple techniques such as transmitter-specific lesions, and also localized administration of pharmacological toxins including agonists and antagonists of selected receptors have been applied. More recently, modern genetic tools have permitted cell-type selective interferences, for example by expression of light-sensitive channels followed by optogenetic stimulation in behaviourally meaningful settings or by engineered channels termed DREADDS that respond to peripherally administered drugs...
December 2017: Behavioural Pharmacology
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