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Toxin channel

Rui Yan, Seonah Moon, Samuel J Kenny, Ke Xu
As an elegant integration of the spatial and temporal dimensions of single-molecule fluorescence, single-molecule localization microscopy (SMLM) overcomes the diffraction-limited resolution barrier of optical microscopy by localizing single molecules that stochastically switch between fluorescent and dark states over time. While this type of super-resolution microscopy (SRM) technique readily achieves remarkable spatial resolutions of ∼10 nm, it typically provides no spectral information. Meanwhile, current scanning-based single-location approaches for mapping the positions and spectra of single molecules are limited by low throughput and are difficult to apply to densely labeled (bio)samples...
February 14, 2018: Accounts of Chemical Research
Fernanda C Cardoso, Mahadhi Hasan, Tianjiao Zhao, Richard J Lewis
PURPOSE OF REVIEW: Pain is a distressing protective sensory experience warning of actual or potential tissue damage. Natural toxins have evolved to exploit pain and related neuronal pathways to facilitate prey capture and for defence, often producing either numbness, paralysis or intense pain by selectively modulating ion channels and receptors in pain pathways. Understanding how toxins modulate pain pathways can enhance our understanding of the physiological and pathological basis of pain...
February 12, 2018: Current Opinion in Supportive and Palliative Care
Mathilde R Israel, Michael Morgan, Bryan Tay, Jennifer R Deuis
Toxins have been used as tools for decades to study the structure and function of neuronal ion channels and receptors. The biological origin of these toxins varies from single cell organisms, including bacteria and algae, to complex multicellular organisms, including a wide variety of plants and venomous animals. Toxins are a structurally and functional diverse group of compounds that often modulate neuronal function by interacting with an ion channel or receptor. Many of these toxins display high affinity and exquisite selectivity, making them valuable tools to probe the structure and function of neuronal ion channels and receptors...
February 6, 2018: Neuroscience Letters
M K Hamad, K He, H F Abdulrazeq, A M Mustafa, J Nakhla, M M Herzallah, A Mammis
Neuropathic pain is a subset of chronic pain that is caused by neurons that are damaged or firing aberrantly in the peripheral or central nervous systems. The treatment guidelines for neuropathic pain include antidepressants, calcium channel α 2 delta ligands, topical therapy, and opioids as a second line option. Unfortunately, pharmacotherapy has not been effective in the treatment of neuropathic pain except in the treatment of trigeminal neuralgia with carbamazepine. The inability to properly treat neuropathic pain causes frustration in both the patients and their treating physicians...
February 5, 2018: World Neurosurgery
Armando Alexei Rodríguez, Anoland Garateix, Emilio Salceda, Steve Peigneur, André Junqueira Zaharenko, Tirso Pons, Yúlica Santos, Roberto Arreguín, Ludger Ständker, Wolf-Georg Forssmann, Jan Tytgat, Rosario Vega, Enrique Soto
Sea anemones produce proteinaceous toxins for predation and defense, including peptide toxins that act on a large variety of ion channels of pharmacological and biomedical interest. Phymanthus crucifer is commonly found in the Caribbean Sea; however, the chemical structure and biological activity of its toxins remain unknown, with the exception of PhcrTx1, an acid-sensing ion channel (ASIC) inhibitor. Therefore, in the present work, we focused on the isolation and characterization of new P. crucifer toxins by chromatographic fractionation, followed by a toxicity screening on crabs, an evaluation of ion channels, and sequence analysis...
February 7, 2018: Toxins
Steen Nedergaard, Mogens Andreasen
The ketogenic diet (KD), a high-fat, carbohydrate-restricted diet, is used as an alternative treatment for drug-resistant epileptic patients. Evidence suggests that compromised glucose metabolism has a significant role in the anticonvulsant action of the KD, however, it is unclear what part of the glucose metabolism that is important. The present study investigates how selective alterations in glycolysis and oxidative phosphorylation influence epileptiform activity induced by blocking K+ currents, GABAA and NMDA receptors in the hippocampal slice preparation...
February 7, 2018: Journal of Neurophysiology
Tarek Mohamed Abd El-Aziz, Sawsan Al Khoury, Lucie Jaquillard, Mathilde Triquigneaux, Guillaume Martinez, Sandrine Bourgoin-Voillard, Michel Sève, Christophe Arnoult, Rémy Beroud, Michel De Waard
Background: Sperm contains a wealth of cell surface receptors and ion channels that are required for most of its basic functions such as motility and acrosome reaction. Conversely, animal venoms are enriched in bioactive compounds that primarily target those ion channels and cell surface receptors. We hypothesized, therefore, that animal venoms should be rich enough in sperm-modulating compounds for a drug discovery program. Our objective was to demonstrate this fact by using a sperm-based phenotypic screening to identify positive modulators from the venom of Walterinnesia aegyptia...
2018: Journal of Venomous Animals and Toxins Including Tropical Diseases
Xiongzhi Zeng, Pengpeng Li, Bo Chen, Juan Huang, Ren Lai, Jingze Liu, Mingqiang Rong
Jingzhaotoxin-34 (JZTX-34) is a selective inhibitor of tetrodotoxin-sensitive (TTX-S) sodium channels. In this study, we found that JZTX-34 selectively acted on Nav1.7 with little effect on other sodium channel subtypes including Nav1.5. If the DIIS3-S4 linker of Nav1.5 is substituted by the correspond linker of Nav1.7, the sensitivity of Nav1.5 to JZTX-34 extremely increases to 1.05 µM. Meanwhile, a mutant D816R in the DIIS3-S4 linker of Nav1.7 decreases binding affinity of Nav1.7 to JZTX-34 about 32-fold...
February 2, 2018: Toxins
Gerusa D Dalmolin, Kirsty Bannister, Leonor Gonçalves, Shafaq Sikandar, Ryan Patel, Marta do Nascimento Cordeiro, Marcus Vinícius Gomez, Juliano Ferreira, Anthony H Dickenson
Introduction: Drugs that counteract nociceptive transmission in the spinal dorsal horn preferentially after nerve injury are being pursued as possible neuropathic pain treatments. In a previous behavioural study, the peptide toxin Tx3-3, which blocks P/Q- and R-type voltage-gated calcium channels, was effective in neuropathic pain models. Objectives: In the present study, we aimed to investigate the effect of Tx3-3 on dorsal horn neuronal responses in rats under physiological conditions and neuropathic pain condition induced by spinal nerve ligation (SNL)...
July 2017: Pain Reports (Baltimore, Md.)
Ayoub Ksouri, Kais Guedira, Rahma Ben Abderrazek, B A Gowri Shankar, Alia Ben Kahla, Ozlem Tanstan Bishop, Balkiss Bouhaouala-Zahar
Scorpion envenoming and its treatment is a public health problem in many parts of the world due to highly toxic venom polypeptides diffusing rapidly within the body of severely envenomed victims. Recently, 38 AahII-specific Nanobody sequences (Nbs) were retrieved from which the performance of NbAahII10 nanobody candidate, to neutralize the most poisonous venom compound namely AahII acting on sodium channels, was established. Herein, structural computational approach is conducted to elucidate the Nb-AahII interactions that support the biological characteristics, using Nb multiple sequence alignment (MSA) followed by modeling and molecular docking investigations (RosettaAntibody, ZDOCK software tools)...
January 27, 2018: Biochemical and Biophysical Research Communications
Maha Alqahtani, Zhuo Ma, Harshada Ketkar, Ragavan Varadharajan Suresh, Meenakshi Malik, Chandra Shekhar Bakshi
Francisella tularensis; the causative agent of tularemia lacks typical bacterial virulence factors and toxins, but still exhibits extreme virulence. The bacterial multi-drug efflux systems consist of an inner membrane, a transmembrane membrane fusion protein and an outer membrane (OM) component that form a contiguous channel for secretion of multitude of bacterial products. Francisella contains three orthologs of the OM proteins; two of these termed as TolC and FtlC are important for tularemia pathogenesis...
January 29, 2018: Journal of Bacteriology
Mathilde R Israel, Panumart Thongyoo, Jennifer R Deuis, David J Craik, Irina Vetter, Thomas Durek
We report the chemical synthesis of scorpion toxin Cn2; a potent and highly-selective activator of the human voltage-gated sodium channel NaV1.6. In an attempt to decouple channel activation from channel binding, we also synthesised the first analogue of this toxin, Cn2[E15R]. This mutation caused uncoupling of the toxin's excitatory and depressant activities, effectively resulting in a NaV1.6 inhibitor. In agreement with the in vitro observations, Cn2[E15R] is anti-nociceptive in mouse models of NaV1.6-mediated pain...
January 29, 2018: Journal of Medicinal Chemistry
Sandra Cortes, Caroline Barette, Rémy Beroud, Michel De Waard, Béatrice Schaack
Using a cell-free expression system, we produced the Kv1.3 protein embedded in one step within detergent micelles. The protein was then purified and relipidated into mixed lipid bilayers. These proteoliposomes held an average of 0.8 protein per liposome. We examined channel forming activity using an oxonol VI fluorescent probe and verified its inhibition using margatoxin and ShK toxins. This assay was automatized and optimized so as to get a Z' statistical factor acceptable for venom fraction screening. We obtained a sensible amount of membrane protein using the cell-free assay, that proved to be active when embedded in liposomes...
January 20, 2018: Protein Expression and Purification
Aaron B Bradford, James B Machamer, Trisha M Russo, Patrick M McNutt
Botulinum neurotoxins (BoNTs) are exceedingly potent neurological poisons that prevent neurotransmitter release from peripheral nerve terminals by cleaving presynaptic proteins required for synaptic vesicle fusion. The ensuing neuromuscular paralysis causes death by asphyxiation. Although no antidotal treatments exist to block toxin activity within the nerve terminal, aminopyridine antagonists of voltage-gated potassium channels have been proposed as symptomatic treatments for botulism toxemia. However, clinical evaluation of aminopyridines as symptomatic treatments for botulism has been inconclusive, in part because mechanisms responsible for reversal of paralysis in BoNT-poisoned nerve terminals are not understood...
January 20, 2018: Toxicology and Applied Pharmacology
Lei Luo, Bowen Li, Sheng Wang, Fangming Wu, Xiaochen Wang, Ping Liang, Rose Ombati, Junji Chen, Xiancui Lu, Jianmin Cui, Qiumin Lu, Longhua Zhang, Ming Zhou, Changlin Tian, Shilong Yang, Ren Lai
Centipedes can subdue giant prey by using venom, which is metabolically expensive to synthesize and thus used frugally through efficiently disrupting essential physiological systems. Here, we show that a centipede (Scolopendra subspinipes mutilans, ∼3 g) can subdue a mouse (∼45 g) within 30 seconds. We found that this observation is largely due to a peptide toxin in the venom, SsTx, and further established that SsTx blocks KCNQ potassium channels to exert the lethal toxicity. We also demonstrated that a KCNQ opener, retigabine, neutralizes the toxicity of a centipede's venom...
January 22, 2018: Proceedings of the National Academy of Sciences of the United States of America
Silvia Zambrana, Lena C E Lundqvist, Virginia Veliz, Sergiu-Bogdan Catrina, Eduardo Gonzales, Claes-Göran Östenson
Diabetes Mellitus Type 2 prevalence is increasing worldwide; thus efforts to develop novel therapeutic strategies are required. Amaranthus caudatus (AC) is a pseudo-cereal with reported anti-diabetic effects that is usually consumed in food preparations in Bolivia. This study evaluated the anti-diabetic nutraceutical property of an AC hydroethanolic extract that contains mainly sugars and traces of polyphenols and amino acids (as shown by nalysis with liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR)), in type 2 diabetic Goto-Kakizaki (GK) rats and healthy Wistar (W) rats...
January 15, 2018: Nutrients
Ana C N Freitas, Steve Peigneur, Flávio H P Macedo, José E Menezes-Filho, Paul Millns, Liciane F Medeiros, Maria A Arruda, Jader Cruz, Nicholas D Holliday, Jan Tytgat, Gareth Hathway, Maria E de Lima
The synthetic peptide PnPP-19 comprehends 19 amino acid residues and it represents part of the primary structure of the toxin δ-CNTX-Pn1c (PnTx2-6), isolated from the venom of the spider Phoneutria nigriventer. Behavioural tests suggest that PnPP-19 induces antinociception by activation of CB1, μ and δ opioid receptors. Since the peripheral and central antinociception induced by PnPP-19 involves opioid activation, the aim of this work was to identify whether this synthetic peptide could directly activate opioid receptors and investigate the subtype selectivity for μ-, δ- and/or κ-opioid receptors...
January 15, 2018: Toxins
C V F Batista, J G Martins, R Restano-Cassulini, F I V Coronas, F Z Zamudio, R Procópio, L D Possani
The soluble venom from the scorpion Tityus metuendus was characterized by various methods. In vivo experiments with mice showed that it is lethal. Extended electrophysiological recordings using seven sub-types of human voltage gated sodium channels (hNav1.1 to 1.7) showed that it contains both α- and β-scorpion toxin types. Fingerprint analysis by mass spectrometry identified over 200 distinct molecular mass components. At least 60 sub-fractions were recovered from HPLC separation. Five purified peptides were sequenced by Edman degradation, and their complete primary structures were determined...
January 11, 2018: Toxicon: Official Journal of the International Society on Toxinology
Riadh Maatoug, Jed Jebali, Régis Guieu, Michel De Waard, Riadh Kharrat
This work reports the purification of new potent scorpion neuropeptide, named BotAF, by an activity-guided screening approach. BotAF is a 64-residue long-chain peptide that shares very high similarity with the original β-like scorpion toxin group, in which several peptides have been characterized to be anti-nociceptive in rodents. BotAF administration to rodents does not produce any toxicity or motor impairment, including at high doses. In all models investigated, BotAF turned out to be an efficient peptide in abolishing acute and inflammatory (both somatic and visceral) pain in rodents...
January 11, 2018: Toxicon: Official Journal of the International Society on Toxinology
Darragh P O'Brien, Ana Cristina Sotomayor Perez, Johanna Karst, Sara E Cannella, Véronique Yvette Ntsogo Enguéné, Audrey Hessel, Dorothée Raoux-Barbot, Alexis Voegele, Orso Subrini, Marilyne Davi, J Inaki Guijarro, Bertrand Raynal, Bruno Baron, Patrick England, Belen Hernandez, Mahmoud Ghomi, Véronique Hourdel, Christian Malosse, Julia Chamot-Rooke, Patrice Vachette, Dominique Durand, Sébastien Brier, Daniel Ladant, Alexandre Chenal
The adenylate cyclase toxin (CyaA) plays an essential role in the early stages of respiratory tract colonization by Bordetella pertussis, the causative agent of whooping cough. Once secreted, CyaA invades eukaryotic cells, leading to cell death. The cell intoxication process involves a unique mechanism of translocation of the CyaA catalytic domain directly across the plasma membrane of the target cell. Herein, we review our recent results describing how calcium is involved in several steps of this intoxication process...
January 11, 2018: Toxicon: Official Journal of the International Society on Toxinology
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