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https://www.readbyqxmd.com/read/28805686/lengths-of-the-c-terminus-and-interconnecting-loops-impact-stability-of-spider-derived-gating-modifier-toxins
#1
Akello J Agwa, Yen-Hua Huang, David J Craik, Sónia T Henriques, Christina I Schroeder
Spider gating modifier toxins (GMTs) are potent modulators of voltage-gated ion channels and have thus attracted attention as drug leads for several pathophysiological conditions. GMTs contain three disulfide bonds organized in an inhibitory cystine knot, which putatively confers them with high stability; however, thus far, there has not been a focused study to establish the stability of GMTs in physiological conditions. We examined the resistance of five GMTs including GpTx-1, HnTx-IV, HwTx-IV, PaurTx-3 and SgTx-1, to pH, thermal and proteolytic degradation...
August 12, 2017: Toxins
https://www.readbyqxmd.com/read/28803761/an-in-silico-perspective-on-the-toxicodynamic-of-tetrodotoxin-and-analogues-a-tool-for-supporting-the-hazard-identification
#2
Luca Dellafiora, Gianni Galaverna, Chiara Dall'Asta
Tetrodotoxin (TTX) is a potent neurotoxin naturally found in terrestrial and marine animals targeting the voltage-gated sodium channels. Historically, TTX has raised food safety concerns mainly in the Asian countries due to the consumption of the typical pufferfish-derived delicacy fugu. However, the diffusion of TTX is getting wider today, reasonably threating in a close future a broader number of consumers than before. The understanding of TTX group toxicity is still incomplete as most of the analogues and metabolites found together with TTX are largely understudied...
August 10, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28803056/analysis-of-microcystin-lr-and-nodularin-using-triple-quad-liquid-chromatography-tandem-mass-spectrometry-and-histopathology-in-experimental-fish
#3
Daljit Vudathala, Stephen Smith, Lester Khoo, David D Kuhn, Mary E Mainous, James Steadman, Lisa Murphy
Microcystins (MCs) are hepatotoxic cyanobacterial metabolites produced sporadically in aquatic environments under favorable environmental conditions. Affinity of these toxins to covalently bind with protein phosphatases poses a challenge in their detection. Lemieux oxidation to release 2-methyl-3-methoxy-4-phenylbutyric acid (MMPB), a common moiety to all MCs congeners, has been used in detection of these compounds, however a lack of sensitivity has limited the usefulness of the method. In this study, modifications of the oxidation and solid phase extraction procedures, combined with a sensitive LC/MS/MS (liquid chromatography/mass spectrometry) detection, have resulted in 25 ng/g method detection limits in both liver and plasma samples...
August 10, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28794591/patient-treatment-preferences-for-symptomatic-refractory-urodynamic-idiopathic-detrusor-overactivity
#4
Christina L Fontaine, Ian Rudd, Mahreen Pakzad, Rizwan Hamid, Jeremy L Ockrim, Tamsin J Greenwell
INTRODUCTION: There is a multiplicity of treatments currently available for patients with symptomatic refractory urodynamic idiopathic detrusor overactivity (SRU IDO). We have assessed patient treatment preferences and their outcomes over a 12-month period from January 1 2009 to December 31 2009. PATIENTS AND METHODS: A retrospective database of all patients with SRU IDO was reviewed for patient demographics, treatment preference, and outcome. All patients attending for treatment in the time period were offered: no further treatment, repeat bladder training ± antimuscarinic (BT ± AM), acupuncture, intravesical botulinum toxin injection, sacral neuromodulation (SNM), clam cystoplasty ± Mitrofanoff channel formation, and ileal conduit...
July 2017: Urology Annals
https://www.readbyqxmd.com/read/28782041/a-bimodal-activation-mechanism-underlies-scorpion-toxin-induced-pain
#5
Shilong Yang, Fan Yang, Bei Zhang, Bo Hyun Lee, Bowen Li, Lei Luo, Jie Zheng, Ren Lai
Venomous animals use peptide toxins for hunting and self-defense. To achieve these goals, toxins need to bind to their targets with high affinity due to the small amount that a single bite or sting can deliver. The scorpion toxin BmP01 is linked to sting-induced excruciating pain; however, the reported minimum concentrations for activating TRPV1 channel or inhibiting voltage-gated potassium (Kv) channels (both in the micromolar range) appear too high to be biologically relevant. We show that the effective concentration of BmP01 is highly pH-dependent-it increases by about 10-fold in inhibiting Kv channels upon a 1-U drop in pH but decreases more than 100-fold in activating TRPV1...
August 2017: Science Advances
https://www.readbyqxmd.com/read/28780195/calcium-mitochondrial-dysfunction-and-slowing-the-progression-of-parkinson-s-disease
#6
REVIEW
D James Surmeier, Glenda M Halliday, Tanya Simuni
Parkinson's disease is characterized by progressively distributed Lewy pathology and neurodegeneration. The motor symptoms of cPD are unequivocally linked to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several features of these neurons appear to make them selectively vulnerable to factors thought to cause cPD, like aging, genetic mutations and environmental toxins. Among these features, Ca(2+) entry through Cav1 channels is particularly amenable to pharmacotherapy in early stage cPD patients...
August 2, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28774677/conorfamide-sr3-a-structurally-novel-specific-inhibitor-of-the-shaker-k-channel
#7
Elba Campos-Lira, Elisa Carrillo, Manuel B Aguilar, Joanna Gajewiak, Froylán Gómez-Lagunas, Estuardo López-Vera
Conorfamides (CNFs) are toxins initially characterized from the venom duct of the venomous marine snail Conus spurius from the Gulf of Mexico; at their C-termini, these toxins are amidated and have high sequence similarity with the molluskan cardioexcitatory tetrapeptide Phe-Met-Arg-Phe-NH2 (FMRFamide or FMRFa) and other FMRFa-related peptides (FaRPs) found in the five molluskan classes, and in other invertebrate and vertebrate phyla. These peptides were the first FaRPs found to be present in any venom, and they are biologically active in mice, limpets, and/or freshwater snails...
July 31, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28771427/cystine-knot-growth-factors-and-their-functionally-versatile-proregions
#8
Elisabeth Schwarza
The cystine knot disulfide pattern has been found to be wide-spread in nature, since it has been detected in proteins from plants, marine snails, spiders and mammals. Cystine knot proteins are secreted proteins. Their functions range from defense mechanisms as toxins, e.g. ion channel or enzyme inhibitors, to hormones, blood factors and growth factors. Cystine knot proteins can be divided into two superordinate groups: (i) The cystine knot peptides, also referred to - with other non-cystine knot proteins - as knottins, with linear and cyclic polypeptide chains...
August 28, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28766743/mouse-retinal-ganglion-cell-signalling-is-dynamically-modulated-through-parallel-anterograde-activation-of-cannabinoid-and-vanilloid-pathways
#9
Andrew O Jo, Jennifer M Noel, Monika Lakk, Oleg Yarishkin, Daniel A Ryskamp, Koji Shibasaki, Maureen A McCall, David Križaj
How retinal ganglion cells (RGCs) process and integrate synaptic, mechanical, swelling stimuli with light inputs is an area of intense debate. The nociceptive cation channel TRPV1 (transient receptor potential vanilloid type 1) modulates RGC Ca(2+) signals and excitability yet the proportion of RGCs that express it remains unclear. Further, TRPV1's response to endocannabinoids (eCBs), the putative endogenous retinal activators unknown, as is the potential modulation by cannabinoid receptors (CBRs). The expression of TRPV1 in RGCs from the Ai9:Trpv1 reporter mouse was nonuniform with peak density in the early- and mid-peripheral retina...
August 2, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28751219/structural-studies-with-bnsp-7-reveal-an-atypical-oligomeric-conformation-compared-to-phospholipases-a2-like-toxins
#10
Lino Fernando G de Lima, Rafael J Borges, Maria Alejandra Viviescas, Carlos A H Fernandes, Marcos R M Fontes
There are 2.5 million cases of snakebite per year and approximately 100,000 at 150,000 deaths. Thus, it is considered an important public health problem by the World Health Organization. Snakes from the Bothrops genus may cause severe local effects in the victims, so it is important to develop inhibitors to treat local effects in patients. In addition, approximately 30 different species of bothropic snakes have been described that may present differences in their venom composition. Small structural differences in the venom proteins may result in different ligands binding...
July 24, 2017: Biochimie
https://www.readbyqxmd.com/read/28749537/sodium-channels-and-pain-from-toxins-to-therapies
#11
REVIEW
Fernanda C Cardoso, Richard J Lewis
Voltage-gated sodium channels (NaV ) are essential to initiation and propagation of action potentials that critically influence our ability to respond to a diverse range of stimuli. Physiological and pharmacological studies have linked abnormal function of Nav channels to many human disorders, including chronic neuropathic pain. These findings, along with the description of the functional properties and expression pattern of NaV channels subtypes, are helping to uncover subtype specific roles in acute and chronic pain, and revealing potential opportunities to target these with selective inhibitors...
July 27, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28735770/to4-the-first-tityus-obscurus-%C3%AE-toxin-fully-electrophysiologically-characterized-on-human-sodium-channel-isoforms
#12
Harry Morales Duque, Caroline Barbosa Farias Mourão, Diogo Vieira Tibery, Eder Alves Barbosa, Leandro Ambrósio Campos, Elisabeth Ferroni Schwartz
Many scorpion toxins that act on sodium channels (NaScTxs) have been characterized till date. These toxins may act modulating the inactivation or the activation of sodium channels and are named α- or β-types, respectively. Some venom toxins from Tityus obscurus (Buthidae), a scorpion widely distributed in the Brazilian Amazon, have been partially characterized in previous studies; however, little information about their electrophysiological role on sodium ion channels has been published. In the present study, we describe the purification, identification and electrophysiological characterization of a NaScTx, which was first described as Tc54 and further fully sequenced and renamed To4...
July 21, 2017: Peptides
https://www.readbyqxmd.com/read/28735099/subcellular-expression-of-aquaporin-4-in-substantia-nigra-of-normal-and-mptp-treated-mice
#13
Agnete Prydz, Katja Stahl, Maja Puchades, Nina Davarpaneh, Maria Nadeem, Ole Petter Ottersen, Vidar Gundersen, Mahmood Amiry-Moghaddam
Aquaporin-4 (AQP4) is the predominant water channel in mammalian CNS where it is localized at the perivascular astrocytic foot processes abutting brain microvessels. Several lines of evidence suggest that AQP4 is involved in important homeostatic functions and that mislocalization of the perivascular pool of AQP4 is implicated in several different brain disorders. A recent study suggests that the differential susceptibility of midbrain dopaminergic neurons to the parkinsonogenic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) depends on the expression of AQP4...
July 19, 2017: Neuroscience
https://www.readbyqxmd.com/read/28726749/ladder-shaped-ion-channel-ligands-current-state-of-knowledge
#14
REVIEW
Yuri B Shmukler, Denis A Nikishin
Ciguatoxins (CTX) and brevetoxins (BTX) are polycyclic ethereal compounds biosynthesized by the worldwide distributed planktonic and epibenthic dinoflagellates of Gambierdiscus and Karenia genera, correspondingly. Ciguatera, evoked by CTXs, is a type of ichthyosarcotoxism, which involves a variety of gastrointestinal and neurological symptoms, while BTXs cause so-called neurotoxic shellfish poisoning. Both types of toxins are reviewed together because of similar mechanisms of their action. These are the only molecules known to activate voltage-sensitive Na⁺-channels in mammals through a specific interaction with site 5 of its α-subunit and may compete for it, which results in an increase in neuronal excitability, neurotransmitter release and impairment of synaptic vesicle recycling...
July 20, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28719742/integrated-smartphone-app-chip-system-for-on-site-parts-per-billion-level-colorimetric-quantitation-of-aflatoxins
#15
Xiaochun Li, Fan Yang, Jessica X H Wong, Hua-Zhong Yu
We demonstrate herein an integrated, smartphone-app-chip (SPAC) system for on-site quantitation of food toxins, as demonstrated with aflatoxin B1 (AFB1), at parts-per-billion (ppb) level in food products. The detection is based on an indirect competitive immunoassay fabricated on a transparent plastic chip with the assistance of a microfluidic channel plate. A 3D-printed optical accessory attached to a smartphone is adapted to align the assay chip and to provide uniform illumination for imaging, with which high-quality images of the assay chip are captured by the smartphone camera and directly processed using a custom-developed Android app...
August 10, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28716449/venom-derived-peptides-inhibiting-kir-channels-past-present-and-future
#16
REVIEW
Craig A Doupnik
Inwardly rectifying K+ (Kir) channels play a significant role in vertebrate and invertebrate biology by regulating the movement of K+ ions involved in membrane transport and excitability. Yet unlike other ion channels including their ancestral K + -selective homologs, there are very few venom toxins known to target and inhibit Kir channels with the potency and selectivity found for the Ca2+-activated and voltage-gated K+ channel families. It is unclear whether this is simply due to a lack of discovery, or instead a consequence of the evolutionary processes that drive the development of venom components towards their targets based on a collective efficacy to 1) elicit pain for defensive purposes, 2) promote paralysis for prey capture, or 3) facilitate delivery of venom components into the circulation...
July 14, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28712915/comparative-analyses-and-implications-for-antivenom-serotherapy-of-four-moroccan-scorpion-buthus-occitanus-venoms-subspecies-tunetanus-paris-malhommei-and-mardochei
#17
Bruna Luiza Emerich, Maria Elena De Lima, Marie-France Martin-Eauclaire, Pierre E Bougis
Temporary passive immunity such as serotherapy against venoms requires the full knowledge of all venom's components. Here, four venoms from Moroccan common yellow scorpions belonging to Buthus occitanus, subspecies tunetanus, paris, malhommei, and mardochei, all collected in four different restricted areas, were analysed in deep. They were fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) and their molecular masse profile determined by off-line MALDI-TOF mass spectrometry. Characterisation of their main components was achieved by enzyme-linked immunosorbent assay (ELISA) using specific antisera against the major lethal scorpion toxins identified so far, i...
July 13, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28712884/the-supraorbital-region-revisited-an-anatomic-exploration-of-the-neuro-vascular-bundle-with-regard-to-frontal-migraine-headache
#18
Valeria Berchtold, Hannes Stofferin, Bernhard Moriggl, Erich Brenner, Reinhard Pauzenberger, Marko Konschake
BACKGROUND: Recent findings on the pathogenesis of frontal migraine headache support, besides a central vasogenic cause, an alternative peripheral mechanism involving compressed craniofacial nerves. This is further supported by the efficiency of botulinum toxin injections as a new treatment option in frontal migraine headache patients. METHODS: The supraorbital regions of 22 alcohol-glycerine-embalmed facial halves of both sexes were dissected. Both the supratrochlear and supraorbital nerves (STN and SON, respectively) were identified, and their relationship with the corrugator supercilii muscle (CSM) was investigated by dissection and ultrasound...
June 27, 2017: Journal of Plastic, Reconstructive & Aesthetic Surgery: JPRAS
https://www.readbyqxmd.com/read/28701928/the-hyperpolarization-activated-current-determines-synaptic-excitability-calcium-activity-and-specific-viability-of-substantia-nigra-dopaminergic-neurons
#19
Carmen Carbone, Alessia Costa, Gustavo Provensi, Guido Mannaioni, Alessio Masi
Differential vulnerability between Substantia Nigra pars compacta (SNpc) and Ventral Tegmental Area (VTA) dopaminergic (DAergic) neurons is a hallmark of Parkinson's disease (PD). Understanding the molecular bases of this key histopathological aspect would foster the development of much-needed disease-modifying therapies. Non-heterogeneous DAergic degeneration is present in both toxin-based and genetic animal models, suggesting that cellular specificity, rather than causing factors, constitutes the background for differential vulnerability...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28694658/anti-steatotic-and-anti-fibrotic-effects-of-the-kca3-1-channel-inhibitor-senicapoc-in-non-alcoholic-liver-disease
#20
Latha Paka, David E Smith, Dawoon Jung, Siobhan McCormack, Ping Zhou, Bin Duan, Jing-Song Li, Jiaqi Shi, Yong-Jie Hao, Kai Jiang, Michael Yamin, Itzhak D Goldberg, Prakash Narayan
AIM: To evaluate a calcium activated potassium channel (KCa3.1) inhibitor attenuates liver disease in models of non-alcoholic fatty liver disease (NAFLD). METHODS: We have performed a series of in vitro and in vivo studies using the KCa3.1 channel inhibitor, Senicapoc. Efficacy studies of Senicapoc were conducted in toxin-, thioacetamide (TAA) and high fat diet (HFD)-induced models of liver fibrosis in rats. Efficacy and pharmacodynamic effects of Senicapoc was determined through biomarkers of apoptosis, inflammation, steatosis and fibrosis...
June 21, 2017: World Journal of Gastroenterology: WJG
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