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https://www.readbyqxmd.com/read/27890480/chemerin-induced-arterial-contraction-is-gi-and-calcium-dependent
#1
David J Ferland, Emma S Darios, Richard R Neubig, Benita Sjögren, Nguyen Truong, Rosa Torres, Thomas S Dexheimer, Janice M Thompson, Stephanie W Watts
Chemerin is an adipokine associated with increased blood pressure, and may link obesity with hypertension. We tested the hypothesis that chemerin-induced contraction of the vasculature occurs via calcium flux in smooth muscle cells. Isometric contraction of rat aortic rings was performed in parallel with calcium kinetics of rat aortic smooth muscle cells to assess the possible signaling pathway. Chemerin-9 (nonapeptide of the chemerin S(157) isoform) caused a concentration-dependent contraction of isolated aorta (EC50 100nM) and elicited a concentration-dependent intracellular calcium response (EC50 10nM)...
November 23, 2016: Vascular Pharmacology
https://www.readbyqxmd.com/read/27871874/functional-and-immuno-reactive-characterization-of-a-previously-undescribed-peptide-from-the-venom-of-the-scorpion-centruroides-limpidus
#2
Timoteo Olamendi-Portugal, Rita Restano-Cassulini, Lidia Riaño-Umbarila, Baltazar Becerril, Lourival D Possani
A previously undescribed toxic peptide named Cl13 was purified from the venom of the Mexican scorpion Centruroides limpidus. It contains 66 amino acid residues, including four disulfide bonds. The physiological effects assayed in 7 different subtypes of voltage gated Na(+)-channels, showed that it belongs to the β-scorpion toxin type. The most notorious effects were observed in subtypes Nav1.4, Nav1.5 and Nav1.6. Although having important sequence similarities with two other lethal toxins from this scorpion species (Cll1m and Cll2), the recently developed single chain antibody fragments (scFv) of human origin were not capable of protecting against Cl13...
November 18, 2016: Peptides
https://www.readbyqxmd.com/read/27871064/benzopyrimido-pyrrolo-oxazine-dione-cftr-inhibitor-r-bpo-27-for-anti-secretory-therapy-of-diarrheas-caused-by-bacterial-enterotoxins
#3
Onur Cil, Puay-Wah Phuan, Anne Marie Gillespie, Sujin Lee, Lukmanee Tradtrantip, Jianyi Yin, Ming Tse, Nicholas C Zachos, Ruxian Lin, Mark Donowitz, Alan S Verkman
Secretory diarrheas caused by bacterial enterotoxins, including cholera and traveler's diarrhea, remain a major global health problem. Inappropriate activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel occurs in these diarrheas. We previously reported that the benzopyrimido-pyrrolo-oxazinedione (R)-BPO-27 inhibits CFTR chloride conductance with low-nanomolar potency. Here, we demonstrate using experimental mouse models and human enterocyte cultures the potential utility of (R)-BPO-27 for treatment of secretory diarrheas caused by cholera and Escherichia coli enterotoxins...
November 8, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27869701/the-role-of-individual-disulfide-bonds-of-%C3%AE-conotoxin-giiia-in-the-inhibition-of-nav1-4
#4
Penggang Han, Kang Wang, Xiandong Dai, Ying Cao, Shangyi Liu, Hui Jiang, Chongxu Fan, Wenjian Wu, Jisheng Chen
μ-Conotoxin GIIIA, a peptide toxin isolated from Conus geographus, preferentially blocks the skeletal muscle sodium channel NaV1.4. GIIIA folds compactly to a pyramidal structure stabilized by three disulfide bonds. To assess the contributions of individual disulfide bonds of GIIIA to the blockade of NaV1.4, seven disulfide-deficient analogues were prepared and characterized, each with one, two, or three pairs of disulfide-bonded Cys residues replaced with Ala. The inhibitory potency of the analogues against NaV1...
November 18, 2016: Marine Drugs
https://www.readbyqxmd.com/read/27856903/asymmetric-synthesis-of-batrachotoxin-enantiomeric-toxins-show-functional-divergence-against-nav
#5
Matthew M Logan, Tatsuya Toma, Rhiannon Thomas-Tran, J Du Bois
The steroidal neurotoxin (-)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (NaVs). Here we report concise asymmetric syntheses of the natural (-) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate-modified derivative. Electrophysiological characterization of these molecules against NaV subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (-)-batrachotoxin...
November 18, 2016: Science
https://www.readbyqxmd.com/read/27854272/impact-of-dendrimer-terminal-group-chemistry-on-blockage-of-the-anthrax-toxin-channel-a-single-molecule-study
#6
Goli Yamini, Nnanya Kalu, Ekaterina M Nestorovich
Nearly all the cationic molecules tested so far have been shown to reversibly block K⁺ current through the cation-selective PA63 channels of anthrax toxin in a wide nM-mM range of effective concentrations. A significant increase in channel-blocking activity of the cationic compounds was achieved when multiple copies of positively charged ligands were covalently linked to multivalent scaffolds, such as cyclodextrins and dendrimers. Even though multivalent binding can be strong when the individual bonds are relatively weak, for drug discovery purposes we often strive to design multivalent compounds with high individual functional group affinity toward the respective binding site on a multivalent target...
November 15, 2016: Toxins
https://www.readbyqxmd.com/read/27826409/the-relaxant-effect-of-the-montivipera-bornmuelleri-snake-venom-on-vascular-contractility
#7
Claudine Accary, Souad Hraoui-Bloquet, Riyad Sadek, Asma Alameddine, Ziad Fajloun, Jean-Claude Desfontis, Yassine Mallem
Molecular richness of snake venoms is an important source of proteins and toxins with potent effects on the cardiovascular system. The alteration of the vascular system in the victim after a venomous snake bite is usually expressed by a significant decrease in blood pressure. Therefore, exploring snake venom to extract and characterize its biomolecules is of considerable medical interest, and formed the basis of this study. We assessed the potential of the venom of Montivipera bornmuelleri, a viper from Lebanon, to induce relaxant effect on isolated Wistar rat aorta via several mechanisms of action...
2016: Journal of Venom Research
https://www.readbyqxmd.com/read/27819327/structure-and-function-of-fs50-a-salivary-protein-from-the-flea-xenopsylla-cheopis-that-blocks-the-sodium-channel-nav1-5
#8
Xueqing Xu, Bei Zhang, Shilong Yang, Su An, José M C Ribeiro, John F Andersen
Naturally occurring toxins have been invaluable tools for the study of structural and functional relationships of voltage-gated sodium channels (VGSC). Few studies have been made of potential channel-modulating substances from blood-feeding arthropods. He we describe the characterization FS50, a salivary protein from the flea, Xenopsylla cheopis, that exhibits an inhibitory activity against the NaV1.5 channel with an IC50 of 1.58 μM. The pore-blocking mechanism of this toxin is evident from the kinetics of activation and inactivation suggesting that FS50 does not interfere with the voltage sensor of NaV1...
November 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27810559/interaction-site-for-the-inhibition-of-tarantula-jingzhaotoxin-xi-on-voltage-gated-potassium-channel-kv2-1
#9
Huai Tao, Xia Chen, Meichun Deng, Yucheng Xiao, Yuanyuan Wu, Zhonghua Liu, Sainan Zhou, Yingchun He, Songping Liang
Jingzhaotoxin-XI (JZTX-XI) is a 34-residue peptide from the Chinese tarantula Chilobrachys jingzhao venom that potently inhibits both voltage-gated sodium channel Nav1.5 and voltage-gated potassium channel Kv2.1. In the present study, we further showed that JZTX-XI blocked Kv2.1 currents with the IC50 value of 0.39 ± 0.06 μM. JZTX-XI significantly shifted the current-voltage (I-V) curves and normalized conductance-voltage (G-V) curves of Kv2.1 channel to more depolarized voltages. Ala-scanning mutagenesis analyses demonstrated that mutants I273A, F274A, and E277A reduced toxin binding affinity by 10-, 16-, and 18-fold, respectively, suggesting that three common residues (I273, F274, E277) in the Kv2...
December 15, 2016: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/27807200/molecular-determinants-of-bk-channel-functional-diversity-and-functioning
#10
REVIEW
Ramon Latorre, Karen Castillo, Willy Carrasquel-Ursulaez, Romina V Sepulveda, Fernando Gonzalez-Nilo, Carlos Gonzalez, Osvaldo Alvarez
Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels play many physiological roles ranging from the maintenance of smooth muscle tone to hearing and neurosecretion. BK channels are tetramers in which the pore-forming α subunit is coded by a single gene (Slowpoke, KCNMA1). In this review, we first highlight the physiological importance of this ubiquitous channel, emphasizing the role that BK channels play in different channelopathies. We next discuss the modular nature of BK channel-forming protein, in which the different modules (the voltage sensor and the Ca(2+) binding sites) communicate with the pore gates allosterically...
January 2017: Physiological Reviews
https://www.readbyqxmd.com/read/27795317/the-colicin-e1-tolc-box-identification-of-a-domain-required-for-colicin-e1-cytotoxicity-and-tolc-binding
#11
Karen S Jakes
: Colicins are protein toxins made by Escherichia coli to kill related bacteria that compete for scarce resources. All colicins must cross the target cell outer membrane in order to reach their intracellular targets. Normally, the first step in the intoxication process is the tight binding of the colicin to an outer membrane receptor protein via its central receptor-binding domain. It is shown here that for one colicin, E1, that step, though greatly increasing the efficiency of killing, is not absolutely necessary...
October 24, 2016: Journal of Bacteriology
https://www.readbyqxmd.com/read/27793656/isolation-of-two-insecticidal-toxins-from-venom-of-the-australian-theraphosid-spider-coremiocnemis-tropix
#12
Maria P Ikonomopoulou, Jennifer J Smith, Volker Herzig, Sandy S Pineda, Sławomir Dziemborowicz, Sing-Yan Er, Thomas Durek, John Gilchrist, Paul F Alewood, Graham M Nicholson, Frank Bosmans, Glenn F King
Sheep flystrike is caused by parasitic flies laying eggs on soiled wool or open wounds, after which the hatched maggots feed on the sheep flesh and often cause large lesions. It is a significant economic problem for the livestock industry as infestations are difficult to control due to ongoing cycles of larval development into flies followed by further egg laying. We therefore screened venom fractions from the Australian theraphosid spider Coremiocnemis tropix to identify toxins active against the sheep blowfly Lucilia cuprina, which is the primary cause of flystrike in Australia...
October 25, 2016: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/27782050/a-combinational-strategy-upon-rna-sequencing-and-peptidomics-unravels-a-set-of-novel-toxin-peptides-in-scorpion-mesobuthus-martensii
#13
Ning Luan, Wang Shen, Jie Liu, Bo Wen, Zhilong Lin, Shilong Yang, Ren Lai, Siqi Liu, Mingqiang Rong
Scorpion venom is deemed to contain many toxic peptides as an important source of natural compounds. Out of the two hundred proteins identified in Mesobuthus martensii (M. martensii), only a few peptide toxins have been found so far. Herein, a combinational approach based upon RNA sequencing and Liquid chromatography-mass spectrometry/mass spectrometry (LC MS/MS) was employed to explore the venom peptides in M. martensii. A total of 153 proteins were identified from the scorpion venom, 26 previously known and 127 newly identified...
October 5, 2016: Toxins
https://www.readbyqxmd.com/read/27771354/paradoxical-lower-sensitivity-of-locus-coeruleus-than-substantia-nigra-pars-compacta-neurons-to-acute-actions-of-rotenone
#14
Andrew G Yee, Peter S Freestone, Ji-Zhong Bai, Janusz Lipski
Parkinson's disease (PD) is not only associated with degeneration of dopaminergic (DAergic) neurons in the Substantia Nigra, but also with profound loss of noradrenergic neurons in the Locus Coeruleus (LC). Remarkably, LC degeneration may exceed, or even precede the loss of nigral DAergic neurons, suggesting that LC neurons may be more susceptible to damage by various insults. Using a combination of electrophysiology, fluorescence imaging and electrochemistry, we directly compared the responses of LC, nigral DAergic and nigral non-dopaminergic (non-DAergic) neurons in rat brain slices to acute application of rotenone, a mitochondrial toxin used to create animal and in vitro models of PD...
October 19, 2016: Experimental Neurology
https://www.readbyqxmd.com/read/27763551/the-snake-with-the-scorpion-s-sting-novel-three-finger-toxin-sodium-channel-activators-from-the-venom-of-the-long-glanded-blue-coral-snake-calliophis-bivirgatus
#15
Daryl C Yang, Jennifer R Deuis, Daniel Dashevsky, James Dobson, Timothy N W Jackson, Andreas Brust, Bing Xie, Ivan Koludarov, Jordan Debono, Iwan Hendrikx, Wayne C Hodgson, Peter Josh, Amanda Nouwens, Gregory J Baillie, Timothy J C Bruxner, Paul F Alewood, Kelvin Kok Peng Lim, Nathaniel Frank, Irina Vetter, Bryan G Fry
Millions of years of evolution have fine-tuned the ability of venom peptides to rapidly incapacitate both prey and potential predators. Toxicofera reptiles are characterized by serous-secreting mandibular or maxillary glands with heightened levels of protein expression. These glands are the core anatomical components of the toxicoferan venom system, which exists in myriad points along an evolutionary continuum. Neofunctionalisation of toxins is facilitated by positive selection at functional hotspots on the ancestral protein and venom proteins have undergone dynamic diversification in helodermatid and varanid lizards as well as advanced snakes...
October 18, 2016: Toxins
https://www.readbyqxmd.com/read/27756538/block-of-voltage-gated-calcium-channels-by-peptide-toxins
#16
Emmanuel Bourinet, Gerald W Zamponi
Venoms from various predatory species, such as fish hunting mollusks scorpions, snakes and arachnids contain a large spectrum of toxins that include blockers of voltage-gated calcium channels. These peptide blockers act by two principal manners - physical occlusion of the pore and prevention of activation gating. Many of the calcium channel-blocking peptides have evolved to tightly occupy their binding pocket on the principal pore forming subunit of the channel, often rendering block poorly reversible. Moreover, several of the best characterized blocking peptides have developed a high degree of channel subtype selectivity...
October 15, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27743460/insecticidal-activity-of-a-recombinant-knottin-peptide-from-loxosceles-intermedia-venom-and-recognition-of-these-peptides-as-a-conserved-family-in-the-genus
#17
F H Matsubara, G O Meissner, V Herzig, H C Justa, B C L Dias, D Trevisan-Silva, L H Gremski, W Gremski, A Senff-Ribeiro, O M Chaim, G F King, S S Veiga
Loxosceles intermedia venom comprises a complex mixture of proteins, glycoproteins and low molecular mass peptides that act synergistically to immobilize envenomed prey. Analysis of a venom-gland transcriptome from L. intermedia revealed that knottins, also known as inhibitor cystine knot peptides, are the most abundant class of toxins expressed in this species. Knottin peptides contain a particular arrangement of intramolecular disulphide bonds, and these peptides typically act upon ion channels or receptors in the insect nervous system, triggering paralysis or other lethal effects...
October 15, 2016: Insect Molecular Biology
https://www.readbyqxmd.com/read/27729239/scorpion-toxin-peptide-action-at-the-ion-channel-subunit-level
#18
David M Housley, Gary D Housley, Michael J Liddell, Ernest A Jennings
This review categorizes functionally validated actions of defined scorpion toxin (SCTX) neuropeptides across ion channel subclasses, highlighting key trends in this rapidly evolving field. Scorpion envenomation is a common event in many tropical and subtropical countries, with neuropharmacological actions, particularly autonomic nervous system modulation, causing significant mortality. The primary active agents within scorpion venoms are a diverse group of small neuropeptides that elicit specific potent actions across a wide range of ion channel classes...
October 8, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27720686/role-of-pannexin-1-in-clostridium-perfringens-beta-toxin-caused-cell-death
#19
Soshi Seike, Masaya Takehara, Keiko Kobayashi, Masahiro Nagahama
BACKGROUND: Beta-toxin produced by Clostridium perfringens is a key virulence factor of fatal hemorrhagic enterocolitis and enterotoxemia. This toxin belongs to a family of β-pore-forming toxins (PFTs). We reported recently that the ATP-gated P2X7 receptor interacts with beta-toxin. The ATP-release channel pannexin 1 (Panx1) is an important contributor to P2X7 receptor signaling. Hence, we investigated the involvement of Panx1 in beta-toxin-caused cell death. METHODS: We examined the effect of Panx1 in beta-toxin-induced cell death utilizing selective antagonists, knockdown of Panx1, and binding using dot-blot analysis...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27716538/molecular-dynamics-of-the-honey-bee-toxin-tertiapin-binding-to-kir3-2
#20
Daxu Li, Rong Chen, Shin-Ho Chung
Tertiapin (TPN), a short peptide isolated from the venom of the honey bee, is a potent and selective blocker of the inward rectifier K(+) (Kir) channel Kir3.2. Here we examine in atomic detail the binding mode of TPN to Kir3.2 using molecular dynamics, and deduce the key residue in Kir3.2 responsible for TPN selectivity. The binding of TPN to Kir3.2 is stable when the side chain of either Lys16 (TPN(K16)-Kir3.2) or Lys17 (TPN(K17)-Kir3.2) of the toxin protrudes into the channel pore. However, the binding affinity calculated from only TPN(K17)-Kir3...
September 30, 2016: Biophysical Chemistry
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