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  • 1
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    Conus Venom Peptide Pharmacology [Review Articles] (2012)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2012-06-20
    Description: Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (~0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conopeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail venom peptide families acting at voltage-gated ion channels (-, μ-, μO-, -, -, and -conotoxins), ligand-gated ion channels (α-conotoxins, -conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (-conopeptides, conopressins, and contulakins), and neurotransmitter transporters (-conopeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopeptides have had as both research probes and leads to new therapies.
    Print ISSN: 0031-6997
    Electronic ISSN: 1521-0081
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 2
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    Identification and Characterization of ProTx-III [{mu}-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens [Articles] (2015)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2015-06-21
    Description: Spider venoms are a rich source of ion channel modulators with therapeutic potential. Given the analgesic potential of subtype-selective inhibitors of voltage-gated sodium (Na V ) channels, we screened spider venoms for inhibitors of human Na V 1.7 (hNa V 1.7) using a high-throughput fluorescent assay. Here, we describe the discovery of a novel Na V 1.7 inhibitor, μ -TRTX-Tp1a (Tp1a), isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens . Recombinant and synthetic forms of this 33-residue peptide preferentially inhibited hNa V 1.7 〉 hNa V 1.6 〉 hNa V 1.2 〉 hNa V 1.1 〉 hNa V 1.3 channels in fluorescent assays. Na V 1.7 inhibition was diminished (IC 50 11.5 nM) and the association rate decreased for the C-terminal acid form of Tp1a compared with the native amidated form (IC 50 2.1 nM), suggesting that the peptide C terminus contributes to its interaction with hNa V 1.7. Tp1a had no effect on human voltage-gated calcium channels or nicotinic acetylcholine receptors at 5 μ M. Unlike most spider toxins that modulate Na V channels, Tp1a inhibited hNa V 1.7 without significantly altering the voltage dependence of activation or inactivation. Tp1a proved to be analgesic by reversing spontaneous pain induced in mice by intraplantar injection in OD1, a scorpion toxin that potentiates hNa V 1.7. The structure of Tp1a as determined using NMR spectroscopy revealed a classic inhibitor cystine knot (ICK) motif. The molecular surface of Tp1a presents a hydrophobic patch surrounded by positively charged residues, with subtle differences from other ICK spider toxins that might contribute to its different pharmacological profile. Tp1a may help guide the development of more selective and potent hNa V 1.7 inhibitors for treatment of chronic pain.
    Print ISSN: 0026-895X
    Electronic ISSN: 1521-0111
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 3
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    Activating and Inhibitory Functions of WNT/{beta}-Catenin in the Induction of Cytochromes P450 by Nuclear Receptors in HepaRG Cells [Articles] (2015)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2015-05-01
    Description: The WNT/ β -catenin signaling pathway has been identified as an important endogenous regulator of hepatic cytochrome P450 (P450) expression in mouse liver. In particular, it is involved in the regulation of P450 expression in response to exposure to xenobiotic agonists of the nuclear receptors constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AhR), and Nrf2. To systematically elucidate the effect of the WNT/ β -catenin pathway on the regulation and inducibility of major human P450 enzymes, HepaRG cells were treated with either the WNT/ β -catenin signaling pathway agonist, WNT3a, or with small interfering RNA directed against β -catenin, alone or in combination with a panel of activating ligands for AhR [2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD)], CAR [6-(4-chlorophenyl)imidazo[2,1- b ][1,3]thiazole-5-carbaldehyde- O -(3,4-dichlorobenzyl)oxime (CITCO)], pregnane X receptor (PXR) [rifampicin], and peroxisome proliferator–activated receptor (PPAR) α [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14,643)]. Assessment of P450 gene expression and enzymatic activity after downregulation or activation of the WNT/ β -catenin pathway revealed a requirement of β -catenin in the AhR-, CAR-, and PXR-mediated induction of CYP1A, CYP2B6 and CYP3A4 (for CAR and PXR), and CYP2C8 (for PXR) gene expression. By contrast, activation of the WNT/ β -catenin pathway prevented PPAR α -mediated induction of CYP1A, CYP2C8, CYP3A4, and CYP4A11 genes, suggesting a dominant-negative role of β -catenin in PPAR α -mediated regulation of these genes. Our data indicate a significant effect of the WNT/ β -catenin pathway on the regulation of P450 enzymes in human hepatocytes and reveal a novel crosstalk between β -catenin and PPAR α signaling pathways in the regulation of P450 expression.
    Print ISSN: 0026-895X
    Electronic ISSN: 1521-0111
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 4
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    Comparative Analysis and Functional Characterization of HC-AFW1 Hepatocarcinoma Cells: Cytochrome P450 Expression and Induction by Nuclear Receptor Agonists [Articles] (2015)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2015-10-14
    Description: Enzymatic conversion of most xenobiotic compounds is accomplished by hepatocytes in the liver, which are also an important target for the manifestation of the toxic effects of foreign compounds. Most cell lines derived from hepatocytes lack important toxifying or detoxifying enzymes or are defective in signaling pathways that regulate expression and activity of these enzymes. On the other hand, the use of primary human hepatocytes is complicated by scarce availability of cells and high interdonor variability. Thus, analyses of drug metabolism and hepatotoxicity in vitro are a difficult task. The cell line HC-AFW1 was isolated from a pediatric hepatocellular carcinoma and so far has been used for tumorigenicity and chemotherapy resistance studies. Here, a comprehensive characterization of xenobiotic metabolism in HC-AFW1 cells is presented along with studies on the functionality of the most important transcriptional regulators of drug-metabolizing enzymes. Results from HC-AFW1 cells were compared with commercially available HepaRG cells and cultured primary human hepatocytes. Data show that the nuclear receptors and xenosensors AHR (aryl hydrocarbon receptor), CAR (constitutive androstane receptor), PXR (pregnane-X-receptor), NRF2 [nuclear factor (erythroid-derived 2)–like 2], and PPAR α (peroxisome proliferator–activated receptor α ) are functional in HC-AFW1 cells, comparable to HepaRG and primary cells. HC-AFW1 cells possess considerable activities of different cytochrome P450 enzymes, which, however, are lower than corresponding enzyme activities in HepaRG cells or primary hepatocytes. In summary, HC-AFW1 are a new promising tool for studying the mechanisms of the regulation of drug metabolism in human liver cells in vitro.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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