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Special Issue "Marine Toxins Affecting Cholinergic System"

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (31 May 2019)

Special Issue Editors

Guest Editor
Prof. Tom Turk

Department of Biology, Biotechnical Faculty, University of Ljubljana, Slovenia
Website | E-Mail
Phone: 386 41 514 682
Interests: marine toxins; pore forming toxins; toxins acting on nAChRs and cancer cells
Guest Editor
Prof. William R. Kem

Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Fla. USA
Website | E-Mail
Phone: 352 378 9491
Interests: marine toxins; including nemertine toxins acting on cholinergic system; cognition; treatment of Alzheimer disease; addictive behavior; schizophrenia

Special Issue Information

Dear Colleagues,

This Special Issue on “Marine Toxins Affecting Cholinergic Systems” will focus on marine toxins and other marine natural compounds which interfere with cholinergic systems. Among possible sources of such compounds, which have been already identified as producers, are dinoflagellate toxins, marine sponges, nemerteans, bryozoans, soft corals, and peptides from cone snails. Papers using marine compounds that act as agonists/antagonists/inhibitors/modulators on peripheral cholinergic systems, as well as those affecting various nicotinic acetylcholine receptors in the central nervous system or in cancer cells are welcome. We are especially interested in studies that report on the involvement of cholinergic system and interfering compounds with cell signalling. Papers that describe the possible therapeutic uses of such compounds are also welcome.

As Guest Editors of this Special Issue of Marine Drugs, we invite you to provide your valuable contributions to this Special Issue on “Marine Toxins Affecting Cholinergic Systems”.

Sincerely yours,

Prof. Tom Turk
Prof. William R. Kem
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • toxins
  • marine natural compounds
  • nAChR
  • cholinergic system
  • cancer
  • cognition
  • cell signaling
  • inflammation
  • pain

Published Papers (4 papers)

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Research

Open AccessFeature PaperArticle
Synthetic Pinnatoxins A and G Reversibly Block Mouse Skeletal Neuromuscular Transmission In Vivo and In Vitro
Mar. Drugs 2019, 17(5), 306; https://doi.org/10.3390/md17050306
Received: 7 May 2019 / Revised: 17 May 2019 / Accepted: 21 May 2019 / Published: 24 May 2019
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Abstract
Pinnatoxins (PnTXs) A-H constitute an emerging family belonging to the cyclic imine group of phycotoxins. Interest has been focused on these fast-acting and highly-potent toxins because they are widely found in contaminated shellfish. Despite their highly complex molecular structure, PnTXs have been chemically [...] Read more.
Pinnatoxins (PnTXs) A-H constitute an emerging family belonging to the cyclic imine group of phycotoxins. Interest has been focused on these fast-acting and highly-potent toxins because they are widely found in contaminated shellfish. Despite their highly complex molecular structure, PnTXs have been chemically synthetized and demonstrated to act on various nicotinic acetylcholine receptor (nAChR) subtypes. In the present work, PnTX-A, PnTX-G and analogue, obtained by chemical synthesis with a high degree of purity (>98%), have been studied in vivo and in vitro on adult mouse and isolated nerve-muscle preparations expressing the mature muscle-type (α1)2β1δε nAChR. The results show that PnTX-A and G acted on the neuromuscular system of anesthetized mice and blocked the compound muscle action potential (CMAP) in a dose- and time-dependent manner, using a minimally invasive electrophysiological method. The CMAP block produced by both toxins in vivo was reversible within 6–8 h. PnTX-A and G, applied to isolated extensor digitorum longus nerve-muscle preparations, blocked reversibly isometric twitches evoked by nerve stimulation. The action of PnTX-A was reversed by 3,4-diaminopyridine. Both toxins exerted no direct action on muscle fibers, as revealed by direct muscle stimulation. PnTX-A and G blocked synaptic transmission at mouse neuromuscular junctions and PnTX-A amino ketone analogue (containing an open form of the imine ring) had no effect on neuromuscular transmission. These results indicate the importance of the cyclic imine for interacting with the adult mammalian muscle-type nAChR. Modeling and docking studies revealed molecular determinants responsible for the interaction of PnTXs with the muscle-type nAChR. Full article
(This article belongs to the Special Issue Marine Toxins Affecting Cholinergic System)
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Open AccessArticle
Cervical Cancer Correlates with the Differential Expression of Nicotinic Acetylcholine Receptors and Reveals Therapeutic Targets
Mar. Drugs 2019, 17(5), 256; https://doi.org/10.3390/md17050256
Received: 10 March 2019 / Revised: 22 April 2019 / Accepted: 23 April 2019 / Published: 28 April 2019
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Abstract
Nicotinic acetylcholine receptors (nAChRs) are associated with various cancers, but the relation between nAChRs and cervical cancer remains unclear. Therefore, this study investigated the differential expression of nAChR subunits in human cervical cancer cell lines (SiHa, HeLa, and CaSki) and in normal ectocervical [...] Read more.
Nicotinic acetylcholine receptors (nAChRs) are associated with various cancers, but the relation between nAChRs and cervical cancer remains unclear. Therefore, this study investigated the differential expression of nAChR subunits in human cervical cancer cell lines (SiHa, HeLa, and CaSki) and in normal ectocervical cell lines (Ect1/E6E7) at mRNA and protein levels. Two specific nAChR subtype blockers, αO-conotoxin GeXIVA and α-conotoxin TxID, were then selected to treat different human cervical cancer cell lines with specific nAChR subtype overexpression. The results showed that α3, α9, α10, and β4 nAChR subunits were overexpressed in SiHa cells compared with that in normal cells. α9 and α10 nAChR subunits were overexpressed in CaSki cells. α*-conotoxins that targeted either α9α10 or α3β4 nAChR were able to significantly inhibit cervical cancer cell proliferation. These findings may provide a basis for new targets for cervical cancer targeted therapy. Full article
(This article belongs to the Special Issue Marine Toxins Affecting Cholinergic System)
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Open AccessArticle
Identification of Novel Gymnodimines and Spirolides from the Marine Dinoflagellate Alexandrium ostenfeldii
Mar. Drugs 2018, 16(11), 446; https://doi.org/10.3390/md16110446
Received: 13 September 2018 / Revised: 26 October 2018 / Accepted: 5 November 2018 / Published: 14 November 2018
Cited by 1 | PDF Full-text (3942 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Cyclic imine toxins are neurotoxic, macrocyclic compounds produced by marine dinoflagellates. Mass spectrometric screenings of extracts from natural plankton assemblages revealed a high chemical diversity among this toxin class, yet only few toxins are structurally known. Here we report the structural characterization of [...] Read more.
Cyclic imine toxins are neurotoxic, macrocyclic compounds produced by marine dinoflagellates. Mass spectrometric screenings of extracts from natural plankton assemblages revealed a high chemical diversity among this toxin class, yet only few toxins are structurally known. Here we report the structural characterization of four novel cyclic-imine toxins (two gymnodimines (GYMs) and two spirolides (SPXs)) from cultures of Alexandrium ostenfeldii. A GYM with m/z 510 (1) was identified as 16-desmethylGYM D. A GYM with m/z 526 was identified as the hydroxylated degradation product of (1) with an exocyclic methylene at C-17 and an allylic hydroxyl group at C-18. This compound was named GYM E (2). We further identified a SPX with m/z 694 as 20-hydroxy-13,19-didesmethylSPX C (10) and a SPX with m/z 696 as 20-hydroxy-13,19-didesmethylSPX D (11). This is the first report of GYMs without a methyl group at ring D and SPXs with hydroxyl groups at position C-20. These compounds can be conceived as derivatives of the same nascent polyketide chain, supporting the hypothesis that GYMs and SPXs are produced through common biosynthetic genes. Both novel GYMs 1 and 2 were detected in significant amounts in extracts from natural plankton assemblages (1: 447 pg; 2: 1250 pg; 11: 40 pg per mL filtered seawater respectively). Full article
(This article belongs to the Special Issue Marine Toxins Affecting Cholinergic System)
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Open AccessArticle
APS8 Delays Tumor Growth in Mice by Inducing Apoptosis of Lung Adenocarcinoma Cells Expressing High Number of α7 Nicotinic Receptors
Mar. Drugs 2018, 16(10), 367; https://doi.org/10.3390/md16100367
Received: 7 September 2018 / Revised: 21 September 2018 / Accepted: 29 September 2018 / Published: 3 October 2018
PDF Full-text (4467 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The alkylpyridinium polymer APS8, a potent antagonist of α7 nicotinic acetylcholine receptors (nAChRs), selectively induces apoptosis in non-small cell lung cancer cells but not in normal lung fibroblasts. To explore the potential therapeutic value of APS8 for at least certain types of lung [...] Read more.
The alkylpyridinium polymer APS8, a potent antagonist of α7 nicotinic acetylcholine receptors (nAChRs), selectively induces apoptosis in non-small cell lung cancer cells but not in normal lung fibroblasts. To explore the potential therapeutic value of APS8 for at least certain types of lung cancer, we determined its systemic and organ-specific toxicity in mice, evaluated its antitumor activity against adenocarcinoma xenograft models, and examined the in-vitro mechanisms of APS8 in terms of apoptosis, cytotoxicity, and viability. We also measured Ca2+ influx into cells, and evaluated the effects of APS8 on Ca2+ uptake while siRNA silencing of the gene for α7 nAChRs, CHRNA7. APS8 was not toxic to mice up to 5 mg/kg i.v., and no significant histological changes were observed in mice that survived APS8 treatment. Repetitive intratumoral injections of APS8 (4 mg/kg) significantly delayed growth of A549 cell tumors, and generally prevented regrowth of tumors, but were less effective in reducing growth of HT29 cell tumors. APS8 impaired the viability of A549 cells in a dose-dependent manner and induced apoptosis at micro molar concentrations. Nano molar APS8 caused minor cytotoxic effects, while cell lysis occurred at APS8 >3 µM. Furthermore, Ca2+ uptake was significantly reduced in APS8-treated A549 cells. Observed differences in response to APS8 can be attributed to the number of α7 nAChRs expressed in these cells, with those with more AChRs (i.e., A549 cells) being more sensitive to nAChR antagonists like APS8. We conclude that α7 nAChR antagonists like APS8 have potential to be used as therapeutics for tumors expressing large numbers of α7 nAChRs. Full article
(This article belongs to the Special Issue Marine Toxins Affecting Cholinergic System)
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