SEARCH · PubMed Health

Results for “Polyether Toxins”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources

PubMed2004

Altered brain activity in brevetoxin-exposed bluegill, Lepomis macrochirus, visualized using in vivo 14C 2-deoxyglucose labeling.

This study investigated the neurological effects of sublethal brevetoxin (PbTx-2) exposure in bluegill (Lepomis macrochirus) by measuring alterations in 2-deoxyglucose (2-DG) uptake in the brains of exposed fish. Changes in regional brain activity were quantified using digitized autoradiographs from exposed and control fish. Brains of brevetoxin-exposed fish had significantly higher labeling of 2-DG than brains of control fish. Regional increases in labeling were observed in the optic lobes, telencephalon, and cerebrum of PbTx-2 exposed fish. From these observations, we conclude that sublethal brevetoxin exposure in vivo in bluegill increases neurological stimulation, measured through quantification of [14C]2-DG uptake in the brain. Increases in the uptake of [14C]2-DG from this study may be indicative of differences in neural activity in the PbTx-exposed fish and are likely associated with the action of PbTx-2 on voltage-gated sodium channels (VGSC), as well as neurological alterations in calcium and neurotransmitter release downstream resulting from VGSC activation. These techniques quantify physiological alterations in fish brain activity resulting from exposure to brevetoxin and possibly other harmful algal bloom toxins.

Animals↗

PubMed2005

Effects of marine algal toxins on thermoregulation in mice.

Hypothermia is often seen in mice and rats exposed acutely to marine algal toxins, but the mechanism of action of these toxins on thermoregulation is not well understood. Our laboratory has assessed the thermoregulatory mechanisms of two marine algal toxins, maitotoxin and brevetoxin in the mouse. Radiotelemetry was used to measure core temperature in the unrestrained mouse while it was housed in a temperature gradient allowing the exhibition of thermoregulatory behavior. Both maitotoxin (338 ng/kg) and brevetoxin (180 microg/kg) were shown to elicit profound hypothermic responses accompanied by a preference for cooler ambient temperatures in the gradient. This behavioral response would suggest that the toxins alter the central neural control of body temperature, resulting in a regulated reduction in body temperature. Following recovery from the acute hypothermic effects of brevetoxin, mice developed an elevation in their daytime core temperature that persisted for several days after exposure. This fever-like response may represent a delayed toxicological effect of the marine algal toxins that is manifested through the thermoregulatory system. Overall, algal toxins have acute and delayed effects on temperature regulation in the mouse. A better understanding of the mechanisms of action of the toxins on thermoregulation should lead to improved methods for treating victims of ciguatera and other toxin exposures.

Animals↗

PubMed2004

Is there a risk of human poisoning by azaspiracids from shellfish harvested at the Portuguese coast?

Azaspiracid poisoning (AZP), the most recently discovered human gastrointestinal illness resulting from consumption of contaminated shellfish, so far has been found in coastal areas of northern Europe. This is the first report of a survey carried out for contamination of shellfish harvested in costal areas of Portugal for the presence of azaspiracids. The study design covered the commercial species usually more contaminated by toxins from dinoflagellates (blue mussel, common cockle, donax clam) in coastal areas representative of the NW, SW and south coasts. A method based on liquid chromatography-mass spectrometry was setup for the first time for this purpose. No azaspiracids were found on 300 samples tested between 2002 and 2003. On at least three samples a peak with a retention time matching that of AZA2 was found, never surpassing one tenth of the current EU limit. Unambiguous identification of any known AZA did not occur yet. The risk for human outbreaks of AZP seems to be very low, comparatively with amnesic shellfish poisoning (ASP), where levels close to the allowance level are found sparsely, or to diarrhetic shellfish poisoning (DSP) and paralytic shellfish poisoning (PSP), where high levels and registered human outbreaks have been found in recent years.

Animals↗

PubMed2005

Teratogenic effects of azaspiracid-1 identified by microinjection of Japanese medaka (Oryzias latipes) embryos.

Azaspiracid-1 (AZA-1) is a newly identified phycotoxin that accumulates in commercially important bivalve molluscs harvested in several European countries and causes severe human intoxications. Molluscan shellfish are known vectors for accumulation and subsequent transfer of phycotoxins such as brevetoxin and domoic acid through various trophic levels within food webs. Finfish can also accumulate phycotoxins, both directly from toxic algae or from consumption of contaminated shellfish and smaller intoxicated fish. To evaluate the teratogenic potential of AZA-1 and its relevancy to toxin accumulation in finfish, we have utilized a microinjection technique to mimic the maternal-egg toxin transfer of an AZA-1 reference standard and a shellfish extract containing azaspiracids in an embryonic Japanese medaka (Oryzias latipes) fish model. Microinjection of purified AZA-1 caused dose-dependent effects on heart rate, developmental rate, hatching success, and viability in medaka embryos. Within 4 days of exposure to doses > or = 40 pg AZA-1/egg, substantial retardation in development was observed as reduced somatic growth and yolk absorption, and delayed onset of blood circulation and pigmentation. Embryos treated to > or =40 pg AZA-1/egg had slower heart rates (bradycardia) for the 9 days in ovo period, followed by reduced hatching success. Microinjection of a contaminated mussel (Mytilus edulis) extract containing AZAs (AZA-1, -2, and -3), okadaic acid, and dinophysistoxin-2 resulted in similar responses from the fish embryos at equivalent doses. These studies demonstrate that AZA-1 is a potent teratogen to finfish. This work will complement future investigations on AZA-1 accumulation in marine food webs and provide a basis for understanding its toxicity at different trophic levels.

Animals↗

PubMed2005

Cytotoxic and cytoskeletal effects of azaspiracid-1 on mammalian cell lines.

Azaspiracid-1 (AZA-1) is a newly identified phycotoxin reported to accumulate in molluscs from several northern European countries and documented to have caused severe human intoxications. The mechanism of action of AZA-1 is unknown. Our initial investigations have shown that AZA-1 is cytotoxic to a range of cell types. Cytotoxicity was evident in all seven cell types tested, suggesting a broad-spectrum mode of action, and was both time- and concentration-dependent. However, AZA-1 took an unusually long time (>24 h) to cause complete cytotoxicity in most cell types, with the exception of the rat pituitary GH(4)C(1). Extended exposure times did not always lower the EC(50) value for a given cell line, but always resulted in more complete cytotoxicity over a very narrow concentration range. The Jurkat cell line (human lymphocyte T) appeared to be very sensitive to AZA-1, although the EC(50) values (24-72 h) for all the cell types were in the low nanomolar range (0.9-16.8 nM). The effect of AZA-1 on membrane integrity was tested on Jurkat cells and these data confirm our visual observations of cytotoxicity and necrotic cell lysis following exposure of Jurkat cells to AZA-1 and suggest that AZA-1 has some properties unique among marine algal toxins. Additionally, there were dramatic effects of AZA-1 on the arrangement of F-actin with the concurrent loss of pseudopodia, cytoplasmic extensions that function in mobility and chemotaxis. Although these phycotoxin-specific effects of AZA-1 suggest a possible site of action, further work using cell-based approaches is needed to determine the precise mode of action of AZA-1.

Actins↗

PubMed2006

Characterization of polar brevetoxin derivatives isolated from Karenia brevis cultures and natural blooms.

Several novel brevetoxin derivatives were isolated and identified in Karenia brevis cultures and natural blooms by using solid phase extraction (SPE) and LC/MS(MS) techniques. These analogs were more polar compared with previously described brevetoxins, and were poorly extractable by conventional non-polar solvent (chloroform) partitioning. Brevetoxin analogs were structurally confirmed as hydrolyzed (open A-ring) forms of brevetoxins PbTx-1, PbTx-7, PbTx-2, and PbTx-3, and of oxidized PbTx-1 and PbTx-2. Some of these open A-ring derivatives were in greater abundance than their non-hydrolyzed counterparts. All were in much greater abundance in bloom water filtrate compared with cell-rich fractions. Open A-ring compounds were cytotoxic in mouse neuroblastoma (N2a) cell assay. In the K. brevis bloom-exposed Eastern oyster, brevetoxin metabolites with opened A rings were identified (e.g., open-ring cysteine-PbTx conjugates), contributing to their overall toxin burden.

Animals↗

PubMed2002

Characterization of F-actin depolymerization as a major toxic event induced by pectenotoxin-6 in neuroblastoma cells.

Pectenotoxins are a group of marine toxins produced by dinoflagellates and formerly included within the group of diarrhetic shellfish poison or toxins (DSP or DST) because of their physico-chemical properties. However, toxicological data on pectenotoxins are still very scarce and its mechanism of action is largely unknown, but toxicity in laboratory animals has been demonstrated by intraperitoneal injection. In this report, we present results of in vitro toxicological assessment of pectenotoxin-6, a derivative of the parental toxin pectenotoxin-2 first isolated from toxic scallops. Results obtained demonstrate an specific time- and dose-dependent depolymerization of F-actin in neuroblastoma cells exposed to pectenotoxin-6 (half-maximal effect about 700 nM at 24 hr). The change in the state of polymerization of actin was not accompanied by other major effects on specific signal transduction pathways or cell survival rate. Pectenotoxin-6 does not modify cytosolic calcium levels either in a calcium containing or calcium-free medium in human lymphocytes. Only when capacitative calcium influx was first activated, the toxin addition significantly decreased the following calcium influx. In these cells, pectenotoxin-6 only modifies cAMP (adenosine 3',5'-cyclic monophosphate) levels in calcium-free conditions. In addition, no effect on cell attachment or apoptosis induction was observed at micromolar concentrations of pectenotoxin-6. Therefore, we conclude that cytoskeletal disruption is a key mechanism of PTX6-induced toxicity in eukaryotic cells.

Actins↗

PubMed2003

Studies of the effect of Psi-APONIN from Nannochloris sp. on the Florida red tide organism Karenia brevis.

Studies were conducted on the conditions under which the red tide organism, Karenia brevis (a.k.a., Gymnodinium breve), was treated with Nannochloris sp. The latter organism is known to produce cytolytic agents called Apparent Oceanic Naturally Occurring Cytolin (APONINs). Conventional wisdom might suggest that brevetoxins would be released upon destruction of the single-celled dinoflagellate K. brevis and that efforts to treat red tide outbreaks would lead to release of brevetoxins and enhanced toxicity toward marine species. Earlier studies described conditions by which K. brevis cells were converted to a non-motile form when cultures of K. brevis were treated with an isolate (Psi-APONIN) produced by Nannochloris sp. but when centrifuged only a small amount of the toxin was released. The present study confirms that the toxin is not released when the K. brevis is undisturbed, however, when the culture is stressed (stirred with a magnetic stirring bar for 24, 48, and 72h) toxin was released, and the toxicity could be measured using a Microtox analyzer. In the study, it was found that at as few as eighty cells of K. brevis produced a toxic effect of 20% as measured by the effect on Vibrio fischeri. Nannochloris sp. had no effect on the bacteria used in the Microtox analyzer, nor did interaction of Nannochloris sp. with K. brevis in the short term. This effect is presumed to be due to the production of Psi-APONIN and conversion of K. brevis to a non-motile or resting form.

Animals↗

PubMed2002

Azaspiracid-1, a potent, nonapoptotic new phycotoxin with several cell targets.

This paper reports on potential cellular targets of azaspiracid-1 (AZ-1), a new phycotoxin that causes diarrhoeic and neurotoxic symptoms and whose mechanism of action is unknown. In excitable neuroblastoma cells, the systems studied were membrane potential, F-actin levels and mitochondrial membrane potential. AZ-1 does not modify mitochondrial activity but decreases F-actin concentration. These results indicate that the toxin does not have an apoptotic effect but uses actin for some of its effects. Therefore, cytoskeleton seems to be an important cellular target for AZ-1 effect. AZ-1 does not induce any modification in membrane potential, which does not support for neurotoxic effects. In human lymphocytes, cAMP, cytosolic calcium and cytosolic pH (pHi) levels were also studied. AZ-1 increases cytosolic calcium and cAMP levels and does not affect pHi (alkalinization). Cytosolic calcium increase seems to be dependent on both the release of calcium from intracellular Ca(2+) pools and the influx from extracellular media through Ni(2+)-blockable channels. AZ-1-induced Ca(2+) increase is negatively modulated by protein kinase C (PKC) activation, protein phosphatases 1 and 2A (PP1 and PP2A) inhibition and cAMP increasing agents. The effect of AZ-1 in cAMP is not extracellularly Ca(2+) dependent and insensitive to okadaic acid (OA).

Actin Cytoskeleton↗

PubMed2006

Total synthesis and structural elucidation of azaspiracid-1. Construction of key building blocks for originally proposed structure.

Syntheses of the three key building blocks (65, 98, and 100) required for the total synthesis of the proposed structure of azaspiracid-1 (1a) are described. Key steps include a TMSOTf-induced ring-closing cascade to form the ABC rings of tetracycle 65, a neodymium-catalyzed internal aminal formation for the construction of intermediate 98, and a Nozaki-Hiyama-Kishi coupling to assemble the required carbon chain of fragment 100. The synthesized fragments, obtained stereoselectively in both their enantiomeric forms, were expected to allow for the construction of all four stereoisomers proposed as possible structures of azaspiracid-1 (1a-d), thus allowing the determination of both the relative and absolute stereochemistry of the natural product.

Crystallography, X-Ray↗

PubMed2006

Total synthesis and structural elucidation of azaspiracid-1. Synthesis-based analysis of originally proposed structures and indication of their non-identity to the natural product.

The key building blocks (6, 7, and 8) for the intended construction of the originally proposed structures of azaspiracid-1, a potent marine-derived neurotoxin, were coupled and the products elaborated to the targeted compounds (1a,b) and their C-20 epimers (2 and 3). The assembly of the three intermediates was accomplished by a dithiane-based coupling reaction that united the C(1)-C(20) (7) and C(21)-C(27) (8) fragments, followed by a Stille-type coupling which allowed the incorporation of the C(28)-C(40) fragment (6) into the growing substrate. Neither of the final products (1a,b) matched the natural substance by TLC or (1)H NMR spectroscopic analysis, suggesting one or more errors in the originally proposed structure for this notorious biotoxin.

Crystallography, X-Ray↗

PubMed2006

Antibodies with broad specificity to azaspiracids by use of synthetic haptens.

The development of general, sensitive, portable, and quantitative assays for the azaspiracid (AZA) class of marine toxins is urgently needed. Use of a synthetic hapten containing rings F-I of AZA to generate antibodies that cross-react with the AZAs via their common C28-C40 domain and use of these antibodies in ELISA and immunoaffinity columns are reported. This approach has many advantages over using intact azaspiracids (AZAs) derived from environmental samples or total synthesis as haptens for antibody development. A derivative of the levorotatory C28-C40 azaspiracid domain (1) was synthesized efficiently using a one-pot Staudinger reduction/intramolecular aza-Wittig reaction-imine capture sequence to form the H-I ring spiroaminal and a double intramolecluar hetero-Michael addition to assemble the F-G ring ketal. Conjugation of the hapten 1 to cBSA and immunization in sheep generated antibodies that recognized and bound to ovalbumin-conjugated 1 in the absence of AZA1. This binding was inhibited by 1 in a concentration-dependent manner. A mixture of AZA1, AZA2, AZA3, and AZA6 caused a degree of inhibition of antibody binding consistent with its total AZA content, rather than just its content of AZA1. This result suggests that the antibodies also have a similar affinity for AZA2, AZA3, and AZA6 as they do for AZA1 and that such antibodies are suitable for analysis of AZAs in shellfish samples.

Antibodies↗

PubMed2000

Studies directed toward the total synthesis of azaspiracid: stereoselective construction of C(1)-C(12), C(13)-C(19), and C(21)-C(25) fragments.

[reaction: see text] The efficient entry to the C(1)-C(12), C(13)-C(19), and C(21)-C(25) fragments of azaspiracid is outlined. The C(1)-C(12) portion is constructed using a key asymmetric allenyl borane addition to the corresponding alpha,beta-unsaturated aldehyde. The synthesis of the C(13)-C(19) portion utilizes an Evans asymmetric alkylation followed by Sharpless asymmetric dihydroxylation. In addition, a novel solution to the mismatched effects of a neighboring chiral oxazolidinone during a Sharpless dihydroxylation is detailed.

Animals↗

PubMed2004

Synthesis of the azaspiracid-1 trioxadispiroketal.

The de novo analysis, design, and synthesis of the azaspiracid-1 trioxadispiroketal system is described. A revised structural model was developed on the basis of an independent analysis of the NMR spectral data of the natural product that fit all of the data and the thermodynamically favored spiroketal paradigm. This model was then tested via synthesis using a novel trioxadispiroketalization process and supported by spectroscopic correlation.

Furans↗

PubMed1999

Maitotoxin induces calpain but not caspase-3 activation and necrotic cell death in primary septo-hippocampal cultures.

Maitotoxin is a potent toxin that activates voltage and receptor-mediated Ca2+ channels, resulting in Ca2+ overload and rapid cell death. We report that maitotoxin-induced cell death is associated with activation of calpain but not caspase-3 proteases in septo-hippocampal cell cultures. Calpain and caspase-3 activation were examined by accumulation of protease-specific breakdown products to alpha-spectrin. Cell death manifested exclusively necrotic-like characteristics including round, shrunken nuclei, even distribution of chromatin, absence of DNA fragmentation and failure of protein synthesis inhibition to reduce cell death. Necrotic cell death was observed in neurons and astroglia. Calpain inhibitor II inhibited calpain-specific processing of alpha-spectrin and significantly reduced cell death. The pan-caspase inhibitor, Z-D-DCB, nominally attenuated cell death. Results suggest that: (1) calpain, but not caspase-3, is activated as a result of maitotoxin-induced Ca2+ influx; (2) necrotic cell death caused by maitotoxin exposure is partially mediated by calpain activation; (3) maitotoxin is a useful tool to investigate pathological mechanisms of necrosis.

Animals↗

PubMed2006

Marine natural products: synthetic aspects.

An overview of marine natural products synthesis during 2004 is provided. As with the previous installment of this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.

Alkaloids↗

PubMed2006

Synthesis of the ABC tricyclic fragment of the pectenotoxins via stereocontrolled cyclization of a gamma-hydroxyepoxide appended to the AB spiroacetal unit.

The stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing tricyclic fragment of pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully synthesized via acid catalyzed cyclization of protected ketone precursor 28 that was readily prepared from aldehyde 12 and sulfone 13. The syn stereochemistry in aldehyde 12 was installed using an asymmetric aldol reaction proceeding via a titanium enolate. The stereogenic centre in sulfone 13 was derived from (R)-(+)-glycidol. The absolute stereochemistry of the final spiroacetal aldehyde 9 was confirmed by NOE studies establishing the (S)-stereochemistry of the spiroacetal centre. Construction of the tetrahydrofuran C ring system began with Wittig olefination of the AB spiroacetal aldehyde 9 with (carbethoxyethylidene)triphenylphosphorane 10 affording the desired (E)-olefin 32. Appendage of a three carbon chain to the AB spiroacetal fragment was achieved via addition of acetylene 11 to the unstable allylic iodide 39. Epoxidation of (E)-enyne 8 via in situ formation of L-fructose derived dioxirane generated the desired syn-epoxide 36. Semi-hydrogenation of the resulting epoxide 36 followed by dihydroxylation of the alkene effected concomitant cyclization, thus completing the synthesis of the ABC spiroacetal ring fragment 6.

Epoxy Compounds↗

PubMed1984

Interactions of maitotoxin with voltage-sensitive calcium channels in cultured neuronal cells.

The dinoflagellate toxin maitotoxin (MTX) stimulated 45Ca2+ uptake in cultured NG108-15 neuroblastoma X glioma cells. Depolarizing stimuli (e.g., 50 mM K+) produced an immediate stimulation in Ca2+ uptake, whereas that produced by MTX occurred only after a lag period of about 2 min. MTX did not stimulate Ca2+ uptake into fibroblasts. Both 50 mM K+- and MTX-stimulated Ca2+ uptake was blocked by organic calcium channel antagonists (nitrendipine, D-600, diltiazem) at very low concentrations. Cd2+ was also a potent blocker. The novel dihydropyridine BAY K8644 enhanced Ca2+ uptake in the presence of 50 mM K+ but had no effect in 5 mM Ca2+. However, in the presence of MTX, BAY K8644 stimulated Ca2+ uptake in 5 mM K+. The effects of MTX were not blocked by tetrodotoxin but were decreased in Na+-free medium. MTX did not stimulate Na+ uptake into NG108-15 cells and did not alter [3H]nitrendipine binding to rat brain cortical synaptosomes. It is concluded that MTX may alter the voltage dependence of calcium-channel activation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗