Pertussis toxin (IAP) enhances maitotoxin (a putative Ca2+ channel agonist)-induced Ca2+ entry into synaptosomes.
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Animals↗
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Prophylactic and therapeutic use of an anti-brevetoxin (PbTx-2) antibody in conscious rats.
A polyclonal antiserum was investigated for prophylactic and therapeutic use in the treatment of brevetoxin intoxication. Conscious, tethered male rats were pre-treated with 1 ml of anti-brevetoxin IgG (PbAb) or control IgG by a 10 min infusion, then given brevetoxin (25 micrograms/kg) by a 1 hr infusion. Rats pre-treated with control IgG demonstrated signs of brevetoxin intoxication; these signs were absent in rats pre-treated with PbAb. In therapy studies, rats were infused for 1 hr with 100 micrograms/kg brevetoxin, followed immediately by 2 ml of either PbAb or control IgG. During toxin infusion, both groups showed signs of brevetoxin intoxication. Rats treated with control antibody died within 6 hr. In rats treated with PbAb, respiratory rates began to return toward baseline almost immediately, and fewer neurological signs developed. After 24 hr, nearly all neurological signs had disappeared and both core and peripheral temperatures had returned to normal. There was a time differential between two groups of signs, suggesting high and low accessibility compartments for the antibody. These compartments probably represent central and peripheral nervous system. All animals treated with PbAb survived at least 8 days. These results suggest that PbAb has both therapeutic and prophylactic potential in the treatment of brevetoxin intoxication. Further, because of the differential in efficacy in reversing central and peripheral nervous system signs of brevetoxin intoxication, it provides useful new information on the mechanism of action of this toxin.
Animals↗
Clinical and laboratory findings implicating palytoxin as cause of ciguatera poisoning due to Decapterus macrosoma (mackerel).
A near fatal case of ciguatera-related intoxication following consumption of smoked Decapterus macrosoma is documented. In addition to some of the hallmark symptoms of ciguatera poisoning, the patient exhibited acute respiratory distress and severe muscle spasms. Laboratory results showed large elevations in a number of blood enzymes, indicative of muscle damage. The responsible agent was extracted from corresponding fish samples and identified as palytoxin.
Acrylamides↗
Effect of interleukin 1 beta on transducing mechanisms in 235-1 clonal pituitary cells. Part II: Modulation of calcium fluxes.
In the present study we investigated the effect of the interleukin 1 beta on intracellular free calcium concentrations in 235-1 cell line both in basal conditions and after stimulation by the calcium channel activator maitotoxin. Interleukin 1 beta (from 0.01 pM to 10 nM) was unable to significantly affect basal cytosolic free calcium levels in acute conditions. The preincubation of these cells with interleukin 1 beta for 48h modulates maitotoxin stimulation of calcium fluxes without modifying basal intracellular free calcium levels. Low concentrations of interleukin 1 beta (0.01 pM, 1 pM) caused a marked reduction of intracellular free calcium concentrations increase induced by maitotoxin while higher doses of the monokine potentiated maitotoxin stimulation of calcium fluxes. The specificity of interleukin 1 beta effect was tested by means of polyclonal anti-interleukin 1 beta antibody (titer 1:100) which significantly abolished the inhibitory effect of interleukin 1 beta on free cytosolic calcium levels. These results show that a long lasting interaction of interleukin 1 beta with its receptor is able to influence voltage-sensitive calcium channels activation induced by maitotoxin in 235-1 cells.
Animals↗
Acute and delayed thermoregulatory response of mice exposed to brevetoxin.
Thermal dysthesia, characterized by a painful sensation of warm and cool surfaces, is one of many ailments in humans exposed to various marine algal toxins such as brevetoxin (PbTx). There is no animal model to study thermal dysthesia and little is known of the mechanism of action. There is also little known on the acute and delayed thermoregulatory effects of PbTx. In this study, we developed a behavioral system to assess the possible development of thermal dysthesia in mice exposed to PbTx. Female mice were implanted with radiotransmitters to monitor core temperature (Tc) and motor activity (MA). In one experiment, mice were dosed with the control vehicle or 180 microg/kg PbTx and placed on a floor temperature gradient to measure the selected foot temperature (SFT) while air temperature was kept constant. PbTx-treated mice underwent a 10 degrees C reduction in SFT concomitant with a 3 degrees C reduction in Tc within 30 min after exposure. In another study, Tc and MA were monitored in mice maintained in their home cages after dosing with 180 microg/kg PbTx. Tc but not MA increased for 2-5 days after exposure. SFT was unaffected by PbTx when tested 1-12 days after exposure. However, PbTx-treated mice underwent an increase in Tc when placed in the temperature gradient for up to 12 days after exposure. This suggests that PbTx augments the stress-induced hyperthermia from being placed in a novel environment. Overall, acute PbTx exposure leads to a regulated reduction in Tc as characterized by a preference for cooler SFTs and a reduced Tc. Thermal dysthesia was not apparent, but the exaggerated hyperthermic response with a normal SFT in the temperature gradient may suggest an altered processing of thermal stimuli in mice treated with PbTx.
Animals↗
Novel electrochemical immunosensors for seafood toxin analysis.
The current work describes the optimisation of a screen-printed electrode (SPE) system for measurement of a variety of seafood toxins, such as okadaic acid, brevetoxin, domoic acid and tetrodotoxin. A disposable screen-printed carbon electrode coupled with amperometric detection of p-aminophenol at +300 mV vs. Ag/AgCl, produced by the label, alkaline phosphatase, was used for signal measurement. ELISA was primarily used to develop all toxin systems, prior to transferring to SPE. The sensors incorporate a relevant range for toxin detection, by which humans become ill, with detection limits achieved at SPE to the order of ng ml (-1) (ppb) or lower in some cases. The SPE system is simple and cost-effective due to their disposable nature, and analysis time is complete in 30 min. In addition, analyses can be achieved outside of a laboratory environment allowing for in-field measurements. Recovery experiments on selected toxins using the relevant working ranges highlighted the functionality of these systems yielding a +/-10% deviation for the true value.
Animals↗
Total synthesis of brevetoxin B.
The convergent total synthesis of brevetoxin B (1) has been achieved. The intramolecular allylation of the O,S-acetal 20, prepared from the alpha-chlorosulfide 17 and the alcohol 5, was carried out using AgOTf as a Lewis acid to give the diene 21, predominantly. Ring-closing metathesis of 21 with the Grubbs catalyst 23 afforded the hexacyclic ether 25 which was converted to the A-G ring segment 2 through several steps. The intramolecular allylation of the alpha-acetoxy ether 42, prepared from 2 and the J-K ring segment 3, followed by ring-closing metathesis provided the polycyclic ether framework 44. A series of reactions of 44, including oxidation of the A ring, deprotection of the silyl ethers, and selective oxidation of the resulting allylic alcohol, furnished 1.
Marine Toxins↗
Convergent, stereoselective synthesis of the GHIJ fragment of brevetoxin A.
[reaction: see text] A stereoselective synthesis of the GHIJ fragment of brevetoxin A utilizing a convergent assembly strategy is described. Glycolate alkylation, ring-closing metathesis, and Hosomi-Sakurai reactions were central operations in the construction of the G ring and J ring subunits, which were united through a Horner-Wadsworth-Emmons coupling. Subsequent dehydrative cyclization produced an endocyclic enol ether that was further elaborated to the tetracyclic GHIJ fragment of brevetoxin A.
Marine Toxins↗
Synthetic study of azaspiracid-1: synthesis of the EFGHI-ring fragment.
Here, we report a synthesis of the lower half C21-C40 fragment of the shellfish toxin, azaspiracid-1. The C28-C40 fragment was synthesized by a coupling between the C28-C35 epoxide and the C36-C40 dithioacetal anion, followed by the HI-ring spiroaminal formation. An aldehyde corresponding to the C28-C40 fragment was then coupled with the C21-C27 allylic stannane by using InCl3. Finally, the FG-ring was constructed by HF.pyridine to accomplish the synthesis of the suitably protected C21-C40 fragment.
Marine Toxins↗
The structure elucidation and biological activities of high molecular weight algal toxins: maitotoxin, prymnesins and zooxanthellatoxins.
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Lipoproteins↗
Synthesis of the ABCD and ABCDE ring systems of azaspiracid-1.
The efficient syntheses of the ABCD ring system of the originally proposed structure of azaspiracid-1 and the ABCDE ring system of the revised structure of azaspiracid-1 containing the correct stereochemistry at C(6), C(10), C(13), C(14), C(16), C(17), C(19), C(21), C(22), C(24) and C(25) have been achieved.
Magnetic Resonance Spectroscopy↗
Exogenous gangliosides stimulate breakdown of neuro-2A phosphoinositides in a manner unrelated to neurite outgrowth.
Gangliosides administered exogenously are well-known effectors of differentiation in many neuroblastoma lines and primary neuronal cultures. Previous studies suggested the phosphoinositide signaling mechanism could be a contributing factor. We have found that treatment of Neuro-2A cells with bovine brain ganglioside mixture (BBG) causes breakdown of phosphoinositides, as measured by increased levels of inositol phosphates. The effect was optimal at 60 min and required a minimal BBG concentration of 25 microM. However, addition of neomycin, which blocked phosphoinositide breakdown, had no observable effect on ganglioside-stimulated neurite outgrowth. A similar result was obtained with psi-tectorigenin, which also inhibited phosphoinositide hydrolysis. When cells were treated with maitotoxin, an agent that promotes phosphoinositide breakdown, there was no enhancement of neurite outgrowth. These findings indicate that although exogenous gangliosides elevate inositol phosphate formation over a prolonged period in neuro-2A cells, this reaction is not integral to the differentiation of these cells. The possibility of secondary effects influencing neurite type and structure cannot be excluded.
Adenosine Triphosphate↗
Identification of cytoskeletal [14C]carboplatin-binding proteins reveals reduced expression and disorganization of actin and filamin in cisplatin-resistant cell lines.
Cisplatin resistant (CP-r) cells often show decreased uptake of cisplatin in association with reduced cell surface proteins and decreased endocytosis. In this report, two major [14C]carboplatin-binding proteins were identified as filamin and actin by photoaffinity labeling and mass spectrometry. Decreased expression of these two proteins was found in two different human CP-r cell lines (KB-CP20 and 7404-CP20), in comparison with their parental cell lines (KB-3-1 and BEL-7404), respectively. Disorganization of beta-actin and filamin 250 and 90 was also detected in these CP-r cells by confocal microscopy. Transfection of a wild-type actin-enhanced green fluorescent protein (EGFP) expression vector into 7404-CP20 cells resulted in a nonfilamentous actin-EGFP distribution compared with a normal distribution in the cisplatin-sensitive BEL-7404 cells, suggesting that cytoskeletal organization is disturbed in the CP-r cells. The identification of actin and filamin as [14C]carboplatin-binding proteins and decreased expression and disorganization of several cytoskeletal proteins in CP-r cells provide a molecular and cellular basis for the known defect in endocytosis in these cells.
Actins↗
Blockade of maitotoxin-induced endothelial cell lysis by glycine and L-alanine.
The maitotoxin (MTX)-induced cell death cascade in bovine aortic endothelial cells (BAECs) is a model for oncotic/necrotic cell death. The cascade is initiated by an increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)), which is followed by the biphasic uptake of vital dyes. The initial phase of dye entry reflects activation of large pores and correlates with surface membrane bleb formation; the second phase reflects cell lysis. In the present study, the effect of the cytoprotective amino acid glycine was examined. Glycine had no effect on MTX-induced change in [Ca(2+)](i) or on the first phase of vital dye uptake but produced a concentration-dependent (EC(50) approximately 1 mM) inhibition of the second phase of dye uptake. No cytoprotective effect was observed with l-valine, l-proline, or d-alanine, whereas l-alanine was equieffective to glycine. Furthermore, glycine had no effect on MTX-induced bleb formation. To test the hypothesis that glycine specifically blocks formation of a lytic "pore," the loss of fluorescence from BAECs transiently expressing GFP and concatemers of GFP ranging in size from 27 to 162 kDa was examined using time-lapse videomicroscopy. MTX-induced loss of GFP was rapid, correlated with the second phase of dye uptake, and was relatively independent of molecular size. The MTX-induced loss of GFP from BAECs was completely blocked by glycine. The data suggest that the second "lytic" phase of MTX-induced endothelial cell death reflects formation of a novel permeability pathway that allows macromolecules such as GFP or LDH to escape, yet can be prevented by the cytoprotective agents glycine and l-alanine.
Alanine↗
Effects of apical vs. basolateral palytoxin on LLC-PK1 renal epithelia.
Research on palytoxin focuses on its action as a tumor promoter and its ionophoretic action in cell membranes. The first property is unusual because palytoxin is not a protein kinase C activator. The second property is remarkable in that it may require interaction with the Na(+)-K(+)-adenosinetriphosphatase (ATPase). Our studies here with palytoxin exposure to the LLC-PK1 renal epithelial cells have yielded the following results: 1) unlike protein kinase C-activating tumor promoters (tetradecanoylphorbol 12,13-acetate or teleocidin), palytoxin does not produce a specific effect on the tight junctions between epithelia; 2) palytoxin instead produces an irreversible cytotoxic effect characterized by a pronounced cell swelling associated with sharply elevated levels of intracellular Na+ and decreased levels of intracellular K+; 3) these fluctuations in intracellular Na+ and K+ levels are explained by marked elevations in the membrane flux of 22Na+ and 86Rb+; 4) the electrophysiological reflection of these altered ion fluxes is a pronounced depolarization of the cell sheet if palytoxin is presented to the basolateral cell surface and a pronounced hyperpolarization (due to sharply elevated apical Na+ flux and transepithelial short-circuit current) if palytoxin is administered apically; 5) the apical effect of palytoxin can be blocked by apical ouabain; and 6) this apical effect of palytoxin decreases as a function of the age of the cell sheet. This first report of palytoxin action in a polar epithelial cell system provides additional evidence for palytoxin effects being mediated by contact with the Na(+)-K(+)-ATPase. It also adds to a growing literature suggesting the existence of Na(+)-K(+)-ATPase in the apical cell surface of epithelia under certain conditions.
Acrylamides↗
Maitotoxin stimulates steroid and peptide hormone secretion by swine luteal tissue.
The impact of calcium influx on the secretion of steroidal and nonsteroidal ovarian products was tested using a novel marine toxin, maitotoxin, a putative activator of endogenous calcium channels. In incubations of swine luteal minces in balanced salt solution, maitotoxin induced dose-dependent (3-12.5 ng/ml) and time-dependent (15-60 min) secretion of progesterone and relaxin. The magnitude of these stimulatory effects approached that observed for luteinizing hormone (LH) and was explicitly dependent on the presence of extracellular calcium ions. Maitotoxin's actions were not significantly impeded by substitution of choline for sodium ions in the incubation medium. Moreover, measurements of tissue calcium content by atomic absorption spectrometry indicated that maitotoxin augmented the total cellular content of calcium by 44 +/- 3.1% within 1 min. This time course was distinct from that observed for LH. The specificity of these actions on the calcium pathway was further suggested by the absence of any measurable effects of maitotoxin on luteal cAMP generation. We conclude that maitotoxin transiently increases luteal calcium content without altering cAMP generation and elicits concomitant release of both a steroidal (progesterone) and nonsteroidal (relaxin) product of the corpus luteum. Such actions are dependent on extracellular calcium but not sodium ions. These observations provide evidence for a calcium-dependent stimulatory pathway that activates both steroidal and nonsteroidal mechanisms of secretion in the swine corpus luteum.
Adenosine↗
Downregulation of sodium channels during anoxia: a putative survival strategy of turtle brain.
In contrast to mammalian brain, which exhibits rapid degeneration during anoxia, the brains of certain species of turtles show an extraordinary capacity to survive prolonged anoxia. The decrease in energy expenditure shown by the anoxic turtle brain is likely to be a key factor for anoxic survival. The "channel arrest" hypothesis proposes that ion channels, which regulate brain electrical activity in normoxia, may be altered during anoxia in the turtle brain as a mechanism to spare energy. Goals of present research were to test this hypothesis and to determine whether down-regulation of sodium channels is a possible explanation for spike threshold shifts seen during anoxia in isolated turtle cerebellum. We report here that anoxia induced a significant (42%) decline in voltage-gated sodium channel density as determined by studies of the binding of a sodium channel ligand, [3H]brevetoxin. This study demonstrates that sodium channel densities in brain may be regulated by tissue oxygenation or by physiological events associated with anoxia. Moreover, it also suggests that downregulation of sodium channels may be a basis for changes in action potential thresholds, the electrical depression and energy conservation that provide the unique anoxic tolerance of turtle brain.
Animals↗
Structures of azaspiracid analogs, azaspiracid-4 and azaspiracid-5, causative toxins of azaspiracid poisoning in Europe.
Two new analogs of azaspiracid, azaspiracid-4 and azaspiracid-5, isolated from the mussel Mytilus edulis, involved in a newly emerged shellfish poisoning in Europe were determined to be 3-hydroxy-22-demethylazaspiracid and 23-hydroxy-22-demethylazaspiracid, respectively.
Animals↗