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Patrizia Ciminiello - One of the best experts on this subject based on the ideXlab platform.
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Palytoxin and an Ostreopsis Toxin Extract Increase the Levels of mRNAs Encoding Inflammation-Related Proteins in Human Macrophages via p38 MAPK and NF-
2016Co-Authors: Rita Crinelli, Patrizia Ciminiello, Martino Forino, Ernesto Fattorusso, Elisa Carloni, Elisa Giacomini, Antonella Penna, Sabrina Dominici, Cecilia Battocchi, Luciana TartaglioneAbstract:Background: Palytoxin and, likely, its analogues produced by the dinoflagellate genus Ostreopsis, represent a class of non-proteinaceous compounds displaying high toxicity in animals. Owing to the wide distribution and the poisonous effects of these toxins in humans, their chemistry and mechanism of action have generated a growing scientific interest. Depending on the exposure route, Palytoxin and its Ostreopsis analogues may cause several adverse effects on human health, including acute inflammatory reactions which seem more typical of cutaneous and inhalation contact. These observations have led us to hypothesize that these toxins may activate pro-inflammatory signalling cascades. Methodology and Principal Findings: Here we demonstrate that Palytoxin and a semi-purified Ostreopsis cf. ovata toxin extract obtained from a cultured strain isolated in the NW Adriatic Sea and containing a putative Palytoxin and all the ovatoxins so far known – including the recently identified ovatoxin-f – significantly increase the levels of mRNAs encoding inflammation-related proteins in immune cells, i.e. monocyte-derived human macrophages, as assessed by Real-Time PCR analysis. Western immunoblot and electrophoretic mobility shift assays revealed that nuclear transcription factor-kB (NF-kB) is activated in cells exposed to toxins in coincidence with reduced levels of the inhibitory protein IkB-a. Moreover, Mitogen-Activated Protein Kinases (MAPK) were phosphorylated in response to Palytoxin, as also reported by others, and to the Ostreopsis toxin extract, as shown here for the first time. By using specific chemical inhibitors, the involvement of NF-k
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Liquid chromatography–high-resolution mass spectrometry for Palytoxins in mussels
Analytical and Bioanalytical Chemistry, 2015Co-Authors: Patrizia Ciminiello, Carmela Dell’aversano, Emma Iacovo, Martino Forino, Luciana TartaglioneAbstract:Palytoxins from Ostreopsis cf. ovata (a putative Palytoxin and ovatoxins) are emerging toxins in the Mediterranean basin and are not yet regulated, although there is evidence that they can accumulate in seafood and thus enter the human food chain. This poses serious concerns for human health, because Palytoxin itself is among the most potent marine toxins known. In 2009, the European Food Safety Authority (EFSA) announced the need for optimization of efficient analytical methods for detecting Palytoxins and for preparing standards. Herein, we propose a procedure including a one-step extraction, solid-phase-extraction (SPE) clean-up, and liquid chromatography-high resolution mass spectrometry (LC–HRMS) detection of individual Palytoxins in mussels. The method enabled efficient chromatographic separation of individual compounds, including structural isomers, with good sensitivity, reproducibility, and linearity in a large dynamic range (14–1000 ng mL^−1 in matrix). As a result, the putative Palytoxin from Ostreopsis cf. ovata was identified as an isomer of Palytoxin itself and re-named isobaric Palytoxin. The whole procedure (sample preparation and LC–HRMS analysis) proved able to detect Palytoxins in both spiked and natural mussel samples at levels as low as 70 μg kg^−1 in crude mussel extracts and 15 μg kg^−1 after SPE clean-up. Although full validation of the method is currently prevented by the unavailability of Palytoxin(s) certified standards and reference material, this study constitutes a first step towards achieving this.
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stereoisomers of 42 hydroxy Palytoxin from hawaiian palythoa toxica and p tuberculosa stereostructure elucidation detection and biological activities
Journal of Natural Products, 2014Co-Authors: Patrizia Ciminiello, Martino Forino, Luciana Tartaglione, Carmela Dellaversano, Emma Dello Iacovo, Marco Pelin, Silvio Sosa, Olivier Chaloin, Aurelia Tubaro, Mark PoliAbstract:Palytoxin ranks among the most potent marine biotoxins. Its lethality was well known to native Hawaiians that used to smear a “moss” containing the toxin on their spears to cause instant death to their victims. Human intoxications due to exposure to Palytoxin and to its many congeners have been reported worldwide. Currently, Palytoxins constitute the main threat to public health across the Mediterranean Sea. In the present work we report on the isolation and stereostructural determination of a new Palytoxin analogue from a Hawaiian Palythoa tuberculosa sample. This new toxin is a stereoisomer of 42-hydroxyPalytoxin isolated from Palythoa toxica. The whole absolute configuration of this latter toxin is also reported in the paper. Interestingly, the two 42-hydroxyPalytoxins do not share the same biological activity. The stereoisomer from P. tuberculosa showed cytotoxicity toward skin HaCaT keratinocytes approximately 1 order of magnitude lower than that of 42-hydroxyPalytoxin from P. toxica and about 2 orde...
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Palytoxin and an ostreopsis toxin extract increase the levels of mrnas encoding inflammation related proteins in human macrophages via p38 mapk and nf κb
PLOS ONE, 2012Co-Authors: Rita Crinelli, Patrizia Ciminiello, Carmela Dellaversano, Ernesto Fattorusso, Elisa Carloni, Elisa Giacomini, Antonella Penna, Sabrina Dominici, Cecilia Battocchi, Martino ForinoAbstract:Background Palytoxin and, likely, its analogues produced by the dinoflagellate genus Ostreopsis, represent a class of non-proteinaceous compounds displaying high toxicity in animals. Owing to the wide distribution and the poisonous effects of these toxins in humans, their chemistry and mechanism of action have generated a growing scientific interest. Depending on the exposure route, Palytoxin and its Ostreopsis analogues may cause several adverse effects on human health, including acute inflammatory reactions which seem more typical of cutaneous and inhalation contact. These observations have led us to hypothesize that these toxins may activate pro-inflammatory signalling cascades. Methodology and Principal Findings Here we demonstrate that Palytoxin and a semi-purified Ostreopsis cf. ovata toxin extract obtained from a cultured strain isolated in the NW Adriatic Sea and containing a putative Palytoxin and all the ovatoxins so far known – including the recently identified ovatoxin-f – significantly increase the levels of mRNAs encoding inflammation-related proteins in immune cells, i.e. monocyte-derived human macrophages, as assessed by Real-Time PCR analysis. Western immunoblot and electrophoretic mobility shift assays revealed that nuclear transcription factor -κB (NF-κB) is activated in cells exposed to toxins in coincidence with reduced levels of the inhibitory protein IκB-α. Moreover, Mitogen-Activated Protein Kinases (MAPK) were phosphorylated in response to Palytoxin, as also reported by others, and to the Ostreopsis toxin extract, as shown here for the first time. By using specific chemical inhibitors, the involvement of NF-κB and p38 MAPK in the toxin-induced transcription and accumulation of Cycloxigenase-2, Tumor Necrosis Factor-α, and Interleukin-8 transcripts has been demonstrated. Conclusions and Significance The identification of specific molecular targets of Palytoxin and its Ostreopsis analogues, besides contributing to expand the still limited knowledge of the intracellular signalling cascades affected by these toxins, may have important implications in setting up focused pharmacological interventions, replacing currently used symptomatic treatments.
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unique toxin profile of a mediterranean ostreopsis cf ovata strain hr lc msn characterization of ovatoxin f a new Palytoxin congener
Chemical Research in Toxicology, 2012Co-Authors: Patrizia Ciminiello, Martino Forino, Luciana Tartaglione, Carmela Dellaversano, Emma Dello Iacovo, Ernesto Fattorusso, Rita Crinelli, Elisa Carloni, Cecilia Battocchi, Mauro MagnaniAbstract:Currently, the benthic dinoflagellate Ostreopsis cf. ovata represents a serious concern to human health in the whole Mediterranean basin due to the production of Palytoxin congeners, a putative Palytoxin and ovatoxins (ovatoxin-a, -b, -c, -d/-e), listed among the most potent marine toxins. High resolution liquid chromatography–mass spectrometry (HR LC-MS) based investigation of a North Western Adriatic strain of Ostreopsis cf. ovata collected at Portonovo (Italy) in 2008 is reported herein. Toxin profile was different from those previously reported for other O. cf. ovata, both qualitatively and quantitatively. For the first time, ovatoxin-a did not dominate the toxin profile, and a new Palytoxin congener, here named ovatoxin-f, was detected. Ovatoxin-f and its elemental formula present C2H4 more than ovatoxin-a. HR CID MSn experiments allowed us to restrict structural differences between ovatoxin-a and -f to the region between C-95 and C-102, a region not previously been described to be modified in other ...
Elizabeth V Wattenberg - One of the best experts on this subject based on the ideXlab platform.
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modulation of protein kinase signaling cascades by Palytoxin
Toxicon, 2011Co-Authors: Elizabeth V WattenbergAbstract:Abstract Although known for its acutely toxic action, Palytoxin has also been identified as a type of carcinogenic agent called a tumor promoter. In general tumor promoters do not damage DNA, but instead contribute to carcinogenesis by disrupting the regulation of cellular signaling. The identification of Palytoxin as a tumor promoter, together with the recognition that the Na + , K + -ATPase is its receptor, led to research on how Palytoxin triggers the modulation of signal transduction pathways. This review focuses on mitogen activated protein (MAP) kinases as mediators of Palytoxin-stimulated signaling. MAP kinases are a family of serine/threonine kinases that relay a variety of signals to the cellular machinery that regulates cell fate and function. The studies discussed in this review investigated how Palytoxin stimulates MAP kinase activity and, in turn, how MAP kinases mediate the response of cells to Palytoxin.
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extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter Palytoxin
Toxicology and Applied Pharmacology, 2009Co-Authors: Aaron T Charlson, Nicholette A Zeliadt, Elizabeth V WattenbergAbstract:Palytoxin is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor because it does not bind to or activate protein kinase C. Palytoxin is thus a novel tool for investigating alternative signaling pathways that may affect carcinogenesis. We previously showed that Palytoxin activates three major members of the mitogen activated protein kinase (MAPK) family, extracellular signal regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Here we report that Palytoxin also activates another MAPK family member, called ERK5, in HeLa cells and in keratinocytes derived from initiated mouse skin (308 cells). By contrast, TPA does not activate ERK5 in these cell lines. The major cell surface receptor for Palytoxin is the Na+,K+-ATPase. Accordingly, ouabain blocked the ability of Palytoxin to activate ERK5. Ouabain alone did not activate ERK5. ERK5 thus represents a divergence in the signaling pathways activated by these two agents that bind to the Na+,K+-ATPase. Cycloheximide, okadaic acid, and sodium orthovanadate did not mimic the effect of Palytoxin on ERK5. These results indicate that the stimulation of ERK5 by Palytoxin is not simply due to inhibition of protein synthesis or inhibition of serine/threonine or tyrosine phosphatases. Therefore, the mechanism by which Palytoxin activates ERK5 differs from that by which it activates ERK1/2, JNK, and p38. Finally, studies that used pharmacological inhibitors and shRNA to block ERK5 action indicate that ERK5 contributes to Palytoxin-stimulated c-Fos gene expression. These results suggest that ERK5 can act as an alternative mediator for transmitting diverse tumor promoter-stimulated signals.
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Palytoxin exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis
American Journal of Physiology-cell Physiology, 2007Co-Authors: Elizabeth V WattenbergAbstract:Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tum...
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extracellular signal regulated kinase transmits Palytoxin stimulated signals leading to altered gene expression in mouse keratinocytes
Toxicology and Applied Pharmacology, 2002Co-Authors: Janel K Warmka, Nicholette A Zeliadt, Susanna E Winston, Elizabeth V WattenbergAbstract:We have been probing the molecular mechanisms of tumor promoters that stimulate distinct initial signals to define critical downstream biochemical events in carcinogenesis. The action of the novel skin tumor promoter Palytoxin on signaling and gene expression in keratinocytes, the primary target cells of tumor promoters, was therefore investigated. Palytoxin stimulated an increase in mRNA for matrix metalloproteinase-13 (MMP-13), an enzyme implicated in carcinogenesis, in a keratinocyte cell line derived from initiated mouse skin (308). Palytoxin stimulated an increase in c-Fos binding to the activator protein-1 (AP-1) site present in the promoter of the mouse MMP-13 gene. This effect was specific because Palytoxin had little effect on c-Jun, JunB, JunD, FosB, Fra-1, or Fra-2 binding or on overall levels of transcription factor binding. The increase in c-Fos binding corresponded to a Palytoxin-stimulated increase in c-Fos protein levels. Palytoxin stimulated the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase, and p38. The MAPK kinase inhibitor PD 98059 blocked Palytoxin-stimulated ERK activation. PD 98059 also blocked the Palytoxin-stimulated increases in c-Fos protein levels, c-Fos binding to the AP-1 site, and MMP-13 mRNA. These studies identify important differences between Palytoxin-stimulated signaling in keratinocytes derived from initiated mouse skin, the biologically relevant cell type, and other cell lines. Specifically, our data suggest that, in keratinocytes derived from initiated mouse skin, ERK plays an important role in transmitting Palytoxin-stimulated signals to three downstream targets that are likely to affect carcinogenesis: c-Fos, AP-1, and MMP-13.
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differential activation of mitogen activated protein kinases by Palytoxin and ouabain two ligands for the na k atpase
Toxicology and Applied Pharmacology, 1998Co-Authors: Elizabeth V WattenbergAbstract:We previously demonstrated that the marine toxin and skin tumor promoter Palytoxin activates the stress-activated protein kinase/c-Jun N-terminal kinase (JNK), but not the extracellular signal-regulated kinase (ERK), which is typically activated by mitogenic agents. JNK, ERK, and p38, another stress-activated protein kinase, are members of the mitogen-activated protein (MAP) kinase family of serine/threonine kinases, which coordinate the transmission of various signals through the cell. The Na+,K+-ATPase is the putative Palytoxin receptor. Therefore, we hypothesized that the Na+,K+-ATPase inhibitor ouabain might also stimulate signaling pathways that activate MAP kinases. Using HeLa and COS7 cells, we found that, although there are similarities between the protein kinase cascades by which Palytoxin and ouabain activate JNK, there are also significant differences between the activation of specific MAP kinases by Palytoxin and ouabain. Transient expression of dominant negative mutants indicates that ouabain, like Palytoxin, activates JNK through a protein kinase cascade that involves the JNK kinase SEK1 but does not require the GTPase Ras. Palytoxin activates JNK and p38 to a greater extent than ouabain. By contrast, ouabain activates ERK to a greater extent than Palytoxin. Ouabain blocked Palytoxin-stimulated activation of JNK and p38, but not anisomycin-stimulated activation of these kinases, supporting the conclusion that ouabain and Palytoxin bind to the same site on the Na+,K+-ATPase. These results suggest that the Na+,K+-ATPase can differentially mediate the activation of MAP kinases by two diverse ligands, Palytoxin and ouabain.
Martino Forino - One of the best experts on this subject based on the ideXlab platform.
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Palytoxin and an Ostreopsis Toxin Extract Increase the Levels of mRNAs Encoding Inflammation-Related Proteins in Human Macrophages via p38 MAPK and NF-
2016Co-Authors: Rita Crinelli, Patrizia Ciminiello, Martino Forino, Ernesto Fattorusso, Elisa Carloni, Elisa Giacomini, Antonella Penna, Sabrina Dominici, Cecilia Battocchi, Luciana TartaglioneAbstract:Background: Palytoxin and, likely, its analogues produced by the dinoflagellate genus Ostreopsis, represent a class of non-proteinaceous compounds displaying high toxicity in animals. Owing to the wide distribution and the poisonous effects of these toxins in humans, their chemistry and mechanism of action have generated a growing scientific interest. Depending on the exposure route, Palytoxin and its Ostreopsis analogues may cause several adverse effects on human health, including acute inflammatory reactions which seem more typical of cutaneous and inhalation contact. These observations have led us to hypothesize that these toxins may activate pro-inflammatory signalling cascades. Methodology and Principal Findings: Here we demonstrate that Palytoxin and a semi-purified Ostreopsis cf. ovata toxin extract obtained from a cultured strain isolated in the NW Adriatic Sea and containing a putative Palytoxin and all the ovatoxins so far known – including the recently identified ovatoxin-f – significantly increase the levels of mRNAs encoding inflammation-related proteins in immune cells, i.e. monocyte-derived human macrophages, as assessed by Real-Time PCR analysis. Western immunoblot and electrophoretic mobility shift assays revealed that nuclear transcription factor-kB (NF-kB) is activated in cells exposed to toxins in coincidence with reduced levels of the inhibitory protein IkB-a. Moreover, Mitogen-Activated Protein Kinases (MAPK) were phosphorylated in response to Palytoxin, as also reported by others, and to the Ostreopsis toxin extract, as shown here for the first time. By using specific chemical inhibitors, the involvement of NF-k
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Liquid chromatography–high-resolution mass spectrometry for Palytoxins in mussels
Analytical and Bioanalytical Chemistry, 2015Co-Authors: Patrizia Ciminiello, Carmela Dell’aversano, Emma Iacovo, Martino Forino, Luciana TartaglioneAbstract:Palytoxins from Ostreopsis cf. ovata (a putative Palytoxin and ovatoxins) are emerging toxins in the Mediterranean basin and are not yet regulated, although there is evidence that they can accumulate in seafood and thus enter the human food chain. This poses serious concerns for human health, because Palytoxin itself is among the most potent marine toxins known. In 2009, the European Food Safety Authority (EFSA) announced the need for optimization of efficient analytical methods for detecting Palytoxins and for preparing standards. Herein, we propose a procedure including a one-step extraction, solid-phase-extraction (SPE) clean-up, and liquid chromatography-high resolution mass spectrometry (LC–HRMS) detection of individual Palytoxins in mussels. The method enabled efficient chromatographic separation of individual compounds, including structural isomers, with good sensitivity, reproducibility, and linearity in a large dynamic range (14–1000 ng mL^−1 in matrix). As a result, the putative Palytoxin from Ostreopsis cf. ovata was identified as an isomer of Palytoxin itself and re-named isobaric Palytoxin. The whole procedure (sample preparation and LC–HRMS analysis) proved able to detect Palytoxins in both spiked and natural mussel samples at levels as low as 70 μg kg^−1 in crude mussel extracts and 15 μg kg^−1 after SPE clean-up. Although full validation of the method is currently prevented by the unavailability of Palytoxin(s) certified standards and reference material, this study constitutes a first step towards achieving this.
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stereoisomers of 42 hydroxy Palytoxin from hawaiian palythoa toxica and p tuberculosa stereostructure elucidation detection and biological activities
Journal of Natural Products, 2014Co-Authors: Patrizia Ciminiello, Martino Forino, Luciana Tartaglione, Carmela Dellaversano, Emma Dello Iacovo, Marco Pelin, Silvio Sosa, Olivier Chaloin, Aurelia Tubaro, Mark PoliAbstract:Palytoxin ranks among the most potent marine biotoxins. Its lethality was well known to native Hawaiians that used to smear a “moss” containing the toxin on their spears to cause instant death to their victims. Human intoxications due to exposure to Palytoxin and to its many congeners have been reported worldwide. Currently, Palytoxins constitute the main threat to public health across the Mediterranean Sea. In the present work we report on the isolation and stereostructural determination of a new Palytoxin analogue from a Hawaiian Palythoa tuberculosa sample. This new toxin is a stereoisomer of 42-hydroxyPalytoxin isolated from Palythoa toxica. The whole absolute configuration of this latter toxin is also reported in the paper. Interestingly, the two 42-hydroxyPalytoxins do not share the same biological activity. The stereoisomer from P. tuberculosa showed cytotoxicity toward skin HaCaT keratinocytes approximately 1 order of magnitude lower than that of 42-hydroxyPalytoxin from P. toxica and about 2 orde...
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Palytoxin and an ostreopsis toxin extract increase the levels of mrnas encoding inflammation related proteins in human macrophages via p38 mapk and nf κb
PLOS ONE, 2012Co-Authors: Rita Crinelli, Patrizia Ciminiello, Carmela Dellaversano, Ernesto Fattorusso, Elisa Carloni, Elisa Giacomini, Antonella Penna, Sabrina Dominici, Cecilia Battocchi, Martino ForinoAbstract:Background Palytoxin and, likely, its analogues produced by the dinoflagellate genus Ostreopsis, represent a class of non-proteinaceous compounds displaying high toxicity in animals. Owing to the wide distribution and the poisonous effects of these toxins in humans, their chemistry and mechanism of action have generated a growing scientific interest. Depending on the exposure route, Palytoxin and its Ostreopsis analogues may cause several adverse effects on human health, including acute inflammatory reactions which seem more typical of cutaneous and inhalation contact. These observations have led us to hypothesize that these toxins may activate pro-inflammatory signalling cascades. Methodology and Principal Findings Here we demonstrate that Palytoxin and a semi-purified Ostreopsis cf. ovata toxin extract obtained from a cultured strain isolated in the NW Adriatic Sea and containing a putative Palytoxin and all the ovatoxins so far known – including the recently identified ovatoxin-f – significantly increase the levels of mRNAs encoding inflammation-related proteins in immune cells, i.e. monocyte-derived human macrophages, as assessed by Real-Time PCR analysis. Western immunoblot and electrophoretic mobility shift assays revealed that nuclear transcription factor -κB (NF-κB) is activated in cells exposed to toxins in coincidence with reduced levels of the inhibitory protein IκB-α. Moreover, Mitogen-Activated Protein Kinases (MAPK) were phosphorylated in response to Palytoxin, as also reported by others, and to the Ostreopsis toxin extract, as shown here for the first time. By using specific chemical inhibitors, the involvement of NF-κB and p38 MAPK in the toxin-induced transcription and accumulation of Cycloxigenase-2, Tumor Necrosis Factor-α, and Interleukin-8 transcripts has been demonstrated. Conclusions and Significance The identification of specific molecular targets of Palytoxin and its Ostreopsis analogues, besides contributing to expand the still limited knowledge of the intracellular signalling cascades affected by these toxins, may have important implications in setting up focused pharmacological interventions, replacing currently used symptomatic treatments.
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unique toxin profile of a mediterranean ostreopsis cf ovata strain hr lc msn characterization of ovatoxin f a new Palytoxin congener
Chemical Research in Toxicology, 2012Co-Authors: Patrizia Ciminiello, Martino Forino, Luciana Tartaglione, Carmela Dellaversano, Emma Dello Iacovo, Ernesto Fattorusso, Rita Crinelli, Elisa Carloni, Cecilia Battocchi, Mauro MagnaniAbstract:Currently, the benthic dinoflagellate Ostreopsis cf. ovata represents a serious concern to human health in the whole Mediterranean basin due to the production of Palytoxin congeners, a putative Palytoxin and ovatoxins (ovatoxin-a, -b, -c, -d/-e), listed among the most potent marine toxins. High resolution liquid chromatography–mass spectrometry (HR LC-MS) based investigation of a North Western Adriatic strain of Ostreopsis cf. ovata collected at Portonovo (Italy) in 2008 is reported herein. Toxin profile was different from those previously reported for other O. cf. ovata, both qualitatively and quantitatively. For the first time, ovatoxin-a did not dominate the toxin profile, and a new Palytoxin congener, here named ovatoxin-f, was detected. Ovatoxin-f and its elemental formula present C2H4 more than ovatoxin-a. HR CID MSn experiments allowed us to restrict structural differences between ovatoxin-a and -f to the region between C-95 and C-102, a region not previously been described to be modified in other ...
Luis M Botana - One of the best experts on this subject based on the ideXlab platform.
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acute and chronic in vivo toxicity of the marine toxin Palytoxin
2021Co-Authors: Andrea Boentejuncal, Carmen M Louzao, Sandra Raposogarcia, Celia Costas, Paz Otero, Carmen Vale, Luis M BotanaAbstract:Palytoxin (PLTX) is a marine toxin that nowadays is recognized amongst the most toxic compounds isolated from natural products. Originally, the toxin was only identified in a single tidal pool of the island of Maui (Hawaii). Currently, this compound is considered as an emergent toxin in Europe and its prevalence in continental European waters has increased during the last years. The high toxicity of Palytoxin is related with the binding to the Na+-K+ ATPase, converting this ubiquitously distributed enzyme in a permeant cation channel [1-3]. Several reports have shown that this toxin is responsible for human fatal intoxications, either after inhalation of toxin-containing marine aerosols or after ingestion of marine products contaminated with PLTX, such as crabs, groupers, mackerel, and parrotfish. So far, different groups have explored the acute oral toxicity of PLTX in mice however, discrepancies in the PLTX source as well as in the monitoring time for the toxic effects yielded controversial results. Although the presence of Palytoxin in marine products is not yet currently regulated in Europe, the European Food Safety Authority (EFSA) expressed its opinion on PLTX toxicity and prompted the need to obtain more data regarding the in vivo toxicity of this compound [4]. Therefore, in this study, the acute and chronic toxicity of Palytoxin was evaluated after oral administration of the toxin to mice either in a single dose and in a follow-up period of 96 hours or after chronic administration during a 28-day period. After chronic exposure of mice to the toxin, a lethal dose 50 (LD50) of 0.44 µg/kg of PLTX, much lower than that observed in the acute experiments, and a No-Observed-Adverse-Effect Level (NOAEL) of 0.03 µg/kg for repeated daily oral administration of PLTX were determined. Therefore, these data indicate a much higher chronic toxicity of PLTX and a lower NOAEL than that previously described in shorter treatment periods remarking the need to further evaluate the potential teratogenic effects of this emerging marine toxin in mammals. References Artigas, P.; Gadsby, D.C. Ion occlusion/deocclusion partial reactions in individual Palytoxin-modified Na+/K+ pumps. Ann N Y Acad Sci 2003, 986, 116-126. Artigas, P.; Gadsby, D.C. Na+/K+-pump ligands modulate gating of Palytoxin-induced ion channels. Proc Natl Acad Sci U S A 2003, 100, 501-505. Artigas, P.; Gadsby, D.C. Large diameter of Palytoxin-induced Na+/K+ pump channels and modulation of Palytoxin interaction by Na+/K+ pump ligands. J Gen Physiol 2004, 123, 357-376. EFSA. Panel on contaminants in the food chain (CONTAM). Scientific Opinion on marine biotoxins in shellfish–Palytoxin group. EFSA Journal, 2009; Vol. 7, p 1393.
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the kinetic mechanistic and cytomorphological effects of Palytoxin in human intestinal cells caco 2 explain its lower than parenteral oral toxicity
FEBS Journal, 2013Co-Authors: D Fernandez, Begoña Espiña, Mercedes R Vieytes, Carmen M Louzao, Natalia Vilarino, Maria Fraga, Albina Roman, Mark Poli, Luis M BotanaAbstract:Palytoxin is one of the most toxic marine toxins known. Distributed worldwide, it poses a potential human health risk linked to the consumption of contaminated seafood. Despite its high parenteral toxicity, the lethal oral dose of Palytoxin is several times higher than the intraperitoneal lethal dose. In the present study, we investigated the passage of Palytoxin through the human intestinal barrier by employing a well-characterized and accepted in vitro model of intestinal permeability that uses differentiated Caco-2 cell monolayers. Trans-epithelial electric resistance measurements showed that Palytoxin disrupts the integrity of Caco-2 monolayers at concentrations > 0.135 nm. However, confocal microscopy imaging showed that the tight-junction protein occludin was not affected by Palytoxin in the nanomolar range. This finding was supported by transmission electron microscopy imaging, where tight-junctions appeared to be unaffected by Palytoxin treatment. In addition, the nuclear envelope does not appear to be altered by high concentrations of Palytoxin. However, Palytoxin-treated cells showed electron-dense and damaged mitochondria. Toxin exposure also induced the disappearance of the differentiated Caco-2 microvilli and organelles, as well as chromatin de-condensation. Permeability assays showed that Palytoxin could not significantly pass the Caco-2 monolayer, despite the lack of epithelium integrity, suggesting that Palytoxins would be poorly transported to blood, which may explain its lower oral toxicity. These data can help to achieve a better understanding of Palytoxin poisoning. However, more studies regarding its repeated administration and chronic effects are needed.
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cytotoxic effect of Palytoxin on mussel
Toxicon, 2010Co-Authors: Carmen M Louzao, Begoña Espiña, Eva Cagide, Mercedes R Vieytes, Isabel R Ares, Amparo Alfonso, Luis M BotanaAbstract:Palytoxin is a large and complex polyhydroxylated molecule with potent neurotoxic activity. Dinoflagellates from the Ostreopsis genera were demonstrated to be producers of this compound and analogues. Even though initially Palytoxin appearance was restricted to tropical areas, the recent occurrence of Ostreopsis outbreaks in Mediterranean Sea point to a worldwide dissemination probably related to climatic change. Those dinoflagellates can bioaccumulate in shellfish, especially in filter-feeding mollusks and have been involved in damaging effects in seafood or human toxic outbreaks. The present study describes Palytoxins effect on metabolic activity of mantle and hepatopancreas cells from the mussel Mytilus galloprovincialis Lmk. Our results indicate that Palytoxin is highly cytotoxic to mussel cells; unlike it happens with other toxins more common in European coasts such as okadaic acid and azaspiracid. These findings have a special significance for the marine environment and aquiculture since they are evidence for the ability of Palytoxin to affect the integrity of bivalve mollusks that are not adapted to the presence of this toxin.
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production of functionally active Palytoxin like compounds by mediterranean ostreopsis cf siamensis
Cellular Physiology and Biochemistry, 2009Co-Authors: Eva Cagide, Takeshi Yasumoto, Begoña Espiña, Mercedes R Vieytes, David Jaen, Luz Maman, Carmen M Louzao, Luis M BotanaAbstract:Background and purpose: Dinoflagellates from the genus Ostreopsis have been related to the production of Palytoxin and analogues. Based on that, this paper describes functional stud
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Palytoxins specific and dynamic detection by in vitro microplate assay with human neuroblastoma cells
Bioscience Reports, 2008Co-Authors: Begoña Espiña, Eva Cagide, M. Carmen Louzao, Maria Martinez-fernandez, Mercedes R Vieytes, Panagiota Katikou, Adriano Villar, David Jaen, Luz Maman, Luis M BotanaAbstract:Palytoxin is one of the most complex and biggest molecules known showing extreme acute toxicity. During the last years, the dinoflagellate Ostreopsis spp, the producer organism of Palytoxin, has shown a world-wide distribution thus making Palytoxin an emerging toxin. Rat derived hepatocytes Clone 9 and BE (2)-M17 human neuroblastoma were used to test Palytoxin or Palytoxin -like compounds by measuring cell metabolic rate with Alamar Blue. The dose-dependent decrease in viability was specifically inhibited by ouabain in the case of BE (2)-M17 neuroblastoma cells. This is a functional, dynamic and simple test for Palytoxins with high sensitivity as low as 0.2 ng/ mL. This method was useful for toxin detection in Ostreopsis extracts and naturally contaminated mussel samples. A comparative study testing toxic mussel extracts by LC-MS/MS, MBA, hemolysis neutralization assay and cytotoxicity test indicated that our method is suitable for the routine determination and monitoring of Palytoxins and Palytoxin-like compounds.
Luciana Tartaglione - One of the best experts on this subject based on the ideXlab platform.
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Palytoxin and an Ostreopsis Toxin Extract Increase the Levels of mRNAs Encoding Inflammation-Related Proteins in Human Macrophages via p38 MAPK and NF-
2016Co-Authors: Rita Crinelli, Patrizia Ciminiello, Martino Forino, Ernesto Fattorusso, Elisa Carloni, Elisa Giacomini, Antonella Penna, Sabrina Dominici, Cecilia Battocchi, Luciana TartaglioneAbstract:Background: Palytoxin and, likely, its analogues produced by the dinoflagellate genus Ostreopsis, represent a class of non-proteinaceous compounds displaying high toxicity in animals. Owing to the wide distribution and the poisonous effects of these toxins in humans, their chemistry and mechanism of action have generated a growing scientific interest. Depending on the exposure route, Palytoxin and its Ostreopsis analogues may cause several adverse effects on human health, including acute inflammatory reactions which seem more typical of cutaneous and inhalation contact. These observations have led us to hypothesize that these toxins may activate pro-inflammatory signalling cascades. Methodology and Principal Findings: Here we demonstrate that Palytoxin and a semi-purified Ostreopsis cf. ovata toxin extract obtained from a cultured strain isolated in the NW Adriatic Sea and containing a putative Palytoxin and all the ovatoxins so far known – including the recently identified ovatoxin-f – significantly increase the levels of mRNAs encoding inflammation-related proteins in immune cells, i.e. monocyte-derived human macrophages, as assessed by Real-Time PCR analysis. Western immunoblot and electrophoretic mobility shift assays revealed that nuclear transcription factor-kB (NF-kB) is activated in cells exposed to toxins in coincidence with reduced levels of the inhibitory protein IkB-a. Moreover, Mitogen-Activated Protein Kinases (MAPK) were phosphorylated in response to Palytoxin, as also reported by others, and to the Ostreopsis toxin extract, as shown here for the first time. By using specific chemical inhibitors, the involvement of NF-k
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Liquid chromatography–high-resolution mass spectrometry for Palytoxins in mussels
Analytical and Bioanalytical Chemistry, 2015Co-Authors: Patrizia Ciminiello, Carmela Dell’aversano, Emma Iacovo, Martino Forino, Luciana TartaglioneAbstract:Palytoxins from Ostreopsis cf. ovata (a putative Palytoxin and ovatoxins) are emerging toxins in the Mediterranean basin and are not yet regulated, although there is evidence that they can accumulate in seafood and thus enter the human food chain. This poses serious concerns for human health, because Palytoxin itself is among the most potent marine toxins known. In 2009, the European Food Safety Authority (EFSA) announced the need for optimization of efficient analytical methods for detecting Palytoxins and for preparing standards. Herein, we propose a procedure including a one-step extraction, solid-phase-extraction (SPE) clean-up, and liquid chromatography-high resolution mass spectrometry (LC–HRMS) detection of individual Palytoxins in mussels. The method enabled efficient chromatographic separation of individual compounds, including structural isomers, with good sensitivity, reproducibility, and linearity in a large dynamic range (14–1000 ng mL^−1 in matrix). As a result, the putative Palytoxin from Ostreopsis cf. ovata was identified as an isomer of Palytoxin itself and re-named isobaric Palytoxin. The whole procedure (sample preparation and LC–HRMS analysis) proved able to detect Palytoxins in both spiked and natural mussel samples at levels as low as 70 μg kg^−1 in crude mussel extracts and 15 μg kg^−1 after SPE clean-up. Although full validation of the method is currently prevented by the unavailability of Palytoxin(s) certified standards and reference material, this study constitutes a first step towards achieving this.
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stereoisomers of 42 hydroxy Palytoxin from hawaiian palythoa toxica and p tuberculosa stereostructure elucidation detection and biological activities
Journal of Natural Products, 2014Co-Authors: Patrizia Ciminiello, Martino Forino, Luciana Tartaglione, Carmela Dellaversano, Emma Dello Iacovo, Marco Pelin, Silvio Sosa, Olivier Chaloin, Aurelia Tubaro, Mark PoliAbstract:Palytoxin ranks among the most potent marine biotoxins. Its lethality was well known to native Hawaiians that used to smear a “moss” containing the toxin on their spears to cause instant death to their victims. Human intoxications due to exposure to Palytoxin and to its many congeners have been reported worldwide. Currently, Palytoxins constitute the main threat to public health across the Mediterranean Sea. In the present work we report on the isolation and stereostructural determination of a new Palytoxin analogue from a Hawaiian Palythoa tuberculosa sample. This new toxin is a stereoisomer of 42-hydroxyPalytoxin isolated from Palythoa toxica. The whole absolute configuration of this latter toxin is also reported in the paper. Interestingly, the two 42-hydroxyPalytoxins do not share the same biological activity. The stereoisomer from P. tuberculosa showed cytotoxicity toward skin HaCaT keratinocytes approximately 1 order of magnitude lower than that of 42-hydroxyPalytoxin from P. toxica and about 2 orde...
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unique toxin profile of a mediterranean ostreopsis cf ovata strain hr lc msn characterization of ovatoxin f a new Palytoxin congener
Chemical Research in Toxicology, 2012Co-Authors: Patrizia Ciminiello, Martino Forino, Luciana Tartaglione, Carmela Dellaversano, Emma Dello Iacovo, Ernesto Fattorusso, Rita Crinelli, Elisa Carloni, Cecilia Battocchi, Mauro MagnaniAbstract:Currently, the benthic dinoflagellate Ostreopsis cf. ovata represents a serious concern to human health in the whole Mediterranean basin due to the production of Palytoxin congeners, a putative Palytoxin and ovatoxins (ovatoxin-a, -b, -c, -d/-e), listed among the most potent marine toxins. High resolution liquid chromatography–mass spectrometry (HR LC-MS) based investigation of a North Western Adriatic strain of Ostreopsis cf. ovata collected at Portonovo (Italy) in 2008 is reported herein. Toxin profile was different from those previously reported for other O. cf. ovata, both qualitatively and quantitatively. For the first time, ovatoxin-a did not dominate the toxin profile, and a new Palytoxin congener, here named ovatoxin-f, was detected. Ovatoxin-f and its elemental formula present C2H4 more than ovatoxin-a. HR CID MSn experiments allowed us to restrict structural differences between ovatoxin-a and -f to the region between C-95 and C-102, a region not previously been described to be modified in other ...
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high resolution lc msn fragmentation pattern of Palytoxin as template to gain new insights into ovatoxin a structure the key role of calcium in ms behavior of Palytoxins
Journal of the American Society for Mass Spectrometry, 2012Co-Authors: Patrizia Ciminiello, Martino Forino, Carmela Dellaversano, Emma Dello Iacovo, Ernesto Fattorusso, Laura Grauso, Luciana TartaglioneAbstract:Palytoxin is a potent marine toxin and one of the most complex natural compounds ever described. A number of compounds identified as Palytoxin congeners (e.g., ovatoxins, mascarenotoxins, ostreocins, etc.) have not been yet structurally elucidated due to lack of pure material in quantities sufficient to an NMR-based structural investigation. In this study, the complex fragmentation pattern of Palytoxin in its positive high resolution liquid chromatography tandem mass spectra (HR LC-MSn) was interpreted. Under the used conditions, the molecule underwent fragmentation at many sites of its backbone, and a large number of diagnostic fragment ions were identified. The natural product itself was used with no need for derivatization. Interestingly, most of the fragments contained calcium in their elemental formula. Evidence for Palytoxin tendency to form adduct ions with calcium and other divalent cations in its mass spectra was obtained. Fragmentation pattern of Palytoxin was used as template to gain detailed structural information on ovatoxin-a, the main toxin produced by Ostreopsis ovata, (observe correct font) a benthic dinoflagellate that currently represents the major harmful algal bloom threat in the Mediterranean area. Either the regions or the specific sites where ovatoxin-a and Palytoxin structurally differ have been identified.
