
Patrizia Ciminiello- MD, PhD
- Professor (Full) at University of Naples Federico II
Patrizia Ciminiello
- MD, PhD
- Professor (Full) at University of Naples Federico II
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154
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Introduction
Skills and Expertise
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August 1982 - present
Publications
Publications (154)
Palytoxin (PLTX) and its congeners are emerging toxins held responsible for a number of human poisonings following the inhalation of toxic aerosols, skin contact, or the ingestion of contaminated seafood. Despite the strong structural analogies, the relative toxic potencies of PLTX congeners are quite different, making it necessary to isolate them...
Blooms of the toxic dinoflagellates Ostreopsis have become common along rocky shores of the Mediterranean Sea. In addition to health problems for beach-goers, Ostreopsis toxins may accumulate in benthic marine animals used for human consumption, which however at times have shown signals of stress and even mortality. In order to elucidate the actual...
Fifty-five strains of Ostreopsis were collected in the Mediterranean Sea and analysed to characterize their toxin profiles. All the strains were grown in culture under the same experimental conditions and identified by molecular PCR assay based on the ITS-5.8S rDNA. A liquid chromatography-high resolution multiple stage mass spectrometry (LC-HRMSn)...
Azadinium dexteroporum is the first species of the genus described from the Mediterranean Sea and it produces different azaspiracids (AZA). The aims of this work were to characterize the toxin profile of the species and gain structural information on azaspiracids produced by the A. dexteroporum strain SZN-B848 isolated from the Gulf of Naples. Liqu...
Palytoxin (PLTX) is a lethal natural toxin often found in Palythoa zoantharians that, together with its congeners, may induce adverse effects in humans after inhalation of toxic aerosols both in open-air and domestic environments, namely in the vicinity of public and private aquaria. In this study, we describe a poisoning of an aquarium hobbyist wh...
The new benthic toxic dinoflagellate, Ostreopsis fattorussoi sp. nov., is described from the Eastern Mediterranean Sea, Lebanon and Cyprus coasts, and is supported by morphological and molecular data. The plate formula, Po, 3 0 , 7″, 6c, 7s, 5‴, 2 0000 , is typical for the Ostreopsis genus. It differs from all other Ostreopsis species in that (i) t...
http://authors.elsevier.com/a/1TNWC5aloFCBTG
The dinoflagellate Ostreopsis cf. ovata proliferates seasonally in the Mediterranean Sea, producing
palytoxin-like compounds (ovatoxins) which are considered among the most potent marine toxins.
Blooms have been related to several toxic events in which respiratory problems in humans and mortality
of bent...
This study provides the first evaluation of the cytotoxic effects of the recently-identified palytoxin (PLTX) analog, ovatoxin-a (OVTX-a), the major toxin produced by Ostreopsis cf. ovata in the Mediterranean Sea. Its increasing detection during Ostreopsis blooms and in seafood highlights the need to characterize its toxic effects and to set up app...
Anecdotal reports exist of aquarium hobbyists that experienced severe respiratory distress and/or skin injury following cleaning operation of home aquaria containing Palythoa sp. soft corals. Hundreds of cases of respiratory illness and/or dermatitis have been recorded in proximity to the sea concomitantly with algal blooms of Ostreopsis spp. in th...
Blooms of benthic dinoflagellates of the genus Ostreopsis (mainly O. cf. ovata and occasionally O. cf. siamensis) represent a serious concern for humans in the Mediterranean area, due to production of palytoxin-like compounds listed among the most potent marine toxins known. In this work, six strains of Ostreopsis sp. from Cyprus Island were analyz...
Paralytic shellfish poisoning (PSP) is a serious human illness caused by the ingestion of seafood contaminated with saxitoxin and its derivatives (STXs). These toxins are produced by some species of marine dinoflagallates within the genus Alexandrium. In the Mediterranean Sea, toxic Alexadrium spp. blooms, especially of A. minutum, are frequent and...
The palytoxin-group toxins are complex polyhydroxylated compounds with both lipophilic and hydrophilic areas. The parent compound, palytoxin, was first isolated from a zoanthid, Palythoa toxica, in 1971. This toxin and its analogues were subsequently reported in other living organisms including algae, crabs, fishes, bacteria, and mainly in benthic...
Blooms of the benthic dinoflagellate Ostreopsis cf. ovata are a concern in the Mediterranean Sea, since this species produces a wide range of palytoxin-like compounds listed among the most potent marine toxins. This study focused on two analogs of palytoxin found in cultures of six strains of O. cf. ovata isolated from the south of Catalonia (NW Me...
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...
Ostreopsis cf. ovata is a harmful benthic dinoflagellate, widespread along most of Mediterranean coasts. It produces several toxins and variable amount of mucus that may totally cover substrates, especially during the stationary phase of blooms, in which cells are aggregated. Studies on different aspects of the biology and ecology of Ostreopsis spp...
The genus Ostreopsis Schmidt includes harmful benthic species that have been reported worldwide in both tropical and temperate regions. To date, genetic studies confirmed the presence of two genotypes corresponding to the morphotypes of O. cf. ovata and O. cf. siamensis in the Mediterranean Sea; recently a new genotype of Ostreopsis sp. was found a...
This study describes for the first time, toxic effects and chemical-molecular aspects of the Cypriot genotype of Ostreopsis sp. (marine free-living dinoflagellates).
The dinoflagellate Alexandrium minutum is known for the production of potent neurotoxins affecting the health of human seafood consumers via paralytic shellfish poisoning (PSP). The aim of this study was to investigate the relationship between the toxin content and the expression level of the genes involved in paralytic shellfish toxin (PST) produc...
Harmful Algal Blooms (HABs) are massive proliferations of toxic algal species that occur under appropriate climatic and environmental conditions. HABs can exert their adverse impacts both on the environment and on particular living organisms through the production of marine biotoxins. Consumption of contaminated seafood or direct exposure to marine...
Since the late 1990's, a respiratory syndrome has been repetitively observed in humans concomitant with Ostreopsis spp. blooms (mainly O. cf. ovata) in the Mediterranean area. Previous studies have demonstrated that O. cf. ovata produces analogues of palytoxin (ovatoxins and a putative palytoxin), one of the most potent marine toxins. Based on the...
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 t...
More than forty years after its isolation, the understanding of how palytoxin interacts with biological systems has yet to be fully determined. Na+, K+-ATPase pump constitutes a molecular receptor for palytoxin that is able to convert the pump into an open channel, with consequent loss of cellular K+ and remarkable rise of cytosolic Na+ levels. In...
The harmful dinoflagellate Ostreopsis cf. ovata has been causing toxic events along the Mediterranean coasts and other temperate and tropical areas, with increasing frequency during the last decade. Despite many studies, important biological features of this species are still poorly known. An integrated study, using different microscopy and molecul...
Blooms of Ostreopsis spp. once confined to tropical and subtropical areas have recently spread to more temperate regions such as the Mediterranean and the Southern-Atlantic coasts of Europe. However, while O. confronta (cf.) ovata has caused several toxic outbreaks, the presence of O. cf. siamensis has been reported rather occasionally and in very...
Ostreopsis cf. ovata depigmented cells stained with Nile Red. Cells were fixed with 2% paraformaldehyde (5 min at RT), depigmented upon washing 3 times with an 1∶1 acetone:hexane solution for 5 min and stained with Nile Red. Bright field microscopy (A,C); epifluorescence microscopy (B,D). Cells show a weak red and yellow orange fluorescence. Strong...
Raman maps depicting poly-unsaturated lipids and starch concentration of fixed and depigmented O. cf. ovata cells in the stationary and senescence phases. Raman maps depicting poly-unsaturated lipid concentration based on the un-normalized intensity at 1559 cm−1 of a fixed and depigmented O. cf. ovata cell in the stationary (a) and in the senescenc...
The Northern Adriatic Sea is the area of the Mediterranean Sea where eutrophication and episodes related to harmful algae have occurred most frequently since the 1970s. In this area, which is highly exploited for mollusk farming, the first occurrence of human intoxication due to shellfish consumption occurred in 1989, nearly 10 years later than oth...
Proliferation of the benthic dinoflagellates Ostreopsis spp. are reported in many tropical and
temperate regions worldwide. In the last decade, blooms of O. cf. ovata have become
increasingly frequent in the Mediterranean Sea, as well as other tropical and temperate areas
worldwide, and resulted in relevant benthic biocenosis sufferings and huma...
Ovatoxin-a is the main toxin produced by Ostreopsis ovata, a benthic dinoflagellate that has bloomed massively across the Mediterranean basin over the past years, inflicting both human and environmental suffering. Ovatoxin-a has recently been isolated from cultures of O. ovata and structurally identified as an analogue of palytoxin: in comparison w...
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 inter...
Bacteria associated to benthic dinoflagellate Ostreopsis cf. ovata cultures were removed to assess their effects on algal growth and toxins' production. Bacteria were removed using an antibiotic cocktail (streptomycin, ciprofloxacin, gentamicin and penicillin G). The actual axenic status of antibiotic treated cultures and bacterial growth in contro...
Mass appearances of the toxic dinoflagellate genus Ostreopsis are known to cause dangerous respiratory symptoms in humans exposed to aerosols. The outbreaks can appear in shallow marine waters of temperate regions around the globe. We followed a massive bloom event on a public beach on the northern Adriatic coast near Rovinj, Croatia. We identified...
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...
There may be biogeographic aspects of interactions between toxic phytoplankton and their zooplankton
grazers. Grazers that naturally co-occur with a given species of toxic phytoplankton may have evolved
mechanisms to counteract adverse effects of phytoplankton toxins. Conversely, grazers that have no coevolutionary
experience with a toxic phytoplan...
Ostreopsis cf. ovata is an epiphytic/benthic dinoflagellate that produces palytoxin-like compounds (putative palytoxin, ovatoxin-a, -b, -c, d and -e). Here we report on effects of nitrogen (N) and phosphorous (P) limited conditions on cell growth, cell size, biovolume, and toxin production of an O. cf. ovata strain isolated from the Adriatic Sea (I...
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 thi...
Since 2005, the benthic dinoflagellate Ostreopsis cf. ovata has bloomed across the Mediterranean basin, provoking serious toxic outbreaks. LC/MS studies have identified a number of palytoxin-like compounds, termed ovatoxins, along with trace amounts of putative palytoxin as the causative agents of the O. cf. ovata -related human sufferings. So far,...
Once believed to affect only scattered areas of the world, nowadays, harmful algal blooms (HAB) plague virtually any coastal area of the planet. Usually caused by a pool of microalgae, HAB-related outbreaks not only harm human health but wreak havoc on maritime economy. Over the past decades, following the steadily increase of human poisonings, an...
In the Mediterranean Sea, blooms of Ostreopsis cf. ovata and Ostreopsis siamensis have become increasingly frequent in the last decade and O. cf. ovata was found to produce palytoxin-like compounds (putative palytoxin, ovatoxin-a, -b, -c, -d and -e), a class of highly potent toxins. The environmental conditions seem to play a key role in influencin...
Intense blooms of the benthic dinoflagellate Ostreopsis cf. ovata have occurred in the northern Adriatic Sea since 2006. These blooms are associated with noxious effects on human health and with the mortality of benthic organisms because of the production of palytoxin-like compounds. The O. cf. ovata bloom and its relationships with nutrient concen...
Proliferation of the benthic dinoflagellates Ostreopsis spp. are reported in many tropical and temperate regions worldwide. In the last decade, blooms of O. cf. ovata have become increasingly frequent in the Mediterranean Sea and resulted in relevant benthic biocenosis sufferings and human health problems. Besides putative palytoxin, new compounds,...
Ostreopsis cf. ovata, a benthic dinoflagellate often blooming along the Mediterranean coasts, has been associated with toxic events ranging from dyspnea to mild dermatitis. In late September 2009, an Ostreopsis cf. ovata bloom occurred in the Gulf of Trieste (Northern Adriatic Sea; Italy), causing pruritus and mild dermatitis in beachgoers. An inte...
Blooms of Ostreopsis spp. have been recently reported along the Mediterranean coasts of Spain, France, Italy, and Greece posing serious risks to human health. Occurrence of Ostreopsis spp. may result in palytoxin contamination of seafood and, in order to prevent sanitary risks, the need exists to develop efficient extraction procedures to be couple...
Six new nitrogenous sesquiterpenes (1–6), which form two new isocyanide-isothiocyanate-formamide series, have been isolated from the marine sponge Axinellacannabina. The structure elucidation of these compounds is based upon spectral data, including 2D-nmr, and chemical interconversions. The complete assignment of all proton and carbon resonances i...
The acute oral toxicity of a new palytoxin congener, 42-hydroxy-palytoxin (42-OH-PLTX), was investigated in female CD-1 mice. The toxin (300-1697 μg/kg), administered by gavage, induced scratching, jumping, respiratory distress, cyanosis, paralysis and death of mice, with an LD₅₀ of 651 μg/kg (95% confidence limits: 384-1018 μg/kg) within 24 h. Hem...
Palytoxins are a class of extremely potent non-proteic marine biotoxins, whose main biological target is the Na+/K+-ATPase. Since its isolation in 1971 from samples of Hawaiian Palythoa spp., palytoxin has drawn scientists’ attention from across the world because of its high toxicity, intriguing chemical structural
architecture, and involvement in...
Alexandrium ostenfeldii is a widespread toxic dinoflagellate that has recently bloomed across the Adriatic Sea, seriously threatening both shellfish consumers and aquacultures. In 2007 we reported on preliminary studies carried out on field samples and cultures of A. ostenfeldii. At the time, along with three major spirolides - among which 27-hydro...
The state of the art of LC-MS of palytoxin and its analogues is reported in the present review. MS data for palytoxin, 42-hydroxy-palytoxin, ostreocin-D, mascarenotoxins, and ovatoxins, obtained using different ionization techniques, namely fast-atom bombardment (FAB), matrix assisted laser desorption ionization (MALDI), and electrospray ionization...
Around the turn of the century, blooms of O. ovata have become very popular among scientists and the general public. Besides pathological problems in beach-goers, signals of stress and/or mortality have been detected in benthic organisms during blooms, while toxins have been shown to accumulate in marine animals used for human consumption (Rhodes e...
Over the past decades, Italian coastlines have been plagued by recurring presence of the benthic dinoflagellate Ostreopsis ovata. Such an alga has caused severe sanitary emergencies and economic losses due to its production of palytoxin-like compounds. Previous studies have confirmed the presence of ovatoxin-a (OVTX-a) as the major toxin of the alg...
Since its isolation dated back to as far as 1971, palytoxin has all along drawn scientists’ attention from across the world because of its high toxicity and fascinating chemical architecture. Commitment of the international scientific community to the study of this extremely potent non-proteic toxin has led to discover quite a number of palytoxin a...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Marine toxins from harmful algae are listed among the most important causative agents of poisoning episodes, occasionally involving seafood consumers. These toxins normally occur in small quantities and do not pose any serious problem to public health. Proliferations of harmful algae may mostly happen as massive “red tides” or blooms of cells capab...
This paper reports on the analysis of the toxin content from Palythoa tuberculosa and Palythoa toxica samples collected off of the Hawaiian coast. Our work, based on in-depth high-resolution liquid chromatography−mass spectrometry analysis along with extensive NMR study, led us to structurally characterize 42-hydroxy-palytoxin, a new palytoxin cong...
The relative stereochemistry of 13,19-didesmethyl spirolide C was determined through careful analysis of NMR parameters strongly dependent upon molecular conformations supported and extended by computational studies. This work has also shed light on the conformational behavior of spirolides in solution. An equilibrium between two possible conformer...
This paper reports on the determination of toxin profile of mussels (Mytilus galloprovincialis) collected in November-December 2003 along the Emilia Romagna coasts (Italy) when a high concentration of Alexandrium ostenfeldii cells was detected in seawater. Detailed liquid chromatography-mass spectrometry (LC-MS) analyses were performed on the crude...
Massive blooms of the benthic dinoflagellate Ostreopsis ovata Fukuyo have recently occurred along the whole Italian coastlines, both Tyrrhenian and Adriatic, resulting sometimes in benthonic biocenosis sufferings and, occasionally, in human health problems. In this work, two strains of O. ovata collected in 2006 along the Adriatic and Tyrrhenian co...
The north-western coasts of the Adriatic sea have long been subjected to recurring cases of harmful algae blooms and concomitant mussel contamination. In 1995, yessotoxins (YTXs) were detected for the first time in Adriatic mussels and their presence was subsequently linked to the presence of Protoceratium reticulatum and occasionally Lingulodinium...
In this article we report on the liquid chromatography tandem mass spectrometry (LC-MS) investigation of plankton samples collected in the summer of 2006 along the Ligurian coasts, coinciding with a massive bloom of the tropical microalga Ostreopsis ovata. LC-MS analyses indicated the occurrence of putative palytoxin along with a much more abundant...
Yessotoxins (YTXs) represent a group of polycyclic ether compounds, structurally closely related to brevetoxins and ciguatoxins. Several reviews on this topic have been previously published. Most of them report on YTXs within a wider survey including other biotoxins;1-6 a review focused on the occurrence, detection, chemistry, and pharmacology of Y...
This paper reports on the determination of the toxin profile of batch cultures of Alexandrium ostenfeldii established from water samples collected along the Emilia-Romagna coasts (Italy) in November 2003. Combined use of LC-MS/MS and 1D and 2D NMR techniques led us to identify 13,19-didesmethylspirolide C and 13-desmethylspirolide C as products of...
Two oxazinins, namely oxazinin-5 and -6, along with a related linear precursor (preoxazinin-7) were isolated from toxic mussels collected along the Northern Adriatic coasts in October 2005. Determination of the planar structure of these novel compounds was achieved through extensive NMR spectroscopic analysis, whereas a synthetic approach was cruci...
The toxic dinoflagellate Protoceratium reticulatum (Claparède & Lachmann) Buetschli is recurrently present in the Adriatic sea. It is the producing organism of yessotoxin (YTX) and some of its analogues and thus its presence in seawater often results in shellfish farm closure for long periods. However, molluscs become highly toxic also at the prese...
Two new desulfated yessotoxin (YTX) analogues were isolated from a toxic batch of Adriatic mussels collected in October 2004. Their stereostructures were elucidated through extensive NMR and MS-based analysis. The finding of these desulfocarboxyhomoYTXs in shellfish poses additional problems to those institutions entitled to control seafood safety,...
The analysis of a batch of toxic mussels (Mytilus galloprovincialis) from the Northern Adriatic Sea led to the isolation of a novel oxazinin, oxazinin-4. Its structure including the relative stereochemistry has been elucidated through extensive NMR analysis. A synthetic route to oxazinins has been crucial in establishing the absolute stereochemistr...
Molluscs of many sorts, which are high in protein and trace minerals, have always been a substantial portion of the human
diet. A great variety of mollusc species are therefore of commercial importance throughout the world. Episodes of poisoning
occasionally happen to the consumers of molluscs, the main hazard being represented by bivalve molluscs....
A new method for sensitive, specific, and direct determination of palytoxin is proposed herein. It is based on combination of reversed-phase liquid chromatography with mass spectrometry (LC-MS). The new method was set up on a turbo ion spray-triple quadrupole MS instrument operating in selected ion monitoring (SIM) and multiple reaction monitoring...
This paper reports on the first occurrence of fairly high numbers of Alexandrium ostenfeldii along the Emilia Romagna coasts (Italy). Detailed liquid chromatography-mass spectrometry (LC-MS) analyses of the toxin profile were performed on a strain of the organism collected in November 2003, isolated during the event and grown in culture. Selected i...
Samples of Mytilus galloprovincialis were harvested from five different locations in Thermaikos gulf, Greece after harmful algae bloom. All of the mussel samples were found positive by mouse bioassay for diarrhetic shellfish poisoning (DSP) toxins. Liquid chromatography (LC) coupled with mass spectrometry (MS) was used to search for the following l...
Molluscs of many sorts, which are high in protein and trace minerals, have always been a substantial portion of the human diet. A great variety of mollusc species are therefore of commercial importance throughout the world. Episodes of poisoning occasionally happen to the consumers of molluscs, the main hazard being represented by bivalve molluscs....
This paper describes a new method for sensitive, specific and direct determination of domoic acid (DA), the causative toxin of amnesic shellfish poisoning (ASP) syndrome, in shellfish. It is based on combination of hydrophilic interaction liquid chromatography with mass spectrometry (HILIC/MS). The high percentage of organic modifier in the mobile...
A detailed analysis of toxic shellfish collected in the Adriatic sea in October 2000 allowed us to isolate a new cytotoxic chlorosulfolipid (3). Its gross structure has been elucidated through an extensive NMR analysis including various 2D techniques; the relative stereochemistry has been solved by applying the Murata's method. Compound 3 showed to...
The structure-activity relationship of yessotoxins (YTX) has been probed by measuring the potency of several YTX analogues to cause the accumulation of a 100 kDa MW fragment of E-cadherin in MCF-7 breast cancer cells. Under our experimental conditions, the EC(50) of YTX, the reference compound, was 0.55 nM. The introduction of a methylene unit adja...
During our investigation on toxic mussels from the Northern Adriatic sea, initiated about ten years ago, a number of polyether toxins have been isolated and characterized, some of which represent new additions to the diarrhetic shellfish poisoning (DSP) class of biotoxins and seem to be specific to the Adriatic. In addition, we have also isolated n...
From a further investigation of the extracts from the marine sponge Axinella cannabina, three novel sesquiterpenes based on the epi-maaliane skeleton, carrying an isonitrile, isothiocyanate, or formylamino function were isolated in addition to bicyclogermacrene (4), and their structures determined on the basis of chemical and spectroscopic evidence...
The structure of (22E)-cholesta-4,6,8(14),22-tetraen-3-one [1], isolated from the Demospongia Dictyonella incisa, has been elucidated by spectroscopic analyses (1H-nmr, uv, ir, and ms), and confirmed via synthesis.
A detailed analysis of the secondary metabolites of a sponge, Verongula sp., has been performed. Eleven compounds have been identified, of which two (10a and 11) are novel bromotyrosine derivatives. Structural assignments of the brominated compounds 10a and 11 were based on spectroscopic analysis.
The diarrhetic poisoning by bivalve molluscs, diarrhetic shellfish poisoning, is due to consumption of mussels containing biotoxins produced by some Dinoflagellate species. Toxic effects of yessotoxin (YTX) include morphological alterations of mitochondria from heart and liver but the biochemical basis for these alterations is completely unknown. T...