Dinoflagellate Phycotoxins: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Pharmacology & Pharmacy
Contributor:
Kichul Cho

Dinoflagellates are single-celled eukaryotes constitute an important group of phytoplanktons, characterized by two dissimilar flagella and distinctive features of both plants and animals.

  • harmful algal bloom
  • dinoflagellate
  • phycotoxin
  • algae
  • metabolite
  • toxin
  • toxicity

1. Introduction

Microalgae are photosynthetic microorganisms belonging to diverse phyla [1]. Over the past few decades, several green microalgae, such as Chlorella spp., Scenedesmus spp., and Dunaliella spp., have been recognized as useful bioresources for producing commercial materials, namely cosmetics, pharmaceuticals, dietary supplements, biofuels, and biofertilizers [2][3][4][5][6][7]. In contrast, phycotoxin-producing cyanobacteria, dinoflagellates, and raphidophytes are known to generate frequent harmful algal blooms (HABs), thereby causing severe losses to the fishing industry and aquatic ecosystem [8][9][10][11]. For instance, Lake Erie in the United States is a well-recognized recreational place, but the ecosystem services are under threat owing to cyanobacterial-generated HABs. The annual economic loss of fishing expenditures in Lake Erie was estimated to be approximately USD 2.25–5.58 million during bloom formation [12]. Additionally, massive HABs caused by the dinoflagellate Karenia mikimotoi resulted in a mass mortality of abalones, with a loss of over USD 290 million in China [11].

Several factors that cause the death of aquatic organisms have been reported, including direct reactive oxygen species production, phycotoxins, and bioactive fatty acids generation [13]. For instance, the raphidophyte Chattonella marina produces superoxide anion via an NAD(P)H oxidase-related mechanism [14], and cyanobacterial species, including Anabaena spp. and Microcystis spp., produce cellular microcystin, which has previously demonstrated human hepatotoxicity via bioaccumulation in the food chain [15]. Among the algal taxa, dinoflagellate is considered a major HAB-forming group, which causes red tide in coastal areas. Many dinoflagellate species show a mixotrophic nature, practicing both photosynthesis and prey ingestion simultaneously [16]. Furthermore, many species produce phycotoxins, such as saxitoxins (STXs), hemolysins (HL), and yessotoxins (YTX), which exhibit intrinsic modes of action. Although managing and monitoring dinoflagellates has been under the spotlight for the past few decades, industrial applications of phycotoxins have not garnered much attention.

2. Effects of HABs Produced by Dinoflagellates

Dinoflagellates are unicellular eukaryotes belonging to phylum Dinoflagellata. Many of its species cause red tide in coastal areas, which significantly damages aquatic life and causes paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), diarrhetic shellfish poisoning (DSP), and ciguatera in humans worldwide [10][11][17][18][19][20]. There are more than 2000 identified dinoflagellate species, and they exhibit distinct characteristics, including those of the autotrophs, heterotrophs, and mixotrophs [21]. Morphological characteristics of dinoflagellates include two dissimilar flagella arising from the ventral cell side. These organisms are capable of producing diverse phycotoxins and render HAB-derived damage [22]. During the 1990s, Cochlodinium spp. (mostly C. polykrikoides and C. fulvescens) caused damage to the fishing industry with an estimated annual loss of more than USD 100 million in South Korea [23][24]. Out of these, C. polykrikoides caused an economic loss of approximately USD 69.5 million in 1995. Moreover, a massive bloom of the dinoflagellate Karlodinium digitatum caused approximately USD 32 million damage to the fishing industry of Hong Kong [11]. Additionally, K. mikimotoi caused a massive economic detriment of more than USD 290 million to the fishing industry in China in 2012 [11].

Harmful effects of dinoflagellate-generated HABs associated with other organisms have been extensively investigated over the past few decades. For instance, Chen et al. reported that a polar lipid-soluble component derived from K. mikimotoi extract inhibited proliferation, disrupted cell membrane, and increased lipid peroxidation (increased malondialdehyde content) in mammalian cells [25]. Further, the addition of K. concordia extract induced anesthesia in brine shrimp [26] and the PSP (e.g., STX)-producing Alexandrium fundyense consumed by copepods was lethal to fish [27].

However, biotoxins derived from diverse organisms have potential applications. In particular, botulinum toxin produced by the bacterium Clostridium botulinum is widely used for the treatment of migraine headaches, muscle spasticity, and other muscle disorders [28][29][30]. Additionally, pufferfish-derived tetrodotoxin is therapeutically used to manage acute heroin withdrawal syndrome and alleviate cancer pain [31][32]. These biotoxins have specific modes of action, and they have potential and extensive industrial applications. Although a lot of phycotoxins derived from dinoflagellates have been extensively studied, their industrial application based on their specific modes of action is still poorly understood.

3. Dinoflagellate Phycotoxins and Their Modes of Action

Table 1 summarizes the reported dinoflagellate-produced phycotoxins. Alexandrium spp. are considered PSP-producing harmful organisms. The causative paralytic toxins of Alexandrium spp. include STX, gonyautoxin (GTX), neosaxitoxin (NSTX), and HL [33][34][35][36]. Among these, STXs are well-known marine algal toxins that block the cellular sodium channel. STX is included in the guanidinium neurotoxin group, sharing the common chemical feature of guanidinium moieties and interacting with voltage-gated sodium channels with high binding affinity and ion flux blockage capacity. This blockage induces the reduced influx of Na+ ions into a cell and causes inhibition of the propagation of action potentials in excitable membranes. This process ultimately induces neuromuscular paralysis [37]. The symptoms of PSP induced by STX and its analogue, NSTX, include numbness of the lips and gastrointestinal disorders [35]. Lefebvre et al. [34] reported that measurable levels of STX were detected in both field and cultured Alexandrium spp. using a receptor-binding assay and enzyme-linked immunosorbent assay. The structure and analogues of STX were previously well-described by Wiese et al. [38]. Gymnodinium catenatum and Pyrodinium bahamense produce STXs as well [39][40]. Landsberg et al. [40] reported that the source of STXs detected in pufferfish skin, muscle, and viscera was putatively derived from P. bahamense. In addition, Sako et al. [39] purified and characterized sulfotransferase-specific STX analogues from the cytosolic fraction of G. catenatum. GTXs influence the mammalian nervous system by binding to site 1 of the α-subunit of the voltage-dependent sodium channel in the postsynaptic membrane, thereby preventing synaptic function [41].

Table 1. List of phycotoxins derived from diverse dinoflagellates and their modes of action.

Dinoflagellate Toxins Mode of Action References
Alexandrium spp. Saxitoxin (STX) Inhibits sodium channel [34][35]
Gonyautoxin (GTX) Inhibits sodium channel [33][35][36]
Neosaxitoxin (NSTX) Inhibits sodium channel [35][36]
Haemolysin (HL) Hydrolyses phospholipids in the bilayer [36][42]
Form pores in phospholipid bilayers
Amphidinium carterae Haemolysin (HL) Hydrolyses phospholipids in the bilayer [33][36]
Forms pores in phospholipid bilayers
Azadinium spinosum Azaspiracids (AZA) Blocks hERG (human ether-a-go-go related gene) potassium channel by binding to it [43]
Cochlodinium polykrikoides Haemolysin (HL) Hydrolyses phospholipids in the bilayer [36][44][45]
Forms pores in phospholipid bilayers
Coolia spp. Cooliatoxin (CTX) Blocks unmyelinated nerves [36][46]
Yessotoxin (YTX) Activates calcium channel [47][48][49][50]
Decreases cytosolic 3′,5′-cyclic adenosine monophosphate (cAMP) levels
Dinophysis spp. Okadaic acid (OA) Inhibits protein phosphatases (serine/threonine phosphatases) [51][52][53][54][55]
Dinophysistoxin (DPX) Inhibits protein phosphatases (serine/threonine phosphatases) [56]
Pectenotoxin (PTX) Inhibits protein phosphatases (serine/threonine phosphatases) [35][57][58][59]
Depolymerizes actin filaments
Disrupts actin cytoskeleton
Gambierdiscus toxicus Maitotoxin (MTX) Activates calcium channel [60]
Gonyaulax spp. Haemolysin (HL) Hydrolyses phospholipids in the bilayer [46]
Forms pores in phospholipid bilayers
Yessotoxin (YTX) Activates calcium channel [49][50][61]
Decreases cytosolic 3′,5′-cyclic adenosine monophosphate (cAMP) levels
Gymnodinium catenatum Saxitoxin (STX) Inhibits sodium channel [39]
Heterocapsa circularisquama Haemolysin (HL) Hydrolyses phospholipids in the bilayer [48]
Forms pores in phospholipid bilayers
Karlodinium spp. Karmitoxin (KTX) Unknown (Ichthyotoxic) [62][63]
Karlotoxin (KmTx) Disrupts cell membrane by specific binding to cholesterol [63][64]
Karenia mikimotoi Brevetoxin (PbTx) Activates voltage-gated sodium channels [20][65][66]
Gymnocin (GC) Unknown [67][68]
Haemolysin (HL) Hydrolyses phospholipids in the bilayer [69]
Forms pores in phospholipid bilayers
Lingulodinium polyedrum Yessotoxin (YTX) Activates calcium channel [49][50][70]
Decreases cytosolic 3′,5′-cyclic adenosine monophosphate (cAMP) levels
Ostreopsis spp. Palytoxin (PLTX) Turns Na+/K+ pump into a shape that allows the passive transport of sodium and potassium ions [36][71][72]
Prorocentrum spp. Okadaic acid (OA) Inhibits protein phosphatases (serine/threonine phosphatases) [35][36][73]
Depolymerizes actin filaments
Induces apoptosis through suppression of the nuclear factor ƙB signaling pathway
Dinophysistoxin (DPX) Inhibits protein phosphatase [56][74]
Prorocentrolides (PC) Acts on nicotinic acetylcholine receptors (nAChRs) [75]
Borbotoxin (BTX) Blocks postsynaptic nAChRs [76]
Protoceratium reticulatum Yessotoxin (YTX) Activates calcium channel [49][70]
Decreases cytosolic adenosine 3′,5′-cyclic monophosphate (cAMP) levels
Pyrodinium bahamense Saxitoxin (STX) Blocks sodium channel [40]

Altered hemolytic activity of A. peruvianum under different nutrient ratios indicated the presence of cellular HL [42]. Although the modes of action of dinoflagellate HL are poorly understood and algal species-specific, a possible mechanism could be the hydrolysis of phospholipids and subsequent pore formation in phospholipid bilayers, a mechanism similar to other hemolytic toxins [77][78]. Modes of action of HLs detected in Amphidinium carterae, C. polykrikoides, Heterocapsa circularisquama, K. mikimotoi, and Gonyaulax monilata are described briefly in Table 1 [77][78][77][78].

Azadinium spinosum produces azaspiracids (AZA), a group of toxic lipophilic polyether compounds. This toxin caused human intoxication symptoms, such as nausea, vomiting, severe diarrhea, and stomach cramps in a study conducted in the Netherlands [43][79]. AZA was originally believed to be a toxic compound produced by Protoperidinium crassipes [80]. However, it was later demonstrated that the toxins in P. crassipes were a consequence of its feeding on the dinoflagellate A. spinosum, which was in turn reported to be the source of the AZA [81]. This toxin causes damage to the intestinal epithelium, lamina propria, liver, and villi as an acute toxic effect, and causes lung tumors and malignant lymphomas at high concentrations with long-term exposure [82][83][84]. AZAs include more than 30 analogues, and among these, only AZA1, AZA2, and AZA3 are currently regulated in edible shellfish by the European Union through their toxic equivalency factors (TEFs) [85]. It exhibited its action by blocking the human ether-a-go-go-related gene (hERG) potassium channel [86]. AZA interacts with the channel’s central pore (F656) within the S6 transmembrane domain and physically blocks the potassium-conductance pathway of the hERG1 channels [86]. Pelin et al. [87] previously reported that the exposure of immortalized human hepatocyte (IHH) cell line to AZA analogues induced mitochondrial electron transport chain complex-dependent mitochondrial dehydrogenases activity (MDA) in a concentration-dependent manner. The MDA was suppressed in the K+, Cl−, and Na+ free media, and by specific inhibitors of KATP (glibenclamide), hERG potassium channels (cisapride), Na+/K+, ATPase (ouabain), and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels (CFTR(inh)-172). These results revealed that the AZA-induced MDA is derived from an imbalance of intracellular levels of K+ and Cl− ions [87]. The toxic effects, structure, and analogues of AZA were well-described in previous studies [79][88][89][90][91][92].

Another dinoflagellate genus, Coolia, produces cooliatoxin (CTX) and YTX [46][47]. Holmes et al. [46] purified a novel toxin from C. monotis isolated from Australia and named it CTX. This toxin is considered a monosulfate polyether analogue of YTX and caused initial blockage of unmyelinated nerves in vitro, as reported by Holmes et al. [46]. Additionally, sulfated polyether analogues of YTX have been detected in C. malayensis through chemical analysis using NanoLiquid chromatography–mass spectrometry [47]. YTX is a diarrhea-causing toxin and exhibits its toxicity by activating nifedipine and the SKF-96365 sensitive calcium channel [49], and by decreasing cytosolic 3′,5′-cyclic adenosine monophosphate (cAMP) levels [50]. YTX-producing dinoflagellates include Gonyaulax spinifera, Lingulodinium polyedrum, and Protoceratium reticulatum [61][70]. The structure and analogues of YTX were previously well-described by Paz et al. [93].

Karlodinium armiger produces karmitoxin (KTX), which is an amine-containing polyhydroxy-polyene toxin [63]. Although its specific mode of action is not yet identified, ichthyotoxic effects of this toxin toward fish larvae and juveniles have been demonstrated recently [94]. The structure of KTX was previously reported by Rasmussen et al. [63]. Additionally, Karlodinium spp. produces karlotoxin (KmTx), which is structurally similar to amphidinols and is the causative toxin for membrane permeabilization [64]. KmTx is produced by K. armiger and K. veneficum, and its mode of mechanism is the disruption of the cell membrane by specifically binding to cholesterol [63]. The structure and several analogues of KmTx were reported by Van Wagoner et al. [95].

Dinophysis is a medium-sized dinoflagellate that produces DSP toxins, including okadaic acid (OA), pectenotoxin (PTX), and dinophysistoxin (DPX) [36][54]. OA is a polyether fatty acid, and its structure is highly similar to that of acanthifolicin [52]. DPXs are considered analogues of OA, whereas PTXs are a type of polyether lactones [96][97]. The mode of action of OA and DPXs is an inhibition of the serine/threonine (Ser/Thr) phosphatases that further induces tumor growth promotion and neuronal cell death [52][53][98][99]. The structures and analogues of OA and DPX were previously reported by Uchida et al. [100] and Fernandez et al. [101]. PTXs demonstrate diverse physiological functions, including inhibiting Ser/Thr phosphatases, depolymerizing actin filaments, and disrupting the actin cytoskeleton [35][36][57][58][59]. According to Espiña et al. [102], marked depolymerization of F-actin, associated with an improved G-actin level in hepatocyte cell line by PTX-1, PTX-2, and PTX-11 (1–1000 nM) treatments, was observed via confocal image analysis. However, no activity was observed by treatment with PTX-2 seco acid (PTX-2 SA), which is an enzymatically digested derivative of PTX-2 [102]. PTXs were initially classified into the DSP-producing group; however, mice toxicity tests confirmed that this toxin does not induce diarrheic symptoms but causes severe hepatotoxicity [103]. Specifically, Miles et al. [104] previously developed an effective method to isolate pectenotoxins from dinoflagellate cells, and they showed isolated PTX-2 caused acute toxicity in mice, whereas its derivative, PTX-2 SA, had no effect at 5000 µg/kg. Additionally, no diarrhea was observed in mice receiving either PTX-2 or PTX-2 SA treatments [104]. The structures and analogues of PTXs were previously described by Allingham et al. [57] and Wilkins et al. [105]. OA can be produced by dinoflagellates D. acuta, D. acuminate, D. fortii, Prorocentrum concavum, P. rhathymum, P. belizeanum, P. lima, and P. arenarium [106][107][108][109]. DPXs are produced by D. acuta, D. acuminate, P. foraminosum, and P. lima [74][110][111][112], whereas PTXs are produced by D. fortii, D. acuta, D. acuminate, and D. caudata [109][113][114].

Gambierdiscus toxicus produces ciguatera-inducing maitotoxin (MTX) [115]. Holmes and Lewisk purified G. toxicus-derived distinct MTXs using high-pressure liquid chromatography and reported that these compounds caused contractile responses of the muscle [105]. MTX is considered one of the largest natural products (3422 Da) that can activate cellular calcium channels [60][116]. Takahashi et al. [60] showed the association of increased calcium influx and calcium-dependent release of [3H] norepinephrine in a pheochromocytoma cell line. Their findings indicated that MTX’s mode of action is the activation of cellular calcium channels. The structures and analogues were previously described by Reyes et al. [117].

Karenia spp. dinoflagellates, including K. brevis and K. mikimotoi, are well-recognized as harmful algae in Japan and the USA [110][111]; these species produce brevetoxin (PbTx) and gymnocin (GC), respectively [66][67][68]. PbTx activates mammalian voltage-gated sodium channels, thereby causing NSP [20][65][118]. Further, aerosolized PbTx in sea spray causes reduced respiratory function and asthma [113]. The structures, analogues, and toxicity of PbTx were previously well-elucidated by European Food Safety Authority (EFSA) panels [119]. GCs are polyether toxins that include GC-A and GC-B [67][68]. Although their modes of action are still poorly understood, GCs are carboxylic acids and show moderate cytotoxicity activity against mouse lymphoid P388 cells [67][68]. The structures of GC-A and gymnocin-B were determined by Satake et al. [67][120]. Additionally, Tanaka et al. [68] determined the structures of GC analogues, including GC-A carboxylic acid and GC-A2.

Ostreopsis spp. are well-recognized, harmful algae worldwide due to their spread to many tropical and temperate regions. They produce aerosolized palytoxin (PLTX) along with its analogues, which have caused myalgia, respiratory problems, impairment of the neuromuscular apparatus, and abnormalities in cardiac function [121][122]. PLTX is considered one of the most lethal marine toxins, and its mode of action is unique wherein it causes the Na+/K+ pump to turn into a shape that allows the passive transport of sodium and potassium ions [35][72]. PLTXs and their analogues can be produced by the dinoflagellates O. siamensis, O. ovata, and O. mascarenensis [123][124][125]. The structure, analogues, and toxicity of PLTXs were previously represented by Ramos and Vasconcelos [126].

Prorocentrum spp. produce species-specific diverse phycotoxins, such as OA, DPX, prorocentrolides (PC), and borbotoxin (BTX) (Table 1). PCs are a member of the cyclic imine phycotoxins family produced by P. lima and P. maculosum, and they act on both muscle and neuronal nicotinic acetylcholine receptors (nAChRs) [75][127][128]. P. borbonicum produces BTX-A that was purified by Ten-Hage et al. [76] and has a similar mode of action on nAChRs. The general structure, analogues, and modes of action of PCs and BTX were reported by Amar et al. [75] and Ten-Hage et al. [76].

This entry is adapted from the peer-reviewed paper 10.3390/toxins12120805

References

  1. Heimann, K.; Huerlimann, R. Microalgal classification: Major classes and genera of commercial microalgal species. In Handbook of Marine Microalgae; Academic Press: New York, NY, USA, 2015; pp. 25–41. [Google Scholar]
  2. Gupta, S.K.; Ansari, F.A.; Shriwastav, A.; Sahoo, N.K.; Rawat, I.; Bux, F. Dual role of Chlorella sorokiniana and Scenedesmus obliquus for comprehensive wastewater treatment and biomass production for bio-fuels. J. Clean. Prod. 2016, 115, 255–264. [Google Scholar] [CrossRef]
  3. Moulton, T.P.; Borowitzka, L.J.; Vincent, D.J. The mass culture of Dunaliella salina for β-carotene: From pilot plant to production plant. In Twelfth International Seaweed Symposium; Springer: Dordrecht, The Netherlands, 1987; pp. 99–105. [Google Scholar]
  4. Priyadarshani, I.; Rath, B. Commercial and industrial applications of micro algae—A review. J. Algal Biomass Utln. 2012, 3, 89–100. [Google Scholar]
  5. Pulz, O.; Gross, W. Valuable products from biotechnology of microalgae. Appl. Microbiol. Biotechnol. 2004, 65, 635–648. [Google Scholar] [CrossRef] [PubMed]
  6. Safi, C.; Zebib, B.; Merah, O.; Pontalier, P.Y.; Vaca-Garcia, C. Morphology, composition, production, processing and applications of Chlorella vulgaris: A review. Renew. Sustain. Energy Rev. 2014, 35, 265–278. [Google Scholar] [CrossRef]
  7. Spolaore, P.; Joannis-Cassan, C.; Duran, E.; Isambert, A. Commercial applications of microalgae. J. Biosci. Bioeng. 2006, 101, 87–96. [Google Scholar] [CrossRef] [PubMed]
  8. Handy, S.M.; Coyne, K.J.; Portune, K.J.; Demir, E.; Doblin, M.A.; Hare, C.E.; Cary, S.C.; Hutchins, D.A. Evaluating vertical migration behavior of harmful raphidophytes in the Delaware Inland Bays utilizing quantitative real-time PCR. Aquat. Microb. Ecol. 2005, 40, 121–132. [Google Scholar] [CrossRef]
  9. Kim, S.H.; Kim, K.Y.; Kim, C.H.; Lee, W.S.; Chang, M.; Lee, J.H. Phylogenetic analysis of harmful algal bloom (HAB)-causing dinoflagellates along the Korean coasts, based on SSU rRNA gene. J. Microbiol. Biotechnol. 2004, 14, 959–966. [Google Scholar]
  10. Landsberg, J.H. The effects of harmful algal blooms on aquatic organisms. Rev. Fish. Sci. 2002, 10, 113–390. [Google Scholar] [CrossRef]
  11. Sakamoto, S.; Lim, W.A.; Lu, D.; Dai, X.; Orlova, T.; Iwataki, M. Harmful algal blooms and associated fisheries damage in East Asia: Current status and trends in China, Japan, Korea and Russia. Harmful Algae 2020, 101787, (In Press, Available Online). [Google Scholar] [CrossRef]
  12. Wolf, D.; Georgic, W.; Klaiber, H.A. Reeling in the damages: Harmful algal blooms’ impact on Lake Erie’s recreational fishing industry. J. Environ. Manag. 2017, 199, 148–157. [Google Scholar] [CrossRef]
  13. Dorantes-Aranda, J.J.; Seger, A.; Mardones, J.I.; Nichols, P.D.; Hallegraeff, G.M. Progress in understanding algal bloom-mediated fish kills: The role of superoxide radicals, phycotoxins and fatty acids. PLoS ONE 2015, 10, 0133549. [Google Scholar] [CrossRef] [PubMed]
  14. Kim, D.; Nakamura, A.; Okamoto, T.; Komatsu, N.; Oda, T.; Iida, T.; Ishimatsu, A.; Muramatsu, T. Mechanism of superoxide anion generation in the toxic red tide phytoplankton Chattonella marina: Possible involvement of NAD (P) H oxidase. Biochim. Biophys. Acta Gen. Subj. 2000, 1524, 220–227. [Google Scholar] [CrossRef]
  15. Martins, J.C.; Vasconcelos, V.M. Microcystin dynamics in aquatic organisms. J. Toxicol. Environ. Health B Crit. Rev. 2009, 12, 65–82. [Google Scholar] [CrossRef] [PubMed]
  16. Stoecker, D.K. Mixotrophy among Dinoflagellates 1. J. Eukaryot. Microbiol. 1999, 46, 397–401. [Google Scholar] [CrossRef]
  17. Fraga, S.; Rodríguez, F.; Bravo, I.; Zapata, M.; Marañón, E. Review of the main ecological features affecting benthic dinoflagellate blooms. Cryptogam. Algol. 2012, 33, 171–179. [Google Scholar] [CrossRef]
  18. Hallegraeff, G.M. A review of harmful algal blooms and their apparent global increase. Phycologia 1993, 32, 79–99. [Google Scholar] [CrossRef]
  19. Hallegraeff, G.M. Manual on harmful marine microalgae. In International Oceanographic Commission Manuals and Guides Number 33; United National Educational; Scientific, and Cultural Organization: Landais, France, 2003; pp. 1–22. [Google Scholar]
  20. Wang, D.Z. Neurotoxins from marine dinoflagellates: A brief review. Mar. Drugs 2008, 6, 349–371. [Google Scholar] [CrossRef]
  21. Gómez, F. A checklist and classification of living dinoflagellates (Dinoflagellata, Alveolata). CICIMAR Ocean. 2012, 27, 65–140. [Google Scholar]
  22. Camacho, F.G.; Rodríguez, J.G.; Mirón, A.S.; García, M.C.; Belarbi, E.H.; Chisti, Y.; Grima, E.M. Biotechnological significance of toxic marine dinoflagellates. Biotechnol. Adv. 2007, 25, 176–194. [Google Scholar] [CrossRef]
  23. Kim, H.G. Recent harmful algal blooms and mitigation strategies in Korea. Ocean. Polar Res. 1997, 19, 185–192. [Google Scholar]
  24. Kudela, R.M.; Gobler, C.J. Harmful dinoflagellate blooms caused by Cochlodinium sp.: Global expansion and ecological strategies facilitating bloom formation. Harmful Algae 2012, 14, 71–86. [Google Scholar] [CrossRef]
  25. Chen, I.C.; Hill, J.K.; Ohlemüller, R.; Roy, D.B.; Thomas, C.D. Rapid range shifts of species associated with high levels of climate warming. Science 2011, 333, 1024–1026. [Google Scholar] [CrossRef] [PubMed]
  26. Chang, F.H.; Gall, M. Pigment compositions and toxic effects of three harmful Karenia species, Karenia concordia, Karenia brevisulcata and Karenia mikimotoi (Gymnodiniales, Dinophyceae), on rotifers and brine shrimps. Harmful Algae 2013, 27, 113–120. [Google Scholar] [CrossRef]
  27. Samson, J.C.; Shumway, S.E.; Weis, J.S. Effects of the toxic dinoflagellate, Alexandrium fundyense on three species of larval fish: A food-chain approach. J. Fish. Biol. 2008, 72, 168–188. [Google Scholar] [CrossRef]
  28. Scott, A.B. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. J. Pediatr. Ophthalmol. Strabismus 1980, 17, 21–25. [Google Scholar] [CrossRef]
  29. Barrientos, N.; Chana, P. Botulinum toxin type a in prophylactic treatment of migraine headaches: A preliminary study. J. Headache Pain 2003, 4, 146–151. [Google Scholar] [CrossRef]
  30. Hambleton, P. Clostridium botulinum toxins: A general review of involvement in disease, structure, mode of action and preparation for clinical use. J. Neurol. 1992, 239, 16–20. [Google Scholar] [CrossRef]
  31. Song, H.; Li, J.; Lu, C.L.; Kang, L.; Xie, L.; Zhang, Y.Y.; Zhou, X.B.; Zhong, S. Tetrodotoxin alleviates acute heroin withdrawal syndrome: A multicentre, randomized, double-blind, placebo-controlled study. Clin. Exp. Pharmacol. Physiol. 2011, 38, 510–514. [Google Scholar] [CrossRef]
  32. Hagen, N.A.; Lapointe, B.; Ong–Lam, M.; Dubuc, B.; Walde, D.; Gagnon, B.; Love, R.; Goel, R.; Hawley, P.; Ngoc, A.H.; et al. multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain. Curr. Oncol. 2011, 18, e109. [Google Scholar] [CrossRef]
  33. Baig, H.S.; Saifullah, S.M.; Dar, A. Occurrence and toxicity of Amphidinium carterae Hulburt in the North Arabian Sea. Harmful Algae 2006, 5, 133–140. [Google Scholar] [CrossRef]
  34. Lefebvre, K.A.; Bill, B.D.; Erickson, A.; Baugh, K.A.; O’Rourke, L.; Costa, P.R.; Nance, S.; Trainer, V.L. Characterization of intracellular and extracellular saxitoxin levels in both field and cultured Alexandrium spp. samples from Sequim Bay, Washington. Mar. Drugs 2008, 6, 103–116. [Google Scholar] [CrossRef] [PubMed]
  35. Stonik, V.A.; Stonik, I.V. Toxins Produced by Marine Microorganisms: A Mini Review. In Marine and Freshwater Toxins; Gopalakrishnakone, P., Haddad, V., Jr., Kem, W., Tubaro, A., Kim, E., Eds.; Springer: Dordrecht, The Netherlands, 2014. [Google Scholar]
  36. Zingone, A.; Siano, R.; D’Alelio, D.; Sarno, D. Potentially toxic and harmful microalgae from coastal waters of the Campania region (Tyrrhenian Sea, Mediterranean Sea). Harmful Algae 2006, 5, 321–337. [Google Scholar] [CrossRef]
  37. Durán-Riveroll, L.M.; Cembella, A.D. Guanidinium toxins and their interactions with voltage-gated sodium ion channels. Mar. Drugs 2017, 15, 303. [Google Scholar] [CrossRef]
  38. Wiese, M.; D’agostino, P.M.; Mihali, T.K.; Moffitt, M.C.; Neilan, B.A. Neurotoxic alkaloids: Saxitoxin and its analogs. Mar. Drugs 2010, 8, 2185–2211. [Google Scholar] [CrossRef]
  39. Sako, Y.; Yoshida, T.; Uchida, A.; Arakawa, O.; Noguchi, T.; Ishida, Y. Purification and characterization of a sulfotransferase specific to N-21 of saxitoxin and gonyautoxin 2+ 3 from the toxic dinoflagellate Gymnodinium catenatum (Dinophyceae). J. Phycol. 2001, 37, 1044–1051. [Google Scholar] [CrossRef]
  40. Landsberg, J.H.; Hall, S.; Johannessen, J.N.; White, K.D.; Conrad, S.M.; Abbott, J.P.; Flewelling, L.J.; Richardson, R.W.; Dickey, R.W.; Jester, E.L.E.; et al. Saxitoxin puffer fish poisoning in the United States, with the first report of Pyrodinium bahamense as the putative toxin source. Environ. Health Perspect. 2006, 114, 1502–1507. [Google Scholar] [CrossRef]
  41. Andrinolo, D.; Michea, L.F.; Lagos, N. Toxic effects, pharmacokinetics and clearance of saxitoxin, a component of paralytic shellfish poison (PSP), in cats. Toxicon 1999, 37, 447–464. [Google Scholar] [CrossRef]
  42. Tatters, A.O.; Van Wagoner, R.M.; Wright, J.L.; Tomas, C.R. Regulation of spiroimine neurotoxins and hemolytic activity in laboratory cultures of the dinoflagellate Alexandrium peruvianum (Balech & Mendiola) Balech & Tangen. Harmful Algae 2012, 19, 160–168. [Google Scholar]
  43. Salas, R.; Tillmann, U.; John, U.; Kilcoyne, J.; Burson, A.; Cantwell, C.; Hess, P.; Jauffrais, T.; Silke, J. The role of Azadinium spinosum (Dinophyceae) in the production of azaspiracid shellfish poisoning in mussels. Harmful Algae 2011, 10, 774–783. [Google Scholar] [CrossRef]
  44. Dorantes-Aranda, J.J.; García-de la Parra, L.M.; Alonso-Rodríguez, R.; Morquecho, L. Hemolytic activity and fatty acids composition in the ichthyotoxic dinoflagellate Cochlodinium polykrikoides isolated from Bahía de La Paz, Gulf of California. Mar. Pollut. Bull. 2009, 58, 1401–1405. [Google Scholar] [CrossRef] [PubMed]
  45. Kim, C.S.; Lee, S.G.; Kim, H.G.; Lee, J.S. Screening for toxic compounds in the red tide dinoflagellate Cochlodinium polykrikoides: Is it toxic plankton? ALGAE 2001, 16, 457–462. [Google Scholar]
  46. Holmes, M.J.; Lewis, R.J.; Jones, A.; Hoy, A.W.W. Cooliatoxin, the first toxin from Coolia monotis (Dinophyceae). Nat. Toxins 1995, 3, 355–362. [Google Scholar] [CrossRef]
  47. Wakeman, K.C.; Yamaguchi, A.; Roy, M.C.; Jenke-Kodama, H. Morphology, phylogeny and novel chemical compounds from Coolia malayensis (Dinophyceae) from Okinawa, Japan. Harmful Algae 2015, 44, 8–19. [Google Scholar] [CrossRef]
  48. de Azevedo Tibiriga, C.E.J.; Sibat, M.; Fernandes, L.F.; Bilien, G.; Chomerat, N.; Hess, P.; Mafra, L.L., Jr. Diversity and Toxicity of the Genus Coolia Meunier in Brazil, and Detection of 44-methyl Gambierone in Coolia tropicalis. Toxins 2020, 12, 327. [Google Scholar]
  49. de la Rosa, L.A.; Alfonso, A.; Vilariño, N.; Vieytes, M.R.; Botana, L.M. Modulation of cytosolic calcium levels of human lymphocytes by yessotoxin, a novel marine phycotoxin. Biochem. Pharmacol. 2001, 61, 827–833. [Google Scholar] [CrossRef]
  50. Alfonso, A.; Vieytes, M.R.; Botana, L.M. Yessotoxin, a promising therapeutic tool. Mar. Drugs 2016, 14, 30. [Google Scholar] [CrossRef] [PubMed]
  51. Bodero, M.; Hoogenboom, R.L.; Bovee, T.F.; Portier, L.; de Haan, L.; Peijnenburg, A.; Hendriksen, P.J. Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol. In Vitro 2018, 46, 102–112. [Google Scholar] [CrossRef] [PubMed]
  52. Cohen, P.; Holmes, C.F.; Tsukitani, Y. Okadaic acid: A new probe for the study of cellular regulation. Trends Biochem. Sci. 1990, 15, 98–102. [Google Scholar] [CrossRef]
  53. Kamat, P.K.; Rai, S.; Swarnkar, S.; Shukla, R.; Nath, C. Molecular and cellular mechanism of okadaic acid (OKA)-induced neurotoxicity: A novel tool for Alzheimer’s disease therapeutic application. Mol. Neurobiol. 2014, 50, 852–865. [Google Scholar] [CrossRef]
  54. Reguera, B.; Riobó, P.; Rodríguez, F.; Díaz, P.A.; Pizarro, G.; Paz, B.; José, M.F.; Blanco, J. Dinophysis toxins: Causative organisms, distribution and fate in shellfish. Mar. Drugs 2014, 12, 394–461. [Google Scholar] [CrossRef]
  55. Sathasivam, R.; Radhakrishnan, R.; Hashem, A.; Abd_Allah, E.F. Microalgae metabolites: A rich source for food and medicine. Saudi J. Biol. Sci. 2019, 26, 709–722. [Google Scholar] [CrossRef]
  56. Vale, C.; Botana, L.M. Marine toxins and the cytoskeleton: Okadaic acid and dinophysistoxins. FEBS J. 2008, 275, 6060–6066. [Google Scholar] [CrossRef]
  57. Allingham, J.S.; Miles, C.O.; Rayment, I. A structural basis for regulation of actin polymerization by pectenotoxins. J. Mol. Biol. 2007, 371, 959–970. [Google Scholar] [CrossRef]
  58. Basti, L.; Nagai, S.; Go, J.; Okano, S.; Nagai, K.; Watanabe, R.; Suzuki, T.; Tanaka, Y. Differential inimical effects of Alexandrium spp. and Karenia spp. on cleavage, hatching, and two larval stages of Japanese pearl oyster Pinctada fucata martensii. Harmful Algae 2015, 43, 1–12. [Google Scholar] [CrossRef]
  59. Rossini, G.P.; Hess, P. Phycotoxins: Chemistry, mechanisms of action and shellfish poisoning. In Molecular, Clinical and Environmental Toxicology. Volume2: Clinical Toxicology; Luch, A., Ed.; Birkhäuser: Basel, Switzerland, 2010; pp. 65–122. [Google Scholar]
  60. Takahashi, M.; Ohizumi, Y.; Yasumoto, T. Maitotoxin, a Ca2+ channel activator candidate. J. Biol. Chem. 1982, 257, 7287–7289. [Google Scholar] [PubMed]
  61. Rhodes, L.; McNabb, P.; De Salas, M.; Briggs, L.; Beuzenberg, V.; Gladstone, M. Yessotoxin production by Gonyaulax spinifera. Harmful Algae 2006, 5, 148–155. [Google Scholar] [CrossRef]
  62. Andersen, A.J.C.; De Medeiros, L.S.; Binzer, S.B.; Rasmussen, S.A.; Hansen, P.J.; Nielsen, K.F.; Jørgensen, K.; Larsen, T.O. HPLC-HRMS Quantification of the Ichthyotoxin Karmitoxin from Karlodinium armiger. Mar. Drugs 2017, 15, 278. [Google Scholar] [CrossRef] [PubMed]
  63. Rasmussen, S.A.; Binzer, S.B.; Hoeck, C.; Meier, S.; De Medeiros, L.S.; Andersen, N.G.; Place, A.; Nielsen, K.F.; Hansen, P.J.; Larsen, T.O. Karmitoxin: An amine-containing polyhydroxy-polyene toxin from the marine dinoflagellate Karlodinium armiger. J. Nat. Prod. 2017, 80, 1287–1293. [Google Scholar] [CrossRef]
  64. Van Wagoner, R.M.; Deeds, J.R.; Satake, M.; Ribeiro, A.A.; Place, A.R.; Wright, J.L. Isolation and characterization of karlotoxin 1, a new amphipathic toxin from Karlodinium veneficum. Tetrahedron Lett. 2008, 49, 6457–6461. [Google Scholar] [CrossRef]
  65. Bourdelais, A.J.; Campbell, S.; Jacocks, H.; Naar, J.; Wright, J.L.; Carsi, J.; Baden, D.G. Brevenal is a natural inhibitor of brevetoxin action in sodium channel receptor binding assays. Cell. Mol. Neurobiol. 2004, 24, 553–563. [Google Scholar] [CrossRef]
  66. Novoveská, L.; Robertson, A. Brevetoxin-Producing Spherical Cells Present in Karenia brevis Bloom: Evidence of Morphological Plasticity? J. Mar. Sci. Eng. 2019, 7, 24. [Google Scholar] [CrossRef]
  67. Satake, M.; Tanaka, Y.; Ishikura, Y.; Oshima, Y.; Naoki, H.; Yasumoto, T. Gymnocin-B with the largest contiguous polyether rings from the red tide dinoflagellate, Karenia (formerly Gymnodinium) mikimotoi. Tetrahedron Lett. 2005, 46, 3537–3540. [Google Scholar]
  68. Tanaka, Y.; Satake, M.; Yotsu-Yamashita, M.; Oshima, Y. Gymnocin-A carboxylic acid and gymnocin-A2, cytotoxic polyethers from the red tide dinoflagellate Karenia mikimotoi. Heterocycles 2013, 87, 2037–2046. [Google Scholar]
  69. Kim, D.; Li, W.; Matsuyama, Y.; Matsuo, A.; Yagi, M.; Cho, K.; Yamasaki, Y.; Takeshita, S.; Yamaguchi, K.; Oda, T. Strain-dependent lethal effects on abalone and haemolytic activities of the dinoflagellate Karenia mikimotoi. Aquaculture 2020, 520, 734953. [Google Scholar] [CrossRef]
  70. Paz, B.; Riobó, P.; Fernández, M.L.; Fraga, S.; Franco, J.M. Production and release of yessotoxins by the dinoflagellates Protoceratium reticulatum and Lingulodinium polyedrum in culture. Toxicon 2004, 44, 251–258. [Google Scholar] [CrossRef] [PubMed]
  71. Ciminiello, P.; Dell’Aversano, C.; Iacovo, E.D.; Fattorusso, E.; Forino, M.; Tartaglione, L.; Benedettini, G.; Onorari, M.; Serena, F.; Battocchi, C.; et al. First finding of Ostreopsis cf. ovata toxins in marine aerosols. Environ. Sci. Technol. 2014, 48, 3532–3540. [Google Scholar] [PubMed]
  72. Wu, C.H. Palytoxin: Membrane mechanisms of action. Toxicon 2009, 54, 1183–1189. [Google Scholar] [CrossRef] [PubMed]
  73. Campos, A.; Freitas, M.; de Almeida, A.M.; Martins, J.C.; Domínguez-Pérez, D.; Osório, H.; Vasconcelos, V.; Costa, P.R. OMICs Approaches in Diarrhetic Shellfish Toxins Research. Toxins 2020, 12, 493. [Google Scholar] [CrossRef]
  74. Kameneva, P.A.; Efimova, K.V.; Rybin, V.G.; Orlova, T.Y. Detection of dinophysistoxin-1 in clonal culture of marine dinoflagellate Prorocentrum foraminosum (Faust MA, 1993) from the Sea of Japan. Toxins 2015, 7, 3947–3959. [Google Scholar] [CrossRef]
  75. Amar, M.; Aráoz, R.; Iorga, B.I.; Yasumoto, T.; Servent, D.; Molgó, J. Prorocentrolide-A from cultured Prorocentrum lima dinoflagellates collected in Japan blocks sub-types of nicotinic acetylcholine receptors. Toxins 2018, 10, 97. [Google Scholar] [CrossRef]
  76. Ten-Hage, L.; Robillot, C.; Turquet, J.; Le Gall, F.; Le Caer, J.P.; Bultel, V.; Guyot, M.; Molgó, J. Effects of toxic extracts and purified borbotoxins from Prorocentrum borbonicum (Dinophyceae) on vertebrate neuromuscular junctions. Toxicon 2002, 40, 137–148. [Google Scholar] [CrossRef]
  77. Chalmeau, J.; Monina, N.; Shin, J.; Vieu, C.; Noireaux, V. α-Hemolysin pore formation into a supported phospholipid bilayer using cell-free expression. Biochim. Biophys. Acta Biomembr. 2011, 1808, 271–278. [Google Scholar] [CrossRef]
  78. Bhakdi, S.; Mackman, N.; Menestrina, G.; Gray, L.; Hugo, F.; Seeger, W.; Holland, I.B. The hemolysin of Escherichia coli. Eur. J. Epidemiol. 1988, 4, 135–143. [Google Scholar] [CrossRef]
  79. Satake, M.; Ofuji, K.; Naoki, H.; James, K.J.; Furey, A.; McMahon, T.; Silke, J.; Yasumoto, T. Azaspiracid, a new marine toxin having unique spiro ring assemblies, isolated from Irish mussels, Mytilus edulis. J. Am. Chem. Soc. 1998, 120, 9967–9968. [Google Scholar] [CrossRef]
  80. James, K.J.; Moroney, C.; Roden, C.; Satake, M.; Yasumoto, T.; Lehane, M.; Furey, A. Ubiquitous ‘benign’alga emerges as the cause of shellfish contamination responsible for the human toxic syndrome, azaspiracid poisoning. Toxicon 2003, 41, 145–151. [Google Scholar]
  81. Botana, L.M.; Alfonso, A.; Vale, C.; Vilariño, N.; Rubiolo, J.; Alonso, E.; Cagide, E. The mechanistic complexities of phycotoxins: Toxicology of azaspiracids and yessotoxins. In Advances in Molecular Toxicology; Elsevier: Amsterdam, The Netherlands, 2014; Volume 8, pp. 1–3. [Google Scholar]
  82. Klontz, K.C.; Abraham, A.; Plakas, S.M.; Dickey, R.W. Mussel-associated azaspiracid intoxication in the United States. Ann. Intern. Med. 2009, 150, 361. [Google Scholar] [CrossRef]
  83. Ito, E.; Satake, M.; Ofuji, K.; Kurita, N.; McMahon, T.; James, K.; Yasumoto, T. Multiple organ damage caused by a new toxin azaspiracid, isolated from mussels produced in Ireland. Toxicon 2000, 38, 917–930. [Google Scholar] [CrossRef]
  84. Pelin, M.; Sosa, S.; Brovedani, V.; Kilcoyne, J.; Nulty, C.; Hess, P.; Tubaro, A. In vitro effects of three azaspiracid analogues on hepatocytes. Toxicon 2016, 100, 85–86. [Google Scholar] [CrossRef]
  85. Pelin, M.; Kilcoyne, J.; Nulty, C.; Crain, S.; Hess, P.; Tubaro, A.; Sosa, S. Toxic equivalency factors (TEFs) after acute oral exposure of azaspiracid 1,− 2 and− 3 in mice. Toxicol. Lett. 2018, 282, 136–146. [Google Scholar] [CrossRef] [PubMed]
  86. Twiner, M.J.; Doucette, G.J.; Rasky, A.; Huang, X.P.; Roth, B.L.; Sanguinetti, M.C. Marine algal toxin azaspiracid is an open-state blocker of hERG potassium channels. Chem. Res. Toxicol. 2012, 25, 1975–1984. [Google Scholar] [CrossRef] [PubMed]
  87. Pelin, M.; Kilcoyne, J.; Florio, C.; Hess, P.; Tubaro, A.; Sosa, S. Azaspiracids increase mitochondrial dehydrogenases activity in hepatocytes: Involvement of potassium and chloride ions. Mar. Drugs 2019, 17, 276. [Google Scholar] [CrossRef] [PubMed]
  88. Hess, P.; Twiner, J.M.; Kilcoyne, J.; Sosa, S. Azaspiracid toxins: Toxicological profile. In Marine and Freshwater Toxins; Springer: Dordrecht, The Netherlands, 2015; pp. 1–19. [Google Scholar]
  89. Kilcoyne, J.; Twiner, M.J.; McCarron, P.; Crain, S.; Giddings, S.D.; Foley, B.; Rise, F.; Hess, P.; Wilkins, A.L.; Miles, C.O. Structure elucidation, relative LC–MS response and in vitro toxicity of azaspiracids 7–10 isolated from mussels (Mytilus edulis). J. Agric. Food Chem. 2015, 63, 5083–5091. [Google Scholar] [CrossRef]
  90. Kilcoyne, J.; McCarron, P.; Twiner, M.J.; Rise, F.; Hess, P.; Wilkins, A.L.; Miles, C.O. Identification of 21, 22-dehydroazaspiracids in mussels (Mytilus edulis) and in vitro toxicity of azaspiracid-26. J. Nat. Prod. 2018, 81, 885–893. [Google Scholar] [CrossRef]
  91. Ofuji, K.; Satake, M.; McMahon, T.; JAMES, K.J.; Naoki, H.; Oshima, Y.; Yasumoto, T. Structures of azaspiracid analogs, azaspiracid-4 and azaspiracid-5, causative toxins of azaspiracid poisoning in Europe. Biosci. Biotechnol. Biochem. 2001, 65, 740–742. [Google Scholar] [CrossRef]
  92. Twiner, M.J.; Hess, P.; Doucette, G.J. Azaspiracids: Toxicology, Pharmacologiy, and Risk Assessment. In Seafood and Freshwater Toxins; CRC Press: Boca Raton, FL, USA, 2014; pp. 823–856. [Google Scholar]
  93. Paz, B.; Daranas, A.H.; Norte, M.; Riobó, P.; Franco, J.M.; Fernández, J.J. Yessotoxins, a group of marine polyether toxins: An overview. Mar. Drugs 2008, 6, 73–102. [Google Scholar] [CrossRef]
  94. Binzer, S.B.; Varga, E.; Andersen, A.J.C.; Svenssen, D.K.; De Medeiros, L.S.; Rasmussen, S.A.; Larsen, T.O.; Hansen, P.J. Karmitoxin production by Karlodinium armiger and the effects of K. armiger and karmitoxin towards fish. Harmful Algae 2020, 99, 101905. [Google Scholar] [CrossRef]
  95. Van Wagoner, R.M.; Deeds, J.R.; Tatters, A.O.; Place, A.R.; Tomas, C.R.; Wright, J.L. Structure and relative potency of several karlotoxins from Karlodinium veneficum. J. Nat. Prod. 2010, 73, 1360–1365. [Google Scholar] [CrossRef]
  96. Murata, M.; Sano, M.; Iwashita, T.; Naoki, H.; YasuMoto, T. The structure of pectenotoxin-3, a new constituent of diarrhetic shellfish toxins. Agric. Biol. Chem. 1986, 50, 2693–2695. [Google Scholar]
  97. Twiner, M.J.; Doucette, G.J.; Pang, Y.; Fang, C.; Forsyth, C.J.; Miles, C.O. Structure–activity relationship studies using natural and synthetic okadaic acid/dinophysistoxin toxins. Mar. Drugs 2016, 14, 207. [Google Scholar] [CrossRef] [PubMed]
  98. Arias, C.; Becerra-García, F.; Arrieta, I.; Tapia, R. The Protein Phosphatase Inhibitor Okadaic Acid Induces Heat Shock Protein Expression and Neurodegeneration in Rat Hippocampusin Vivo. Exp. Neurol. 1998, 153, 242–254. [Google Scholar] [CrossRef] [PubMed]
  99. Fujiki, H.; Suganuma, M.; Suguri, H.; Yoshizawa, S.; Takagi, K.; Uda, N.; Wakamatsu, K.; Yamada, K.; Murata, M.; Yasumoto, T.; et al. Diarrhetic shellfish toxin, dinophysistoxin-1, is a potent tumor promoter on mouse skin. Jpn. J. Cancer Res. 1988, 79, 1089–1093. [Google Scholar] [CrossRef]
  100. Uchida, H.; Watanabe, R.; Matsushima, R.; Oikawa, H.; Nagai, S.; Kamiyama, T.; Matsuyama, Y. Toxin profiles of okadaic acid analogues and other lipophilic toxins in Dinophysis from Japanese coastal waters. Toxins 2018, 10, 457. [Google Scholar] [CrossRef]
  101. Fernandez, J.J.; Candenas, M.L.; Souto, M.L.; Trujillo, M.M.; Norte, M. Okadaic acid, useful tool for studying cellular processes. Curr. Med. Chem. 2002, 9, 229–262. [Google Scholar] [CrossRef]
  102. Espina, B.; Louzao, M.C.; Ares, I.R.; Cagide, E.; Vieytes, M.R.; Vega, F.V.; Rubiolo, J.A.; Miles, C.O.; Suzuki, T.; Yasumoto, T.; et al. Cytoskeletal toxicity of pectenotoxins in hepatic cells. Br. J. Pharmacol. 2008, 155, 934–944. [Google Scholar] [CrossRef]
  103. Espiña, B.; Rubiolo, J.A. Marine toxins and the cytoskeleton: Pectenotoxins, unusual macrolides that disrupt actin. FEBS J. 2008, 275, 6082–6088. [Google Scholar] [CrossRef]
  104. Miles, C.O.; Wilkins, A.L.; Munday, R.; Dines, M.H.; Hawkes, A.D.; Briggs, L.R.; Sandvik, M.; Jensen, D.J.; Cooney, J.M.; Holland, P.T.; et al. Isolation of pectenotoxin-2 from Dinophysis acuta and its conversion to pectenotoxin-2 seco acid, and preliminary assessment of their acute toxicities. Toxicon 2004, 43, 1–9. [Google Scholar] [CrossRef]
  105. Wilkins, A.L.; Rehmann, N.; Torgersen, T.; Rundberget, T.; Keogh, M.; Petersen, D.; Hess, P.; Rise, F.; Miles, C.O. Identification of fatty acid esters of pectenotoxin-2 seco acid in blue mussels (Mytilus edulis) from Ireland. J. Agric. Food Chem. 2006, 54, 5672–5678. [Google Scholar] [CrossRef]
  106. MacKenzie, L.; Beuzenberg, V.; Holland, P.; McNabb, P.; Suzuki, T.; Selwood, A. Pectenotoxin and okadaic acid-based toxin profiles in Dinophysis acuta and Dinophysis acuminata from New Zealand. Harmful Algae 2005, 4, 75–85. [Google Scholar] [CrossRef]
  107. Dickey, R.W.; Bobzin, S.C.; Faulkner, D.J.; Bencsath, F.A.; Andrzejewski, D. Identification of okadaic acid from a Caribbean dinoflagellate, Prorocentrum concavum. Toxicon 1990, 28, 371–377. [Google Scholar] [CrossRef]
  108. An, T.; Winshell, J.; Scorzetti, G.; Fell, J.W.; Rein, K.S. Identification of okadaic acid production in the marine dinoflagellate Prorocentrum rhathymum from Florida Bay. Toxicon 2010, 55, 653–657. [Google Scholar] [CrossRef] [PubMed]
  109. Ten-Hage, L.; Delaunay, N.; Pichon, V.; Couté, A.; Puiseux-Dao, S.; Turquet, J. Okadaic acid production from the marine benthic dinoflagellate Prorocentrum arenarium Faust (Dinophyceae) isolated from Europa Island coral reef ecosystem (SW Indian Ocean). Toxicon 2000, 38, 1043–1054. [Google Scholar] [CrossRef]
  110. Nielsen, L.T.; Krock, B.; Hansen, P.J. Production and excretion of okadaic acid, pectenotoxin-2 and a novel dinophysistoxin from the DSP-causing marine dinoflagellate Dinophysis acuta–effects of light, food availability and growth phase. Harmful Algae 2013, 23, 34–45. [Google Scholar] [CrossRef]
  111. Kim, T.; Suzuki, T. Production of dinophysistoxin-1 and pectenotoxin-2 by a culture of Dinophysis acuminata (Dinophyceae). Harmful Algae 2009, 8, 312–317. [Google Scholar]
  112. Jeffrey, L.C. Identification of DTX-4, a new water-soluble phosphatase inhibitor from the toxic dinoflagellate Prorocentrum lima. J. Chem. Soc. Chem. Commun. 1995, 597–599. [Google Scholar]
  113. Suzuki, T.; Mitsuya, T.; Matsubara, H.; Yamasaki, M. Determination of pectenotoxin-2 after solid-phase extraction from seawater and from the dinoflagellate Dinophysis fortii by liquid chromatography with electrospray mass spectrometry and ultraviolet detection: Evidence of oxidation of pectenotoxin-2 to pectenotoxin-6 in scallops. J. Chromatogr. A 1998, 815, 155–160. [Google Scholar]
  114. Suzuki, T.; Beuzenberg, V.; Mackenzie, L.; Quilliam, M.A. Liquid chromatography–mass spectrometry of spiroketal stereoisomers of pectenotoxins and the analysis of novel pectenotoxin isomers in the toxic dinoflagellate Dinophysis acuta from New Zealand. J. Chromatogr. 2003, 992, 141. [Google Scholar]
  115. Holmes, M.J.; Lewis, R.J. Purification and characterisation of large and small maitotoxins from cultured Gambierdiscus toxicus. Nat. Toxins 1994, 2, 64–72. [Google Scholar] [CrossRef]
  116. Murata, M.; Naoki, H.; Iwashita, T.; Matsunaga, S.; Sasaki, M.; Yokoyama, A.; Yasumoto, T. Structure of maitotoxin. J. Am. Chem. Soc. 1993, 115, 2060–2062. [Google Scholar] [CrossRef]
  117. Reyes, J.G.; Sánchez-Cárdenas, C.; Acevedo-Castillo, W.; Leyton, P.; López-González, I.; Felix, R.; Gandini, M.A.; Treviño, M.B.; Treviño, C.L. Maitotoxin: An enigmatic toxic molecule with useful applications in the biomedical sciences. In Seafood and Freshwater Toxins: Pharmacology, Physiology and Detection; Botana, L.M., Ed.; CRC Press (Taylor & Francis Group): Boca Raton, FL, USA, 2014; pp. 677–694. [Google Scholar]
  118. Morohashi, A.; Satake, M.; Naoki, H.; Kaspar, H.F.; Oshima, Y.; Yasumoto, T. Brevetoxin B4 isolated from greenshell mussels Perna canaliculus, the major toxin involved in neurotoxic shellfish poisoning in New Zealand. Nat. Toxins 1999, 7, 45–48. [Google Scholar] [CrossRef]
  119. EFSA Panel on Contaminants in the Food Chain (CONTAM). Scientific Opinion on marine biotoxins in shellfish–Emerging toxins: Brevetoxin group. EFSA J. 2010, 8, 1677. [Google Scholar] [CrossRef]
  120. Satake, M.; Shoji, M.; Oshima, Y.; Naoki, H.; Fujita, T.; Yasumoto, T. Gymnocin-A, a cytotoxic polyether from the notorious red tide dinoflagellate, Gymnodinium mikimotoi. Tetrahedron Lett. 2002, 43, 5829–5832. [Google Scholar] [CrossRef]
  121. Pistocchi, R.; Pezzolesi, L.; Guerrini, F.; Vanucci, S.; Dell’Aversano, C.; Fattorusso, E. A review on the effects of environmental conditions on growth and toxin production of Ostreopsis ovata. Toxicon 2011, 57, 421–428. [Google Scholar] [CrossRef]
  122. Tubaro, A.; Durando, P.; Del Favero, G.; Ansaldi, F.; Icardi, G.; Deeds, J.R.; Sosa, S. Case definitions for human poisonings postulated to palytoxins exposure. Toxicon 2011, 57, 478–495. [Google Scholar] [CrossRef]
  123. Usami, M.; Satake, M.; Ishida, S.; Inoue, A.; Kan, Y.; Yasumoto, T. Palytoxin analogs from the din1flagellate Ostreopsis siamensis. J. Am. Chem. Soc. 1995, 117, 5389–5390. [Google Scholar] [CrossRef]
  124. Lenoir, S.; Ten-Hage, L.; Turquet, J.; Quod, J.P.; Bernard, C.; Hennion, M.C. First evidence of palytoxin analogues from an Ostreopsis mascarenensis (dinophyceae) benthic bloom in southwestern indian Ocean 1. J. Phycol. 2004, 40, 1042–1051. [Google Scholar] [CrossRef]
  125. Bravo, I.; Vila, M.; Casabianca, S.; Rodriguez, F.; Rial, P.; Riobó, P.; Penna, A. Life cycle stages of the benthic palytoxin-producing dinoflagellate Ostreopsis cf. ovata (Dinophyceae). Harmful Algae 2012, 18, 24–34. [Google Scholar] [CrossRef]
  126. Ramos, V.; Vasconcelos, V. Palytoxin and analogs: Biological and ecological effects. Mar. Drugs 2010, 8, 2021–2037. [Google Scholar] [CrossRef]
  127. Torigoe, K.; Murata, M.; Yasumoto, T.; Iwashita, T. Prorocentrolide, a toxic nitrogenous macrocycle from a marine dinoflagellate, Prorocentrum lima. J. Am. Chem. Soc. 1988, 110, 7876–7877. [Google Scholar] [CrossRef]
  128. Hu, T.; DeFreitas, A.S.; Curtis, J.M.; Oshima, Y.; Walter, J.A.; Wright, J.L. Isolation and structure of prorocentrolide B, a fast-acting toxin from Prorocentrum maculosum. J. Nat. Prod. 1996, 59, 1010–1014. [Google Scholar] [CrossRef] [PubMed]
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback