Diarrhetic effect of okadaic acid could be related with its neuronal action: Changes in neuropeptide Y

Louzao, M. Carmen; Fernández, Diego A.; Abal, Paula; Fraga-Corral, María; Vilariño, Natalia; Vieytes, Mercedes R.; Botana, Luís M.

doi:10.1016/j.toxlet.2015.06.004

Cited by 36 publications

(31 citation statements)

References 53 publications

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“…Although most effects of this group of toxins are related to the inhibition of protein phosphatases, there are reports of other possible targets of action relevant to the toxicity of toxins of the OA-group [10]. In this sense, Louzao et al [11] report that doses of 50-100 nM of OA in SH-SY5Y neuroblastoma cells cause decreased cellular expression of neuropeptide Y, which has a protective effect against diarrhea. Furthermore, Espiña et al [12] reported that methyl okadaate, an artificial derivative of OA, is able to disaggregate the actin cytoskeleton and is able to decrease the metabolic expenditure in normal and immortalized rat hepatocytes by an independent route to the inhibition of PP1 and PP2A.…”

Section: Introductionmentioning

confidence: 99%

Toxins of Okadaic Acid-Group Increase Malignant Properties in Cells of Colon Cancer

Jiménez-Carcamo

Garcı́a

Contreras

2020

Toxins

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Diarrhetic shellfish poisoning (DSP) is a syndrome caused by the intake of shellfish contaminated with a group of lipophilic and thermostable toxins, which consists of okadaic acid (OA), dinophysistoxin-1 (DTX-1) and dinophysistoxin-2 (DTX-2). These toxins are potent protein Ser/Thr phosphatase inhibitors, mainly type 1 protein phosphatase (PP1) and type 2A protein phosphatase (PP2A). Different effects have been reported at the cellular, molecular and genetic levels. In this study, changes in cell survival and cell mobility induced by OA, DTX-1 and DTX-2 were determined in epithelial cell lines of the colon and colon cancer. The cell viability results showed that tumoral cell lines were more resistant to toxins than the nontumoral cell line. The results of the functional assays for testing cell migration, evaluation of cell death and the expression of proteins associated with cell adhesion showed a dual effect of toxins since in the nontumoral cell line, a greater induction of cell death, presumably by anoikis, was detected. In the tumoral cell lines, there was an induction of a more aggressive phenotype characterized by increased resistance to toxins, increased migration and increased FAK activation. In tumoral cell lines of colon cancer, OA, DTX-1/DTX-2 induce a more aggressive phenotype.

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Section: Introductionmentioning

confidence: 99%

Toxins of Okadaic Acid-Group Increase Malignant Properties in Cells of Colon Cancer

Jiménez-Carcamo

Garcı́a

Contreras

2020

Toxins

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“…These toxins are lipophilic and accumulate in shellfish and are potent inhibitors of serine/threonine protein phosphatases 2A (PP2A), 1B, and 2B [25], which are vital for the regulation of cell metabolism, DNA replication, transcription, RNA splicing, cell cycle progression, differentiation, and oncogenesis through the dephosphorylating phosphor-serine and phosphor-threonine residues of their substrates [34]; these toxins are potential tumor promoters [35,36,37] in the human digestive system [38]. Moreover, OA induces apoptosis [39,40,41,42,43,44], cytotoxicity [45,46], DNA adduct formation [47], chromosome loss [48], DNA breaks and cell cycle arrest [42], as well as changes in neuropeptide Y [49]. …”

Section: Introductionmentioning

confidence: 99%

The Mechanism of Diarrhetic Shellfish Poisoning Toxin Production in Prorocentrum spp.: Physiological and Molecular Perspectives

Lee

Fong

et al. 2016

Toxins

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Diarrhetic shellfish poisoning (DSP) is a gastrointestinal disorder caused by the consumption of seafood contaminated with okadaic acid (OA) and dinophysistoxins (DTXs). OA and DTXs are potent inhibitors of protein phosphatases 2A, 1B, and 2B, which may promote cancer in the human digestive system. Their expression in dinoflagellates is strongly affected by nutritional and environmental factors. Studies have indicated that the level of these biotoxins is inversely associated with the growth of dinoflagellates at low concentrations of nitrogen or phosphorus, or at extreme temperature. However, the presence of leucine or glycerophosphate enhances both growth and cellular toxin level. Moreover, the presence of ammonia and incubation in continuous darkness do not favor the toxin production. Currently, studies on the mechanism of this biotoxin production are scant. Full genome sequencing of dinoflagellates is challenging because of the massive genomic size; however, current advanced molecular and omics technologies may provide valuable insight into the biotoxin production mechanism and novel research perspectives on microalgae. This review presents a comprehensive analysis on the effects of various nutritional and physical factors on the OA and DTX production in the DSP toxin-producing Prorocentrum spp. Moreover, the applications of the current molecular technologies in the study on the mechanism of DSP toxin production are discussed.

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“…Cellular Physiology and Biochemistry gastrointestinal motility and secretion due to OA induced changes in NPY [10]. TEM analysis revealed that neither OA nor DTX1 changed tight junctions, therefore fluid accumulation in the intestine and diarrhea could not be related to increase in paracellular permeability along with tight junctions disruption as was previously suggested [11].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 60%

“…It was previously suggested that PPs inhibition was responsible for the diarrheic effect of OA and derivatives [8]. However, other actions not related to PP inhibition [9,10], have been reported suggesting that the mechanism of toxicity of these compounds must be re-evaluated [11].…”

Section: Introductionmentioning

confidence: 99%

Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study

Abal

Louzao

Suzuki

et al. 2018

Cell Physiol Biochem

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Background/Aims: Okadaic acid (OA) and the structurally related compounds dinophysistoxin-1 (DTX1) and dinophysistoxin-2 (DTX2) are marine phycotoxins that cause diarrheic shellfish poisoning (DSP) in humans due to ingestion of contaminated shellfish. In order to guarantee consumer protection, the regulatory authorities have defined the maximum level of DSP toxins as 160 µg OA equivalent kg^-1 shellfish meat. For risk assessment and overall toxicity determination, knowledge of the relative toxicities of each analogue is required. In absence of enough information from human intoxications, oral toxicity in mice is the most reliable data for establishing Toxicity Equivalence Factors (TEFs). Methods: Toxins were administered to mice by gavage, after that the symptomatology and mice mortality was registered over a period of 24 h. Organ damage data were collected at necropsy and transmission electron microscopy (TEM) was used for ultrastructural studies. Toxins in urine, feces and blood were analyzed by HPLC-MS/MS. The evaluation of in vitro potencies of OA, DTX1 and DTX2 was performed by the protein phosphatase 2A (PP2A) inhibition assay. Results: Mice that received DSP toxins by gavage showed diarrhea as the main symptom. Those toxins caused similar gastrointestinal alterations as well as intestine ultrastructural changes. However, DSP toxins did not modify tight junctions to trigger diarrhea. They had different toxicokinetics and toxic potency. The lethal dose 50 (LD₅₀) was 487 µg kg^-1 bw for DTX1, 760 µg kg^-1 bw for OA and 2262 µg kg^-1 bw for DTX2. Therefore, the oral TEF values are: OA = 1, DTX1 = 1.5 and DTX2 = 0.3. Conclusion: This is the first comparative study of DSP toxins performed with accurate well-characterized standards and based on acute toxicity data. Results confirmed that DTX1 is more toxic than OA by oral route while DTX2 is less toxic. Hence, the current TEFs based on intraperitoneal toxicity should be modified. Also, the generally accepted toxic mode of action of this group of toxins needs to be reevaluated.

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Diarrhetic effect of okadaic acid could be related with its neuronal action: Changes in neuropeptide Y

Cited by 36 publications

References 53 publications

Toxins of Okadaic Acid-Group Increase Malignant Properties in Cells of Colon Cancer

Toxins of Okadaic Acid-Group Increase Malignant Properties in Cells of Colon Cancer

The Mechanism of Diarrhetic Shellfish Poisoning Toxin Production in Prorocentrum spp.: Physiological and Molecular Perspectives

Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study

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