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Marine Drugs Aug 2022Okadaic acid (OA) is a marine biotoxin associated with diarrhetic shellfish poisoning (DSP), posing some threat to human beings. The oral toxicity of OA is complex, and...
Okadaic acid (OA) is a marine biotoxin associated with diarrhetic shellfish poisoning (DSP), posing some threat to human beings. The oral toxicity of OA is complex, and the mechanism of toxicity is not clear. The interaction between OA and gut microbiota may provide a reasonable explanation for the complex toxicity of OA. Due to the complex environment in vivo, an in vitro study may be better for the interactions between OA and gut microbiome. Here, we conducted an in vitro fermentation experiment of gut bacteria in the presence of 0-1000 nM OA. The remolding ability of OA on bacterial composition was investigated by 16S rDNA sequencing, and differential metabolites in fermentation system with different concentration of OA was detected by LC-MS/MS. We found that OA inhibited some specific bacterial genera but promoted others. In addition, eight possible metabolites of OA, including dinophysistoxin-2 (DTX-2), were detected in the fermentation system. The abundance of was strongly correlated with the possible metabolites of OA, suggesting that may be involved in the metabolism of OA in vitro. Our findings confirmed the direct interaction between OA and gut bacteria, which helps to reveal the metabolic process of OA and provide valuable evidence for elucidating the complex toxicity of OA.
Topics: Animals; Chromatography, Liquid; DNA, Ribosomal; Gastrointestinal Microbiome; Humans; Marine Toxins; Okadaic Acid; Pyrans; Rats; Tandem Mass Spectrometry
PubMed: 36135745
DOI: 10.3390/md20090556 -
Toxicology May 2022Okadaic acid (OA, C₄₄H₆₈O₁₃) is a neurotoxin and phosphatase inhibitor produced by several dinoflagellate species. OA is widely known to accumulate in black...
Okadaic acid (OA, C₄₄H₆₈O₁₃) is a neurotoxin and phosphatase inhibitor produced by several dinoflagellate species. OA is widely known to accumulate in black sponges and is associated with seafood poisoning. Humans can be exposed to OA by consuming contaminated shellfish that have accumulated toxins during algal blooms. Evidence from in vitro and in vivo studies demonstrate that OA exposure causes neurotoxicity in addition to diarrheal syndrome. It is unclear whether exposure to OA affects retinal function, a part of the central nervous system. We evaluated the toxicity of OA in human retinal pigment epithelial cells (ARPE-19) and in zebrafish retinas. Cell-based assays determined that OA significantly decreased cell viability in a dose-dependent manner and increased oxidative stress, inflammation and cell death compared to the untreated control group. In the in vivo study, zebrafish embryos at 24 h post fertilization (hpf) were treated with/without OA for four days, endpoint measurements including mortality, malformations, delayed hatching, altered heartbeat and reduced movement were performed. OA exposure increased mortality, decreased hatching, heartbeat rate, and caused morphological abnormalities. OA exposure also markedly decreased the expression of antioxidant genes and a significantly increased inflammation as well as evoking a loss of photoreceptors in zebrafish embryos. The data suggest that consuming OA-contaminated seafood can induce retinal toxicity.
Topics: Animals; Humans; Inflammation; Okadaic Acid; Oxidative Stress; Retina; Zebrafish
PubMed: 35577138
DOI: 10.1016/j.tox.2022.153209 -
The FEBS Journal Dec 2008Okadaic acid (OA) and its analogs, the dinophysistoxins, are potent inhibitors of protein phosphatases 1 and 2A. This action is well known to cause diarrhea and... (Review)
Review
Okadaic acid (OA) and its analogs, the dinophysistoxins, are potent inhibitors of protein phosphatases 1 and 2A. This action is well known to cause diarrhea and gastrointestinal symptons when the toxins reach the digestive tract by ingestion of mollusks. A less well-known effect of these group of toxins is their effect in the cytoskeleton. OA has been shown to stimulate cell motility, loss of stabilization of focal adhesions and a consequent loss of cytoskeletal organization due to an alteration in the tyrosine-phosphorylated state of the focal adhesion kinases and paxillin. OA causes cell rounding and loss of barrier properties through mechanisms that probably involve disruption of filamentous actin (F-actin) and/or hyperphosphorylation and activation of kinases that stimulate tight junction disassembly. Neither methyl okadaate (a weak phosphatase inhibitor) nor OA modify the total amount of F-actin, but both toxins cause similar changes in the F-actin cytoskeleton, with strong retraction and rounding, and in many cases cell detachment. OA and dinophysistoxin-1 (35S-methylokadaic acid) cause rapid changes in the structural organization of intermediate filaments, followed by a loss of microtubules, solubilization of intermediate filament proteins, and disruption of desmosomes. The detailed pathways that coordinate all these effects are not yet known.
Topics: Actins; Animals; Cell Line, Tumor; Cytoskeleton; Diarrhea; Humans; Marine Toxins; Mollusca; Okadaic Acid; Protein Phosphatase 1; Protein Phosphatase 2; Shellfish
PubMed: 19016863
DOI: 10.1111/j.1742-4658.2008.06711.x -
Toxins Jul 2019Several planktonic dinoflagellate species of the genus produce one or two groups of lipophilic toxins: (i) okadaic acid (OA) and its derivatives, the dinophysistoxins...
Several planktonic dinoflagellate species of the genus produce one or two groups of lipophilic toxins: (i) okadaic acid (OA) and its derivatives, the dinophysistoxins (DTXs), and (ii) pectenotoxins (PTXs) [...].
Topics: Animals; Biological Monitoring; Dinoflagellida; Food Contamination; Humans; Marine Toxins; Okadaic Acid; Pyrans; Shellfish
PubMed: 31315196
DOI: 10.3390/toxins11070413 -
Marine Drugs Mar 2013Mammalian Ste20-like kinases 1 and 2 (MST1 and MST2) are activated in NIH3T3 cells exposed to okadaic acid. The Hippo pathway is a newly emerging signaling that... (Review)
Review
Mammalian Ste20-like kinases 1 and 2 (MST1 and MST2) are activated in NIH3T3 cells exposed to okadaic acid. The Hippo pathway is a newly emerging signaling that functions as a tumor suppressor. MST1 and MST2 work as core kinases of the Hippo pathway and their activities depend on the autophosphorylation, which is negatively regulated by protein phosphatase 2A (PP2A). Okadaic acid has been frequently used to enhance the phosphorylation of MST1 and MST2 and to trigger the activation of the Hippo pathway. However other components of the Hippo pathway could also be targets of okadaic acid. In this review we first briefly summarize the molecular architecture of the Hippo pathway for the reference of researchers outside the field. We explain how MST kinases are regulated by PP2A and how okadaic acid activates MST2. Thereafter we discuss which components of the Hippo pathway are candidate substrates of protein phosphatases and which points we need to consider in the usage of okadaic acid to study the Hippo pathway.
Topics: Animals; Hippo Signaling Pathway; Humans; Mice; NIH 3T3 Cells; Okadaic Acid; Phosphoprotein Phosphatases; Phosphorylation; Protein Phosphatase 2; Protein Serine-Threonine Kinases; Serine-Threonine Kinase 3; Signal Transduction
PubMed: 23493077
DOI: 10.3390/md11030896 -
Toxins Aug 2023Okadaic acid (OA), a marine biotoxin produced by microalgae, poses a significant threat to mariculture, seafood safety, and human health. The establishment of a novel,...
Okadaic acid (OA), a marine biotoxin produced by microalgae, poses a significant threat to mariculture, seafood safety, and human health. The establishment of a novel, highly sensitive detection method for OA would have significant practical and scientific implications. Therefore, the purpose of this study was to develop an innovative approach for OA detection. A competitive amplified luminescent proximity homogeneous assay (AlphaLISA) was developed using the principle of specific antigen-antibody binding based on the energy transfer between chemiluminescent microspheres. The method was non-washable, sensitive, and rapid, which could detect 2 × 10-200 ng/mL of OA within 15 min, and the detection limit was 4.55 × 10 ng/mL. The average intra- and inter-assay coefficients of variation were 2.54% and 6.26%, respectively. Detection of the actual sample results exhibited a good correlation with high-performance liquid chromatography. In conclusion, a simple, rapid, sensitive, and accurate AlphaLISA method was established for detecting OA and is expected to significantly contribute to marine biotoxin research.
Topics: Humans; Okadaic Acid; Biological Assay; Chromatography, High Pressure Liquid; Luminescent Measurements; Microalgae
PubMed: 37624258
DOI: 10.3390/toxins15080501 -
Marine Drugs Oct 2013Okadaic acid (OA) is one of the most frequent and worldwide distributed marine toxins. It is easily accumulated by shellfish, mainly bivalve mollusks and fish, and,... (Review)
Review
Okadaic acid (OA) is one of the most frequent and worldwide distributed marine toxins. It is easily accumulated by shellfish, mainly bivalve mollusks and fish, and, subsequently, can be consumed by humans causing alimentary intoxications. OA is the main representative diarrheic shellfish poisoning (DSP) toxin and its ingestion induces gastrointestinal symptoms, although it is not considered lethal. At the molecular level, OA is a specific inhibitor of several types of serine/threonine protein phosphatases and a tumor promoter in animal carcinogenesis experiments. In the last few decades, the potential toxic effects of OA, beyond its role as a DSP toxin, have been investigated in a number of studies. Alterations in DNA and cellular components, as well as effects on immune and nervous system, and even on embryonic development, have been increasingly reported. In this manuscript, results from all these studies are compiled and reviewed to clarify the role of this toxin not only as a DSP inductor but also as cause of alterations at the cellular and molecular levels, and to highlight the relevance of biomonitoring its effects on human health. Despite further investigations are required to elucidate OA mechanisms of action, toxicokinetics, and harmful effects, there are enough evidences illustrating its toxicity, not related to DSP induction, and, consequently, supporting a revision of the current regulation on OA levels in food.
Topics: Animals; Environmental Monitoring; Humans; Marine Toxins; Okadaic Acid; Shellfish Poisoning
PubMed: 24184795
DOI: 10.3390/md11114328 -
Food and Chemical Toxicology : An... Nov 2022Okadaic acid (OA) is an important marine lipophilic phycotoxin responsible for diarrhetic shellfish poisoning (DSP). This toxin inhibits protein phosphatases (PPs) like...
Okadaic acid (OA) is an important marine lipophilic phycotoxin responsible for diarrhetic shellfish poisoning (DSP). This toxin inhibits protein phosphatases (PPs) like PP2A and PP1, though, this action does not explain OA-induced toxicity and symptoms. Intestinal epithelia comprise the defence barrier against external agents where transport of fluid and electrolytes from and to the lumen is a tightly regulated process. In some intoxications this balance becomes dysregulated appearing diarrhoea. Therefore, we evaluated diarrhoea in orally OA-treated mice as well as in mice pre-treated with several doses of cyproheptadine (CPH) and then treated with OA at different times. We assessed stools electrolytes and ultrastructural alteration of the intestine, particularly evaluating tight and adherens junctions. We detected increased chloride and sodium faecal concentrations in the OA-exposed group, suggesting a secretory diarrhoea. Pre-treatment with CPH maintains chloride concentration in values similar to control mice. Intestinal cytomorphological alterations were observed for OA mice, whereas CPH pre-treatment attenuated OA-induced damage in proximal colon and jejunum at 2 h. Conversely, tight junctions' distance was only affected by OA in jejunum at the moment diarrhoea occurred. In this study we found cellular mechanisms by which OA induced diarrhoea revealing the complex toxicity of this compound.
Topics: Animals; Mice; Chlorides; Cyproheptadine; Diarrhea; Okadaic Acid; Phosphoprotein Phosphatases; Sodium; Tight Junctions; Jejunum
PubMed: 36206954
DOI: 10.1016/j.fct.2022.113449 -
Marine Drugs Oct 2015Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of... (Review)
Review
Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of apoptotic cell death. Their intracellular targets are the major serine/threonine protein phosphatases. This review summarizes mechanisms believed to be responsible for the death induction and tumor promotion with focus on the interdependent production of reactive oxygen species (ROS) and activation of Ca(2+)/calmodulin kinase II (CaM-KII). New data are presented using inhibitors of specific ROS producing enzymes to curb nodularin/MC-induced liver cell (hepatocyte) death. They indicate that enzymes of the arachidonic acid pathway, notably phospholipase A2, 5-lipoxygenase, and cyclooxygenases, may be required for nodularin/MC-induced (and presumably OA-induced) cell death, suggesting new ways to overcome at least some aspects of OA and MC toxicity.
Topics: Animals; Apoptosis; Carcinogens; Cell Death; Enzyme Inhibitors; Humans; Marine Toxins; Microcystins; Okadaic Acid; Oxazoles; Peptides, Cyclic; Phosphoprotein Phosphatases; Reactive Oxygen Species
PubMed: 26506362
DOI: 10.3390/md13106505 -
Organic Letters Jul 2023After a recent total synthesis had resolved all issues surrounding the constitution and stereostructure of prorocentin, it was possible to devise a new approach aiming...
After a recent total synthesis had resolved all issues surrounding the constitution and stereostructure of prorocentin, it was possible to devise a new approach aiming at an improved supply of this scarce marine natural product; this compound is a cometabolite of the prototypical phosphatase inhibitor okadaic acid but still awaits detailed biological profiling. The revised entry starts from 2-deoxy-d-glucose; keys to success were a telescoped hemiacetal reduction/acetal cleavage and an exquisitely selective gold/Brønsted acid-cocatalyzed spiroacetalization.
Topics: Okadaic Acid; Enzyme Inhibitors; Furans; Acetals
PubMed: 37358405
DOI: 10.1021/acs.orglett.3c01720