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EXCLI Journal 2022Okadaic acid (OA) is an algae-produced lipophilic marine biotoxin that accumulates in the fatty tissue of filter-feeding shellfish. Ingestion of contaminated shellfish...
Okadaic acid (OA) is an algae-produced lipophilic marine biotoxin that accumulates in the fatty tissue of filter-feeding shellfish. Ingestion of contaminated shellfish leads to the diarrheic shellfish poisoning syndrome. Furthermore, several other effects of OA like genotoxicity, liver toxicity and tumor-promoting properties have been observed, probably linked to the phosphatase-inhibiting properties of the toxin. It has been shown that at high doses OA can disrupt the physical barrier of the intestinal epithelium. As the intestine and the liver do not only constitute a physical, but also a metabolic barrier against xenobiotic exposure, we here investigated the impact of OA on the expression of cytochrome P450 (CYP) enzymes and transporter proteins in human HepaRG cells liver cells at non-cytotoxic concentrations. The interplay of OA with known CYP inducers was also studied. Data show that the expression of various xenobiotic-metabolizing CYPs was downregulated after exposure to OA. Moreover, OA was able to counteract the activation of CYPs by their inducers. A number of transporters were also mainly downregulated. Overall, we demonstrate that OA has a significant effect on xenobiotic metabolism barrier in liver cells, highlighting the possibility for interactions of OA exposure with the metabolism of drugs and xenobiotics.
PubMed: 36172076
DOI: 10.17179/excli2022-5033 -
Angewandte Chemie (International Ed. in... Apr 2024Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently,...
Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (K=6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.
Topics: Humans; Alzheimer Disease; Neurons; Okadaic Acid; Phosphorylation; tau Proteins; Tauopathies; Aptamers, Nucleotide
PubMed: 38407551
DOI: 10.1002/anie.202402007 -
Toxins Nov 2022Because of their trace existence, exquisite structure and unique role, highly toxic marine biotoxins have always led to the development of natural product...
Because of their trace existence, exquisite structure and unique role, highly toxic marine biotoxins have always led to the development of natural product identification, structure and function research, chemistry and biosynthesis, and there are still many deficiencies in the injury and protection of highly toxic organisms, toxin biosynthesis, rapid detection, poisoning and diagnosis and treatment. In this study, a mouse intestine organoid (MIO) model was constructed to explore the effects of the marine toxins okadaic acid (OA) and conotoxin (CgTx) on MIO. The results showed that the cell mortality caused by the two toxins at middle and high concentrations was significantly higher than the cell mortality of the control group, the ATPase activity in each group exposed to OA was significantly lower than the ATPase activity of the control group, all the CgTx groups were significantly higher than that of the control group, and the number of apoptotic cells was not significantly higher than the number of apoptotic cells of the control group. Through RNA-Seq differential genes, Gene Ontology (GO) and pathway analysis, and Gene Set Enrichment Analysis (GSEA) experimental results, it was demonstrated that OA reduced cell metabolism and energy production by affecting cell transcription in MIO. Ultimately, cell death resulted. In contrast, CgTx upregulated the intracellular hormone metabolism pathway by affecting the nuclear receptor pathway of MIO, which resulted in cell death and the generation of energy in large amounts.
Topics: Animals; Mice; Adenosine Triphosphatases; Conotoxins; Intestines; Okadaic Acid; Organoids; Cell Death
PubMed: 36548726
DOI: 10.3390/toxins14120829 -
Toxicon : Official Journal of the... Jul 2019Tetrodotoxin (TTX) is a neurotoxin mainly responsible for severe neurological illness, and okadaic acid (OA) is another important lipophilic toxin to humans. In this...
Tetrodotoxin (TTX) is a neurotoxin mainly responsible for severe neurological illness, and okadaic acid (OA) is another important lipophilic toxin to humans. In this study, we developed a gold strip for simultaneous detection of OA and TTX in real seafood samples. In the assay, the prepared nanoparticles (about 40 nm) was applied to conjugate with specific monoclonal antibodies against OA and TTX, and the resulted mixtures were used to capture its corresponding toxin in test strip. OA and TTX conjugates were coated as two test lines on the nitrocellulose membrane, and goat anti-mouse IgG was used to form the control line, forming three lines on the test strip. The visual detection limits (vLOD) of this immunoassay for OA and TTX were 0.75 and 15 ng/mL, respectively, and no cross reactions were observed in the process of detection. The visual assay for OA and TTX detection could be finished within 10 min. This study might provide a feasible method and good understanding for rapidly simultaneous detection for toxins based on immunoassay.
Topics: Cross Reactions; Food Contamination; Gold Colloid; Immunoassay; Okadaic Acid; Seafood; Tetrodotoxin
PubMed: 31029635
DOI: 10.1016/j.toxicon.2019.04.011 -
Archives of Toxicology Oct 2021Diarrhetic shellfish-poisoning (DSP) toxins such as okadaic acid and dinophysistoxins harm the human gastrointestinal tract, and therefore, their levels are regulated to...
The diarrhetic shellfish-poisoning toxin, okadaic acid, provokes gastropathy, dysbiosis and susceptibility to bacterial infection in a non-rodent bioassay, Galleria mellonella.
Diarrhetic shellfish-poisoning (DSP) toxins such as okadaic acid and dinophysistoxins harm the human gastrointestinal tract, and therefore, their levels are regulated to an upper limit of 160 μg per kg tissue to protect consumers. Rodents are used routinely for risk assessment and studies concerning mechanisms of toxicity, but there is a general move toward reducing and replacing vertebrates for these bioassays. We have adopted insect larvae of the wax moth Galleria mellonella as a surrogate toxicology model. We treated larvae with environmentally relevant doses of okadaic acid (80-400 μg/kg) via intrahaemocoelic injection or gavage to determine marine toxin-related health decline: (1) whether pre-exposure to a sub-lethal dose of toxin (80 μg/kg) enhances susceptibility to bacterial infection, or (2) alters tissue pathology and bacterial community (microbiome) composition of the midgut. A sub-lethal dose of okadaic acid (80 μg/kg) followed 24 h later by bacterial inoculation (2 × 10 Escherichia coli) reduced larval survival levels to 47%, when compared to toxin (90%) or microbial challenge (73%) alone. Histological analysis of the midgut depicted varying levels of tissue disruption, including nuclear aberrations associated with cell death (karyorrhexis, pyknosis), loss of organ architecture, and gross epithelial displacement into the lumen. Moreover, okadaic acid presence in the midgut coincided with a shift in the resident bacterial population over time in that substantial reductions in diversity (Shannon) and richness (Chao-1) indices were observed at 240 μg toxin per kg. Okadaic acid-induced deterioration of the insect alimentary canal resembles those changes reported for rodent bioassays.
Topics: Animals; Biological Assay; Disease Susceptibility; Dose-Response Relationship, Drug; Dysbiosis; Escherichia coli; Escherichia coli Infections; Larva; Moths; Okadaic Acid; Toxicity Tests
PubMed: 34374792
DOI: 10.1007/s00204-021-03132-x -
Toxicon : Official Journal of the... Jun 2021Prorocentrum lima (CSIRCSMCRI005) was isolated from the coastal seawater of Thonithurai, Tamil Nadu, India. Morphology of the isolate was studied using light microscopy...
Prorocentrum lima (CSIRCSMCRI005) was isolated from the coastal seawater of Thonithurai, Tamil Nadu, India. Morphology of the isolate was studied using light microscopy (LM) and scanning electron microscopy (SEM) while phylogenetic analyses of the internal transcribed spacer region (ITS1-5.8s-ITS2), 18S rDNA, and large subunit (LSU) rDNA were also carried out. Growth of the isolate was studied, and okadaic acid (OA) production was examined using liquid chromatography with electrospray ionization and quadrupole time of flight mass spectroscopy (LC-ESI-Q-ToF-MS). Morphological features observed including oval cell shape with a broad middle region, narrow anterior and round posterior end, large central pyrenoid with starch sheath, smooth thecal surface, and V-shaped periflagellar area consisting of eight platelets matched with the description of the type species and those reported elsewhere. The ITS, 18S, and LSU sequence phylogenetic analysis revealed that the isolate was closely related to other strains reported from the pacific. The growth rate (μ) was 0.05 div. day. P. lima CSIRCSMCRI005 produced okadaic acid and related esters. The production of free and total OA was 20.12 ± 4.77 and 22.30 fg cell respectively. The findings of this study contribute useful information concerning the regional risk of diarrheic shellfish poisoning in the North East Indian Ocean and the global distribution and toxic potential of Prorocentrum lima. Further studies on the ecophysiology of this strain will be helpful. This manuscript reports the detailed morphological, phylogenetic, and toxicological characterization of this species from the Bay of Bengal and the North Indian Ocean as a whole.
Topics: Bays; Dinoflagellida; India; Indian Ocean; Marine Toxins; Okadaic Acid; Phylogeny
PubMed: 33781795
DOI: 10.1016/j.toxicon.2021.03.017 -
Harmful Algae Mar 2021Published baseline data on biotoxin exposure in cetaceans is sparse but critical for interpreting mortality events as harmful algal blooms increase in frequency and...
Published baseline data on biotoxin exposure in cetaceans is sparse but critical for interpreting mortality events as harmful algal blooms increase in frequency and duration. We present the first synthesis of domoic acid (DA), saxitoxin (STX), okadaic acid (OA), and microcystin detections in the feces and urine of stranded and bycaught southern California cetaceans, over an 18 year period (2001-2018), along with corresponding stomach content data. DA was detected in 13 out of 19 cetacean species, most often in harbor porpoise (Phocoena phocoena) (81.8%, n = 22) and long-beaked common dolphins (Delphinus delphis bairdii) (74%, n = 231). Maximum DA concentrations of 324,000 ng/g in feces and 271, 967 ng/ml in urine were observed in D. d. bairdii. DA was detected more frequently and at higher concentrations in male vs. female D. d. bairdii. Higher fecal DA concentrations in D. d. bairdii were associated with a greater proportion of northern anchovy (Engraulis mordax) in the diet, indicating it may be a primary vector of DA. Fecal DA concentrations for D. d. bairdii off Point Conception were greater than those from animals sampled off Los Angeles and San Diego counties, reflecting greater primary productivity and higher Pseudo-nitzschia spp. abundance in that region and a greater abundance of E. mordax in the diet. STX was detected at low levels (fecal max = 7.5 ng/g, urine max = 17 ng/ml) in 3.6% (n = 165) of individuals from 3 out of 11 species. The occurrence of E. mordax in 100% of the 3 examined stomachs suggests this species could be a primary vector of the detected STX. OA was detected in 2.4% of tested individuals (n = 85) at a maximum fecal concentration of 422.8 ng/g. Microcystin was detected in 14.3% (n = 7) of tested individuals with a maximum liver concentration of 96.8 ppb.
Topics: Animals; California; Cetacea; Environmental Monitoring; Harmful Algal Bloom; Saxitoxin
PubMed: 33980440
DOI: 10.1016/j.hal.2021.102000 -
Marine Drugs Nov 2016Okadaic acid (OA) and the closely related dinophysistoxins (DTXs) are algal toxins that accumulate in shellfish and are known serine/threonine protein phosphatase...
Okadaic acid (OA) and the closely related dinophysistoxins (DTXs) are algal toxins that accumulate in shellfish and are known serine/threonine protein phosphatase (ser/thr PP) inhibitors. Phosphatases are important modulators of enzyme activity and cell signaling pathways. However, the interactions between the OA/DTX toxins and phosphatases are not fully understood. This study sought to identify phosphatase targets and characterize their structure-activity relationships (SAR) with these algal toxins using a combination of phosphatase activity and cytotoxicity assays. Preliminary screening of 21 human and yeast phosphatases indicated that only three ser/thr PPs (PP2a, PP1, PP5) were inhibited by physiologically saturating concentrations of DTX2 (200 nM). SAR studies employed naturally-isolated OA, DTX1, and DTX2, which vary in degree and/or position of methylation, in addition to synthetic 2--DTX2. OA/DTX analogs induced cytotoxicity and inhibited PP activity with a relatively conserved order of potency: OA = DTX1 ≥ DTX2 >> 2--DTX. The PPs were also differentially inhibited with sensitivities of PP2a > PP5 > PP1. These findings demonstrate that small variations in OA/DTX toxin structures, particularly at the head region (i.e., C1/C2), result in significant changes in toxicological potency, whereas changes in methylation at C31 and C35 (tail region) only mildly affect potency. In addition to this being the first study to extensively test OA/DTX analogs' activities towards PP5, these data will be helpful for accurately determining toxic equivalence factors (TEFs), facilitating molecular modeling efforts, and developing highly selective phosphatase inhibitors.
Topics: Antineoplastic Agents; Cell Survival; Enzyme Inhibitors; Eutrophication; Humans; Jurkat Cells; Marine Toxins; Okadaic Acid; Phosphoprotein Phosphatases; Pyrans; Shellfish Poisoning; Structure-Activity Relationship
PubMed: 27827901
DOI: 10.3390/md14110207 -
Harmful Algae Mar 2017Many toxic secondary metabolites used for defense are also toxic to the producing organism. One important way to circumvent toxicity is to store the toxin as an inactive...
Many toxic secondary metabolites used for defense are also toxic to the producing organism. One important way to circumvent toxicity is to store the toxin as an inactive precursor. Several sulfated diesters of the diarrhetic shellfish poisoning (DSP) toxin okadaic acid have been reported from cultures of various dinoflagellate species belonging to the genus Prorocentrum. It has been proposed that these sulfated diesters are a means of toxin storage within the dinoflagellate cell, and that a putative enzyme mediated two-step hydrolysis of sulfated diesters such as DTX-4 and DTX-5 initially leads to the formation of diol esters and ultimately to the release of free okadaic acid. However, only one diol ester and no sulfated diesters of DTX-1, a closely related DSP toxin, have been isolated leading some to speculate that this toxin is not stored as a sulfated diester and is processed by some other means. DSP components in organic extracts of two large scale Prorocentrum lima laboratory cultures have been investigated. In addition to the usual suite of okadaic acid esters, as well as the free acids okadaic acid and DTX-1, a group of corresponding diol- and sulfated diesters of both okadaic acid and DTX-1 have now been isolated and structurally characterized, confirming that both okadaic acid and DTX-1 are initially formed in the dinoflagellate cell as the non-toxic sulfated diesters.
Topics: Animals; Dinoflagellida; Marine Toxins; Okadaic Acid; Pyrans; Shellfish Poisoning
PubMed: 28366404
DOI: 10.1016/j.hal.2017.01.012 -
Bulletin of Experimental Biology and... Jan 2022This study was performed to investigate whether okadaic acid (200 ng/kg) produces a protective effect in experimental liver injury induced by intragastric administration...
This study was performed to investigate whether okadaic acid (200 ng/kg) produces a protective effect in experimental liver injury induced by intragastric administration of 1000, 2000, and 4000 mg/kg amoxicillin in Sprague-Dawley rats (n=50). The control group was given carboxymethylcellulose sodium solution. Liver injury was assessed by the relative organ weight index, serum ALT activity, and liver malondialdehyde content. Histopathological examination of the liver from rats treated with amoxicillin revealed cell swelling, congestion, apoptosis, and necrosis. The relative liver weight index, ALT activity, and liver malondialdehyde content in these animals were higher than in the control. Administration of okadaic acid reduced the degree of amoxicillin-induced damage to hepatocytes. Thus, okadaic acid can alleviate liver injury caused by amoxicillin.
Topics: Alanine Transaminase; Amoxicillin; Animals; Chemical and Drug Induced Liver Injury; Liver; Malondialdehyde; Okadaic Acid; Rats; Rats, Sprague-Dawley
PubMed: 35006487
DOI: 10.1007/s10517-022-05386-6