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Aquatic Toxicology (Amsterdam,... Jul 2023The lipophilic okadaic acid (OA)-group toxins produced by some species of Dinophysis spp. and Prorocentrum spp. marine dinoflagellates have been frequently and widely...
The lipophilic okadaic acid (OA)-group toxins produced by some species of Dinophysis spp. and Prorocentrum spp. marine dinoflagellates have been frequently and widely detected in natural seawater environments, e.g. 2.1∼1780 ng/L in Spanish sea and 5.63∼27.29 ng/L in the Yellow Sea of China. The toxicological effects of these toxins dissolved in seawater on marine fish is still unclear. Effects of OA on the embryonic development and 1-month old larvae of marine medaka (Oryzias melastigma) were explored and discussed in this study. Significantly increased mortality and decreased hatching rates occurred for the medaka embryos exposed to OA at 1.0 μg/mL. Diverse malformations including spinal curvature, dysplasia and tail curvature were also observed in the embryos exposed to OA and the heart rates significantly increased at 11 d post fertilization. The 96 h LC of OA for 1-month old larvae was calculated at 3.80 μg/mL. The reactive oxygen species (ROS) was significantly accumulated in medaka larvae. Catalase (CAT) enzyme activity was significantly increased in 1-month old larvae. Acetylcholinesterase (AChE) activity significantly increased with a dose-dependent pattern in 1-month old larvae. Differentially expressed genes (DEGs) were enriched in 11 KEGG pathways with Q value < 0.05 in 1-month old medaka larvae exposed to OA at 0.38 μg/mL for 96 h, which were mainly related to cell division and proliferation, and nervous system. Most of DEGs involved in DNA replication, cell cycle, nucleotide excision repair, oocyte meiosis, and mismatch repair pathways were significantly up-regulated, while most of DEGs involved in synaptic vesicle cycle, glutamatergic synapse, and long-term potentiation pathways were markedly down-regulated. This transcriptome analysis demonstrated that a risk of cancer developing was possibly caused by OA due to DNA damage in marine medaka larvae. In addition, the neurotoxicity of OA was also testified for marine fish, which potentially cause major depressive disorder (MDD) via the up-regulated expression of NOS1 gene. The genotoxicity and neurotoxicity of OA to marine fish should be paid attention to and explored further in the future.
Topics: Animals; Oryzias; Okadaic Acid; Acetylcholinesterase; Depressive Disorder, Major; Water Pollutants, Chemical; Dinoflagellida; Larva
PubMed: 37196507
DOI: 10.1016/j.aquatox.2023.106576 -
Cells Feb 2023Okadaic acid (OA) is a marine biotoxin that is produced by algae and accumulates in filter-feeding shellfish, through which it enters the human food chain, leading to...
Okadaic acid (OA) is a marine biotoxin that is produced by algae and accumulates in filter-feeding shellfish, through which it enters the human food chain, leading to diarrheic shellfish poisoning (DSP) after ingestion. Furthermore, additional effects of OA have been observed, such as cytotoxicity. Additionally, a strong downregulation of the expression of xenobiotic-metabolizing enzymes in the liver can be observed. The underlying mechanisms of this, however, remain to be examined. In this study, we investigated a possible underlying mechanism of the downregulation of cytochrome P450 (CYP) enzymes and the nuclear receptors pregnane X receptor (PXR) and retinoid-X-receptor alpha (RXRα) by OA through NF-κB and subsequent JAK/STAT activation in human HepaRG hepatocarcinoma cells. Our data suggest an activation of NF-κB signaling and subsequent expression and release of interleukins, which then activate JAK-dependent signaling and thus STAT3. Moreover, using the NF-κB inhibitors JSH-23 and Methysticin and the JAK inhibitors Decernotinib and Tofacitinib, we were also able to demonstrate a connection between OA-induced NF-κB and JAK signaling and the downregulation of CYP enzymes. Overall, we provide clear evidence that the effect of OA on the expression of CYP enzymes in HepaRG cells is regulated through NF-κB and subsequent JAK signaling.
Topics: Humans; Cytochrome P-450 Enzyme System; Liver Neoplasms; NF-kappa B; Okadaic Acid; Signal Transduction; Xenobiotics; Janus Kinases; STAT Transcription Factors
PubMed: 36899906
DOI: 10.3390/cells12050770 -
Neurotoxicity Research Apr 2019Alzheimer's disease (AD) is the most common cause of progressive decline of memory function in aged humans. To study about a disease mechanism and progression, animal...
Alzheimer's disease (AD) is the most common cause of progressive decline of memory function in aged humans. To study about a disease mechanism and progression, animal models for the specific disease are needed. For AD, although highly valid animal models exist, none of the existing models recapitulates all aspects of human AD. The pathogenic mechanisms involved in AD are diverse and thus it is difficult to recapitulate human AD in model organisms. Intracerebroventricular (ICV) injection of okadaic acid (OKA), a protein phosphatase 2A (PP2A) inhibitor, in rats causes neurotoxicity associated with neurofibrillary degeneration. However, this model lacks amyloid pathology as observed in AD. We aimed at combining two different treatments and hence producing a better animal model of AD which may mimic most of the neuropathological, neurobehavioral, and neurochemical changes observed in AD. For this, OKA (200 ng) was microinjected bilaterally into the hippocampus of male Wistar rats followed by exposure of same rats to hypoxic conditions (10%) for 3 days. The result of which, the combination model exhibited tau hyperphosphorylation along with Aβ upregulation as evident by western blotting and immunohistochemistry. The observed changes were accompanied with dysfunction of neurotransmitter system, i.e., decreased acetylcholine activity and expression. This combinatorial model also exhibited cognitive deficiency which was assessed by Morris water maze and avoidance tests along with enhanced oxidative stress which is thought to be a major player in AD pathogenesis. Taken together, we established an easily reproducible and reliable rat model for sporadic dementia of Alzheimer's type in rats which allows effective testing of new therapeutic strategies.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Avoidance Learning; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Hypoxia; Male; Maze Learning; Microinjections; Neurons; Okadaic Acid; Oxidative Stress; Rats, Wistar; Stereotaxic Techniques
PubMed: 30729451
DOI: 10.1007/s12640-019-0005-9 -
Molecular Neurobiology Dec 2014Okadaic acid (OKA), a polyether C38 fatty acid toxin extracted from a black sponge Hallichondria okadaii, is a potent and selective inhibitor of protein phosphatase, PP1... (Review)
Review
Okadaic acid (OKA), a polyether C38 fatty acid toxin extracted from a black sponge Hallichondria okadaii, is a potent and selective inhibitor of protein phosphatase, PP1 and PP2A. OKA has been proved to be a powerful probe for studying the various regulatory mechanisms and neurotoxicity. Because of its property to inhibit phosphatase activity, OKA is associated with protein phosphorylation; it is implicated in hyperphosphorylation of tau and in later stages causes Alzhiemer's disease (AD)-like pathology. AD is a progressive neurodegenerative disorder, pathologically characterized by extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The density of tau tangles in AD pathology is associated with cognitive dysfunction. Recent studies have highlighted the importance of serine/threonine protein phosphatases in many processes including apoptosis and neurotoxicity. Although OKA causes neurotoxicity by various pathways, the exact mechanism is still not clear. The activation of major kinases, such as Ser/Thr, MAPK, ERK, PKA, JNK, PKC, CaMKII, Calpain, and GSK3β, in neurons is associated with AD pathology. These kinases, associated with abnormal hyperphosphorylation of tau, suggest that the cascade of these kinases could exclusively be involved in the pathogenesis of AD. The activity of serine/threonine protein phosphatases needs extensive study as these enzymes are potential targets for novel therapeutics with applications in many diseases including cancer, inflammatory diseases, and neurodegeneration. There is a need to pay ample attention on MAPK kinase pathways in AD, and OKA can be a better tool to study cellular and molecular mechanism for AD pathology. This review elucidates the regulatory mechanism of PP2A and MAPK kinase and their possible mechanisms involved in OKA-induced apoptosis, neurotoxicity, and AD-like pathology.
Topics: Alzheimer Disease; Animals; Humans; Neurons; Neurotoxins; Okadaic Acid; Phosphorylation; Signal Transduction
PubMed: 24710687
DOI: 10.1007/s12035-014-8699-4 -
The Science of the Total Environment Dec 2023As an emerging environmental pollutant, nanoplastics (NPs) have attracted wide attention in terms of their impact on the ecological environment and human health....
As an emerging environmental pollutant, nanoplastics (NPs) have attracted wide attention in terms of their impact on the ecological environment and human health. Currently, researches on the cytotoxicity of NPs mainly focus on oxidative stress, damage to the cell membrane and organelles, induction of immune response and genotoxicity. Okadaic acid (OA) is the main component of diarrheal shellfish toxin. Based on the previous combined toxicity exploration of polystyrene (PS) NPs and (OA) to human gastric adenocarcinoma (AGS) cells, cell-derived exosomes were extracted and exosomal miRNA profiles were analyzed for the first time in this study. The results showed that the composition of miRNAs varied after the exposure of NPs and OA. Specifically, the expression of miR-1-3p in both PS-Exo and PS-OA-Exo was significantly reduced. And the expression of miR-1248 was upregulated most significantly by comparing the DE miRNAs between PS-Exo and PS-OA-Exo. MiR-1-3p and miR-1248 may be the key genes for the combined toxicity of NPs and OA. After analysis, we found that both the decreased expression of miR-1-3p and the increased expression of miR-1248 can increase the expression of FN1 and affect DNA replication, which was surprisingly consistent with the results of our previous cytotoxicity studies. Since exosomal miRNAs are selectively encapsulated by donor cell, we speculate that the changes of exosomal miRNAs may due to the synchronous changes of intracellular environment and the downregulation of intracellular FN1 may be attributed to decreased expression of miR-1-3p and increased expression of miR-1248 in donor cells. Accordingly, we come to the conclusion that the changes of miRNAs in the exosomes derived from AGS cells after environmental stimulation could reflect the biological effects of donor cells.
Topics: Humans; MicroRNAs; Microplastics; Okadaic Acid; Down-Regulation
PubMed: 37722421
DOI: 10.1016/j.scitotenv.2023.167010 -
Neurobiology of Learning and Memory Feb 2019Protein phosphorylation states have a pivotal role in regulation of synaptic plasticity and long-term modulation of synaptic transmission. Serine/threonine protein...
Protein phosphorylation states have a pivotal role in regulation of synaptic plasticity and long-term modulation of synaptic transmission. Serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) have a critical effect on various regulatory mechanisms involved in synaptic plasticity, learning and memory. Okadaic acid (OKA), a potent inhibitor of PP1 and PP2A, reportedly leads to cognitive decline and Alzheimer's disease (AD)-like pathology. The aim of this study was to examine the effect of OKA on electrophysiological characteristics of hippocampal dentate gyrus (DG) neurons in vivo. Male Wistar rats were divided into two control and OKA groups. OKA was injected intracerebroventricularly (i.c.v.) into lateral ventricles and after two weeks the long-term potentiation (LTP) and paired-pulse responses recorded from hippocampal perforant path-DG synapses in order to assess short-term and long-term synaptic plasticity. Results of this study revealed that OKA-induced inhibition of PP1 and PP2A activity drastically attenuates the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude following paired pulse and high frequency stimulation (HFS) of hippocampal DG neurons indicating pre- and post-synaptic involvement in electrical activity of these neurons. Administration of OKA impaired the short-term and long-term spatial memories conducted by Y-maze and passive avoidance tests, respectively. OKA-induced attenuation in electrophysiological activity and consequent memory deficits also provide a beneficial tool for studying neurodegenerative disorders such as AD.
Topics: Animals; Behavior, Animal; Dentate Gyrus; Disease Models, Animal; Enzyme Inhibitors; Injections, Intraventricular; Male; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Neuronal Plasticity; Okadaic Acid; Protein Phosphatase 1; Protein Phosphatase 2; Rats; Rats, Wistar; Spatial Memory
PubMed: 30630043
DOI: 10.1016/j.nlm.2019.01.007 -
Journal of Chromatography. A Oct 2023A novel three-dimensional covalent organic framework (3D-COF) with content-tunable and active hydroxyl groups (OH) on the pore walls was developed and adopted for the...
A novel three-dimensional covalent organic framework (3D-COF) with content-tunable and active hydroxyl groups (OH) on the pore walls was developed and adopted for the high-performance capture of okadaic acid (OA) marine toxins. Using pore-surface engineering, the integration of linear building blocks (4,4'-diamino-3,3'-biphenyldiol, BD(OH) and benzidine, BD) with the 3D structural building block backbone (4,4',4'',4'''-methane-tetrayltetrabenzaldehyde, TFPM) was achieved. By adjusting the ratio of BD(OH), functional multicomponent-COFs [OH]-BD-TFPM COFs (X = 25%) were synthesized, which offered ideal access to convert a conventional COF into a functional platform with multiple-mode interactions of hydrophobic and hydrophilic groups for OA capture. [OH]-BD-TFPM was characterized using SEM, XRD, FT-IR, and BET. The adsorption features and analytical performance of OA were screened and evaluated. Optimization of dispersive solid-phase extraction using [OH]-BD-TFPM was accomplished, and the method was verified for sensitive quantitative detection of OA in clam and mussel samples. Coupled with LC-MS/MS, the resultant [OH]-BD-TFPM COF demonstrated the ability to analyze OA, and the limit of detection for OA in shellfish was determined to be 0.005 μg/kg. A significant improvement in trace OA detection was observed compared to previously reported SPE materials without adjustable hydrophilic interactions. The recoveries of OA in the fortified clam and mussel samples were in the ranges of 93.9‒105.1% and 96.7‒110.2%, respectively. This study highlights that OH-group surface engineering in channel walls is a facile and powerful strategy for developing functional 3D-COFs with multiple interactions for high-performance target capture.
Topics: Okadaic Acid; Chromatography, Liquid; Metal-Organic Frameworks; Spectroscopy, Fourier Transform Infrared; Tandem Mass Spectrometry
PubMed: 37660560
DOI: 10.1016/j.chroma.2023.464334 -
Journal of Cancer Research and Clinical... Dec 2018The okadaic acid class of tumor promoters, which are inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A), induced tumor promotion in mouse skin, rat glandular... (Review)
Review
PURPOSE
The okadaic acid class of tumor promoters, which are inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A), induced tumor promotion in mouse skin, rat glandular stomach, and rat liver. Endogenous protein inhibitors of PP2A, SET and CIP2A, were up-regulated in various human cancers, so it is vital to review the essential mechanisms of tumor promotion by the okadaic acid class compounds, together with cancer progression by SET and CIP2A in humans.
RESULTS AND DISCUSSION
The first part of this review introduces the okadaic acid class compounds and the mechanism of tumor promotion: (1) inhibition of PP1 and PP2A activities of the okadaic acid class compounds; (2) some topics of tumor promotion; (3) TNF-α gene expression as a central mediator in tumor promotion; (4) exposure to the okadaic acid class of tumor promoters in relation to human cancer. The second part emphasizes the overexpression of SET and CIP2A in cancer progression, and the anticancer activity of SET antagonists as follows: (5) isolation and characterization of SET; (6) isolation and characterization of CIP2A; (7) progression of leukemia with SET; (8) progression of breast cancer with SET and CIP2A; (9) progression of lung cancer with SET; (10) anti-carcinogenic effects of SET antagonists OP449 and FTY720; and also (11) TNF-α-inducing protein of Helicobacter pylori, which is a clinical example of the okadaic acid pathway.
CONCLUSIONS
The overexpression of endogenous protein inhibitors of PP2A, SET and CIP2A, is tightly linked to the progression of various human cancers, as well as Alzheimer's disease.
Topics: Animals; Autoantigens; Biomarkers, Tumor; Cell Transformation, Neoplastic; DNA-Binding Proteins; Disease Progression; Environmental Exposure; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Histone Chaperones; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Molecular Targeted Therapy; Neoplasms; Okadaic Acid; Protein Phosphatase 2; Signal Transduction; Transcription Factors; Tumor Necrosis Factor-alpha
PubMed: 30341686
DOI: 10.1007/s00432-018-2765-7 -
Marine Drugs Jan 2018Lipophilic phycotoxins are secondary metabolites produced by phytoplanktonic species. They accumulate in filter-feeding shellfish and can cause human intoxication.... (Review)
Review
Lipophilic phycotoxins are secondary metabolites produced by phytoplanktonic species. They accumulate in filter-feeding shellfish and can cause human intoxication. Regulatory limits have been set for individual toxins, and the toxicological features are well characterized for some of them. However, phycotoxin contamination is often a co-exposure phenomenon, and toxicological data regarding mixtures effects are very scarce. Moreover, the type and occurrence of phycotoxins can greatly vary from one region to another. This review aims at summarizing the knowledge on (i) multi-toxin occurrence by a comprehensive literature review and (ii) the toxicological assessment of mixture effects. A total of 79 publications was selected for co-exposure evaluation, and 44 of them were suitable for toxin ratio calculations. The main toxin mixtures featured okadaic acid in combination with pectenotoxin-2 or yessotoxin. Only a few toxicity studies dealing with co-exposure were published. In vivo studies did not report particular mixture effects, whereas in vitro studies showed synergistic or antagonistic effects. Based on the combinations that are the most reported, further investigations on mixture effects must be carried out.
Topics: Animals; Drug Synergism; Humans; Marine Toxins; Okadaic Acid; Phytoplankton
PubMed: 29385038
DOI: 10.3390/md16020046 -
Neurotoxicology Dec 2019This study aimed to explore effects and mechanisms of 004 (IMM-H004), a novel coumarin derivative, in OKA (okadaic acid)-induced AD (Alzheimer's disease)-like model. In...
This study aimed to explore effects and mechanisms of 004 (IMM-H004), a novel coumarin derivative, in OKA (okadaic acid)-induced AD (Alzheimer's disease)-like model. In vitro, MTT, LDH, and Annexin V/FITC flow cytometry assay were used to test cell survival. In vivo, OKA microinjection was conducted to simulate AD-like neuropathology. Morris water maze and Nissl staining were used to detect spatial memory function and neuronal damage respectively. Western blot and immunohistochemistry were used to study the mechanisms of 004 in Tau pathology. The results showed that 004 reduced cell death and increased survival in PC12 cells, and decreased neuronal injury in the hippocampus in rats. 004 improved learning and memory functions in OKA-treated rats. The mechanistic studies indicated that 004 inhibited phosphorylation of Tau protein by down-regulating the activity of protein kinases CDK5 and GSK3β and increasing PP2A activity. Overall, 004 improved spatial memory impairments and neuron cells injury induced by OKA; on the other hand, 004 inhibited Tau hyperphosphorylation by regulating CDK5, GSK3β and PP2A.
Topics: Alzheimer Disease; Animals; Apoptosis; Blotting, Western; Coumarins; Disease Models, Animal; Flow Cytometry; Male; Maze Learning; Neuroprotective Agents; Okadaic Acid; PC12 Cells; Rats; Rats, Sprague-Dawley; tau Proteins
PubMed: 31562916
DOI: 10.1016/j.neuro.2019.09.012