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1.
Chem Biol Interact ; 317: 108937, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926150

RESUMO

The biotoxin okadaic acid (OA) is a lipophilic secondary metabolite of marine microalgae. Therefore, OA accumulates in the fatty tissue of various shellfish and may thus enter the food chain. The ingestion of OA via contaminated marine species can lead to the diarrhetic shellfish poisoning syndrome characterized by the occurrence of a series of acute gastrointestinal symptoms in humans. In addition, genotoxicity and tumor-promoting properties of OA might constitute a long-term threat to human health. In order to deepen our understanding of the molecular effects of OA, we compared long-term (14 d) and short-term (24 h and 48 h) apoptotic effects of the compound on human HepaRG hepatocarcinoma cells. Cells were treated either with single doses for 24 and 48 h, respectively, or seven times over a period of 14 d, so that the cumulated quantities of OA in the long-term approach were equal to the single doses upon short-term treatment. Both short-term treatment scenarios led to the induction of apoptosis. Specific caspase activation assays and transcriptional analysis of mRNAs encoding proteins involved in the regulation of apoptosis suggest that OA-induced apoptosis occurs presumably by activation of the intrinsic apoptotic pathway. In contrast, effects were much less pronounced in case of long-term treatment. This is possibly linked to cellular protective mechanisms against low amounts of toxins, e.g. transporter-mediated efflux. In conclusion, our results show a clear concentration- and time-dependency of OA-mediated apoptotic effects in HepaRG cells and contribute to the elucidation of molecular effects of OA.


Assuntos
Apoptose/efeitos dos fármacos , Carcinógenos/toxicidade , Hepatócitos/efeitos dos fármacos , Ácido Okadáico/toxicidade , Carcinógenos/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ácido Okadáico/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
2.
Life Sci ; 238: 116969, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628912

RESUMO

AIMS: Glutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the ß-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD. MATERIALS AND METHODS: Male Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 µl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses. KEY FINDINGS: Results of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats. SIGNIFICANCE: Therefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ceftriaxona/farmacologia , Giro Denteado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Antibacterianos/farmacologia , Carcinógenos/toxicidade , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/patologia , Ácido Okadáico/toxicidade , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos
3.
Ecotoxicol Environ Saf ; 180: 192-201, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31085430

RESUMO

As a main marine phycotoxin, okadaic acid (OA) is mainly responsible for diarrheic shellfish poisoning (DSP), through specifically inhibiting phosphatase (PP1 and PP2A). It has been shown that isotope labelled-OA could cross the placental barrier in mice. However, it remains obscure how OA exposure could affect the formation of neural crest cells (NCCs), especially cranial NCCs in early embryo development. Here, we explored the effects of OA exposure on the generation of neural crest cells during embryonic development using the classic chick embryo model. We found that OA exposure at 100 nM (80.5 µg/L) could cause craniofacial bone defects in the developing chick embryo and delay the development of early chick embryos. Immunofluorescent staining of HNK-1, Pax7, and Ap-2α demonstrated that cranial NCC generation was inhibited by OA exposure. Double immunofluorescent staining with Ap-2α/PHIS3 or Pax7/c-Caspase3 manifested that both NCC proliferation and apoptosis were restrained by OA exposure. Furthermore, the expression of Msx1 and BMP4 were down-regulated in the developing chick embryonic neural tubes, which could contribute the inhibitive production of NCCs. We also discovered that expression of EMT-related adhesion molecules, such as Cadherin 6B (Cad6B) and E-cadherin, was altered following OA exposure. In sum, OA exposure negatively affected the development of embryonic neural crest cells, which in turn might result in cranial bone malformation.


Assuntos
Inibidores Enzimáticos/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Crista Neural/efeitos dos fármacos , Ácido Okadáico/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Embrião de Galinha , Regulação para Baixo , Desenvolvimento Embrionário/efeitos dos fármacos , Crista Neural/citologia , Crista Neural/embriologia , Tubo Neural/efeitos dos fármacos , Tubo Neural/metabolismo , Crânio/anormalidades
4.
Toxins (Basel) ; 11(4)2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934968

RESUMO

In Andalusia, the official monitoring program for toxic phytoplankton and marine biotoxins was launched in 1994 to comply with European legislation. Since then, there have been numerous episodes of DST (Diarrhetic shellfish toxins) associated with the proliferation of Dinophysis species. This article reviews two decades of time series data and assesses the effectiveness of the program established. The testing of lipophilic toxins and toxic phytoplankton is based on official methods harmonized and accredited since 2007 according to the standard UNE-EN-ISO 17025. The major species of Dinophysis identified were D. acuminata complex, D. caudata, D. acuta and D. fortii, with the main growth season being from early spring until the end of autumn. Both D. acuminata complex and D. acuta have been clearly associated with toxicity in molluscs. Despite the complexity of data obtained through monitoring programs, it is possible to provide early warning of potential health risks for most situations. This is the first report of Dinophysis species and their relation to DST events in a time series from Andalusia.


Assuntos
Dinoflagelados , Animais , Monitoramento Ambiental , Moluscos/efeitos dos fármacos , Ácido Okadáico/toxicidade , Intoxicação por Frutos do Mar , Espanha
5.
Toxicol In Vitro ; 58: 150-160, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30926360

RESUMO

Okadaic acid (OA) is a lipophilic phycotoxin that accumulates in the hepatopancreas and fatty tissue of shellfish. Consumption of highly OA-contaminated seafood leads to diarrhetic shellfish poisoning which provokes severe gastrointestinal symptoms associated with a disruption of the intestinal epithelium. Since the molecular mechanisms leading to intestinal barrier disruption are not fully elucidated, we investigated the influence of OA on intestinal tight junction proteins (TJPs) in differentiated Caco-2 cells. We found a concentration- and time-dependent deregulation of genes encoding for intestinal TJPs of the claudin family, occludin, as well as zonula occludens (ZO) 1 and 2. Immunofluorescence staining showed concentration-dependent effects on the structural organization of TJPs already after treatment with a subtoxic but human-relevant concentration of OA. In addition, changes in the structural organization of cytoskeletal F-actin as well as its associated protein ZO-1 were observed. In summary, we demonstrated effects of OA on TJPs in intestinal Caco-2 cells. TJP expressions were affected after treatment with food-relevant OA concentrations. These results might explain the high potential of OA to disrupt the intestinal barrier in vivo as its first target. Thereby the present data contribute to a better understanding of the OA-dependent induction of molecular effects within the intestinal epithelium.


Assuntos
Toxinas Marinhas/toxicidade , Ácido Okadáico/toxicidade , Proteínas de Junções Íntimas/metabolismo , Células CACO-2 , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Proteínas de Junções Íntimas/genética
6.
Artigo em Inglês | MEDLINE | ID: mdl-30724672

RESUMO

Okadaic acid group (OA-group) is a set of lipophilic toxins which are characterised by being produced by species associated with the genera Dinophysis and Prorocentrum. OA-group has been regularly detected in endemic shellfish species from the southern zone of Chile only through the mouse bioassay. The purpose of this work was to determine the variability of OA-group toxins in endemic aquatic organisms (bivalves, crabs, gastropods and fish) and to establish the relationship with the concentration of fatty acids (FAs) detected in the evaluated species. The toxicity of OA-group and the FA profiles were determined using LC-MS/MS and gas chromatography with flame-ionisation detection, respectively. In the study area, the dinoflagellate Dinophysis acuta was detected in densities ≈2000 cells ml-1 with a toxicity ≈18.3 pg OA equiv cel-1. The analysis identified OA and dinophysistoxin-1 in shellfish in a range of ≈90 to ≈225 µg OA eq kg-1, where no toxins in fish were detected. A positive relationship between the FA level and the concentration of OA-group toxins in the digestive glands of bivalves and gastropods was established, noted for high levels of saturated FAs (C14:0 and C16:0). The toxic variability of OA-group toxins determined in the different species allowed us to establish that the consumption of these vectors, regulated by non-analytical methods, can be harmful when consumed by humans, thus suggesting that the sanitary regulations for the control of OA-group in Chile should be updated.


Assuntos
Organismos Aquáticos/química , Ácidos Graxos/análise , Toxinas Marinhas/química , Toxinas Marinhas/toxicidade , Ácido Okadáico/química , Ácido Okadáico/toxicidade , Animais , Bivalves/química , Braquiúros/química , Cromatografia Líquida , Peixes , Gastrópodes/química , Especificidade da Espécie , Espectrometria de Massas em Tandem
7.
Toxicon ; 160: 1-7, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639658

RESUMO

Okadaic acid (OA), a potent polyether marine toxin, accumulates in the digestive glands of marine mollusks and therefore can severely threaten the health of humans after ingestion of contaminated shellfish. In vivo and in vitro studies have revealed that exposure of various cells, including human embryonic amniotic cells, hepatocytes, neuroblastoma cells, to OA induces morphological and functional modifications as well as the death of cells. As the number of reports on OA poisoning has increased, this toxin has gradually attracted the public's attention, and researchers are trying to study it. This review summarizes the current literature on the toxicity effects of OA, in addition to its detection and detoxification.


Assuntos
Dinoflagelados/química , Ácido Okadáico/toxicidade , Animais , Humanos , Inativação Metabólica , Toxinas Marinhas/toxicidade , Moluscos/química , Ácido Okadáico/análise , Ácido Okadáico/metabolismo , Intoxicação por Frutos do Mar
8.
Mol Med Rep ; 19(3): 1767-1774, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628698

RESUMO

Okadaic acid (OA)­induced neurotoxicity may be considered a novel tool used to study Alzheimer's disease (AD) pathology, and may be helpful in the development of a novel therapeutic approach. It has been reported that galangin inhibits ß­site amyloid precursor protein­cleaving enzyme 1 expression, which is a key enzyme for amyloid ß (Aß) generation and is a potential drug candidate for AD therapy. However, further studies are required to confirm its neuroprotective effects in other AD models. The present study aimed to explore the neuroprotective effects of galangin on OA­induced neurotoxicity in PC12 cells. The cells were divided into the following groups: Control group, model group (175 nM OA for 48 h) and galangin groups (0.25, 0.5 and 1 µg/ml). Beclin­1, phosphorylated (p)­protein kinase B (Akt), p­glycogen synthase kinase (GSK)3ß and p­mechanistic target of rapamycin (mTOR) expression was also measured in the following PC12 cell groups: Control group, model group, 3­methyladenine group (5 nM), rapamycin group (100 nM) and galangin group (1 µg/ml). The levels of ß­secretase, Aß42 and p­tau were detected by ELISA, Beclin­1 expression was examined by immunohistochemistry and the protein expression levels of p­Akt, p­mTOR p­GSK3ß, and Beclin­1 were detected by western blotting. Galangin treatment enhanced cell viability in cells treated with OA, and decreased ß­secretase, Aß42 and p­tau levels. In addition, it suppressed Beclin­1 and p­GSK3ß expression, but promoted p­Akt and p­mTOR expression by regulating the Akt/GSK3ß/mTOR pathway. These results indicated that galangin protected PC12 cells from OA­induced cytotoxicity and inhibited autophagy via the Akt/GSK3ß/mTOR pathway, thus suggesting that it may be considered a potential therapeutic agent for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Autofagia/efeitos dos fármacos , Flavonoides/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/genética , Animais , Autofagia/genética , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Ácido Okadáico/toxicidade , Células PC12 , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Proteínas tau/genética
9.
ALTEX ; 36(2): 203-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30462829

RESUMO

The mouse bioassay for the detection of marine biotoxins in shellfish products is 40 years old and still in use. A full ban or total replacement of this in vivo test has been postponed because of the fear that current chemical-based detection methods could miss a new emerging toxin. In order to fully replace the mouse bioassay, more efforts are needed on the search for functional assays with specific endpoints. Gene expression elicited by diarrheic shellfish poisons in Caco-2 cells allowed us to determine three 'DSP profiles', i.e. OA/DTX, AZA-YTX and PTX profiles. Twelve marker genes were selected to envision the three profiles. qRT-PCR is relatively cheap and easy, and although its multiplex capacity is limited to 5 genes, this turned out to be sufficient to show the three expected profiles. The use of the multiplex magnetic bead-based assay turned out to be even a slightly better alternative, allowing the use of all twelve selected marker genes and 2 reference genes, and resulting in clear profiles with for some genes even higher induction factors as obtained by qRT-PCR. When analysing blank and contaminated shellfish samples with this multiplex magnetic bead-based assay, the contaminated samples could easily be distinguished from the blank samples, showing the expected profiles. This work is one step further on the final replacement of the mouse bioassay, e.g. by combining the neuro-2a bioassay for screening and detection with analytical chemical analyses and the multiplex magnetic bead-based assay for confirmation of known and unknown toxins respectively.


Assuntos
Bioensaio , Células CACO-2 , Diarreia/induzido quimicamente , Toxinas Marinhas , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/genética , Intoxicação por Frutos do Mar , Animais , Humanos , Toxinas Marinhas/análise , Toxinas Marinhas/toxicidade , Camundongos , Ácido Okadáico/toxicidade
10.
Toxins (Basel) ; 10(12)2018 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-30544794

RESUMO

Mycotoxins are emerging toxins in the marine environment, which can co-occur with algal toxins to exert synergistic or antagonistic effects for human seafood consumption. The current study assesses the cytotoxicity of the algal toxin okadaic acid, shellfish, and dust storm-associated mycotoxins alone or in combination on human intestinal (HT-29) and neuroblastoma (SH-SY5Y) cell lines. Based on calculated IC50 (inhibitory concentration 50%) values, mycotoxins and the algal toxin on their own exhibited increased cytotoxicity in the order of sydowinin A < sydowinin B << patulin < alamethicin < sydowinol << gliotoxin ≈ okadaic acid against the HT-29 cell line, and sydowinin B < sydowinin A << alamethicin ≈ sydowinol < patulin, << gliotoxin < okadaic acid against the SH-SY5Y cell line. Combinations of okadaic acid⁻sydowinin A, ⁻alamethicin, ⁻patulin, and ⁻gliotoxin exhibited antagonistic effects at low-moderate cytotoxicity, but became synergistic at high cytotoxicity, while okadaic acid⁻sydowinol displayed an antagonistic relationship against HT-29 cells. Furthermore, only okadaic acid⁻sydowinin A showed synergism, while okadaic acid⁻sydowinol, ⁻alamethicin, ⁻patulin, and ⁻gliotoxin combinations demonstrated antagonism against SH-SY5Y. While diarrhetic shellfish poisoning (DSP) from okadaic acid and analogues in many parts of the world is considered to be a comparatively minor seafood toxin syndrome, our human cell model studies suggest that synergisms with certain mycotoxins may aggravate human health impacts, depending on the concentrations. These findings highlight the issues of the shortcomings of current regulatory approaches, which do not regulate for mycotoxins in shellfish and treat seafood toxins as if they occur as single toxins.


Assuntos
Micotoxinas/toxicidade , Ácido Okadáico/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Interações de Medicamentos , Humanos , Intestinos/citologia , Neuroblastoma
11.
Toxins (Basel) ; 10(11)2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30404158

RESUMO

The identification and quantification of okadaic acid (OA)/dinophysistoxin (DTX) analogues and pectenotoxins (PTXs) in Dinophysis samples collected from coastal locations around Japan were evaluated by liquid chromatography mass spectrometry. The species identified and analyzed included Dinophysis fortii, D. acuminata, D. mitra (Phalacroma mitra), D. norvegica, D. infundibulus, D. tripos, D. caudata, D. rotundata (Phalacroma rotundatum), and D. rudgei. The dominant toxin found in D. acuminata was PTX2 although some samples contained DTX1 as a minor toxin. D. acuminata specimens isolated from the southwestern regions (Takada and Hiroshima) showed characteristic toxin profiles, with only OA detected in samples collected from Takada. In contrast, both OA and DTX1, in addition to a larger proportion of PTX2, were detected in D. acuminata from Hiroshima. D. fortii showed a toxin profile dominated by PTX2 although this species had higher levels of DTX1 than D. acuminata. OA was detected as a minor toxin in some D. fortii samples collected from Yakumo, Noheji, and Hakata. PTX2 was also the dominant toxin found among other Dinophysis species analyzed, such as D. norvegica, D. tripos, and D. caudata, although some pooled picked cells of these species contained trace levels of OA or DTX1. The results obtained in this study re-confirm that cellular toxin content and profiles are different even among strains of the same species.


Assuntos
Alveolados/química , Organismos Aquáticos , Ácido Okadáico/análogos & derivados , Ácido Okadáico/toxicidade , Água do Mar/microbiologia , Cromatografia Líquida , Monitoramento Ambiental/métodos , Japão , Toxinas Marinhas/análise , Espectrometria de Massas em Tandem
12.
Cell Physiol Biochem ; 49(2): 743-757, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30176657

RESUMO

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.


Assuntos
Peso Corporal/efeitos dos fármacos , Ácido Okadáico/toxicidade , Piranos/toxicidade , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Coração/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/ultraestrutura , Camundongos , Miocárdio/ultraestrutura , Ácido Okadáico/análise , Ácido Okadáico/urina , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/metabolismo , Piranos/análise , Piranos/urina , Estômago/efeitos dos fármacos , Estômago/patologia , Espectrometria de Massas em Tandem , Testes de Toxicidade
13.
J Med Chem ; 61(17): 7640-7656, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30078314

RESUMO

Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3ß and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC50 values toward GSK-3ß, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 µM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas tau/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/efeitos adversos , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacologia , Dicroísmo Circular , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Transferência Ressonante de Energia de Fluorescência , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Células Hep G2 , Humanos , Microscopia de Força Atômica , Terapia de Alvo Molecular/métodos , Ácido Okadáico/toxicidade , Fosforilação/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Suínos , Tiazolidinedionas/química , Proteínas tau/antagonistas & inibidores
14.
Toxins (Basel) ; 10(8)2018 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-30060565

RESUMO

To reveal the molecular mechanisms triggered by okadaic acid (OA)-exposure in the detoxification and immune system of bay scallops, we studied differentially-expressed genes (DEGs) and the transcriptomic profile in bay scallop gill tissue after 48 h exposure to 500 nM of OA using the Illumina HiSeq 4000 deep-sequencing platform. De novo assembly of paired-end reads yielded 55,876 unigenes, of which 3204 and 2620 genes were found to be significantly up- or down-regulated, respectively. Gene ontology classification and enrichment analysis of the DEGs detected in bay scallops exposed to OA revealed four ontologies with particularly high functional enrichment, which were 'cellular process' (cellular component), 'metabolic process' (biological process), 'immune system process' (biological process), and 'catalytic process' (molecular function). The DEGs revealed that cyclic AMP-responsive element-binding proteins, acid phosphatase, toll-like receptors, nuclear erythroid 2-related factor, and the NADPH2 quinone reductase-related gene were upregulated. In contrast, the expression of some genes related to glutathione S-transferase 1, C-type lectin, complement C1q tumor necrosis factor-related protein, Superoxide dismutase 2 and fibrinogen C domain-containing protein, decreased. The outcomes of this study will be a valuable resource for the study of gene expression induced by marine toxins, and will help understanding of the molecular mechanisms underlying the scallops' response to OA exposure.


Assuntos
Brânquias/efeitos dos fármacos , Toxinas Marinhas/toxicidade , Ácido Okadáico/toxicidade , Pectinidae/fisiologia , Transcriptoma/efeitos dos fármacos , Animais , Perfilação da Expressão Gênica , Brânquias/fisiologia , Transcriptoma/imunologia
15.
Toxins (Basel) ; 10(8)2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30096904

RESUMO

Marine biotoxins are produced by aquatic microorganisms and accumulate in shellfish or finfish following the food web. These toxins usually reach human consumers by ingestion of contaminated seafood, although other exposure routes like inhalation or contact have also been reported and may cause serious illness. This review shows the current data regarding the symptoms of acute intoxication for several toxin classes, including paralytic toxins, amnesic toxins, ciguatoxins, brevetoxins, tetrodotoxins, diarrheic toxins, azaspiracids and palytoxins. The information available about chronic toxicity and relative potency of different analogs within a toxin class are also reported. The gaps of toxicological knowledge that should be studied to improve human health protection are discussed. In general, gathering of epidemiological data in humans, chronic toxicity studies and exploring relative potency by oral administration are critical to minimize human health risks related to these toxin classes in the near future.


Assuntos
Toxinas Marinhas/toxicidade , Intoxicação por Frutos do Mar , Acrilamidas/toxicidade , Animais , Humanos , Ácido Okadáico/toxicidade , Compostos de Espiro/toxicidade
16.
Toxicon ; 152: 16-22, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30003918

RESUMO

Okadaic acid (OA) is one of the most common and widespread marine toxins and causes acute gastrointestinal symptoms known as diarrheic shellfish poisoning (DSP) in humans. Although OA is not classified as a typical neurotoxin, an increasing number of studies have reported its neurotoxic effects. However, most of the available studies have focused on OA-induced inhibition of serine/threonine protein phosphatases, while the molecular mechanism of OA-induced neurotoxicity remains largely unclear. To better understand the potentially toxicological profile of OA, cell cycle arrest, DNA damage and alterations in gene expression in the human neuroblastoma cell line SHSY5Y upon OA exposure were determined using flow cytometry, comet assay, and transcriptome microarray. The results showed that OA could induce cell cycle arrest at S phase and might be involved in significant DNA strand breaks. Gene expression profiling indicated that the differentially expressed genes after OA exposure were significantly enriched in the "DNA replication" and "cell cycle" pathways. Real-time PCR result had further validated that down-regulation of the Cdc45/Mcm2-7/GINS complex might be the major factor regulating those alterations. These findings provide new insight into the molecular mechanisms of OA-induced neurotoxicity, and the current data may also provide a basis for future studies.


Assuntos
Proteínas de Ciclo Celular/fisiologia , Ácido Okadáico/toxicidade , Fase S/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Regulação para Baixo , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Toxinas Marinhas/toxicidade
17.
Bioorg Med Chem ; 26(13): 3812-3824, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-29960728

RESUMO

To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent ß-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC50 = 1.7 and 2.7 µM, respectively), Aß1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aß1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25 µM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H2O2, okadaic acid (OA) and Aß1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.


Assuntos
Carbolinas/química , Inibidores da Colinesterase/síntese química , Desenho de Drogas , Fármacos Neuroprotetores/síntese química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Sítios de Ligação , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Carbolinas/metabolismo , Carbolinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Humanos , Peróxido de Hidrogênio/toxicidade , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia , Ácido Okadáico/toxicidade , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
18.
Mar Pollut Bull ; 133: 911-919, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30041395

RESUMO

The occurrence of okadaic acid (OA) group toxins in bivalve mollusk collected from Vietnamese coastal areas was investigated from April 2016 to April 2017. OA group toxins were detected in mollusk by UPLC-MS/MS with the highest level of 11.3 ng/g and detection frequency of 11.8%. Toxins were detected more frequently in dry season (14.4% of analyzed samples) than in wet season (7.9%). Toxins were also detected more frequently at sampling locations in the northern parts (≥10.4%) than in the southern part (≤8.3%) of Vietnamese coastline. Results of this study were similar to those obtained in long-term studies in regions geographically close to Vietnam, confirming decisive influence of geographic location on the accumulation of toxins in mollusks. Within the scope of the study, toxin levels in all contaminated samples were below the regulation limit (160 ng/g), but the presence of OA group toxins in bivalve mollusk suggests the need of a more stringent control of toxins in bivalve mollusk in Vietnam.


Assuntos
Bivalves/química , Toxinas Marinhas/química , Intoxicação por Frutos do Mar/etiologia , Animais , Cromatografia Líquida de Alta Pressão , Humanos , Toxinas Marinhas/toxicidade , Ácido Okadáico/análise , Ácido Okadáico/toxicidade , Estações do Ano , Intoxicação por Frutos do Mar/epidemiologia , Análise Espacial , Espectrometria de Massas em Tandem , Vietnã/epidemiologia
19.
Brain Res ; 1690: 1-11, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29596798

RESUMO

Abnormal phosphorylation of tau, one of the most common symptoms of dementia, has become increasingly important in the study of the etiology and development of Alzheimer's disease. Paeoniflorin, the main bioactive component of herbaceous peony, is a monoterpene glycoside, which has been reported to exert beneficial effects on neurodegenerative disease. However, the effect of paeoniflorin on tauopathies remains ambiguous. SH-SY5Y cells were treated with okadaic acid (OA) for 8 h to induce tau phosphorylation and no cell death was observed. Optical microscopy results showed that paeoniflorin ameliorated okadaic acid induced morphological changes, including cell swelling and synapsis shortening. Western blotting data illustrated that paeoniflorin reversed okadaic acid induced tau hyperphosphorylation, which was enhanced by inhibiting the activities of calpain, Akt and GSK-3ß. Transmission electron microscopy results showed that paeoniflorin alone can reduce the number of autophagosomes and stabilize the microtubule structure. In addition, calpastain and paeoniflorin enhance the effect of paeoniflorin on stabilizing microtubules. In addition, calpastain markedly enhanced the effect of paeoniflorin on reversing okadaic acid-lowered fluorescence intensity of both MAP-2 and ß III-tubulin, two microtubule-associated proteins. This study shows that paeoniflorin protected SH-SY5Y cells against okadaic acid assault by interfering with the calpain/Akt/GSK-3ß-related pathways, in which autophagy might be involved. Besides, paeoniflorin is found to relieve the stress response of the microtubule structure system caused by okadaic acid treatment. The results presented in this study suggest that paeoniflorin potentially plays an important role in tauopathies.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Calpaína/metabolismo , Linhagem Celular Tumoral , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ácido Okadáico/toxicidade , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
20.
J Vet Med Sci ; 80(4): 616-619, 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29491228

RESUMO

The mouse bioassay for diarrhetic shellfish poisoning toxins has been used worldwide. In this study, dinophysistoxin-1 (DTX-1) and okadaic acid (OA) were compared for toxicity. The lethality rate increased and the median survival time decreased in a dose-dependent manner in both DTX-1 and OA. The median lethal dose value was 150.4 µg/kg (95% confidence interval=130.1-171.2 µg/kg) for DTX-1 and 185.6 µg/kg (95% confidence interval=161.2-209.6 µg/kg) for OA. The toxicity equivalent factor 1:1 has been used for OA and DTX-1 in the EU and Japan. Thus, it may be considered that toxicity potential of DTX-1 has remained underestimated as compared to that of OA and DTX-1 might be more toxic than OA.


Assuntos
Ácido Okadáico/toxicidade , Piranos/toxicidade , Animais , Bioensaio , Bivalves/química , Relação Dose-Resposta a Droga , Dose Letal Mediana , Camundongos , Ácido Okadáico/química , Piranos/química , Testes de Toxicidade
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