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1.
Molecules ; 26(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669839

RESUMO

Despite Alzheimer's disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm "one target-one drug-one disease" in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn-ibuprofen drug combination into single-molecule "codrugs." Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn-ibuprofen conjugates (4-6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aß42-amyloid self-aggregation, and their cellular neuroprotective effect against Aß42-induced neurotoxicity. The fact that 6 effectively reduced Aß-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aß42-expressing Drosophila and to improve fly locomotor performance.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cromolina Sódica/uso terapêutico , Ibuprofeno/uso terapêutico , Polifarmacologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromolina Sódica/síntese química , Cromolina Sódica/química , Cromolina Sódica/farmacologia , Drosophila/efeitos dos fármacos , Desenho de Fármacos , Endocitose/efeitos dos fármacos , Ibuprofeno/síntese química , Ibuprofeno/química , Ibuprofeno/farmacologia , Imunomodulação/efeitos dos fármacos , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Agregados Proteicos/efeitos dos fármacos , Ratos Wistar
2.
J Vis Exp ; (167)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33554967

RESUMO

Excitotoxic necrosis is a leading form of neurodegeneration. This process of regulated necrosis is triggered by the synaptic accumulation of the neurotransmitter glutamate, and the excessive stimulation of its postsynaptic receptors. However, information on the subsequent molecular events that culminate in the distinct neuronal swelling morphology of this type of neurodegeneration is lacking. Other aspects, such as changes in specific subcellular compartments, or the basis for the differential cellular vulnerability of distinct neuronal subtypes, remain under-explored. Furthermore, a range of factors that come into play in studies that use in vitro or ex vivo preparations might modify and distort the natural progression of this form of neurodegeneration. It is therefore important to study excitotoxic necrosis in live animals by monitoring the effects of interventions that regulate the extent of neuronal necrosis in the genetically amenable and transparent model system of the nematode Caenorhabditis elegans. This protocol describes methods of studying excitotoxic necrosis in C. elegans neurons, combining optical, genetic, and molecular analysis. To induce excitotoxic conditions in C. elegans, a knockout of a glutamate transporter gene (glt-3) is combined with a neuronal sensitizing genetic background (nuls5 [Pglr-1::GαS(Q227L)]) to produce glutamate receptor hyperstimulation and neurodegeneration. Nomarski differential interference contrast (DIC), fluorescent, and confocal microscopy in live animals are methods used to quantify neurodegeneration, follow subcellular localization of fluorescently labeled proteins, and quantify mitochondrial morphology in the degenerating neurons. Neuronal Fluorescence Activated Cell Sorting (FACS) is used to distinctly sort at-risk neurons for cell-type specific transcriptomic analysis of neurodegeneration. A combination of live imaging and FACS methods as well as the benefits of the C. elegans model organism allow researchers to leverage this system to obtain reproducible data with a large sample size. Insights from these assays could translate to novel targets for therapeutic intervention in neurodegenerative diseases.


Assuntos
Caenorhabditis elegans/citologia , Imageamento Tridimensional , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/patologia , Neurotoxinas/toxicidade , Envelhecimento/patologia , Criação de Animais Domésticos , Animais , Apoptose , Tampões (Química) , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Ácido Glutâmico/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Necrose , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neuroproteção/efeitos dos fármacos , RNA/isolamento & purificação , Fatores de Risco , Transcriptoma/genética
3.
Aquat Toxicol ; 231: 105715, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341507

RESUMO

This study was conceptualized in order to assess the 96-h LC50 of bifenthrin (BF) in O. niloticus and also to measure the biochemical, behavioral, and molecular responses of the fish suchronically exposed to a sub-lethal concentration of the insecticide. The role of Petroselinum crispum essential oil (PEO) supplementation in mitigating the resulted neurotoxic insult was also investigated. The acute toxicity study revealed that the 96-h LC50 of BF is 6.81 µg/L, and varying degrees of behavioral changes were recorded in a dose-dependent manner. The subchronic study revealed reduction of dissolved oxygen and increased ammonia in aquaria of BF-exposed fish. Clinical signs revealed high degree of discomfort and aggressiveness together with reductions in survival rate and body weight gain. The levels of monoamines in brain, and GABA and amino acids in serum were reduced, together with decreased activities of Na+/K+-ATPase and acetylcholine esterases (AchE). The activities of antioxidant enzymes were also diminshed in the brain while oxdative damage and DNA breaks were elevated. Myeloperoxidase (MPO) activity in serum increased with overexpression of the pro-inflammatory cytokines in the brain tissue. BF also upregulated the expression of brain-stress related genes HSP70, Caspase-3 and P53. Supplemention of PEO to BF markedly abrogated the toxic impacts of the insecticide, specially at the high level. These findings demonstrate neuroprotective, antioxidant, genoprotective, anti-inflammatory and antiapoptic effects of PEO in BF-intoxicated fish. Based on these mechanistic insights of PEO, we recommend its use as an invaluable supplement in the fish feed.


Assuntos
Encéfalo/patologia , Ciclídeos/fisiologia , Suplementos Nutricionais , Inflamação/patologia , Óleos Voláteis/farmacologia , Petroselinum/química , Piretrinas/toxicidade , Acetilcolinesterase/metabolismo , Aminoácidos/metabolismo , Animais , Antioxidantes/metabolismo , Comportamento Animal , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Ciclídeos/crescimento & desenvolvimento , Citocinas/metabolismo , Dano ao DNA , Regulação da Expressão Gênica/efeitos dos fármacos , Inseticidas/metabolismo , Dose Letal Mediana , Neurotoxinas/toxicidade , Neurotransmissores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Análise de Sobrevida , Poluentes Químicos da Água/toxicidade , Qualidade da Água , Ácido gama-Aminobutírico/metabolismo
4.
Proc Natl Acad Sci U S A ; 117(52): 33608-33618, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318181

RESUMO

Mitochondrial and metabolic dysfunction are often implicated in neurological disease, but effective mechanism-based therapies remain elusive. We performed a genome-scale forward genetic screen in a Drosophila model of tauopathy, a class of neurodegenerative disorders characterized by the accumulation of the protein tau, and identified manipulation of the B-vitamin biotin as a potential therapeutic approach in tauopathy. We show that tau transgenic flies have an innate biotin deficiency due to tau-mediated relaxation of chromatin and consequent aberrant expression of multiple biotin-related genes, disrupting both carboxylase and mitochondrial function. Biotin depletion alone causes mitochondrial pathology and neurodegeneration in both flies and human neurons, implicating mitochondrial dysfunction as a mechanism in biotin deficiency. Finally, carboxylase biotin levels are reduced in mammalian tauopathies, including brains of human Alzheimer's disease patients. These results provide insight into pathogenic mechanisms of human biotin deficiency, the resulting effects on neuronal health, and a potential therapeutic pathway in the treatment of tau-mediated neurotoxicity.


Assuntos
Biotina/farmacologia , Mitocôndrias/patologia , Neurotoxinas/toxicidade , Tauopatias/patologia , Doença de Alzheimer/patologia , Animais , Animais Geneticamente Modificados , Biotina/deficiência , Biotinilação , Encéfalo/metabolismo , Modelos Animais de Doenças , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Feminino , Regulação da Expressão Gênica , Testes Genéticos , Humanos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia
6.
Toxicon ; 187: 86-92, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32889025

RESUMO

Acetylcholine binding proteins (AChBPs), structural and functional surrogates of the extracellular binding domain of nicotinic acetylcholine receptor (nAChRs), in complex with various antagonists and agonists have provided detailed insights into the neurotransmitter binding site of nAChRs. The classical long-chain α-neurotoxins bungarotoxin (44-fold) and cobratoxin (7-fold) bind to Lymnaea stagnalis (Ls)-AChBP with higher affinity compared to Aplysia californica (Ac)-AChBP. In this study, we describe a novel long chain α-neurotoxin Drysdalin, which has higher binding affinity (7-fold) to Ac-AChBP when compared to Ls-AChBP. This suggests an involvement of different regions or modes of interaction of drysdalin, when compared to the bungarotoxin and cobratoxin. We also found that the C-terminal 24-amino acid residues of drysdalin are critical for the binding to Ac-AChBP and its removal caused ~90-fold reduction in affinity. Further to understand the interaction of drysdalin with Ac-AChBP, we studied the role of three non-conserved amino acid residues of drysdalin, namely Arg30, Leu34 and Ala37. Substitution of Arg30 with the conserved Phe residue caused a ~100-fold reduction, Leu34 with conserved Arg caused a ~6-fold reduction, whereas substitution of Ala37 with conserved Arg enhanced the binding by 3-fold. The dramatic influence of this carboxyl terminal sequence enriched in arginine and proline residues suggests that the toxin binding pose is influenced primarily by this extended sequence.


Assuntos
Acetilcolina/metabolismo , Aplysia , Lymnaea , Neurotoxinas/toxicidade , Venenos de Serpentes/toxicidade , Sequência de Aminoácidos , Animais , Sítios de Ligação , Transporte Biológico , Bungarotoxinas , Proteínas de Transporte , Modelos Moleculares , Neurotoxinas/metabolismo , Conformação Proteica , Receptores Nicotínicos , Venenos de Serpentes/metabolismo , Serpentes
7.
Proc Natl Acad Sci U S A ; 117(38): 23815-23822, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32900920

RESUMO

Prions are infectious agents which cause rapidly lethal neurodegenerative diseases in humans and animals following long, clinically silent incubation periods. They are composed of multichain assemblies of misfolded cellular prion protein. While it has long been assumed that prions are themselves neurotoxic, recent development of methods to obtain exceptionally pure prions from mouse brain with maintained strain characteristics, and in which defined structures-paired rod-like double helical fibers-can be definitively correlated with infectivity, allowed a direct test of this assertion. Here we report that while brain homogenates from symptomatic prion-infected mice are highly toxic to cultured neurons, exceptionally pure intact high-titer infectious prions are not directly neurotoxic. We further show that treatment of brain homogenates from prion-infected mice with sodium lauroylsarcosine destroys toxicity without diminishing infectivity. This is consistent with models in which prion propagation and toxicity can be mechanistically uncoupled.


Assuntos
Neurotoxinas , Doenças Priônicas , Príons , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Química Encefálica , Modelos Animais de Doenças , Camundongos , Neurônios/efeitos dos fármacos , Neurotoxinas/isolamento & purificação , Neurotoxinas/metabolismo , Neurotoxinas/toxicidade , Doenças Priônicas/metabolismo , Doenças Priônicas/fisiopatologia , Príons/isolamento & purificação , Príons/metabolismo , Príons/patogenicidade
8.
Plant Foods Hum Nutr ; 75(4): 512-517, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32761299

RESUMO

Emerging data support that plant food based isoflavones have ameliorating effects on a variety of neurodegenerative diseases including Parkinson's disease (PD). Our previous investigation revealed that dietary isoflavones including genistein (GEN), daidzein (DAI), and equol (EQL; a gut microbial metabolite of DAI) showed promising blood-brain barrier permeability and anti-neuroinflammatory activity in murine microglial BV2 cells. However, the neuroprotective effects of EQL against neurotoxins induced toxicity in PD related models remains unclear. Herein, EQL, along with GEN and DAI, were evaluated for their cytoprotective effect in a non-contact co-culture model with LPS-BV2-conditioned media and human neuroblastoma SH-SY5Y cells. In addition, their neuroprotective effects against PD related neurotoxins including 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+) induced cytotoxicity were evaluated in SH-SY5Y cells. Furthermore, EQL was evaluated for its neuroprotective effects against MPP+ induced neurotoxicity using in vivo PD model including Caenorhabditis elegans lifespan assay. DAI (10 µM) and EQL (10 and 20 µM) showed cytoprotective effects by decreasing LPS-BV2-conditioned media induced cytotoxicity in SH-SY5Y cells by 29.2, 32.4 and 27.2%, respectively. EQL (10 and 20 µM) also showed neuroprotective effects by decreasing 6-OHDA and MPP+ induced cytotoxicity in SH-SY5Y cells by 30.6-34.5 and 17.9-18.9%, respectively. Additionally, data from the in vivo assay supported EQL's neuroprotective effect as it increases survival of C. elegans exposed to MPP+ from 72 to 108 h. Our findings support a growing body of evidence of the neuroprotective effects of dietary isoflavones and further studies are warranted to elucidate their mechanisms of action.


Assuntos
Microbioma Gastrointestinal , Isoflavonas , Neuroblastoma , Fármacos Neuroprotetores , Animais , Apoptose , Barreira Hematoencefálica , Caenorhabditis elegans , Linhagem Celular Tumoral , Equol/farmacologia , Humanos , Isoflavonas/farmacologia , Camundongos , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade
9.
J Vis Exp ; (162)2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32831302

RESUMO

Neurite outgrowth assay and neurotoxicity assessment are two major studies that can be performed using the presented method herein. This protocol provides reliable analysis of neuronal morphology together with quantitative measurements of modifications on neurite length and synaptic protein localization and abundance upon treatment with small molecule compounds. In addition to the application of the presented method in neurite outgrowth studies, neurotoxicity assessment can be performed to assess, distinguish and rank commercial chemical compounds based on their potential developmental neurotoxicity effect. Even though cell lines are nowadays widely used in compound screening assays in neuroscience, they often differ genetically and phenotypically from their tissue origin. Primary cells, on the other hand, maintain important markers and functions observed in vivo. Therefore, due to the translation potential and physiological relevance that these cells could offer neurite outgrowth assay and neurotoxicity assessment can considerably benefit from using human neural progenitor cells (hNPCs) as the primary human cell model. The presented method herein can be utilized to screen for the ability of compounds to induce neurite outgrowth and neurotoxicity by taking advantage of the human neural progenitor cell-derived neurons, a cell model closely representing human biology."


Assuntos
Bioensaio/métodos , Células-Tronco Neurais/patologia , Crescimento Neuronal , Neurônios/patologia , Neurotoxinas/toxicidade , Animais , Diferenciação Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Epigênese Genética/efeitos dos fármacos , Fluorescência , Congelamento , Humanos , Células-Tronco Neurais/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Software , Coloração e Rotulagem
10.
PLoS Negl Trop Dis ; 14(8): e0008581, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32857757

RESUMO

The aim of this study was to develop an in vitro assay for use in place of in vivo assays of snake venom lethality and antivenom neutralizing potency. A novel in vitro assay has been developed based on the binding of post-synaptically acting α-neurotoxins to nicotinic acetylcholine receptor (nAChR), and the ability of antivenoms to prevent this binding. The assay gave high correlation in previous studies with the in vivo murine lethality tests (Median Lethal Dose, LD50), and the neutralization of lethality assays (Median Effective Dose, ED50) by antisera against Naja kaouthia, Naja naja and Bungarus candidus venoms. Here we show that, for the neurotoxic venoms of 20 elapid snake species from eight genera and four continents, the in vitro median inhibitory concentrations (IC50s) for α-neurotoxin binding to purified nAChR correlated well with the in vivo LD50s of the venoms (R2 = 0.8526, p < 0.001). Furthermore, using this assay, the in vitro ED50s of a horse pan-specific antiserum against these venoms correlated significantly with the corresponding in vivo murine ED50s, with R2 = 0.6896 (p < 0.01). In the case of four elapid venoms devoid or having a very low concentration of α-neurotoxins, no inhibition of nAChR binding was observed. Within the philosophy of 3Rs (Replacement, Reduction and Refinement) in animal testing, the in vitro α-neurotoxin-nAChR binding assay can effectively substitute the mouse lethality test for toxicity and antivenom potency evaluation for neurotoxic venoms in which α-neurotoxins predominate. This will greatly reduce the number of mice used in toxicological research and antivenom production laboratories. The simpler, faster, cheaper and less variable in vitro assay should also expedite the development of pan-specific antivenoms against various medically important snakes in many parts of the world.


Assuntos
Bioensaio/métodos , Venenos Elapídicos/química , Neurotoxinas/química , Receptores Nicotínicos/química , África , América , Animais , Ásia , Austrália , Venenos Elapídicos/imunologia , Venenos Elapídicos/toxicidade , Elapidae/imunologia , Cavalos , Humanos , Soros Imunes/imunologia , Camundongos , Neurotoxinas/imunologia , Neurotoxinas/toxicidade , Testes de Neutralização , Mordeduras de Serpentes/imunologia , Mordeduras de Serpentes/mortalidade
11.
Int J Nanomedicine ; 15: 4407-4415, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606685

RESUMO

Objective: Silica nanoparticles (SiO2 NPs) have been extensively employed in biomedical field. SiO2 NPs are primarily designed to enter the circulatory system; however, little information is available on potential adverse effects of SiO2 NPs on the nervous system. Methods: The neurotoxicity of SiO2 NPs at different concentrations (3, 6, 12 ng/nL) on zebrafish embryos was determined using immunofluorescence and microarray techniques, and subsequently confirmed by qRT-PCR. Results: SiO2 NPs disrupt the axonal integrity and decrease the length of axons in Tg (NBT: EGFP) transgenic lines. The number of apoptotic cells in the brain and central nervous system of zebrafish embryos was increased in the presence of 12 ng/nL of SiO2 NPs, but the difference did not reach statistical significance. Screening for changes in the expression of genes involved in the neuroactive ligand-receptor interaction pathway was performed by microarray and confirmed by qRT-PCR. These analyses demonstrated that SiO2 NPs markedly downregulated genes associated with neural function (grm6a, drd1b, chrnb3b, adrb2a, grin2ab, npffr2.1, npy8br, gabrd, chrma3, gabrg3, gria3a, grm1a, adra2b, and glra3). Conclusion: The obtained results documented that SiO2 NPs can induce developmental neurotoxicity by affecting the neuroactive ligand-receptor interaction signaling pathway. This new evidence may help to clarify the mechanism of SiO2 NPs-mediated neurotoxicity.


Assuntos
Embrião não Mamífero/metabolismo , Nanopartículas/toxicidade , Neurotoxinas/toxicidade , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Dióxido de Silício/toxicidade , Peixe-Zebra/embriologia , Animais , Apoptose/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Ligantes , Transdução de Sinais/efeitos dos fármacos
12.
Environ Health Prev Med ; 25(1): 30, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680455

RESUMO

Methylmercury is an environmental pollutant that causes neurotoxicity. Recent studies have reported that the ubiquitin-proteasome system is involved in defense against methylmercury toxicity through the degradation of proteins synthesizing the pyruvate. Mitochondrial accumulation of pyruvate can enhance methylmercury toxicity. In addition, methylmercury exposure induces several immune-related chemokines, specifically in the brain, and may cause neurotoxicity. This summary highlights several molecular mechanisms of methylmercury-induced neurotoxicity.


Assuntos
Quimiocinas/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Neurotoxinas/toxicidade , Proteólise/efeitos dos fármacos , Animais , Quimiocinas/metabolismo , Humanos , Camundongos , Ratos , Saccharomyces cerevisiae/efeitos dos fármacos
13.
J Toxicol Sci ; 45(5): 271-280, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32404559

RESUMO

Environmental neurotoxins such as paraquat (PQ), manganese, and 1-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are associated with a higher risk of Parkinson's disease (PD). These parkinsonian toxins exert certain common toxicological effects on astroglia; however, their role in the regulatory functions of astroglial secretory proteins remains unclear. In a previous study, we observed that secretogranin II (SCG2) and secretogranin III (SCG3), which are important components of the regulated secretory pathway, were elevated in PQ-activated U118 astroglia. In the current study, we used the parkinsonian toxins dopamine (DA), active metabolite of MPTP (MPP+), MnCl2, and lipopolysaccharide (LPS) as inducers, and studied the potential regulation of SCG2 and SCG3. Our results showed that all the parkinsonian toxins except LPS affected astroglial viability but did not cause apoptosis. Exposure to DA, MPP+, and MnCl2 upregulated glial fibrillary acidic protein (GFAP), a marker for astrocyte activation, and stimulated the levels of several astrocytic-derived factors. Further, DA, MPP+, and MnCl2 exposure impeded astroglial cell cycle progression. Moreover, the expression of SCG3 was elevated, while its exosecretion was inhibited in astroglia activated by parkinsonian toxins. The level of SCG2 remained unchanged. In combination with our previous findings, the results of this study indicate that SCG3 may act as a cofactor in astrocyte activation stimulated by various toxins, and the regulation of SCG3 could be involved in the toxicological mechanism by which parkinsonian toxins affect astroglia.


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cromograninas/fisiologia , Intoxicação por MPTP/complicações , Neurotoxinas/toxicidade , Doença de Parkinson Secundária/etiologia , Ciclo Celular/efeitos dos fármacos , Cloretos/efeitos adversos , Cloretos/toxicidade , Cromograninas/metabolismo , Dopamina/administração & dosagem , Dopamina/toxicidade , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Compostos de Manganês/efeitos adversos , Paraquat/toxicidade , Secretogranina II/metabolismo , Secretogranina II/fisiologia , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos
14.
Environ Health Perspect ; 128(4): 47005, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32271623

RESUMO

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a diverse class of industrial chemicals with widespread environmental occurrence. Exposure to long-chain PFAS is associated with developmental toxicity, prompting their replacement with short-chain and fluoroether compounds. There is growing public concern over the safety of replacement PFAS. OBJECTIVE: We aimed to group PFAS based on shared toxicity phenotypes. METHODS: Zebrafish were developmentally exposed to 4,8-dioxa-3H-perfluorononanoate (ADONA), perfluoro-2-propoxypropanoic acid (GenX Free Acid), perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonic acid (PFESA1), perfluorohexanesulfonic acid (PFHxS), perfluorohexanoic acid (PFHxA), perfluoro-n-octanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), or 0.4% dimethyl sulfoxide (DMSO) daily from 0-5 d post fertilization (dpf). At 6 dpf, developmental toxicity and developmental neurotoxicity assays were performed, and targeted analytical chemistry was used to measure media and tissue doses. To test whether aliphatic sulfonic acid PFAS cause the same toxicity phenotypes, perfluorobutanesulfonic acid (PFBS; 4-carbon), perfluoropentanesulfonic acid (PFPeS; 5-carbon), PFHxS (6-carbon), perfluoroheptanesulfonic acid (PFHpS; 7-carbon), and PFOS (8-carbon) were evaluated. RESULTS: PFHxS or PFOS exposure caused failed swim bladder inflation, abnormal ventroflexion of the tail, and hyperactivity at nonteratogenic concentrations. Exposure to PFHxA resulted in a unique hyperactivity signature. ADONA, PFESA1, or PFOA exposure resulted in detectable levels of parent compound in larval tissue but yielded negative toxicity results. GenX was unstable in DMSO, but stable and negative for toxicity when diluted in deionized water. Exposure to PFPeS, PFHxS, PFHpS, or PFOS resulted in a shared toxicity phenotype characterized by body axis and swim bladder defects and hyperactivity. CONCLUSIONS: All emerging fluoroether PFAS tested were negative for evaluated outcomes. Two unique toxicity signatures were identified arising from structurally dissimilar PFAS. Among sulfonic acid aliphatic PFAS, chemical potencies were correlated with increasing carbon chain length for developmental neurotoxicity, but not developmental toxicity. This study identified relationships between chemical structures and in vivo phenotypes that may arise from shared mechanisms of PFAS toxicity. These data suggest that developmental neurotoxicity is an important end point to consider for this class of widely occurring environmental chemicals. https://doi.org/10.1289/EHP5843.


Assuntos
Fluorcarbonetos/toxicidade , Neurotoxinas/toxicidade , Propionatos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Relação Dose-Resposta a Droga , Distribuição Tecidual , Peixe-Zebra/crescimento & desenvolvimento
15.
Oxid Med Cell Longev ; 2020: 2786139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184914

RESUMO

It is generally accepted that the amyloid ß (Aß) peptide toxicity contributes to neuronal loss and is involved in the initiation and progression of Alzheimer's disease (AD). Cold-inducible RNA-binding protein (CIRBP) is reported to be a general stress-response protein, which is induced by different stress conditions. Previous reports have shown the neuroprotective effects of CIRBP through the suppression of apoptosis via the Akt and ERK pathways. The objective of this study is to examine the effect of CIRBP against Aß-induced toxicity in cultured rat primary cortical neurons and attempt to uncover its underlying mechanism. Here, MTT, LDH release, and TUNEL assays showed that CIRBP overexpression protected against both intracellular amyloid ß- (iAß-) induced and Aß 25-35-induced cytotoxicity in rat primary cortical neurons. Electrophysiological changes responsible for iAß-induced neuronal toxicity, including an increase in neuronal resting membrane potentials and a decrease in K+ currents, were reversed by CIRBP overexpression. Western blot results further showed that Aß 25-35 treatment significantly increased the level of proapoptotic protein Bax, cleaved caspase-3, and cleaved caspase-9 and decreased the level of antiapoptotic factor Bcl-2, but were rescued by CIRBP overexpression. Furthermore, CIRBP overexpression prevented the elevation of ROS induced by Aß 25-35 treatment by decreasing the activities of oxidative biomarker and increasing the activities of key enzymes in antioxidant system. Taken together, our findings suggested that CIRBP exerted protective effects against neuronal amyloid toxicity via antioxidative and antiapoptotic pathways, which may provide a promising candidate for amyloid-based AD prevention or therapy.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Córtex Cerebral/patologia , Proteínas e Peptídeos de Choque Frio/metabolismo , Neurônios/patologia , Proteínas de Ligação a RNA/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley
16.
Anal Chim Acta ; 1106: 61-70, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32145856

RESUMO

Analysis of C.elegans by droplet microfluidics has been widely used in study of locomotive behavior responses to neurotoxicity due to the capacity of high-throughput manipulating single cells. However, it has been difficult to manipulate droplets flexibly and actively on account of the limitation of the dimension of individual C. elegans droplets. In this study, a novel MiDMS (Micro-injection Droplet Microfluidic System) was proposed, which consisted of three parts: single C. elegans droplet generator, droplets drug micro-injection channels and drug-incubation observation array. Individual C.elegans droplets were produced initially by regulating the flow rates between oil and water phase as well as the concentration of C.elegans in suspension. Then, the drug solution was precisely injected into each C.elegans droplet, which by electricity induced surface tension of droplet changing. In addition, the effect of neurotoxic Cu2+ on locomotive behavior of C. elegans was evaluated at single cell resolution. The results showed that the neurotoxicity induced behavioral disorder of the C. elegans was more obvious with the increase of Cu2+ concentration or treatment time, and these dose-effect and time-effect relationship in MiDMS were similar as in petri dish. This study will provide a powerful platform for the study of the response of C. elegans to quantitative drug at single cell resolution.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Cobre/toxicidade , Técnicas Analíticas Microfluídicas , Microinjeções , Neurotoxinas/toxicidade , Animais , Caenorhabditis elegans/metabolismo , Cobre/análise , Relação Dose-Resposta a Droga , Neurotoxinas/análise , Tamanho da Partícula , Propriedades de Superfície , Fatores de Tempo
17.
Aquat Toxicol ; 222: 105422, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32112996

RESUMO

The proliferations of cyanobacteria are increasingly prevalent in many rivers and water bodies due especially to eutrophication. This work aims to study in female medaka fish the toxicity, the transfer and the depuration of the anatoxin-a, a neurotoxin produced by benthic cyanobacterial biofilms. This work will provide answers regarding acute toxicity induced by single gavage by anatoxin-a and to the risks of exposure by ingestion of contaminated fish flesh, considering that data on these aspects remain particularly limited. The oral LD50 and NOAEL of a single dose of (±)-anatoxin-a were determined at 11.50 and 6.67 µg.g-1, respectively. Subsequently, the toxico-kinetics of the (±)-anatoxin-a was observed in the guts, the livers and the muscles of female medaka fish for 10 days. Anatoxin-a was quantified by high-resolution qTOF mass spectrometry coupled upstream to a UHPLC chromatographic chain. The toxin could not be detected in the liver after 12 h, and in the gut and muscle after 3 days. Overall, the medaka fish do not appear to accumulate (±)-anatoxin-a and to largely recover after 24 h following a single sub-acute oral liquid exposure at the NOAEL.


Assuntos
Toxinas Marinhas/toxicidade , Neurotoxinas/toxicidade , Oryzias/metabolismo , Tropanos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Cianobactérias/metabolismo , Eutrofização , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Dose Letal Mediana , Fígado/efeitos dos fármacos , Fígado/metabolismo , Toxinas Marinhas/metabolismo , Modelos Teóricos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Neurotoxinas/metabolismo , Nível de Efeito Adverso não Observado , Rios/química , Toxicocinética , Tropanos/metabolismo , Poluentes Químicos da Água/metabolismo
18.
Environ Health ; 19(1): 31, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32160895

RESUMO

BACKGROUND: The overwhelming number of potentially toxic chemicals in consumer products and in our daily environment makes it unrealistic to carry out in-depth analyses of each product with the objective of banning and eliminating toxic chemicals from our environment. OBJECTIVES: To present the challenges that environmental toxicology and epidemiology are currently facing in the context of ubiquitous chemical pollution. DISCUSSION: We propose a realistic and pragmatic approach to this Herculean problem.


Assuntos
Poluentes Ambientais/toxicidade , Síndromes Neurotóxicas/etiologia , Neurotoxinas/toxicidade , Medição de Risco/métodos , Testes de Toxicidade/métodos , Substâncias Perigosas/toxicidade , Humanos
19.
Toxicol Lett ; 326: 31-51, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32145396

RESUMO

Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person's quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer's disease.


Assuntos
Doença de Alzheimer/induzido quimicamente , Cognição/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Exposição Ambiental/efeitos adversos , Neurotoxinas/toxicidade , Praguicidas/toxicidade , Animais , Feminino , Humanos , Masculino , Modelos Animais , Medição de Risco/métodos
20.
PLoS Negl Trop Dis ; 14(3): e0008060, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32163415

RESUMO

The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak took place in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the quantity of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.


Assuntos
Morte Celular/efeitos dos fármacos , Microcefalia/patologia , Envenenamento/complicações , Envenenamento/patologia , Saxitoxina/toxicidade , Infecção por Zika virus/complicações , Infecção por Zika virus/patologia , Animais , Toxinas Bacterianas/análise , Toxinas Bacterianas/toxicidade , Encéfalo/patologia , Brasil/epidemiologia , Células Cultivadas , Modelos Animais de Doenças , Surtos de Doenças , Feminino , Humanos , Incidência , Toxinas Marinhas/análise , Toxinas Marinhas/toxicidade , Camundongos Endogâmicos C57BL , Microcistinas/análise , Microcistinas/toxicidade , Modelos Teóricos , Neurotoxinas/análise , Neurotoxinas/toxicidade , Saxitoxina/análise , Água/química
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