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1.
Toxins (Basel) ; 15(11)2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37999522

RESUMO

The Great Salt Lake in Utah is the largest saline lake in the Western hemisphere and one of the largest terminal lakes in the world. Situated at the eastern edge of the Great Basin, it is a remnant of the freshwater Lake Bonneville whose water level precipitously lowered about 12,000 years ago due to a natural break in Red Rock pass to the north. It contains a diverse assemblage of cyanobacteria which vary spatially dependent on salinity. In 1984, the waters of the Great Salt Lake occupied 8500 km2. Nearly four decades later, the waters occupy 2500 km2-a reduction in surface area of 71%. With predominantly westerly winds, there is a potential for the adjacent metropolitan residents to the east to be exposed to airborne cyanobacteria- and cyanotoxin-containing dust. During the summer and fall months of 2022, air and dried sediment samples were collected and assessed for the presence of BMAA which has been identified as a risk factor for ALS. Collection of air samples equivalent to a person breathing for 1 h resulted in BMAA and isomers being found in some air samples, along with their presence in exposed lakebed samples. There was no clear relationship between the presence of these toxins in airborne and adjacent lakebed samples, suggesting that airborne toxins may originate from diffuse rather than point sources. These findings confirm that continued low water levels in the Great Salt Lake may constitute an increasing health hazard for the 2.5 million inhabitants of communities along the Wasatch Front.


Assuntos
Cianobactérias , Lagos , Humanos , Lagos/microbiologia , Água , Utah , Toxinas de Cianobactérias
2.
RNA Biol ; 20(1): 140-148, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-37042019

RESUMO

Micro RNAs (miRNAs) are short, non-coding RNAs with significant potential as diagnostic and prognostic biomarkers. However, a lack of reproducibility across studies has hindered their introduction into clinical settings. Inconsistencies between studies include a lack of consensus on the miRNAs associated with a specific disease and the direction of regulation. These differences may reflect the heterogenous nature of pathologies with multiple phenotypes, such as amyotrophic lateral sclerosis (ALS). It is also possible that discrepancies are due to different sampling, processing, and analysis protocols across labs. Using miRNA extracted from L1CAM immunoaffinity purified extracellular vesicles (neural-enriched extracellular vesicles or NEE), we thrice replicated an 8-miRNA fingerprint diagnostic of ALS, which includes the miRNA species and direction of regulation. We aimed to determine if the extra purification steps required to generate NEE created a unique extracellular vesicle (EV) fraction that might contribute to the robustness and replicability of our assay. We compared three fractions from control human plasma: 1) total heterogenous EVs (T), 2) L1CAM/neural enriched EVs (NEE), and 3) the remaining total-minus-NEE fraction (T-N). Each fraction was characterized for size, total protein content, and protein markers, then total RNA was extracted, and qPCR was run on 20 miRNAs. We report that the miRNA expression within NEE was different enough compared to T and T-N to justify the extra steps required to generate this fraction. We conclude that L1CAM immunocapture generates a unique fraction of EVs that consistently and robustly replicates a miRNA fingerprint which differentiates ALS patients from controls.


Assuntos
Esclerose Lateral Amiotrófica , Vesículas Extracelulares , MicroRNAs , Molécula L1 de Adesão de Célula Nervosa , Humanos , MicroRNAs/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Reprodutibilidade dos Testes , Vesículas Extracelulares/metabolismo
3.
Toxicol Rep ; 10: 87-96, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36691605

RESUMO

Introduction: Cyanobacterial blooms produce toxins that may become aerosolized, increasing health risks through inhalation exposures. Health related effects on the lower respiratory tract caused by these toxins are becoming better understood. However, nasal exposures to cyanotoxins remain understudied, especially for those with neurotoxic potential. Here, we present a case series study evaluating exposure to ß-N-methylamino-l-alanine (BMAA), a cyanobacterial toxin linked to neurodegenerative disease, in postmortem olfactory tissues of individuals with varying stages of Alzheimer's disease (AD). Methods: Olfactory bulb (Ob) tissues were collected during autopsies performed between 2014 and 2017 from six South Florida brain donors (ages 47-78) with residences less than 140 m from a freshwater body. A triple quadrupole tandem mass spectrometry (UHPLC-MS/MS) method validated according to peer AOAC International guidelines was used to detect BMAA and two BMAA isomers: 2,4-diaminobutyric acid (2,4-DAB) and N-(2-aminoethyl)glycine (AEG). Quantitative PCR was performed on the contralateral Ob to evaluate the relative expression of genes related to proinflammatory cytokines (IL-6 & IL-18), apoptotic pathways (CASP1 & BCL2), and mitochondrial stress (IRF1 & PINK1). Immunohistochemistry was also performed on the adjacent olfactory tract (Ot) to evaluate co-occurring neuropathology with BMAA tissue concentration. Results: BMAA was detected in the Ob of all cases at a median concentration of 30.4 ng/g (Range

4.
J Neurol Sci ; 442: 120396, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36081303

RESUMO

BACKGROUND AND OBJECTIVES: We examined miRNA biomarkers for ALS extracted from extracellular vesicles in blood samples using a large and diverse patient and control population. Different blood collection and storage protocols by different investigators could impact repeatability of miRNA analysis. We tested the hypotheses that miRNA extracted from extracellular vesicles using immunoaffinity purification techniques are robust and repeatable across investigators, laboratories and in a broad ALS population. METHODS: De-identified patient blood plasma samples obtained from the U.S. National ALS Biorepository were compared with plasma from non-ALS controls. Extracellular vesicles were extracted and isolated using L1CAM immunoaffinity purification. Total RNA was extracted, and miRNA quantified using qPCR following careful quality control measures. Gene fold expressions of eight miRNAs were compared using a Mann-Whitney two-tailed test. RESULTS: One hundred blinded, blood plasma samples were analyzed. Thirty-five men and 15 women with ALS were compared with controls consisting of 30 men and 20 women. None of the ALS patient cohort reported family members with ALS suggesting sporadic ALS. Five of the eight biomarkers previously published were found to significantly discriminate ALS patient samples from control samples. DISCUSSION: The methods used in this study provide a repeatable measure of miRNA biomarkers that statistically differentiate ALS patient samples from control samples. The broad inclusion criteria for both the ALS patient cohort and controls along with the collection of blood samples by different investigators suggest that these methods are robust and represent good candidates for further research and development aimed at clinical application.


Assuntos
Esclerose Lateral Amiotrófica , Vesículas Extracelulares , MicroRNAs , Molécula L1 de Adesão de Célula Nervosa , Masculino , Humanos , Feminino , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , MicroRNAs/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Vesículas Extracelulares/metabolismo , Biomarcadores
5.
PLoS One ; 17(4): e0267407, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35446894

RESUMO

We sought to identify a usable biomarker from blood samples to characterize early-stage Alzheimer's disease (AD) patients, in order to facilitate rapid diagnosis, early therapeutic intervention, and monitoring of clinical trials. We compared metabolites from blood plasma in early-stage Alzheimer's disease patients with blood plasma from healthy controls using two different analytical platforms: Amino Acid Analyzer and Tandem Mass-Spectrometer. Early-stage Alzheimer's patient blood samples were obtained during an FDA-approved Phase IIa clinical trial (Clinicaltrial.gov NCT03062449). Participants included 25 early-stage Alzheimer's patients and 25 healthy controls in the United States. We measured concentrations of 2-aminoethyl dihydrogen phosphate and taurine in blood plasma samples. We found that plasma concentrations of a phospholipid metabolite, 2-aminoethyl dihydrogen phosphate, normalized by taurine concentrations, distinguish blood samples of patients with early-stage AD. This possible new Alzheimer's biomarker may supplement clinical diagnosis for early detection of the disease.


Assuntos
Doença de Alzheimer , Biomarcadores , Doença de Alzheimer/sangue , Doença de Alzheimer/tratamento farmacológico , Biomarcadores/sangue , Ensaios Clínicos Fase II como Assunto , Humanos , Fosfatos , Plasma , Taurina/uso terapêutico
6.
J Nat Prod ; 85(1): 34-46, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35044783

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive cancer originating in the brain, with a median survival of 12 months. Most patients do not respond to or develop resistance to the only effective chemotherapeutic drug, temozolomide (TMZ), used to treat gliomas. Novel treatment methods are critically needed. Cyclotides are plant peptides that may be promising adjuvants to TMZ chemotherapy. They exhibit antitumor activity and chemosensitize cells to doxorubicin in breast cancer studies. During this research, we optimized cyclotide isolation techniques, and several cyclotides (CyO2, CyO13, kalata B1, and varv peptide A) exhibited dose-dependent cytotoxicity in MTT assays with IC50 values of 2.15-7.92 µM against human brain astrocytoma cells (U-87 MG) and human bone marrow derived neuroblastoma cells (SH-SY5Y). CyO2 and varv peptide A increased TMZ-induced cell death in U-87 MG cultures alone and when coexposed with CyO2 or varv peptide A plus TMZ. Phase contrast microscopy of glioblastoma cells exposed to cyclotides alone and coexposed to TMZ indicated shrunken, granular cells with blebbing, and the most pronounced effects were observed with coexposure treatments of cyclotides and TMZ. Cumulative results provide the proof-of-concept that cyclotides may enhance TMZ chemotherapy, and in vivo pharmacokinetic investigations of cyclotides are warranted with respect to GBM.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/patologia , Ciclotídeos/farmacologia , Glioblastoma/patologia , Temozolomida/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Estudo de Prova de Conceito , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Biomedicines ; 11(1)2022 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-36672612

RESUMO

Neurodegenerative diseases feature changes in cognition, and anxiety-like and autism-like behaviors, which are associated with epigenetic alterations such as DNA methylation and histone modifications. The amino acid L-serine has been shown to have beneficial effects on neurological symptoms. Here, we found that growth hormone-releasing hormone knockout (GHRH-KO) mice, a GH-deficiency mouse model characterized by extended lifespan and enhanced insulin sensitivity, showed a lower anxiety symptom and impairment of short-term object recognition memory and autism-like behaviors. Interestingly, L-serine administration exerted anxiolytic effects in mice and ameliorated the behavioral deficits in GHRH-KO. L-serine treatment upregulated histone epigenetic markers of H3K4me, H3K9ac, H3K14ac and H3K18ac in the hippocampus and H3K4me in the cerebral cortex in both GHRH-KO mice and wild type controls. L-serine-modulated epigenetic marker changes, in turn, were found to regulate mRNA expression of BDNF, grm3, foxp1, shank3, auts2 and marcksl1, which are involved in anxiety-, cognitive- and autism-like behaviors. Our study provides a novel insight into the beneficial effects of L-serine intervention on neuropsychological impairments.

8.
Toxins (Basel) ; 13(10)2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34678990

RESUMO

Dolphins are well-regarded sentinels for toxin exposure and can bioaccumulate a cyanotoxin called ß-N-methylamino-l-alanine (BMAA) that has been linked to human neurodegenerative disease. The same dolphins also possessed hallmarks of Alzheimer's disease (AD), suggesting a possible association between toxin exposure and neuropathology. However, the mechanisms of neurodegeneration in dolphins and the impact cyanotoxins have on these processes are unknown. Here, we evaluate BMAA exposure by investigating transcription signatures using PCR for dolphin genes homologous to those implicated in AD and related dementias: APP, PSEN1, PSEN2, MAPT, GRN, TARDBP, and C9orf72. Immunohistochemistry and Sevier Münger silver staining were used to validate neuropathology. Methylmercury (MeHg), a synergistic neurotoxicant with BMAA, was also measured using PT-GC-AFS. We report that dolphins have up to a three-fold increase in gene transcription related to Aß+ plaques, neurofibrillary tangles, neuritic plaques, and TDP-43+ intracytoplasmic inclusions. The upregulation of gene transcription in our dolphin cohort paralleled increasing BMAA concentration. In addition, dolphins with BMAA exposures equivalent to those reported in AD patients displayed up to a 14-fold increase in AD-type neuropathology. MeHg was detected (0.16-0.41 µg/g) and toxicity associated with exposure was also observed in the brain. These results demonstrate that dolphins develop neuropathology associated with AD and exposure to BMAA and MeHg may augment these processes.


Assuntos
Diamino Aminoácidos/toxicidade , Golfinhos Comuns , Toxinas de Cianobactérias/toxicidade , Agonistas de Aminoácidos Excitatórios/toxicidade , Compostos de Metilmercúrio/toxicidade , Doenças Neurodegenerativas/veterinária , Poluentes Químicos da Água/toxicidade , Animais , Feminino , Masculino , Massachusetts , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/patologia
9.
Toxins (Basel) ; 13(9)2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34564664

RESUMO

Cyanobacteria are capable of producing a wide range of bioactive compounds with many considered to be toxins. Although there are a number of toxicological outcomes with respect to cyanobacterial exposure, this review aims to examine those which affect the central nervous system (CNS) or have neurotoxicological properties. Such exposures can be acute or chronic, and we detail issues concerning CNS entry, detection and remediation. Exposure can occur through a variety of media but, increasingly, exposure through air via inhalation may have greater significance and requires further investigation. Even though cyanobacterial toxins have traditionally been classified based on their primary mode of toxicity, increasing evidence suggests that some also possess neurotoxic properties and include known cyanotoxins and unknown compounds. Furthermore, chronic long-term exposure to these compounds is increasingly being identified as adversely affecting human health.


Assuntos
Toxinas de Cianobactérias/toxicidade , Cianobactérias/química , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Humanos
10.
Biol Methods Protoc ; 6(1): bpab015, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34423131

RESUMO

One consequence of the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is an interruption to the supply of laboratory consumables, particularly those used for RNA extraction. This category includes column-based RNA extraction kits designed to retain short RNA species (defined as having fewer than 200 nucleotides), from small sample volumes, e.g. exosomes or extracellular vesicles (EVs). Qiagen manufactures several kits for the extraction and enrichment of short RNA species, such as microRNA (miRNA), which contain silica-membrane columns called "RNeasy MinElute Spin Columns." These kits, which also contain buffers and collection tubes, range in price from USD380 to greater than USD1000 and have been subject to fulfillment delays. Scientists seeking to reduce single-use plastics and costs may wish to order the columns separately; however, Qiagen does not sell the RNeasy MinElute Spin Columns (in reasonable quantities) as an individual item. Thus, we sought an alternative product and found RNA Tini Spin columns from Enzymax LLC. We conducted a systematic comparison of the efficiency of RNA extraction for miRNA quantitative real-time PCR (qPCR) using the Qiagen RNeasy MinElute Spin Columns and Enzymax LLC RNA Tini Spin columns and the Qiagen total RNA extraction protocol that enriches for short RNA species. We compared the efficiency of extraction of five spike-in control miRNAs, six sample signal miRNAs, and nine low- to medium-abundance miRNAs by qPCR. The RNA was extracted from EV preparations purified from human plasma using CD81 immunoprecipitation. We report no statistically significant differences in extraction efficiencies between the two columns for any of the miRNAs examined. Therefore, we conclude that the Enzymax RNA Tini Spin columns are adequate substitutes for the Qiagen RNeasy MinElute Spin Columns for short RNA species enrichment and downstream qPCR from EVs in the miRNAs we examined.

11.
Neurotox Res ; 39(1): 42-48, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32557323

RESUMO

The fate and persistence of the neurotoxin ß-N-methylamino-L-alanine (BMAA) and its isomers N-(2aminoethyl)glycine (AEG) and 2,4-diaminobuytric acid (DAB) in soil profiles is poorly understood. In desert environments, these cyanotoxins are commonly found in both terrestrial and adjacent marine ecosystems; they accumulate in biocrusts and groundwater catchments, and have been previously shown to persist in soil as deep as 25 cm. To determine the depth that BMAA and its isomers can be found, samples were incrementally collected every 5 cm from bedrock to surface in triplicate soil cores in a biocrust field in the terrestrial desert of Qatar. Biocrust surface samples were also collected from each core priorly. Toxins were extracted from soil sub-samples, derivatized, and analyzed with UPLC-MS/MS. All toxins were detected in all soil cores at all depths. AEG and DAB were within a quantifiable concentration threshold; however, the low concentration of BMAA was considered below the threshold for quantification. This may have environmental health implications if these toxins are able to infiltrate and contaminate the bedrock aquifer, as well as the sand and gravel aquifers. Human and animal health may also be impacted through exposure to contaminated groundwater wells or through inhalation of aerosolized particles of soil, resuspended during construction or recreational activities.


Assuntos
Diamino Aminoácidos/análise , Toxinas de Cianobactérias/análise , Clima Desértico , Poluentes do Solo/análise , Catar
12.
Neurotox Res ; 39(1): 1-5, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33196951

RESUMO

In this volume, studies springing from a BMAA symposium held in Salt Lake City, Utah, in April 2019 are presented. Although most studies of neurotoxicity consider the effects of BMAA as an isolated molecule, it is now known that environmental exposures can be to a combination of BMAA-related molecules, including enantiomers, isomers, other co-occurring cyanotoxins, and BMAA carbamates. Within the body, BMAA may exist in equilibrium with α- and ß-carbamates formed in the presence of bicarbonate. BMAA and its isomers 2,4-DAB and AEG, accumulate over decades in biocrusts and persist at depths in soil profiles of the Gulf deserts. In Florida, releases of cyanobacterially ladened water from Lake Okeechobee can extend into coastal environments where diatoms and possibly dinoflagellates also produce BMAA and isomers in addition to brevetoxins. Along the African Lake Chad, neurotoxic risks from consumption of dried cyanobacterial cakes may, however, be outweighed by their amino acid addition to otherwise protein-deficient diets. Discrepancies in the detection and quantification of BMAA from different laboratories likely originate in the use of different analytical methods. C-18 columns, used to study derivatized BMAA, can efficiently separate BMAA from its isomers in validated methods, while validation is not possible for HILIC columns in the study of underivatized BMAA, since they do not adequately separate BMAA from its isomer BAMA. The presence of BMAA dimers, metal adducts, and carbamates may result in underestimation of BMAA by mass spectrometry. BMAA research led to the identification of the dietary amino acid L-serine as a neuroprotective molecule. In animal and clinical trials, L-serine appears to slow neurodegeneration, although the modes of action are still under study. Based on zebra fish sensitivity to platinum-based chemotherapeutic agents, investigators have found that L-serine reduces reactive oxygen species (ROS) but does not protect auditory hybridoma cells from cisplatin. Another possible mode of action of L-serine, induction of autophagic-lysosomal enzymes, is also being explored. The hypothesis that cyanobacterial exposures in general, and chronic exposures to BMAA in particular, may prove to be risk factors for neurodegenerative illnesses has not been without critics. Emerging from the symposium, a multi-authored response to one such critical paper appears in this collection of articles. Instead of waiting until there is a conclusive proof of risk, the adoption of the "precautionary default principle," proposed by Ingvar Brandt and his colleagues in Sweden, is suggested. Avoidance of exposures to cyanobacterial blooms and other sources of BMAA is suggested, until further research indicates such precautions to be unnecessary.


Assuntos
Diamino Aminoácidos/toxicidade , Toxinas de Cianobactérias/toxicidade , Doenças Neurodegenerativas/fisiopatologia , Neuroproteção , Animais , Congressos como Assunto , Humanos
13.
Open Biol ; 10(6): 200116, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574550

RESUMO

Biomarkers for amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are currently not clinically available for disease diagnosis or analysis of disease progression. If identified, biomarkers could improve patient outcomes by enabling early intervention and assist in the determination of treatment efficacy. We hypothesized that neural-enriched extracellular vesicles could provide microRNA (miRNA) fingerprints with unequivocal signatures of neurodegeneration. Using blood plasma from ALS/MND patients and controls, we extracted neural-enriched extracellular vesicle fractions and conducted next-generation sequencing and qPCR of miRNA components of the transcriptome. We here report eight miRNA sequences which significantly distinguish ALS/MND patients from controls in a replicated experiment using a second cohort of patients and controls. miRNA sequences from patient blood samples using neural-enriched extracellular vesicles may yield unique insights into mechanisms of neurodegeneration and assist in early diagnosis of ALS/MND.


Assuntos
Esclerose Lateral Amiotrófica/genética , Vesículas Extracelulares/genética , MicroRNAs/genética , Doença dos Neurônios Motores/genética , Análise de Sequência de RNA/métodos , Esclerose Lateral Amiotrófica/sangue , Impressões Digitais de DNA , Feminino , Regulação da Expressão Gênica , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Doença dos Neurônios Motores/sangue , Projetos Piloto
14.
J Neuropathol Exp Neurol ; 79(4): 393-406, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32077471

RESUMO

The early neuropathological features of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are protein aggregates in motor neurons and microglial activation. Similar pathology characterizes Guamanian ALS/Parkinsonism dementia complex, which may be triggered by the cyanotoxin ß-N-methylamino-l-alanine (BMAA). We report here the occurrence of ALS/MND-type pathological changes in vervets (Chlorocebus sabaeus; n = 8) fed oral doses of a dry powder of BMAA HCl salt (210 mg/kg/day) for 140 days. Spinal cords and brains from toxin-exposed vervets were compared to controls fed rice flour (210 mg/kg/day) and to vervets coadministered equal amounts of BMAA and l-serine (210 mg/kg/day). Immunohistochemistry and quantitative image analysis were used to examine markers of ALS/MND and glial activation. UHPLC-MS/MS was used to confirm BMAA exposures in dosed vervets. Motor neuron degeneration was demonstrated in BMAA-dosed vervets by TDP-43+ proteinopathy in anterior horn cells, by reactive astrogliosis, by activated microglia, and by damage to myelinated axons in the lateral corticospinal tracts. Vervets dosed with BMAA + l-serine displayed reduced neuropathological changes. This study demonstrates that chronic dietary exposure to BMAA causes ALS/MND-type pathological changes in the vervet and coadministration of l-serine reduces the amount of reactive gliosis and the number of protein inclusions in motor neurons.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Doença dos Neurônios Motores/patologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Serina/administração & dosagem , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Diamino Aminoácidos/toxicidade , Esclerose Lateral Amiotrófica/induzido quimicamente , Animais , Chlorocebus aethiops , Toxinas de Cianobactérias , Modelos Animais de Doenças , Masculino , Microglia/efeitos dos fármacos , Microglia/patologia , Doença dos Neurônios Motores/induzido quimicamente , Tratos Piramidais/efeitos dos fármacos , Tratos Piramidais/patologia
15.
PLoS One ; 14(3): e0213346, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30893348

RESUMO

Dolphin stranding events occur frequently in Florida and Massachusetts. Dolphins are an excellent sentinel species for toxin exposures in the marine environment. In this report we examine whether cyanobacterial neurotoxin, ß-methylamino-L-alanine (BMAA), is present in stranded dolphins. BMAA has been shown to bioaccumulate in the marine food web, including in the muscles and fins of sharks. Dietary exposure to BMAA is associated with the occurrence of neurofibrillary tangles and ß-amyloid plaques in nonhuman primates. The findings of protein-bound BMAA in brain tissues from patients with Alzheimer's disease has advanced the hypothesis that BMAA may be linked to dementia. Since dolphins are apex predators and consume prey containing high amounts of BMAA, we examined necropsy specimens to determine if dietary and environmental exposures may result in the accumulation of BMAA in the brains of dolphins. To test this hypothesis, we measured BMAA in a series of brains collected from dolphins stranded in Florida and Massachusetts using two orthogonal analytical methods: 1) high performance liquid chromatography, and 2) ultra-performance liquid chromatography with tandem mass spectrometry. We detected high levels of BMAA (20-748 µg/g) in the brains of 13 of 14 dolphins. To correlate neuropathological changes with toxin exposure, gross and microscopic examinations were performed on cortical brain regions responsible for acoustico-motor navigation. We observed increased numbers of ß-amyloid+ plaques and dystrophic neurites in the auditory cortex compared to the visual cortex and brainstem. The presence of BMAA and neuropathological changes in the stranded dolphin brain may help to further our understanding of cyanotoxin exposure and its potential impact on human health.


Assuntos
Diamino Aminoácidos/toxicidade , Encéfalo/metabolismo , Encéfalo/patologia , Cianobactérias/patogenicidade , Golfinhos/metabolismo , Neurotoxinas/toxicidade , Diamino Aminoácidos/análise , Animais , Golfinho Nariz-de-Garrafa/metabolismo , Encéfalo/efeitos dos fármacos , Golfinhos Comuns/metabolismo , Toxinas de Cianobactérias , Monitoramento Ambiental , Cadeia Alimentar , Proliferação Nociva de Algas , Humanos , Massachusetts , Neurotoxinas/análise , Placa Amiloide/patologia , Espécies Sentinelas
16.
Neurotox Res ; 33(1): 178-183, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28540663

RESUMO

The cyanobacterial toxin ß-N-methylamino-L-alanine (BMAA) now appears to be a cause of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Its production by cyanobacteria throughout the world combined with multiple mechanisms of BMAA neurotoxicity, particularly to vulnerable subpopulations of motor neurons, has significantly increased interest in investigating exposure to this non-protein amino acid as a possible risk factor for other forms of neurodegenerative illness. We here provide a brief overview of BMAA studies and provide an introduction to this collection of scientific manuscripts in this special issue on BMAA.


Assuntos
Diamino Aminoácidos/toxicidade , Esclerose Lateral Amiotrófica/induzido quimicamente , Agonistas de Aminoácidos Excitatórios/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Diamino Aminoácidos/química , Esclerose Lateral Amiotrófica/epidemiologia , Animais , Toxinas de Cianobactérias , Agonistas de Aminoácidos Excitatórios/química , Humanos , Transtornos Parkinsonianos/epidemiologia
17.
Neurotox Res ; 33(1): 24-32, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28478528

RESUMO

The theory that ß-N-methylamino-L-alanine (BMAA), a cyanobacterial toxin, contaminates traditional food supplies of the Chamorro people of Guam is supported by the recent finding that chronic dietary exposure to L-BMAA in vervets (Chlorocebus sabaeus) triggers the formation of neurofibrillary tangles (NFT) and ß-amyloid plaques in the brain. In the first experiment, we found that all four vervets receiving a 210 mg/kg dose for 140 days developed NFT and sparse amyloid deposits. In the second experiment, all eight vervets receiving a 210 mg/kg dose for 140 days developed NFT and amyloid deposits, as well as all eight vervets that received only 21 mg/kg. Based on dietary surveys of the Chamorro people, we estimated lifetime chronic BMAA exposure at a high and a low level: 1) adult male Chamorros eating two flying foxes per month plus one 30 g serving of cycad flour per week; and 2) adult male Chamorros eating one 30 g serving of cycad flour per day combined with the consumption of eight flying foxes per month. The resultant cumulative lifetime Chamorro exposures ranged from 1 to 41 g/kg and are comparable to the total lifetime vervet exposures in our experiments of 2 and 22 g/kg, respectively. Furthermore, measured protein-bound BMAA concentrations of vervets fed L-BMAA powder are comparable to measured protein-bound BMAA concentrations in postmortem brain tissues of Chamorros who died with ALS/PDC.


Assuntos
Diamino Aminoácidos/toxicidade , Esclerose Lateral Amiotrófica/induzido quimicamente , Modelos Animais de Doenças , Agonistas de Aminoácidos Excitatórios/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Chlorocebus aethiops , Toxinas de Cianobactérias , Relação Dose-Resposta a Droga , Guam , Humanos , Masculino , Emaranhados Neurofibrilares/patologia , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Placa Amiloide/metabolismo
19.
Amino Acids ; 49(8): 1427-1439, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28620737

RESUMO

Chronic dietary exposure to the cyanobacterial toxin ß-N-methylamino-L-alanine (BMAA) triggers neuropathology in non-human primates, providing support for the theory that BMAA causes a fatal neurodegenerative illness among the indigenous Chamorro people of Guam. However, since there are two stereoisomers of BMAA, it is important to know if both can occur in nature, and if so, what role they might play in disease causation. As a first step, we analysed both BMAA enantiomers in cyanobacteria, cycads, and in mammals orally dosed with L-BMAA, to determine if enantiomeric changes could occur in vivo. BMAA in cyanobacteria and cycads was found only as the L-enantiomer. However, while the L-enantiomer in mammals was little changed after digestion, we detected a small pool of D-BMAA in the liver (12.5%) of mice and in the blood plasma of vervets (3.6%). Chiral analysis of cerebrospinal fluid of vervets and hindbrain of mice showed that the free BMAA in the central nervous system was the D-enantiomer. In vitro toxicity investigations with D-BMAA showed toxicity, mediated through AMPA rather than NMDA receptors. These findings raise important considerations concerning the neurotoxicity of BMAA and its relationship to neurodegenerative disease.


Assuntos
Diamino Aminoácidos/toxicidade , Toxinas Bacterianas/toxicidade , Cianobactérias/efeitos dos fármacos , Cycadopsida/efeitos dos fármacos , Toxinas Marinhas/toxicidade , Microcistinas/toxicidade , Diamino Aminoácidos/análise , Animais , Toxinas Bacterianas/análise , Toxinas de Cianobactérias , Toxinas Marinhas/análise , Camundongos , Camundongos Endogâmicos C57BL , Microcistinas/análise , Estereoisomerismo
20.
Curr Nutr Rep ; 6(1): 24-31, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28331770

RESUMO

PURPOSE OF REVIEW: Ogimi village is renowned for its aging population. We sought to determine if the l-serine content of their diet could account for their neurological health. RECENT FINDINGS: The most frequently consumed food items, including tofu and seaweeds, are rich in the dietary amino acid l-serine. l-serine content of the Ogimi diet >8 grams/day for Ogimi women significantly exceeds the average American dietary intake of 2.5 grams/day for women >70 years old. SUMMARY: Our hypothesis that the high l-serine content of the Ogimi diet is related to the paucity of tangle diseases among villagers is buttressed by in vivo results with non-human primates where dietary l-serine slowed development of neurofibrillary tangles and ß-amyloid plaques by up to 85% and a human clinical trial finding that l-serine at 15 grams/day twice daily slows functional decline in ALS patients. Analysis of the Ogimi diet suggests that l-serine should be evaluated for therapeutic potential as a neuroprotective agent.

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