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1.
Biomolecules ; 14(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38927056

RESUMO

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal-protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.


Assuntos
Neuropatias Amiloides Familiares , Pré-Albumina , Humanos , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/epidemiologia , Pré-Albumina/genética , Pré-Albumina/metabolismo , Mineração , Polineuropatias/genética , Polineuropatias/epidemiologia , Polineuropatias/etiologia , Portugal/epidemiologia
2.
ACS Chem Neurosci ; 14(15): 2618-2633, 2023 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-37487115

RESUMO

Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions, including Alzheimer's disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the deposition of amyloid plaques, consisting mainly of amyloid-ß (Aß) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aß aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aß production, and these metals bind to Aß peptides and modulate their aggregation. The possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aß peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aß peptides with affinities in the micromolar range, induce structural changes in Aß monomers and oligomers, and inhibit Aß fibrillization. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation.


Assuntos
Doença de Alzheimer , Urânio , Animais , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Íons/química , Amiloide
3.
J Trace Elem Med Biol ; 78: 127165, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37018859

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive muscle wasting, paralysis, and respiratory failure. Whereas approximately 10-15 % of ALS cases are familial, the etiology of the remaining, sporadic ALS cases remains largely unknown. Environmental exposures have been suggested as causative factors for decades, and previous studies have found elevated concentrations of metals in ALS patients. PURPOSE: This meta-analysis aims to assess metal concentrations in body fluids and tissues of ALS patients. METHODS: We searched the MEDLINE and EMBASE databases on December 7th, 2022 for cross-sectional, case-control, and cohort studies which measure metal concentrations in whole blood, blood plasma, blood serum, cerebrospinal fluid (CSF), urine, erythrocytes, nail, and hair samples of ALS patients. Meta-analysis was then performed when three or more articles existed for a comparison. FINDINGS: Twenty-nine studies measuring 23 metals were included and 13 meta-analyses were performed from 4234 screened entries. The meta-analysis results showed elevated concentrations of lead and selenium. Lead, measured in whole blood in 6 studies, was significantly elevated by 2.88 µg/L (95 % CI: 0.83-4.93, p = 0.006) and lead, measured in CSF in 4 studies, was significantly elevated by 0.21 µg/L (95 % CI: 0.01 - 0.41, p = 0.04) in ALS patients when compared to controls. Selenium, measured in serum/plasma in 4 studies, was significantly elevated by 4.26 µg/L (95% CI: 0.73 - 7.79, p = 0.02) when compared to controls.Analyses of other metal concentrations showed no statistically significant difference between the groups. CONCLUSION: Lead has been discussed as a possible causative agent in ALS since 1850. Lead has been found in the spinal cord of ALS patients, and occupational exposure to lead is more common in ALS patients than in controls. Selenium in the form of neurotoxic selenite has been shown to geochemically correlate to ALS occurrence in Italy. Although no causal relationship can be established from the results of this meta-analysis, the findings suggest an involvement of lead and selenium in the pathophysiology of ALS. After a thorough meta-analysis of published studies on metal concentrations in ALS it can only be concluded that lead and selenium are elevated in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Selênio , Humanos , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Chumbo , Soro , Unhas , Estudos Transversais , Plasma , Cabelo
4.
J Trace Elem Med Biol ; 78: 127163, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37004478

RESUMO

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown aetiology. Metals have been suspected to contribute to ALS pathogenesis since mid-19th century, yet studies on measured metal concentrations in ALS patients have often yielded conflicting results, with large individual variation in measured values. Calculating metal concentration ratios can unveil possible synergistic effects of neurotoxic metals in ALS pathogenesis. The aim of this study was to investigate if ratios of different metal concentrations in cerebrospinal fluid (CSF) and blood plasma, respectively, differ between ALS patients and healthy controls. METHODS: Cerebrospinal fluid and blood plasma were collected from 17 ALS patients and 10 controls. Samples were analysed for 22 metals by high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS), and all possible 231 metal ratios calculated in each body fluid. RESULTS: Fifty-three metal ratios were significantly elevated in ALS cases as compared to controls (p < 0.05); five in blood plasma, and 48 in CSF. The finding of fewer elevated ratios in blood plasma may indicate specific transport of metals into the central nervous system. The elevated metal ratios in CSF include Cd/Se (p = 0.031), and 16 ratios with magnesium, such as Mn/Mg (p = 0.005) and Al/Mg (p = 0.014). CONCLUSION: Metal ratios may be used as biomarkers in ALS diagnosis and as guidelines for preventive measures.


Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Humanos , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Sistema Nervoso Central , Magnésio , Biomarcadores
5.
Health Phys ; 124(4): 285-300, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36727932

RESUMO

ABSTRACT: Uranium aerosol exposure can be a health risk factor for workers in the nuclear fuel industry. Good knowledge about aerosol dissolution and absorption characteristics in the gastrointestinal tract is imperative for solid dose assessments and risk management. In this study, an in vitro dissolution model of the GI tract was used to experimentally study solubility of size-fractionated aerosols. The aerosols were collected from four major workshops in a nuclear fuel fabrication plant where uranium compounds such as uranium hexafluoride (UF 6 ), uranium dioxide (UO 2 ), ammonium uranyl carbonate, AUC [UO 2 CO 3 ·2(NH 4 ) 2 CO 3 ] and triuranium octoxide (U 3 O 8 ) are present. The alimentary tract transfer factor, f A , was estimated for the aerosols sampled in the study. The transfer factor was derived from the dissolution in the small intestine in combination with data on absorption of soluble uranium. Results from the conversion workshop indicated a f A in line with what is recommended (0.004) by the ICRP for inhalation exposure to Type M materials. Obtained transfer factors, f A , for the powder preparation and pelletizing workshops where UO 2 and U 3 O 8 are handled are lower for inhalation and much lower for ingestion than those recommended by the ICRP for Type M/S materials f A = 0.00029 and 0.00016 vs. 0.0006 and 0.002, respectively. The results for ingestion and inhalation f A indicate that ICRP's conservative recommendation of f A for inhalation exposure is applicable to both ingestion and inhalation of insoluble material in this study. The dissolution- and subsequent absorption-dependence on particle size showed correlation only for one of the workshops (pelletizing). The absence of correlation at the other workshops may be an effect of multiple chemical compounds with different size distribution and/or the reported presence of agglomerated particles at higher cut points having more impact on the dissolution than particle size. The impact on dose coefficients [committed effective dose (CED) per Bq] of using experimental f A vs. using default f A recommended by the ICRP for the uranium compounds of interest for inhalation exposure was not significant for any of the workshops. However, a significant impact on CED for ingestion exposure was observed for all workshops when comparing with CED estimated for insoluble material using ICRP default f A . This indicates that the use of experimentally derived site-specific f A can improve dose assessments. It is essential to acquire site-specific estimates of the dissolution and absorption of uranium aerosols as this provides more realistic and accurate dose- and risk-estimates of worker exposure. In this study, the results indicate that ICRP's recommendations for ingestion of insoluble material might overestimate absorption and that the lower f A found for inhalation could be more realistic for both inhalation and ingestion of insoluble material.


Assuntos
Compostos de Urânio , Urânio , Humanos , Doses de Radiação , Solubilidade , Urânio/análise , Tamanho da Partícula , Fator de Transferência , Aerossóis/análise
6.
Sci Rep ; 13(1): 3341, 2023 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-36849796

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-ß (Aß) peptides, and Aß oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aß peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods-mainly spectroscopy and imaging techniques-to characterize Aß/Ni(II) interactions in vitro, for different Aß variants: Aß(1-40), Aß(1-40)(H6A, H13A, H14A), Aß(4-40), and Aß(1-42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aß monomers. Equimolar amounts of Ni(II) ions retard Aß aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aß binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aß dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aß monomers, while in a membrane-mimicking environment (SDS micelles) coil-coil helix interactions appear to be induced. For SDS-stabilized Aß oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aß aggregation processes that are involved in AD brain pathology.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Biofísica , Encéfalo , Íons , Placa Amiloide , Níquel/química
8.
ACS Omega ; 7(33): 28924-28931, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36033665

RESUMO

Mercury intoxication typically produces more severe outcomes in people with the APOE-ε4 gene, which codes for the ApoE4 variant of apolipoprotein E, compared to individuals with the APOE-ε2 and APOE-ε3 genes. Why the APOE-ε4 allele is a risk factor in mercury exposure remains unknown. One proposed possibility is that the ApoE protein could be involved in clearing of heavy metals, where the ApoE4 protein might perform this task worse than the ApoE2 and ApoE3 variants. Here, we used fluorescence and circular dichroism spectroscopies to characterize the in vitro interactions of the three different ApoE variants with Hg(I) and Hg(II) ions. Hg(I) ions displayed weak binding to all ApoE variants and induced virtually no structural changes. Thus, Hg(I) ions appear to have no biologically relevant interactions with the ApoE protein. Hg(II) ions displayed stronger and very similar binding affinities for all three ApoE isoforms, with K D values of 4.6 µM for ApoE2, 4.9 µM for ApoE3, and 4.3 µM for ApoE4. Binding of Hg(II) ions also induced changes in ApoE superhelicity, that is, altered coil-coil interactions, which might modify the protein function. As these structural changes were most pronounced in the ApoE4 protein, they could be related to the APOE-ε4 gene being a risk factor in mercury toxicity.

9.
Sci Total Environ ; 841: 156672, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35705128

RESUMO

Multiple sclerosis (MS) affects some 3 million people around the world and the prevalence is increasing. The MS incidence increases with distance from the equator forming a north-to-south gradient. The cause of this gradient and the cause of MS in general are largely unknown. Sulphide-bearing marine and lake sediments, when exposed to oxygen after drainage, form sulphuric acid resulting in the development of acid sulphate soils. From these soils major neurotoxic metals such as iron, aluminum and manganese and trace metals such as nickel, copper and cadmium are released into the surrounding environment. As these soils are largely used for farming, obvious routes to human metal exposure exist. Here we compare the distribution of acid sulphate soils in Finland to the geographic localisation of MS cases using data from a national acid sulphate soil mapping project and historical MS distribution data. Finland has among the highest MS prevalences in the world and several independent nationwide surveys have shown the highest prevalence in western Finland, stable over time. Acid sulphate soil distribution colocalizes with MS, both on a regional (nationwide) scale and local (proximity to rivers) scale. A toxicokinetic LADME model for MS pathogenesis is presented. We propose that neurotoxic metals leaching from acid sulphate soils contribute to the clustering of MS in Finland.


Assuntos
Metais Pesados , Esclerose Múltipla , Poluentes do Solo , Finlândia/epidemiologia , Humanos , Metais/análise , Esclerose Múltipla/epidemiologia , Rios , Solo , Poluentes do Solo/análise , Sulfatos
10.
Health Phys ; 123(1): 11-27, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35522165

RESUMO

ABSTRACT: Inhalation exposure to uranium aerosols can be a concern in nuclear fuel fabrication. The ICRP provides default absorption parameters for various uranium compounds but also recommends determination of material-specific absorption parameters to improve dose calculations for individuals exposed to airborne radioactivity. Aerosol particle size influences internal dosimetry calculations in two potentially significant ways: the efficiency of particle deposition in the various regions of the respiratory tract is dependent on aerodynamic particle size, and the dissolution rate of deposited materials can vary according to particle size, shape, and porosity because smaller particles tend to have higher surface-to-volume ratios than larger particles. However, the ICRP model assumes that deposited particles of a given material dissolve at the same rate regardless of size and that uptake to blood of dissolved material normally occurs instantaneously in all parts of the lung (except the anterior portion of the nasal region, where zero absorption is assumed). In the present work, the effect of particle size on dissolution in simulated lung fluid was studied for uranium aerosols collected at the plant, and its influence on internal dosimetry calculations was evaluated. Size fractionated uranium aerosols were sampled at a nuclear fuel fabrication plant using portable cascade impactors. Absorption parameters, describing dissolution of material according to the ICRP Human Respiratory Tract Model, were determined in vitro for different size fractions using simulated lung fluid. Samples were collected at 16 time-points over a 100-d period. Uranium content of samples was determined using inductively coupled plasma mass spectrometry and alpha spectrometry. In addition, supplementary experiments to study the effect of pH drift and uranium adsorption on filter holders were conducted as they could potentially influence the derived absorption parameters. The undissolved fraction over time was observed to vary with impaction stage cut-point at the four main workshops at the plant. A larger fraction of the particle activity tended to dissolve for small cut-points, but exceptions were noted. Absorption parameters (rapid fraction, rapid rate, and slow rate), derived from the undissolved fraction over time, were generally in fair agreement with the ICRP default recommendations for uranium compounds. Differences in absorption parameters were noted across the four main workshops at the plant (i.e., where the aerosol characteristics are expected to vary). The pelletizing workshop was associated with the most insoluble material and the conversion workshop with the most soluble material. The correlation between derived lung absorption parameters and aerodynamic particle size (impactor stage cut-point) was weak. For example, the mean absorption parameters derived from impaction stages with low (taken to be <5 µm) and large (≥5 µm) cut-points did not differ significantly. Drift of pH and adsorption on filter holders appeared to be of secondary importance, but it was found that particle leakage can occur. Undissolved fractions and to some degree derived lung absorption parameters were observed to vary depending on the aerodynamic size fraction studied, suggesting that size fractionation (e.g., using cascade impactors) is appropriate prior to conducting in vitro dissolution rate experiments. The 0.01-0.02 µm and 1-2 µm size ranges are of particular interest as they correspond to alveolar deposition maxima in the Human Respiratory Tract Model (HRTM). In the present work, however, the dependency on aerodynamic size appeared to be of minor importance, but it cannot be ruled out that particle bounce obscured the results for late impaction stages. In addition, it was noted that the time over which simulated lung fluid samples are collected (100 d in our case) influences the curve-fitting procedure used to determine the lung absorption parameters, in particular the slow rate that increased if fewer samples were considered.


Assuntos
Compostos de Urânio , Urânio , Aerossóis/análise , Humanos , Pulmão , Tamanho da Partícula , Solubilidade , Urânio/análise , Compostos de Urânio/análise
11.
Biomolecules ; 12(5)2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35625641

RESUMO

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson's disease, Friedreich's disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood-brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.


Assuntos
Distúrbios do Metabolismo do Ferro , Distrofias Neuroaxonais , Doenças Neurodegenerativas , Encéfalo/patologia , Humanos , Ferro/farmacologia , Distúrbios do Metabolismo do Ferro/patologia , Distrofias Neuroaxonais/patologia , Doenças Neurodegenerativas/patologia
12.
Int J Mol Sci ; 22(22)2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34830074

RESUMO

Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.


Assuntos
Esclerose Lateral Amiotrófica , Exposição Ambiental/efeitos adversos , Metais , Mutação , Esclerose Lateral Amiotrófica/etiologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Metais/metabolismo , Metais/toxicidade , Agregação Patológica de Proteínas/etiologia , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
13.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502369

RESUMO

The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer's disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased Aß generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-Aß cross-linking and up-regulation of RAGE expression. Moreover, Aß glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and Aß, as well as inhibiting AGE accumulation and metal-induced neurotoxicity.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Produtos Finais de Glicação Avançada/metabolismo , Peptídeos beta-Amiloides/metabolismo , Quelantes/farmacologia , Cobre/metabolismo , Índice Glicêmico/fisiologia , Humanos , Ferro/metabolismo , Metabolismo dos Lipídeos/fisiologia , Síndrome Metabólica/fisiopatologia , Metais/farmacologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/farmacologia , Selênio/metabolismo
14.
Acta Biochim Pol ; 68(2): 169-179, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33909969

RESUMO

Alzheimer's disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has showed promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-ß (Aß) peptides aggregated into amyloid fibrils. The plaques contain also metal ions of e.g. Cu, Fe, and Zn, and such ions are known to interact with Aß peptides and modulate their aggregation and toxicity. The interactions between Aß peptides and Li+ ions have however not been well investigated. Here, we use a range of biophysical techniques to characterize in vitro interactions between Aß peptides and Li+ ions. We show that Li+ ions display weak and non-specific interactions with Aß peptides, and have minor effects on Aß aggregation. These results indicate that possible beneficial effects of Li on AD pathology are not likely caused by direct interactions between Aß peptides and Li+ ions.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Lítio/metabolismo , Doença de Alzheimer/patologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/química , Animais , Encéfalo/metabolismo , Cobre/metabolismo , Humanos , Íons/metabolismo , Lítio/química , Espectroscopia de Ressonância Magnética/métodos , Metais/química , Metais/metabolismo , Camundongos , Agregados Proteicos , Agregação Patológica de Proteínas/metabolismo
15.
Biol Trace Elem Res ; 199(10): 3618-3624, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33230634

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss and widespread muscular atrophy. Despite intensive investigations on genetic and environmental factors, the cause of ALS remains unknown. Recent data suggest a role for metal exposures in ALS causation. In this study we present a patient who developed ALS after a traditional medical procedure in Kenya. The procedure involved insertion of a black metal powder into several subcutaneous cuts in the lower back. Four months later, general muscle weakness developed. Clinical and electrophysiological examinations detected widespread denervation consistent with ALS. The patient died from respiratory failure less than a year after the procedure. Scanning electron microscopy and X-ray diffraction analyses identified the black powder as potassium permanganate (KMnO4). A causative relationship between the systemic exposure to KMnO4 and ALS development can be suspected, especially as manganese is a well-known neurotoxicant previously found to be elevated in cerebrospinal fluid from ALS patients. Manganese neurotoxicity and exposure routes conveying this toxicity deserve further attention.


Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Esclerose Lateral Amiotrófica/induzido quimicamente , Humanos , Quênia , Manganês , Medicina Tradicional
16.
Nanoscale ; 12(43): 22298-22306, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33146209

RESUMO

The main structural element defining the cell is the lipid membrane, which is an integral part of regulating the fluxes of ion and nutrition molecules in and out of the cell. Surprisingly, copper ions were found to have anomalous membrane permeability. This led us to consider a broader spectrum of cations and further a new approach for using liposomes as nanoreactors for synthesis of metal and metal alloy nanoparticles. In the present study, the high membrane permeability of Cu2+ and its neighbouring transition elements in the periodic table was investigated. The permeability of Ni2+, Cu2+, Zn2+, Ag+, Au3+, Mg2+, Ca2+ and Lu3+ was assessed, and we report that Zn2+, Cu2+, Ag+ and Au3+ surprisingly are able to cross lipid bilayers. This knowledge is highly relevant for understanding trafficking of cations in biological systems, as well as for design of novel nanoparticle and nanoreactor systems. An example of its use is presented as a platform for synthesizing single highly uniform gold nanoparticles inside liposomal nanoreactors. We envision that this approach could provide a new nanoreactor methodology for forming highly structurally constrained uniform metal and metal alloy nanoparticles, as well as new methods for in vivo tracking of liposomes.


Assuntos
Nanopartículas Metálicas , Cobre , Ouro , Nanotecnologia , Permeabilidade , Prata , Zinco
17.
Neurobiol Aging ; 87: 140.e1-140.e3, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31785838

RESUMO

We conducted a mendelian randomization study to investigate the association between serum 25-hydroxyvitamin D (S-25OHD) concentrations and amyotrophic lateral sclerosis (ALS). Summary-level data for genetic predictors of S-25OHD concentrations were acquired from 2 genome-wide association studies, comprising up to 79,366 individuals. The corresponding data for ALS were collected from 12,577 ALS cases and 23,475 controls. None of 7 single-nucleotide polymorphisms predicting S-25OHD concentrations was associated with ALS, and there was no overall association of genetic predisposition to higher S-25OHD concentrations with ALS. The odds ratio of ALS per genetically predicted one standard deviation increase of S-25OHD concentrations was 0.96 (95% confidence interval: 0.86-1.08; p = 0.52). We conclude that increasing S-25OHD concentrations will unlikely reduce ALS incidence.


Assuntos
Esclerose Lateral Amiotrófica/genética , Vitamina D/análogos & derivados , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue , Vitamina D/genética
18.
Talanta ; 204: 769-775, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357364

RESUMO

93Mo (4000 y half-life) formed through the 93Nb(p,n)93Mo reaction was isolated from a niobium target foil previously used in a low energy medical cyclotron. 93Mo has identical characteristic x-ray emission and mass as the isomer 93mNb and stable Nb present in the target foil at much higher concentrations. This makes distinction between 93Mo, 93mNb and stable Nb difficult using radiometric or mass spectrometric methods. An anion exchange method in combination with x-ray spectrometry and ICP-MS/OES enabled quantitative isolation of about 0.4 µg 93Mo (14 kBq) from 93mNb with a separation factor >104 on a single column. An extraction chromatography column (TEVA) was used to reach a93mNb/93Mo activity ratio of <10-6 and an atom ratio 93Nb/93Mo <1% making the 93Mo suitable for both radiometric and mass spectrometric testing. 93Mo is the only radioisotope of molybdenum with a long enough half-life suitable for this purpose. Calibration of the 93Mo isotope solution was done through x-ray spectrometry using a characterized BEGe-detector in combination with a99mTc solution. This is the first reported isolation of a93Mo solution in the literature and the first time a LSC-spectrum of 93Mo is shown.

19.
Appl Radiat Isot ; 151: 30-38, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158703

RESUMO

Sources of background and background variation in a BEGe type HPGe detector located in a surface laboratory were identified. Different strategies for background reduction were applied. A cosmic veto was installed, and optimised using a digital acquisition system in list-mode with time-stamped data. This resulted in the reduction of total background by a factor of 1.4. Thermal and fast neutron fluxes were also calculated. The radon induced background component and its variation were significantly reduced.


Assuntos
Poluentes Radioativos do Ar/análise , Monitoramento de Radiação/métodos , Radônio/análise , Espectrometria gama/métodos
20.
J Trace Elem Med Biol ; 52: 48-52, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30732898

RESUMO

The causes of neurodegenerative disorders are largely unknown. Environmental factors seem to contribute to neurodegeneration in genetically susceptible individuals. Increasing evidence point towards a key role for environmental exposure in the causation of neurodegenerative disorders and specifically for metal exposure. Alterations of metalloproteins seem to be a common motif in neurodegeneration and enough evidence has now accumulated to designate these disorders as metallopathies. Paired sampling refers to the simultaneous sampling of CSF and blood and by comparing metal concentrations between CSF and blood conclusions about exposure and barrier properties can be drawn. However previous reports on metal concentrations in body fluids in neurodegenerative disorders show a wide variation in results hampering firm conclusions on the role of metals in degeneration of nerve cells. Here we suggest some steps and measures to minimise this variation, most important sampling performed in a cleanroom with filtered air and the use of acid washed perfluoroalkoxy vials. By strict adherence to ultraclean paired sampling technique conclusive results concerning the role of metals in neurodegenerative disorders can be generated.


Assuntos
Exposição Ambiental/análise , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/diagnóstico , Oligoelementos/sangue , Humanos , Espectrometria de Massas
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