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1.
Chem Commun (Camb) ; 59(7): 888-891, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36598060

RESUMO

Cyclam-picolinate chelators were functionalized via click chemistry with an additional carboxyl group for subsequent bioconjugation to antibodies or for the modification of the overall charge of the corresponding 64Cu-radiocomplexes. The C-aryl functionalization strategy developed here preserves the chemical properties of the radiocomplexes whilst deeply enhancing their applications within nuclear medicine.


Assuntos
Ciclamos , Compostos Heterocíclicos , Distribuição Tecidual , Compostos Heterocíclicos/química , Ácidos Picolínicos , Quelantes/química
2.
Int J Nanomedicine ; 18: 243-261, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36660336

RESUMO

Purpose: This study aimed to evaluate the radiosensitizing potential of Au@DTDTPA(Gd) nanoparticles when combined with conventional external X-ray irradiation (RT) to treat GBM. Methods: Complementary biological models based on U87 spheroids including conventional 3D invasion assay, organotypic brain slice cultures, chronic cranial window model were implemented to investigate the impact of RT treatments (10 Gy single dose; 5×2 Gy or 2×5 Gy) combined with Au@DTDTPA(Gd) nanoparticles on tumor progression. The main tumor mass and its infiltrative area were analyzed. This work focused on the invading cancer cells after irradiation and their viability, aggressiveness, and recurrence potential were assessed using mitotic catastrophe quantification, MMP secretion analysis and neurosphere assays, respectively. Results: In vitro clonogenic assays showed that Au@DTDTPA(Gd) nanoparticles exerted a radiosensitizing effect on U87 cells, and in vivo experiments suggested a benefit of the combined treatment "RT 2×5 Gy + Au@DTDTPA(Gd)" compared to RT alone. Invasion assays revealed that invasion distance tended to increase after irradiation alone, while the combined treatments were able to significantly reduce tumor invasion. Monitoring of U87-GFP tumor progression using organotypic cultures or intracerebral grafts confirmed the anti-invasive effect of Au@DTDTPA(Gd) on irradiated spheroids. Most importantly, the combination of Au@DTDTPA(Gd) with irradiation drastically reduced the number, the viability and the aggressiveness of tumor cells able to escape from U87 spheroids. Notably, the combined treatments significantly reduced the proportion of escaped cells with stem-like features that could cause recurrence. Conclusion: Combining Au@DTDTPA(Gd) nanoparticles and X-ray radiotherapy appears as an attractive therapeutic strategy to decrease number, viability and aggressiveness of tumor cells that escape and can invade the surrounding brain parenchyma. Hence, Au@DTDTPA(Gd)-enhanced radiotherapy opens up interesting perspectives for glioblastoma treatment.


Assuntos
Glioblastoma , Nanopartículas Metálicas , Humanos , Ouro/farmacologia , Glioblastoma/radioterapia , Gadolínio , Linhagem Celular Tumoral , Nanopartículas Metálicas/uso terapêutico , Meios de Contraste , Quelantes
3.
PLoS One ; 18(1): e0280807, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36689492

RESUMO

Ethylenediaminetetraacetic acid (EDTA) is a divalent cation chelator and chemical preservative that has been shown to be the active ingredient of the popular DNA preservative DESS. EDTA may act to reduce DNA degradation during tissue storage by sequestering divalent cations that are required by nucleases naturally occurring in animal tissues. Although EDTA is typically used between pH 7.5 and 8 in preservative preparations, the capacity of EDTA to chelate divalent cations is known to increase with increasing pH. Therefore, increasing the pH of EDTA-containing preservative solutions may improve their effectiveness as DNA preservatives. To test this hypothesis, we stored tissues from five aquatic species in 0.25 M EDTA adjusted to pH 8, 9, and 10 for 12 months at room temperature before DNA isolation. For comparison, tissues from the same specimens were also stored in 95% ethanol. DNA extractions performed on tissues preserved in EDTA pH 9 or 10 resulted in as great or greater percent recovery of high molecular weight DNA than did extractions from tissues stored at pH 8. In all cases examined, percent recovery of high molecular weight DNA from tissues preserved in EDTA pH 10 was significantly better than that observed from tissues preserved in 95% ethanol. Our results support the conclusion that EDTA contributes to DNA preservation in tissues by chelating divalent cations and suggest that preservative performance can be improved by increasing the pH of EDTA-containing DNA preservative solutions.


Assuntos
DNA , Etanol , Animais , Ácido Edético/química , Peso Molecular , Cátions Bivalentes , Quelantes , Conservantes Farmacêuticos , Concentração de Íons de Hidrogênio
4.
Food Chem ; 409: 135335, 2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-36599292

RESUMO

This study describes the development of 2-hydrazinobenzothiazole modified-amide/imide co-polymers for the extraction/pre-concentration of trace As(III), from edible vegetable oils. Their characterization was realized by help of instrumental techniques. The method is based on pH-dependent complexation between As(III) and co-polymeric chelators in presence of 35-fold excess As(V), their selective extraction into the mixed micellar phase, and detected at pH 2.0 and 6.0 by UV-vis spectrophotometer. The variables affecting extraction efficiency were optimized. From pre-concentration of 20-mL sample, the good linear relationships were obtained in range of 1-40 and 3-75 µg/L with DLs of 0.32 and 1.00 µg/L. The accuracy was verified by analysis of a certified sample without and with spiking. The method was applied into the analysis of iAs levels of samples. The results show that the functional co-polymers are efficient chelators, and exhibit great potential for the selective extraction of As(III) from edible vegetable oils.


Assuntos
Óleos Vegetais , Verduras , Óleos Vegetais/química , Polímeros , Quelantes , Estirenos/análise
5.
Health Phys ; 124(2): 113-124, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36625835

RESUMO

ABSTRACT: Accidental inhalation of plutonium at the workplace is a non-negligible risk, even when rigorous safety standards are in place. The intake and retention of plutonium in the human body may be a source of concern. Thus, if there is a suspicion of a significant intake of plutonium, medical countermeasures such as chelation treatment may be administered to the worker. The present work aimed to interpret the bioassay data of a worker involved in an inhalation incident due to a glovebox breach at Los Alamos National Laboratory's plutonium facility. The worker was treated with intravenous injections of calcium salts of diethylenetriaminepentaacetic acid (DTPA) in an attempt to reduce the amount of plutonium from the body and therefore reduce the internal radiation dose. It is well known in the internal dosimetry field that the administration of chelation treatment poses additional challenges to the dose assessment. Hence, a recently developed chelation model was used for the modeling of the bioassay data. The objectives of this work are to describe the incident, model the chelation-affected and non-affected bioassay data, estimate the plutonium intake, and assess the internal radiation dose.


Assuntos
Plutônio , Lesões por Radiação , Humanos , Plutônio/análise , Lesões por Radiação/etiologia , Lesões por Radiação/prevenção & controle , Lesões por Radiação/tratamento farmacológico , Quelantes/uso terapêutico , Ácido Pentético
6.
Sensors (Basel) ; 23(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36617069

RESUMO

A new Near InfraRed (NIR) fluorescent chemosensor for metal ions and anions is herein presented. The fluorophore is based on a styrylflavylium dye, a synthetic analogue of the natural anthocyanin family, with a di-(2-picolyl)amine (DPA) moiety as the metal chelating unit. The substitution pattern of the styrylflavylium core (with tertiary amines on positions 7 and 4') shifts the optical properties of the dye towards the NIR region of the electronic spectra, due to a strong push-pull character over the π-conjugated system. The NIR chemosensor is highly sensitive to the presence of Zn2+, which induces a strong CHelation Enhanced Fluorescence (CHEF) effect upon binding to the DPA unit (2.7 fold increase). The strongest competing ion is Cu2+, with a complete fluorescence quenching, while other metals induce lower responses on the optical properties of the chemosensor. Subsequent anion screening of the Zn2+-chemosensor coordination compound has demonstrated a distinct selectivity towards adenosine 5'-triphosphate (ATP) and adenosine 5'-diphosphate (ADP), with high association constants (K ~ 106 M-1) and a strong CHEF effect (2.4 and 2.9 fold fluorescence increase for ATP and ADP, respectively). Intracellular studies with the Zn2+-complexed sensor showed strong luminescence in the cellular membrane of Gram- bacteria (E. coli) and mitochondrial membrane of mammalian cells (A659), which highlights its possible application for intracellular labelling.


Assuntos
Aminas , Zinco , Animais , Aminas/química , Zinco/química , Fosfatos , Escherichia coli , Metais , Trifosfato de Adenosina , Íons , Ânions , Quelantes , Adenosina , Corantes Fluorescentes/química , Espectrometria de Fluorescência , Mamíferos
7.
Bull Environ Contam Toxicol ; 110(1): 37, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607448

RESUMO

Phytoextraction is an efficient strategy for remediating heavy metal-contaminated soil. Chelators can improve the bioavailability of heavy metals and increase phytoextraction efficiency. However, traditional chelators have gradually been replaced due to secondary pollution. In this study, a typical organic acid (citric acid, CA) and a novel biodegradable chelator (poly-glutamic acid, PGA), were investigated using pot experiments to compare the phytoextraction efficiency of Solanum nigrum L. (a Cd (hyper)accumulator) for cadmium (Cd) and lead (Pb) in contaminated soil. The results showed CA and PGA significantly improved plant growth, and total Cd and Pb amounts of S. nigrum, both CA and PGA significantly increased the shoot Cd and Pb concentrations. However, only PGA significantly increased the root Pb concentration. CA and PGA application promoted the bioavailability of Cd and Pb in rhizosphere soils and their translocations from roots to shoots in S. nigrum. Both CA and PGA increased the phytoextraction efficiency of Cd and Pb in S. nigrum plants, and the PGA for Cd and Pb phytoextraction was more effective than CA. Our findings demonstrate that the biodegradable chelator PGA has great potential for enhancing phytoextraction from compound Cd-Pb contaminated soils, suggesting that biodegradable chelator-assisted phytoextraction with (hyper)accumulator is strongly recommended in severely contaminated sites.


Assuntos
Metais Pesados , Poluentes do Solo , Solanum nigrum , Cádmio/análise , Ácido Glutâmico , Chumbo , Ácido Cítrico , Biodegradação Ambiental , Poluentes do Solo/análise , Metais Pesados/análise , Quelantes/farmacologia , Solo
8.
Int J Mol Sci ; 24(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36674772

RESUMO

Biometals are all metal ions that are essential for all living organisms. About 40% of all enzymes with known structures require biometals to function correctly. The main target of damage by biometals is the central nervous system (CNS). Biometal dysregulation (metal deficiency or overload) is related to pathological processes. Chronic occupational and environmental exposure to biometals, including iron and copper, is related to an increased risk of developing Parkinson's disease (PD). Indeed, biometals have been shown to induce a dopaminergic neuronal loss in the substantia nigra. Although the etiology of PD is still unknown, oxidative stress dysregulation, mitochondrial dysfunction, and inhibition of both the ubiquitin-proteasome system (UPS) and autophagy are related to dopaminergic neuronal death. Herein, we addressed the involvement of redox-active biometals, iron, and copper, as oxidative stress and neuronal death inducers, as well as the current metal chelation-based therapy in PD.


Assuntos
Doença de Parkinson , Oligoelementos , Humanos , Doença de Parkinson/patologia , Cobre , Metais , Ferro , Estresse Oxidativo , Oxirredução , Neurônios Dopaminérgicos/patologia , Quelantes/farmacologia , Quelantes/uso terapêutico
9.
J Chromatogr A ; 1687: 463706, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36521242

RESUMO

Immobilized metal affinity chromatography (IMAC) ensures the specific purification of proteins containing histidine tags through high affinity with transition metal chelators, which has various applications in biological protein separation. Most chromatographic separations currently use a fixed bed. In this form, internal flow pressure drops very sharply, accompanied by uneven solution flow, pore blockages, etc., all of which greatly reduce separation efficiency. Therefore, this study uses hollow fiber membranes (HFMs) with micron-scale inner diameters as a base, thus reducing operating pressure and significantly enhancing mass transmission. Batch adsorption experiments were performed using flat plate membranes to obtain the reaction's thermodynamic and kinetic model parameters for use in a dynamic column breakthrough simulation. The numerical simulation was based on a single HFM model and established a mathematical model for computational fluid dynamics (CFD) in ANSYS Fluent software. Model accuracy was validated by combining the simulation with experiments. The effects of different module and process parameters on the breakthrough curve were investigated by varying parameters such as flow rate, initial feed concentration, and HFM inner diameter. Design parameters and operating conditions contributing to module utilization were subsequently obtained.


Assuntos
Hidrodinâmica , Modelos Teóricos , Adsorção , Cromatografia de Afinidade/métodos , Simulação por Computador , Quelantes
10.
Dalton Trans ; 52(4): 892-901, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36537287

RESUMO

12-Membered pyridinophanes are the focus of many studies as biological mimics, chelators, and catalytic precursors. Therefore, the desire to tune the reactivity of pyridinophanes to better control the applications of derivative metal complexes has inspired many structure-activity relationship studies. However, the separation of structural versus electronic changes imparted by ligand modification has made these structure-activity relationship studies of transition metal catalysts challenging to define. In this work we show that 4-substitution of the pyridine ring in 12-membered tetra-aza pyridinophanes successfully provides a regulatory handle on the electronic properties of the metal center and, therefore, the catalytic C-C coupling activity of the respective iron complexes. The C-C coupling reaction catalyzed by Fe(L1-L6) provides a range of yields (32-58%) that directly correlate with iron redox potentials (ΔE1/2 = 152 mV) and metal binding constants (Δlog ß = 3.45), while the geometry of the complexes was virtually indistinguishable. These are the first results to definitively show the redox potential and metal binding as independent properties from the coordination chemistry in one ligand series. Adjustments to these chemical properties were then shown to provide a regulatory handle for the C-C coupling reactivity tuned via pyridine substitution in pyridinophanes.


Assuntos
Complexos de Coordenação , Elementos de Transição , Ligantes , Complexos de Coordenação/química , Ferro/química , Quelantes , Piridinas
11.
FEMS Microbiol Lett ; 3702023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36521842

RESUMO

The recent surge in beta-lactamase resistance has created superbugs, which pose a current and significant threat to public healthcare. This has created an urgent need to keep pace with the discovery of inhibitors that can inactivate these beta-lactamase producers. In this study, the in vitro and in vivo activity of 1,4,7-triazacyclononane-1,4,7 triacetic acid (NOTA)-a potential metallo-beta-lactamase (MBL) inhibitor was evaluated in combination with meropenem against MBL producing bacteria. Time-kill studies showed that NOTA restored the efficacy of meropenem against all bacterial strains tested. A murine infection model was then used to study the in vivo pharmacokinetics and efficacy of this metal chelator. The coadministration of NOTA and meropenem (100 mg/kg.bw each) resulted in a significant decrease in the colony-forming units of Klebsiella pneumoniae NDM-1 over an 8-h treatment period (>3 log10 units). The findings suggest that chelators, such as NOTA, hold strong potential for use as a MBL inhibitor in treating carbapenem-resistant Enterobacterale infections.


Assuntos
Carbapenêmicos , Inibidores de beta-Lactamases , Animais , Camundongos , Inibidores de beta-Lactamases/farmacologia , Meropeném/farmacologia , Carbapenêmicos/farmacologia , Antibacterianos/farmacologia , Quelantes/farmacologia , Testes de Sensibilidade Microbiana , beta-Lactamases
12.
J Trace Elem Med Biol ; 76: 127113, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36516571

RESUMO

BACKGROUND: Aluminium (Al) overload has toxic effects on multiple organ systems, especially the nervous system. Al accumulation in the brain, especially the hippocampus, is an important factor contributing to Alzheimer's disease (AD). Deferiprone (DFP), a metal chelator, is used as a potential treatment for AD. In this study, we investigated the combined effect of taurine and DFP on Al chelation and hippocampal apoptosis in Al-exposed rats, as well as the underlying mechanisms of these effects to explore a possible therapy for AD. METHODS: Male Wistar rats were divided into seven groups: negative control group (administered saline), Al-exposure group (administered AlCl3 and saline), and five experimental groups (administered AlCl3 and taurine, varying doses of DFP, or taurine with varying doses of DFP). After 8 weeks of treatment, the rats were sacrificed, and the terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labelling (TUNEL) assay was used to detect hippocampal apoptotic cells. Real-time quantitative PCR was used to assess the expression of the Bcl2 and Bax genes, and a western blotting assay was used to evaluate BCL2, BAX, and cleaved caspase-3 levels. RESULTS: Compared to the negative control group, the number of apoptotic cells in the hippocampus increased, Bcl2 expression significantly decreased, and BAX and cleaved caspase-3 levels increased in the Al-exposure group. The combination of taurine and DFP exerted a protective effect by inhibiting hippocampal cell apoptosis through the BCL2, BAX, and caspase-3 signalling pathways. Compared with the taurine-administered group, the group administered taurine with DFP showed a significantly increased Bcl2 and decreased Bax expression. CONCLUSION: The combination of taurine and DFP is a potential candidate for the treatment of AD induced by Al exposure.


Assuntos
Alumínio , Doença de Alzheimer , Ratos , Animais , Masculino , Deferiprona/farmacologia , Alumínio/metabolismo , Caspase 3/metabolismo , Ratos Wistar , Proteína X Associada a bcl-2/metabolismo , Taurina/farmacologia , Taurina/metabolismo , Hipocampo , Apoptose , Quelantes/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Doença de Alzheimer/metabolismo
13.
Food Funct ; 14(2): 978-989, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36541828

RESUMO

This study was designed to prepare a cattle bone-derived collagen peptide-calcium chelate by the ultrasound method (CP-Ca-US), and its structure, stability, and bioactivity on MC3T3-E1 cells were characterized. Single-factor experiments optimized the preparation conditions: ultrasound power 90 W, ultrasound time 40 min, CaCl2/peptides ratio 1/2, pH 7. Under these conditions, the calcium-chelating ability reached 39.48 µg mg-1. The result of Fourier transform-infrared spectroscopy indicated that carboxyl oxygen and amino nitrogen atoms were chelation sites. Morphological analysis indicated that CP-Ca-US was characterized by a porous surface and large particles. Stability analysis demonstrated that CP-Ca-US was stable in the thermal environment and under intestinal digestion. CP-Ca-US showed more stability in gastric juice than the chelate prepared by the hydrothermal method. Cell experiments indicated that CP-Ca-US increased osteoblast proliferation (proliferation rate 153% at a concentration of 300 µg mL-1) and altered the cell cycle. Significantly, CP-Ca-US enhanced calcium absorption by interacting with calcium-sensing receptors and promoted the mineralization of MC3T3-E1 cells. This study provides the scientific basis for applying the ultrasound method to prepare peptide-calcium chelates and clarifies the positive role of chelates in bone building.


Assuntos
Cálcio , Colágeno , Animais , Bovinos , Cálcio/metabolismo , Colágeno/metabolismo , Peptídeos/metabolismo , Minerais/metabolismo , Quelantes/química , Osteoblastos
14.
Talanta ; 255: 123902, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36580807

RESUMO

In this study, for the first time, a novel separation and preconcentration method of direct immersion dual-drop microextraction (DIDDME) was proposed for the species of inorganic chromium (Cr(III) and Cr(VI)) followed by graphite furnace atomic absorption spectrometry detection. The methodology is based on that two organic drops hold on the needle tips of microsyringes were concurrently immersed in a stirred sample solution. Each drop contains a chelating reagent, which can react with a specific species under the same pH value. Therefore, Cr(III) and Cr(VI) can be selectively extracted into different drops. This procedure did not require tedious and complicated pre-oxidation/pre-reduction and centrifugation/filtration operations, which may lead to the risk of sample contamination and analysis errors. Main parameters influencing separation, preconcentration and identification of the target species were investigated. An enrichment factor of 400-fold was obtained for Cr(III) and Cr(VI). Under the optimized conditions, detection limits for this method were 1.1 ng L-1 and 1.4 ng L-1 for Cr(III) and Cr(VI) with relative standard deviations of 5.1 and 6.3%, respectively. This procedure was applied for the separation, preconcentration and determination of Cr(III) and Cr(VI) in environmental water samples and certified reference materials with satisfactory results. Recoveries of spiked experiments ranged from 86.0 to 112%.


Assuntos
Imersão , Poluentes Químicos da Água , Cromo/química , Quelantes/química , Água , Concentração de Íons de Hidrogênio , Espectrofotometria Atômica/métodos , Poluentes Químicos da Água/análise
15.
Environ Res ; 216(Pt 2): 114518, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36273594

RESUMO

For many years, copper-based fungicides have been used in viticulture and have contributed to increasing concentrations in soils. Today, it is not uncommon to find vineyard soils with total copper topsoil concentrations above 100 mg kg-1, which may have consequences for both the environment and human health. Phytoremediation, the use of plants to remove heavy metals from soils, is a promising and environmentally-friendly method to extract copper from soils. The objectives of this study were to review and synthesise the current knowledge on copper phytoremediation in vineyard soils and identify future applications. A systematic literature search in Web of Science was conducted on 19 July 2022 and resulted in twenty-seven papers meeting the inclusion criteria. Approximately one third of the papers were from Brazil and most of the experiments had been carried out in pots. In some studies, the addition of bacteria or chelators was also evaluated. Some species, such as Plantago lanceolata L. or Ricinus communis L., can accumulate copper in their tissues at concentrations above 1000 mg kg-1. Addition of bacteria and chelators to the soil can also increase the copper uptake capacity by plants. However, most of the species evaluated accumulate copper in the roots, rather than in the shoots, thus limiting the implementation of this method in practice. Further studies are thus needed to find other hyperaccumulator plants. Future research should focus primarily on the ability of plants to accumulate copper in their aerial parts, their ability to transfer copper from roots to shoots, and their biomass production under high soil copper concentrations. Longer-term experiments and more in situ testing are also needed to evaluate the potential for development and use of copper phytoremediation in vineyards. To conclude, species of the Poaceae and Lamiaceae families are the most promising so far for phytoremediation. Identifying plants able to translocate copper from the roots to the aerial parts will be an important factor in the success of this method.


Assuntos
Metais Pesados , Poluentes do Solo , Humanos , Biodegradação Ambiental , Solo , Cobre/análise , Poluentes do Solo/análise , Metais Pesados/análise , Quelantes
16.
Inorg Chem ; 62(4): 1362-1376, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36490364

RESUMO

Radioisotopes of Cu, such as 64Cu and 67Cu, are alluring targets for imaging (e.g., positron emission tomography, PET) and radiotherapeutic applications. Cyclen-based macrocyclic polyaminocarboxylates are one of the most frequently examined bifunctional chelators in vitro and in vivo, including the FDA-approved 64Cu radiopharmaceutical, Cu(DOTATATE) (Detectnet); however, connections between the structure of plausible reactive intermediates and their stability under physiologically relevant conditions remain to be established. In this study, we share the synthesis of a cyclen-based, N,N-alkylated spirocyclic chelate, H2DO3AC4H8, which serves as a model for N-protonation. Our combined experimental (in vitro and in vivo) and computational studies unravel complex pH-dependent speciation and enable side-by-side comparison of N- and O-protonated species of relevant 64Cu radiopharmaceuticals. Our studies suggest that N-protonated species are not inherently unstable species under physiological conditions and demonstrate the potential of N,N-alkylation as a tool for the rational design of future radiopharmaceuticals.


Assuntos
Ciclamos , Compostos Radiofarmacêuticos/química , Radioisótopos de Cobre/química , Distribuição Tecidual , Tomografia por Emissão de Pósitrons/métodos , Quelantes/química , Alquilação
17.
Sci Rep ; 12(1): 20722, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36456643

RESUMO

Smoke emissions produced by firearms contain hazardous chemicals, but little is known if their properties change depending on firearm and ammunition type and whether such changes affect toxicity outcomes. Pulmonary toxicity was assessed in mice exposed by oropharyngeal aspiration to six different types of smoke-related particulate matter (PM) samples; (1) handgun PM, (2) rifle PM, (3) copper (Cu) particles (a surrogate for Cu in the rifle PM) with and without the Cu chelator penicillamine, (4) water-soluble components of the rifle PM, (5) soluble components with removal of metal ions, and (6) insoluble components of the rifle PM. Gun firing smoke PM was in the respirable size range but the chemical composition varied with high levels of Pb in the handgun and Cu in the rifle smoke. The handgun PM did not induce appreciable lung toxicity at 4 and 24 h post-exposure while the rifle PM significantly increased lung inflammation and reduced lung function. The same levels of pure Cu particles alone and the soluble components from the rifle fire PM increased neutrophil numbers but did not cause appreciable cellular damage or lung function changes when compared to the negative (saline) control. Penicillamine treated rifle PM or Cu, slightly reduced lung inflammation and injury but did not improve the lung function decrements. Chelation of the soluble metal ions from the rifle fire PM neutralized the lung toxicity while the insoluble components induced the lung toxicity to the same degree as the rifle PM. The results show that different firearm types can generate contrasting chemical spectra in their emissions and that the rifle PM effects were mostly driven by water-insoluble components containing high levels of Cu. These findings provide better knowledge of hazardous substances in gun firing smoke and their potential toxicological profile.


Assuntos
Armas de Fogo , Material Particulado , Animais , Camundongos , Material Particulado/toxicidade , Penicilamina , Substâncias Perigosas , Quelantes , Água , Pulmão
18.
Int J Mol Sci ; 23(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36499479

RESUMO

Cadmium (Cd) is an environmental pollutant known to pose a public health issue. The mechanism of Cd toxicity on the uterus, including the protective role of metallothionein (MT), is still not fully understood. The aim of the study was to evaluate the degree of MT-Cd binding in the uterus of rats exposed per os to Cd at daily doses of 0.09, 0.9, 1.8 and 4.5 mg Cd/kg b.w. for 90 days. To assess the permanence of the bond, the rats were observed over long observation periods: 90 and 180 days after termination of exposure. Additionally, uterine concentration of Zn, Cu, Ca, Mg was determined. Cd leads immediately after exposure to a max. 30-fold increase in the concentration of Cd in the uterus, with only small amounts being bound to MT. After 90 days following termination of exposure, and especially after 180 days, an increase in MT-Cd concentration was noted for the three highest doses; even so, the degree of Cd binding by MT was still small. Additionally, the accumulation of Cd in the uterus disturbs the homeostasis of determined essential elements, manifested by a significant increase in Cu concentration and a decrease in Zn, Mg and Ca, especially 180 days after termination of exposure. The obtained results indicate that MT has only a slight protective role in the uterus and that Cd ions may have harmful effects not related to MT: directly on the uterine tissue, and indirectly by disturbing the homeostasis of its essential elements.


Assuntos
Intoxicação por Cádmio , Metalotioneína , Feminino , Ratos , Animais , Metalotioneína/metabolismo , Cádmio/metabolismo , Cobre/metabolismo , Fígado/metabolismo , Intoxicação por Cádmio/metabolismo , Quelantes/farmacologia
19.
Int J Mol Sci ; 23(23)2022 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-36499617

RESUMO

Double-PHD fingers 3 (DPF3) is a BAF-associated human epigenetic regulator, which is increasingly recognised as a major contributor to various pathological contexts, such as cardiac defects, cancer, and neurodegenerative diseases. Recently, we unveiled that its two isoforms (DPF3b and DPF3a) are amyloidogenic intrinsically disordered proteins. DPF3 isoforms differ from their C-terminal region (C-TERb and C-TERa), containing zinc fingers and disordered domains. Herein, we investigated the disorder aggregation properties of C-TER isoforms. In agreement with the predictions, spectroscopy highlighted a lack of a highly ordered structure, especially for C-TERa. Over a few days, both C-TERs were shown to spontaneously assemble into similar antiparallel and parallel ß-sheet-rich fibrils. Altered metal homeostasis being a neurodegeneration hallmark, we also assessed the influence of divalent metal cations, namely Cu2+, Mg2+, Ni2+, and Zn2+, on the C-TER aggregation pathway. Circular dichroism revealed that metal binding does not impair the formation of ß-sheets, though metal-specific tertiary structure modifications were observed. Through intrinsic and extrinsic fluorescence, we found that metal cations differently affect C-TERb and C-TERa. Cu2+ and Ni2+ have a strong inhibitory effect on the aggregation of both isoforms, whereas Mg2+ impedes C-TERb fibrillation and, on the contrary, enhances that of C-TERa. Upon Zn2+ binding, C-TERb aggregation is also hindered, and the amyloid autofluorescence of C-TERa is remarkably red-shifted. Using electron microscopy, we confirmed that the metal-induced spectral changes are related to the morphological diversity of the aggregates. While metal-treated C-TERb formed breakable and fragmented filaments, C-TERa fibrils retained their flexibility and packing properties in the presence of Mg2+ and Zn2+ cations.


Assuntos
Proteínas Intrinsicamente Desordenadas , Humanos , Proteínas Intrinsicamente Desordenadas/química , Amiloide/metabolismo , Metais , Quelantes/química , Isoformas de Proteínas , Cátions Bivalentes
20.
Inorg Chem ; 61(51): 20964-20976, 2022 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-36516446

RESUMO

Zirconium-89 has quickly become a favorite radionuclide among academics and clinicians for nuclear imaging. This radiometal has a relatively long half-life, which matches the biological half-life of most antibodies, suitable decay properties for positron emission tomography (PET), and efficient and affordable cyclotron production and purification. The "gold standard" chelator for [89Zr]Zr4+ is desferrioxamine B (DFO), and although it has been used both preclinically and clinically for immunoPET with great success, it has revealed its suboptimal stability in vivo. DFO can only bind to [89Zr]Zr4+ through its six available coordination sites made up by three hydroxamic acid (HA) moieties, which is not sufficient to saturate the coordination sphere (CN 7-8). In this study, we have designed, synthesized, and characterized a new octadentate chelator we have called DFO-Em, which is an improved derivative of our previously published dodecadentate chelator DFO2. This octadentate DFO-Em chelator is smaller than DFO2 but still satisfies the coordination sphere of zirconium-89 and forms a highly stable radiometal-chelator complex. DFO-Em was synthesized by tethering a hydroxamic acid monomer to commercially available DFO using glutamic acid as a linker, providing an octadentate chelator built on a modular amino acid-based synthesis platform. Radiolabeling performance and radiochemical stability of DFO-Em were assessed in vitro by serum stability, ethylenediamine tetraacetic acid (EDTA), and hydroxyapatite challenges. Furthermore, [89Zr]Zr-(DFO-Em) and [89Zr]Zr-DFO were injected in healthy mice and measured in vivo by PET/CT imaging and ex vivo biodistribution. Additionally, the coordination of DFO-Em with Zr(IV) and its isomers was studied using density functional theory (DFT) calculations. The radiolabeling studies revealed that DFO-Em has a comparable radiolabeling profile to the gold standard chelator DFO. The in vitro stability evaluation showed that [89Zr]Zr-(DFO-Em) was significantly more stable than [89Zr]Zr-DFO, and in vivo both had similar clearance in healthy mice with a small decrease in tissue retention for [89Zr]Zr-(DFO-Em) at 24 h post injection. The DFT calculations also confirmed that Zr-(DFO-Em) can adopt highly stable 8-coordinate geometries, which along with NMR characterization suggest no fluxional behavior and the presence of a single isomer. The modular design of DFO-Em means that any natural or unnatural amino acid can be utilized as a linker to gain access to different chemistries (e.g., thiol, amine, carboxylic acid, azide) while retaining an identical coordination sphere to DFO-Em.


Assuntos
Quelantes , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Animais , Camundongos , Quelantes/química , Desferroxamina/química , Radioquímica , Distribuição Tecidual , Radioisótopos/química , Tomografia por Emissão de Pósitrons/métodos , Zircônio/química , Ácidos Hidroxâmicos/química , Linhagem Celular Tumoral
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