RESUMO
This study investigated the in vitro bioaccessibility of aluminum, copper, iron, manganese, lead, selenium, and zinc in three important species of farmed insects: the yellow mealworm (Tenebrio molitor), the house cricket (Acheta domesticus) and the migratory locust (Locusta migratoria). Results show that all three insect species constitute excellent sources of essential elements (Fe, Cu and Zn) for the human diet, contributing to the recommended dietary allowance, i.e., 10%, 50%, and 92%, respectively. A higher accumulation of Se (≥1.4 mg Se/kg) was observed with increasing exposure concentration in A. domesticus, showing the possibility of using insects as a supplements for this element. The presence of Al and Fe nanoparticles was confirmed in all three species using single particle-inductively coupled plasma-mass spectrometry and transmission electron microscopy. The results also indicate that Fe bioaccessibility declines with increasing Fe-nanoparticle concentration. These findings contribute to increase the nutritional and toxicological insights of farmed insects.
Assuntos
Alumínio , Gryllidae , Ferro , Tenebrio , Oligoelementos , Animais , Oligoelementos/análise , Oligoelementos/metabolismo , Ferro/análise , Ferro/metabolismo , Gryllidae/metabolismo , Gryllidae/química , Tenebrio/química , Tenebrio/metabolismo , Alumínio/análise , Alumínio/metabolismo , Alumínio/química , Gafanhotos/química , Gafanhotos/metabolismo , Disponibilidade Biológica , Nanopartículas/química , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/análise , Insetos Comestíveis/química , Insetos Comestíveis/metabolismo , Insetos/química , Insetos/metabolismoRESUMO
Human African trypanosomiasis (HAT, sleeping sickness) and American trypanosomiasis (Chagas disease) are endemic zoonotic diseases caused by genomically related trypanosomatid protozoan parasites (Trypanosoma brucei and Trypanosoma cruzi, respectively). Just a few old drugs are available for their treatment, with most of them sharing poor safety, efficacy, and pharmacokinetic profiles. Only fexinidazole has been recently incorporated into the arsenal for the treatment of HAT. In this work, new multifunctional Ru(II) ferrocenyl compounds were rationally designed as potential agents against these pathogens by including in a single molecule 1,1'-bis(diphenylphosphino)ferrocene (dppf) and two bioactive bidentate ligands: pyridine-2-thiolato-1-oxide ligand (mpo) and polypyridyl ligands (NN). Three [Ru(mpo)(dppf)(NN)](PF6) compounds and their derivatives with chloride as a counterion were synthesized and fully characterized in solid state and solution. They showed in vitro activity on bloodstream T. brucei (EC50 = 31-160 nM) and on T. cruzi trypomastigotes (EC50 = 190-410 nM). Compounds showed the lowest EC50 values on T. brucei when compared to the whole set of metal-based compounds previously developed by us. In addition, several of the Ru compounds showed good selectivity toward the parasites, particularly against the highly proliferative bloodstream form of T. brucei. Interaction with DNA and generation of reactive oxygen species (ROS) were ruled out as potential targets and modes of action of the Ru compounds. Biochemical assays and in silico analysis led to the insight that they are able to inhibit the NADH-dependent fumarate reductase from T. cruzi. One representative hit induced a mild oxidation of low molecular weight thiols in T. brucei. The compounds were stable for at least 72 h in two different media and more lipophilic than both bioactive ligands, mpo and NN. An initial assessment of the therapeutic efficacy of one of the most potent and selective candidates, [Ru(mpo)(dppf)(bipy)]Cl, was performed using a murine infection model of acute African trypanosomiasis. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described, but was unable to control parasite proliferation in vivo, probably because of its rapid clearance or low biodistribution in the extracellular fluids. Future studies should investigate the pharmacokinetics of this compound in vivo and involve further research to gain deeper insight into the mechanism of action of the compounds.
Assuntos
Compostos Ferrosos , Rutênio , Tripanossomicidas , Trypanosoma cruzi , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Compostos Ferrosos/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Ligantes , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Animais , Rutênio/química , Rutênio/farmacologia , Camundongos , Metalocenos/química , Metalocenos/farmacologia , Metalocenos/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Estrutura Molecular , Compostos Organometálicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese químicaRESUMO
Metallomics is an emerging area of omics approaches that has grown enormously in the past few years. It integrates research related to metals in biological systems, in symbiosis with genomics and proteomics. These omics approaches can provide in-depth insights into the mechanisms of action of potential metallodrugs, including their physiological metabolism and their molecular targets. Herein, we review the most significant advances concerning cellular uptake and subcellular distribution assays of different potential metallodrugs with activity against Trypanosma cruzi, the protozoan parasite that causes Chagas disease, a pressing health problem in high-poverty areas of Latin America. Furthermore, the first multiomics approaches including metallomics, proteomics, and transcriptomics for the comprehensive study of potential metallodrugs with anti-Trypanosoma cruzi activity are described.
RESUMO
Moringa stenopetala is considered a superfood due to the many bioactive compounds that it provides to the diet. However, like all edible plants, it is mandatory to guarantee food safety. Thus it is necessary to develop analytical methods that can rapidly and accurately determine hazardous pollutants, to evaluate compliance with food regulations. In this regard, two multi-component procedures were developed trying to cover some of the main organic and inorganic potential contaminants. A microwave-assisted digestion followed by electrothermal atomic absorption spectrometry was used for arsenic, cadmium, and lead determination, while a modification of the QuEChERS protocol followed by gas chromatography-tandem mass spectrometry was employed for the determination of 55 pesticides from different families. Both analytical methods were thoroughly validated according to international guidelines. The analyzed samples obtained from the Uruguayan market showed compliance with both, national and international, food regulations. The holistic approach employed in this research is not commonly presented in the literature, thus constituting a novel way to face food safety.
Assuntos
Contaminação de Alimentos , Inocuidade dos Alimentos , Moringa , Espectrofotometria Atômica , Contaminação de Alimentos/análise , Espectrofotometria Atômica/métodos , Inocuidade dos Alimentos/métodos , Moringa/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Arsênio/análise , Espectrometria de Massas em Tandem/métodos , Chumbo/análise , Praguicidas/análise , Micro-OndasRESUMO
Aim: To perform an exposure assessment of arsenic, manganese, mercury and lead levels in hair samples from children from poor neighborhoods. Materials & methods: A total of 38 Caucasian children were recruited with the consent of their parents or tutors. Determinations were performed by atomic absorption spectrometry. Results & conclusion: Results were 0.045-0.12 µg/g-1 (arsenic), 0.56-2.05 µg/g-1 (manganese) and 0.34-27.8 µg/g-1 (lead). Lead results did not correlate with those previously reported in blood from the same individuals, suggesting that hair is not useful for exposure assessment of this contaminant. Mercury was determined for the first time in Uruguayan children showing levels <0.083 µg/g-1. Results revealed low-to-moderate metal exposure, except for some high lead findings.
Assuntos
Arsênio , Poluentes Ambientais , Mercúrio , Criança , Humanos , Chumbo/análise , Arsênio/análise , Mercúrio/análise , Manganês/análise , Monitoramento Biológico , Exposição Ambiental/análise , Poluentes Ambientais/análise , Cabelo/químicaRESUMO
Hair is good bioindicator of exposure, due to its ability to store and retain trace elements for long periods of time. But it can be especially useful when hair dyes are used since they may contain potentially toxic salts in their composition. In this context, analytical methods for the determination of bismuth, cadmium, lead, and silver in scalp human hair by electrothermal atomic absorption spectrometry were successfully validated. A total of 60 samples obtained from women between 18 and 60 years were analyzed: 34 dyed hairs and 26 untreated hairs (control). Average results expressed in dry weight (dyed/control) for each element were 2.34/0.49 µg g-1 (silver), 0.142/0.139 µg g-1 (bismuth), 0.055/0.054 µg g-1 (cadmium), and 2.09/0.99 µg g-1 (lead), respectively. These results agreed with those previously reported for non-exposed populations. A statistically significant higher Ag concentration in dyed hairs was observed, suggesting the bioaccumulation of this element. The associations between metal concentration and variables of interest (age, education, smoking habit, dye brand, use of dietary supplements) were investigated. A strong Pearson correlation was found for the pair Ag/Pb (r = 0.494, p < 0.05). Also, strong associations between lead levels and all the selected variables were observed (p < 0.05), while strong associations between silver levels with age and dye brand and association between cadmium levels and smoking habit were found. Furthermore, several commercial hair dye brands were analyzed to verify compliance with cosmetic regulations. This constitutes the first study of such characteristics performed in Uruguay, with worldwide relevance.
RESUMO
The aim of this work was to study the distribution of relevant inorganic contaminants in environmental samples from Ciudad de la Costa, the second most populated city of Uruguay. For this task aluminum (Al), cadmium (Cd), chromium (Cr), nickel (Ni) and lead (Pb) levels were determined in sand, water, and plant material from six beaches that are located in the area. Analytical methods were successfully validated. Accuracy was ensured by using certified reference materials and spiking procedures. Average metal concentrations in sand and water samples were compared with the maximum limits established by international or national regulations (when available), being far below these limits in all cases. This may indicate that the inorganic contamination in the studied area is rather low, despite the rapid increase in anthropic activities in recent years. To give a deeper characterization of the ecosystem, metal accumulation and mobility within a common plant of the zone, Ammophila arenaria, were studied. Results showed that concentrations in roots were one order of magnitude higher in comparison to aerial parts. In addition, the bioaccumulation coefficient (BAC) showed that the plant accumulates Cd, Cr and Ni, while a low accumulation for Pb was observed. Finally, a Cr(VI) speciation analysis in Ammophila arenaria was performed, showing Cr(VI) percentages below 4.6%, which is relevant from the (eco)toxicological point of view due to the high environmental mobility and bioavailability of this valence state. This work constitutes the first environmental surveillance report of this kind, regarding this populated area of the country.
Assuntos
Cádmio , Metais Pesados , Cádmio/análise , Areia , Uruguai , Ecossistema , Chumbo/análise , Níquel , Monitoramento Ambiental , Água/análise , Metais Pesados/análiseRESUMO
Current treatment for Chagas' disease is based on two drugs, Nifurtimox and Benznidazol, which have limitations that reduce the effectiveness and continuity of treatment. Thus, there is an urgent need to develop new, safe and effective drugs. In previous work, two new metal-based compounds with trypanocidal activity, Pd-dppf-mpo and Pt-dppf-mpo, were fully characterized. To unravel the mechanism of action of these two analogous metal-based drugs, high-throughput omics studies were performed. A multimodal mechanism of action was postulated with several candidates as molecular targets. In this work, we validated the ergosterol biosynthesis pathway as a target for these compounds through the determination of sterol levels by HPLC in treated parasites. To understand the molecular level at which these compounds participate, two enzymes that met eligibility criteria at different levels were selected for further studies: phosphomevalonate kinase (PMK) and lanosterol 14-α demethylase (CYP51). Molecular docking processes were carried out to search for potential sites of interaction for both enzymes. To validate these candidates, a gain-of-function strategy was used through the generation of overexpressing PMK and CYP51 parasites. Results here presented confirm that the mechanism of action of Pd-dppf-mpo and Pt-dppf-mpo compounds involves the inhibition of both enzymes.
RESUMO
Chagas' disease (American Trypanosomiasis) is an ancient and endemic illness in Latin America caused by the protozoan parasite Trypanosoma cruzi. Although there is an urgent need for more efficient and less toxic chemotherapeutics, no new drugs to treat this disease have entered the clinic in the last decades. Searching for metal-based prospective antichagasic drugs, in this work, multifunctional Re(I) tricarbonyl compounds bearing two different bioactive ligands were designed: a polypyridyl NN derivative of 1,10-phenanthroline and a monodentate azole (Clotrimazole CTZ or Ketoconazol KTZ). Five fac-[Re(CO)3(NN)(CTZ)](PF6) compounds and a fac-[Re(CO)3(NN)(KTZ)](PF6) were synthesized and fully characterized. They showed activity against epimastigotes (IC50 3.48-9.42 µM) and trypomastigotes of T. cruzi (IC50 0.61-2.79 µM) and moderate to good selectivity towards the parasite compared to the VERO mammalian cell model. In order to unravel the mechanism of action of our compounds, two potential targets were experimentally and theoretically studied, namely DNA and one of the enzymes involved in the parasite ergosterol biosynthetic pathway, CYP51 (lanosterol 14-α-demethylase). As hypothesized, the multifunctional compounds shared in vitro a similar mode of action as that disclosed for the single bioactive moieties included in the new chemical entities. Additionally, two relevant physicochemical properties of biological interest in prospective drug development, namely lipophilicity and stability in solution in different media, were determined. The whole set of results demonstrates the potentiality of these Re(I) tricarbonyls as promising candidates for further antitrypanosomal drug development.
Assuntos
Antiprotozoários , Doença de Chagas , Compostos Organometálicos , Trypanosoma cruzi , Humanos , Doença de Chagas/tratamento farmacológico , Compostos Organometálicos/química , Antiprotozoários/química , Cetoconazol/químicaRESUMO
Human African trypanosomiasis (sleeping sickness) and leishmaniasis are prevalent zoonotic diseases caused by genomically related trypanosomatid protozoan parasites (Trypanosoma brucei and Leishmania spp). Additionally, both are co-endemic in certain regions of the world. Only a small number of old drugs exist for their treatment, with most of them sharing poor safety, efficacy, and pharmacokinetic profiles. In this work, new multifunctional Ru(II) ferrocenyl compounds were rationally designed as potential agents against these trypanosomatid parasites by including in a single molecule 1,1'-bis(diphenylphosphino)ferrocene (dppf) and two bioactive bidentate ligands: 8-hydroxyquinoline derivatives (8HQs) and polypyridyl ligands (NN). Three [Ru(8HQs)(dppf)(NN)](PF6) compounds were synthesized and fully characterized. They showed in vitro activity on bloodstream Trypanosoma brucei (IC50 140-310 nM) and on Leishmania infantum promastigotes (IC50 3.0-4.8 µM). The compounds showed good selectivity towards T. brucei in respect to J774 murine macrophages as mammalian cell model (SI 15-38). Changing hexafluorophosphate counterion by chloride led to a three-fold increase in activity on both parasites and to a two to three-fold increase in selectivity towards the pathogens. The compounds affect in vitro at least the targets of the individual bioactive moieties included in the new chemical entities: DNA and generation of ROS. The compounds are stable in solution and are more lipophilic than the free bioactive ligands. No clear correlation between lipophilicity, interaction with DNA or generation of ROS and activity was detected, which agrees with their overall similar anti-trypanosoma potency and selectivity. These compounds are promising candidates for further drug development.