RESUMEN

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.

Asunto(s)

Compuestos Ferrosos , Rutenio , Tripanocidas , Trypanosoma cruzi , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Compuestos Ferrosos/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Ligandos , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Animales , Rutenio/química , Rutenio/farmacología , Ratones , Metalocenos/química , Metalocenos/farmacología , Metalocenos/síntesis química , Trypanosoma brucei brucei/efectos de los fármacos , Pruebas de Sensibilidad Parasitaria , Estructura Molecular , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química

RESUMEN

Iron deficiency is the leading cause of anaemia. In Argentina, the prevalence of anaemia and iron deficiency is very high; for that reason, the Argentine Society of Pediatrics recommends daily ferrous sulphate supplementation as a preventive treatment strategy. Alternatively, weekly ferrous sulphate supplementation has also been shown to be effective for anaemia prevention. Excess iron could be related to oxidative stress, which may in turn cause cytomolecular damage. Both can be prevented with vitamin E supplementation. We evaluated the effect of both daily and weekly ferrous sulphate supplementation combined with two doses of vitamin E on cell viability, oxidative stress and cytomolecular damage in peripheral blood cultured in vitro. The experimental design included the following groups: untreated negative control, two vitamin E controls (8·3 and 16·6 µg/ml), weekly ferrous sulphate supplementation (0·55 mg/ml) with each vitamin E dose, daily ferrous sulphate supplementation (0·14 mg/ml) with each vitamin E dose and a positive control. Daily ferrous sulphate supplementation decreased cell viability and increased the levels of reactive oxygen species, lipid peroxidation and cytomolecular damage (P < 0·5) compared with the weekly supplementation, probably due to the excess iron observed in the former. Vitamin E seemed to reduce ferrous sulphate-induced oxidative stress and genomic damage.

Asunto(s)

Anemia Ferropénica , Anemia , Deficiencias de Hierro , Sobrecarga de Hierro , Humanos , Niño , Vitamina E/farmacología , Vitamina E/uso terapéutico , Suplementos Dietéticos , Compuestos Ferrosos/farmacología , Compuestos Ferrosos/uso terapéutico , Hierro , Genómica , Modelos Teóricos

RESUMEN

Immunomodulatory agents are widely used for the treatment of immune-mediated diseases, but the range of side effects of the available drugs makes necessary the search for new immunomodulatory drugs. Here, we investigated the immunomodulatory activity of new ferrocenyl-N-acyl hydrazones derivatives (SintMed(141−156). The evaluated N-acyl hydrazones did not show cytotoxicity at the tested concentrations, presenting CC50 values greater than 50 µM. In addition, all ferrocenyl-N-acyl hydrazones modulated nitrite production in immortalized macrophages, showing inhibition values between 14.4% and 74.2%. By presenting a better activity profile, the ferrocenyl-N-acyl hydrazones SintMed149 and SintMed150 also had their cytotoxicity and anti-inflammatory effect evaluated in cultures of peritoneal macrophages. The molecules were not cytotoxic at any of the concentrations tested in peritoneal macrophages and were able to significantly reduce (p < 0.05) the production of nitrite, TNF-α, and IL-1ß. Interestingly, both molecules significantly reduced the production of IL-2 and IFN-γ in cultured splenocytes activated with concanavalin A. Moreover, SintMed150 did not show signs of acute toxicity in animals treated with 50 or 100 mg/kg. Finally, we observed that ferrocenyl-N-acyl hydrazone SintMed150 at 100 mg/kg reduced the migration of neutrophils (44.6%) in an acute peritonitis model and increased animal survival by 20% in an LPS-induced endotoxic shock model. These findings suggest that such compounds have therapeutic potential to be used to treat diseases of inflammatory origin.

Asunto(s)

Hidrazonas , Agentes Inmunomoduladores , Animales , Hidrazonas/química , Metalocenos , Compuestos Ferrosos/farmacología , Compuestos Ferrosos/química , Lipopolisacáridos

RESUMEN

A simple and fast methodology under microwave irradiation for the synthesis of 2-aminopyrimidine and pyrazole derivatives using Atwal reaction is reported. After the optimization of the reaction conditions, eight 2-aminolpyrimidines containing ferrocene and heterocycles and three ferrocene pyrazoles were synthesized from the respective chalcones in good yields. Eight compounds had their structure determined by X-ray diffraction. The molecular hybrid 6a-h and 9a-c were tested on four cancer cell lines - HCT116, PC3, HL60 and SNB19 - where four pyrimidine 6a, 6f-h and one pyrazole 9c derivatives show promising antiproliferative activity. In addition, docking simulation and machine learning methods were carried out to explain the biological activity achieved by the synthetized compounds.

Asunto(s)

Antineoplásicos/farmacología , Compuestos Ferrosos/farmacología , Aprendizaje Automático , Metalocenos/farmacología , Microondas , Simulación del Acoplamiento Molecular , Pirazoles/farmacología , Pirimidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Humanos , Metalocenos/síntesis química , Metalocenos/química , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad

RESUMEN

A series of novel water-soluble short peptide-bioconjugates containing a ferrocenoyl (Fc) or ruthenocenoyl (Rc) unit was synthesized and characterized to combine the unique activity of ferrocene and the isoelectronic ruthenocene with precisely designed peptide structures. We aim at evaluating these bioconjugates as a new class of OrganoMetallic Short AntiMicrobial Peptides (OM-SAMPs). The series of OM-SAMPs was designed with a set of linear and "head-to-tail" cyclic metallocene-based hexapeptides derived from the homo-sequence H-KKKKKK-NH2 by substitution of lysine (K) by tryptophan (W) and by orthogonal derivatization of the ε-N-amine group of lysine by a metallocene moiety. Peptide conjugates were characterized by RP-HPLC, mass spectrometry (ESI and MALDI-TOF) and circular dichroism (CD) spectroscopy. Gram-positive and Gram-negative antibacterial activity testings were carried out to explore the role of insertion of the metallocene fragment into the peptide, and the effect of the modification of the cationic charge and aromatic residues on the physiochemical properties of these OM-SAMPs. These results show that the insertion of two tryptophan residues and ferrocenoyl/ruthenocenoyl moieties into a linear homo-sequence peptides increase significantly their antibacterial activity with minimum inhibitory concentration values as low as 5 µM for the most active compounds. However, "head-to-tail" cyclic metallocene-based hexapeptides were not active against Gram-negative bacteria up to concentrations of 50 µM. These studies provide a better understanding of the role of structural modifications to enhance antibacterial peptide activity, which is promising for their therapeutic application.

Asunto(s)

Antibacterianos/farmacología , Compuestos Ferrosos/farmacología , Metalocenos/farmacología , Oligopéptidos/farmacología , Compuestos Organometálicos/farmacología , Técnicas de Síntesis en Fase Sólida , Antibacterianos/síntesis química , Antibacterianos/química , Compuestos Ferrosos/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Metalocenos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Compuestos Organometálicos/química , Solubilidad , Agua/química

RESUMEN

The main goal of this work was to evaluate the in vitro biological activity of two ferrocenyl chalcones (FcC-1 and FcC-2) against Haemonchus contortus (third-stage larvae (L3)) and Nacobbus aberrans (second-stage juveniles (J2)). Both compounds were synthesized and characterized by usual spectroscopic methods and their molecular structures were confirmed by single-crystal X-ray diffractometry. Nematode strains were examined in terms of percentage mortality of H. contortus (L3) by the action of FcC-1, which showed an effectivity of 100% at a concentration of 342 µM in 24 h, with EC50 = 20.33 µM and EC90 = 162.76 µM, whereas FcC-2 had an effectivity of 72% at a concentration of 342 µM in 24 h, with EC50 = 167.39 µM and EC90 = 316.21 µM. The effect of FcC-1 against nematode phytoparasite N. aberrans showed a better percentage of 95% at a concentration of 342 µM, with EC50 = 7.18 µM and EC90 = 79.25 µM, whereas the effect of FcC-2 was 87% at 342 µM, with EC50 = 168 µM and EC90 = 319.56 µM at 36 h. After treatment, the scanning electron micrographs revealed deformities in the dorsal flank and posterior part close to the tail of H. contortus L3. They showed moderate in vitro nematicidal activity against H. contortus L3 and N. aberrans J2.

Asunto(s)

Antinematodos/farmacología , Chalconas/farmacología , Compuestos Ferrosos/farmacología , Haemonchus/efectos de los fármacos , Tylenchoidea/efectos de los fármacos , Animales , Antinematodos/química , Chalconas/química , Compuestos Ferrosos/química , Hemoncosis/parasitología , Larva/efectos de los fármacos , Extractos Vegetales/farmacología

RESUMEN

Antibiotics and other antimicrobial compounds are the backbone of clinical medicine. Antimicrobial resistance can cause serious diseases to man. Nanotechnology can improve therapeutic potential of medicinal molecules and related agents. Widespread application of antibiotics and other antimicrobial compounds led to development of multidrug-resistant microbes, so there is need to develop novel therapeutic agents. Novel synthesized nanometric delafossite was assayed against two Gram-positive bacteria (Staphylococcus aureus and Micrococcus luteus), two Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae), four opportunistic fungi (Aspergillus flavus, A. fumigatus, A. niger, and Fusarium solani), and four Candida species (C. albicans, C. parapsilosis, C. krusei, and C. tropicalis) using diffusion assay method. The minimum inhibitory concentration (MIC) of the novel synthesized nanometric delafossite was determined using the dilution method. The assayed compounds showed different degrees of antifungal and antibacterial activities, depending on the annealing temperature of preparation of these compounds. Compounds prepared at room temperature showed greater antimicrobial activities than those prepared at higher temperatures. The antimicrobial activity depends also on the susceptibility of the test microbe.

Asunto(s)

Antiinfecciosos/farmacología , Cobre/farmacología , Compuestos Ferrosos/farmacología , Hongos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Pruebas de Sensibilidad Microbiana

RESUMEN

Of all cyanobacteria, Microcystis aeruginosa is the most commonly found species in bloom episodes all over the world. This species is known to produce cyanopeptides with hepatotoxic effects, namely microcystins (MCs). In this regard, Advanced Oxidation Processes (AOPs) have been widely studied for cyanotoxin degradation, but very few studies focused on cyanobacteria inactivation combined with toxin removal. To our knowledge, this is the first report of the photo-Fenton process application focusing on M. aeruginosa inactivation and microcystin-LR (MC-LR) degradation. This research work aimed to evaluate the photo-Fenton process under three different conditions with regard to Fe2+/H2O2 ratios (0.6/10, 5/50, and 20/100 mg L-1) at the initial near-neutral pH. Process efficiency was measured by immediate cell density reduction, growth inhibition, effect on MC-LR concentrations, and scanning electron microscopy (SEM) to analyze any alterations in cell morphology. Growth inhibition test (GIT) results pointed to cell inactivation under all conditions tested, and MC-LR concentrations were reduced below WHO's maximum limit at medium and higher concentrations of reagents. The possible mechanisms of cell inactivation by oxidative species are discussed.

Asunto(s)

Toxinas Marinas/metabolismo , Microcistinas/metabolismo , Microcystis/metabolismo , Compuestos Ferrosos/análisis , Compuestos Ferrosos/farmacología , Peróxido de Hidrógeno/análisis , Peróxido de Hidrógeno/farmacología , Concentración de Iones de Hidrógeno , Microcystis/citología , Microcystis/efectos de los fármacos , Oxidación-Reducción

RESUMEN

Iron deficiency is the most prevalent nutritional deficiency and the main cause of anemia worldwide. Since children aged 6-24 months are among the most vulnerable groups at risk, daily supplementation with ferrous sulfate is recommended by the Argentine Society of Pediatrics as preventive treatment of anemia. However, a single weekly dose would have fewer adverse side effects and has been therefore proposed as an alternative treatment. Ferrous sulfate is known by its pro-oxidative properties, which may lead to increased oxidative stress as well as lipid, protein, and DNA damage. We analyzed the effect of daily and weekly preventive treatment of iron deficiency anemia (IDA) on cell viability, oxidative stress, chromosome, and cytomolecular damage in peripheral blood cultured in vitro. The study protocol included the following: untreated negative control; bleomycin, hydrogen peroxide, or ethanol-treated positive control; daily 0.14 mg ferrous sulfate-supplemented group; and weekly 0.55 mg ferrous sulfate-supplemented group. We assessed cell viability (methyl-thiazolyl-tetrazolium and neutral red assays), lipid peroxidation (thiobarbituric acid reactive substances assay), antioxidant response (superoxide dismutase and catalase enzyme analysis), chromosome damage (cytokinesis-blocked micronucleus cytome assay), and cytomolecular damage (comet assay). Lipid peroxidation, antioxidant response, and chromosome and cytomolecular damage decreased after weekly ferrous sulfate supplementation (p < 0.05), suggesting less oxygen free radical production and decreased oxidative stress and genomic damage. Such a decrease in oxidative stress and genomic damage in vitro positions weekly supplementation as a better alternative for IDA treatment. Further studies in vivo would be necessary to corroborate whether weekly supplementation could improve IDA preventive treatment compliance in children.

Asunto(s)

Anemia Ferropénica/tratamiento farmacológico , Cromosomas/efectos de los fármacos , Daño del ADN , Compuestos Ferrosos/farmacología , Estrés Oxidativo/efectos de los fármacos , Adulto , Anemia Ferropénica/sangre , Anemia Ferropénica/prevención & control , Supervivencia Celular/efectos de los fármacos , Cromosomas/genética , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Ferrosos/administración & dosificación , Humanos , Relación Estructura-Actividad , Adulto Joven

RESUMEN

Searching for prospective agents against infectious diseases, four new ferrocenyl derivatives, [M(L)(dppf)4](PF6), with M = Pd(II) or Pt(II), dppf = 1,1'-bis(dipheny1phosphino) ferrocene and HL = tropolone (HTrop) or hinokitiol (HHino), were synthesized and characterized. Complexes and ligands were evaluated against the bloodstream form of T. brucei, L. infantum amastigotes, M. tuberculosis (MTB) sensitive strain and MTB clinical isolates. Complexes showed a significant increase of the anti-T. brucei activity with respect to the free ligands (>28- and >46-fold for Trop and 6- and 22-fold for Hino coordinated to Pt-dppf and Pd-dppf, respectively), yielding IC50 values < 5 µM. The complexes proved to be more potent than the antitrypanosomal drug Nifurtimox. The new ferrocenyl derivatives were more selective towards the parasite than the free ligands. The Pt compounds were less toxic on J774 murine macrophages (mammalian cell model), than the Pd ones, showing selectivity index values (SI = IC50 murine macrophage/IC50T. brucei) up to 23. Generation of the {M-dppf} compounds lead to a slightly positive impact on the anti-leishmanial potency. Although the ferrocenyl derivatives were more active on sensitive MTB than the free ligands (MIC90 = 9.88-14.73 µM), they showed low selectivity towards the pathogen. Related to the mechanism of action, the antiparasitic effect cannot be ascribed to an interference of the compounds with the thiol-redox homeostasis of the pathogen. Fluorescence measurements pointed at DNA as a probable target of the new compounds. [Pt(Trop)(dppf)](PF6) and [Pt(Hino)(dppf)](PF6) could be considered prospective anti-T. brucei agents that deserve further research.

Asunto(s)

Antituberculosos , Compuestos Ferrosos , Mycobacterium tuberculosis/crecimiento & desarrollo , Tripanocidas , Trypanosoma brucei brucei/crecimiento & desarrollo , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Línea Celular , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Humanos , Leishmania infantum/crecimiento & desarrollo , Ratones , Tripanocidas/química , Tripanocidas/farmacología

RESUMEN

INTRODUCTION: Micronutrient deficiencies are one of the most important public health issues worldwide and iron (Fe) deficiency anemia is the most prevalent micronutrient deficiency. Iron deficiency often coexists with calcium deficiency and iron and calcium supplementation often overlap. This has led to investigations into the interaction between these two minerals, and whether calcium may inhibit iron absorption in the gut. OBJECTIVE: To determine the effect of various calcium salts on non-heme iron bioavailability in fasted women of childbearing age. METHODS: A randomized and single blinded trial was conducted on 27 women of childbearing age (35-45 years old) divided into 2 groups (n1 = 13 and n2 = 14, respectively). On four different days, after an overnight fast, they received 5 mg of Fe as FeSO4 (labeled with 55Fe or 59Fe) with 800 mg of elemental calcium in the form of either calcium chloride, calcium gluconate, calcium citrate, calcium carbonate, calcium lactate, calcium sulfate or calcium phosphate. Calcium chloride was used as the control salt in both groups. Iron was labeled with the radioisotopes 59Fe or 55Fe, and the absorption of iron was measured by erythrocyte incorporation of radioactive Fe RESULTS: 800 mg of elemental calcium as calcium citrate produced a significant decrease in non-heme iron bioavailability (repeated measures ANOVA, F = 3.79, p = 0.018). CONCLUSION: Of the various calcium salts tested, calcium citrate was the only salt that decreased non-heme iron bioavailability relative to the calcium chloride control when taken on an empty stomach. These results suggest that inhibition of non-heme iron absorption in fasted individuals is dependent upon the calcium salt in question and not solely dependent on the presence of calcium.

Asunto(s)

Calcio/farmacología , Hierro/metabolismo , Adulto , Anemia Ferropénica , Disponibilidad Biológica , Fosfatos de Calcio/farmacología , Femenino , Compuestos Ferrosos/farmacología , Humanos , Absorción Intestinal/efectos de los fármacos , Persona de Mediana Edad , Método Simple Ciego

RESUMEN

ABSTRACT Soybean (Glycine max L.) seed contains amounts of protein, lipid, carbohydrate and mineral elements, which protein and lipid have been known as a main part for soybean's trade value. In this study, in order to investigate the effect of ferrous nano-oxide particles on nutritional compounds of soybean seed, an experiment with 5 treatments and 3 replications was conducted as a randomized complete block design. Treatments were 5 concentrations of ferrous nano-oxide particles including 0, 0.25, 0.5, 0.75 and 1 g L-1 which were sprayed 3 times at 4 and 8 leaves stage and pod initiation. Lipid and protein contents, fatty acids profile, some of mineral elements such as Fe, Mg, Ca and P, chlorophyll a, b and total chlorophyll content were determined. Results showed that solution containing ferrous nano-oxide particles had significant effect on nutritional compounds of soybean seed (P<0.01) compared to control. The highest content of lipid and protein (25.4 and %33.8, respectively) observed by applying 0.75 g L-1 of ferrous nano-oxide and the lowest content was also in control. Changes in the trends of fatty acids profile (palmitic, oleic, linoleic and linolenic acids), some of mineral elements (Fe, Mg, Ca and P) and chlorophyll contents were similar to lipid and protein levels which by increasing in concentration of ferrous nano-oxide from 0 to 0.75 g L-1 all measured parameters also increased, but reduction in all parameters was observed in concentration from 0.75 to 1 g L-1. In conclusion, application of 0.75 to 1 g L-1 ferrous nano-oxide had the best effect on the nutrient composition of soybean seed.

Asunto(s)

Semillas/efectos de los fármacos , Semillas/química , Glycine max/efectos de los fármacos , Glycine max/química , Compuestos Ferrosos/farmacología , Nanopartículas del Metal/química , Valores de Referencia , Semillas/fisiología , Glycine max/fisiología , Oligoelementos/análisis , Proteínas/análisis , Distribución Aleatoria , Clorofila/análisis , Análisis de Regresión , Reproducibilidad de los Resultados , Ácidos Grasos/análisis , Fertilizantes , Lípidos/análisis

RESUMEN

Increased concentrations of nutrients in water bodies caused by effluent discharge, fertilizers and other inputs can lead to artificial eutrophication, increasing the primary productivity, bringing well-known and serious consequences to the environment (such as excessive macrophyte and microalgae growth). Most strategies for phytoplankton control in aquatic ecosystems result in metal accumulation or toxic by-product formation after chlorination. Concerning this matter, the photo-Fenton process (usually applied in wastewater treatment and degradation of a variety of contaminants) has been studied for water and effluent disinfection. However, its application in microalgae inactivation has not been reported until now. Therefore, this work aimed to evaluate the process effectiveness in inactivating microalgae, using Desmodesmus subspicatus as a model. Photo-Fenton experiments were carried out at the lab scale, at 105 cells per mL with 20 mg L-1 of H2O2 and 5 mg L-1 of Fe2+ (complexed with oxalic acid). The cell concentration and Growth Inhibition Test (GIT) were used to evaluate the process efficiency and Scanning Electron Microscopy (SEM) to analyze any alterations in the cell morphology. After performing the photo-Fenton reaction, the individual contribution of the reactants and radiation was investigated. The cell concentration was not significantly reduced during the photo-Fenton reaction, but SEM images indicated possible morphology alterations and the GIT showed the loss of cell viability after 30 minutes of exposure. Effects on the cell growth were also observed when exposed only to hydrogen peroxide.

Asunto(s)

Chlorophyta/metabolismo , Microalgas/metabolismo , Eliminación de Residuos Líquidos , Contaminantes Químicos del Agua/metabolismo , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Chlorophyta/citología , Chlorophyta/efectos de los fármacos , Compuestos Ferrosos/farmacología , Peróxido de Hidrógeno/farmacología , Microalgas/citología , Microalgas/efectos de los fármacos , Microscopía Electrónica de Rastreo , Procesos Fotoquímicos , Especies Reactivas de Oxígeno/metabolismo , Contaminantes Químicos del Agua/química

RESUMEN

Soybean (Glycine max L.) seed contains amounts of protein, lipid, carbohydrate and mineral elements, which protein and lipid have been known as a main part for soybean's trade value. In this study, in order to investigate the effect of ferrous nano-oxide particles on nutritional compounds of soybean seed, an experiment with 5 treatments and 3 replications was conducted as a randomized complete block design. Treatments were 5 concentrations of ferrous nano-oxide particles including 0, 0.25, 0.5, 0.75 and 1 g L-1 which were sprayed 3 times at 4 and 8 leaves stage and pod initiation. Lipid and protein contents, fatty acids profile, some of mineral elements such as Fe, Mg, Ca and P, chlorophyll a, b and total chlorophyll content were determined. Results showed that solution containing ferrous nano-oxide particles had significant effect on nutritional compounds of soybean seed (P<0.01) compared to control. The highest content of lipid and protein (25.4 and %33.8, respectively) observed by applying 0.75 g L-1 of ferrous nano-oxide and the lowest content was also in control. Changes in the trends of fatty acids profile (palmitic, oleic, linoleic and linolenic acids), some of mineral elements (Fe, Mg, Ca and P) and chlorophyll contents were similar to lipid and protein levels which by increasing in concentration of ferrous nano-oxide from 0 to 0.75 g L-1 all measured parameters also increased, but reduction in all parameters was observed in concentration from 0.75 to 1 g L-1. In conclusion, application of 0.75 to 1 g L-1 ferrous nano-oxide had the best effect on the nutrient composition of soybean seed.

Asunto(s)

Compuestos Ferrosos/farmacología , Glycine max/química , Glycine max/efectos de los fármacos , Nanopartículas del Metal/química , Semillas/química , Semillas/efectos de los fármacos , Clorofila/análisis , Ácidos Grasos/análisis , Fertilizantes , Lípidos/análisis , Proteínas/análisis , Distribución Aleatoria , Valores de Referencia , Análisis de Regresión , Reproducibilidad de los Resultados , Semillas/fisiología , Glycine max/fisiología , Oligoelementos/análisis

RESUMEN

IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Mycobacterium tuberculosis Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the katG gene. The katG(S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpression of the InhA(S94A) protein caused IQG-607's resistance.

Asunto(s)

Antituberculosos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Compuestos Ferrosos/farmacología , Isoniazida/análogos & derivados , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Proteínas Bacterianas/genética , ADN Bacteriano/genética , Farmacorresistencia Bacteriana/genética , Humanos , Isoniazida/farmacología , Mutación/genética , Mycobacterium tuberculosis/genética , Secuenciación Completa del Genoma/métodos

RESUMEN

M. tuberculosis and parasites of the genus Leishmania present the type II fatty acid biosynthesis system (FASII). The pentacyano(isoniazid)ferrate(II) compound, named IQG-607, inhibits the enzyme 2-trans-enoyl-ACP(CoA) reductase from M. tuberculosis, a key component in the FASII system. Here, we aimed to evaluate the inhibitory activity of IQG-607 against promastigote and amastigote forms of Leishmania (Viannia) braziliensis isolated from patients with different clinical forms of L. braziliensis infection, including cutaneous, mucosal and disseminated leishmaniasis. Importantly, IQG-607 inhibited the proliferation of three different isolates of L. braziliensis promastigotes associated with cutaneous, mucosal and disseminated leishmaniasis. The IC50 values for IQG-607 ranged from 32 to 75 µM, for these forms. Additionally, IQG-607 treatment decreased the proliferation of intracellular amastigotes in infected macrophages, after an analysis of the percentage of infected cells and the number of intracellular parasites/100 cells. IQG-607 reduced from 58% to 98% the proliferation of L. braziliensis from cutaneous, mucosal and disseminated strains. Moreover, IQG-607 was also evaluated regarding its potential toxic profile, by using different cell lines. Cell viability of the lineages Vero, HaCat and HepG2 was significantly reduced after incubation with concentrations of IQG-607 higher than 2 mM. Importantly, IQG-607, in a concentration of 1 mM, did not induce DNA damage in HepG2 cells, when compared to the untreated control group. Future studies will confirm the mechanism of action of IQG-607 against L. braziliensis.

Asunto(s)

Compuestos Ferrosos/farmacología , Isoniazida/análogos & derivados , Leishmania braziliensis/efectos de los fármacos , Animales , Isoniazida/farmacología , Leishmania braziliensis/crecimiento & desarrollo

RESUMEN

Trace elements such as Zinc and Iron are essential components of metalloproteins and serve as cofactors or structural elements for enzymes involved in several important biological processes in almost all organisms. Because either excess or insufficient levels of Zn and Fe can be harmful for the cells, the homeostatic levels of these trace minerals must be tightly regulated. The Zinc regulated transporter, Iron regulated transporter-like Proteins (ZIP) comprise a diverse family, with several paralogues in diverse organisms and are considered essential for the Zn and Fe uptake and homeostasis. Zn and Fe has been shown to regulate expression of proteins involved in metabolism and pathogenicity mechanisms in the protozoan pathogen Trichomonas vaginalis, in contrast high concentrations of these elements were also found to be toxic for T. vaginalis trophozoites. Nevertheless, Zn and Fe uptake and homeostasis mechanisms is not yet clear in this parasite. We performed a genome-wide analysis and localized the 8 members of the ZIP gene family in T. vaginalis (TvZIP1-8). The bioinformatic programs predicted that the TvZIP proteins are highly conserved and show similar properties to the reported in other ZIP orthologues. The expression patterns of TvZIP1, 3, 5 and 7 were diminished in presence of Zinc, while the rest of the TvZIP genes showed an unchanged profile in this condition. In addition, TvZIP2 and TvZIP4 showed a differential expression pattern in trophozoites growth under different Iron conditions. These results suggest that TvZIP genes encode membrane transporters that may be responsible for the Zn and Fe acquisition in T. vaginalis.

Asunto(s)

Proteínas de Transporte de Catión/genética , Genoma de Protozoos , Hierro/metabolismo , Proteínas Protozoarias/genética , Trichomonas vaginalis/genética , Zinc/metabolismo , Secuencia de Aminoácidos , Arabidopsis , Proteínas de Transporte de Catión/metabolismo , Biología Computacional , Compuestos Ferrosos/farmacología , Regulación de la Expresión Génica , Homeostasis , Transporte Iónico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Protozoarias/metabolismo , Saccharomyces cerevisiae , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Trichomonas vaginalis/efectos de los fármacos , Trichomonas vaginalis/metabolismo , Sulfato de Zinc/farmacología

RESUMEN

Hepatic fibrosis is an extracellular matrix deposition by hepatic stellate cells (HSC). Fibrosis can be caused by iron, which will lead to hydroxyl radical production and cell damage. Fructose-1,6-bisphosphate (FBP) has been shown to deliver therapeutic effects in many pathological situations. In this work, we aimed to test the effects of FBP in HSC cell line, GRX, exposed to an excess of iron (Fe). The Fe-treatment increased cell proliferation and FBP reversed this effect, which was not due to increased necrosis, apoptosis or changes in cell cycle. Oil Red-O staining showed that FBP successfully increased lipid content and lead GRX cells to present characteristics of quiescent HSC. Fe-treatment decreased PPAR-γ expression and increased Col-1 expression. Both effects were reversed by FBP which also decreased TGF-ß1 levels in comparison to both control and Fe groups. FBP, also, did not present scavenger activity in the DPPH assay. The treatment with FBP resulted in decreased proliferation rate, Col-1 expression and TGF-ß1 release by HSC cells. Furthermore, activated PPAR-γ and increased lipid droplets induce cells to become quiescent, which is a key event to reversion of hepatic fibrosis. FBP also chelates iron showing potential to improve Cell redox state.

Asunto(s)

Compuestos Ferrosos/antagonistas & inhibidores , Fructosadifosfatos/farmacología , Células Estrelladas Hepáticas/efectos de los fármacos , Quelantes del Hierro/farmacología , Animales , Compuestos de Bifenilo/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Compuestos Ferrosos/farmacología , Regulación de la Expresión Génica , Células Estrelladas Hepáticas/citología , Células Estrelladas Hepáticas/metabolismo , Gotas Lipídicas/efectos de los fármacos , Gotas Lipídicas/metabolismo , Ratones , Oxidación-Reducción , PPAR gamma/genética , PPAR gamma/metabolismo , Picratos/química , Transducción de Señal , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo

RESUMEN

Abstract Resistance to benznidazole in certain strains of Trypanosoma cruzi may be caused by the increased production of enzymes that act on the oxidative metabolism, such as mitochondrial tryparedoxin peroxidase which catalyses the reduction of peroxides. This work presents cytotoxicity assays performed with ferrocenyl diamine hydrochlorides in six different strains of T. cruzi epimastigote forms (Y, Bolivia, SI1, SI8, QMII, and SIGR3). The last four strains have been recently isolated from triatominae and mammalian host (domestic cat). The expression of mitochondrial tryparedoxin peroxidase was analyzed by the Western blotting technique using polyclonal antibody anti mitochondrial tryparedoxin peroxidase obtained from a rabbit immunized with the mitochondrial tryparedoxin peroxidase recombinant protein. All the tested ferrocenyl diamine hydrochlorides were more cytotoxic than benznidazole. The expression of the 25.5 kDa polypeptide of mitochondrial tryparedoxin peroxidase did not increase in strains that were more resistant to the ferrocenyl compounds (SI8 and SIGR3). In addition, a 58 kDa polypeptide was also recognized in all strains. Ferrocenyl diamine hydrochlorides showed trypanocidal activity and the expression of 25.5 kDa mitochondrial tryparedoxin peroxidase is not necessarily increased in some T. cruzi strains. Most likely, other mechanisms, in addition to the over expression of this antioxidative enzyme, should be involved in the escape of parasites from cytotoxic oxidant agents.

Asunto(s)

Animales , Gatos , Conejos , Peroxidasas/metabolismo , Compuestos Ferrosos/farmacología , Proteínas Protozoarias/metabolismo , Oxidantes/farmacología , Diaminas/farmacología , Mitocondrias/enzimología , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimología , Western Blotting , Mitocondrias/efectos de los fármacos

RESUMEN

4-nitroquinoline-1-oxide (4-NQO) is a pro-oxidant carcinogen bioactivated by xenobiotic metabolism (XM). We investigated if antioxidants lycopene [0.45, 0.9, 1.8 µM], resveratrol [11, 43, 172 µM], and vitamin C [5.6 mM] added or not with FeSO4 [0.06 mM], modulate the genotoxicity of 4-NQO [2 mM] with the Drosophila wing spot test standard (ST) and high bioactivation (HB) crosses, with inducible and high levels of cytochromes P450, respectively. The genotoxicity of 4-NQO was higher when dissolved in an ethanol - acetone mixture. The antioxidants did not protect against 4-NQO in any of both crosses. In the ST cross, resveratrol [11 µM], vitamin C and FeSO4 resulted in genotoxicity; the three antioxidants and FeSO4 increased the damage of 4-NQO. In the HB cross, none of the antioxidants, neither FeSO4, were genotoxic. Only resveratrol [172 µM] + 4-NQO increased the genotoxic activity in both crosses. We concluded that the effects of the antioxidants, FeSO4 and the modulation of 4-NQO were the result of the difference of Cyp450s levels, between the ST and HB crosses. We propose that the basal levels of the XM's enzymes in the ST cross interacted with a putative pro-oxidant activity of the compounds added to the pro-oxidant effects of 4-NQO.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Ácido Ascórbico/farmacología , Carotenoides/farmacología , Compuestos Ferrosos/farmacología , Estilbenos/farmacología , Animales , Antioxidantes/farmacología , Ácido Ascórbico/efectos adversos , Carcinógenos/toxicidad , Carotenoides/efectos adversos , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Femenino , Compuestos Ferrosos/efectos adversos , Larva/efectos de los fármacos , Licopeno , Masculino , Resveratrol , Estilbenos/efectos adversos , Pruebas de Toxicidad/métodos , Alas de Animales/efectos de los fármacos , Xenobióticos/toxicidad