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We have previously demonstrated significant in vitro natriuretic effects of anandamide (AEA) nanoformulation in polymeric nanoparticles, whose size prevents their accumulation in organs, such as the kidneys. Therefore, it is of particular interest to design and test nanostructures that can pharmacologically accumulate in these organs. In this regard, we prepared and characterized polymeric nanomicelles (~14 and 40 nm). Likewise, their biodistribution was determined. Spontaneously hypertensive rats (SHR) and normotensive rats (WKY), n = 3 per group, were divided into five treatment conditions: control, sham, free AEA freshly dispersed in aqueous solution or 24 h after its dispersion, and AEA encapsulated in nanomicelles. The kidneys were the main site of accumulation of the nanoformulation after 24 h. Freshly dispersed free AEA showed its classical triphasic response in SHR, which was absent from all other treatments. Nanoformulated AEA produced a sustained antihypertensive effect over 2 h, accompanied by a significant increase in fractional sodium excretion (FSE %). These effects were not observed in WKY, sham, or free AEA-treated rats after 24 h of its aqueous dispersion. Without precedent, we demonstrate in vivo natriuretic, diuretic, and hypotensive effects of AEA nanoformulation in polymeric nanomicelles, suggesting its possible use as a new antihypertensive agent with intravenous administration and passive renal accumulation.

Along with the AgNP applications development, the concern about their possible toxicity has increasingly gained attention. As the respiratory system is one of the main exposure routes, the aim of this study was to evaluate the harmful effects developed in the lung after an acute AgNP exposure. In vivo studies using Balb/c mice intranasally instilled with 0.1 mg AgNP/kg b.w, were performed. 99mTc-AgNP showed the lung as the main organ of deposition, where, in turn, AgNP may exert barrier injury observed by increased protein content and total cell count in BAL samples. In vivo acute exposure showed altered lung tissue O2 consumption due to increased mitochondrial active respiration and NOX activity. Both O2 consumption processes release ROS triggering the antioxidant system as observed by the increased SOD, catalase and GPx activities and a decreased GSH/GSSG ratio. In addition, increased protein oxidation was observed after AgNP exposure. In A549 cells, exposure to 2.5 μg/mL AgNP during 1 h resulted in augment NOX activity, decreased mitochondrial ATP associated respiration and higher H2O2 production rate. Lung 3D tissue model showed AgNP-initiated barrier alterations as TEER values decreased and morphological alterations. Taken together, these results show that AgNP exposure alters O2 metabolism leading to alterations in oxygen metabolism lung toxicity. AgNP-triggered oxidative damage may be responsible for the impaired lung function observed due to alveolar epithelial injury.

There is an increasing concern over the harmful effects that metallic nanoparticles (NP) may produce on human health. Due to their redox properties, nickel (Ni) and Ni-containing NP are particularly relevant. Hence, the aim of this study was to establish the toxicological mechanisms in the cardiorespiratory oxidative metabolism initiated by an acute exposure to Ni-doped-NP. Mice were intranasally instilled with silica NP containing Ni (II) (Ni-NP) (1 mg Ni (II)/kg body weight) or empty NP as control, and 1 h after exposure lung, plasma, and heart samples were obtained to assess the redox metabolism. Results showed that, NP were mainly retained in the lungs triggering a significantly increased tissue O2 consumption rate, leading to Ni-NP-increased reactive oxygen species production by NOX activity, and mitochondrial H2O2 production rate. In addition, an oxidant redox status due to an altered antioxidant system showed by lung GSH/GSSG ratio decreased, and SOD activity increased, resulting in an increased phospholipid oxidation. Activation of circulating polymorphonuclear leukocytes, along with GSH/GSSG ratio decreased, and phospholipid oxidation were found in the Ni-NP-group plasma samples. Consequently, in distant organs such as heart, Ni-NP inhalation alters the tissue redox status. Our results showed that the O2 metabolism analysis is a critical area of study following Ni-NP inhalation. Therefore, this work provides novel data linking the redox metabolisms alterations elicited by exposure to Ni (II) adsorbed to NP and cardiorespiratory toxicity.

Bevacizumab is an FDA approved monoclonal antibody (anti VEGF) indicated in many cancers, mostly metastatic ones. D-α-tocopheryl polyethylene glycol succinate (TPGS) is the water-soluble form of vitamin E which usually forms micelles. This work aims to report preliminary results of the biodistribution of a TPGS based nano-micelle delivery system for bevacizumab in a gastric cancer xenograft model. Evaluation of the biodistribution of micelles/bevacizumab-99mTc was performed in Balb/c nude mice carrying MKN45 cell line xenograft. The nano-radiopharmaceutical (3.7 MBq/0.2 mL) was administered intraocularly and biodistribution was assesed 1 h post administration. The activity in each organ and blood was determined by a gamma counter. Mean size was 10 ± 1 nm for pure TPGS and 11 ± 1 nm for bevacizumab-TPGS respectively. Biodistribution showed that the highest uptake was found in both lungs and liver. Kidneys had also an important uptake. The tumor accumulated moderate to low radiolabeled nanomicelles, nevertheless tumor/blood ratio was very high. These preliminary results may help as a start point to continue evaluating the potential of radiolabeled bevacizumab-TPGS based nanomicelles to be used as a theranostic agent. Fil: Tesan, Fiorella Carla. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Cerqueira Coutinho, Cristal. Universidade Federal do Rio de Janeiro; Brasil Fil: Salgueiro, María Jimena. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Albernaz, Marta de Souza. Universidade Federal do Rio de Janeiro; Brasil Fil: Pinto, Suyenne Rocha. Universidade Estadual da Zona Oeste; Brasil Fil: Reis, Sara Rhaissa Rezende Dos. Universidade Estadual da Zona Oeste; Brasil Fil: Bernardes, Emerson Soares. Instituto de Pesquisas Energéticas e Nucleares; Brasil Fil: Chiapetta, Diego. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Zubillaga, Marcela Beatriz. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Santos Oliveira, Ralph. Universidade Estadual da Zona Oeste; Brasil

Tuberculosis (TB) stands as the second “most deadly infectious disease” behind AIDS. Rifampicin (RIF) represents one of the most effective anti-TB drugs of the “short-term” oral TB therapy. However, the main limitations of the oral treatment are related with the lack of patient adherence and the development of multi-drug resistant Mycobacterium tuberculosis (Mtb) strains. Recently, the pulmonary administration of anti-TB drugs has become an attractive alternative to improve TB therapy. Hence, we have developed a respirable nanocarrier based on RIF-loaded polymeric micelles (PMs), employing a commercially available graft-copolymer of poly (vinyl caprolactam)-poly (vinyl acetate)-poly (ethylene glycol) (Soluplus). The RIF apparent aqueous solubility was increased (14.3-fold) and the micellar system was ranged in the nanoscale (~107 nm). Then, according to its in vitro aerodynamic behavior, our nanoformulation represented a suitable system for deep lung drug delivery. Interestingly, these inhalable RIF-loaded PMs enhanced (up to 2.5-fold) the in vitro drug microbicidal activity in Mtb-infected THP-1 macrophages versus a RIF solution. In addition, the biodistribution studies of the radiolabelled (99mTc) PMs demonstrated their lung accumulation over 24 hs in rats. Overall, this novel nanoformulation stands as an attractive platform for a potential inhalable TB therapy.

The bioavailability of stabilized ferrous sulfate was studied by means of the prophylactic-preventive test in rats. For comparative purposes, ferrous sulfate was used as reference standard. The test was performed in male weaned rats during 3 weeks, which were randomized into three groups of ten animals each. A control group received a basal diet of low iron content while the other groups received the same diet added with iron at a dose of 15 mg/kg as FeSO4 7H2O and stabilized ferrous sulfate, respectively. Individual hemoglobin concentrations and weights were determined at the beginning and at the end of the study, and food intake was daily registered. Iron bioavailability (BioFe) of each source was calculated as the ratio between the amount of iron incorporated into hemoglobin during the treatment and the total iron intake per animal. A relative biological value was obtained as the ratio between the BioFe of stabilized ferrous sulfate and the reference standard given a value of 96%. Stabilized ferrous sulfate showed a high bioavailability, and when it is used to fortify dairy products as cheese and fluid milk in a dose of 15-20 mg of iron per kilogram, it behaved inertly in relation to the sensorial properties of the fortified food. These results suggest that this iron compound is a promising source to be use in food fortification.

The aim of the study was to determine the relative bioavailability of zinc gluconate stabilized with glycine in a Petit Suisse cheese from an infant dessert. Weight gain and bone zinc content were the nutritional responses evaluated for the diets of different zinc content: 2 ppm (basal) and 5, 10, and 30 ppm from zinc gluconate stabilized with glycine and zinc sulfate. Nonlinear regression analysis of the fitted curves for weight gain determined a relative zinc bioavailability of 100% for the YI-max ratio and 96% for Ymax/t1/2 ratio for zinc gluconate stabilized with glycine (R2=0.7996 for zinc sulfate and 0.8665 for zinc gluconate stabilized with glycine). The slope ratio analysis from linear regression of femur zinc determined a relative zinc bioavailability of 93% for zinc gluconate stabilized with glycine (RI+2=0.8693 for zinc sulfate and 0.8307 for zinc gluconate stabilized with glycine). Zinc gluconate stabilized with glycine has similar bioavailability as zinc sulfate in a Petit Suisse cheese nutritional matrix, with the advantage that the stabilized compound does not modify the sensorial characteristics of the fortified cheese.

Zinc and iron are crucial mineral components of human diet, because their deficiency leads to several disorders, including alterations of the immune function. It has been demonstrated, in both humans and rodents, that a diminished number of lymphoid cells and a loss of lymphocyte activity accompany deprivation of these essential minerals. The aim of this work was to analyze if iron and/or zinc imbalances regulate lymphocyte activity and the intracellular signals involved in the effect. Mice from the BALB/c strain were fed with iron- and/or zinc-deficient or mineral-supplemented diets, according to the American Institute of Nutrition Rodent Diets. Levels of iron and zinc were assessed in blood, liver, or bone samples. Selective mitogen stimulation of T- and B-lymphocytes were performed. We found a diminished proliferative response in T- and B-lymphocytes from zinc- and/or iron-deficient animals with respect to controls. These effects were related to decreased mitogen-induced translocation of protein kinase C (PKC) activity to cell membranes on both cell types from all animals fed with deficient diets. Our results demonstrate that iron and zinc deficiencies affect both T- and B-lymphocyte function by PKC-dependent mechanisms.

Helicobacter pylori causes a chronic gastric infection, which is usually life-long. Many epidemiological studies have shown that this is probably one of the most common bacterial infections throughout the world involving 30% of the population living in developed countries and up to 80-90% of the population in developing regions. Concomitantly, developing regions also have high prevalence of micronutrient malnutrition. In the last few years, some studies have suggested that H. pylori infection may affect the homeostasis of different micronutrients including iron, vitamin B12, folic acid, alpha-tocopherol, vitamin C and beta-carotene. In this article, we discuss the current scientific information of the effect that H. pylori infection may produce on micronutrient malnutrition.

Iron plays many roles in human physiology. In this article, we summarize the basic and current knowledge of this essential micronutrient on human metabolism.

We compared the absorption of BioZn, SFE-171, SO4Fe (reference standard) and SO4Zn (reference standard) alone or in combination in water and in an infant dessert. When mineral interactions were evaluated, zinc and iron were administered in a 1:1 molar relation. There 160 rats divided in 16 groups of 10 animals each which received: SO465Zn, Bio65Zn, SO465Zn + SO4Fe, Bio65Zn + SFE-171, SO459Fe, 59SFE-171, SO459Fe + SO4Zn and 59SFE-171 + BioZn either in water or an infant dessert. The results showed that BioZn has bioavailability similar to SO4Zn both in water (23.36 ± 3.14% vs. 21.48 ± 6.03%. respectively) and in an infant dessert (19.89 ± 3.27% vs. 18.31 ± 4.76%, respectively). When these zinc compounds were administered with iron no statistical difference of zinc absorption was found (Bio65Zn + SFE-171 in water 22.70 ± 6.30%, Bio65Zn + SFE-171 in the infant dessert 18.07 ± 5.89%, SO465Zn + SO4Fe in water 24.67 ± 5.70% and SO465Zn + SO4Fe in the infant dessert 20.56 ± 5.20%). For iron, the absorption of 59SFE-171 in water was higher (p < .01) than SO459Fe in water and 59SFE-171 + BioZn in water (32.35 ± 8.32% vs. 26.27 ± 8.83% vs. 23.69 ± 8.37%, respectively). Iron absorption from SO459Fe in water was higher (p < .01) than SO459Fe + SO4Zn in water (26.27 ± 8.83% vs. 20.21 ± 8.72%, respectively). Iron absorption in the infant dessert was higher (p < .01) for 59SFE-171 + BioZn than SO459Fe, 59SFE-171 and SO459Fe + SO4Zn (22.81 ± 6.97% vs. 16.12 ± 6.14% vs. 16.90 ± 6.23% vs. 15.04 ± 6.25%, respectively). Statistical differences (p < .01) were found between iron absorption from 59SFE-171 in water and the infant dessert (32.35 ± 8.32% vs. 16.90 ± 6.23%, respectively) and for SO459Fe (26.27 ± 8.83% vs. 16.12 ± 6.14% respectively). Zinc and iron interactions evaluated in a 1:1 molar relation of the minerals were observed only for iron absorption in water but not in infant dessert. No negative effect was found for zinc absorption neither in water nor in infant dessert.

The bioavailability of iron from a new commercial source containing ferric gluconate stabilized with glycine sold under the trade name Bioferrico™ was studied in this work by means of the prophylactic-preventive test in rats. NaFeEDTA was also studied by the same methodology for comparative purposes and ferrous sulfate was used as the reference standard. The test was conducted for 4 wk with male weaned rats, which were randomized into four groups of at least eight animals each. A control group received a basal diet of low-iron content, whereas the other groups received the same diet with iron added at a dose of 20 mg/kg as FeSO4·7H2O, NaFeEDTA, and Bioferrico, respectively. Individual hemoglobin concentrations (HbC) and weights were determined at the beginning and at the end of the study and food intake was daily registered. The iron bioavailability (BioFe) of each source was calculated as the ratio between the amount of iron incorporated into hemoglobin during the treatment (HbFe) and the total iron intake per animal (ToFeIn). A relative biological value (RBV) was obtained for each iron source under study as the ratio between the BioFe of the tested compound and that of the reference standard. The RBVs were 98% and 86% for Bioferrico and NaFeEDTA, respectively. Bioferrico showed a high bioavailability and behaved inertly in relation to the sensorial properties of the fortified food when it was added to flour. These qualities emphasize Bioferrico as a promising source for iron fortification.

[(99m)Tc]pentetate ([(99m)Tc]DTPA) is the most commonly used radiopharmaceutical renography agent. The aim of this work was to validate an alternative method for assessing [(99m)Tc]DTPA radiochemical purity (RCP), according to the ICH Q2(R1) guidance: "Validation of Analytical Procedures". The proposed method is composed of two chromatographic systems. System A is a miniaturized system of thin layer chromatography (TLC) silica gel impregnated aluminum strips as stationary phase (SP) and distilled water as mobile phase (MP). System B consists of Whatman 1 paper strips as SP and methyl ethyl ketone as MP. Results indicate that the proposed RCP method has been validated, as it is specific, precise, accurate, linear and robust. Therefore, it can be used as an alternative method for RCP quality control purposes and as stability indicator as well.

In this research, we measure the iron bioavailability of micronized ferric orthophosphate when it is used to fortify low-fat fluid milk enriched with calcium and petit suisse cheese using the prophylactic-preventive method in rats. Four groups of male weaned rats received a basal diet (control diet; 6.5 ppm Fe), a reference standard diet (SO4Fe; 18.2 ppm Fe), a basal diet using iron-fortified fluid milk as the iron source (milk diet; Fe ppm 17.9), and a basal diet using iron-fortified petit suisse cheese as the iron source (cheese diet; 18.0 ppm Fe) for 22 d. The iron bioavailability of the different sources was calculated as the ratio between the mass of iron incorporated into hemoglobin during the experiment and the total iron intake per animal. The relative biological values with regard to the reference standard (RBV%) were 61% and 69% for the milk and cheese diet, respectively. These results show that according to this method, the iron bioavailability in both fortified foods can be considered as medium bioavailability rates.

Anaemia and nutritional iron deficiency significantly affect the world population. In this article we discuss the main causes and consequences that this nutritional deficiency produces on human health.

Food fortification has been shown to be an effective strategy to overcome iron malnutrition. When a new iron compound is developed for this purpose, it must be evaluated from a nutritional and technological point of view before adding it into foods. In this way, we have evaluated ferrous gluconate stabilized by glycine as a new iron source to be used in wheat flour fortification. We performed biological studies in rats as well as sensory perceptions by human subjects in wheat flour fortified with this iron source. The productions of pentane as a rancidity indicator as well as the change of the sensorial properties of the biscuits made with stabilized ferrous gluconate-fortified wheat flour were negligible. Iron absorption in water from this iron source was similar to the reference standard ferrous sulfate. Nevertheless, because of the phytic acid content, iron absorption from fortified wheat flour decrease 40% for both iron sources. The addition of zinc from different sources did not modify iron absorption from ferrous sulfate and stabilized ferrous gluconate in water and wheat flour. The iron absorption mechanism as well as the biodistribution studies demonstrate that the biological behavior of this iron source does not differ significantly from the reference standard. These results demonstrate that the iron source under study has adequate properties to be used in wheat flour fortification. Nevertheless, more research is needed before considering this iron source for its massive use in food fortification.

Fortification of a Petit Suisse cheese with zinc sulfate and zinc gluconate stabilized with glycine was used as a tool to overcome zinc-deficiency effects on total-body growth and skeletal growth. Animals were divided in 4 groups of 10 rats: basal (B), control (C), depletion-repletion 1 (DR1), and depletion-repletion 2 (DR2). These four groups were fed with four diets: basal (2 ppm Zn), control (30 ppm Zn), DR1, and DR2; they received a basal diet for 14 d and a control diet for the other 14 d of the experiment, using zinc sulfate for DR1 and zinc gluconate stabilized with glycine for DR2. After 28 d of the experiment, total-body weight and weight gain of the control and DR1 and DR2 animals were not statistically different (p

Iron is an essential micronutrient involved in multiple biochemical and physiological process. In this review we discuss the most relevant aspect of its metabolism in order to reach a better comprehension of the relevant roll that this micronutrient plays in human health.