Ferric citrate-induced colonic mucosal damage associated with oxidative stress, inflammation responses, apoptosis, and the changes of gut microbial composition.

Ferric citrate (FC) has been used as an iron fortifier and nutritional supplement, which is reported to induce colitis in rats, however the underlying mechanism remains to be elucidated. We performed a 16-week study of FC in male healthy C57BL/6 mice (nine-month-old) with oral administration of Ctr (0.9 % NaCl), 1.25 % FC (71 mg/kg/bw), 2.5 % FC (143 mg/kg/bw) and 5 % FC (286 mg/kg/bw). FC-exposure resulted in colon iron accumulation, histological alteration and reduce antioxidant enzyme activities, such as glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC), together with enhanced lipid peroxidation level, including malondialdehyde (MDA) level and 4-Hydroxynonenal (4-HNE) protein expression. Exposure to FC was associated with upregulated levels of the interleukin (IL)- 6, IL-1ß, IL-18, IL-8 and tumor necrosis factor α (TNF-α), while down-regulated levels of IL-4 and IL-10. Exposure to FC was positively associated with the mRNA and protein expressions of cysteine-aspartic proteases (Caspase)- 9, Caspase-3, Bcl-2-associated X protein (Bax), while negatively associated with B-cell lymphoma 2 (Bcl2) in mitochondrial apoptosis signaling pathway. FC-exposure changed the diversity and composition of gut microbes. Additionally, the serum lipopolysaccharide (LPS) contents increased in FC-exposed groups when compared with the control group, while the expression of colonic tight junction proteins (TJPs), such as Claudin-1 and Occludin were decreased. These findings indicate that the colonic mucosal injury induced by FC-exposure are associated with oxidative stress generation, inflammation response and cell apoptosis, as well as the changes in gut microbes diversity and composition.

Stabilized ferrous gluconate as iron source for food fortification: bioavailability and toxicity studies in rats.

The iron bioavailability and acute oral toxicity in rats of a ferrous gluconate compound stabilized with glycine (SFG), designed for food fortification, was studied in this work by means of the prophylactic method and the Wilcoxon method, respectively. For the former studies, SFG was homogeneously added to a basal diet of low iron content, reaching a final iron concentration of 20.1 +/- 2.4 mg Fe/kg diet. A reference standard diet using ferrous sulfate as an iron-fortifying source (19.0 +/- 2.1 mg Fe/kg diet) and a control diet without iron additions (9.3 +/- 1.4 mg Fe/kg diet) were prepared in the laboratory in a similar way. These diets were administered to three different groups of weaning rats during 23 d as the only type of solid nourishment. The iron bioavailability of SFG was calculated as the relationship between the mass of iron incorporated into hemoglobin during the treatment and the total iron intake per animal. This parameter resulted in 36.6 +/- 6.2% for SFG, whereas a value of 35.4 +/- 8.0% was obtained for ferrous sulfate. The acute toxicological studies were performed in two groups of 70 female and 70 male Sprague-Dawley rats that were administered increasing doses of iron from SFG. The LD50 values of 1775 and 1831 mg SFG/kg body wt were obtained for female and male rats, respectively, evidencing that SFG can be considered as a safe compound from a toxicological point of view.

Estimating the potential for vitamin A toxicity in women and young children.

This paper describes usual intakes of vitamin A from diet plus low dose supplements, reviews methods for assessing vitamin A toxicity and applies a kinetic analysis of vitamin A turnover to estimate the effect of high dose supplements on vitamin A liver stores in infants and young children. In the United States, the 95th percentile of intake by preschoolers from foods and supplements exceeds the tolerable upper level (UL) but is below the no-observed-adverse-effect level (NOAEL). The 95th percentile of vitamin A intake from foods and supplements for nonpregnant, nonlactating women aged 19-30 y also exceeds the UL but is below the NOAEL for women of reproductive age. In low income populations in developing countries, vitamin A intakes of preschoolers and women consuming foods plus low dose supplements can also exceed the UL but are unlikely to exceed the NOAEL. There are few data on which to establish thresholds for excessive vitamin A intake or vitamin A concentrations in tissues. To assess the potential toxicity of the new recommendations (see article by Ross in this issue) for high dose vitamin A supplements for infants and children, we used a kinetic approach to estimate accumulation of the vitamin in liver. The new recommendations are unlikely to result in toxic levels (>300 microg per gram of liver) even if high dose supplements are inadvertently given monthly. The kinetic analysis also illustrates that a constant supply of vitamin A from breast milk (and/or complementary foods) is vital for preventing depletion of liver vitamin A stores between high dose supplements.

[The effect of fermented hydrolyzed whey enriched with lactates on the morphological structure of the internal organs in laboratory animals]. / Vliianie fermentativno-gidrolizovannoi molochnoi syvorotki, obogashchennoi laktatami, na morfologicheskuiu strukturu vnutrennikh organov laboratornykh zhivotnykh.

Results of pathomorphological investigation of rat organs fed during 1 and 3 months the diet containing 8% of protein as milk whey protein partly hydrolysed by enzymes and enriched by lactates (SGOL-1) are presented. The conducted investigation have not revealed of pathological effect of a product SGOL-1 on morphological structures of investigated internal bodies and tissues of the laboratory animals. A increase of body mass of animals and contents of RNAS in cells of practically all bodies and tissues of the animals were also marked.

Desarrollo y evaluación de un panqué enriquecido con harina de algodón / Development and evaluation of an enriched cake with cottonsedd meal

En Venezuela, los problemas nutricionales, específicamente la desnutrición caloricoproteica, se ha acentuado en los últimos años. Una posible solución lo constituye el enriquecimiento de alimentos con fuentes de proteínas, como las que contiene el residuo o torta de la extracción del aceite de las semillas de algodón. En este trabajo se caracterizaron las harinas de algodón obtenidas industrialmente y se utilizó hasta en un 15 por ciento en un panqué enriquecido, susceptible a ser utilizado en la merienda escolar. Se seleccionó el panqué de vainilla con 45 por ciento de harina de algodón debido a que la aceptabilidad a nivel de laboratorio fue de 97 por ciento. Se probó en una escuela con 1.009 niños de distintas edades, la aceptabilidad fue de 97 por ciento. Se concluyó que este producto, que suministra 395 Kcal y 13 g de proteínapor cada 100 g, podría ser utilizado para mejorar el aporte calóricoproteico de la merienda escolar

Influence of dietary iron overload on cell proliferation and intestinal tumorigenesis in mice.

Iron-enriched diets caused an increase of tumor rate in two models of dimethylhydrazine(DMH)-induced colon tumorigenesis in mice. The effect was independent of the time the iron-diet was fed, i.e. during DMH-treatment or following the DMH-treatment period. The increase of tumor rate depended on the iron concentration in the diet (0.5-3.5%). The concentration-dependent iron accumulation in the colonic mucosa of mice was paralleled by increments of malonaldehyde contents indicating lipid peroxidation, another factor known to be involved in tumor development. It is suggested that iron exerts cocarcinogenic activity in the DMH-model by stimulating cell proliferation and inducing oxidative stress in the colonic mucosa. This effect of iron is independent of the time of tumor-initiation by DMH, as it is also observed in the period of tumor-promotion/progression after DMH-treatment.

Enzyme histochemical and immunohistochemical characterization of oval and parenchymal cells proliferating in livers of rats fed a choline-deficient/DL-ethionine-supplemented diet.

Male outbred Sprague-Dawley rats were fed a choline-deficient diet containing 0.10% DL-ethionine for up to 30 weeks. Liver slices from rats killed 4, 6, 10, 14, 22 and 30 weeks after starting the treatment were histochemically analyzed for the following parameters: basophilia, expression of cytokeratin 19 (which in the liver is bile duct epithelial cell-specific), glycogen content and activities of glycogen synthetase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6PASE), glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glycerin-3-phosphate dehydrogenase (G3PDH), 'malic enzyme' (MDH), alkaline phosphatase (ALKPASE) and gamma-glutamyltranspeptidase (GGT). The diet induced necrosis of single parenchymal cells and a massive proliferation of oval cells within 4-6 weeks; thereafter cholangiofibroses, cystic cholangiomas and some cholangiofibromas, but no cholangiocarcinomas, were observed. Oval cells, cholangiofibroses, cystic cholangiomas and cholangiofibromas expressed cytokeratin 19, whereas parenchymal cells, foci of altered hepatocytes and hepatocellular adenomas did not; this observation does not support a precursor-product relationship between oval and parenchymal cells. SYN, PHO, G6PASE, G6PDH, GAPDH, G3PDH, MDH, ALKPASE and GGT activities were detected in oval cells; cholangiofibrotic lesions, cystic cholangiomas and cholangiofibromas stained strongly for GAPDH, G3PDH and MDH. In livers from rats fed the diet for 10 weeks, single hepatocytes storing high amounts of glycogen appeared in the parenchyma. There was no indication of a transition from the oval cell population to hepatocytes storing glycogen in excess. Foci of glycogen-storing cells were scattered all over the lobes after 14 and 22 weeks; they had increased G6PASE, G6PDH, ALKPASE and GGT activities. Mixed cell foci and hepatocellular adenomas developed within 22-30 weeks and exhibited a remarkable decrease of G6PASE activity, a strong increase of G6PDH, GAPDH, G3PDH and MDH activities as well as extremely high ALKPASE and GGT activities. The data support the concept that during hepatocarcinogenesis, a number of sequential changes in the activities of various enzymes involved in carbohydrate metabolism occur and that a correlation between morphology and enzyme pattern in the focal lesions does in fact exist. Furthermore, our results suggest that two different cell lineages are involved in the development of cholangiocellular tumors from oval cells and hepatocellular tumors from hepatocytes.

Iron, infection, and neoplasia.

In nearly all forms of life, the number and diversity of enzymes that contain iron or that depend on the presence of this metal for activity are impressive. Not surprisingly, chemical mechanisms have been evolved by many organisms that permit them to solubilize and acquire iron while at the same time depriving their competitors or their pathogens of this element. Proteins such as transferrin and lactoferrin that are employed by vertebrate hosts for iron transport and acquisition can, to some extent, withhold the metal from the siderophores of invading bacteria and fungi. Attempts also are made by animal hosts to withhold iron from protozoa and neoplastic cells. Unfortunately, pathogenic microorganisms have developed a variety of counter measures that are especially dangerous in hosts stressed by iron overload in specific fluids, tissues, or cells. In recent years, however, a number of possible methods and agents for strengthening iron-withholding defense have become apparent. Nearly 3,000 papers on various aspects of iron withholding are contained in the 18-year Medline Database and numerous reviews have been published since 1966. The present paper will focus on developments that have been reported within the past 2 1/2 years.

[Hygienic evaluation of the meat of pigs given a feed concentrate prepared from overflow active sludge]. / K voprosu gigienicheskoi otsenki miasa svinei, poluchavshikh v sostave ratsiona kormovoi kontsentrat iz izbytochnogo aktivnogo ila.

The authors studied the chemical composition of the meat of pigs given the diet containing a feed concentrate obtained from excess active sludge and the effects on the laboratory animals of such meat fed for a year. As compared to the accepted standards, the meat of pigs given the feed concentrate showed high cadmium content in the kidneys and high lead content in the liver and muscles. Starting from the 6th month of being kept on the meat of experimental pigs, the rats demonstrated an appreciable increase in the count of peripheral blood reticulocytes which remained almost unchanged to the end of experiments. The data obtained indicate that excess trace elements including heavy metals contained by active sludge from the purification works of the city of Kiev interfere with its use on a large scale as a feed additive.