Iron supplementation in suckling piglets : an ostensibly easy therapy of neonatal iron deficiency anemia

In pigs, iron deficiency anemia (IDA) is the most prevalent deficiency disorder during the early postnatal period, frequently developing into a serious illness. On the other hand, in humans, only low-birth-weight infants, including premature infants, are especially susceptible to developing IDA. In both human and pig neonates, the initial cause of IDA is low birth iron stores. In piglets this shortage of stored iron results mainly from genetic selection over the past few decades for large litter sizes and high birth weights. As a consequence, pregnant sows cannot provide a sufficient amount of iron to the increasing number of developing fetuses. Supplementation with iron is a common practice for the treatment of IDA in piglets. For decades, the preferred procedure for delivering iron supplements during early life stages has been through the intramuscular injection of a large amount of iron dextran. However, this relatively simple therapy, which in general, efficiently corrects IDA, may generate toxic effects, and by inducing hepcidin expression, may decrease bioavailability of supplemental iron. New iron supplements are considered herein with the aim to combine the improvement of hematological status, blunting of hepcidin expression, and minimizing the toxicity of the administered iron. We propose that iron-deficient piglets constitute a convenient animal model for performing pre-clinical studies with iron supplements

Mottled mice and non-mammalian models of Menkes disease

Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterised by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a Copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the CNS across the blood-brain-barrier and blood–cerebrospinal fluid- barrier. Cu is essential for synaptogenesis and axonal development. In cells, ATP7A participates in the incorporation of copper into Cu-dependent enzymes during the course of its maturation in the secretory pathway. There is a high degree of homology (>80% ) between the human ATP7A and murine Atp7a genes. Mice with mutations in the Atp7a gene, called mottled mutants, are well-established and excellent models of Menkes disease. Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals

Mice Overexpressing Both Non-Mutated Human SOD1 and Mutated SOD1G93A Genes: A Competent Experimental Model for Studying Iron Metabolism in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by degeneration and loss of motor neurons in the spinal cord, brainstem and motor cortex. Up to 10% of ALS cases are inherited (familial, fALS) and associated with mutations, frequently in the superoxide dismutase 1 (SOD1) gene. Rodent transgenic models of ALS are often used to elucidate a complex pathogenesis of this disease. Of importance, both ALS patients and animals carrying mutated human SOD1 gene show symptoms of oxidative stress and iron metabolism misregulation. The aim of our study was to characterize changes in iron metabolism in one of the most commonly used models of ALS – transgenic mice overexpressing human mutated SOD1G93A gene. We analyzed the expression of iron-related genes in asymptomatic, 2-month old and symptomatic, 4-month old SOD1G93A mice. In parallel, respective age-matched mice overexpressing human non-mutated SOD1 transgene and control mice were analyzed. We demonstrate that the overexpression of both SOD1 and SOD1G93A genes account for a substantial increase in SOD1 protein levels and activity in selected tissues and that not all the changes in iron metabolism genes expression are specific for the overexpression of the mutated form of SOD1

Exacerbation of neonatal hemolysis and impaired renal iron handling in heme oxygenase 1-deficient mice

In most mammals, neonatal intravascular hemolysis is a benign and moderate disorder that usually does not lead to anemia. During the neonatal period, kidneys play a key role in detoxification and recirculation of iron species released from red blood cells (RBC) and filtered out by glomeruli to the primary urine. Activity of heme oxygenase 1 (HO1), a heme-degrading enzyme localized in epithelial cells of proximal tubules, seems to be of critical importance for both processes. We show that, in HO1 knockout mouse newborns, hemolysis was prolonged despite a transient state and exacerbated, which led to temporal deterioration of RBC status. In neonates lacking HO1, functioning of renal molecular machinery responsible for iron reabsorption from the primary urine (megalin/cubilin complex) and its transfer to the blood (ferroportin) was either shifted in time or impaired, respectively. Those abnormalities resulted in iron loss from the body (excreted in urine) and in iron retention in the renal epithelium. We postulate that, as a consequence of these abnormalities, a tight systemic iron balance of HO1 knockout neonates may be temporarily affected

Decreased expression of the Slc31a1 gene and cytoplasmic relocalization of membrane CTR1 protein in renal epithelial cells : a potent protective mechanism against copper nephrotoxicity in a mouse model of Menkes disease

Kidneys play an especial role in copper redistribution in the organism. The epithelial cells of proximal tubules perform the functions of both copper uptake from the primary urine and release to the blood. These cells are equipped on their apical and basal membrane with copper transporters CTR1 and ATP7A. Mosaic mutant mice displaying a functional dysfunction of ATP7A are an established model of Menkes disease. These mice exhibit systemic copper deficiency despite renal copper overload, enhanced by copper therapy, which is indispensable for their life span extension. The aim of this study was to analyze the expression of Slc31a1 and Slc31a2 genes (encoding CTR1/CTR2 proteins) and the cellular localization of the CTR1 protein in suckling, young and adult mosaic mutants. Our results indicate that in the kidney of both intact and copper-injected 14-day-old mutants showing high renal copper content, CTR1 mRNA level is not up-regulated compared to wild-type mice given a copper injection. The expression of the Slc31a1 gene in 45-day-old mice is even reduced compared with intact wild-type animals. In suckling and young copper-injected mutants, the CTR1 protein is relocalized from the apical membrane to the cytoplasm of epithelial cells of proximal tubules, the process which prevents copper transport from the primary urine and, thus, protects cells against copper toxicity

Urinary hepcidin levels in iron-deficient and iron-supplemented piglets correlate with hepcidin hepatic mRNA and serum levels and with body iron status

Among livestock, domestic pig (Sus scrofa) is a species, in which iron metabolism has been most intensively examined during last decade. The obvious reason for studying the regulation of iron homeostasis especially in young pigs is neonatal iron deficiency anemia commonly occurring in these animals. Moreover, supplementation of essentially all commercially reared piglets with iron entails a need for monitoring the efficacy of this routine practice followed in the swine industry for several decades. Since the discovery of hepcidin many studies confirmed its role as key regulator of iron metabolism and pointed out the assessment of its concentrations in biological fluids as diagnostic tool for iron-related disorder. Here we demonstrate that urine hepcidin-25 levels measured by a combination of weak cation exchange chromatography and time-of-flight mass spectrometry (WCX-TOF MS) are highly correlated with mRNA hepcidin expression in the liver and plasma hepcidin-25 concentrations in anemic and iron-supplemented 28-day old piglets. We also found a high correlation between urine hepcidin level and hepatic non-heme iron content. Our results show that similarly to previously described transgenic mouse models of iron disorders, young pigs constitute a convenient animal model to explore accuracy and relationship between indicators for assessing systemic iron status

Iron Supplementation of Pregnant Sows to Prevent Iron Deficiency Anemia in Piglets: A Procedure of Questionable Effectiveness

In pigs, iron deficiency anemia (IDA) is a common disorder that occurs during the early postnatal period, leading to the stunted growth and increased mortality of piglets. The main cause of IDA is low iron stores in the liver of newborn piglets; these stores constitute the main source of iron needed to satisfy the erythropoietic requirements of the piglets in their first weeks of life. Insufficient iron stores in piglets are usually due to the inadequate placental iron transfer from the sow to the fetuses. Therefore, iron supplementation in pregnant sows has been implemented to enhance placental iron transfer and increase iron accumulation in the liver of the fetuses. Over the years, several oral and parenteral approaches have been attempted to supplement sows with various iron preparations, and consequently, to improve piglets’ red blood cell indices. However, there is debate with regard to the effectiveness of iron supplementation in pregnant sows for preventing IDA in newborn piglets. Importantly, this procedure should be carried out with caution to avoid iron over-supplementation, which can lead to iron toxicity. This article aims to critically review and evaluate the use of iron supplementation in pregnant sows as a procedure for preventing IDA in piglets

Alcohol and iron metabolism

Spożywanie alkoholu wiąże się z zaburzeniem metabolizmu żelaza. U pacjentów z alkoholową chorobą wątroby stwierdza się często zwiększoną zawartość żelaza w wątrobie, będącą skutkiem zwiększonej absorpcji żelaza w dwunastnicy. W ostatnich 12 latach dokonał się ogromny postęp w poznaniu molekularnych podstaw homeostazy żelaza u ssaków. Odkrycie hepcydyny, peptydu syntetyzowanego w wątrobie oraz jej roli w regulacji uwalniania żelaza z enterocytów absorpcyjnych i z makrofagów miało szczególnie duże znaczenie w poznaniu szlaków cyrkulacji żelaza w organizmie. Wiązanie się hepcydyny z występującą na błonie enterocytów ferroportyną, jedynym jak dotąd poznanym u ssaków eksporterem żelaza, powoduje przemieszczenie jej do wnętrza enterocytów a następnie degradację w lizosomach, co prowadzi do zahamowania absorpcji żelaza z diety. Molekularny mechanizm leżący u podłoża nadmiernej akumulacji żelaza w organizmie wywołanej przez spożywanie alkoholu polega na zahamowaniu ekspresji hepcydyny, co w konsekwencji prowadzi do zwiększenia transportu żelaza z enterocytów do krwioobiegu. Stres oksydacyjny wywołany przez alkohol ulega zaostrzeniu przez nadmierną akumulację żelaza wątrobie i jest przyczyną uszkodzenie wątroby u pacjentów z alkoholową chorobą wątroby.Consumption of alcohol is known to be associated with misregulation of iron metabolism. Patients with alcoholic liver disease frequently exhibit increased hepatic iron content, which is caused by the increased iron absorption in duodenum. Within the past 12 years an enormous progress has been made in understanding molecular basis of mammalian iron homeostasis. In particular, the discovery of liver-derived peptide, hepcidin, and its role in the concerted regulation of iron release from absorptive enterocytes and macrophages through interaction with ferroportin, the sole cellular iron exporter known in mammalian cells, has proved to be fundamental in the understanding of iron circulation in the body. The binding of hepcidin to ferroportin expressed at the surface of enterocytes induces its internalization and degradation, which in turn inhibits iron absorption from the diet. The molecular mechanisms underlying alcohol-induced iron accumulation in the body involves suppression of hepcidin expression in hepatocytes, which in consequence leads to increased duodenal iron transport. Exacerbation of alcohol-induced oxidative stress in the liver by iron overload is responsible for liver injury observed in the alcoholic liver disease

Effect of Omega-3 Fatty Acids on Telomeres—Are They the Elixir of Youth?

Telomeres are complexes consisting of tandem repeat DNA combined with associated proteins that play a key role in protecting the ends of chromosomes and maintaining genome stability. They are considered a biological clock, as they shorten in parallel with aging. Furthermore, short telomeres are associated with several age-related diseases. However, the variability in telomere shortening independent of chronological age suggests that it is a modifiable factor. In fact, it is regulated inter alia by genetic damage, cell division, aging, oxidative stress, and inflammation. A key question remains: how can we prevent accelerated telomere attrition and subsequent premature replicative senescence? A number of studies have explored the possible impact of omega-3 fatty acids on telomere shortening. This review summarizes published cross-sectional studies, randomized controlled trials, and rodent studies investigating the role of omega-3 fatty acids in telomere biology. It also covers a broad overview of the mechanism, currently favored in the field, that explains the impact of omega-3 fatty acids on telomeres—the food compound’s ability to modulate oxidative stress and inflammation. Although the results of the studies performed to date are not consistent, the vast majority indicate a beneficial effect of omega-3 fatty acids on telomere length