Impact of litter size on the hematological and iron status of gilts, sows and newborn piglets: a comparative study of domestic pigs and wild boars.

BACKGROUND: The critically low hepatic iron stores of newborn piglets are considered to be a major cause of neonatal iron deficiency in modern breeds of domestic pig (Sus domestica). The main factor believed to contribute to this phenomenon is large litter size, which has been an objective of selective breeding of pigs for decades. As consequence, iron transferred from the pregnant sow has to be distributed among a greater number of fetuses. RESULTS: Here, we investigated whether litter size influences red blood cell (RBC) indices and iron parameters in Polish Large White (PLW) piglets and gilts. Small and large litters were produced by the transfer of different numbers of embryos, derived from the same superovulated donor females, to recipient gilts. Piglets from large litters obtained following routine artificial insemination were also examined. Our results clearly demonstrated that varying the number of piglets in a litter did not affect the RBC and iron status of 1-day-old piglets, with all showing iron deficiency anemia. In contrast, gilts with small litters displayed higher RBC and iron parameters compared to mothers with large litters. A comparative analysis of the RBC status of wild boars (having less than half as many piglets per litter as domestic pigs) and PLW pigs, demonstrated higher RBC count, hemoglobin level and hematocrit value of both wild boar sows and piglets, even compared to small-litter PLW animals. CONCLUSIONS: These findings provide evidence that RBC and iron status in newborn PLW piglets are not primarily determined by litter size, and indicate the need to study the efficiency of iron transport across the placenta in domestic pig and wild boar females.

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.

Marginally reduced maternal hepatic and splenic ferroportin under severe nutritional iron deficiency in pregnancy maintains systemic iron supply.

The demand for iron is high in pregnancy to meet the increased requirements for erythropoiesis. Even pregnant females with initially iron-replete stores develop iron-deficiency anemia, due to inadequate iron absorption. In anemic females, the maternal iron supply is dedicated to maintaining iron metabolism in the fetus and placenta. Here, using a mouse model of iron deficiency in pregnancy, we show that iron recycled from senescent erythrocytes becomes a predominant source of this microelement that can be transferred to the placenta in females with depleted iron stores. Ferroportin is a key protein in the molecular machinery of cellular iron egress. We demonstrate that under iron deficiency in pregnancy, levels of ferroportin are greatly reduced in the duodenum, placenta and fetal liver, but not in maternal liver macrophages and in the spleen. Although low expression of both maternal and fetal hepcidin predicted ferroportin up-regulation in examined locations, its final expression level was very likely correlated with tissue iron status. Our results argue that iron released into the circulation of anemic females is taken up by the placenta, as evidenced by high expression of iron importers on syncytiotrophoblasts. Then, a substantial decrease in levels of ferroportin on the basolateral side of syncytiotrophoblasts, may be responsible for the reduced transfer of iron to the fetus. As attested by the lowest decrease in iron content among analyzed tissues, some part is retained in the placenta. These findings confirm the key role played by ferroportin in tuning iron turnover in iron-deficient pregnant mouse females and their fetuses.

Molecular Regulation of Copper Homeostasis in the Male Gonad during the Process of Spermatogenesis.

Owing to its redox properties, copper is a cofactor of enzymes that catalyze reactions in fundamental metabolic processes. However, copper-oxygen interaction, which is a source of toxic oxygen radicals generated by the Fenton reaction, makes copper a doubled-edged-sword in an oxygen environment. Among the microelements influencing male fertility, copper plays a special role because both copper deficiency and overload in the gonads worsen spermatozoa quality and disturb reproductive function in mammals. Male gametes are produced during spermatogenesis, a multi-step process that consumes large amounts of oxygen. Germ cells containing a high amount of unsaturated fatty acids in their membranes are particularly vulnerable to excess copper-mediated oxidative stress. In addition, an appropriate copper level is necessary to initiate meiosis in premeiotic germ cells. The balance between essential and toxic copper concentrations in germ cells at different stages of spermatogenesis and in Sertoli cells that support their development is handled by a network of copper importers, chaperones, recipient proteins, and exporters. Here, we describe coordinated regulation/functioning of copper-binding proteins expressed in germ and Sertoli cells with special emphasis on copper transporters, copper transporting ATPases, and SOD1, a copper-dependent antioxidant enzyme. These and other proteins assure copper bioavailability in germ cells and protection against copper toxicity.

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.

Copper therapy reduces intravascular hemolysis and derepresses ferroportin in mice with mosaic mutation (Atp7amo-ms): An implication for copper-mediated regulation of the Slc40a1 gene expression.

Mosaic mutant mice displaying functional dysfunction of Atp7a copper transporter (the Menkes ATPase) are an established animal model of Menkes disease and constitute a convenient tool for investigating connections between copper and iron metabolisms. This model allows to explore changes in iron metabolism in suckling mutant mice suffering from systemic copper deficiency as well as in young and adult ones undergone copper therapy, which reduces lethal effect of the Atp7a gene mutation. Our recent study demonstrated that 14-day-old mosaic mutant males display blood cell abnormalities associated with intravascular hemolysis, and show disturbances in the functioning of the hepcidin-ferroportin regulatory axis, which controls systemic iron homeostasis. We thus aimed to check whether copper supplementation recovers mutants from hemolytic insult and rebalance systemic iron regulation. Copper supplementation of 14-day-old mosaic mutants resulted in the reestablishment of hematological status, attenuation of hepicidin and concomitant induction of the iron exporter ferroportin/Slc40a1 expression in the liver, down-regulated in untreated mutants. Interestingly, treatment of wild-type males with copper, induced hepcidin-independent up-regulation of ferroportin protein level in hepatic macrophages in both young and adult (6-month-old) animals. Stimulatory effect of copper on ferroportin mRNA and protein levels was confirmed in bone marrow-derived macrophages isolated from both wild-type and mosaic mutant males. Our study indicates that copper is an important player in the regulation of the Slc40a1 gene expression.

Role of copper in the process of spermatogenesis.

Copper (Cu) is an essential trace element required for the normal development of living organisms. Due to its redox potential, copper is a cofactor in many enzymes responsible for important processes in cells. Copper deficiency has a significant influence on the reduction or the total eradication of copper-dependent enzymes in the body, thereby inhibiting cell life processes. On the other hand, copper is a very reactive element and in its free state, it can trigger the production of large amounts of free radicals, which will consequently lead to the damage of proteins and DNA. Because of those reasons, living organisms have developed precise mechanisms regulating the concentration of copper in cells. Copper also plays a very important role in male fertility. It is an essential element for the production of male gametes. The significant role of copper is also described in the processes of cell division - mitotic and meiotic. Copper-dependent enzymes such as ceruloplasmin, superoxide dismutase SOD1 and SOD3, group of metallothionein and cytochrome c oxidase are present at all stages of gametogenesis as well as in the somatic cells of the testis and in the somatic cells of epididymis. Substantial amounts of copper can also be found in liquids associated with sperm in the epididymis and prostate. Copper also affects the integral androgen distribution in terms of fertility on the line hypothalamic-pituitary-testis. Both copper increase and deficiency leads to a significant reduction in male fertility, which spans the entire spectrum of abnormalities at the sperm level, male gonad, production of hormones and distribution of micronutrients such as zinc and iron. Nowadays, the effects of copper on gametes production have become more important and are connected with the increasing levels of pollution with heavy metals in environment.

Transcriptional regulation of copper metabolism genes in the liver of fetal and neonatal control and iron-deficient rats.

Copper and iron metabolism have been known to interact for many years. We have previously shown, during pregnancy, that copper levels in the maternal liver rise as a consequence of iron deficiency, but that levels in the fetal liver decrease. In this paper, we measure expression of genes involved in copper metabolism in fetal and postnatal liver, to test whether alterations can explain this observation. Additionally, we study the extent to which gene expression changes in the latter stages of pregnancy and in the perinatal period. Ctr1 expression levels dropped to term, rising again thereafter. There was no difference in gene expression between control and iron deficient animals. Atox1 expression remained approximately stable until term, and then there was a rise to a maximum at about Day 8. Atp7a expression levels remained constant, except for a brief drop at term. Atp7b levels, in contrast, decreased from a maximum early in gestation to low levels in the term and post-natal livers. Ceruloplasmin expression appeared to be diametrically opposite to Atp7b. The other two metallochaperones showed the same pattern of expression as Atox1, with a decrease to term, a rise at Day 1, or a rise after birth followed by a brief decrease at about Day 3. None of the genes were significantly affected by iron deficiency, suggesting that changes in expression cannot explain the altered copper levels in the fetal and neonatal liver.

Ferroportin expression in haem oxygenase 1-deficient mice.

HO1 (haem oxygenase 1) and Fpn (ferroportin) are key proteins for iron recycling from senescent red blood cells and therefore play a major role in controlling the bioavailability of iron for erythropoiesis. Although important aspects of iron metabolism in HO1-deficient (Hmox1-/-) mice have already been revealed, little is known about the regulation of Fpn expression and its role in HO1 deficiency. In the present study, we characterize the cellular and systemic factors influencing Fpn expression in Hmox1-/- bone marrow-derived macrophages and in the liver and kidney of Hmox1-/- mice. In Hmox1-/- macrophages, Fpn protein was relatively highly expressed under high levels of hepcidin in culture medium. Similarly, despite high hepatic hepcidin expression, Fpn is still detected in Kupffer cells and is also markedly enhanced at the basolateral membrane of the renal tubules of Hmox1-/- mice. Through the activity of highly expressed Fpn, epithelial cells of the renal tubules probably take over the function of impaired system of tissue macrophages in recycling iron accumulated in the kidney. Moreover, although we have found increased expression of FLVCR (feline leukaemia virus subgroup C receptor), a haem exporter, in the kidneys of Hmox1-/- mice, haem level was increased in these organs. Furthermore, we show that iron/haem-mediated toxicity are responsible for renal injury documented in the kidneys of Hmox1-/- mice.

Increased prostaglandin E2-EP2 signalling in cumulus cells of female mice sired by males with the Y-chromosome long-arm deletion.

Cumuli oophori surrounding ovulated oocytes of B10.BR(Y(del)) females (sired by males with the Y-chromosome long-arm deletion) are more resistant to hyaluronidase digestion than cumuli oophori around eggs of genetically identical females but sired by males with the intact Y chromosome (B10.BR). This has been interpreted as a result of differences in paternal genome imprinting, which females of both groups inherit from their fathers. The following study shows that it is not hyaluronan, but rather excessive protein concentration, that makes the cumulus extracellular matrix of B10.BR(Y(del)) oocytes more resistant to enzymatic treatment. It was revealed, additionally, that cumulus cells around ovulating oocytes of B10.BR(Y(del)) females display higher surface accumulation of prostaglandin EP2 subtype receptors and higher expression of the Ptgs2 gene (encoding a rate-limiting enzyme of prostaglandin E2 synthesis) in relation to the cells of control B10.BR females. The expression levels of the prostaglandin-dependent Tnfaip6 and Ccl2 genes were also altered in B10.BR(Y(del)) cumulus cells in a manner indicating increased prostaglandin signalling. The study provides further evidence for the divergence in reproductive phenotypes between B10.BR and B10.BR(Y(del)) female mice. It supports the hypothesis that genes of the Y-chromosome long arm may be involved in establishment of epigenetic marks in X-bearing spermatozoa.

Co-administration of angiotensin II and simvastatin triggers kidney injury upon heme oxygenase-1 deficiency.

Kidneys are pivotal organ in iron redistribution and can be severely damaged in the course of hemolysis. In our previous studies, we observed that induction of hypertension with angiotensin II (Ang II) combined with simvastatin administration results in a high mortality rate or the appearance of signs of kidney failure in heme oxygenase-1 knockout (HO-1 KO) mice. Here, we aimed to address the mechanisms underlying this effect, focusing on heme and iron metabolism. We show that HO-1 deficiency leads to iron accumulation in the renal cortex. Higher mortality of Ang II and simvastatin-treated HO-1 KO mice coincides with increased iron accumulation and the upregulation of mucin-1 in the proximal convoluted tubules. In vitro studies showed that mucin-1 hampers heme- and iron-related oxidative stress through the sialic acid residues. In parallel, knock-down of HO-1 induces the glutathione pathway in an NRF2-depedent manner, which likely protects against heme-induced toxicity. To sum up, we showed that heme degradation during heme overload is not solely dependent on HO-1 enzymatic activity, but can be modulated by the glutathione pathway. We also identified mucin-1 as a novel redox regulator. The results suggest that hypertensive patients with less active HMOX1 alleles may be at higher risk of kidney injury after statin treatment.

Suramin Affects the Renal VEGF-A/VEGFR Axis in Short-Term Streptozotocin-Induced Diabetes.

Diabetic nephropathy (DN) accounts for approximately 50% of end-stage renal diseases. Vascular endothelial growth factor A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in DN, but its role is unclear. The lack of pharmacological tools to modify renal concentrations further hinders the understanding of its role in DN. In this study, rats were evaluated after 3 weeks of streptozotocin-induced diabetes and two suramin treatments (10 mg/kg, ip). Vascular endothelial growth factor A expression was evaluated by western blot of glomeruli and immunofluorescence of the renal cortex. RT-PCR for receptors Vegfr1 mRNA and Vegfr2 mRNA quantitation was performed. The soluble adhesive molecules (sICAM-1, sVCAM-1) in blood were measured by ELISA and the vasoreactivity of interlobar arteries to acetylcholine was evaluated using wire myography. Suramin administration reduced the expression and intraglomerular localisation of VEGF-A. Increased VEGFR-2 expression in diabetes was reduced by suramin to non-diabetic levels. Diabetes reduced the sVCAM-1 concentrations. Suramin in diabetes restored acetylcholine relaxation properties to non-diabetic levels. In conclusion, suramin affects the renal VEGF-A/VEGF receptors axis and has a beneficial impact on endothelium-dependent relaxation of renal arteries. Thus, suramin may be used as a pharmacological agent to investigate the potential role of VEGF-A in the pathogenesis of renal vascular complications in short-term diabetes.

Impaired iron recycling from erythrocytes is an early hallmark of aging.

Aging affects iron homeostasis, as evidenced by tissue iron loading and anemia in the elderly. Iron needs in mammals are met primarily by iron recycling from senescent red blood cells (RBCs), a task chiefly accomplished by splenic red pulp macrophages (RPMs) via erythrophagocytosis. Given that RPMs continuously process iron, their cellular functions might be susceptible to age-dependent decline, a possibility that has been unexplored to date. Here, we found that 10- to 11-month-old female mice exhibit iron loading in RPMs, largely attributable to a drop in iron exporter ferroportin, which diminishes their erythrophagocytosis capacity and lysosomal activity. Furthermore, we identified a loss of RPMs during aging, underlain by the combination of proteotoxic stress and iron-dependent cell death resembling ferroptosis. These impairments lead to the retention of senescent hemolytic RBCs in the spleen, and the formation of undegradable iron- and heme-rich extracellular protein aggregates, likely derived from ferroptotic RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation in RPMs, enhances their ability to clear erythrocytes, and reduces damage. Consequently, this diet ameliorates hemolysis of splenic RBCs and reduces the burden of protein aggregates, mildly increasing serum iron availability in aging mice. Taken together, we identified RPM collapse as an early hallmark of aging and demonstrated that dietary iron reduction improves iron turnover efficacy.

Sperm migration and selection in the reproductive tract of female mice is mostly affected by male genotype.

The aim of the present study is to assess the influence of male and female genotypes on the transport of sperm to the site of fertilization. We mated B10.BR, B10.BR-Ydel and BALB/c males with B10.BR and BALB/c females and then analyzed the quality and quantity of spermatozoa found five hours post coitus in three successive parts of the female reproductive tract. We found that B10.BR and B10.BR-Ydel spermatozoa are very effectively selected by the uterotubaljunction and other barriers of the female genital tract. On the contrary, severely deformed BALB/c spermatozoa appeared to be able to cross selective barriers and were present both in oviducts and in cumulus oophorus. It cannot be excluded that these morphologically abnormal male gametes take part in fertilization. B10.BR-Ydel spermatozoa were very rarely observed above the uterotubaljunction. This shows that in vivo they migrate with delay and with difficulties pass the border between uterus and oviducts. This finding is in agreement with previous in vitro analyzes, which revealed many irregularities in movement of B10.BR-Ydel spermatozoa. Sperm quality and quantity in the reproductive tracts of B10.BR and BALB/c females were convergent if they were mated with males belonging to one strain, proving that migration and selection of spermatozoa in the female genital tract depend mostly on male genotype.

Correlation of centromeric heterochromatin C-band polymorphism with breeding failure in mice.

The aim of the present study was to test the hypothesis about the relation between segregation of chromosomes 14 and 18 and the deterioration of mouse fertility and vitality. The analysis was possible because C-banding on chromosome 14 and chromosome 18 of the CBA/Kw and KE strains show size polymorphism. A small sized C-band on chromosome 14 is characteristic for the CBA/Kw mice, while the KE mice show small C-bands on chromosomes 18. Thus, if fertility parameters are affected in a centromere-dependent manner, we should observe non-random inheritance of both chromosome pairs in recombinant inbred (RI) strains. The results showed statistically significant preferential segregation of chromosomes 14 and 18 with small C-bands. Most of the RI strains inherited chromosome 14 from the CBA/Kw strain and chromosome 18 from the KE strain, and did not manifest a deterioration of fertility and vitality. On the contrary, RI strains that inherited chromosomes 14 and 18 from one of the parental strains, particularly the KE strain, stopped breeding or had difficulties in producing the next generation.

[Structure and function of ATP7A and ATP7B proteins--Cu-transporting ATPases]. / Budowa i funkcja bialek ATP7A i ATP7B--ATPaz transportujacych jony miedzi.

Living organisms have developed refined and geneticaly controlled mechanisms of the copper metabolism and transport. ATP7A and ATP7B proteins play the key role in copper homeostasis in the organism. Both proteins are P-type Cu-transporting ATPases and use the energy of ATP hydrolysis to transfer the copper ions across the cellular membranes. Both proteins are localised in Golgi aparatus and involved in regulation of overall copper status in the body and their function is the export of excess copper from the cells and delivery of copper ions to Cu-dependent enzymes. Moreover in organism Cu-transporting ATPases are involved in absorption of dietary copper, Cu removal with the bile, placental copper transport and its secretion to the milk during lactation. Moreover it is known that Cu-transporting ATPases play a role in generation of anti-cancer drug resistance. Disturbances of ATP7A and ATP7B function caused by mutations lead to severe metabolic diseases Menkes and Wilson diseases, respectively.

Effect of Oral Supplementation of Healthy Pregnant Sows with Sucrosomial Ferric Pyrophosphate on Maternal Iron Status and Hepatic Iron Stores in Newborn Piglets.

BACKGROUND: The similarities between swine and humans in physiological and genomic patterns, as well as significant correlation in size and anatomy, make pigs an useful animal model in nutritional studies during pregnancy. In humans and pigs iron needs exponentially increase during the last trimester of pregnancy, mainly due to increased red blood cell mass. Insufficient iron supply during gestation may be responsible for the occurrence of maternal iron deficiency anemia and decreased iron status in neonates. On the other hand, preventive iron supplementation of non-anemic mothers may be of potential risk due to iron toxicity. Several different regimens of iron supplementation have been applied during pregnancy. The majority of oral iron supplementations routinely applied to pregnant sows provide inorganic, non-heme iron compounds, which exhibit low bioavailability and intestinal side effects. The aim of this study was to check, using pig as an animal model, the effect of sucrosomial ferric pyrophosphate (SFP), a new non-heme iron formulation on maternal and neonate iron and hematological status, placental transport and pregnancy outcome; Methods: Fifteen non-anemic pregnant sows were recruited to the experiment at day 80 of pregnancy and randomized into the non-supplemented group (control; n = 5) and two groups receiving oral iron supplementation-sows given sucrosomial ferric pyrophosphate, 60 mg Fe/day (SFP; n = 5) (SiderAL®, Pisa, Italy) and sows given ferrous sulfate 60 mg Fe/day (Gambit, Kutno, Poland) (FeSO4; n = 5) up to delivery (around day 117). Biological samples were collected from maternal and piglet blood, placenta and piglet tissues. In addition, data on pregnancy outcome were recorded.; Results: Results of our study show that both iron supplements do not alter neither systemic iron homeostasis in pregnant sows nor their hematological status at the end of pregnancy. Moreover, we did not detect any changes of iron content in the milk and colostrum of iron supplemented sows in comparison to controls. Neonatal iron status of piglets from iron supplemented sows was not improved compared with the progeny of control females. No statistically significant differences were found in average piglets weight and number of piglets per litter between animals from experimental groups. The placental expression of iron transporters varied depending on the iron supplement.

Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release.

Neutrophil extracellular traps (NETs) contribute to pathological disorders, and their release was directly linked to numerous diseases. With intravital microscopy (IVM), we showed previously that NETs also contribute to the pathology of systemic inflammation and are strongly deposited in liver sinusoids. Over a decade since NET discovery, still not much is known about the metabolic or microenvironmental aspects of their formation. Copper is a vital trace element essential for many biological processes, albeit its excess is potentially cytotoxic; thus, copper levels are tightly controlled by factors such as copper transporting ATPases, ATP7A, and ATP7B. By employing IVM, we studied the impact of copper on NET formation during endotoxemia in liver vasculature on two mice models of copper excess or deficiency, Wilson (ATP7B mutants) and Menkes (ATP7A mutants) diseases, respectively. Here, we show that respective ATP7 mutations lead to diminished NET release during systemic inflammation despite unaltered intrinsic capacity of neutrophils to cast NETs as tested ex vivo. In Menkes disease mice, the in vivo effect is mostly due to diminished neutrophil infiltration of the liver as unmutated mice with a subchronic copper deficiency release even more NETs than their controls during endotoxemia, whereas in Wilson disease mice, excess copper directly diminishes the capacity to release NETs, and this was further confirmed by ex vivo studies on isolated neutrophils co-cultured with exogenous copper and a copper-chelating agent. Taken together, the study extends our understanding on how microenvironmental factors affect NET release by showing that copper is not a prerequisite for NET release but its excess affects the trap casting by neutrophils.

Correction: Mateusz, S., et al. Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia. Pharmaceuticals 2018, 11, 128.

The authors wish to make the following corrections to this paper [¹]: the term "liposomal" should be replaced with the term "sucrosomial" in the following places [...].

Role of the kidneys in the redistribution of heme-derived iron during neonatal hemolysis in mice.

Moderate intravascular hemolysis is a common condition in newborns. It is followed by the accumulation of bilirubin, which is a secondary product of the activity of heme oxygenase-1, an enzyme that catalyzes the breakdown of heme released from disrupted erythrocytes and taken up by hepatic macrophages. Although these cells are a major site of enzymatic heme breakdown in adults, we show here that epithelial cells of proximal tubules in the kidneys perform the functions of both heme uptake and catabolism in mouse neonates. A time-course study examining mouse pups during the neonatal period showed a gradual recovery from hemolysis, and concomitant decreases in the expression of heme-related genes and non-heme iron transporters in the proximal tubules. By adjusting the expression of iron-handling proteins in response to the disappearance of hemolysis in mouse neonates, the kidneys may play a role in the detoxification of iron and contribute to its recirculation from the primary urine to the blood.