Prolactin Drives Iron Release from Macrophages and Uptake in Mammary Cancer Cells through CD44.

Iron is an essential element for human health. In humans, dysregulated iron homeostasis can result in a variety of disorders and the development of cancers. Enhanced uptake, redistribution, and retention of iron in cancer cells have been suggested as an "iron addiction" pattern in cancer cells. This increased iron in cancer cells positively correlates with rapid tumor growth and the epithelial-to-mesenchymal transition, which forms the basis for tumor metastasis. However, the source of iron and the mechanisms cancer cells adopt to actively acquire iron is not well understood. In the present study, we report, for the first time, that the peptide hormone, prolactin, exhibits a novel function in regulating iron distribution, on top of its well-known pro-lactating role. When stimulated by prolactin, breast cancer cells increase CD44, a surface receptor mediating the endocytosis of hyaluronate-bound iron, resulting in the accumulation of iron in cancer cells. In contrast, macrophages, when treated by prolactin, express more ferroportin, the only iron exporter in cells, giving rise to net iron output. Interestingly, when co-culturing macrophages with pre-stained labile iron pools and cancer cells without any iron staining, in an iron free condition, we demonstrate direct iron flow from macrophages to cancer cells. As macrophages are one of the major iron-storage cells and it is known that macrophages infiltrate tumors and facilitate their progression, our work therefore presents a novel regulatory role of prolactin to drive iron flow, which provides new information on fine-tuning immune responses in tumor microenvironment and could potentially benefit the development of novel therapeutics.

Effects of dietary iron supplementation on reproductive performance of sows and growth performance of piglets.

This experiment aimed to investigate the effects of dietary iron supplementation from different sources on the reproductive performance of sows and the growth performance of piglets. A total of 87 sows with similar farrowing time were blocked by body weight at day 85 of gestation, and assigned to one of three dietary treatments (n = 29 per treatment): basal diet, basal diet supplemented with 0.2% ferrous sulfate (FeSO4), and basal diet supplemented with 0.2% iron sucrose, respectively, with 30% iron in both FeSO4 and iron sucrose. Compared with the control (CON) group, iron sucrose supplementation reduced the rate of stillbirth and invalid of neonatal piglets (P < 0.05), and the number of mummified fetuses was 0. Moreover, it also improved the coat color of newborn piglets (P < 0.05). At the same time, the iron sucrose could also achieve 100% estrus rate of sows. Compared with the CON group, FeSO4 and iron sucrose supplementation increased the serum iron content of weaned piglets (P < 0.05). In addition, iron sucrose increased serum transferrin level of weaned piglets (P < 0.05) and the survival rate of piglets (P < 0.05). In general, both iron sucrose and FeSO4 could affect the blood iron status of weaned piglets, while iron sucrose also had a positive effect on the healthy development of newborn and weaned piglets, and was more effective than FeSO4 in improving the performance of sows and piglets.

Sows need more iron to meet the requirements for their and offspring's growth during pregnancy and lactation. Exogenous iron supplementation may improve the reproductive performance of sows and the growth performance of piglets, but different sources of iron have different effects. This study facilitates the understanding of the effects of iron sucrose and ferrous sulfate on the reproductive performance of sows and the growth performance of piglets.

2,4,6-Tri(2'-pyridyl)-1,3,5-triazine for determination of iron(II), Iron(III), and total iron contents on human palms.

When iron-based tools, such as knives or guns, are held, traces of iron can transfer to the skin. However, no previous studies have been published regarding the effect of the elapsed contact time on the transfer of iron species with different valences to the palm. Compared with 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine (PDT), 2,4,6-tri(2'-pyridyl)-1,3,5-triazine (TPTZ) was found to exhibit a higher sensitivity to iron(II) spectrophotometrically. This work employed 2,4,6-tri(2'-pyridyl)-1,3,5-triazine (TPTZ) and UV spectrophotometry to determine the amounts of iron(II), iron(III), and total iron transferred to human palms from iron tools. It was found that the palmar moisture level was an important factor in determining the amounts of total iron, including iron(II), transferred to the palm. For identical contact times, the amounts of total iron transferred to the palm was proportional to the palmar moisture, and the difference between the maximum and minimum amounts was 12 µg per hand. However, the amounts of iron(II) transferred to the palm gradually decreased over time for low palmar moisture levels, but steadily increased over time for high palmar moisture levels. Additionally, for average levels of palm moisture, the amounts of iron(II) and iron(III) transferred to the palm gradually decreased and increased, respectively, with longer contact times. Notably, this research could serve as a theoretical basis and guide for the detection of trace iron species with different valences on human palms for criminal investigations.

Malachite Green, the hazardous materials that can bind to Apo-transferrin and change the iron transfer.

Different groups of synthetic dyes might lead to environmental pollution. The binding affinity among hazardous materials with biomolecules necessitates a detailed understanding of their binding properties. Malachite Green might induce a change in the iron transfer by Apo-transferrin. Spectroscopic studies showed malachite green oxalate (MGO) could form the apo-transferrin-MGO complex and change the Accessible Surface Area (ASA) of the key amino acids for iron transfer. According to the ASA results the accessible surface area of Tyrosine, Aspartate, and Histidine of apo-transferrin significantly were changed, which can be considered as a convincing reason for changing the iron transfer. Moreover, based on the fluorescence data MGO could quench the fluorescence intensity of apo-transferrin in a static quenching mechanism. The experimental and Molecular Dynamic simulation results represented that the binding process led to micro environmental changes, around tryptophan residues and altered the tertiary structure of apo-transferrin. The Circular Dichroism (CD) spectra result represented a decrease in the amount of the α-Helix, as well as, increase in the ß-sheet volumes of the apo-transferrin structure. Moreover, FTIR spectroscopy results showed a hypochromic shift in the peaks of amide I and II. Molecular docking and MD simulation confirmed all the computational findings.

The Placental Ferroxidase Zyklopen Is Not Essential for Iron Transport to the Fetus in Mice.

BACKGROUND: The ferroxidase zyklopen (Zp) has been implicated in the placental transfer of iron to the fetus. However, the evidence for this is largely circumstantial. OBJECTIVES: This study aimed to determine whether Zp is essential for placental iron transfer. METHODS: A model was established using 8- to 12-wk-old pregnant C57BL/6 mice on standard rodent chow in which Zp was knocked out in the fetus and fetal components of the placenta. Zp was also disrupted in the entire placenta using global Zp knockout mice. Inductively coupled plasma MS was used to measure total fetal iron, an indicator of the amount of iron transferred by the placenta to the fetus, at embryonic day 18.5 of gestation. Iron transporter expression in the placenta was measured by Western blotting, and the expression of Hamp1, the gene encoding the iron regulatory hormone hepcidin, was determined in fetal liver by real-time PCR. RESULTS: There was no change in the amount of iron transferred to the fetus when Zp was disrupted in either the fetal component of the placenta or the entire placenta. No compensatory changes in the expression of the iron transport proteins transferrin receptor 1 or ferroportin were observed, nor was there any change in fetal liver Hamp1 mRNA. Hephl1, the gene encoding Zp, was expressed mainly in the maternal decidua of the placenta and not in the nutrient-transporting syncytiotrophoblast. Disruption of Zp in the whole placenta resulted in a 26% increase in placental size (P < 0.01). CONCLUSIONS: Our data indicate that Zp is not essential for the efficient transfer of iron to the fetus in mice and is localized predominantly in the maternal decidua. The increase in placental size observed when Zp is knocked out in the entire placenta suggests that this protein may play a role in placental development.

Expression of iron regulatory proteins in full-term swine placenta.

In swine, even though the pregnant sows were with iron abundance, the inborn iron reserve of piglets was compromised. This indicates the insufficiency of molecular machinery involved in local placental iron flux. Here, we investigated the expression of iron regulatory proteins like hepcidin and ferroportin and also their association with iron reserve, inflammation and oxidative stress in placenta of full-term pregnant sows (n = 6). Amplification and sequencing of placental DNA confirmed the presence of hepcidin (MN579557) and ferroportin (MN565887) sequences and their 100% identity with existing GenBank data. Real-time amplification of placental mRNA revealed significant higher expression of hepcidin (p < .05) than ferroportin. Western blot analysis of placental tissues revealed specific bands for both hepcidin (~8 kDa) and ferroportin (~62 kDa) molecules. Immunohistochemistry revealed the immunoreactivity for both proteins in the cytoplasm and membrane of trophoblastic cells of the placenta. Hepcidin and ferroportin expressions were positively associated with placental non-haem iron reserve (p < .0001; p = .033), lipid peroxidation (p = .0060; p < .0001) and reactive oxygen species level (p = .0092; p = .0292). Hepcidin expression was positively associated with interleukin - 6 (p = .0002) and interferon gamma (p < .0001) expressions but ferroportin expression was negatively associated with interleukin-6 (p = .0005), interleukin-1ß (p = .0226) and interferon gamma (p = .0059) expressions. This indicates hepcidin and ferroportin may have a role in controlling the local placental iron flux by acting as a molecular bridge between iron trafficking and inflammation.

Iron-Sulfur Protein Assembly in Human Cells.

Iron-sulfur (Fe-S) clusters serve as a fundamental inorganic constituent of living cells ranging from bacteria to human. The importance of Fe-S clusters is underscored by their requirement as a co-factor for the functioning of different enzymes and proteins. The biogenesis of Fe-S cluster is a highly coordinated process which requires specialized cellular machinery. Presently, understanding of Fe-S cluster biogenesis in human draws meticulous attention since defects in the biogenesis process result in development of multiple diseases with unresolved solutions. Mitochondrion is the major cellular compartment of Fe-S cluster biogenesis, although cytosolic biogenesis machinery has been reported in eukaryotes, including in human. The core biogenesis pathway comprises two steps. The process initiates with the assembly of Fe-S cluster on a platform scaffold protein in the presence of iron and sulfur donor proteins. Subsequent process is the transfer and maturation of the cluster to a bonafide target protein. Human Fe-S cluster biogenesis machinery comprises the mitochondrial iron-sulfur cluster (ISC) assembly and export system along with the cytosolic Fe-S cluster assembly (CIA) machinery. Impairment in the Fe-S cluster machinery components results in cellular dysfunction leading to various mitochondrial pathophysiological consequences. The current review highlights recent developments and understanding in the domain of Fe-S cluster assembly biology in higher eukaryotes, particularly in human cells.