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Iron Metabolism: Iron Transport and Cellular Uptake Mechanisms
Published in Bo Lönnerdal, Iron Metabolism in Infants, 2020
The iron donating behavior of the transferrin molecule has also been clarified.156,158,214–220 The two monoferric forms of transferrin have identical iron donating capacities,158,215 both in animals and in humans.216–218 The rate of iron donation and pattern of tissue distribution in vivo are identical. Iron release from transferrin to erythroid cells from either mono- or diferric transferrin is an “all or none” phenomenon leaving only apotransferrin.216,221 While receptors cycle transferrin into the cell regardless of its iron content, there is a competitive advantage of diferric over monoferric transferrin.156,220 Apotransferrin is not competitive. These iron-related differences in affinity between transferrin and receptor may well relate to the shape changes of the molecule during iron loading.36,91,209 The higher affinity of the diferric molecule was responsible for the original effects described by Fletcher and Huehns.222
PlasmaThe Non-cellular Components of Blood
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Transferrin is the plasma protein that transports iron. Apotransferrin, its precursor, is produced in the liver. One molecule of transferrin will bind two ferric ions and is normally approximately one-third saturated with iron. Haemopexin is a β-globulin that binds to haem and releases it to the reticuloendothelial system.
Regulation of Cell Functions
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
At least in certain types of cells, the action of thyroid hormone (T3) may be indirect and may be mediated by the local synthesis of an autocrine growth factor. T3 stimulates the division of GH4C1 and GC rat pituitary tumor cells by causing the cells to secrete an autocrine factor that seems to be a stable protein of high molecular weight.692,693 Conditioned medium from the pituitary cells cultured in the presence of physiologic concentrations of T3 stimulates growth of T3-depleted pituitary cell cultures even in the presence of anti-T3 serum. The structure and function of the putative autocrine growth factor induced by thyroid hormone are unknown. In particular, it is not known if this factor acts directly as a growth stimulator, acts permissively to allow expression of another activity, or relieves an inhibition. There is evidence that a thyroid hormone-mediating activity (thyromedin) present in normal serum may be represented by apotransferrin.694
The aging brain: impact of heavy metal neurotoxicity
Published in Critical Reviews in Toxicology, 2020
Omamuyovwi M. Ijomone, Chibuzor W. Ifenatuoha, Oritoke M. Aluko, Olayemi K. Ijomone, Michael Aschner
Iron (Fe) is an important metal found in an ample amount in the brain. It plays essential roles in many physiologic processes of the brain, which include; the synthesis of the neuronal myelin sheath, synthesis and optimal functionality of neurotransmitters, and the generation of ATP (Ashraf et al. 2018). It serves as a cofactor for many enzymes and it is also involved in the modulation of neuronal plasticity and synaptic activity (Wang et al. 2012; Braidy et al. 2017). Thus, the homeostasis of Fe is critical for a plethora of metabolic functions. The homeostatic balance of iron is controlled by the ferritin family (Fe-storage proteins). The ferritin family is made of three subfamilies, which include the canonical ferritin (FTN), the heme-containing bacterioferritin (BFR), and the starved cells’ DNA-binding proteins (DPS). The two subunits of the FTN, H-chain, and L-chain, are responsible for the oxidation of Fe2+ to Fe3+, and the formation of Fe core minerals, respectively (Arosio et al. 2017). Ideally, the BBB prevents the free passage of the iron-regulating proteins including ferritin, transferrin, ceruloplasmin and so on from the blood stream to the CNS. The circulating diferric-transferrin binds to the cerebrovascular endothelial cells of the BBB and the resulting complexes crosses over into the intercellular compartment. Following the dissolution of these complexes, apotransferrin is recycled to the blood where iron, probably via ferrotin, is transported out across the abluminal membrane into the interstitial space (Schipper 2012).
Polysaccharide nanoparticles for oral controlled drug delivery: the role of drug–polymer and interpolymer interactions
Published in Expert Opinion on Drug Delivery, 2020
Annalisa Bianchera, Ruggero Bettini
A patented method was used for the production by sol-oil of doxorubicin-loaded apotransferrin or lactoferrin particles with the purpose of specifically targeting metabolically active cancer cells that commonly hyper-express the receptors for transferrin family proteins [66]. Nanoparticles were assayed in a rat model of hepatocarcinoma and reduced the loss in body weight that is a common side effect associated with doxorubicin treatment. The drug accumulated preferentially in the liver, which was the desired site of action, with respect to kidney, heart, and spleen and determined an increased expression of tumor suppressing genes. These systems are quite promising on small animals but must be adapted to different absorption characteristics and the need for a consistently higher dose for human patients.
A deep dive into future therapies for microcytic anemias and clinical considerations
Published in Expert Review of Hematology, 2023
François Rodrigues, Tereza Coman, Guillemette Fouquet, Francine Côté, Geneviève Courtois, Thiago Trovati Maciel, Olivier Hermine
Apotransferrin (apoTf) is transferrin unbound to iron as opposed to holotransferrin. Apotransferrin administration in a mouse model of thalassemia resulted in increased hemoglobin, hepcidin, maturation of erythroblasts, and red blood cell survival [91]. Apotransferrin also lowered unbound labile iron levels, reticulocytosis, immature erythroid precursors count, and extra-medullary hematopoiesis as witnessed by decreased splenomegaly [91]. The authors speculated that excess availability of transferrin may redistribute iron within the plasma transferrin pool, shifting the ratio of differic to monoferric transferrin in favor of the monoferric form [91]. Type 1 transferrin receptor (TfR1) is responsible for most of the iron import in erythroblasts [91,92]. Differic transferrin shows a sevenfold greater delivery of iron to the erythroid lineage compared to monoferric protein [93]. Administration of apotransferrin could thus limit iron delivery to erythroblasts. This could lead to reduced globin and heme production and thus a decrease in toxic alpha-globin/heme aggregates. Decreased iron delivery could also alleviate oxidative stress. Such mechanisms could cause diminished occurrence of early apoptosis during erythropoiesis as well as increased survival of red blood cells [91]. Effects of apotransferrin on hepcidin are erythroferrone dependent, which hints that they are mediated by the alleviation of ineffective erythropoiesis [94]. Apotransferrin could also modify the activity of the hepcidin-regulating Tfr2/HFE/HJV complex in hepatocytes as well as the function of the TfR2 complex in erythroblasts, modulating EPO sensitivity and erythroferrone production [95]. Details of how apoTf administration modulates these pathways in thalassemia need to be resolved in future studies. Another explanation for diminished IE is that apotransferrin is unable to stimulate the MAPK pathway via TfR1 in contrast to holotransferrin as mentioned before [75,76]. Its administration could thus attenuate the survival signal in erythroblasts. Apotransferrin is currently evaluated in humans with beta-thalassemia in a phase 2 trial [81].