Biomarkers of Nutrition for Development (BOND)—Iron Review

This is the fifth in the series of reviews developed as part of the Biomarkers of Nutrition for Development (BOND) program. The BOND Iron Expert Panel (I-EP) reviewed the extant knowledge regarding iron biology, public health implications, and the relative usefulness of currently available biomarkers of iron status from deficiency to overload. Approaches to assessing intake, including bioavailability, are also covered. The report also covers technical and laboratory considerations for the use of available biomarkers of iron status, and concludes with a description of research priorities along with a brief discussion of new biomarkers with potential for use across the spectrum of activities related to the study of iron in human health. The I-EP concluded that current iron biomarkers are reliable for accurately assessing many aspects of iron nutrition. However, a clear distinction is made between the relative strengths of biomarkers to assess hematological consequences of iron deficiency versus other putative functional outcomes, particularly the relationship between maternal and fetal iron status during pregnancy, birth outcomes, and infant cognitive, motor and emotional development. The I-EP also highlighted the importance of considering the confounding effects of inflammation and infection on the interpretation of iron biomarker results, as well as the impact of life stage. Finally, alternative approaches to the evaluation of the risk for nutritional iron overload at the population level are presented, because the currently designated upper limits for the biomarker generally employed (serum ferritin) may not differentiate between true iron overload and the effects of subclinical inflammation

Models to assess food iron bioavailability

Iron deficiency is the most common global nutritional problem, which can be attributed mainly due to poor dietary iron bioavailability. Although many methods exist in assessing bioavailability, they may not be applicable for large populations. Algorithms have therefore been developed from single meal studies for assessing iron bioavailability. However, based on exaggerated effect of dietary factors on iron absorption, new algorithms based on complete diet studies are needed. The objectives of these studies were to: (i) develop a new algorithm from complete diet studies data (manuscript 1); (ii) estimate iron absorption from the US diet using the new algorithm (manuscript 2); and (iii) investigate the effect of long-term phytate consumption on iron absorption (manuscript 3). We developed the algorithm using data from four complete diet studies in which nonheme iron absorption was measured in each subject for three different dietary periods. In estimating iron absorption from the US diet, we used the National Health and Nutrition Examination Survey (NHANES, 2001-2002), MyPyramid Equivalents Database (MPED), and the Food and Nutrient Database for Dietary Studies (FNDDS). In the third study, iron absorption from a high phytate test meal was measured using the area under the curve (AUC) for serum iron in female subjects with ferritin \u3c 30 µg/L (n=28) before and after an eight week dietary modification with high (n=14) or low (n=14) phytate diets. In the first study, serum ferritin explained 35 % of the variability in iron absorption, whereas the effect of dietary factors was small. In the second study, iron bioavailability from the US diet was 15% compared to the currently used value of 18 %. The third study found a significant increase in absorption in the high phytate group (640 to 905 µmol/L; P \u3c 0.05) and a non-significant decrease (337 to 267 µmol/L) in the low phytate group, indicating that the inhibitory effect of phytate on nonheme iron absorption is dampened among individuals who consume high phytate diet regularly. The findings of these studies have implications for iron nutrition policies for setting recommendations for iron intake and biofortification of high phytate staples with iron

The Biological Speciation and Toxicokinetics of Aluminum

This review discusses recent literature on the chemical and physiological factors that influence the absorption, distribution, and excretion of aluminum in mammals, with particular regard to gastrointestinal absorption and speciation in plasma. Humans encounter aluminum, a ubiquitous yet highly insoluble element in most forms, in foods, drinking water, and pharmaceuticals. Exposure also occurs by inhalation of dust and aerosols, particularly in occupational settings. Absorption from the gut depends largely on pH and the presence of complexing ligands, particularly carboxylic acids, with which the metal can form absorbable neutral aluminum species. Uremic animals and humans experience higher than normal body burdens of aluminum despite increased urinary clearance of the metal. In plasma, 80-90% of aluminum binds to transferrin, an iron-transport protein for which receptors exist in many tissue. The remaining fraction of plasma aluminum takes the form of small-molecule hydroxy species and small complexes with carboxylic acids, phosphate, and, to a much lesser degree, amino acids. Most of these species have not been observed in vivo but are predicted from equilibrium models derived from potentiometric methods and NMR investigations. These models predict that the major small-molecule aluminum species under plasma conditions are charged and hence unavailable for uptake into tissues

Role of Aluminum as a Toxic Element in Causing Parenteral Nutrition Associated Cholestasis

Parenteral nutrition (PN) is an essential life sustaining therapy for premature and critically ill infants. However, prolonged PN therapy can lead to life-threatening liver damage, and cause parenteral nutrition associated cholestasis (PNAC). There has been some recent evidence that aluminum accumulation in the livers of PN-fed subjects may lead to hepatic damage leading to liver injury. This dissertation aimed to investigate the role of aluminum as a toxic component of parenteral nutrition and as a risk factor in developing PNAC. The project composed of two main studies. The objectives of the first study were: 1) Evaluate the early morphological changes in piglet liver after intravenous administration of aluminum chloride hexahydrate at a dose of 1500 µg/kg/d.; 2) Determine whether the morphological changes deteriorate further with increasing duration of exposure and whether these changes correlate with changes in biochemical markers of cholestasis; 3) Identify the appropriate imaging technique for studying the ultrastructural changes in the liver; 4) Determine if intravenous injection of high dose aluminum into neonatal piglets disrupts iron homeostasis in the liver. The results showed that intravenous infusion of aluminum in neonatal piglets led to marked elevation in serum total bile acids, and transmission electron microscopy-energy dispersive microanalysis (TEM-EDX) was suitable in detecting the site of Al deposition in the liver and in demonstrating histopathological changes associated with Al infusion. The objectives of the second part were to: 1) Investigate the role of aluminum as a toxic component of parenteral nutrition and as a risk factor in causing liver injury; 2) Evaluate the effect of reducing aluminum content of parenteral nutrition on liver iron homeostasis; 3) Investigate the effect of low aluminum PN and high aluminum PN (regular PN) on the mRNA expression of Bsep and Mrp2. The results showed that administration of PN solution with lower Al content led to reduced levels of serum and hepatic Al in low Al PN group compared to regular PN group. This reduction was associated with less histopathological changes in the liver. On the other hand, administration of regular PN in piglets led to decreased expression of transporter Mrp2. This work suggests that reducing Al content in PN may reduce the development and severity of liver injury in the piglets

Lysosomes in iron metabolism, ageing and apoptosis

The lysosomal compartment is essential for a variety of cellular functions, including the normal turnover of most long-lived proteins and all organelles. The compartment consists of numerous acidic vesicles (pH ∼4 to 5) that constantly fuse and divide. It receives a large number of hydrolases (∼50) from the trans-Golgi network, and substrates from both the cells’ outside (heterophagy) and inside (autophagy). Many macromolecules contain iron that gives rise to an iron-rich environment in lysosomes that recently have degraded such macromolecules. Iron-rich lysosomes are sensitive to oxidative stress, while ‘resting’ lysosomes, which have not recently participated in autophagic events, are not. The magnitude of oxidative stress determines the degree of lysosomal destabilization and, consequently, whether arrested growth, reparative autophagy, apoptosis, or necrosis will follow. Heterophagy is the first step in the process by which immunocompetent cells modify antigens and produce antibodies, while exocytosis of lysosomal enzymes may promote tumor invasion, angiogenesis, and metastasis. Apart from being an essential turnover process, autophagy is also a mechanism by which cells will be able to sustain temporary starvation and rid themselves of intracellular organisms that have invaded, although some pathogens have evolved mechanisms to prevent their destruction. Mutated lysosomal enzymes are the underlying cause of a number of lysosomal storage diseases involving the accumulation of materials that would be the substrate for the corresponding hydrolases, were they not defective. The normal, low-level diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow formation of lipofuscin in long-lived postmitotic cells, where it occupies a substantial part of the lysosomal compartment at the end of the life span. This seems to result in the diversion of newly produced lysosomal enzymes away from autophagosomes, leading to the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. If autophagy were a perfect turnover process, postmitotic ageing and several age-related neurodegenerative diseases would, perhaps, not take place

Iron as Therapeutic Targets in Human Diseases Volume 2

Iron is an essential element for almost all organisms, a cofactor playing a crucial role in a number of vital functions, including oxygen transport, DNA synthesis, and respiration. However, its ability to exchange electrons renders excess iron potentially toxic, since it is capable of catalyzing the formation of highly poisonous free radicals. As a consequence, iron homeostasis is tightly controlled by sophisticated mechanisms that have been partially elucidated. Because of its biological importance, numerous disorders have been recently linked to the deregulation of iron homeostasis, which include not only the typical disorders of iron overload and deficiency but also cancer and neurodegenerative diseases. This leads iron metabolism to become an interesting therapeutic target for novel pharmacological treatments against these diseases. Several therapies are currently under development for hematological disorders, while other are being considered for different pathologies. The therapeutic targeting under study includes the hepcidin/ferroportin axis for the regulation of systemic iron homeostasis, complex cytosolic machineries for the regulation of the intracellular iron status and its association with oxidative damage, and reagents exploiting proteins of iron metabolism such as ferritin and transferrin receptor. A promising potential target is a recently described form of programmed cell death named ferroptosis, in which the role of iron is essential but not completely clarified. This Special Issue has the aim to summarize the state-of-the-art, and the latest findings published in the iron field, as well as to elucidate future directions

Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics

Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics