Systemic iron status

Iron is one of the essential micronutrients, and as such, is required for growth, development, and normal cellular functioning. In contrast to some other micronutrients such as water-soluble vitamins, there is a significant danger of toxicity if excessive amounts of iron accumulate in the body. A finely tuned feedback control system functions to limit this excessive accumulation by limiting absorption of iron. This chapter will discuss systemic and brain iron homeostasis.     

Hepatic distribution of iron, copper, zinc and cadmium-containing proteins in normal and iron overload mice

Subcellular distribution of metal-containing proteins of Fe, Cu, Zn and Cd were determined in the liver samples of iron overload mice by size exclusion high performance liquid chromatography with on-line coupling to UV and inductively coupled plasma mass spectrometry. Collision cell techniques was used to remove polyatomic interferences for some elements, such as Fe. Comparative molecular weight (MW) information of the elemental fraction was obtained within a retention time of 40 min. Fe was present only in high-MW (HMW) protein; Cu, Zn and Cd were found in different MW proteins. It was also observed that these four elements studied showed predominant association with HMW fractions. Moreover, compared with the normal group, we found that the contents of these elements except Cu significantly increased and the distribution of some elements like Cd changed in iron overload mouse liver. It means that excessive iron accumulation in vivo may affect the metabolism of other element such as Zn and Cd.     

Elucidation of iron homeostasis in Acanthamoeba castellanii

Acanthamoeba castellanii is a ubiquitously distributed amoeba that can be found in soil, dust, natural and tap water, air conditioners, hospitals, contact lenses and other environments. It is an amphizoic organism that can cause granulomatous amoebic encephalitis, an infrequent fatal disease of the central nervous system, and amoebic keratitis, a severe corneal infection that can lead to blindness. These diseases are extremely hard to treat; therefore, a more comprehensive understanding of this pathogen’s metabolism is essential for revealing potential therapeutic targets. To propagate successfully in human tissues, the parasites must resist the iron depletion caused by nutritional immunity. The aim of our study is to elucidate the mechanisms underlying iron homeostasis in A. castellanii. Using a comparative whole-cell proteomic analysis of cells grown under different degrees of iron availability, we identified the primary proteins involved in Acanthamoeba iron acquisition. Our results suggest a two-step reductive mechanism of iron acquisition by a ferric reductase from the STEAP family and a divalent metal transporter from the NRAMP family. Both proteins are localized to the membranes of acidified digestive vacuoles where endocytosed medium and bacteria are trafficked. The expression levels of these proteins are significantly higher under iron-limited conditions, which allows Acanthamoeba to increase the efficiency of iron uptake despite the observed reduced pinocytosis rate. We propose that excessive iron gained while grown under iron-rich conditions is removed from the cytosol into the vacuoles by an iron transporter homologous to VIT/Ccc1 proteins. Additionally, we identified a novel protein that may participate in iron uptake regulation, the overexpression of which leads to increased iron acquisition.     

Effect of different cooking methods on loss of iron and zinc micronutrients in fortified and non-fortified rice

Malnutrition is considered as major public health concern and is emerging challenge to food and nutrition security particularly in developing countries. Rice is the staple food and consumed by the half of the world's population which is the source of daily requirement of the nutrients. Attempts are being made to fortify rice with micronutrients, but the loss or retention of these micronutrients in different cooking methods is not well studied and documented especially in fortified rice. In the present study, paddy seeds of six Indian varieties were fortified with iron and zinc by parboiling process. Consequently, fortified polished rice had higher micronutrient contents (Fe, 106.31 ± 12.56; Zn, 97.72 ± 9.75) than non-fortified polished rice (Fe, 7.44 ± 1.05; Zn, 14.74 ± 2.94) expressed in ppm. Polished rice of both fortified and non-fortified were cooked under five different cooking conditions and analyzed for remaining iron and zinc content. Cooking rice in rice cooker without prior washing (NRC) retained highest concentration of Fe and Zinc in both fortified and non-fortified rice varieties. It also showed that fortified rice suffered higher percentage loss of micronutrient, than the non-fortified rice. But the average retained micronutrient amount measured in ppm, was higher in fortified rice (Fe, 43.54 ± 6.88; Zn, 36.7 ± 3.12) than in non-fortified rice (Fe, 4.24 ± 0.87; Zn, 9.3 ± 2.11). Hence, adopting appropriate cooking method, higher amount of micronutrients will be retained in the cooked food which will in turn help in combating the malnutrition and improve health.     

Iron as a target of chemoprevention for longevity in humans

Abstract

Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases.     

Excessive iron accumulation in the pea mutants dgl and brz: subcellular localization of iron and ferritin

The pea (Pisum sativum L.) mutants dgl and brz are defective in the regulation of iron uptake. Enhanced proton extrusion and constitutively high Fe(III) reductase activities in the roots lead to an accumulation of iron and other divalent cations in different organs of the mutants. Ultrastructural investigations of the basal leaflets of the mutants revealed in the cytoplasm, in mitochondria and especially in, or close to the endoplasmic reticulum numerous electron-dense particles which were absent in the corresponding wild type plants DGV and Sparkle. By means of electron-spectroscopic imaging and electron-energy-loss spectroscopy it could be shown that these electron-dense particles consist mainly of iron. Some of the iron deposits were immunocytochemically identified as the iron-storage protein ferritin. It is suggested that the precipitation of excessive iron in the dgl and brz mutant leaves in the form of electron-dense iron particles combined with the accumulation of ferritin is part of the plant defense mechanism against Fe-mediated oxidative stress. Received: 17 February 1998 / Accepted: 4 July 1998     

Global malnutrition overlaps with pollinator-dependent micronutrient production

Pollinators contribute around 10% of the economic value of crop production globally, but the contribution of these pollinators to human nutrition is potentially much higher. Crops vary in the degree to which they benefit from pollinators, and many of the most pollinator-dependent crops are also among the richest in micronutrients essential to human health. This study examines regional differences in the pollinator dependence of crop micronutrient content and reveals overlaps between this dependency and the severity of micronutrient deficiency in people around the world. As much as 50% of the production of plant-derived sources of vitamin A requires pollination throughout much of Southeast Asia, whereas other essential micronutrients such as iron and folate have lower dependencies, scattered throughout Africa, Asia and Central America. Micronutrient deficiencies are three times as likely to occur in areas of highest pollination dependence for vitamin A and iron, suggesting that disruptions in pollination could have serious implications for the accessibility of micronutrients for public health. These regions of high nutritional vulnerability are understudied in the pollination literature, and should be priority areas for research related to ecosystem services and human well-being.     

Simon Labbé's work on iron and copper homeostasis

Iron and copper have a wealth of functions in biological systems, which makes them essential micronutrients for all living organisms. Defects in iron and copper homeostasis are directly responsible for diseases, and have been linked to impaired development, metabolic syndromes and fungal virulence. Consequently, it is crucial to gain a comprehensive understanding of the molecular bases of iron- and copper-dependent proteins in living systems. Simon Labbé maintains parallel programs on iron and copper homeostasis using the fission yeast Schizosaccharomyces pombe (Schiz. pombe) as a model system. The study of fission yeast transition-metal metabolism has been successful, not only in discerning the genes and pathways functioning in Schiz. pombe, but also the genes and pathways that are active in mammalian systems and for other fungi.     

Dietary Intake of Minerals,Vitamins, and Trace Elements Among Geriatric Population in India

The geriatric population is at a high risk of developing deficiencies of essential micronutrients such as minerals, vitamins, and trace elements and their related deficiency signs and symptoms. Scarce data is available on the dietary intake of essential micronutrients among geriatric subjects in India. Hence, to fill the gap in the existing knowledge, a community-based cross-sectional study was conducted during 2015–2016 in District Nainital, Uttarakhand State, India. A total of 255 geriatric subjects were enrolled from 30 clusters (villages) identified by using population proportionate to size sampling methodology. Data were collected on sociodemographic profile and dietary intake of essential micronutrients (24-h dietary recall, food frequency questionnaire) from all the geriatric subjects. A high percentage of geriatric subjects did not consume the recommended daily intake for essential micronutrients such as energy (78%), protein (78%), calcium (51%), thiamine (33%), riboflavin (64%), niacin (88%), vitamin C (42%), iron (72%), folic acid (72%), magnesium (48%), zinc (98%), copper (81%) and chromium (89%) adequately. Food groups rich in essential micronutrients such as pulses, green leafy vegetables, roots and tubers, other vegetables, fruits, nonvegetarian food items, and milk and milk products were consumed irregularly by the subjects. The overall intake of energy and essential micronutrients was inadequate among the geriatric population in India, possibly due to poor quality and quantity of the diet consumed.     

A copula-based approach for creating an index of micronutrient intakes at household level in Pakistan

Deficiency of micronutrients is considered as the basic cause of health issues. There are a large number of micronutrients to be considered for good health, which are analyzed separately. However, such analyses involve practical as well as methodological complications and it requires construction of an index representing malnutrition of micronutrients. This study proposes copula methodology to categorize malnutrition of micronutrients at household level by combining the dependence structure of various correlated variables. Data of eleven micronutrients are extracted from HIICS- 2015–16 published by Pakistan -Bureau of Statistics. Seven out of the eleven variables are highly correlated, which are considered to construct the index. These include calcium, iron, iodine, zinc, riboflavin, thiamine and phosphorus intakes per capita at household level. Normal probability distribution is found as the best fit to the sample data of all variables. Gaussian copula function is used to derive multivariate probability distribution by combining univariate marginal probability distribution of each micronutrient. The Multivariate distribution of Gaussian copula model is used to calculate cumulative probabilities, which provide a base to categorize households’ malnutrition w.r.t. micronutrients. The results show that 60% households lie in very low or low category of micronutrient intakes, 20% of households fall into medium category while 20% fall into high or very high category of micronutrient consumption. The proposed methodology might be helpful to combine other micronutrients as well as a variety of correlated variables in many other fields having a survey data     

微量元素五项联合红细胞四项检测在小儿缺铁性贫血中的诊断价值

目的:探讨微量元素五项联合红细胞四项检测在小儿缺铁性贫血(IDA)中的诊断价值。方法:选取2013年1月至2016年1月于我院进行治疗的小儿缺铁性贫血(IDA)患儿130例作为缺铁性贫血(IDA)组及同期于我院进行常规体检的健康儿童40例作为对照组。检测和比较其钙、镁、铜、铁、锌、血红蛋白(Hb)、平均红细胞体积(MCV)、平均血红蛋白含量(MCH)、平均血红蛋白浓度(MCHC)水平,并比较微量元素五项、红细胞四项检查以及两者联合对IDA患儿的诊断效能。结果:缺铁性贫血(IDA)组患儿微量元素镁、铁、锌含量以及Hb、MCV、MCH及MCHC水平均明显低于对照组儿童,差异具有统计学意义(P0.05);两组儿童微量元素钙、铜含量比较差异不显著(P0.05)。微量元素五项联合红细胞四项的灵敏度、特异度、阳性预测值及阴性预测值均明显高于微量元素五项和红细胞四项(P0.05)。结论:IDA患儿微量元素镁、铁、锌含量以及Hb、MCV、MCH及MCHC水平较低,微量元素五项联合红细胞四项检测可以提高小儿IDA的检出率。     

Iron and copper in fetal development

Copper and iron are both essential micronutrients. Because they can both accept and donate electrons, they are central to many energy dependent chemical reactions. For example, copper is a critical part of ferroxidase enzymes ceruloplasmin, hephaestin and zyklopen, as well as enzymes such as dopamine-β-monoxygenase, while iron is part of the catalytic site of many cytochromes and enzymes involved in fatty acid desaturation. Unsurprisingly, therefore, copper and iron deficiency, especially during pregnancy, when cell proliferation and differentiation are very active, sub-optimal nutrient status can lead to serious consequences. These problems can persist into adulthood, with an increased risk of mental problems such as schizophrenia and, in animal models at least, hypertension and obesity. In this review, we consider what these problems are and how they may arise. We examine the role of copper and iron deficiencies separately during fetal development, in terms of birth outcome and then how problems with status in utero can have long term sequelae for the offspring. We examine several possible mechanisms of action, both direct and indirect. Direct causes include, for example, reduced enzyme activity, while indirect ones may result from changes in cytokine activity, reductions in cell number or increased apoptosis, to name but a few. We examine a very important area of nutrition-interactions between the micronutrients and conclude that, while we have made significant advances in understanding the relationship between micronutrient status and pregnancy outcome, there is still much to be learned.     

Surface iron polymers and hydroxy acids. A model of iron supply in sideramine-free fungi

Biochemical and electron microscopic evidence is presented that sideramine-free fungi form iron hydroxide polymer layers on the cell surface when grown in an iron containing medium.Iron hydroxide polymer formation on the cell surface is completely prevented in sideramine producing strains of Neurospora crassa. After feeding a sideramine-free mutant of Neurospora crassa with ornithine in order to restore the sideramine synthesis the iron hydroxide coat is gradually dissolved.The addition of excess citrate and malate to the incubation medium also prevents iron polymer adsorption, suggesting that hydroxy acids may be involved in iron supply, when sideramine-free organisms are grown in iron containing media.In order to study the interaction between iron hydroxide polymer deposition upon the cell surface and iron chelating acids in Neurospora crassa, the amount and the proportion of excreted acids was studied under various experimental conditions. Gas chromatographic analysis of the acids produced under iron deficient conditions revealed that succinate, malate and citrate were present within the cells in the early growth phase. The acids were sequentially excreted into the medium in the order succinate, malate and citrate. The amount of succinate decreased after 2 days of cultivation, whereas the amount of malate and citrate continually increased. Although citrate was present within the cells from the 1st day, excretion occurred very late, generally after the 3rd day.It is suggested that sideramine-free fungi first adsorb iron as a hydroxide polymer on the cell surface, and that it is gradually solubilized by excreted hydroxy acids such as citrate or malate. Thus high local concentrations of iron chelated by hydroxy acids provide sideramine-free fungi with a continuous iron supply.Abbreviations BSTFA N,O-Bis(trimethylsilyl)-trifluoracetamide - GC Gaschromatography - EGTA Ethylenglykol-bis(2-aminoethylether) N,N-tetraacetic acid - TMS Trimethylsilyl     

LFR1 ferric iron reductase of Leishmania amazonensis is essential for the generation of infective parasite forms

The protozoan parasite Leishmania is the causative agent of serious human infections worldwide. The parasites alternate between insect and vertebrate hosts and cause disease by invading macrophages, where they replicate. Parasites lacking the ferrous iron transporter LIT1 cannot grow intracellularly, indicating that a plasma membrane-associated mechanism for iron uptake is essential for the establishment of infections. Here, we identify and functionally characterize a second member of the Leishmania iron acquisition pathway, the ferric iron reductase LFR1. The LFR1 gene is up-regulated under iron deprivation and accounts for all the detectable ferric reductase activity exposed on the surface of Leishmania amazonensis. LFR1 null mutants grow normally as promastigote insect stages but are defective in differentiation into the vertebrate infective forms, metacyclic promastigotes and amastigotes. LFR1 overexpression partially restores the abnormal morphology of infective stages but markedly reduces parasite viability, precluding its ability to rescue LFR1 null replication in macrophages. However, LFR1 overexpression is not toxic for amastigotes lacking the ferrous iron transporter LIT1 and rescues their growth defect. In addition, the intracellular growth of both LFR1 and LIT1 null parasites is rescued in macrophages loaded with exogenous iron. This indicates that the Fe(3+) reductase LFR1 functions upstream of LIT1 and suggests that LFR1 overexpression results in excessive Fe(2+) production, which impairs parasite viability after intracellular transport by LIT1.     

白念珠菌铁稳态调控网络研究进展

铁是绝大多数生物生长和代谢过程中必需的营养元素。尽管自然界中铁元素含量非常丰富,但是其生物可利用性却很低。作为一种人体常见的条件致病真菌,白念珠菌在漫长的进化过程中形成了复杂的铁稳态调控网络,能够应答环境中铁浓度的变化,增强菌株对环境的适应力。结合课题组研究工作,简要综述近几年关于铁代谢表达调控途径的研究进展,主要关注白念珠菌在环境铁匮乏条件下铁获得和调控策略,揭示白念珠菌体内铁离子摄取、转运、储存和利用机制。     

Role of iron metabolism in heart failure: From iron deficiency to iron overload

Iron metabolism is a balancing act, and biological systems have evolved exquisite regulatory mechanisms to maintain iron homeostasis. Iron metabolism disorders are widespread health problems on a global scale and range from iron deficiency to iron-overload. Both types of iron disorders are linked to heart failure. Iron play a fundamental role in mitochondrial function and various enzyme functions and iron deficiency has a particular negative impact on mitochondria function. Given the high-energy demand of the heart, iron deficiency has a particularly negative impact on heart function and exacerbates heart failure. Iron-overload can result from excessive gut absorption of iron or frequent use of blood transfusions and is typically seen in patients with congenital anemias, sickle cell anemia and beta-thalassemia major, or in patients with primary hemochromatosis. This review provides an overview of normal iron metabolism, mechanisms underlying development of iron disorders in relation to heart failure, including iron-overload cardiomyopathy, and clinical perspective on the treatment options for iron metabolism disorders.