Angelo D’Alessandro, Alkmini T. Anastasiadi, Vassilis L. Tzounakas, Travis Nemkov, Julie A. Reisz, Anastsios G. Kriebardis, James C. Zimring, Steven L. Spitalnik and Michael P. Busch

Metabolites 2023, 13(7), 793 Full text için tıklayınız

Red blood cells (RBC) are the most abundant cell in the human body, with a central role in oxygen transport and its delivery to tissues. However, omics technologies recently revealed the unanticipated complexity of the RBC proteome and metabolome, paving the way for a reinterpretation of the mechanisms by which RBC metabolism regulates systems biology beyond oxygen transport. The new data and analytical tools also informed the dissection of the changes that RBCs undergo during refrigerated storage under blood bank conditions, a logistic necessity that makes >100 million units available for life-saving transfusions every year worldwide. In this narrative review, we summarize the last decade of advances in the field of RBC metabolism in vivo and in the blood bank in vitro, a narrative largely influenced by the authors’ own journeys in this field. We hope that this review will stimulate further research in this interesting and medically important area or, at least, serve as a testament to our fascination with this simple, yet complex, cell.

Hemodial Int. 2017 Jun; 21(Suppl 1): S6–S20.

Abstract
Iron is an essential element for numerous fundamental biologic processes, but excess iron is toxic. Abnormalities in systemic iron balance are common in patients with chronic kidney disease (CKD) and iron administration is a mainstay of anemia management in many patients. This review provides an overview of the essential role of iron in biology, the regulation of systemic and cellular iron homeostasis, how imbalances in iron homeostasis contribute to disease, and the implications for CKD patients.

Keywords: Iron metabolism, iron deficiency, iron overload, anemia, chronic kidney disease

The International Journal of Biochemistry & Cell Biology 33 (2001) 940–959

With rare exceptions, virtually all studied organisms from Archaea to man are dependent on iron for survival. Despite the ubiquitous distribution and abundance of iron in the biosphere, iron-dependent life must contend with the paradoxical hazards of iron deficiency and iron overload, each with its serious or fatal consequences. Homeostatic mechanisms regulating the absorption, transport, storage and mobilization of cellular iron are therefore of critical importance in iron metabolism, and a rich biology and chemistry underlie all of these mechanisms. A coherent understanding of that biology and chemistry is now rapidly emerging. In this review we will emphasize discoveries of the past decade, which have brought a revolution to the understanding of the molecular events in iron metabolism. Of central importance has been the discovery of new proteins carrying out functions previously suspected but not understood or, more interestingly, unsuspected and surprising. Parallel discoveries have delineated regulatory mechanisms controlling the expression of proteins long known — the transferrin receptor and ferritin — as well as proteins new to the scene of iron metabolism and its homeostatic control. These proteins include the iron regulatory proteins (IRPs 1 and 2), a variety of ferrireductases in yeast an mammalian cells, membrane transporters (DMT1 and ferroportin 1), a multicopper ferroxidase involved in iron export from cells (hephaestin), and regulators of mitochondrial iron balance (frataxin and MFT). Experimental models, making use of organisms from yeast through the zebrafish to rodents have asserted their power in elucidating normal iron metabolism, as well as its genetic disorders and their underlying molecular defects. Iron absorption, previously poorly understood, is now a fruitful subject for research and well on its way to detailed elucidation. The long-sought hemochromatosis gene has been found, and active research is underway to determine how its aberrant functioning results in disease that is easily controlled but lethal when untreated. A surprising connection between iron metabolism and Friedreich’s ataxia has been uncovered. It is no exaggeration to say that the new understanding of iron metabolism in health and disease has been explosive, and that what is past is likely to be prologue to what is ahead.

Trends Pharmacol Sci. 2021 August 01; 42(8): 640–656. doi:10.1016/j.tips.2021.05.001.

Abstract
Iron is essential in many physiological processes, including DNA metabolism, oxygen transport, and cellular energy generation. Deregulated iron metabolism, which results in iron overload or iron deficiency, is observed in many different diseases. We here summarize recent progress in the pathophysiology and pharmacology of iron-overload diseases, such as hereditary hemochromatosis, as well as iron-deficiency disorders, which are typically associated with anemia. The role of iron in immunity and the connection between iron and cancer are also addressed. We finally summarize and discuss the current (pre-) clinical landscape of pharmacotherapies targeting key players involved in iron metabolism.

Keywords: Iron; Anemia; Hemochromatosis; Inflammation; Cancer

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Abstract
Background
Hereditary hemochromatosis (HH) is a genetic disease, leading to iron accumulation and possible organ damage. Patients are usually homozygous for p. Cys282Tyr in the homeostatic iron regulator gene but may have mutations in other genes involved in the regulation of iron. Next-generation sequencing is increasingly being utilized for the diagnosis of patients, leading to the discovery of novel genetic variants. The clinical significance of these variants is often unknown.

Content
Determining the pathogenicity of such variants of unknown significance is important for diagnostics and genetic counseling. Predictions can be made using in silico computational tools and population data, but additional evidence is required for a conclusive pathogenicity classification. Genetic disease models, such as in vitro models using cellular overexpression, induced pluripotent stem cells or organoids, and in vivo models using mice or zebrafish all have their own challenges and opportunities when used to model HH and other iron disorders. Recent developments in gene-editing technologies are transforming the field of genetic disease modeling.

Summary
In summary, this review addresses methods and developments regarding the discovery and classification of genetic variants, from in silico tools to in vitro and in vivo models, and presents them in the context of HH. It also explores recent gene-editing developments and how they can be applied to the discussed models of genetic disease.

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Iron deficiency anaemia is a global health concern affecting children, women and the elderly, whilst also being a common comorbidity in multiple medical conditions. The aetiology is variable and attributed to several risk factors decreasing iron intake and absorption or increasing demand and loss, with multiple aetiologies often coexisting in an individual patient. Although presenting symptoms may be nonspecific, there is emerging evidence on the detrimental effects of iron deficiency anaemia on clinical outcomes across several medical conditions. Increased awareness about the consequences and prevalence of iron deficiency anaemia can aid early detection and management. Diagnosis can be easily made by measurement of haemoglobin and serum ferritin levels, whilst in chronic inflammatory conditions, diagnosis may be more challenging and necessitates consideration of higher serum ferritin thresholds and evaluation of transferrin saturation. Oral and intravenous formulations of iron supplementation are available, and several patient and disease-related factors need to be considered before management decisions are made. This review provides recent updates and guidance on the diagnosis and management of iron deficiency anaemia in multiple clinical settings.

Tam metin

Objective. To provide an overview of nutrients and compounds, which influence human intestinal iron absorption, thereby making a platform for elaboration of dietary recommendations that can reduce iron uptake in patients with genetic haemochromatosis. Design. Review. Setting. A literature search in PubMed and Google Scholar of papers dealing with iron absorption. Results. e most important promoters of iron absorption in foods are ascorbic acid, lactic acid (produced by fermentation), meat factors in animal meat, the presence of heme iron, and alcohol which stimulate iron uptake by inhibition of hepcidin expression. e most important inhibitors of iron uptake are phytic acid/phytates, polyphenols/tannins, proteins from soya beans, milk, eggs, and calcium. Oxalic acid/oxalate does not seem to influence iron uptake. Turmeric/curcumin may stimulate iron uptake through a decrease in hepcidin expression and inhibit uptake by complex formation with iron, but the net effect has not been clarified. Conclusions. In haemochromatosis, iron absorption is enhanced due to a decreased expression of hepcidin. Dietary modifications that lower iron intake and decrease iron bioavailability may provide additional measures to reduce iron uptake from the foods. This could stimulate the patients’ active cooperation in the treatment of their disorder and reduce the number of phlebotomies.

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Giriş
1. Aneminin saptanması
Dünya Sağlık Örgütü’nün tanımlamasına göre anemi: hemoglobinin, 15 yaşın üstünde erkekte 13g/dl altında, 15 yaşın üstünde ve gebe olmayan kadında 12 g/dl nin altında, gebelerde ise 11 g/dl’nin altında olarak tanımlanır.
Demir eksikliğinde iki basamak vardır:
a)Demir eksikliği: vücudun toplam demirinin azalması olarak tanımlanır. Anemi henüz yoktur.
b)Demir eksikliği anemisi: demir eksikliğinin eritropoyezi azaltması sonucu anemi gelişmiştir.
2. DEA, kronik bir hastalık veya hemoglobinopati yoksa eritrosit mikrositozu, hipokromisi ve düşük serum ferritini ile doğrulanmalıdır.
3. DEA düzeyi ne olursa olsun nedeni araştırılmalıdır. Erkek ve menopoz sonrası kadınlarda DEA genellikle kan kaybına bağlıdır. Bu hastalarda gastrointestinal sistemden kanama tüm nedenlerin 1/3’ünü oluşturur.
4. Laboratuvar özellikleri: MCH kan sayımı aygıtlarından ve kanın saklanmasından en az etkilenen eritrosit indeksidir. Mikrositoz ve hipokromi, kronik hastalık, B12 vitamini ve folat eksikliği yoksa DEA için duyarlı göstergelerdir. Mikrositoz ve hipokromi birçok hemoglobinopatide de görülür. Demir eksikliğinin serum göstergeleri düşük ferritin, düşük demir, artmış total demir bağlama kapasitesi, artmış eritrosit protoporfirini ve artmış transferrin bağlayan reseptörlerdir. Serum ferritini demir eksikliğini gösteren en güçlü testdir.
Tanı için sınır değeri 12-15 mg/L olarak belirlenmiştir. Bu değer eşlik eden hastalık yoksa geçerlidir. Eğer eşlik eden kronik hastalık varsa sınır değer <50 mg/L dir.

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Eritropoezis hematopoezisin en önemli basamaklarından biridir. Erişkin bir kişide, günlük kırmızı küre döngüsü 1011 hücre sayısını geçer. Hemoliz ve/veya kanama gibi sebepler ile artmış eritrosit kaybı durumlarında, eritrosit üretimi hızlı ve çok belirgin bir şekilde artar. Bununla birlikte, eritrositlerin aşırı üretimi (örneğin “rebound” polisitemi) çok fazla miktarda eritrosit kaybı durumlarında bile meydana gelmez. Bu sebeple, eritropoezis çok sıkı kontrol edilen ve hızlı cevapla dolaşımdaki eritrositlerin sayılarını dar bir aralıkta tutmaya çalışan bir süreçtir.
Şekil 1’de insanlardaki eritropoezisin temel basamakları gösterilmiştir. Kök hücre faktörü, trombopoietin ve IL-3 gibi bir çok büyüme faktörü ile multipotent hematopoietik kök hücre eritroid progenitörlere yönlendirilir. Eritroid progenitörlerinin en immatür basamağı yaklaşık 7 günde “colony-forming-unit erythroid” (CFU-E)’e farklılaşan “burst-forming-unit erythroid” (BFU-E)’dir. CFU-E aşamasına yaklaşıldıkça progenitörlerin proliferatif potansiyeli azalır. Her bir CFU-E, 7 gün içerisinde birçok farklılaşma basamağından sonra (proeritroblast, bazofilik eritroblast, polikromatofilik eritroblast ve ortokromatofilik eritroblast) 8-64 arasında matür bir eritroblast kümesi geliştirir. Ortokromatofilik eritroblastlar bölünmezler, fakat çekirdekleri ayrılır, (“enükleasyon”) ve dolaşıma salınan, retikülosit olarak isimlendirilen olgunlaşmamış eritrositleri oluştururlar. Dolaşımda bir gün geçirdikten sonra retikülositler eritrositlere dönüşür. Eritroid progenitör hücrelerin normal çoğalması ve farklılaşması demir, folat ve vitamin B12 gibi birçok esansiyel besinlere, stromal hücreler ile etkileşime ve eritropoietin (EPO) uyarısına gereksinim gösterir.
Demir Metabolizması
Demir eritropoetik fonksiyon, oksidatif metabolizma ve hücresel immunite için gerekli olması nedeniyle esansiyel bir elementtir. Erişkin bir erkek için vücuttaki toplam demir miktarı 3500 mg’dır (50 mg/kg). Vücuttaki demirin coğu hemoglobinler içinde dağılım gösterir (% 65; 2300 mg). Yaklaşık olarak % 10’u (350 mg) kas lifleri içinde (miyoglobin) ve diğer dokulardadır (enzimler ve sitokromlar). Kalan demir ise karaciğerde (200mg), retiküloendotelyal sistem makrofajlarında (500mg) ve kemik iliğinde (150mg) depolanmaktadır. Diğer yandan vücudun demiri aktif olarak vücuttan atması için bir yol olmaması sebebiyle atılımı olmadığı için, diyetteki demirin duodenumdan emiliminin düzenlenmesinin, demir homeostazisinde kritik bir rolü vardır. Demir hücresel metabolizmada ve aerobik solunumda esansiyel olduğu için bu regulasyon çok önemlidir ve demir aşırı yüklenmesi
serbest radikal oluşumu ve lipid peroksidasyonu yoluyla hücre ölümüne ve toksisiteye yol açmaktadır. Bunun için demir homeostazisi sıkı bir regulasyon gerektirmektedir. Bu makalenin birinci kısmında demir metabolizmasının ana yollarını ve regülasyonunu (Şekil 2), ikinci kısmında kısımda ise bu yolaklardaki ve regülasyondaki bozuklukları inceleyeceğiz.

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1. Introduction
General Overview of iron homeostasis
Iron is the most abundant transition metal in cellular systems and is an essential micronutrient required for many cellular processes including DNA synthesis, oxidative cell metabolism, haemoglobin synthesis and cell respiration. Despite iron being an absolute requirement for almost all organisms, caution should be taken with an inappropriate disequilibrium in iron levels because excess iron is toxic and a lack of it leads to anaemia.
As a transition metal, iron can exist in various oxidation states (from -2 to +6). Usually, iron exists and switches between two different ionic states (Fe+2 and Fe+3). Iron in the reduced state is known as ferrous iron and has a net positive charge of two (Fe+2). In the oxidized state it is known as ferric iron and has a net positive charge of three (Fe+3). This electron switch property of iron as a metal element allows it to be used as a cofactor by many enzymes involved in oxidation-reduction reactions and also confers its toxicity. Iron toxicity relates to the intracellular labile iron pool (LIP), a pool of transitory, chelatable (i.e. free) and redox-active iron that can catalyze the formation of oxygen-derived free radicals via the
Fenton reaction. Iron-catalyzed oxidative stress causes lipid peroxidation, protein modifications, DNA damage (promoting mutagenesis) and depletion of antioxidant defences.
Iron containing proteins can be classified into 3 groups (for an extensive revision see (Crichton, 2009)):
Haemoproteins, in which iron is bound to four ring nitrogen atoms of a porphyrin molecule called haem and one or two axial ligands from the protein. Examples of haemoproteins are the oxygen transport protein haemoglobin, the muscle oxygen storage protein myoglobin, peroxidases, catalases and electron transport proteins such as the cytochromes a, b and c.
Iron-sulphur proteins are proteins that contain iron atoms bound to sulphur forming a cluster linked to the polypeptide chain by thiol groups of cysteine residues or to non-protein structures by inorganic sulphide and cysteine thiols. Examples of iron-sulphur proteins are the ferredoxins, hydrogenases, nitrogenases, NADH dehydrogenases and aconitases.
Non-haem non iron-sulphur proteins, these proteins can be of three types:
Mononuclear non-haem iron enzymes such as catechol or Rieske dioxygenases, alpha-keto acid dependent enzymes, pterin-dependent hydrolases, lipoxygenases and bacterial superoxide dismutases
Dinuclear non-haem iron enzymes, also known as diiron proteins, like the H-ferritin chain, haemerythrins, ribonucleotide redictase R2 subunit, stearoyl-CoA desaturases and bacterial monoxygenases
Proteins involved in ferric iron transport, for instance the transferrin family that includes serotransferrin, lactotransferrin, ovotransferrin and melanotransferrin and are found in physiological fluids of many vertebrates.
As previously mentioned, many proteins involved in very different cellular pathways contain iron. Therefore, cells require iron to function properly. However, mammals have no physiological excretion mechanisms to release an excess of iron and consequently, iron homeostasis must be tightly controlled on both the systemic and cellular levels to provide just the right amounts of iron at all times. If an adequate balance of iron is not achieved, it will cause a clinical disorder. Iron is therefore crucial for health. Iron deficiency leads to anaemia —a major world-wide public health problem— and iron overload is toxic and increases the oxidative stress of body tissues leading to inflammation, cell death, system organ dysfunction, and cancer (Hentze et al., 2010).
Systemic iron homeostasis is regulated by the hepcidin/ferroportin system in vertebrates (Ganz & Nemeth, 2011). Hepcidin is a liver-specific hormone secreted in response to iron loading and inflammation and is the master regulator of systemic iron homeostasis.
Increased hepcidin levels result in anaemia while decreased expression is a causative feature in most primary iron overload diseases. Transcription of hepcidin in hepatocytes is regulated by a variety of stimuli including cytokines (TNF-TNF-

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Contents
1. Introduction 78
2. free erythrocyte protoporphyrin, erythrocyte protoporphyrin and zinc protoporphyrin 78
2.1 Pregnancy 79
2.2 Infancy 79
2.3 Childhood 80
2.4 Response to iron therapy and complications 81
2.5 Measurement, confounding factors, and units of measurement 82
3. Serum iron, total iron binding capacity and transferrin saturation 85
3.1 Serum iron 85
3.2 Transferrin, total iron binding capacity, transferrin saturation 87
4. Soluble transferrin receptor 88
5. References 91

Gün­cel Pe­di­at­ri 2012; 10: 65-9

Özet
Demir, birkaç bakteri türü hariç tüm canlı organizmalar için “esansiyel” bir elementtir. Demir metabolizması ile ilgili son yıllarda çok sayıda yeni yayınlar çıkmış olup, birçok yeni bulgu açıklanmıştır. Son yıllarda bulunan peptid yapıda bir hormon olan hepsidin, demir metabolizmasını barsaklardaki demir emilimini, makrofajlardan demir çıkışını ve hepatik depolardan demir salınımını etkileyerek düzenler. Hepsidin hücrelerden demir çıkışını, ferroportine bağlanarak ve onun yıkımını uyararak engeller. Hepsidin sentezi, serum demirinin yükselişi ile artar, anemi ve hipoksi durumlarında azalır. Ayrıca intestinal demir emilimi demir regülatuar protein/demir responsive element (IRP/IRE) sistemi tarafından düzenlenmektedir. Demirin sistemik düzenlenmesi, duodenal enterositler tarafından ne kadar demir alınacağı, apikal divalent metal transporter 1 (DMT1) düzeyine bağlıdır ve bu düzey IRP/IRE sistemi tarafından ayarlanır.