Chemotherapy and drug drug design - Dissertation Example

? Chemotherapy and drug design Chemotherapy and drug design Chemotherapy and drug design The role of iron in the body and its homeostasis. The trace element or micronutrient iron plays a major role in some important functions in the body. Iron is a part of several macromolecules in the human body involved with production of energy by the formation of adenosine triphosphate molecules, ribonucleoside reductase activity in DNA synthesis and xenobiotic metabolism (He et al, 2007; MacKenzie et al, 2007). The macromolecules consist of hemoglobin, cytochromes, oxygenases, flavoproteins, and redoxins. This makes iron a significant part of the vital biologic processes in human beings. Iron has a dichromatic nature; it is able to participate favourably in production of energy by electron transfer and can be simultaneously toxic by electron transfer in oxidation-reduction reactions (MacKenzie et al, 2007). Cytoplasmic iron is in the reduced form and therefore ready to undergo oxidation. If nearby lipids are peroxidised, DNA and other macromolecules can be damaged (MacKenzie et al, 2007). This makes severe iron overload and iron deficiency equally disastrous. The concentration of iron in mammalian tissues is not very high because the iron is sequestered by several host proteins like serum transferrin and lactoferrin and is not readily available. The microorganisms which invade the body compete with transferrin for the iron. Secreting siderophores which bind with iron has the property of preventing invasion by pathogenic bacteria (Crossa and Payne, 2004). The growth and multiplication of microorganisms are hindered in the presence of iron present at physiological ph of the body as its solubility is poor. An organism which cannot avail of iron from its many sources would be unsuccessful as a pathogen. Gram negative microorganisms are recognized by the complexes of iron and siderophores at the specific outer membrane receptors. In Gram positive organisms, the iron-siderophore complexes are recognized by the specific binding proteins. Both Gram positive and Gram negative bacteria take the iron from heme (Crossa and Payne, 2004). Gram negative bacteria use two methods. One is the binding to the outer membrane receptors and periplasmic binding of ABC permeases. The secretion of specialized bacteria proteins sequesters heme from other sources in the second method. Proteins acting like siderophores are called hemophores. Hemophilus influenza is known to have hemophores which captures free heme or from haemoglobin or heme from hemopexin. Pseudomonas organisms and Yersinia pestis are known to have a second hemophore system (Crossa, 2004). Erythropoiesis, immune functions and oxidative metabolism use iron (Munoz et al, 2009). Erythropoiesis is the production of red blood cells (RBCs) or erythrocytes, one of the many types of cells in the blood. The daily turnover of 1011 RBCs in the normal adult is possible through the iron. If damage occurs to RBCs by hemolysis or haemorrhage, the production is stepped up as a rapid response. The question of overproduction never arises as the erythropoiesis is well-regulated by key regulatory proteins to maintain the number of circulating RBCs within a normal range (Munoz et al, 2009, MacKenzie, 2007). The stem cell changes into the burst forming unit erythroid in the bone marrow in the first step of the formation of RBCs. The stages from the burst-forming unit erythroid to the orthochromatic erythroblast are influenced by erythropoietin. The orthochromatic erythroblast changes into reticulocytes circulating in the blood to become mature RBCs in another day. For the differentiation and maturing into RBCs, iron is an essential component along with vitamin B12 and folate. Oxidative metabolism Many metabolic processes essentially requires iron for their functions but an excess of iron also can cause damage to the cells through oxidative stress by the release of free hydroxyl radicals which are reactive and harmful (He et al, 2007, MacKenzie et al, 2007). Iron is absorbed but cannot be excreted leading to accumulation by age. An intricate network of proteins has been related to the iron metabolism. Iron is bound to the transferrin receptor in most tissues (He et al, 2007). Various enzymes for the important metabolic cycles require iron for their functions: the citric acid cycle, succinate dehydrogenase and aconitase. Other enzymes have iron incorporated as in the cytochrome oxidases and iron-sulphur complexes of the electron transport chain. The latter is essential for making adenosine triphosphate required for energy for other metabolisms (He et al, 2007). DNA synthesis requires iron for the ribonucleoside reductase activity in the first step of the synthesis. The oligodendrocytes in the central nervous system require iron for myelogenesis and maintenance of the myelin. Disruption of myelin can cause auditory defects in children. Demyelinating diseases have also been associated with defective homeostasis of iron. Neurotransmitters, dopamine, noradrenaline, serotonin need iron for being a co-factor in their synthesis. Parkinson’s disease and mood disorders have been related to defective iron homeostasis (He et al, 2007). Inflammatory-stress response Iron and its homeostasis are linked to inflammatory responses. The anaemia of inflammatory or chronic illnesses is to be combated with the tight control of homeostasis (Wessling-Resnick, 2010). Hepcidin, the peptide hormone which regulates iron homeostasis, has a significant function. The regulation of hepcidin decides how the body responds to the inflammatory process. Elevated iron stores have been found to produce susceptibility to disease and worse responses to inflammatory diseases and infections (Wessling-Resnick, 2010). The balance between nutrition and toxicity is maintained by systemic physiological mechanisms. Iron, unlike other metals, provides a means of controlling illness through iron homeostasis using the survival mechanisms. Homeostasis Total body iron requirement for a 70 kg. male is 3.5 gm. which is 50mg/kg. body weight (Munoz et al, 2009). The iron is mainly found in the haemoglobin of the RBCs which constitute 65% and the myoglobin of muscle fibres (10%). Enzymes and cytochromes hold 350mg. Two hundred mg. are stored in the liver, 500mg in the macrophages and 150mg. in the bone marrow. The total body iron is lesser in pre-menopausal women, mainly the stored fraction by about 250-300 mg. Normal diet contributes 15-20mg. of iron and absorption is 1-2mg/day. The body activities which maintain the level of body iron are the sloughing of intestinal mucosal cells, menstruation and other minor blood losses. Erythropoeisis requires the internal turnover of 20-30mg/day. Excretion of iron is not recognized by research (Munoz et al, 2009). Iron homeostasis is therefore dependent on the daily consumption from the duodenum which is essential for the oxidative metabolism of the cells. However the excess iron is toxic to the cells and leads to cell death by free radical formation with lipid peroxidation (Munoz et al, 2009). Iron homeostasis has to be regulated well for the best results. The non heme tissues have two regulatory proteins which regulate the cellular iron. The primary needs of the body for iron are recycled by the reticulo-endothelial system from the remains of the RBCs (Wessling-Resnick, 2010). In a normal person the iron conserves in the stores is sufficient for the demands of the body. Additional requirement is necessary in conditions of pregnancy, loss of blood in trauma or bleeding illnesses and hypoxia where additional nutritional demand or requirement for RBCs for replacement or demand for more circulating oxygen are reasons. These situations are factors which decide the total iron requirement. The process of making iron available for the body is streamlined by the duodenal enterocytes. Diseased states of the body as in hereditary haemachromatosis upset the management system so that excess iron enters the body and overloads it. In anaemia of inflammation or chronic illnesses, iron absorption becomes limited and retained in the reticulo-endothelial system disturbing the normal flow of events (Wessling-Resnick, 2010). Several proteins are involved in iron homeostasis in the process of absorption and in the RES (Munoz et al, 2009). The regulation of these proteins is significant in the maintenance of iron homeostasis as it is the absorbed iron that decides the body content of iron (Wallander, 2006). Normal diet contains heme and non-heme iron. The heme iron is obtained from meat and easily digested. The digestion is supported by the pancreatic enzymes in the intestine (Johnson-Wimbley and Graham, 2011). The globin moiety is separated from the heme. Non-heme iron is obtained from cereals, beans and vegetables but their absorption is much less and it is either in the ferric (Fe+2) or ferrous state (Fe+3). Bioavailability of dietary iron is enhanced in the acidic ph of the stomach (Johnson-Wimbley and Graham, 2011). Precipitation of ferric iron is prevented in the presence of Vitamin C. The ferric iron if present has to be converted into the ferrous state by the duodenal cytochrome b before absorption. Absorption of non-heme iron is reduced by grains and non-herbal tea. The transfer of iron in heme and non-heme is as ferrous iron across the intestinal mucosa into the enterocyte in absorption. It occurs through export of ferroprotein and oxidation by hephaestin or ceruloplasmin (Wessling-Resnick, 2010; Wallander, 2006). Divalent metal transporter (DMT1) requires an associated ferrireductase activity to reduce Fe(III) to Fe(II) for transporting the non-heme iron in the intestine (Wallender, 2006). This ferrireductase, also known as DYCTB, is a gene which acts on the duodenum in iron deficiency and enhances absorption of iron and it also converts the ferric state to the ferrous state for being transported by the DMTI. Mutation of DMTI hinders the absorption of iron and leads to microcytic anaemia. Heme is absorbed after being degraded by heme oxygenase. This iron gets absorbed into the non-heme part of the cell. The iron then enters the circulation through the exporter ferroprotein and a ferroxidase to help the binding to transferrin. Ferroprotein also enables the export from the macrophages and hepatocytes (Wallander, 2006). Then binding with serum transferrin, iron is delivered to the tissues in the periphery by receptor-mediated endocytosis of transferrin receptor-1(TfR1). Iron is released by membrane translocation by transporters along with STEAP3, a ferrireductase. Relation of the acquisition, transport and the biochemical reactions of iron to its properties. Acquisition Iron repletion and depletion produce a specific set of metabolic changes (Kaplan, 2006). The low iron levels activate the iron-responsive activator in some yeast species. This leads to expression of genes which encode the message for iron acquisition. At the same time the expression of genes having the message for iron-dependent proteins is repressed. In this manner, the most efficient use of the limited amount of iron prevents cell exhaustion. DNA synthesis, replication, repair, and transcription are done by the vital enzymes with the small amount of iron (Drakesmith and Prentice, 2008). Similarly iron overload also does not produce detrimental results. Candida albicans regulates iron-responsive genes by remodelling transcriptional programs (Hsu et al, 2011). Hsu and his co-researchers indicate that low-iron-specific repressor Hap43 is also important for the regulation of iron homeostasis in C. albicans. The action of the high iron-specific repressor had been proven earlier by Lan (2004). Iron is found to have a strong relationship with microbial infections especially zoopathogenic and opportunistic fungi. Therapies restricting iron are found to be effective for treating fungal infections in mouse models (Hsu et al, 2011). The virulence of C. albicans and other pathogenic fungi results from iron-containing proteins. Hsu et al are the first to provide an example of a spreading transcription factor Hap43 which is iron-responsive and becomes active in low-iron situations. It produces virulence in the spreading infection. Gene deletions can cause defective iron uptake. The C. albicans then finds it difficult to survive in the host. Hap43 virulence had not been caused by decreased iron uptake as indicated by Hsu et al (2011). The infective organism of Yersinia Pestis which is the causative organism of bubonic plague has the ability to spread, grow and infect human beings with plague (Pieper et al, 2010). The iron acquisition systems of this organism allow it to initiate a defence mechanism in the host against it. Pieper et al (2010) assessed iron acquisition and intracellular consequences of iron deficiency in the Y. pestis strain KIM6+ at two physiologically relevant temperatures (26°C and 37°C). Proteomic Surveys of Y. pestis in iron-replete against iron-starved has shown the physiological significance of the iron acquisition systems Ybt, Yfe, Yfu, Yiu and Hmu. Pieper et al found the biochemical pathways that were essential for the iron-starvation response in the Y. pestis like the “energy metabolism via the pyruvate oxidase route and Fe-S cluster assembly mediated by the Suf system” (2010). Transport Most of the iron in the body flows between the RBCs and the RES in a well-regulated cycle (Wallander, 2006). Ferroportin facilitates the transfer of iron from the macrophages in the reticulo-endothelial system through recycling of iron from the senescent RBCs to produce heme iron with regulatory control by hepcidin, a peptide hormone (Wessling-Resnick, 2010). The absorption mechanism provides less iron (2mg/day) while the recycling gives 20mg/day. This system enables the body to use available iron for its various functions rather than wait for absorbed iron, which then goes in more for storage (Wessling-Resnick, 2010). The circulation of hepcidin is decided by the total iron content in the body and physiological demands. Conditions that demanded iron, like iron deficiency and hypoxia, are associated with low hepcidin. Conversely iron overloading, inflammations and infections cause more of hepcidin to be available (Wessling-Resnick, 2010). The senescent RBCs are broken down by the macrophages of the RES found in the liver, Kuppfer cells. Ferroprotein with the facilitation of a ferroxidase (could be caeruloplasmin) degrades the heme and exports it (Wallander, 2006). The reticulo-endothelial macrophages obtain iron by delivery with Tf-TfRI or by phagocytosis of the RBCs. The differences in absorption do not influence the export by the macrophages which involve support of ferroportin for transport with ceruloplasmin (Wessling-Resnick, 2010). The iron in the ferric state is transported in a bound state to serum apoTf as holoTf (Wallander, 2006). This holoTf is transported to the bone marrow for manufacture of new red cells completing the cycle. Non-heme iron in the peripheral circulation is also bound to transferrin. The transferrin-binding sites are usually only 30% saturated. Transferrin cannot cross the blood brain barrier and the iron therefore has to be received by the cells at the barrier and transported to the neural tissues. The iron taken to the cells are processed in the mitochondria. The iron remaining after use by the cell would be stored by the cell or transported by transport protein ferroportin (He et al, 2007). Individual cells have mechanisms which can regulate the uptake of iron, sequestration activities and export of iron. Regulatory proteins regulates the iron homeostasis in humans. Biochemical reactions of iron Haemoglobin is an iron-containing protein with a heme group which is a molecule with an iron atom in the centre (Ochiai, 2011). Haemoglobin has a special property of transporting oxygen in the circulatory system. The inorganic iron in haemoglobin is bound to the oxygen molecule. This is expressed as: Fe11 + O2 O2- -- Fe111 (Hb) This reversible reaction shows iron in the haemoglobin binding to oxygen in the lungs and then carrying the bound oxygen through the blood circulation to the peripheral tissues needing oxygen in the forward reaction. The reverse reaction indicates that the oxygen is deposited at the tissues. The iron can transport oxygen only in the Fe11 form or ferric form (Ochiai, 2011). The haemoglobin is red and when it binds to oxygen, the red becomes brighter. However the ferric form provides a bluish colour. Many proteins and enzymes in the body contain heme. Respiration involves the conversion of carbohydrates to energy in the form of ATP (adenosine triphosphate). Carbohydrates provide electrons to oxygen after a number of oxidation steps (Ochiai, 2011). The electrons are transported to the oxygen which gains them and forms water. Iron containing proteins are concerned with the processes involving the movement of electrons. The Fe 11form can be easily converted to the FeIII form and vice versa. These heme-containing proteins are called cytochromes as they provide colour. The heme in haemoglobin does not change the oxygen bound to it. However the heme in iron in some enzymes renders the oxygen more reactive for certain reactions which occur subsequently. The heme iron functions as a catalyst and the enzymes containing the catalyst iron are called heme enzymes. Cytochrome P-450 is a special heme found participating in “monooxygenation”. Progesterone reacts with one oxygen atom of O2 the reaction being catalyzed by cytochrome P-450 converting the C-H bond in progesterone to a C-O-H bond (Ochiai, 2011). Catalases and peroxidases also are heme-enzymes. The conversion of hydrogen peroxide to water and oxygen occurs when the hydrogen peroxide antiseptic solution is applied to a wound. The bubbling seen is due to the oxygen released in the presence of catalase in the blood which catalyzes the reaction. 2H2O2 2H2O + O2 The oxygen formed in the reaction is more reactive than oxygen in air and can kill bacteria by oxidizing them. In some catalytic reactions the iron takes on an oxidation state (FeIV) as Fe2+. The iron-sulphur units having 4 atoms of each participate in some reactions. Photosynthesis uses one such unit called ferredoxins. In humans the energy-obtaining respiratory process through the TCA cycle is catalyzed by aconitase, a heme-containing enzyme with the iron-sulphur unit (Ochiai, 2011). This reaction adds or removes water molecules. Iron is bound to a carrier protein transferrin while in the blood circulation. Ferritin is the protein which stores the iron recovered from aging RBCs (Ochiai, 2011). It does not bind the iron but keeps it as iron hydroxide. Discussion of diseases related to iron deficiency and overload and their treatment Vascular illnesses which are seen due to iron are pre-eclampsia, diabetes, metabolic syndrome, obesity, cardiovascular illnesses of heart failure and atherosclerosis, stroke, macular degeneration (Kell, 2009). Neurological illnesses involved are Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis and Friedrich’s ataxia. Rheumatoid arthritis, lung diseases of bronchial asthma and COPD, psoriasis, gout, renal illnesses and liver diseases also arise due to problems of iron metabolism. Illnesses that are associated with the deficiency of iron are cardiovascular, metabolic, neurological and degenerative diseases (Kell et al, 2009). Kell had indicated that the peroxide and superoxide that occurred in aerobic metabolism were reactive oxygen species which reacted with poorly liganded iron to produce unfavourable results by way of the dangerous hydroxyl radical (2009). This radical is a significant cause of chronic inflammation. The iron-catalysed free hydroxyl radical is the causative factor for most of the diseases mentioned above. Kell had suggested that anti-oxidants and chelation agents could provide relief of redox stress (2009). Anti-oxidants behave as pro-oxidants. The chelating agents remove excess iron found at sites of disease in the body by chelation of the iron. Polyphenolic anti-oxidants can act both as anti-oxidant and as chelating agents. Anaemia due to iron deficiency Anemia is defined as a decrease in the total amount of hemoglobin or the number of red blood cells (Johnson-Wimbley and Graham, 2011). It occurs because there is insufficient iron to produce RBCs. Iron deficiency anaemia occurs because of insufficient intake of iron-containing food, chronic loss of blood or both. The most prevalent nutritional deficiency in the world is due to iron (Johnson-Wimbley and Graham, 2011). Anaemia due to limitation of iron intake through food sources is a condition that can be treated by oral supplementation. In the condition intestinal angiodysplasia, anaemia is due to the blood loss being more than the ability of the intestine to absorb iron. This condition cannot be treated by oral supplementation and remains refractory to treatment. The patients require frequent transfusions and end-organ damage is a possibility. In anaemia, the lesser iron available for absorption leads to some compensatory mechanisms to regulate the iron content in the body. Key proteins like duodenal cytochrome b, divalent metal transporter 1 and ferroportin are produced more. The local regulation of absorption is also facilitated by increased signaling by factors and by inducing hypoxia. This increases the expression of duodenal cytochrome b and divalent metal transporter 1. The iron regulatory proteins enhance the expression of the DMT1 and ferroportin (Johnson-Wimbley and Graham, 2011). The enhancement of the iron absorption is proportional to the deficiency of iron. Similarly the enhancement of actions of the duodenal cytochrome b, transferrin receptor, DMT1, ferritin and ferroportin is dependent on deficiency. Hepcidin which is liver-synthesised and secreted into the blood, regulates the rate of absorption and the release from the stores. Hepcidin is bound to the ferroportin and negatively influences its function. The moderating factors of hepcidin are hypoxia, erythrpopietin, twisted gastrulation (protein secreted by immature RBCs) and growth factor 15 (a factor secreted by erythroblasts in the final stages of erythropoiesis). The action of hepcidin is enhanced by inflammatory cytokines; this is the reason for anaemia of chronic disease (Johnson-Wimbley and Graham, 2011). Iron deficiency anaemia shows microcytic hypochromic RBCs with thrombocytosis. Forty percent of anaemic patients have normocytes. Macrocytic anaemia is also seen when a double deficiency of iron and folate or Vitamin B12 is present (Johnson-Wimbley and Graham, 2011). The peripheral smear shows both macro and microcytes. Low serum ferritin is an accompanying feature. If serum ferritin is normal, care is to be taken to rule out iron deficiency anaemia. Iron deficiency can accompany chronic inflammatory disease when ferritin is normal or increased. In the case of inflammatory disease, the reticulocyte haemoglobin measurement is more interpretive of the iron available for erythropoiesis. The gold standard for diagnosis of iron deficiency anaemia is the bone marrow biopsy (Johnson-Wimbley and Graham, 2011). Causes of iron deficiency anaemia are low bioavailability from diet, decreased absorption and blood loss. Decreased absorption occurs also in atrophic gastritis, malabsorption syndromes (coeliac disease) and partial or total gastrectomy post-surgically. Pre-menopausal women can have the deficiency due to heavy menstruation (Johnson-Wimbley and Graham, 2011). Chronic blood loss of about 100ml / day can be missed as stools would appear normal. However loss of more than 5mg/day for a long time would exceed the compensatory mechanisms for correction of iron homeostasis. Patients consuming aspirin and nonsteroidal anti- inflammatory drugs have the possibility of chronic blood loss. Iron supplementation with enteric coated delayed- release tablets have limited benefit in iron deficiency anaemia; they serve to prevent gastritis but are not as well absorbed as the non-enteric coated tablets. If losses are faster than the absorption, blood transfusions are necessary. Parenteral iron therapy has been suggested for vascular angiodysplasia (Johnson-Wimbley and Graham, 2011). Intravenous therapy increases the serum iron by 2.5-3.5 times while oral supplementation increases serum iron by 4.5 times. Administration of nonviable red cells or iron dextran however greatly elevates the serum iron levels. Iron dextran became unpopular because of fatalities resulting from anaphylaxis. Newer intravenous iron preparations are now available: “iron dextran (INFeD or DexFerrum), iron sucrose (Venofer), sodium ferric gluconate (Ferrlecit), and ferumoxytol (Feraheme) (Johnson-Wimbley and Graham, 2011). Complications associated with these preparations are hypotension, myalgias, nausea and vomiting. Patients with chronic gastrointestinal bleeding can have intravenous infusions of iron at intervals. Iron overload illnesses Haemachromatosis Haemachromatosis is a genetically inherited disorder of iron metabolism whereby too much iron is absorbed and stored in the body (Garrison, 2009). The absorption exceeds the normal 10%. As iron is not excreted and excess is stored, the content of the iron in the body grows to the extent that organs and tissues suffer in the long run especially the liver, pancreas and heart. The extra iron reaching toxic levels or iron overload damages these organs apart from pituitary, thyroid, gonads and joints. Failure of these organs can occur if no treatment is instituted (Garrison, 2009). Symptoms consist of abdominal pain, myalgias, chronic fatigue, weakness and extreme sensitivity to cold. The illnesses that are possible are heart failure, cirrhosis of the liver, cancer of the liver, osteoarthritis, hypothyroidism, hypogonadism, infertility and impotence (Garrison, 2009). Diagnostic tests include serum ferritin, iron-binding capacity and fasting serum iron. Early detection and adequate management can provide a patient his normal life span. Therapy consists of removal of blood at intervals and it is termed therapeutic phlebotomy. Medicines can also remove the extra iron. Iron bound in heaemoglobin transports oxygen but unbound iron produces free radicals which cause harm. These free radicals obtain electrons from all parts of the body in order to get the electrons back. Even the DNA structure can be affected. This produces mutations which are then passed on through generations (Garrison, 2009). Thalassemia The most severe forms of thalassemia, thalassemia major, require blood transfusions for sustenance of life. Chelation therapy is also necessary to prevent iron overload (Mariani, 2009). Patients with the less severe type, thalassemia intermedia, hardly require blood transfusions . However they too develop iron overload because erythropoiesis is defective. The hepcidin. which is dependent on hypoxia, is in a down-regulated state . This leads to increased absorption of iron. Studies reveal that beta thalassemia intermedia causes the iron load to be 3-4 times the normal load (Mariani, 2009). In patients with severe thalassemia but not requiring blood transfusions, the iron load is between 2 and 5 gms. and depends on the severity of erythroid expansion. In patients who received transfusions, the iron overload is twice as much. In thalassemia major there are two reasons for overloading: transfusion-related overloading and absorption overloading because erythropoiesis is poor. The iron overload is inversely related to the haemoglobin content. The capacity of the transferrin, the transport protein of iron, becomes raised in an attempt to bind and detoxify the excess iron. It is the nontransferrin-bound fraction of iron in the plasma that leads to the reactive oxygen species which cause oxygen-related damage. In short, the iron overload produces the damaging effects of thalassemias. Iron chelation is the focus of therapy in thalassemias. The accumulation of iron in the organs produces damage to the essential organs and shortens the lives of thalassemic patients. Sickle cell disease Sickle cell disease (SCD) is a group of inherited disorders of the synthesis of haemoglobin. Hemolytic anaemia, elevated erythropoiesis and chronic inflammatory disease exist in sickle cell disease (Mariani, 2009). The iron metabolism is different in this illness. The chronic inflammation constitutes the activation of the endothelial cells and increased adhesion of RBCs and WBCs (leukocytes). Non transfused patients do not show iron overload. Iron deficiency can be an accompanying feature due to the intravascular hemolysis which forms one-third of the hemolysis that occurs in SCD. This results in increased loss of iron through the urine. The genetic problem causes the incidence of an amino-acid being substituted in the beta globin chain of haemoglobin. SCD is a haemoglobinopathy which initiates polymerization of RBCs as well as an endothelial dysfunction. Clinical complications are of two subphenotypes which overlap partially: a viscosity–vasoocclusion phenotype versus one of hemolysis-endothelial dysfunction. A lower hemolytic rate with an increased haemoglobin level accompanied by a lowered plasma haemoglobin, lactate dehydrogenase , bilirubin and arginase levels are the features of the viscosity-vasoocclusion subphenotype. These patients have complications of vaso-occlusive pain crises, acute chest problems and osteonecrosis. The hemolytic-endothelial dysfunction subphenotype has features of raised hemolytic rate, with decreased haemoglobin, increased plasma haemoglobin, LDH, bilirubin and arginase. The second type shows less nitric oxide bioavailability. Complications include pulmonary hypertension, ulcers on the legs, priapism and stroke. Erythropoiesis is not defective and is enhanced. The SCD patients who do not require transfusions do not exhibit iron overload but show microvascular occlusions, RBC sequestration and splenic infarction which lead to the splenic iron overload. A different picture is seen in non-transfused thalassemic patients. The spleen is bigger in size but is not overloaded with iron for two reasons: due to absence of transfusions and the low level of hepcidin causing mobilization of iron stores from the RES stores. Chronic transfusion therapy is useful for both SCD and thalassemia. In SCD, transfusions reduce the sickle cells down to less than 30% and its symptoms of hemolysis and splenic infarction (Mariani, 2009). References: Crossa, JH, Payne, SM 2004, Iron transport in bacteria. ASM Press, 2004 Drakesmith, H., and A. Prentice. 2008, Viral infection and iron metabolism. Nat. Rev. Microbiol. 6:541–552. Garrison, C 2009, The Iron Disorders Institute Guide to Haemachromatosis. 2nd Ed. Iron Disorders Institute. He, X, Lacovelli, J, Wong, R, King, C, Bhisitkul, R, Massaro-Girodano, M and Dunaief, J 2007, Iron homeostasis and toxicity in retinal degeneration, Prog transport in bacteriaRetin Eye Res. 2007 November ; 26(6): 649–673. Hsu, P-C, Yang, C-Y and Lan, C-Y 2011, Candida albicans Hap43 Is a Repressor Induced under Low-Iron Conditions and Is Essential for Iron-Responsive Transcriptional Regulation and Virulence Eukaryotic Cell, Feb. 2011, p. 207–225 Vol. 10, No. 2 1535-9778/11/ doi:10.1128/EC.00158-10 American Society for Microbiology. Johnson-Wimbley, TD and Graham, DY 2011, Diagnosis and management of iron deficiency anemia in the 21st century. Ther Adv Gastroenterol (2011) 4(3) 177 184 DOI: 10.1177/1756283X11398736 Sage Publications Kaplan, J., D. McVey Ward, R. J. Crisp, and C. C. Philpott 2006, Iron- dependent metabolic remodeling in S. cerevisiae. Biochim. Biophys. Acta 1763:646–651. Kell,DB 2009, Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases BMC Medical Genomics 2009, 2:2 Kornitzer, D. 2009. Fungal mechanisms for host iron acquisition. Curr. Opin. Microbiol. 12:377–383. Lan, C. Y., et al. 2004. Regulatory networks affected by iron availability in Candida albicans. Mol. Microbiol. 53:1451–1469. MacKenzie, E, Iwasaki, K and Tsuji, Y 2008, Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications Antioxidants & Redox Signaling Volume 10, Number 6, 2008. Mary Ann Liebert, Inc. DOI: 10.1089/ars.2007.1893 Mariani, R, Trombini, P, Pozzi, M and Piperno, A 2009, Iron Metabolism in Thalassemia and Sickle Cell Disease. Mediterranean Journal Of Hematology And Infectious Diseases, 1(1): e2009006 DOI 10.4084/MJHID.2009.006 Munoz M, Villar I, Garcia-Erce JA 2009, An update on iron physiology. World J Gastroenterol 2009; 15(37): 4617-4626 Available from: URL: http://www.wjgnet.com/1007-9327/15/4617.asp DOI:http://dx.doi.org/10.3748/wjg.15.4617 Ochiai, E 2011, Chemicals for life and living Published by Springer. Pieper, R.,Huang, S-T, Parmar, PP, Clark, DJ, Alami, H., Fleischmann, RD, Perry, RD and Peterson, SN 2010, Proteomic analysis of iron acquisition, metabolic and regulatory responses of Yersinia pestis to iron starvation,. BMC Microbiology 2010, 10:30 http://www.biomedcentral.com/1471-2180/10/30 Wallander, ML, Leibold, EA and Eisenstein, RS 2006, Molecular control of vertebrate iron homeostasis by iron regulatory proteins, Biochim Biophys Acta. 2006 July ; 1763(7): 668–689. Wessler-Resnick, M 2010, Iron Homeostasis and the Inflammatory Response, Annu Rev Nutr. 2010 August 21; 30: 105–122. doi:10.1146/annurev.nutr.012809.104804. Read More