Hydrophilic Phytochelators in Iron Overload Condition
 
Zohreh Sajadi Hezaveh; MSc¹ & Farzad Shidfar; PhD^*1
 
1 Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
 

ARTICLE INFO		ABSTRACT
REVIEW ARTICLE		Background: Iron overload can cause many complications and damage many organs as well as physiologic functions. Consumption of phetochemicals and flavonoids with iron chelating ability, instead of synthetic iron chelators, can be less harmful and more effective. The aim of this review is to investigate hydrophilic phytochelators in iron overload condition. Methods: In this review, the possible natural iron chelators including quercetin, rutin, bailcalin, silymarin, resveratrol, mimosine, tropolone, curcumine, catechin, kojic acid, and caffeic acid were investigated. Furthermore, the mechanisms through which they chelate iron were discussed. Results: The mentioned antioxidants eliminated excessive iron, decreased iron absorption, exerted antioxidant and anti-inflammatory activity without causing adverse effects and other metal deficiencies in iron overload condition. Conclusion: The combination of synthetic chelators with these antioxidants or their replacement with natural chelators could be possible treatments for iron overload. Keywords: Iron overload; Iron chelation; Iron chelator; Antioxidant, Flavonoid; Polyphenol.
Article history: Received: 7 Apr 2018 Revised: 18 Jun 2018 Accepted: 14 Sep 2018
*Corresponding author Farzadshidfar@yahoo.com Faculty of Para- medicine, Iran University of Medical Sciences, before the Chamran  intersection, East Hemmat highway, Tehran, Iran.   Postal code: 1449614535 Tel: 0+98- 123082922

 
Introduction

The important role of iron in human body is undeniable. Iron is an essential cofactor for hundreds of proteins and enzymes that participates in oxidation and reduction reactions. It is also involved in red blood cell function, myoglobin activity, immune function, cognitive performance, brain function, as well as function and synthesis of neurotransmitters. Therefore, iron deficiency can cause multiple organ malfunctions. However, iron overload can be as destructive and dangerous as its deficiency (Barton, 2007).
Hemochromatosis is a hereditary condition with excessive iron absorption. Hemosiderosis is an iron storage condition that develops in individuals who consume abnormally large amounts of iron or in those with a genetic defect resulting in excessive iron absorption. Iron overload is also observed
in thalassemia, cycle cell disease, and myelodysplasia, which is due to blood transfusion therapy transmitting 200 to 250 mg of iron to the patient's body per unit. Iron overload is attributed to a distinct gene that favors excessive iron absorption and absorbs the iron that exists in the diet. In other words, these patients experience severe iron toxicity (Gallagher, 2012).
Iron must be bound to proteins such as ferritin, hemosiderin, and transferrin to prevent its destructive effects, but by increase in the amount of iron, the liver fails to produce enough protein to store iron. Therefore, excessive free iron will be produced as a result. Since body cannot deal with this large amount of excessive iron, it deposits iron into organs such as the heart, liver, and endocrine organs, which leads to dysfunction of these organs. The consequences of this disease represent as liver dysfunction, cardiomyopathy, diabetes, and even death. Chemically, free iron is a highly reactive element that can interact with oxygen to form intermediates with the potential of damaging cell membranes, degrading DNA, oxidating LDL cholesterol, and finally damaging the cardiovascular system. It also helps to generate excessive amounts of free radicals that attack cellular molecules and develop carcinogenic molecules within cells (Hershko et al., 2003, Shander et al., 2009).
Chelation therapy removes excessive iron effectively. Desferrioxamine (DFO), deferiprone (L1), and deferasirox (1CL670) are currently available chelating drugs, which bind with Fe⁺ molecules from organs and eliminate them through urine or feces. However, regardless of their iron-removing characteristic, these drugs' serious adverse effects overshadow the patient's life. Desferrioxamine causes reactions at infusion
sites, inducing hearing, vision, growth, and
skeletal abnormalities, and Yersinia infection. Agranulocytosis, transient neutropenia, arthralgia, mild gastrointestinal symptoms, and mild aminotransferase elevation are caused by L1. Deferasirox induces skin rash, elevation of serum creatinine, mild gastrointestinal symptom, mild aminotransferase elevations, as well as hearing and vision abnormalities. Another problem of using such drugs is that they remove iron as well as other two valence metals such as zinc and cause micromineral deficiency (Barton, 2007).
Recently, biochemical studies highlighted the possible iron-chelating properties of flavonoids and polyphenolic compounds with at least two iron binding sites. These flavonoids are divided into two categories of lipophilic and hydrophilic chelators. Lipophilic chelators represent the opposite effect to L1 and DFO, increase iron absorption, minimize iron excretion, and increase deposition of excess iron in tissues. Therefore, they are considered to be a possible treatment for iron deficiency anemia. On the other hand, hydrophilic chelators are different. They eliminate excessive iron and decrease iron absorption in addition to exerting antioxidant and anti-inflammatory activity without causing adverse effects and other metal deficiencies (Kontoghiorghe et al., 2015). The combination of synthetic iron chelators with these antioxidants or even replacing them with natural chelators would be a possible treatment for iron overload. Here are some natural hydrophilic iron chelators:
Quercetin
Quercetin is a member of flavones that mainly exists in apples, onions, tea, red wines, and berries. As experimental studies demonstrated, it possesses numerous beneficial effects on human health, many of which are correlated to its antioxidant capability. Quercetin can scavenge free radical species and has synergistic effects with enzymes and physiological antioxidants (Dolatabadi et al., 2014). The catechol moiety is a possible site on Quercetin for the iron chelation and the high binding energy values indicate that Quercetin is a powerful chelating agent that can sequester iron to prevent its involvement in oxidation reaction (Leopoldini et al., 2006).
Studies in iron-dextran induced iron overloaded mice showed that the injected Quercetin could reduce the hepatic iron overload, decrease serum ferritin, and increase the fecal excretion of iron (Zhang et al., 2006). In another study hepatic and renal iron contents significantly decreased after Quercetin supplementation in a dose-dependent manner (Zhang et al., 2011). Tang Y. et al found that quercetin alleviated ethanol-mediated suppression of hepcidin expression in mice (Tang et al., 2014). Lesjack M. et al. also claimed that Quercetin could limit the rate of intestinal iron absorption and decreased subsequent basolateral iron efflux into the blood circulation in rats (Lesjak et al., 2014).
Rutin
Rutin is a glycoside form of quercetin found in citrus fruit (Leopoldini et al., 2006). Since rutin has two binding sites for iron (Guo et al., 2007), it exerts its antioxidant effects by chelating ferric ions (Shimoi et al., 1997). Rutin has a potent iron chelating activity in a dose dependent manner (Oke-Altuntas et al., 2016), However, studies focused more on its free radical scavenging ability rather than iron chelation. Rutin was more effective in inhibition of free radical formation than L1 (Afanas'ev et al., 2000). It also protects kidney by scavenging reactive oxygen species (Ferrali et al., 1997).
Baicalin/ Baicalein
Baicalin and its aglycone, baicalein are the main effective components in the plants of genus Scutellaria (Lamiaceae) namely the root of S. Baicalensis Georgi and Xiao-chaihu-tang (Sho-saiko-to), a hepato-protective Chinese traditional herb medicine mixture (Ohta et al., 1997). Most of the pharmacological activities of baicalin and baicalein are associated with their antioxidant and anti-inflammatory efficacies (Dinda et al., 2017). Zhang Y. et al. found that baicalin could release iron from ferritin and increased its excretion through feces (Zhang et al., 2006). Baicalin can also gradually combine with hepatic non-heme iron, take it into blood stream, and finally excrete it from body (Zhao et al., 2005). However, it is hard to segregate the iron chelation and free radical scavenging activity of baicalin. Furthermore, scarce studies have been conducted on its iron chelating ability; so, this hypothesis needs further experimental support (Yoshino and Murakami, 1998).
Silymarine/ Silibin
Silymarin and its main component, silibin are polyphenols found in milk thistle (Borsari et al., 2001). Silymarin is known to be a powerful iron chelator, which is capable of depleting iron stores and reducing serum ferritin (Hagag et al., 2013). It also reduces intestinal iron absorption by reducing serum level of hepcidin. In other words, lower ferritin levels inhibit the release of extra hepcidin (Moayedi et al., 2013). Although silymarin can effectively reduce serum iron level, it cannot decrease iron deposition in kidney, heart, and liver, even when coadministered with DFO (Adibi et al., 2012). Combined therapy with silymarin and DFO can be more effective in serum ferritin reduction than DFO alone, but combination of L1 and silymarin is not different from L1 alone (Hershko, 2010).
Some studies investigated silibin's affinity for ferric iron. The bioavailability of silibin is higher than silymarin. It can form iron complexes at acidic PH and reduce non heme iron absorption (Borsari et al., 2001, Loguercio and Festi, 2011).
Considering the antioxidant and free radical scavenging abilities of silymarin and silibin alongside iron chelation, they can be a possible chelation therapy for chronic iron overload (Borsari et al., 2001).
Resveratrol
Resveratrol is a flavonoid found in red wine and is mostly popular for its antioxidant effects especially on cardiovascular diseases. However, very little is known about its iron chelating ability. Recent studies suggested that the resveratrol's antioxidantive function might be due to its iron chelation (Imam et al., 2017) since resveratrol and its analogs contain catechol moiety (Mazzone et al., 2013). Resveratrol has been known to reduce bone loss (Zhao et al., 2015) and protect liver (Das et al., 2016) in iron overload condition. A study showed that oral administration of resveratrol could attenuate cardiac iron overload in hemochromatosis patients (Das et al., 2015). Therefore, it may be able to reduce iron deposit in organs. More investigations can clarify the metal binding ability of this flavonoid and its possible role in iron overload diseases.
Mimosine
Mimosine is produced in Leucaena, a legume growing in tropical region (Barros-Rodríguez et al., 2014). Human clinical studies showed that leucaena could be well tolerated up to 5g twice daily, but many toxic side effects were reported in animals feeding on leucaena leaves and seeds. It is believed that mimosine and its goitrogen metabolites are responsible for the side effects; therefore, mimosine has not been used in human studies (Hegarty et al., 1979). However, it has been identified to be effective in animal models for the treatment of iron overload and inhibition of free radical formation (Kontoghiorghes et al., 1986a).
Mimosine has an α-ketohydroxypyridine binding site, which has high affinity for iron and can form stable iron complex in the case of oral consumption (Kontoghiorghes et al., 1987). Different studies suggested different mechanisms for mimosine affecting iron metabolism. A study in rabbits showed that mimosine could excrete iron through urine (Kontoghiorghes et al., 1993). Another study in mice showed that hydrophilic phytochelators such as mimosine reduced iron absorption and inhibited the transfer of iron in many cell types (Kontoghiorghes, 1990a). Some studies compared mimosine to synthetic iron chelators. Kontoghiorghes showed that the ability of mimosine in mobilizing and removing iron from human transferrin was just slightly lower than L1, while DFO and deferasirox were not effective in mobilizing iron (Kontoghiorghes and Evans, 1985). The amount of iron excreted through urine using mimosine was the same as the amount of L1 at the same dose (Kontoghiorghes et al., 1993). The mimosine's ability to reduce iron absorption was also the same as DFO (Kontoghiorghes, 1990a).
Tropolone and its derivatives
Tropolone is another phytochemical found in plants including Red Cedar, Cupressus Llusitanica,  Thuja Plicata, etc., but it is not used as a food product (Saniewski et al., 2007). Its oral activity was mostly studied in animal models. Tropolone has a high affinity for iron and  forms insoluble iron complexes in oral administration, which decreases iron absorption (Kontoghiorghes, 1990b). It also transfers iron across the cell membrane and increases the uptake and incorporation of iron in cells and haem (Kontoghiorghes et al., 2004).  
The toxicity and convulsion observed in animals consuming tropolone hampered further human studies on its iron chelating property. Tropolone was more effective than L1 and DFO in iron excretion. In one study, tropolone was used in a dose, which was 10 times lower than its natural amount found in its dietary sources (20 mg/kg). The results showed that it could excrete iron at equivalent amount as L1 and DFO, but it remained toxic (Kontoghiorghes et al., 1993). Therefore, tropolone is still determined as an effective treatment in iron overload condition.
Purpurogallin is a red pigment with the tropolone ring in its molecule; in other words, it is a biologically active homologus of tropolone. It also can be obtained by oxidation of pyrogallol, which is an antioxidant found in plants like Myriophyllum Spicatum (Inamori et al., 1997). Both purpurogallin and pyrogallol can increase iron excretion and inhibit noxious effects of free radicals induced by iron overload (Kontoghiorghes et al., 1986b). Hinikitol is another tropolone derivative found in the farms of cupressaceous plants that has been widely used in food as an antimicrobial agent (Nakano et al., 2006). Hinikitol is known to play its antioxidant, anti-inflammatory, and anticancer roles by chelating iron (Jayakumar et al., 2013).
Curcuminoids
Curcuminoids are the phenolic yellowish pigment of turmeric or Curcuma longa L. that has been widely used as a coloring agent and spice in many foods. Curcuminoids and its structurally related compound, curcumin, has been known to possess antioxidant and anti-inflammatory properties (Asai and Miyazawa, 2000). Recently, its ferric iron binding capacity has been focused because it is a possible treatment for thalassemia and other iron overload diseases (Srichairatanakool et al., 2007, Thephinlap et al., 2009).
In vitro studies have shown that curcumin is able to reduce hepatic ferritin synthesis and decrease iron level in bone marrow, splin, and liver. It can reduce hepcidin expression, which means that curcumin exerts its iron chelating properties independent of hepcidin. Curcumin could also activate iron-responsive element-binding protein (IRP) and transferrin receptor 1(TfR1) in mice and induce iron deficiency (Jiao et al., 2009). These properties in addition to its modulating redox state and attenuating oxidative stress-induced inflammation (Niu et al., 2016) makes curcumin a potent remedy for iron overload condition.
Catechin and its derivatives
Catechins are strong antioxidants with metal binding capacity, mostly found in green tea and cocoa bean (Yang et al., 2014). They have a catechol moiety metal chelating site through which they bind iron and make insoluble iron complexes (Zijp et al., 2000). Epigallocatechin gallate (EGCG) is a member of catechin family with an extra gallate chelating site, which makes it a stronger iron chelator than catechin and other substituents on the catechol ring that increases its stability (Kontoghiorghe et al., 2015).
The iron chelating activity of EGCG was studied in a few investigations. The results showed that this flavonoid not only helps to restore balanced redox status in patients with iron overload, but also reduces the basolateral iron export in caco-2 cells. So, it reduces iron absorption through gut lumen (Ferlazzo et al., 2016, Ma et al., 2011). Another study reported that EGCG did not impair non-heme iron absorption in women with iron deficiency (Ullmann et al., 2005). It clarifies that EGCG reduces iron absorption only in iron overload condition.
Caffeine/ Caffeic acid
Caffeine is a well-known plant alkaloid found in leaves, seeds, and nuts of a number of plants. It is a major constituent of coffee, cocoa, tea, cola drinks, and chocolate (Ding et al., 2014). Caffeine does not have any metal binding activity, but is conjugated to DFO to improve its cell permeability. DFO-caffeine complex has both iron-scavenging ability and antioxidant properties (Alta et al., 2014, Huayhuaz et al., 2017). Conversely, caffeic acid is known to be an iron chelator, apart from its antioxidative and anti-inflammatory activity (Perron and Brumaghim, 2009, Srichairatanakool et al., 2006). Caffeic acid is a caffeine's derivative found in many plants and occurs in diet as part of fruits, vegetables, tea, and wine (Clifford, 2000).
Caffeic acid has iron binding affinity due to its catechol moiety (Kontoghiorghe et al., 2015). It inhibits free radical formation through both iron chelation and antioxidant activity (Ikeda et al., 2011). Nevertheless, investigations demonstrated that caffeic acid is less effective than catechin in inhibiting the reactive oxygen species formation (Matsui et al., 2017). It also did not cause much increase in iron  incorporation in red blood cells in comparison to tropolone (Kontoghiorghes, 1988).
Kojic acid
Kojic acid is a by-product in the fermentation process of malting rice to be used in the production of Sake, the Japanese rice wine (Bentley, 2006). Its phenolic hydroxyl group makes it a bidendate metal chelator and it is considered as a potent iron chelator (Kotyzova et al., 2004, Nurchi et al., 2011, Ochiai et al., 2012). Kojic acid is also a potent antioxidant and is potentially capable to target oxidative stress pathways (Mohammadpour et al., 2013).
Different studies investigated the antioxidant and iron removal activity of kojic acid in comparison with other natural and synthetic iron chelators. Kojic acid is found to be less effective than catechol in inhibition of oxidative damage (Kontoghiorghes et al., 1986b). It was also less effective than L1 and mimosine in iron mobilization and inhibition of lipid peroxidation (Mostert et al., 1987). Kojic acid could not reinforce iron incorporation in red blood cells (Kontoghiorghes, 1988). So, kojic acid is a powerful iron chelator, although it is less powerful and effective than other chelators.
Discussion
The body iron should be kept in its normal range. Extra iron can contribute to detrimental Reactive oxygen species (ROS) generating process and cause inflammation. It also causes many complications by precipitating in different organs, especially heart, liver, and endocrine organs. Hence, chelation therapy is used in iron overload condition to bind excess iron within the system and remove it from the body. Although thalassemic patients can survive up to the age of 70 years by management of synthetic iron chelators, it should be noted that synthetic iron chelators are still toxic in high doses. A proper iron chelator must be orally active with the lowest toxicity and cost. Nowadays, a large number of patients do not receive any chelation treatment considering the high cost, toxicity, and unpleasant complications of treatments with synthetic iron chelators. In this study, orally active antioxidants were introduced with their possible iron chelating and free radical scavenging capabilities besides their lower cost, toxicity, and complications compared to the synthetic drugs. These natural chelators make complexes with metals in concentrations higher than the physiologic concentration. Therefore, they treat iron overload without causing any other micromineral deficiency. This advantage is lacked in synthetic drugs.
Quercetin, rutin, bailcalin, silymarin, resveratrol, mimosine, tropolone, curcumine, catechin, kojic acid, and caffeic acid contain catechol or gallate moiety that are known as metal binding sites. Iron binds to these sites and eliminates from the body with the help of them. Few in vitro studies provided us with some limited knowledge on mechanisms of iron chelation. Some studies only investigated their antioxidant activity without clarifying whether this effect was due to scavenging reactive oxygen species or chelating excessive iron. Besides iron chelation and free radical scavenging, these antioxidants can be effective in iron overload condition by reducing liver iron load, increasing fecal and urinary excretion of iron, reducing serum ferritin, removing iron from ferritin and transferrin, increasing hepcidin expression, reducing intestinal iron absorption, increasing the uptake and incorporation of iron in haem, as well as inducing osteo- and cardio-protective effects. We should also keep in mind some of these antioxidants' toxic properties and the fact that they should be used in very low doses to be safe.
Some studies focused on foods, but not the antioxidants. African walnut (Olabinri et al., 2010), wheat grass extract(Pole, 2006), and green tea extract (Al-Basher, 2019) showed iron chelating activity, which is probably caused by iron chelator antioxidants that they contain. Other natural compounds also exist with possible iron chelating activity, which have not been investigated yet. These compounds include citrate, nicotinamine, muginic acid, fulvic acid, and humic acid containing carboxylic acid metal binding site (Fang et al., 2015, Korkina and Afanas'ev, 1997, Namba and Murata, 2010, Van Schaik et al., 2008, Weber et al., 2008, Yang and Van Den Berg, 2009). Considering the confined and incomplete knowledge on these compounds' iron chelating ability, we can only guess about the effectiveness of these natural chelators in iron overload conditions. Myrecitin, Ferulic acid, vitamin C, Mevidol, and Anthocyanins can also affect the iron metabolism by reducing hepcidin expression, releasing iron from its stores, increasing
serum iron, and reducing the iron-induced inflammation. Yet, they have not shown any iron binding affinity (Imam et al., 2017).
To determine the possible clinical application of these natural chelators in hemochromatosis, thalassemia, and other iron overload diseases, more investigations are needed to figure out their cellular mechanism of action and clarify the role that iron chelation plays in relation to their anti-inflammatory activity. Some appealing subjects for future studies can be on their bioavailability, safe dosage, most effective way of administration (oral or parenteral), best intervention period, and combined administration of these natural chelators together or with synthetic chelators.
Conclusions
Natural iron chelators are more reliable and safer than the synthetic ones. Application of natural iron chelators alone or with synthetic chelators in iron overload condition can be of less harm and more benefit for patients.
Conflict of interest
The authors declare that they have no conflict of interest. They also did not receive any financial support for this study.
Authors' contribution
Study concept, design, and drafting were prepared by Sajadi Hezaveh Z. Shidfar F did the critical revision of the manuscript for important intellectual contents.

Adibi A, et al. 2012. Therapeutic effects of deferoxamine and silymarin versus deferoxamine alone in β-thalassemia major based on findings of liver MRI. Journal of research in medical sciences. 17 (1 SPL.1): S73-S78.
Afanas'ev IB, Afanas'ev II, Deeva IB & Korkina LG 2000. Free radical formation and oxyhemoglobin oxidation in β-thalassemic red blood cells in the presence of prooxidants: Effects of the free radical scavenger rutin and oral chelator L1. Transfusion science. 23 (3): 237-238.
Al-Basher GI 2019. Green tea activity and iron overload induced molecular fibrogenesis of rat liver. Saudi journal of biological sciences. 26 (3): 531-540.
Alta ECP, et al. 2014. Desferrioxamine-caffeine (DFCAF) as a cell permeant moderator of the oxidative stress caused by iron overload. BioMetals. 27 (6): 1351-1360.
Asai A & Miyazawa T 2000. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life sciences. 67 (23): 2785-2793.
Barros-Rodríguez M, et al. 2014. Leucaena leucocephala in ruminant nutrition. Tropical and subtropical agroecosystems. 17 (2): 173-183.
Barton JC 2007. Chelation therapy for iron overload. Current gastroenterology reports. 9 (1): 74-82.
Bentley R 2006. From miso, sake and shoyu to cosmetics: a century of science for kojic acid. Natural product reports. 23 (6): 1046-1062.
Borsari M, et al. 2001. Silybin, a new iron-chelating agent. Journal of inorganic biochemistry. 85 (2-3): 123-129.
Clifford MN 2000. Chlorogenic acids and other cinnamates - Nature, occurrence, dietary burden, absorption and metabolism. Journal of the science of food and agriculture. 80 (7): 1033-1043.
Das SK, Desaulniers J, Dyck JRB, Kassiri Z & Oudit GY 2016. Resveratrol mediates therapeutic hepatic effects in acquired and genetic murine models of iron-overload. Liver international. 36 (2): 246-257.
Das SK, et al. 2015. Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy. Scientific reports. 5.
Dinda B, et al. 2017. Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. European journal of medicinal chemistry. 131: 68-80.
Ding M, Bhupathiraju SN, Satija A, Van Dam RM & Hu FB 2014. Long-term coffee consumption and risk of cardiovascular disease: A systematic review and a dose-response meta-analysis of prospective cohort studies. Circulation. 129 (6): 643-659.
Dolatabadi JEN, Mokhtarzadeh A, Ghareghoran SM & Dehghan G 2014. Synthesis, characterization and antioxidant property of Quercetin-Tb(III) complex. Advanced pharmaceutical bulletin. 4 (2): 101-104.
Fang K, et al. 2015. Effect of environmental factors on the complexation of iron and humic acid. Journal of environmental sciences (China). 27 (C): 188-196.
Ferlazzo N, et al. 2016. Natural iron chelators: Protective role in A549 cells of flavonoids-rich extracts of Citrus juices in Fe3+-induced oxidative stress. Environmental toxicology and pharmacology. 43: 248-256.
Ferrali M, et al. 1997. Protection against oxidative damage of erythrocyte membrane by the flavonoid quercetin and its relation to iron chelating activity. FEBS Letters. 416 (2): 123-129.
Gallagher ML 2012. Intake: The Nutrients and Their Metabolism In Krause's food the  nutrition care process (ed. L. Mahan, S. Escott-Stump, J. Raymond and M. Krause), pp. 32-135. Elsevier: Canada.
Guo R, Wei P & Liu W 2007. Combined antioxidant effects of rutin and Vitamin C in Triton X-100 micelles. Journal of pharmaceutical and biomedical analysis. 43 (4): 1580-1586.
Hagag AA, Elfrargy MS, Gazar RA & El-Lateef AEA 2013. Therapeutic value of combined therapy with deferasirox and silymarin on iron overload in children with beta thalassemia. Mediterranean journal of hematology and infectious diseases. 5 (1): 1-7.
Hegarty MP, Lee CP, Christie GS, Court RD & Haydock KP 1979. The goitrogen 3-hydroxy-4(1H)-pyridone, a ruminal metabolite from Leucaena leucocephala: effects in mice and rats. Australian journal of biological sciences. 32 (1): 27-40.
Hershko C 2010. Pathogenesis and management of iron toxicity in thalassemia. In Annals of the New York Academy of Sciences, pp. 1-9.
Hershko C, et al. 2003. Objectives and methods of iron chelation therapy. Bioinorganic chemistry and applications. 1 (2): 151-168.
Huayhuaz JAA, et al. 2017. Desferrioxamine and desferrioxamine-caffeine as carriers of aluminum and gallium to microbes via the Trojan Horse Effect. Journal of trace elements in medicine and biology. 41: 16-22.
Ikeda H, Kimura Y, Masaki M & Iwahashi H 2011. Caffeic acid inhibits the formation of 1-hydroxyethyl radical in the reaction mixture of rat liver microsomes with ethanol partly through its metal chelating activity. Journal of clinical biochemistry and nutrition. 48 (3): 187-193.
Imam MU, Zhang S, Ma J, Wang H & Wang F 2017. Antioxidants mediate both iron homeostasis and oxidative stress. Nutrients. 9 (7).
Inamori Y, et al. 1997. Biological activity of purpurogallin. Bioscience, biotechnology and biochemistry. 61 (5): 890-892.
Jayakumar T, et al. 2013. Hinokitiol, a natural tropolone derivative, offers neuroprotection from thromboembolic stroke in vivo. Evidence-based complementary and alternative medicine. 2013.
Jiao Y, et al. 2009. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood. 113 (2): 462-469.
Kontoghiorghe CN, Kolnagou A & Kontoghiorghes GJ 2015. Phytochelators intended for clinical use in iron overload, other diseases of iron imbalance and free radical pathology. Molecules. 20 (11): 20841-20872.
Kontoghiorghes GJ 1988. Structure/red blood cell permeability. Activity of iron(III) chelator complexes. Inorganica chimica acta. 151 (2): 101-106.
Kontoghiorghes GJ 1990a. Chelators affecting iron absorption in mice. Arzneimittel-Forschung. 40 (12): 1332-1335.
Kontoghiorghes GJ 1990b. Chelators affecting iron absorption in mice. Arzneimittel-Forschung/Drug Research. 40 (12): 1332-1335.
Kontoghiorghes GJ, et al. 1987. Effective chelation of iron in β thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. British medical journal 295 (6612): 1509-1512.
Kontoghiorghes GJ, Barr J, Nortey P & Sheppard L 1993. Selection of a new generation of orally active α-ketohydroxypyridine iron chelators intended for use in the treatment of iron overload. American journal of hematology. 42 (4): 340-349.
Kontoghiorghes GJ & Evans RW 1985. Site specificity of iron removal from transferrin by alpha-ketohydroxypyridine chelators. FEBS Lett. 189 (1): 141-144.
Kontoghiorghes GJ, Jackson MJ & Lunec J 1986a. In vitro screening of iron chelators using models of free radical damage. Free radical research. 2 (1-2): 115-124.
Kontoghiorghes GJ, Jackson MJ & Lunec J 1986b. In vitro screening of iron chelators using models of free radical damage. Free radical research communications. 2 (1-2): 115-124.
Kontoghiorghes GJ, Pattichis K, Neocleous K & Kolnagou A 2004. The design and development of deferiprone (L1) and other iron chelators for clinical use: Targeting methods and application prospects. Current medicinal chemistry. 11 (16): 2161-2183.
Korkina LG & Afanas'ev IB 1997. Antioxidant and chelating properties of flavonoids. Advances in pharmacology. 38: 151-163.
Kotyzova D, Eybl V, Koutensky J, Brtko J & Glattre E 2004. Effects of kojic acid on oxidative damage and on iron and trace element level in iron-overloaded mice and rats. Central European journal of public health. 12 Suppl: S41-44.
Leopoldini M, Russo N, Chiodo S & Toscano M 2006. Iron chelation by the powerful antioxidant flavonoid quercetin. Journal of agricultural and food chemistry. 54 (17): 6343-6351.
Lesjak M, et al. 2014. Quercetin inhibits intestinal iron absorption and ferroportin transporter expression in vivo and in vitro. PLoS ONE. 9 (7).
Loguercio C & Festi D 2011. Silybin and the liver: From basic research to clinical practice. World journal of gastroenterology. 17 (18): 2288-2301.
Ma Q, Kim EY, Lindsay EA & Han O 2011. Bioactive Dietary Polyphenols Inhibit Heme Iron Absorption in a Dose-Dependent Manner in Human Intestinal Caco-2 Cells. Journal of food science. 76 (5): H143-H150.
Matsui Y, Tanaka Y & Iwahashi H 2017. A comparative study of the inhibitory effects by caffeic acid, catechins and their related compounds on the generation of radicals in the reaction mixture of linoleic acid with iron ions. Journal of clinical biochemistry and nutrition. 60 (3): 162-168.
Mazzone G, Malaj N, Russo N & Toscano M 2013. Density functional study of the antioxidant activity of some recently synthesized resveratrol analogues. Food chemistry. 141 (3): 2017-2024.
Moayedi B, et al. 2013. A randomized double-blind, placebo-controlled study of therapeutic effects of silymarin in beta-thalassemia major patients receiving desferrioxamine. European journal of haematology. 90 (3): 202-209.
Mohammadpour M, Behjati M, Sadeghi A & Fassihi A 2013. Wound healing by topical application of antioxidant iron chelators: Kojic acid and deferiprone. International wound journal. 10 (3): 260-264.
Mostert LJ, Van Dorst JALM, Koster JF, van Eijk HG & Kontoghiorghes GJ 1987. Free radical and cytotoxic effects of chelators and their iron complexes in the hepatocyte. Free radical research. 3 (6): 379-388.
Nakano H, et al. 2006. Human metallothionein gene expression is upregulated by β-thujaplicin: Possible involvement of protein kinase C and reactive oxygen species. Biological and pharmaceutical bulletin. 29 (1): 55-59.
Namba K & Murata Y 2010. Toward mechanistic elucidation of iron acquisition in barley: Efficient synthesis of mugineic acids and their transport activities. Chemical record. 10 (2): 140-150.
Niu Q, et al. 2016. Proanthocyanidin Protects Human Embryo Hepatocytes from Fluoride-Induced Oxidative Stress by Regulating Iron Metabolism. Biological trace element research. 169 (2): 174-179.
Nurchi VM, et al. 2011. Kojic acid derivatives as powerful chelators for iron(III) and aluminium(III). Dalton transactions. 40 (22): 5984-5998.
Ochiai B, Kamiya M & Endo T 2012. Synthesis and Fe(III)-complexation ability of polyurethane bearing kojic acid skeleton in the main chain prepared by polyaddition of aliphatic hydroxyl groups without protection of phenolic hydroxyl groups. Journal of polymer science, Part A: Polymer chemistry. 50 (17): 3493-3498.
Ohta Y, et al. 1997. Comparative study of oral and parenteral administration of sho-saiko-to (xiao-chaihu-tang) extract on d-galactosamine-induced liver injury in rats. American journal of Chinese medicine. 25 (3-4): 333-342.
Oke-Altuntas F, Aslim B, Duman H & Kartal M 2016. Comparative evaluation of total phenolic/carotenoid contents, chlorogenic acid/rutin profiles, and antioxidant properties of two prangos species (P. Uechtritzii And P. Pabularia). International journal of pharmacy and pharmaceutical sciences. 8 (1): 284-288.
Olabinri BM, Eniyansoro OO, Okoronkwo CO, Olabinri PF & Olaleye MT 2010. Evaluation of chelating ability of aqueous extract of Tetracarpidium conophorum (African walnut) in vitro. International journal of applied research in natural products. 3 (3): 13-18.
Perron NR & Brumaghim JL 2009. A review of the antioxidant mechanisms of polyphenol compounds related to iron binding. Cell biochemistry and biophysics. 53 (2): 75-100.
Pole SN 2006. Wheat grass juice in thalassemia. Indian pediatrics. 43 (1): 79-80.
Saniewski M, Saniewska A & Kanlayanarat S 2007. Biological activities of tropolone and hinokitiol: The tools in plant physiology and their practical use. In Acta horticulturae, pp. 133-142.
Shander A, Cappellini MD & Goodnough LT 2009. Iron overload and toxicity: The hidden risk of multiple blood transfusions. Vox sanguinis. 97 (3): 185-197.
Shimoi K, et al. 1997. Protection by αG-Rutin, a water-soluble antioxidant flavonoid, against renal damage in mice treated with ferric nitrilotriacetate. Japanese journal of cancer research. 88 (5): 453-460.
Srichairatanakool S, et al. 2006. Iron-chelating and free-radical scavenging activities of microwave-processed green tea in iron overload. Hemoglobin. 30 (2): 311-327.
Srichairatanakool S, Thephinlap C, Phisalaphong C, Porter JB & Fucharoen S 2007. Curcumin contributes to in vitro removal of non-transferrin bound iron by deferiprone and desferrioxamine in thalassemic plasma. Medicinal chemistry. 3 (5): 469-474.
Tang Y, et al. 2014. Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway. Journal of nutritional biochemistry. 25 (6): 675-682.
Thephinlap C, Phisalaphong C, Fucharoen S, Porter JB & Srichairatanakool S 2009. Efficacy of curcuminoids in alleviation of iron overload and lipid peroxidation in thalassemic mice. Medicinal chemistry. 5 (5): 474-482.
Ullmann U, Haller J, Bakker GCM, Brink EJ & Weber P 2005. Epigallocatechin gallate (EGCG) (TEAVIGO™) does not impair nonhaem-iron absorption in man. Phytomedicine. 12 (6-7): 410-415.
Van Schaik JWJ, Persson I, Kleja DB & Gustafsson JP 2008. EXAFS study on the reactions between iron and fulvic acid in acid aqueous solutions. Environmental science and technology. 42 (7): 2367-2373.
Weber G, Von Wirén N & Hayen H 2008. Investigation of ascorbate-mediated iron release from ferric phytosiderophores in the presence of nicotianamine. BioMetals. 21 (5): 503-513.
Yang CS, Chen G & Wu Q 2014. Recent scientific studies of a traditional Chinese medicine, tea, on prevention of chronic diseases. Journal of traditional and complementary medicine. 4 (1): 17-23.
Yang R & Van Den Berg CMG 2009. Metal complexation by humic substances in seawater. Environmental science and technology. 43 (19): 7192-7197.
Yoshino M & Murakami K 1998. Interaction of iron with polyphenolic compounds: Application to antioxidant characterization. Analytical biochemistry. 257 (1): 40-44.
Zhang Y, Gao Z, Liu J & Xu Z 2011. Protective effects of baicalin and quercetin on an iron-overloaded mouse: Comparison of liver, kidney and heart tissues. Natural product research. 25 (12): 1150-1160.
Zhang Y, Li H, Zhao Y & Gao Z 2006. Dietary supplementation of baicalin and quercetin attenuates iron overload induced mouse liver injury. European journal of pharmacology. 535 (1-3): 263-269.
Zhao L, et al. 2015. Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character. Journal of nutritional biochemistry. 26 (11): 1174-1182.
Zhao Y, Li H, Gao Z & Xu H 2005. Effects of dietary baicalin supplementation on iron overload-induced mouse liver oxidative injury. European journal of pharmacology. 509 (2-3): 195-200.
Zijp IM, Korver O & Tijburg LBM 2000. Effect of tea and other dietary factors on iron absorption. Critical reviews in food science and nutrition. 40 (5): 371-398.