iron is bad for malaria and other diseases

iron chelators in malaria

One of the first mistakes of Western medicine in Africa was the iron supplementation to the Somali nomads in 1968. Blood analysis of these nomads had shown that according to European standards they were suffering from anemia. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J. 1978 Oct 21;2(6145):1113-5. But iron administration was associated with a significant increase of the disease it was supposed to suppress and even to reactivation of pre-existing diseases. The conclusion of the authors was that iron deficiency eventually plays a part in supressing certain infections. Since that date it has been documented by many authors that anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. A more recent paper even shows that placental malaria increases the infant’s susceptibility to the infection translating into an increased number of clinical episodes Moya-Alvarez V, Bodeau-Livinec F, Cot M. Iron and malaria: a dangerous liaison? Nutr Rev. 2016 Oct;74(10):612-23. doi: 10.1093/nutrit/nuw021. Epub 2016 Aug 26. Moya-Alvarez V, Cottrell G, Ouédraogo S, Accrombessi M, Massougbodgi A, Cot M. Does Iron Increase the Risk of Malaria in Pregnancy? Open Forum Infect Dis. 2015 Mar 20;2(2):ofv038. doi: 10.1093/ofid/ofv038. Plasmodium falciparum infects iron-deficient erythrocytes less efficiently, but the mechanisms remain obscure. Clark MA, Goheen MM, Fulford A, Prentice AM, Elnagheeb MA, Patel 3, Fisher N, Taylor SM, Kasthuri RS5, Cerami C3. Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum. Nat Commun. 2014 Jul 25;5:4446. doi: 10.1038/ncomms5446. Iron deficiency accelerates suicidal erythrocyte death. Moreover, iron deficiency impairs in vitro intraerythrocytic growth and infection of erythrocytes. In mice, iron-deficient erythrocytes are more rapidly cleared from circulating blood. Iron deficiency favourably influences the course of malaria, an effect partially due to accelerated suicidal death and subsequent clearance of infected erythrocytes. Koka S, Bobbala D, Lang C, Boini KM, Huber SM, Lang F. Influence of paclitaxel on parasitemia and survival of Plasmodium berghei infected mice. Cell Physiol Biochem. 2009;23(1-3):191-8. doi: 10.1159/000204107. Epub 2009 Feb 18. Green tea, coffee are well known to reduce nonheme-iron absorption. Catechins, gallic acid, chlorogenic acid, rosmarinic acid, ellagitannins are the main chelating agents. Tea has a potent inhibitory effect on the absortion of non-heme iron. A cup of tea reduced iron absorption from a humburger meal by 64%, a cup of coffee by 39%. TA Morck, SR Lynch, JD Cook, Inhibition of food iron absorption by coffee. Am J Clinical Nutrit. 1983. 37, 416-420. PB Disler, SR Lynch, RW Charlton, F Mayet. The effect of tea on iron absoption. Gut. 1975, 16, 193-200. A similar iron absorption effect exists for coffee. TA Morck, S Lynch, J Cook, Inhibition of food iron absorption by coffee. Amer J Clin Nutrition 1983, 416-420. Other authors find that the chelating effect of tea only works with ionic iron but is most unlikely to form complexes with haem, and indeed the abosprion of crystallized haem was not affected. Conrad, M. E. Factors affecting iron absorption. In Iron. Deficiency. Pathogenesis: Clinical Aspects: Therapy, edited by L. Hallberg, H. G. Harworth, and A. Vannotti, (1970). pp. 87-120. Academic Press, New York and London. The action of polyphenol compounds on iron mediated antioxidant and pro-oxidant effects is complex. They are related to the stability constants of one or more polyphenols binding to an iron ion in aqueous solution. For rutin and quercetin they were among the highest. Perron NR, Hodges JN, Jenkins M, Brumaghim JL. Predicting how polyphenol antioxidants prevent DNA damage by binding to iron. Inorg Chem. 2008 Jul 21;47(14):6153-61. doi: 10.1021/ic7022727. Lesjak M, Hoque R, Balesaria S, Skinner V3, Debnam ES, Srai SK, Sharp PA. Quercetin inhibits intestinal iron absorption. Quercetin inhibits intestinal iron absorption and ferroportin transporter expression in vivo and in vitro. PLoS One. 2014 Jul 24;9(7):e102900. doi: 10.1371/journal.pone.0102900. eCollection 2014. It is known that iron chelators reduce parasite load. In a dooble blind trial the treatment with desferrioxamine was associated with an almost 10-fold enhancement with the rate of parasite clearance. VR Gordeuk. Iron chelation with desferrioxamine in adults. Blood 1992, 79 308-312. Glucoside rutin present in most Artemisia species is even a stronger inhibitor. As iron supplements preferably accumulate in the liver where sporozoites need iron for their multiplication into thousands of merozoites, this is a critical control element. Quercetin as it is found in aqueous extracts of Artemisia also has very strong antihemolytic properties Naqinezhad A, Nabavi SM, Nabavi SF, Ebrahimzadeh MA. Antioxidant and antihemolytic activities of flavonoid rich fractions of Artemisia tschernieviana Besser. Eur Rev Med Pharmacol Sci. 2012 Jul;16 Suppl 3:88-94. Artemisia annua from Cameroon contains 4 times more rutin than Artemisia annua from Luxembourg. This might explain its stronger inhibition of beta-hematin. Luteolin, one of the main constituants in Artemisia afra, is also a strong chelator of iron, it reduces the absorption of free iron from food, inhibiting the Fenton reaction which generates OH radicals. Ai-Hong Yang, Xue-Ying Shi, Xue Li,a Fang-Fang Li, Qin-Qin Zhang, Shu-Xin Jiang, Jian-Zhong Cui and Hong-ling Gao . Spectroscopic and electrochemical studies on the evaluation of the radical scavenging activities of luteolin by chelating iron. RSC Adv., 2014,4, 25227-25233. DOI: 10.1039/C4RA01396D Iron supplements should be handled with caution for an additional reason. African children carry an unfavorable ratio of fecal enterobacteria to bifidobacteria and lactobacilli, which is increased by iron fortification. And it is well known that iron supplements enhance the susceptibility to malaria infection. Zimmermann MB, Chassard C, Rohner F, N'goran EK, Nindjin C, Dostal A, Utzinger J, Ghattas H, Lacroix C, Hurrell RF. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. Am J Clin Nutr. 2010 Dec;92(6):1406-15. doi: 10.3945/ajcn.110.004564. Proanthocyanidins are also strong iron chelators and Artemisia plants are rich in condensed tannins. The inclusion of cranberry juice in bacterial growth media was found to significantly impact the doubling time of E. coli. The iron depletion effect was confirmed by adding exogenous iron to the growth media Lin B, Johnson BJ, Rubin RA, Malanoski AP, Ligler FS. Iron chelation by cranberry juice and its impact on Escherichia coli growth. Biofactors. 2011 Mar-Apr;37(2):121-30. doi: 10.1002/biof.110. Iffat, A.T., Maqsood, Z.T. and Fatima, N. (2004). Study of Formation of Fe(III) with Tanicacid, J. Chem. Soc. Pak., 27(2), 174-178). Karamac, M. 2009. Chelation of Cu(II), Zn(II), and Fe(II) by tannin constituents of selected edible nuts. Int. J. Mol. Sci. 10:5485-5497. An excellent list of concentrations of proanthocyanidins in common foods is available on J Nutr March 1 vol 134 3, 613-617

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