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Potassium,sodium, phospholipids and hemozoin

March 19, 2016 - 21:05 -- Pierre Lutgen

Upon infection of human erythrocytes, the phospholipid content of Plasmodium falciparum increases by at least 5 to 6-fold. The main molecules are phosphatidylinositol (PI), phosphatidylcholine (PC) and others. They are often called lecithin although this substance contains many other molecules

The rapid multiplication of the parasite within human erythrocytes requires an active production of new membranes. PC is the most abundant phospholipid in Plasmodium membranes followed by others like PI. It has been demonstrated that PI and PC localize to the food vacuole membrane and the apicoplast. During invasion this phospholipid is injected from the apical end of the merozoite into the host membrane (RB Mikkelsen et al., Proc Natl Acad Sci, 1988, 85, 5956- 5960). The parasite is able to modulate PC and PI synthesis metabolizing choline (ML Ancelyn et al., Biochim Biophys Acta 1989 1001, 82-89). Malaria infection accelerates this metabolism mainly during the ring stage and the beginning of trophozoite maturation (BD Beaumelle et al., J Cell Physiol, 1988 135, 94-100). Cancer cells and tumors have a similar aberrant choline phospholipid metabolism (E Ackerstaff et aal., J Cell Biochem, 2003, 90, 525-33).

The lipid profiles of erythrocytes during gametocytogenesis are still enigmatic. In particular the lipid metabolism, despite being central to cellular regulation, is not well explored. Cholesterol is one of the major fuels in asexual and sexual stages and the blood is depleted of this molecule. The focus on phospholipids has grown after several indications that hemozoin crystals were found in intimate contact with amphiphilic structures such as phospholipid membranes and lipid droplets. Recent work has shown that hemozoin is aligned in association with the surface of the digestive vacuole inner membrane, rather than encapsulated in neutral lipid droplets. Thus the mode of heme interaction with lipid membranes seems a key aspect to understand the process of heme crystallization. In vitro experiments have shown that beta-hematin crystals grow parallel to the water surface, indicating that hydroxyl groups play a central role. Phospholipids mediate heme crystallization not only in Plasmodium falciparum, but also in other parasites like Rhodnius prolixus (R Stiebler et al., PLoS One 2014, 9, e88976).

PC and PI are ubiquitous in eukaryotic cells but is only present in small amounts in mammalian cells. PC and PI offer thus new possibilities for antimalarial therapy (T Tawk et al., Eukaryotic Cell, 2010 9, 1519-30). Choline necessary for their synthesis is found in food, especially eggs and meat, but also several plants, peanuts, soya and moringa for example. It has been demonstrated that phosphocholine biosynthesis can be interrupted by hexadecyltrimethylammonium bromide and that this results in the death of the parasite (V Choubey et al., Antimicr Ag and Chemother, 2007. 51, 696-706). The inhibition by amodiaquine, chloroquine, primaquine has also been studied but is not very efficient with IC50 values over 500 microM (Soon Goo Lee et al., Bioorg Med Chem Let 2012 22, 4990-4993).

POTASSIUM AND PHOSPHOLIPIDS

Eukaryotes need exogenous inorganic phosphate for maximum growth and for the production of phospholipids. The influx into the food vacuole of Plasmodium falciparum is mediated by Na⁺. The activation energy for uptake decreases with extracellular Na⁺ concentration. As the concentration of Na⁺ increases with parasite maturation, the efficiency of the phosphate uptake by the parasite increases (K Saliba et al., Nature, 2006, doi 10.1038). Replacement of Na⁺ by K⁺in the in vitro culture decreased the phosphate influx by more than 95%. There was even an efflux of phosphate into the Na⁺ free medium.

A similar effect of Na⁺concentration on phosphate transport was noticed in Xenopus oocytes (K Saliba op.cit.).Also in Trypanosoma rangeli it was found that the inorganic phosphate influx is Na⁺ dependent (CF Dick et al., Biochim Biophys Acta , 2012, 1820 1001-1008)..

ARTEMISIAS ARE RICH IN POTASSIUM AND POOR IN SODIUM Among all the medicinal plants those of the Artemisia family have the highest potassium content. The first to report this were E Brisibe, P de Magalhaes, J Ferreira et al, (Food Chemistry, 2008, 115, 1240-46). Potassium concentrations in Artemisia annua at 2.6 % in dry leaves are 10 to 100 times higher than those of other minerals, particularly sodium which is only present in traces. A study in Morocco measured the potassium content of four medicinal plants. For Artemisia herba alba it is the highest (R Imelouane et al., J Mater Envir Si 2011, 2, 104-11). A more complete study in Pakistan, comparing 10 medicinal plants finds that potassium content in Artemisia annua is the highest (I Hussain et al., World Appl Sci J., 2011, 12, 1464-1468). A Tunesian study finds higher concentrations of potassium in Artemisia herba alba and A campestris than in Rosmarinus or Thymus. An extensive study at the University of Islamabad analyzed the elemental content in 17 indigenous species of Artemisia that are commonly used against ailments in Pakistan. (A. scoparia, A. absinthium, A. indica, A. santolinifolia, A. maritima, A. vulgaris, A. japonica, A. nilagirica, A. herba-alba, A. annua, A. brevifolia, A. moorcroftiana, A. dracunculus, A. roxburghiana and A. dubia). In all potassium concentrations are high in a fairly narrow range around 16 000 ppm and most of them are known to have antimalarial properties (M Ashraf et al., J Med Plant Res 2010, 4, 2256-63). In 1982 already the University of Wyoming conducted a study on minerals in Artemisia filigrana. Again potassium was very high and much more in the young plants (F Rauzi, Journal of Range Mgmt, 35, 1982, 679-680). In our own research work with the University of Dakar (T Alassane et al., Afr J Biotech, 2013, 12 4179-86) we had found that the concentrations of potassium in Artemisia annua from different origins was twice as high as in Camelia sinensis.

In vivo there is a strong increase of sodium concentration in the erythrocytes after Plasmodium infection and a loss up to 75-80% of potassium. The influence of sodium, potassium an ionic strength on the growth of Plasmodium is complex. The parasite has learned to adjust to high variations in ionic environment when moving from liver to blood cells and than back to plasma. For the first time in 1986 it was noticed that the growth of Plasmodium falciparum was enhanced in sodium-enriched medium (K Tanabe et al., Am J Tro Med Hyg 1986, 3, 476-478). Studying the invasion of uninfected erythrocytes by merozoites in a standard culture medium it was found that a high potassium concentration in this medium inhibited the invasion (W Tracer et al., J Eukaryot Microbiol 1984, 31-4). High concentrations of potassium and low concentrations of sodium are detrimental for the parasite. Cl¯ ions are also needed by the parasite for its growth. Merozoite egress decreases monotonically with ionic strength. The authors conclude that obviously additional studies are needed to reveal the molecular targets and the corresponding role of the ions in parasite physiology. Hormesis certainly plays a role (AD Pillai et al., Mol Microbiol 2013 88, 20-34).

Potassium strongly inhibits Il-1β and sodium enhances it (I Walev et al., The EMBO Journal, 1995, 8, 1607-14). Studies of sodium and potassium concentrations in the blood cells of patients with hypertension have suggested that red cell sodium concentration is frequently greater in Negro than in Caucasian subjects. Results like these also need to be integrated in research (A. D. MUNRO-FAURE ET AL Nature 231, 457 - 458 (18 June 1971); doi:10.1038/23145). As well as the recent finding that digestive food vacuoles are Ca⁺⁺ stores with concentrations 4 times higher than in the cytosol (GA Biagini et al., J Biol Chem. 2003, 278, 27910-15). Cytoplasmic calcium is essential for malaria parasite egress from infected erythrocytes. A steady increase is found to preceed this egress (S Glushakova et al., Malaria Journal, 2013 12 :41). In Toxoplasma gondii it has been obsserved that the reduction in the host cell potassium causes an increase in cytoplasmic calcium.

There is also the finding of the University of Al Quds that Artemisia annua leaf infusions prepared using salt water (0.5 NaCl /150ml water) had higher efficiency in inhibiting β-hematin formation than those infusions done with distilled water (M Akkawi et al., Med Aromat Plants, 2014, 3-1).

CONCLUSION

Artemisia with its specific salt content may starve and suffocate the parasites.

Pierre Lutgen 15 mar 2016