BackgroundIron is an essential micronutrient required by all living organisms including malaria parasites (Plasmodium spp.) for many biochemical reactions, especially growth and multiplication processes. Therefore, malaria parasite needs to take up the iron from outside or/and inside the parasitized red blood cells (PRBC). Iron chelators are widely used for the treatment of thalassaemia-related iron overload and also inhibit parasite growth at levels that are non-toxic to mammalian cells.MethodsInhibitory effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and green tea extract (GTE) on the growth of malaria parasite Plasmodium falciparum was compared with standard chelators including desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX). A flow cytometric technique was used to enumerate PRBC stained with SYBR Green I fluorescent dye. The labile iron pool (LIP) was assayed using the calcein-acetoxymethyl fluorescent method.ResultsThe IC50 values of DFO, GTE, CM1, DFX and DFP against P. falciparum were 14.09, 21.11, 35.14, 44.71 and 58.25 µM, respectively. Importantly, CM1 was more effective in reducing LIP levels in the P. falciparum culture than DFP (p < 0.05).ConclusionsCM1 and GTE exhibit anti-malarial activity. They could interfere with uptake of exogenous iron or deplete the intracellular labile iron pool in malaria parasites, leading to inhibition of their growth.

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Inhibitors for Plasmodium falciparum dihydrofolate reductase (DHFR) form an important class of antimalarial drugs widely used for malaria treatment, but have been compromised by development of resistance to the drugs. Mutations in DHFR are the main contributing factors to the resistance. Although new, rationally designed antifolates active against resistant P. falciparum, such as P218, have been developed, the activity against the quadruple mutant P. falciparum (V1/S) has only been demonstrated in vitro, and in vivo activity has only been shown in SCID mice. A convenient in vivo model for antifolate testing is desirable. In this study, the endogenous P. berghei dihydrofolate reductase-thymidylate synthase (Pbdhfr-ts) gene was successfully replaced by quadruple dhfr-ts mutant gene from P. falciparum (N51I+C59R+S108N+I164L). The transgenic parasite gained resistance to pyrimethamine but not to other class of antimalarial drugs. While 30 mg/kg of pyrimethamine could not inhibit the transgenic parasite, P218 could inhibit the transgenic parasite with the ED50 of 0.11±0.02 mg/kg, a level similar to the P. falciparum in SCID mice model. These results demonstrated the validity of our model and showed that P218 was very potent against quadruple Pfdhfr-ts mutant parasite, in vivo.

We investigated the effect of perilla leaf extract (PLE) containing polyphenols on various biological functions including antioxidant activity, iron chelation, and red blood cell haemolysis protection. The total phenolic and flavonoid content were determined by colorimetric assay and HPLC analysis. The antioxidant activity was determined by DPPH and ABTS assay. The iron chelating effect was examined by the colorimetric method. Free radical scavenging activity was determined by haemoglobin-induced lipid peroxidation in a linoleic acid model system. Reactive oxygen species (ROS) inhibition was investigated in peripheral blood mononuclear cells. The antihaemolytic activity by AAPHinduced free radicals. The results revealed that PLE contained high levels of total phenolic compounds and total flavonoids (mainly rosmarinic acid). The IC 50 values of PLE by DPPH and ABTS radical scavenging assay were 34.3 ± 3.4 and 9.69 ± 0.14 µg/ml, respectively. The iron-binding effect of PLE was exhibited by complex formation with Fe 3+-NTA. The iron-chelating activity displayed a moderate IC 50 value of 10.1 ± 0.6 mg/ml. The PLE concentration of 200 µg/ml, significantly inhibited intracellular ROS 45%. The scavenging activity of PLE in haemoglobin-induced lipid peroxidation resulted in 27% inhibition. PLE also prevented AAPH-induced RBC haemolysis. In conclusion, PLE containing phenolic compounds plays a vital role in free radical scavenging and iron-chelating activities and subsequently prevents lipid peroxidation resulting from RBC haemolysis due to oxidative stress. Perilla products may be developed as health supplements, which could probably be used in prophylaxis and treatment of non-communicable diseases.