Malaria in pregnancy regulates P-glycoprotein (P-gp/Abcb1a) and ABCA1 efflux transporters in the Mouse Visceral Yolk Sac.

Malaria in pregnancy (MiP) induces intrauterine growth restriction (IUGR) and preterm labour (PTL). However, its effects on yolk sac morphology and function are largely unexplored. We hypothesized that MiP modifies yolk sac morphology and efflux transport potential by modulating ABC efflux transporters. C57BL/6 mice injected with Plasmodium berghei ANKA (5 × 105 infected erythrocytes) at gestational day (GD) 13.5 were subjected to yolk sac membrane harvesting at GD 18.5 for histology, qPCR and immunohistochemistry. MiP did not alter the volumetric proportion of the yolk sac's histological components. However, it increased levels of Abcb1a mRNA (encoding P-glycoprotein) and macrophage migration inhibitory factor (Mif chemokine), while decreasing Abcg1 (P < 0.05); without altering Abca1, Abcb1b, Abcg2, Snat1, Snat2, interleukin (Il)-1ß and C-C Motif chemokine ligand 2 (Ccl2). Transcripts of Il-6, chemokine (C-X-C motif) ligand 1 (Cxcl1), Glut1 and Snat4 were not detectible. ABCA1, ABCG1, breast cancer resistance protein (BCRP) and P-gp were primarily immunolocalized to the cell membranes and cytoplasm of endodermic epithelium but also in the mesothelium and in the endothelium of mesodermic blood vessels. Intensity of P-gp labelling was stronger in both endodermic epithelium and mesothelium, whereas ABCA1 labelling increased in the endothelium of the mesodermic blood vessels. The presence of ABC transporters in the yolk sac wall suggests that this fetal membrane acts as an important protective gestational barrier. Changes in ABCA1 and P-gp in MiP may alter the biodistribution of toxic substances, xenobiotics, nutrients and immunological factors within the fetal compartment and participate in the pathogenesis of malaria-induced IUGR and PTL.

Antiplasmodial activity of alkyl-substituted 1,2-dioxetanes against Plasmodium falciparum.

This article reports the in vitro antiplasmodial activity of two endoperoxides of the class 1,2-dioxetanes against Plasmodium falciparum: bis(adamantyl)-1,2-dioxetane and 3,3,4,4-tetramethyl-1,2-dioxetane. The results reveal that bis(adamantyl)-1,2-dioxetane displays substantial antiplasmodial activity, at least two orders of magnitude higher than that of artemisinin, while 3,3,4,4-tetramethyl-1,2-dioxetane is less active.

Anti-plasmodial activity of bradykinin and analogs.

To find effective new candidate antimalarial drugs, bradykinin and its analogs were synthesized and tested for effectiveness against Plasmodium gallinaceum sporozoites and Plasmodium falciparum on erythrocytes. Among them, bradykinin and its P2 analog presented high activity against Plasmodium gallinaceum, but they degrade in plasma. On the other hand, RI-BbKI did not degrade and reached high activity. No analog was active against Plasmodium falciparum.

Targeting Angiotensin II Type-1 Receptor (AT1R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8+ T Cells during Blood-Stage Malaria.

CD8+ T-cell response is critical in the pathogenesis of cerebral malaria during blood-stage. Our group and other have been shown that angiotensin II (Ang II) and its receptor AT1 (AT1R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT1R signaling protects mice against the lethal disease induced by Plasmodium berghei ANKA infection However, most of the Ang II/AT1R actions were characterized by using only pharmacological approaches, the effects of which may not always be due to a specific receptor blockade. In addition, the mechanisms of action of the AT1R in inducing the pathogenic activity of Plasmodium-specific CD8+ T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT1R axis promotes the harmful response of Plasmodium-specific CD8+ T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT1R-/-Plasmodium-specific CD8+ T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT Plasmodium-specific CD8+ T cells were treated with losartan (AT1R antagonist) or captopril (ACE inhibitor). Both, AT1R-/- OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2Rα expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT1R-/- OT-I cells also exhibit lower expression of the integrin LFA-1 and the chemokine receptors CCR5 and CXCR3, known to play a key role in the development of cerebral malaria. Moreover, AT1R-/- OT-I cells produce lower amounts of IFN-γ and TNF-α and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT1R-induced harmful phenotype of Plasmodium-specific CD8+ T cells during blood-stage malaria.

Antimalarial Effect of 3-Methoxy-1,2-Dioxetanes on the Erythrocytic Cycle of Plasmodium falciparum.

The antimalarial activity of peroxides most likely originates from their interaction with iron(II) species located inside the malaria parasite, which forms destructive radical species through a Fenton-like mechanism. This article reports the first evaluation of the in vitro antimalarial activity of three peroxides of the class 1,2-dioxetanes against Plasmodium falciparum; the results reveal that the studied 3-methoxy-1,2-dioxetanes display significant antimalarial activity, at a similar level as artemisinin and also that their reactivity toward iron(II) correlate linearly with their antimalarial activity.