RESUMO
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.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Regulação da Expressão Gênica , Malária/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Saco Vitelino/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Transporte Biológico , Citocinas/biossíntese , Citocinas/genética , Feminino , Retardo do Crescimento Fetal/etiologia , Inflamação , Malária/complicações , Malária/genética , Proteínas de Membrana Transportadoras/biossíntese , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Plasmodium berghei , Gravidez , Complicações Infecciosas na Gravidez/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Saco Vitelino/ultraestruturaRESUMO
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.