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Article

Inhibitory Mechanisms of DHA/CQ on pH and Iron Homeostasis of Erythrocytic Stage Growth of Plasmodium falciparum

by 1,2, 1,2, 1,2, 1,2, 1, 1,2 and 1,*
1
Tang Center for Herbal Medicine Research, China Academy of Traditional Chinese Medical Sciences, Beijing 100700, China
2
Artemisinin Research Center and Institute of Chinese Meteria Medica, China Academy of Traditional Chinese Medical Sciences, Beijing 100700, China
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(10), 1941; https://doi.org/10.3390/molecules24101941
Received: 3 April 2019 / Revised: 11 May 2019 / Accepted: 13 May 2019 / Published: 20 May 2019
Malaria is an infectious disease caused by Plasmodium group. The mechanisms of antimalarial drugs DHA/CQ are still unclear today. The inhibitory effects (IC50) of single treatments with DHA/CQ or V-ATPase inhibitor Baf-A1 or combination treatments by DHA/CQ combined with Baf-A1 on the growth of Plasmodium falciparum strain 3D7 was investigated. Intracellular cytoplasmic pH and labile iron pool (LIP) were labeled by pH probe BCECF, AM and iron probe calcein, AM, the fluorescence of the probes was measured by FCM. The effects of low doses of DHA (0.2 nM, 0.4 nM, 0.8 nM) on gene expression of V-ATPases (vapE, vapA, vapG) located in the membrane of DV were tested by RT-qPCR. DHA combined with Baf-A1 showed a synergism effect (CI = 0.524) on the parasite growth in the concentration of IC50. Intracellular pH and irons were effected significantly by different doses of DHA/Baf-A1. Intracellular pH was decreased by CQ combined with Baf-A1 in the concentration of IC50. Intracellular LIP was increased by DHA combined with Baf-A1 in the concentration of 20 IC50. The expression of gene vapA was down-regulated by all low doses of DHA (0.2/0.4/0.8 nM) significantly (p < 0.001) and the expression of vapG/vapE were up-regulated by 0.8 nM DHA significantly (p < 0.001). Interacting with ferrous irons, affecting the DV membrane proton pumping and acidic pH or cytoplasmic irons homeostasis may be the antimalarial mechanism of DHA while CQ showed an effect on cytoplasmic pH of parasite in vitro. Lastly, this article provides us preliminary results and a new idea for antimalarial drugs combination and new potential antimalarial combination therapies. View Full-Text
Keywords: malaria; drug combinations; dihydroartemisinin; chloroquine; baflomycin-A1; V-type proton ATPase inhibitor; Plasmodium falciparum; digestive vacuole; calcein; BCECF malaria; drug combinations; dihydroartemisinin; chloroquine; baflomycin-A1; V-type proton ATPase inhibitor; Plasmodium falciparum; digestive vacuole; calcein; BCECF
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MDPI and ACS Style

Tang, T.; Xu, W.; Ma, J.; Wang, H.; Cui, Z.; Jiang, T.; Li, C. Inhibitory Mechanisms of DHA/CQ on pH and Iron Homeostasis of Erythrocytic Stage Growth of Plasmodium falciparum. Molecules 2019, 24, 1941. https://doi.org/10.3390/molecules24101941

AMA Style

Tang T, Xu W, Ma J, Wang H, Cui Z, Jiang T, Li C. Inhibitory Mechanisms of DHA/CQ on pH and Iron Homeostasis of Erythrocytic Stage Growth of Plasmodium falciparum. Molecules. 2019; 24(10):1941. https://doi.org/10.3390/molecules24101941

Chicago/Turabian Style

Tang, Tian, Wenhui Xu, Ji Ma, Huajing Wang, Zhao Cui, Tingliang Jiang, and Canghai Li. 2019. "Inhibitory Mechanisms of DHA/CQ on pH and Iron Homeostasis of Erythrocytic Stage Growth of Plasmodium falciparum" Molecules 24, no. 10: 1941. https://doi.org/10.3390/molecules24101941

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