DHA/CQ 对疟原虫红内期生长的 pH 和铁稳态的抑制机制
Inhibitory Mechanisms of DHA/CQ on pH and Iron Homeostasis of Erythrocytic Stage Growth of .
机构信息
Tang Center for Herbal Medicine Research, China Academy of Traditional Chinese Medical Sciences, Beijing 100700, China.
Artemisinin Research Center and Institute of Chinese Meteria Medica, China Academy of Traditional Chinese Medical Sciences, Beijing 100700, China.
出版信息
Molecules. 2019 May 20;24(10):1941. doi: 10.3390/molecules24101941.
Malaria is an infectious disease caused by group. The mechanisms of antimalarial drugs DHA/CQ are still unclear today. The inhibitory effects (IC) 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 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 IC. 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 IC. Intracellular LIP was increased by DHA combined with Baf-A1 in the concentration of 20 IC. The expression of gene vapA was down-regulated by all low doses of DHA (0.2/0.4/0.8 nM) significantly ( < 0.001) and the expression of vapG/vapE were up-regulated by 0.8 nM DHA significantly ( < 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.
疟疾是一种由 引起的传染病。抗疟药物 DHA/CQ 的作用机制尚不清楚。本文研究了 DHA/CQ 单药治疗、V-ATPase 抑制剂巴弗洛霉素 A1（Baf-A1）单药治疗以及 DHA/CQ 联合 Baf-A1 联合治疗对 3D7 株生长的抑制作用。通过 pH 探针 BCECF、AM 和铁探针 calcein，AM 标记细胞内细胞质 pH 和不稳定铁池（LIP），通过 FCM 测量探针的荧光。通过 RT-qPCR 检测低剂量 DHA（0.2 nM、0.4 nM、0.8 nM）对位于 DV 膜上的 V-ATPases（vapE、vapA、vapG）基因表达的影响。DHA 联合 Baf-A1 在 IC 浓度下对寄生虫生长表现出协同作用（CI = 0.524）。不同剂量的 DHA/Baf-A1 对细胞内 pH 和铁有显著影响。在 IC 浓度下，CQ 联合 Baf-A1 使细胞内 pH 降低。在 20 IC 浓度下，DHA 联合 Baf-A1 使细胞内 LIP 增加。所有低剂量 DHA（0.2/0.4/0.8 nM）均显著下调 vapA 基因的表达（<0.001），0.8 nM DHA 显著上调 vapG/vapE 基因的表达（<0.001）。与亚铁离子相互作用，影响 DV 膜质子泵和酸性 pH 或细胞质铁稳态可能是 DHA 的抗疟机制，而 CQ 在体外对寄生虫细胞质 pH 有影响。最后，本文为抗疟药物联合应用和新的潜在抗疟联合治疗方案提供了初步结果和新的思路。
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