Current medicinal chemistry · 2026
Antimalarial Effects of Dobinin K against Chloroquine-resistant Plasmodium falciparum Through Disruption of the Parasite's Redox System.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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He Long-Fei, Sun He, Cang Li-Qi, Wang Jin-Da, Xiao Chao-Jiang, Jiang Bei, Shen Lei
Аннотация
OBJECTIVE: The current study was designed to systematically evaluate the antiplasmodial ability of Dobinin K against the chloroquine-resistant strain of Plasmodium falciparum (P. falciparum) Dd2 and investigate its potential mechanism of action.
METHODS: The effects of Dobinin K against Dd2 were assessed by both SYBR Green I fluorescence assay and Giemsa staining assay. Transcriptomic analysis was performed to examine global gene expression changes in P. falciparum following Dobinin K treatment. To explore the acting mechanism of Dobinin K on Dd2, contents of redox substrates and metabolites, as well as the activities of enzymes, were examined using the corresponding kit. Ultrastructural analysis was performed using transmission electron microscopy. The mitochondrial membrane potential (ΔΨm) was assessed based on JC-1 fluorescence intensity. The mRNA expression levels were analyzed through qRT-PCR. DNA fragmentation during apoptosis was evaluated using the TUNEL assay.
RESULTS: Dobinin K exhibited antiplasmodial activity against Dd2 that was both concentration- and time-dependent, affecting all developmental stages of the parasite. Transcriptomic analysis suggested that the mechanism of action of Dobinin K refers to the disruption of the redox system in the parasite. Dobinin K increased the levels of oxidative products, elevated the GSSG / GSH ratio, inhibited the activities of antioxidant enzymes, including PfGR, PfTrxR, and PfSOD, decreased the NADP+ / NADPH ratio, disruptedΔΨm, upregulated mRNA expression of most essential apicoplast metabolic enzymes, and ultimately induced apoptosis in Dd2.
DISCUSSION: Artemisinin-based combination therapies for chloroquine-resistant malaria face tremendous challenges due to the occurrence of artemisinin resistance. Our findings suggested that Dobinin K exerted its antimalarial effects by disrupting the parasite's redox homeostasis, a mechanism that differs from artemisinin. This further supports redox system targeting as an effective strategy against chloroquine-resistant P. falciparum.
CONCLUSION: Dobinin K disrupts the redox system of P. falciparum, subsequently disturbing mitochondrial and apicoplast functions and triggering apoptosis in Dd2.
METHODS: The effects of Dobinin K against Dd2 were assessed by both SYBR Green I fluorescence assay and Giemsa staining assay. Transcriptomic analysis was performed to examine global gene expression changes in P. falciparum following Dobinin K treatment. To explore the acting mechanism of Dobinin K on Dd2, contents of redox substrates and metabolites, as well as the activities of enzymes, were examined using the corresponding kit. Ultrastructural analysis was performed using transmission electron microscopy. The mitochondrial membrane potential (ΔΨm) was assessed based on JC-1 fluorescence intensity. The mRNA expression levels were analyzed through qRT-PCR. DNA fragmentation during apoptosis was evaluated using the TUNEL assay.
RESULTS: Dobinin K exhibited antiplasmodial activity against Dd2 that was both concentration- and time-dependent, affecting all developmental stages of the parasite. Transcriptomic analysis suggested that the mechanism of action of Dobinin K refers to the disruption of the redox system in the parasite. Dobinin K increased the levels of oxidative products, elevated the GSSG / GSH ratio, inhibited the activities of antioxidant enzymes, including PfGR, PfTrxR, and PfSOD, decreased the NADP+ / NADPH ratio, disruptedΔΨm, upregulated mRNA expression of most essential apicoplast metabolic enzymes, and ultimately induced apoptosis in Dd2.
DISCUSSION: Artemisinin-based combination therapies for chloroquine-resistant malaria face tremendous challenges due to the occurrence of artemisinin resistance. Our findings suggested that Dobinin K exerted its antimalarial effects by disrupting the parasite's redox homeostasis, a mechanism that differs from artemisinin. This further supports redox system targeting as an effective strategy against chloroquine-resistant P. falciparum.
CONCLUSION: Dobinin K disrupts the redox system of P. falciparum, subsequently disturbing mitochondrial and apicoplast functions and triggering apoptosis in Dd2.