Profiling molecular factors associated with pyknosis and developmental arrest induced by an opioid receptor antagonist and dihydroartemisinin in Plasmodium falciparum

Malaria continues to be a devastating disease, largely caused by Plasmodium falciparum infection. We investigated the effects of opioid and cannabinoid receptor antagonists on the growth of intraerythrocytic P. falciparum. The delta opioid receptor antagonist 7-benzylidenenaltrexone (BNTX) and the c...

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Veröffentlicht in:PloS one 2017-09, Vol.12 (9), p.e0184874
Hauptverfasser: Asahi, Hiroko, Inoue, Shin-Ichi, Niikura, Mamoru, Kunigo, Keisuke, Suzuki, Yutaka, Kobayashi, Fumie, Sendo, Fujiro
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container_issue 9
container_start_page e0184874
container_title PloS one
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creator Asahi, Hiroko
Inoue, Shin-Ichi
Niikura, Mamoru
Kunigo, Keisuke
Suzuki, Yutaka
Kobayashi, Fumie
Sendo, Fujiro
description Malaria continues to be a devastating disease, largely caused by Plasmodium falciparum infection. We investigated the effects of opioid and cannabinoid receptor antagonists on the growth of intraerythrocytic P. falciparum. The delta opioid receptor antagonist 7-benzylidenenaltrexone (BNTX) and the cannabinoid receptor antagonists rimonaband and SR144528 caused growth arrest of the parasite. Notably BNTX and the established antimalarial drug dihydroartemisinin induced prominent pyknosis in parasite cells after a short period of incubation. We compared genome-wide transcriptome profiles in P. falciparum with different degrees of pyknosis in response to drug treatment, and identified 11 transcripts potentially associated with the evoking of pyknosis, of which three, including glutathione reductase (PfGR), triose phosphate transporter (PfoTPT), and a conserved Plasmodium membrane protein, showed markedly different gene expression levels in accordance with the degree of pyknosis. Furthermore, the use of specific inhibitors confirmed PfGR but not PfoTPT as a possible factor contributing to the development of pyknosis. A reduction in total glutathione levels was also detected in association with increased pyknosis. These results further our understanding of the mechanisms responsible for P. falciparum development and the antimalarial activity of dihydroartemisinin, and provide useful information for the development of novel antimalarial agents.
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subjects Acids
Antimalarial activity
Antimalarial agents
Antimalarials - pharmacology
Artemisinins - pharmacology
Benzylidene Compounds - pharmacology
Biology and Life Sciences
Bornanes - pharmacology
Cannabinoid Receptor Antagonists - pharmacology
Cannabinoid receptors
Causes of
Cell Death - drug effects
Cell Death - physiology
Chromatin - drug effects
Chromatin - metabolism
Comparative analysis
Dihydroartemisinin
Dose-Response Relationship, Drug
Drugs
Erythrocytes
Gene expression
Gene Expression Profiling
Genetic aspects
Genomes
Glutathione
Glutathione - metabolism
Glutathione reductase
Health aspects
Infectious diseases
Malaria
Medicine
Medicine and Health Sciences
Membrane proteins
Metabolism
Naltrexone - analogs & derivatives
Naltrexone - pharmacology
Narcotic Antagonists - pharmacology
Narcotics
Opioid receptors (type delta)
Oxidation-Reduction
Parasites
Parasitology
Phosphate transporter
Phosphates
Physiological aspects
Piperidines - pharmacology
Plasmodium
Plasmodium falciparum
Plasmodium falciparum - drug effects
Plasmodium falciparum - growth & development
Plasmodium falciparum - metabolism
Pyrazoles - pharmacology
Transcriptome - drug effects
Tropical diseases
Vector-borne diseases
title Profiling molecular factors associated with pyknosis and developmental arrest induced by an opioid receptor antagonist and dihydroartemisinin in Plasmodium falciparum
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