Background Malaria is an extremely devastating disease that continues to affect millions of people each year. A distinctive attribute of malaria infected red blood cells is the presence of malarial pigment or so-called hemozoin. Hemozoin is a biocrystal synthesized by Plasmodium and other blood-feeding parasites to avoid the toxicity of free heme derived from the digestion of hemoglobin during invasion of the erythrocytes. Scope of Review Hemozoin is involved in several aspects of the pathology of the disease as well as in important processes such as the immunogenicity elicited. It is known that the once best antimalarial drug, chloroquine, exerted its effect through interference with the process of hemozoin formation. In the present review we explore what is known about hemozoin, from hemoglobin digestion, to its final structural analysis, to its physicochemical properties, its role in the disease and notions of the possible mechanisms that could kill the parasite by disrupting the synthesis or integrity of this remarkable crystal. Major Conclusions The importance and peculiarities of this biocrystal have given researchers cause to consider it as a target for new antimalarials and to use it through unconventional approaches for diagnostics and therapeutics against the disease. General Significance Hemozoin plays an essential role in the biology of malarial disease. Innovative ideas could use all the existing data on the unique chemical and biophysical properties of this macromolecule to come up with new ways of combating malaria.
Even with access to sufficient nutrients and atmosphere, Plasmodium falciparum can barely be cultured at maximum growth capacity in vitro conditions. Because of this behavior, it has been suggested that P. falciparum has self-regulatory mechanisms in response to density stress. Only recently has this process begun to be acknowledged and characteristics of a programmed cell death been assigned to the parasite at high parasitaemia in vitro cultures. In searching for death signals within the parasite community, we have found that extracellular vesicles (EVs) of P. falciparum from high parasitaemia cultures are able to induce programmed cell death processes in the population. A comparative proteomic analysis of EVs from low (EVL) and high (EVH) parasitaemia cultures was conducted, pointing to lactate dehydrogenase from P. falciparum (PfLDH) as the only parasite protein overexpressed in the later. Although the major function of P. falciparum lactate dehydrogenase (PfLDH) is the conversion of pyruvate to lactate, a key process in the production of energy in most living organisms, we investigated its possible role in the mechanism of parasite density control by intercellular signaling, given that PfLDH had already been listed as a component of extracellular vesicles of P. falciparum. In this study we present evidence of the EV-associated PfLDH regulation of parasite population by inducing apoptosis in highly parasitized cultures.
BackgroundIn order to identify new ways to prevent transmission of vector-borne diseases such as malaria, efforts have been made to understand how insects are attracted to humans. Vector-host interaction studies have shown that several volatile compounds play an important role in attracting mosquitoes to human targets. A headspace solid-phase micro-extraction/gas chromatography-mass spectrometry (HSPME GC-MS) analysis of the volatile organic composition of extracellular vesicles (EVs) and supernatants of ultracentrifugation (SNUs) was carried out in Plasmodium falciparum-infected cultures with high and low parasitemias.ResultsA list of 18 volatile organic compounds (VOCs) was obtained from the EVs of both infected and uninfected RBCs with 1,2,3-Propanetriol, diacetate (diacetin) increased in the infected EVs, regardless of the parasitemia of the culture. The supernatant analysis, however, gave off 56 VOCs, with pentane 2,2,4-trimethyl being present in all the SNUs of uninfected erythrocytes but absent from the parasite-infected ones. Standing out in this study was hexanal, a reported insect attractant, which was the only VOC present in all samples from SNUs from infected erythrocytes and absent from uninfected ones, suggesting that it originates during parasite infection.ConclusionsThe hexanal compound, reportedly a low-level component found in healthy human samples such as breath and plasma, had not been found in previous analyses of P. falciparum-infected patients or cultures. This compound has been reported as an Anopheles gambiae attractant in plants. While the compound could be produced during infection by the malaria parasite in human erythrocytes, the A. gambiae attraction could be used by the parasite as a strategy for transmission.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-017-2157-x) contains supplementary material, which is available to authorized users.
Cocos nucifera ( C . nucifera ) (the coconut palm tree) has been traditionally used to fight a number of human diseases, but only a few studies have tested its components against parasites such as those that cause malaria. In this study, C . nucifera samples were collected from a private natural reserve in Punta Patiño, Darien, Panama. The husk, leaves, pulp, and milk of C . nucifera were extracted and evaluated against the parasites that cause Chagas’ disease or American trypanosomiasis ( Trypanosoma cruzi ), leishmaniasis ( Leishmania donovani ) and malaria ( Plasmodium falciparum ), as well as against a line of breast cancer cells. While there was no activity in the rest of the tests, five and fifteen-minute aqueous decoctions of leaves showed antiplasmodial activity at 10% v/v concentration. Removal of some HPLC fractions resulted in loss of activity, pointing to the presence of synergy between the components of the decoction. Chemical molecules were separated and identified using an ultra-performance liquid chromatography (UPLC) approach coupled to tandem mass spectrometry (LC–MS/MS) using atmospheric pressure chemical ionization quadrupole–time of flight mass spectrometry (APCI–Q–TOF–MS) and molecular networking analysis, revealing the presence of compounds including polyphenol, flavone, sterol, fatty acid and chlorophyll families, among others.
In this study, eight natural isocoumarins (1−8) were isolated from a marinederived Exserohilum sp. fungus. To explore their structure−activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a−1n, 2a, 3a−3c, 4a−4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC 50 values of 1.1, 0.8, 0.4, and 2.6 μM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC 50 /IC 50 = 675), high selectivity, and a notable drug-like profile.
Chemical examination of the octocoral-associated Bacillus species (sp.) DT001 led to the isolation of pumilacidins A (1) and C (2). We investigated the effect of these compounds on the viability of Plasmodium falciparum and the mechanism of pumilacidin-induced death. The use of inhibitors of protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K) was able to prevent the effects of pumilacidins A and C. The results indicated also that pumilacidins inhibit parasite growth via mitochondrial dysfunction and decreased cytosolic Ca2+.
Plasmodium falciparum (P. falciparum) malaria presents serious public health problems worldwide. The parasites resistance to antimalarial drugs has proven to be a significant hurdle in the search for effective treatments against the disease. For this reason, the study of natural products to find new antimalarials remains a crucial step in the fight against malaria. In this study, we aimed to study the in vivo performance of the decoction of C. nucifera leaves in P. berghei-infected mice. We analyzed the effectiveness of different routes of administration and the acute toxicity of the extract. Additionally, we determined the suppressive, curative and prophylactic activity of the extract. The results showed that the decoction of leaves of C. nucifera is most effective when administered intramuscularly to mice in comparison to intraperitoneal, subcutaneous and intragastric methods. We also found that organ signs of acute toxicity appear at 2000 mg/kg/day as evidenced by necropsy examination. Additionally, we found that the prophylactic effect of the extract is of 48% inhibition, however, there is no curative effect. Finally, in a 4-day suppressive assay, we found that the extract can inhibit the growth of the parasite by up to 54% at sub-toxic doses when administered intramuscularly.
The development of resistance to insecticides by the vector of malaria and the increasingly faster appearance of resistance to antimalarial drugs by the parasite can dangerously hamper efforts to control and eradicate the disease. Alternative ways to treat this disease are urgently needed. Here we evaluate the in vitro effect of direct current (DC) capacitive coupling electrical stimulation on the biology and viability of Plasmodium falciparum. We designed a system that exposes infected erythrocytes to different capacitively coupled electric fields in order to evaluate their effect on P. falciparum. The effect on growth of the parasite, replication of DNA, mitochondrial membrane potential and level of reactive oxygen species after exposure to electric fields demonstrate that the parasite is biologically able to respond to stimuli from DC electric fields involving calcium signaling pathways.
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