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Pathophysiology of Plasmodium falciparum-Infected Erythrocytes and Thiol- Mediated Antioxidant Detoxification Systems | OMICS International
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Malaria Control & Elimination
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Pathophysiology of Plasmodium falciparum-Infected Erythrocytes and Thiol- Mediated Antioxidant Detoxification Systems

Paul Chikezie*

Department of Biochemistry, Imo State University, Owerri, Nigeria

*Corresponding Author:
Paul Chikezie
Department of Biochemistry
Imo State University
Owerri, Nigeria
Tel: +2348038935327
E-mail: [email protected]

Received Date: September 09, 2015; Accepted Date: November 05, 2015; Published Date: November 12, 2015

Citation: Chikezie P (2015) Pathophysiology of Plasmodium falciparum-Infected Erythrocytes and Thiol-Mediated Antioxidant Detoxification Systems. Malar Cont Elimination S1:003. doi: 10.4172/2470-6965.1000S1-003

Copyright: © 2015 Chikezie P. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Five species of intracellular protozoa of the genus Plasmodium cause malaria in human. The present review briefly highlighted the pathophysiology of Plasmodium falciparum infected erythrocyte and thiol-mediated antioxidant detoxification systems of P. falciparum that are required for survival of the malarial parasite in hyperoxidative intracellular environment. Scientific search engines such as PubMed, Pubget, Medline, EMBASE, Google Scholar, ScienceDirect and SpringerLink were used to retrieve online publications from 1976 to 2015. Haemoglobin that is taken up by the parasites into their acid food vacuole leads to the spontaneous oxidation of haem iron from Fe2+ to Fe3+, formation of superoxide radicals (O2•−), and subsequently, hydrogen peroxide (H2O2) and hydroxyl radicals (•− OH), which are highly reactive and cytotoxic oxygen intermediates. Additionally, toxic haem (ferri/ferroprotoporhyrin IX (FPIX) that is released upon haemoglobin digestion is biomineralized to form inert haemozoin. P. falciparum reduced glutathione (PfGSH) is a cofactor for glutathione enzyme systems and mediates in direct reductive detoxification of the toxic byproduct of haemoglobin digestion-FPIX. The postulated role of P. falciparum glutathione S-transferase (PfGST) in the development of drug resistance in malarial parasites is still being controversially discussed. However, selective inhibition of PfGST and P. falciparum thioredoxin reductase (PfTrxR) identifies novel drug targets and potential chemotherapeutic strategy to combat malaria.


Erythrocyte; Ferri/ferroprotoporhyrin IX; Glutathione; Thioredoxin; Plasmodium falciparum


Five species of intracellular protozoa of the genus Plasmodium cause malaria in human. The commonly encountered parasites include: Plasmodium falciparum, P. vivax, P. ovale, P. malariae [1,2], and recently, P. knowlesi [3-5]. Among these malarial parasites, P. falciparum remains the most virulent and common devastating human parasitic infection [6,7]. Reports showed that parasitic protozoan, especially malarial infection, is affecting more than 500 million people and causing from 1.7 million to 2.5 million deaths each year of which 25% of children less than 5 years of age, pregnant women and non-immune individuals are preferentially affected [2,6,8-10]. Furthermore, P. falciparum malaria is the commonest type febrile illness in Africa; where an estimation of 1.8 billion US dollars account for direct costs for prevention and care as well as indirect costs such as loss in productivity in hyper-endemic areas [11].

The present review briefly highlighted the pathophysiology of P. falciparum infected erythrocyte and thiol-mediated antioxidant detoxification systems of P. falciparum that are required for survival of the malarial parasite in hyperoxidative intracellular environment it encounters during its development in mammalian and insect hosts.

Evidence acquisition

Scientific search engines such as PubMed, Pubget, Medline, EMBASE, Google Scholar, ScienceDirect and SpringerLink were used to retrieve online publications from 1976 to 2015. Keywords such as ‘Plasmodium falciparum’, ‘malaria’, ‘glutathione detoxification’, ‘ligandins’ ‘ferri/ferroprotoporhyrin IX’ ‘thioredoxin’ etc. were used to collate relevant articles. The results were then cross-referenced to generate a total number of 98 references cited in this review.

Malarial infection

Human beings usually are infected with malaria through bite of sporozoites-infected female mosquitoes (genius Anopheles); although malaria can be transmitted by transfusion of infected blood [12] and by sharing needles [13]. The parasites have a complicated life cycle that requires a vertebrate host for the asexual cycle and female Anopheles mosquitoes for completion of the sexual cycle [14]. During a mosquito blood meal, infectious sporozoites in the mosquito’s saliva enter the host blood stream and invade the hepatocytes. In the hepatocytes, asexual multiplication (exo-erythrocytic schizogony) leads to the production of several thousand merozoites. In one to two weeks, a single sporozoite can give rise to 30, 000 merozoites. The pre-erythrocytic stages induce no illness.

Unlike the P. vivax infection, which is characterized by relapses as a result of the presence of a dormant stage called the hypnozoite that remains in the liver, P. falciparum infection does not elicit relapses [2,13]. Therefore, the sporozoites of P. falciparum develop uniformly producing pre-erythrocytic schizonts, which discharge all the merozoites simultaneously that do not remain dormant as that of P. vivax [13].

The asexual erythrocyte cycle begins when a single merozoite invades a host erythrocyte and enclosed within a parasitophorous vacuole, separate from the host cell cytoplasm. The merozoites released into the blood stream invade more erythrocytes. There are three observable morphologically distinct phases in parasitized erythrocytes. Firstly, the ring stage, which last for approximately 24 hours in P. falciparum infection, accounts for half of the metabolically nondescript intra-erythrocytic stage. It is followed by the trophozoite stage; a very active period during which most of the erythrocytes cytoplasm is consumed. Finally, parasite undergo 4-5 rounds of binary divisions during the schizont stage, producing 8-36 merozoites that burst from the host cell to invade new erythrocytes, and thereby begins another round of infection. This phase of the infection (erythrocytic schizogony) is responsible for malaria pathogenesis.

The rupture of Plasmodium-infected erythrocytes causes much of the morbidity and mortality associated with malaria during the asexual reproductive stage of the parasite. Intense fever occurs in 24- 72 hour intervals, accompanied by nausea, headaches, and muscular pain among other symptoms. Furthermore, a variety of potentially fatal symptoms, including liver failure, renal failure and cerebral pathology are associated with untreated P. falciparum. These symptoms are consequences of the unique ability of the parasites to bind to endothelial surface; this adherence inhibits circulation and causes localized oxygen deprivation and sometimes hemorrhage [15,16].

Instead of producing new schizonts, some merozoites, after invasion of the erythrocyte, arrest their cell cycle and develop into male (micro) and female (macro) gametocytes, the forms that are required for transmission of the mosquito’s parasite (asexual parasites do not survive ingestion by the insect). Inside the mid-gut of the mosquito, fertilization occurs, producing zygotes, which develop into ookinetes. The ookinetes forms oocytes, which then grow, divide, and rupture to give rise to sporozoites, which migrate to the salivary glands. Then the infectious cycle of malaria can repeat itself.

While all five species of Plasmodium have a haemolytic component usually of little consequence, falciparum malaria parasite multiply very rapidly and may occupy 30% or more of the erythrocytes causing a very significant level of haemolysis. One reason for this is that P. falciparum invades erythrocytes of all ages, of which P. vivax and P. ovale prefer younger erythrocytes, whereas P. malariae seeks matured erythrocytes [13]. There are evidence to suggest that geographical distribution of erythrocyte genetic traits such as the thalassemias, sickle cell anaemia and glucose-6-phosphate dehydrogenase (G6PDH) deficiency correlate with reduced severity and incidence of malaria infection [17-19].

Haemoglobin metabolism

During intra-erythrocytic development, P. falciparum ingests large amount of haemoglobin to meet its nutrient requirement [20] and to maintain osmotic stability within the host cell [21]. Specifically, the malaria parasite ingests 25 to 80% of total haemoglobin content [22,23]. Haemoglobin molecules, taken up by endocytosis undergo hydrolysis in the parasite’s digestive acidic vacuole called the food vacuole. Cysteine and aspartic proteases are involved in haemoglobin proteolysis and have reported pH optimums in the range of 4.5-5.0 [24]. A pH homeostasis plays an important role in the pathophysiology of falciparum malaria, such as host cell exploitation and responses to antimalarial drugs [25]. Accordingly, baseline pH values and the mechanisms underpinning pH homeostasis in different parasite compartments have been of interest for several decades [25].

Endogenous production of reactive oxygen species (ROS) in parasitized erythrocytes are triggered following the digestion of haemoglobin and subsequent biochemical reactions in the parasites [26]. Haemoglobin that is taken up by the parasites into their acid food vacuole leads to the spontaneous oxidation of haem iron from Fe2+ to Fe3+ (haemin) and the formation of superoxide radicals (O2 •−). The combination of O2 •− and haemin inevitably leads to the generation of hydrogen peroxide (H2O2) and subsequently, hydroxyl radicals (•−OH), which are highly reactive and cytotoxic oxygen intermediates (Figure 1) [27]. Furthermore, toxic (ferroprotoporphyrin IX; containing Fe2+) and hemin/hematin (ferriprotoporphyrin IX; containing Fe3+) (FPIX) that are released upon haemoglobin digestion must be detoxified within the acid food vacuole to prevent downstream toxicity [19,28]. Most of the released FPIX is biomineralized (up to 90%) [29]; to form inert haemozoin. However, there are reports that substantial amount of FPIX (even as much as 50%) [30,31]; escapes bio-mineralization and has to be degraded or sequestered by other means to prevent membrane damage and parasite death [32-34].


Figure 1: Sources of oxidative stress in Plasmodium falciparum [35].

However, some free FPIX (up to 50% according to [30,31]) from the food vacuole pass into the parasite compartment. The O2 •− resulting from the oxidation of haem-iron of haemoglobin are either detoxified by superoxide dismutase (SOD) to yield H2O2 or in a spontaneous reaction with H2O2, lead to the formation of •−OH [26,35]. In addition, ferric iron (Fe3+) react with molecular oxygen via the Fenton reaction pathways to generate •−OH (Equation 1) [36].

image (1)

image (2)

Equation 1: The Fenton reaction

These radicals are highly reactive and cause, for instance, lipid peroxidation and DNA oxidative damage [35]. Additionally, H2O2 generated by the SOD activity has to be detoxified by reduction reaction to produce water. In P. falciparum, thioredoxin (Trx)-dependent peroxidase pathway plays this role because the parasites lack catalase and glutathione peroxidase [35,37,38], which initially, raised doubts about the relevance of reduced glutathione (GSH) in detoxification of ROS in Plasmodium.

Hyper-oxidative stress of parasitized erythrocytes

Malaria parasites are particularly vulnerable to oxidative stress during the erythrocytic life stages [34,37,39,40] as a result of acute phase response of the infected host immune reaction and intra-erythrocytic parasite’s metabolic processes [26,41-43]. This is not surprising since the parasites live in a pro-oxidant intracellular environment that contains oxygen and iron; the key prerequisite for the formation of ROS via the Fenton reaction [36]. Additionally, in effort to eliminate or impede parasite fecundity, cytotoxic reactive oxygen and nitrogen species (RONS; e.g. peroxynitrite) arising from reaction of nitric oxide (NO-) with O2•− are deployed by the macrophages against invading P. falciparum [26,41], which exacerbate the oxidative stress of the already hyperoxidative parasitized erythrocytes. Expectedly, studies have shown that compromised NO- metabolism may precipitate malaria complications by exacerbated cyto-adherence of infected erythrocytes through enhanced oxidation of redox-sensitive CD36 [44,45].

Notably, not only is the parasite itself under oxidative stress, but the host cell also shows oxidative alterations when infected with Plasmodium as demonstrated by changes in erythrocyte membrane fluidity, most probably, because of the alterations in composition of erythrocyte membrane lipid and protein cross-linking [46-49]. Haemochrome accumulation on the inner surface of the parasitized erythrocytes as well as aggregation of erythrocyte band III and increased occurrence of auto-anti-band III antibodies suggest oxidative damage of the host erythrocytes by the malarial parasites [26,50], which is most apparent in erythrocytes infected with Plasmodium in late parasitic stages [47]. These modifications are reminiscent of those found in erythrocytes of humans with erythrocyte disorders such as sickle cell anaemia, α- and β-thalassaemias and G6PDH deficiency. Studies have shown that the underlying mechanism for these transformations is enhanced oxidative stress in the defective erythrocytes [51-53]. Interestingly, these erythrocyte disorders and G6PDH deficiency confer certain degree of resistance to Plasmodium infection and often limit the severity of the disease [19,54,55]. One hypothesis to explain this is that the increased oxidative stress within the defective erythrocyte causes an impaired infection and growth rate of the parasites [56,57]. Another hypothesis [47,48,58] suggest that defective erythrocytes infected with early stages of P. falciparum are more efficiently phagocytized by the host’s immune system because of earlier occurrence of band III cross-linking which results in the early appearance of band III auto-antibodies. Thus, the recognition of parasitized erythrocytes by the host’s immune system at an early stage of the infection ensures that parasitaemia of the infected individuals is kept low. Similar changes also occur in normal Plasmodium-infected erythrocytes but at a much later stage of the infection when most parasitized erythrocytes are already sequestered in the host’s capillary system and so no longer circulating such that they are not efficiently recognized by the host’s immune system [13].

Diagnostic pathology reports have revealed elevation of oxidative stress indicators of parasitized erythrocytes [41,43,59,60]. Notably, the polyunsaturated fatty acids (PUFAs) of erythrocyte biomembrane are particularly vulnerable to oxidative damage, exemplified by raised levels of end products of lipid peroxidation in serum of malarious individuals [40,61].

Plasmodium falciparum thiol-mediated antioxidant detoxification systems

According to reports, the malarial parasites have evolved a complex network of NADPH dependent redox enzymes, with overlapping but also distinct functions, to neutralized RONS and maintain comparatively reduced intracellular environment during blood stage infection, which are broadly classified in two groups [19,35,62]:

1. A complete glutathione system.

2. Specialized Trx system.

The first system is comprised of the GSH, flavo-enzyme glutathione reductase (GR), glutaredoxin (Grx) and Grx-like proteins, glutathione S-transferases (GSTs), γ-glutamylcysteine synthetase (γ-GCS), and a glutathione-dependent glyoxalase [35,62-64]. Vega-Rodríguez et al., [65] reports suggest that though P. falciparum glutathione (PfGSH) biosynthetic pathway is essential for mosquito stage development of the parasite, it may not be an appropriate target for antimalarials against blood stages of the parasite. However, the correlation between intracellular concentration of PfGSH and the capacity of the parasite to withstand pro-oxidant challenges has been described [66,67]. The second system includes the Trx reductase (TrxR), several Trxs and Trxlike proteins, Trx-dependent peroxidases and imported human protein peroxiredoxin 2 (hPrx-2) [38,68-70]. Study showed that P. falciparum imports hPrx-2 from the human erythrocyte host to its cytosol for the primary purpose to scavenge cytotoxic peroxides and the abundance of hPrx-2 in the parasite increases significantly following chloroquine treatment [70]. It is worthwhile to note that there are other findings over the years, which have contradicted the reports of Rodríguez et al.[65], in which they revealed that glutathione and Trx redox systems are potential targets for the development of new chemotherapeutics for eradication of malaria [71,72].

The tripeptide glutathione {(gamma-glutamyl-cysteinyl-glycine: GSH (reduced form); GSSG (oxidized form)} is the major lowmolecular weight thiol buffer in most aerobic cells [19,26,73]. Generally, GSH is directly involved in antioxidant reactions, for instance, the termination of radical-based chain reactions involving single electrons

transferred from thiyl radicals or disulphide radicals [74]. The ratio of GSH to GSSG is usually between 10:1 and 100:1 and maintained far on the side of reduced form of glutathione [75,76]. Specifically, GSH/GSSG redox ratio in intra-erythrocytic parasites displays highly reducing redox potential E°PfGSH = − 314 mV when compared with the GSH/GSSG redox potential in other organisms [19,67]. Apart from the action of GR, which regenerates GSH from GSSG, there also exist GSSG-efflux pumps that export excess GSSG in order to maintain an adequate intracellular redox balance in the parasite, and in cases of drug resistance, export of PfGSH adducts are excreted from cells via pumps such as P. falciparum multidrug resistance (PfMRP) proteins, which is within the drug/metabolite transporter superfamily of ATP transporters [19,38,76-78]. In addition, de novo biosynthesis of the tripeptide also contributes to sustaining sufficiency high intracellular PfGSH levels [79]. Studies showed that Plasmodium also possesses the two enzymes responsible for the de novo biosynthesis of PfGSH, notably, γ-GCS and glutathione synthetase, respectively [19]. Apart from its role as a general thiol redox buffer, PfGSH acts as a cofactor for a variety of proteins including glutathione-dependent peroxidases, PfGSTs, Grxs and glyoxalases [73,76]. The glyoxalase system is another vital cellular component crucial for survival of the parasite in that it catalyzes the conjugation of 2-oxoaldehydes such as methylglyoxal, a toxic metabolic by-product of glycolysis, to PfGSH leading to the generation of non-toxic hydroxycarboxylic acids such as D-lactate, which are subsequently excreted from the parasite [19,80].

The GSH metabolism of Plasmodium-infected erythrocytes has been the focus of a number of studies, which have revealed that the role of the tripeptide is quite numerous, and not only limited to its redox and antioxidant functions [34,65]. Müller [38], proposed a correlation between intracellular PfGSH levels and susceptibility to oxidative damage and reduced osmotic resistance of Plasmodium-infected erythrocytes, which corroborates recent reports [64]. The reports have further asserted that Plasmodium caused the oxidation large amount of PfGSH, which engendered the need for increased GSSG efflux to maintain an adequate GSH/GSSG thiol redox state in the infected cells, (Figure 2).


Figure 2: GSH metabolism in P. falciparum. Ferri/ferroprotoporhyrin IX (FPIX); xenobiotics (X) for export; GS-X adducts are excreted from cells via pumps such as multidrug resistance proteins [38].

Furthermore, Cappadoro et al., [58] propounded that G6PDHdeficient erythrocytes also exhibit decreased GSH levels, which might be explained by decreased availability of NADPH for reduction of the tripeptide and so the rapid efflux of GSSG from the intracellular compartment of the invading parasite. These observations together suggest that one reason for the increased oxidative damage in Plasmodium-infected erythrocytes and G6PDH-deficient erythrocytes is the inadequate concentration of intracellular GSH.

Despite the efficient biomineralization of free haem into haemozoin following haemoglobin digestion by the parasite, a considerable amount of toxic FPIX remains free [30,31]. Free FPIX is toxic because its detergent-like properties interfere with membrane integrity and has the ability to undergo redox reactions causing the generation of ROS as a result of the presence of bound iron in FPIX. Therefore, FPIX needs to be sequestered and detoxified to prevent peroxidation of membrane structural components and ultimate parasite death. Several reports have shown that degradation and subsequent detoxification of free FPIX occurred through PfGSH mediated non-enzymatic mechanism that was inhibited by chloroquine [31,81-84]. Consequently, failure to inactivate FPIX exterminates the Plasmodium parasite by oxidative damage to biomembrane structural components, digestive proteases and possibly other critical biomolecules [85]. Notably, it had been suggested that PfGSH is involved in drug resistance [72]. Thus, the depletion of PfGSH would result in a less efficient detoxification of free FPIX and consequently death of the parasite. The resistance of P. falciparum to chloroquine is one of the major drawbacks in the fight against severe malaria.

In addition to non-enzymatic detoxification of FPIX, other mechanisms of FPIX removal involves its sequestration by the parasite proteins. Proteins possibly involved in this process include histidinerich protein 2 [86,87], glyceraldehydes-3-phosphate dehydrogenase, protein disulphide isomerase, P. falciparum GR (PfGR) [88] and P. falciparum glutathione S-transferase (PfGST) - referred to in this regard as ‘ligandin’ [19,83,89,90]. Apart from histidine-rich protein 2, which in complex with FPIX appears to develop peroxidase-like activity [91], most of the other FPIXs inhibit their binding proteins. Therefore, it is difficult to judge whether their affinity to FPIX is actually a protective mechanism or whether binding of FPIX has a deleterious effect on the parasites. In the case of glyceraldehyde-3-phosphate dehydrogenase, it is believed that the strong inhibition by FPIX is a mechanism by which the parasite is adapted to survive FPIX-induced oxidative stress. The inhibition of glyceraldehydes-3-phosphate dehydrogenase under elevated FPIX-induced oxidative stress results in glucose being primarily metabolized via the hexose monophosphate shunt rather than glycolysis and this provides increased levels of NADPH that are required for enzymatic antioxidant reactions in the parasite [16].

One of several intracellular antioxidant enzymes that are directly dependent on the availability of GSH is GST. GSTs catalyze the conjugation of GSH to the electrophilic centers of hydrophobic compounds, and thereby detoxify a wide range of mutagens, carcinogenic, pharmacologically active molecules and by-products of oxidative stress. All Plasmodium species studied exhibit GST activity as far as intra-erythrocytic stages [92] and PfGST represent greater than one percent (1%) of the total cellular protein in the parasite [83,89]. The primary structure as well as the three – dimensional x-ray structure of PfGST differ significantly from that of human GSTs, and by implication, PfGST represents a novel GST isoform that cannot be assigned to any of the previously known GST classes [72,90]. Unlike higher eukaryotes, Plasmodium possesses only a single gene encoding GST. Consequently, the low number of GSTs expressed possible reflect that parasitic protozoa such as Plasmodium do not require a great number of xenobiotics detoxification enzymes and their GSTs have different functions from those found in eukaryotes. Nevertheless, inhibition of PfGST is expected to disturb GSH-dependent conjugation processes, which promotes enhance levels of cytotoxic peroxides and increase in the concentration of toxic FPIX [92].

Interestingly, molecular stability studies revealed that PfGST exist as a tetramer (inactive)←→dimer (active) transition states, which is regulated by binding activity of physiologic GSH concentration ≈ 0.7 mM [72]. Furthermore, recent studies have shown that the three dimensional structure of PfGST displays some similarities to Mu-class GSTs [90,93]. However, PfGST appears to have a larger hydrophobic binding pocket than the Mu-class GSTs that makes it more accessible by solvents [72]. Additionally, the C-terminus of PfGST is truncated in comparison to other GST isoforms. Usually, the C-terminal part of Muclass GSTs structurally restricts entry of substrates into the hydrophobic binding pocket, and thus, it is believed that the substrate specifically of PfGST is less restricted, which allows for the detoxification of a wider range of molecules. This could explain why these parasites do not require as many GST isoforms as do other eukaryotes.

Thiol antioxidant systems: attractive targets for new antimalarials

The postulated role of PfGST in the development of drug resistance in malarial parasites is still being controversially discussed [89,92,94]. However, Ahmad and Srivastava, [95] noted that selective inhibition of PfGST activity by protoporphyrin IX, cibacron blue and menadione, coupled with the unique nature of PfGST, may open new vista of potential chemotherapeutic strategy by serving as a novel drug target to combat malaria [72]. In addition to cytosolic PfGST, the presence of membrane bound GSTs, the so called membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) form, in Plasmodium was recently characterized using graph-based information diffusion on compressed supergenomic networks as described [64]. Although evolutionally unrelated to the cytosolic GSTs, the MAPEG is a superfamily of detoxification enzymes that catalyze the conjugation of GSH to a broad spectrum of xenobiotics and hydrophobic electrophiles. Furthermore, the MAPEG exhibit no significant genome sequence homology with the Plasmodium cytosolic GSTs and other known parasite protein sequences. It is instructive to note that the parasitophorous vacuolar membrane antigen PfEXP1 (P. falciparum exported protein 1), is the only known MAPEG with hematin substrate specificity to buffer oxidative stress produced through excess hematin [19,64]. Also, PfEXP1 activity could predict the occurrence of resistant strains of Plasmodium since it is inhibited by artemisinin in a hematin concentration dependent manner [64].

Genetic and chemical tools have demonstrated that P. falciparum TrxR (PfTrxR), in concert with the early stage of the thioredoxin redox cycle, and the enzyme involved in the rate-limiting step of glutathione synthesis-γ-GCS, are essential for the survival of malarial parasite [38,39,76]. Accordingly, some of the enzymes, particularly, PfTrxR has also been proposed to be an attractive targets for the design of new antimalarials because of its structural and functional peculiarities that contribute to the antioxidant defense systems of the parasite [96,97]. Likewise, according to in vitro data from the reports of Gallo et al., [98], human GR (hGR) deficiency and drug-induced hGR inhibition confers protection on erythrocytes against malarial parasites by inducing enhanced ring stage phagocytosis rather than by impairing parasite growth directly.


Intra-erythrocytic P. falciparum ingests large amount of haemoglobin to meet its nutrient requirement, which results in endogenous production of cytotoxic RONS following the digestion of haemoglobin and subsequent biochemical reactions in the parasites. For the survival of P. falciparum in the hostile environment, the parasite is equipped with arrays of antioxidant processes and machineries that ensure the mitigation of intra-erythrocytic hyperoxidative stressors elicited by the generation of RONS. Notable among these antioxidant pathways are the thiol-mediated detoxification systems within the acid food vacuole of the parasite, which serve to prevent downstream toxicity from cytotoxic oxygen intermediates, and perhaps, involved in development of drug resistance in malarial parasites. Accordingly, the selective inhibition of thiol-mediated detoxification systems has been identified to be novel drug targets and potential chemotherapeutic strategy to combat malaria.


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