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A schematic of the key components of the glutathione system in P. falciparum. G6PD, glucose-6-phosphate dehydrogenase; γ-GCS, γ-glutamylcysteine synthetase; GR, glutathione reductase; GS, glutathione synthetase; GSH, reduced glutathione; GSSG, oxidised glutathione disulphide; GST, glutathione-S-transferase; MRP, multidrug resistance-associated protein.
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Chloroquine (CQ) was once a very effective antimalarial drug that, at its peak, was consumed in the hundreds of millions of doses per year. The drug acts against the Plasmodium parasite during the asexual intraerythrocytic phase of its lifecycle. Unfortunately, clinical resistance to this drug is now widespread. Questions remain about precisely how...
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Citations
... In addition, some of the antimalarial drugs, such as chloroquine, target parasite redox homeostasis generating ROS that ultimately cause parasite death (Akide-Ndunge et al., 2009;Nepveu and Turrini, 2013;Coertzen et al., 2018;Siddiqui et al., 2022). The capability of P. falciparum to regulate the oxidative stress, herald the development of drug resistance development (Lehane et al., 2012;Rosenthal and Ng, 2020). It is tempting to speculate that sHsps could play an important role in antimalarial drug resistance. ...
Plasmodium falciparum, the predominant cause of severe malaria, thrives within both poikilotherm mosquitoes and homeotherm humans, navigating challenging temperature shifts during its life cycle. Survival in such varying environments necessitate the development of robust mechanisms, including a sophisticated protein folding system to mitigate proteopathy. The parasite needs to control the survival of its host cells which affects its chances of development and propagation. Central to this system are heat shock proteins (Hsps), among which small Hsps (sHsps) play pivotal roles in maintaining proteostasis (protein homeostasis). In both humans and P. falciparum, numerous sHsps have been identified, making them attractive candidates as biomarkers for diagnostic and drug development strategies. Evidence is accumulating suggesting that these sHsps participate in cell death processes, potentially influencing disease pathogenesis. Despite their significance, the precise functions of sHsps in P. falciparum's adaptation to stress conditions remains largely unknown. Comparative structural analysis of sHsps between human and P. falciparum reveals species-specific variations. Despite conserved tertiary structures, unique motifs are found in parasite sHsps which may modulate specialised chaperone functions. This review discusses the conserved and distinctive motifs of sHsps from the human host and the parasite, offering insights into shared and unique attributes. These findings illuminate the potential for species-specific targeting of sHsps, as players in cell death processes that may foster innovative biomarker identification approaches. As malaria continues to ravage Sub-Saharan Africa, understanding the molecular intricacies guiding parasite survival are essential in the development of interventions with heightened efficacy against this global health crisis.
... The initial activity screening was performed in Dd2, 35 which is chloroquine (CQ) resistant due to a mutation in the DV transporter PfCRT. 36 To examine any effects of this mutation, EC 50 values in the CQ sensitive line 3D7 were also determined. No overt difference in activity was observed, with resistance indices (RIs) of 0.83 for HZ NPDG-I, 2.75 for HZ NPDG-H, and 1.2 for TC HA-II. ...
Our previous study identified 52 antiplasmodial peptaibols isolated from Trichoderma and Hypocrea fungal species. To understand their antiplasmodial mechanism of action, we conducted phenotypic assays, in vitro evolution of resistance, and transcriptome analysis of the most potent peptaibol, harzianin NPDG I (HZ NPDG-I). This, and two additional peptaibols were compared for both their killing action and stage dependency, each showing a loss of digestive vacuole (DV) content in ultrastructural analysis. HZ-NPDG-I demonstrated a stepwise increase in DV pH, along with impaired DV membrane permeability, and the ability to form ion channels upon reconstitution in planar lips membranes. This compound showed no signs of cross resistance to targets of current clinical candidates, and three independent lines evolved to resist HZ NPDG-I acquired non synonymous changes in the P. falciparum multidrug resistance transporter, pfmdr1.Intriguingly, conditional knockdown of PfMDR1 showed varying activity based on peptaibol length, suggesting distinct activities.
... A consequence of hemoglobin digestion is the production of hematin that poisons the parasite by damaging its membrane [108]. Malaria parasites avoid heme toxicity by converting dimers of hematin into inert crystals (called hemozoin), and perhaps also by heme degradation through peroxidative or glutathione mediated pathways [109]. Phytocompounds that interfere with crystal formation would inhibit the malaria parasite with a mechanism similar to that of chloroquine. ...
Background
There has been increasing interest in the research of flavonoids from plant sources because of their versatile effects reported in various biological studies. The bioavailability, metabolism, and biological activity of flavonoids depend on the configuration, the total number of hydroxyl groups, and the substitution of functional groups about their nuclear structure. Plant organs are the main dietary source of flavonoids for humans and have been used as a remedy in traditional medicine. Some examples include Millettia plants which have been reported to contain several flavonoids with pharmacological activity against multifactorial diseases.
Aim of the Study
The present study summarizes up-to-date and comprehensive information on the pharmacological activity of flavonoids from plants of the genus Millettia.
Methods
The literature information was obtained from published and unpublished materials (theses, dissertations, and textbooks), retrieved from databases, such as Science Direct, SciFinder, PubMed (National Library of Medicine), Scopus, Wiley, American Chemical Society, Springer, and Web of Science.
Results
Plants from the genus Millettia contain more than 400 different flavonoids, among which approximately 100 flavonoids were pharmacologically active in in vitro or in vivo studies. These flavonoids exhibited antioxidant, antiprotozoal, anti-inflammatory, and anticancer activities, among others.
Conclusion
Flavonoids from Millettia plants were reported to exhibit in vitro antioxidant, antiprotozoal, anti-inflammatory, anticancer activities, etc. These compounds can be used as a starting point for the development of new agents against multifactorial diseases. However, more in vivo experiments, cytotoxicity tests, and detailed mechanism of action of Millettia bioactive flavonoids should be investigated.
... Chq actions rely mainly on its lysosomotropic properties, causing its effects through its ability to easily accumulate in the lysosomes of cells (Al-Bari, 2014). In malaria, Chq inhibit heme polymerase in lysosomes, leading to accumulation of the toxic by-product hemozoin within the malaria parasite, and subsequent cell death (Klouda and Stone, 2020;Lehane et al., 2012;Slater, 1993). Cellularly, Chq exerts it antiinflammatory mechanisms by reducing CD154 in T cells, and by inhibiting immune activation through reduction of Toll-like receptor signaling and cytokine production. ...
... Postnatal dysregulation of synaptic morphology and plasticity has been linked to altered intracellular redox and oxidative stress during critical points of embryonic development (Gąssowska-Dobrowolska et al., 2020;Khuzakhmetova et al., 2019), and Chq is known to mediate tissue toxicity through the induction of systemic oxidative stress and lipid peroxidation (Giovanella et al., 2015;Klouda and Stone, 2020;Kumar Mishra et al., 2013;Ogunbayo et al., 2006). Chq antimalarial activities anchor mainly on its ability to induce parasite-specific oxidative stress (Herraiz et al., 2019), but there is also strong, albeit less often considered, evidence that Chq can induce genotoxicity and cell death by increasing cellular oxidative stress in general (Farombi, 2006;Farombi et al., 2003;Lehane et al., 2012;Toler et al., 2006). The central roles of oxidative stress and lipid peroxidation in Chq-evoked synaptotoxicity in the present study is spotlighted by the depletion of SOD in the PFC, hippocampus, and cerebellum, and by the upregulation of MDA enzymes in the hippocampus. ...
Despite reports that quinoline antimalarials including chloroquine (Chq) exhibit idiosyncratic neuropsychiatric effects even at low doses, the drug continues to be in widespread use during pregnancy. Surprisingly, very few studies have examined the potential neurotoxic action of Chq exposure at different points of gestation or how this phenomenon may affect neurophysiological well-being in later life. We therefore studied behavior, and the expression of specific genes and neurochemicals modulating crucial neural processes in offspring of rats exposed to prophylactic dose of Chq during different stages of gestation. Pregnant rats were injected 5 mg/kg/day (3 times) of Chq either during early- (first week), mid- (second week), late- (third week), or throughout- (all weeks) gestation, while controls received PBS injection. Behavioral characterization of offspring between postnatal days 15-20 in the open field, Y-maze, elevated plus and elevated zero mazes revealed that Chq evoked anxiogenic responses and perturbed spatial memory in rats, although locomotor activity was generally unaltered. In the prefrontal cortex (PFC), hippocampus and cerebellum of rats prenatally exposed to Chq, RT-qPCR analysis revealed decreased mRNA expression of presynaptic marker synaptophysin, which was accompanied by downregulation of postsynaptic marker PSD95. Synaptic marker PICK1 expression was also downregulated in the hippocampus but was unperturbed in the PFC and cerebellum. In addition to recorded SOD downregulation in cortical and hippocampal lysates, induction of oxidative stress in rats prenatally exposed to Chq was corroborated by lipid peroxidation as evinced by increased MDA levels. Offspring of rats infused with Chq at mid-gestation and weekly treatment throughout gestation were particularly susceptible to neurotoxic changes, especially in the hippocampus. Interestingly, Chq did not cause histopathological changes in any of the brain areas. Taken together, our findings causally link intrauterine exposure to Chq with postnatal behavioral impairment and neurotoxic changes in rats.
... Free heme degradation occurs mainly involving reduced glutathione (Ginsburg and Golenser, 2003 Hydrogen peroxide thus generated is further converted into hydroxyl radical ( • OH) and hydroxyl ions ( -OH) through Fenton reaction, which is known to specifically affect lipids (Atamna and Ginsburg, 1993;Ryter and Tyrrell, 2000). Hydrogen peroxide is detoxified through glutathione based redox system, wherein enzymes like glutathione reductase (GR), glutathione S-transferase (GST), and glutathione peroxidase (GPx) play a major role (Lehane et al., 2012). ...
Malaria remains one of the major health concerns due to resistance in Plasmodium species towards existing drugs warranting an urgent need of new antimalarials. Thymol derivatives were known to exhibit enhanced antimicrobial activities, but not against Plasmodium. In present study, anti-plasmodial activity of thymol derivatives against chloroquine sensitive (NF-54) and resistant (K1) strains of Plasmodium falciparum was evaluated. Among the thymol derivatives tested, 4-Chlorothymol showed potent activity against sensitive and resistant (K1) strains of P. falciparum. 4-Chlorothymol was found to increase the ROS and RNS level. Further, 4-Chlorothymol could perturbed redox balance by modulating the enzyme activity of GST and GR. 4-Chlorothymol also showed synergy with chloroquine against chloroquine resistant P. falciparum. 4-Chlorothymol was found to significantly suppress the parasitemia and increase the mean survival time in in vivo assays. Interestingly, in in vivo assay, 4-Chlorothymol in combination with chloroquine showed higher chemo-suppression as well as enhanced mean survival time at a much lower concentrations as compare to individual doses of chloroquine and 4-Chlorothymol. These observations clearly indicate towards the potential use of 4-Chlorothymol as anti-malarial agent, which may also be effective in combination with exiting anti-plasmodial drugs against chloroquine resistant P. falciparum infection. In vitro cytotoxicity/haemolytic assay evidently suggest that 4-Chlorothymol is safe for further exploration for its therapeutic properties.
... Considerable evidence suggests that parasite-specific oxidative stress induced by CQ/HCQ treatment accounts for the antimalarial activity of these drugs [17]. Less appreciated, however, is evidence (see below) showing that CQ/HCQ, by themselves, are pro-oxidants that can increase oxidative stress parameters [18][19][20][21]. Viral infections are also generally accompanied by oxidative stress with potential pathophysiological consequences [22]. ...
... The historical impetus for studying the relationship between CQ/HCQ and oxidative stress relationship springs from the widely held hypothesis that CQ exerts its antimalarial effect by oxidative stress-killing of Plasmodium falciparum parasites during the intra-RBC phase of their life cycle [21,99]. Moreover, high doses of CQ are associated with oxidative stress-induced retinopathy [100,101]. ...
Chloroquine (CQ) and hydroxychloroquine (HCQ) have been proposed as treatments for COVID-19. These drugs have been studied for many decades, primarily in the context of their use as antimalarials, where they induce oxidative stress-killing of the malarial parasite. Less appreciated, however, is evidence showing that CQ/HCQ causes systemic oxidative stress. In vitro and observational data suggest that CQ/HCQ can be repurposed as potential antiviral medications. This review focuses on the potential health concerns of CQ/HCQ induced by oxidative stress, particularly in the hyperinflammatory stage of COVID-19 disease. The pathophysiological role of oxidative stress in acute respiratory distress syndrome (ARDS) has been well-documented. Additional oxidative stress caused by CQ/HCQ during ARDS could be problematic. In vitro data showing that CQ forms a complex with free-heme that promotes lipid peroxidation of phospholipid bilayers are also relevant to COVID-19. Free-heme induced oxidative stress is implicated as a systemic activator of coagulation, which is increasingly recognized as a contributor to COVID-19 morbidity. This review will also provide a brief overview of CQ/HCQ pharmacology with an emphasis on how these drugs alter proton fluxes in subcellular organelles. CQ/HCQ-induced alterations in proton fluxes influence the type and chemical reactivity of reactive oxygen species (ROS).
... In absence of an effective malaria vaccine, chemotherapy is still an unavoidable strategy to fight the disease. Unfortunately, the resistance of Plasmodium falciparum to several antimalarial drugs, such as chloroquine and mefloquine, is increasing dramatically (Lehane, McDevitt, Kirk, & Fidock, 2012;Price et al., 2004). Combinations of drugs are the most successful strategy used in malaria chemotherapy (Oguche et al., 2014;Sowunmi et al., 2017) Artemether-lumefantrine, artesunate-amodiaquine, dihydroartemisinin-piperaquine, artesunatemefloquine, and artesunate-sulfadoxine-pyrimethamine are first-line treatment protocols used in countries where malaria is endemic - (WHO, 2018). ...
Background and purpose: Artemisinin derivative artemether (ATM) has antimalarial activity with potential neurotoxic and cardiotoxic effects. ATM in nanocapsules (NC-ATM) is more efficient than free-ATM for reducing parasitaemia and increasing survival of Plasmodium berghei infected mice. NCs also prevent prolongation of the QT interval of the electrocardiogram. Here, we assessed cellular cardiotoxicity of ATM and the protection provided by nanoencapsulation of this drug.
Experimental approach: Mice received repeated doses of NC-ATM administered orally at 120 mg/kg twice daily for four days. Other groups of mice received free-ATM, blank-NCs, and vehicle for comparison. We investigated single cell contraction, intracellular Ca²⁺ transient using fluorescent Indo-1AM Ca²⁺ dye, and electrical activity using the patch-clamp technique in freshly isolated left ventricular myocytes. The acute effect of free-ATM was also tested on myocytes of untreated animals.
Key results: Free-ATM prolonged the action potential (AP) upon acute exposure (at 0.1, 1, and 10 μM) of myocytes from untreated mice or after in vivo treatment. This prolongation was unrelated to the blockade of K⁺ currents, an increase of the Ca²⁺ current, or promotion of a sustained Na⁺ current. In contrast, AP lengthening was abolished by NCX inhibitor SEA-0400. Free-ATM promoted irregular Ca²⁺ transients during pacing and spontaneous Ca²⁺ events during resting periods. NC-ATM prevented all effects. Blank-NCs had no effect compared to vehicle.
Conclusion and implications: ATM induces NCX-dependent AP lengthening (explaining QTc prolongation) and disrupted Ca²⁺ handling, both of which lead to pro-arrhythmogenic risks. NCs prevent these adverse effects, providing a safe alternative to the use of ATM alone, especially to treat malaria.
... Here, the inhibition of proteolysis by cysteine proteases due to free hemin allowed by chloroquine was reversed with glutathione. Previously, chloroquine response to Plasmodium berguei, a rodent malaria species, was affected by glutathione levels 67 . Then, inactivation of cysteine proteases by quinoline drugs might occur under conditions of oxidative stress in a deficit of glutathione. ...
Malaria caused by Plasmodium affects millions people worldwide. Plasmodium consumes hemoglobin during its intraerythrocytic stage leaving toxic heme. Parasite detoxifies free heme through formation of hemozoin (β-hematin) pigment. Proteolysis of hemoglobin and formation of hemozoin are two main targets for antimalarial drugs. Quinoline antimarial drugs and analogs (β-carbolines or nitroindazoles) were studied as inhibitors of β-hematin formation. The most potent inhibitors were quinacrine, chloroquine, and amodiaquine followed by quinidine, mefloquine and quinine whereas 8-hydroxyquinoline and β-carbolines had no effect. Compounds that inhibited β-hematin increased free hemin that promoted peroxidative reactions as determined with TMB and ABTS substrates. Hemin-catalyzed peroxidative reactions were potentiated in presence of proteins (i.e. globin or BSA) while antioxidants and peroxidase inhibitors decreased peroxidation. Free hemin increased by chloroquine action promoted oxidative reactions resulting in inhibition of proteolysis by three cysteine proteases: papain, ficin and cathepsin B. Glutathione reversed inhibition of proteolysis. These results show that active quinolines inhibit hemozoin and increase free hemin which in presence of H2O2 that abounds in parasite digestive vacuole catalyzes peroxidative reactions and inhibition of cysteine proteases. This work suggests a link between the action of quinoline drugs with biochemical processes of peroxidation and inhibition of proteolysis.
... These findings suggest that the appearance in Asia of K13 mutations on the Dd2 For instance, ART toxicity to Plasmodium parasites is thought to possibly involve the induction of oxidative stress, as suggested by prior real-time studies of the parasite glutathione (GSH)-dependent redox state (48). Given the prospect that GSH is potentially one of the substrates of PfCRT (49,50), it is plausible that the Dd2 form of PfCRT may help P. falciparum avert oxidative damage, perhaps through PfCRT-mediated transport of GSH into the parasite digestive vacuole (DV), where GSH has been proposed to degrade toxic heme (51,52). Alternatively, these associations might simply reflect the initial emergence of mutant K13 on founder populations that harbored Dd2 PfCRT, whose N326S and I356T mutations are absent in the other common Asian haplotypes Cam734 and GB4 ( Fig. 1 and Table 1). ...
Our study defines the allelic distribution of pfcrt , an important mediator of multidrug resistance in Plasmodium falciparum , in Africa and Asia. We leveraged whole-genome sequence analysis and gene editing to demonstrate how current drug combinations can select different allelic variants of this gene and shape region-specific parasite population structures. We document the ability of PfCRT mutations to modulate parasite susceptibility to current antimalarials in dissimilar, pfcrt allele-specific ways. This study underscores the importance of actively monitoring pfcrt genotypes to identify emerging patterns of multidrug resistance and help guide region-specific treatment options.
... Also, increased selection pressure on P. falciparum has led to mutation of the Chloroquine Resistance Transporter (PfCRT), a 49 kDa protein harboring 10 predicted transmembrane domains that reside in the membrane bounding the parasite's Digestive Vacuole (DV) [34]; mutation of this protein has led to development of CQ resistance (SP resistance has also developed, albeit to a lesser extent). Additional studies show that glutathione levels modulate CQ responses in malaria species that infect rodents, although the contribution of redox to the degree of CQ resistance in species infectious to humans is unclear [35]. ...
Vectors are living organisms that transmit infectious diseases from an infected animal to humans or another animal. Biological vectors such as mosquitoes, ticks, and sand flies carry pathogens that multiply within their bodies prior to delivery to a new host. The increased prevalence of vector-borne diseases (VBDs) such as Aedes-borne dengue, Chikungunya (CHIKV), Zika (ZIKV), malaria, tick-borne disease (TBD), and scrub typhus has a huge impact on the health of both humans and livestock worldwide. In particular, zoonotic diseases transmitted by mosquitoes and ticks place a considerable burden on public health. Vaccines, drugs, and vector control methods have been developed to prevent and treat VBDs and have prevented millions of deaths. However, development of such strategies is falling behind the rapid emergence of VBDs. Therefore, a comprehensive approach to fighting VBDs must be considered immediately. In this review, we I focus on the challenges posed by emerging outbreaks of VBDs and discuss available drugs and vaccines designed to overcome this burden. Research into promising drugs needs to be upgraded and fast-tracked, and novel drugs or vaccines being tested in in vitro and in vivo models need to be moved into human clinical trials. Active preventive tactics, as well as new and upgraded diagnostics, surveillance, treatments, and vaccination strategies, need to be monitored constantly if we are to manage VBDs of medical importance.
