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European Journal of Medicinal Chemistry Oct 2023A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines...
A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta-fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials.
Topics: Animals; Aminacrine; Aminoacridines; Antimalarials; Mammals; Plasmodium berghei; Plasmodium falciparum; Primaquine
PubMed: 37390511
DOI: 10.1016/j.ejmech.2023.115575 -
Immunology Letters Dec 2023The thymus is the anatomical site where T cells undergo a complex process of differentiation, proliferation, selection, and elimination of autorreactive cells which...
The thymus is the anatomical site where T cells undergo a complex process of differentiation, proliferation, selection, and elimination of autorreactive cells which involves molecular signals in different intrathymic environment. However, the immunological functions of the thymus can be compromised upon exposure to different infections, affecting thymocyte populations. In this work, we investigated the impact of malaria parasites on the thymus by using C57BL/6 mice infected with Plasmodium berghei ANKA and Plasmodium yoelii 17XL; these lethal infection models represent the most severe complications, cerebral malaria, and anemia respectively. Data showed a reduction in the thymic weight and cellularity involving different T cell maturation stages, mainly CD4CD8 and CD4CD8 thymocytes, as well as an increased presence of apoptotic cells, leading to significant thymic cortex reduction. Thymus atrophy showed no association with elevated serum cytokines levels, although increased glucocorticoid levels did. The severity of thymic damage in both models reached the same extend although it occurs at different stages of infection, showing that thymic atrophy does not depend on parasitemia level but on the specific host-parasite interaction.
Topics: Animals; Mice; Plasmodium berghei; Plasmodium yoelii; Mice, Inbred C57BL; Malaria; Atrophy; Parasitemia
PubMed: 37875239
DOI: 10.1016/j.imlet.2023.10.006 -
EMBO Reports Jul 2023Eukaryotic cell adhesion and migration rely on surface adhesins connecting extracellular ligands to the intracellular actin cytoskeleton. Plasmodium sporozoites are...
Eukaryotic cell adhesion and migration rely on surface adhesins connecting extracellular ligands to the intracellular actin cytoskeleton. Plasmodium sporozoites are transmitted by mosquitoes and rely on adhesion and gliding motility to colonize the salivary glands and to reach the liver after transmission. During gliding, the essential sporozoite adhesin TRAP engages actin filaments in the cytoplasm of the parasite, while binding ligands on the substrate through its inserted (I) domain. Crystal structures of TRAP from different Plasmodium species reveal the I domain in closed and open conformations. Here, we probe the importance of these two conformational states by generating parasites expressing versions of TRAP with the I domain stabilized in either the open or closed state with disulfide bonds. Strikingly, both mutations impact sporozoite gliding, mosquito salivary gland entry, and transmission. Absence of gliding in sporozoites expressing the open TRAP I domain can be partially rescued by adding a reducing agent. This suggests that dynamic conformational change is required for ligand binding, gliding motility, and organ invasion and hence sporozoite transmission from mosquito to mammal.
Topics: Animals; Sporozoites; Ligands; Plasmodium; Culicidae; Liver; Protozoan Proteins; Plasmodium berghei; Mammals
PubMed: 37306042
DOI: 10.15252/embr.202357064 -
Proceedings of the National Academy of... Oct 2023Malaria remains a devastating disease and, with current measures failing to control its transmission, there is a need for novel interventions. A family of proteins that...
Malaria remains a devastating disease and, with current measures failing to control its transmission, there is a need for novel interventions. A family of proteins that have long been pursued as potential intervention targets are aquaporins, which are channels facilitating the movement of water and other solutes across membranes. We identify an aquaporin in malaria parasites and demonstrate that it is important for completion of development in the mosquito vector. Disruption of AQP2 in the human parasite and the rodent parasite blocks sporozoite production inside oocysts established on mosquito midguts, greatly limiting parasite infection of salivary glands and transmission to a new host. In vivo epitope tagging of AQP2 in , combined with immunofluorescence assays, reveals that the protein is localized in vesicle-like organelles found in the cytoplasm of gametocytes, ookinetes, and sporozoites. The number of these organelles varies between individual parasites and lifecycle stages suggesting that they are likely part of a dynamic endomembrane system. Phylogenetic analysis confirms that AQP2 is unique to malaria and closely related parasites and most closely resembles intracellular aquaporins. Structure prediction analyses identify several unusual features, including a large accessory extracellular loop and an arginine-to-phenylalanine substitution in the selectivity filter principally determining pore function, a unique feature among known aquaporins. This in conjunction with the importance of AQP2 for malaria transmission suggests that AQP2 may be a fruitful target of antimalarial interventions.
Topics: Animals; Aquaporin 2; Malaria; Mosquito Vectors; Phylogeny; Plasmodium berghei; Protozoan Proteins; Sporozoites
PubMed: 37883438
DOI: 10.1073/pnas.2304339120 -
International Journal of Antimicrobial... Dec 2023The clinical use of artemisinin-based combination therapies is threatened by increasing failure rates due to the emergence and spread of multiple drug resistance genes...
BACKGROUND
The clinical use of artemisinin-based combination therapies is threatened by increasing failure rates due to the emergence and spread of multiple drug resistance genes in most human Plasmodium strains. The aim of this study was to generate artemether-resistant (AM) parasites from Plasmodium berghei ANKA (AM), and determine their fitness cost.
METHODS
Artemether resistance was generated by increasing drug pressure doses gradually for 9 months. Effective doses (ED and ED) were determined using the 4-day suppressive test, and the indices of resistance (I) at 50% and 90% (I and I) were determined using the ratio of either ED or ED of AM to AM, respectively. The stability of the AM parasites was evaluated by: five drug-free passages (5DFPs), 3 months of cryopreservation (CP), and drug-free serial passages (DFSPs) for 4 months. Analysis of variance was used to compare differences in growth rates between AM and AM with 95% confidence intervals.
RESULTS
ED and ED of AM were 0.61 and 3.43 mg/kg/day respectively. I and I after 20 cycles of artemether selection pressure were 19.67 and 21.45, respectively; 5DFP values were 39.16 and 15.27, respectively; 3-month CP values were 29.36 and 10.79, respectively; and DFSP values were 31.34 and 12.29, respectively. The mean parasitaemia value of AM (24.70% ± 3.60) relative to AM (37.66% ± 3.68) at Day 7 post infection after DFSPs revealed a fitness cost of 34.41%.
CONCLUSION
A moderately stable AMP. berghei line was generated. Known and unknown mutations may be involved in modulating artemether resistance, and therefore molecular investigations are recommended.
Topics: Animals; Humans; Artemether; Antimalarials; Malaria; Parasites; Plasmodium berghei; Plasmodium falciparum; Drug Resistance
PubMed: 37865152
DOI: 10.1016/j.ijantimicag.2023.107012 -
Frontiers in Immunology 2023Recent studies have suggested that CD8 liver-resident memory T (T) cells are crucial in the protection against liver-stage malaria. We used liver-directed...
Recent studies have suggested that CD8 liver-resident memory T (T) cells are crucial in the protection against liver-stage malaria. We used liver-directed mRNA-containing lipid nanoparticles (mRNA-LNPs) to induce liver T cells in a murine model. Single-dose intravenous injections of ovalbumin mRNA-LNPs effectively induced antigen-specific cytotoxic T lymphocytes in a dose-dependent manner in the liver on day 7. T cells (CD8 CD44 CD62L CD69 KLRG1) were induced 5 weeks after immunization. To examine the protective efficacy, mice were intramuscularly immunized with two doses of circumsporozoite protein mRNA-LNPs at 3-week intervals and challenged with sporozoites of ANKA. Sterile immunity was observed in some of the mice, and the other mice showed a delay in blood-stage development when compared with the control mice. mRNA-LNPs therefore induce memory CD8 T cells that can protect against sporozoites during liver-stage malaria and may provide a basis for vaccines against the disease.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Memory T Cells; Liver; Malaria; RNA, Messenger; Sporozoites
PubMed: 37680630
DOI: 10.3389/fimmu.2023.1116299 -
Molecular Nutrition & Food Research Nov 2023Malaria remains one of the most important infectious diseases in the world. Allyl isothiocyanate (AITC) is a main ingredient of traditional spice Wasabia japonica, which...
SCOPE
Malaria remains one of the most important infectious diseases in the world. Allyl isothiocyanate (AITC) is a main ingredient of traditional spice Wasabia japonica, which is reported to have anti-bacterial and antiparasitic activities. However, there is no information on effects of AITC against malaria. The present study investigates the anti-malarial activity of dietary AITC in vivo and that of AITC metabolites in vitro.
METHODS AND RESULTS
The ad libitum administration of 35, 175, or 350 µM AITC-containing drinking water to ICR mice significantly inhibit the parasitemia induced after infection with Plasmodium berghei. On the other hand, after single oral administration of AITC (20 mg kg body weight), N-acetyl-S-(N-allylthiocarbamoyl)-l-cysteine (NAC-AITC) as one of the AITC metabolites displays a serum C of 11.4 µM at a T of 0.5 h, but AITC is not detected at any time point. Moreover, NAC-AITC shows anti-malarial activity against Plasmodium falciparum in vitro, and its 50% inhibitory concentration (IC ) against parasitemia is 12.6 µM.
CONCLUSIONS
These results indicate that orally administered AITC is metabolized to NAC-AITC and exerts anti-malarial activity against malaria parasites in blood, suggesting that the consumption of AITC-containing food stuffs such as cruciferous plants may prevent malaria.
Topics: Mice; Animals; Antimalarials; Parasitemia; Mice, Inbred ICR; Isothiocyanates; Malaria
PubMed: 37706619
DOI: 10.1002/mnfr.202300185 -
BioMed Research International 2023Emergence of resistance to antimalarial drugs presents a major drawback in efforts to control malaria. To address this problem, there is an urgent and continuous need...
BACKGROUND
Emergence of resistance to antimalarial drugs presents a major drawback in efforts to control malaria. To address this problem, there is an urgent and continuous need for the development of new and effective antimalarial agents. (L.) link extract has exhibited antiplasmodial activity in many pharmacological studies. To our knowledge, data on its antimalarial efficacy is still very limited. A recent study demonstrated that polar extracts from the plant roots inhibit proliferation in a mouse model. This study further describes the efficacy and safety of a methanolic root extract of the plant as an antimalarial agent by demonstrating its effect on hematological, biochemical, and histological parameters of -infected BALB/c mice.
METHODS
Rane's test, a curative approach, was used to evaluate the antimalarial efficacy of methanolic root extract in -infected BALB/c mice. The effect of the extract on both hematological and biochemical parameters was evaluated using automated analyzers. Kidney, liver, lung, spleen, and brain tissues were harvested from euthanized mice and examined for changes in organ architecture.
RESULTS
This study demonstrates that methanolic root extract of significantly inhibited parasitemia in BALB/c mice ( < 0.01). Infected mice that were treated with the extract depicted a significantly low level of total leucocytes ( < 0.01), red blood cell distribution width ( < 0.01), and a significantly high hemoglobin concentration ( < 0.001) compared to the infected animals that were administered with the vehicle only. The infected animals that were treated with the extract exhibited a significantly low level of urea, creatinine, bilirubin, and alkaline phosphatase ( < 0.05), compared to the infected animals that were given the vehicle only. The level of sodium, potassium and chloride ions, lymphocytes, granulocytes, hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein, albumin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total platelets, mean platelet volume (MPV), and platelet distribution width of the infected animals treated with the extract was not significantly different from those of the infected animals that were given the vehicle only ( > 0.05). The extract alleviated organ pathological changes in the infected mice. The extract did not induce any remarkable adverse effect on the growth, hematological, and biochemical parameters of uninfected animals ( > 0.05). In addition, administration of the extract did not alter the gross appearance and histological architecture of the organs, implying that the extract was well tolerated in mice.
CONCLUSIONS
methanolic root extract exhibited good antimalarial activity against and may be safe in mice.
Topics: Mice; Animals; Antimalarials; Plasmodium berghei; Senna Plant; Mice, Inbred BALB C; Alkaline Phosphatase; Plant Extracts
PubMed: 37583959
DOI: 10.1155/2023/8296195 -
Journal of Cell Science Jun 2024Plasmodium sporozoites are the infective forms of the malaria parasite in the mosquito and vertebrate host. Gliding motility allows sporozoites to migrate and invade...
Plasmodium sporozoites are the infective forms of the malaria parasite in the mosquito and vertebrate host. Gliding motility allows sporozoites to migrate and invade mosquito salivary glands and mammalian hosts. Motility and invasion are powered by an actin-myosin motor complex linked to the glideosome, which contains glideosome-associated proteins (GAPs), MyoA and the myosin A tail-interacting protein (MTIP). However, the role of several proteins involved in gliding motility remains unknown. We identified that the S14 gene is upregulated in sporozoite from transcriptome data of Plasmodium yoelii and further confirmed its transcription in P. berghei sporozoites using real-time PCR. C-terminal 3×HA-mCherry tagging revealed that S14 is expressed and localized on the inner membrane complex of the sporozoites. We disrupted S14 in P. berghei and demonstrated that it is essential for sporozoite gliding motility, and salivary gland and hepatocyte invasion. The gliding and invasion-deficient S14 knockout sporozoites showed normal expression and organization of inner membrane complex and surface proteins. Taken together, our data show that S14 plays a role in the function of the glideosome and is essential for malaria transmission.
Topics: Sporozoites; Plasmodium berghei; Protozoan Proteins; Animals; Mice; Malaria; Salivary Glands; Anopheles
PubMed: 38832798
DOI: 10.1242/jcs.261857 -
BMC Microbiology Sep 2023Plasmodium berghei has been used as a preferred model for studying human malaria, but only a limited number of disease-associated genes of P. berghei have been reported...
BACKGROUND
Plasmodium berghei has been used as a preferred model for studying human malaria, but only a limited number of disease-associated genes of P. berghei have been reported to date. Identification of new disease-related genes as many as possible will provide a landscape for better understanding the pathogenesis of P. berghei.
METHODS
Network module analysis method was developed and applied to identify disease-related genes in P. berghei genome. Sequence feature identification, gene ontology annotation, and T-cell epitope analysis were performed on these genes to illustrate their functions in the pathogenesis of P. berghei.
RESULTS
33,314 genes were classified into 4,693 clusters. 4,127 genes shared by six malaria parasites were identified and are involved in many aspects of biological processes. Most of the known essential genes belong to shared genes. A total of 63 clusters consisting of 405 P. berghei genes were enriched in rodent malaria parasites. These genes participate in various stages of parasites such as liver stage development and immune evasion. Combination of these genes might be responsible for P. berghei infecting mice. Comparing with P. chabaudi, none of the clusters were specific to P. berghei. P. berghei lacks some proteins belonging to P. chabaudi and possesses some specific T-cell epitopes binding by class-I MHC, which might together contribute to the occurrence of experimental cerebral malaria (ECM).
CONCLUSIONS
We successfully identified disease-associated P. berghei genes by network module analysis. These results will deepen understanding of the pathogenesis of P. berghei and provide candidate parasite genes for further ECM investigation.
Topics: Humans; Animals; Mice; Plasmodium berghei; Gene Ontology; Genes, Essential; Immune Evasion; Molecular Sequence Annotation
PubMed: 37735351
DOI: 10.1186/s12866-023-03019-0