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Journal of Medicinal Food Jun 2024Malaria impedes the ability of primary cells of the immune system to generate an efficacious inflammatory and immune response. Black seed () is a core dietary supplement...
Malaria impedes the ability of primary cells of the immune system to generate an efficacious inflammatory and immune response. Black seed () is a core dietary supplement and food additive in folklore. This study investigated the antioxidant, immunomodulatory, and anti-inflammatory effects of cookies in -infected mice. Aqueous extract of black seed was prepared, and the total phenol and flavonoid contents were determined. The mice were infected with standard inoculum of the strain NK65 . The mice weight and behavioral changes were observed. The mice were fed with the cookies (2.5%, 5%, and 10%) and 10 mg/kg chloroquine for 5 consecutive days after the infection was established. The reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase, catalase, and hematological parameters (red cell indices, leukocytes, and its differentials) in the infected mice were determined. The inflammatory mediators, C-reactive protein (CRP), and myeloperoxidase (MPO) were also assayed. The result revealed that black seed had a total phenol content of 18.73 mgGAE/g and total flavonoid content of 0.36 mgQUE/g. The infected mice treated with cookies showed significantly decreased parasitaemia, MDA, and ROS levels. Furthermore, the results showed significant suppression in proinflammatory mediators (CRP and MPO) levels and enhanced antioxidant status of infected mice treated with . The study suggests that could function as nutraceuticals in the management of infection associated with inflammatory and immunomodulatory disorders.
Topics: Animals; Plasmodium berghei; Malaria; Oxidative Stress; Mice; Nigella sativa; Seeds; Plant Extracts; Male; Antioxidants; Disease Models, Animal; Reactive Oxygen Species; Malondialdehyde; Inflammation; Anti-Inflammatory Agents; Food, Fortified; C-Reactive Protein; Superoxide Dismutase; Humans; Flavonoids; Peroxidase
PubMed: 38935918
DOI: 10.1089/jmf.2023.0181 -
Life (Basel, Switzerland) May 2024Plakortinic acids C () and D (), an unseparable pair of endoperoxide polyketides isolated and purified from the symbiotic association of Caribbean Sea sponges ,...
Probing the Antiplasmodial Properties of Plakortinic Acids C and D: An Uncommon Pair of Marine Peroxide-Polyketides Isolated from a Two-Sponge Association of and Collected near Puerto Rico.
Plakortinic acids C () and D (), an unseparable pair of endoperoxide polyketides isolated and purified from the symbiotic association of Caribbean Sea sponges , underwent in vitro evaluation for antiplasmodial activity against the malaria parasite using a drug luminescence assay. Initial screening at 10 µM revealed 50% in vitro parasite growth inhibition. The title compounds displayed antiplasmodial activity with an EC of 5.3 µM toward parasites. The lytic activity against erythrocytes was assessed through an erythrocyte cell lysis assay, which showed non-lytic activity at lower concentrations ranging from 1.95 to 3.91 µM. The antiplasmodial activity and the absence of hemolytic activity support the potential of plakortinic acids C () and D () as promising lead compounds. Moreover, drug-likeness (ADMET) properties assessed through the pkCSM server predicted high intestinal absorption, hepatic metabolism, and volume of distribution, indicating favorable pharmacokinetic profiles for oral administration. These findings suggest the potential suitability of these metabolites for further investigations of antiplasmodial activity in multiple parasitic stages in the mosquito and Notably, this study represents the first report of a marine natural product exhibiting the unique 7,8-dioxatricyclo[4.2.2.0]dec-9-ene motif being evaluated against malaria.
PubMed: 38929667
DOI: 10.3390/life14060684 -
ImmunoHorizons Jun 2024Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized...
Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized parasite replication cycle inside RBCs. As immune cells harbor an autonomous circadian clock that controls various aspects of the immune response, we sought to determine whether the intensity of the immune response to Plasmodium spp., the parasite causing malaria, depends on time of infection. To do this, we developed a culture model in which mouse bone marrow-derived macrophages are stimulated with RBCs infected with Plasmodium berghei ANKA (iRBCs). Lysed iRBCs, but not intact iRBCs or uninfected RBCs, triggered an inflammatory immune response in bone marrow-derived macrophages. By stimulating at four different circadian time points (16, 22, 28, or 34 h postsynchronization of the cells' clock), 24-h rhythms in reactive oxygen species and cytokines/chemokines were found. Furthermore, the analysis of the macrophage proteome and phosphoproteome revealed global changes in response to iRBCs that varied according to circadian time. This included many proteins and signaling pathways known to be involved in the response to Plasmodium infection. In summary, our findings show that the circadian clock within macrophages determines the magnitude of the inflammatory response upon stimulation with ruptured iRBCs, along with changes of the cell proteome and phosphoproteome.
Topics: Animals; Macrophages; Mice; Erythrocytes; Malaria; Plasmodium berghei; Circadian Rhythm; Mice, Inbred C57BL; Reactive Oxygen Species; Cytokines; Circadian Clocks; Cells, Cultured; Proteome
PubMed: 38916585
DOI: 10.4049/immunohorizons.2400021 -
Comparative Medicine Jun 2024Malaria is a parasitic disease caused by protozoan species of the genus and transmitted by female mosquitos of the genus and other Culicidae. Most of the parasites of...
Malaria is a parasitic disease caused by protozoan species of the genus and transmitted by female mosquitos of the genus and other Culicidae. Most of the parasites of the genus are highly species specific with more than 200 species described affecting different species of mammals, birds, and reptiles. species strictly affecting humans are , , , and More recently, and other nonhuman primate plasmodia were found to naturally infect humans. Currently, malaria occurs mostly in poor tropical and subtropical areas of the world, and in many of these countries it is the leading cause of illness and death. For more than 100 y, animal models, have played a major role in our understanding of malaria biology. Avian species were the first to be used as models to study human malaria. Malaria parasite biology and immunity were first studied using mainly and . Rodent malarias, particularly and , have been used extensively as models to study malaria in mammals. Several species of from nonhuman primates have been used as surrogate models to study human malaria immunology, pathogenesis, candidate vaccines, and treatments. , , and are important models for studying malaria produced by and , while is used as a model for studying severe malaria. Other nonhuman primate malarias used in research are , , , , and . Very few nonhuman primate species can develop an infection with human malarias. Macaques in general are resistant to infection with , , , and . Only apes and a few species of New World monkeys can support infection with human malarias. Herein we review the most common, and some less common, avian, reptile, and mammal plasmodia species used as models to study human malaria.
PubMed: 38902006
DOI: 10.30802/AALAS-CM-24-000019 -
International Journal of Biological... Jun 2024Artemisinin and its derivatives have been commonly used to treat malaria. However, the emergence of resistance against artemisinin derivatives has posed a critical...
Artemisinin and its derivatives have been commonly used to treat malaria. However, the emergence of resistance against artemisinin derivatives has posed a critical challenge in malaria management. In the present study, we have proposed a combinatorial approach, utilizing pH-responsive acetal-dextran nanoparticles (Ac-Dex NPs) as carriers for the delivery of withaferin-A (WS-3) and artesunate (Art) to improve treatment efficacy of malaria. The optimized WS-3 and Art Ac-Dex NPs demonstrated enhanced pH-responsive release profiles under parasitophorous mimetic conditions (pH 5.5). Computational molecular modeling reveals that Ac-Dex's polymeric backbone strongly interacts with merozoite surface protein-1 (MSP-1), preventing erythrocyte invasion. In-vitro antimalarial activity of drug-loaded Ac-Dex NPs reveals a 1-1.5-fold reduction in IC values compared to pure drug against the 3D7 strain of Plasmodium falciparum. Treatment with WS-3 Ac-Dex NPs (100 mg/kg) and Art Ac-Dex NPs (30 mg/kg) to Plasmodium berghei-infected mice resulted in 78.11 % and 100 % inhibition of parasitemia. Notably, the combination therapy comprised of Art and WS-3 Ac-Dex NPs achieved complete inhibition of parasitemia even at a half dose of Art, indicating the synergistic potential of the combinations. However, further investigations are necessary to confirm the safety and effectiveness of WS-3 and Art Ac-Dex NPs for their successful clinical implications.
PubMed: 38897506
DOI: 10.1016/j.ijbiomac.2024.133220 -
BioRxiv : the Preprint Server For... Jun 2024Rodent malaria models serve as important preclinical antimalarial and vaccine testing tools. Evaluating treatment outcomes in these models often requires manually...
Rodent malaria models serve as important preclinical antimalarial and vaccine testing tools. Evaluating treatment outcomes in these models often requires manually counting parasite-infected red blood cells (iRBCs), a time-consuming process, which can be inconsistent between individuals and labs. We have developed an easy-to-use machine learning (ML)-based software, Malaria Screener R, to expedite and standardize such studies by automating the counting of iRBCs in rodents. This software can process Giemsa-stained blood smear images captured by any camera-equipped microscope. It features an intuitive graphical user interface that facilitates image processing and visualization of the results. The software has been developed as a desktop application that processes images on standard Windows and Mac OS computers. A previous ML model created by the authors designed to count -infected human RBCs did not perform well counting -infected mouse RBCs. We leveraged that model by loading the pre-trained weights and training the algorithm with newly collected data to target and mouse iRBCs. This new model reliably measured both and parasitemia (R = 0.9916). Additional rounds of training data to incorporate variances due to length of Giemsa staining, microscopes etc, have produced a generalizable model, meeting WHO Competency Level 1 for the sub-category of parasite counting using independent microscopes. Reliable, automated analyses of blood-stage parasitemia will facilitate rapid and consistent evaluation of novel vaccines and antimalarials across labs in an easily accessible malaria model.
PubMed: 38895284
DOI: 10.1101/2024.06.05.597554 -
Nucleic Acids Research Jun 2024The human malaria parasite Plasmodium falciparum genome is among the most A + T rich, with low complexity regions (LCRs) inserted in coding sequences including those...
The human malaria parasite Plasmodium falciparum genome is among the most A + T rich, with low complexity regions (LCRs) inserted in coding sequences including those for proteins targeted to its essential relict plastid (apicoplast). Replication of the apicoplast genome (plDNA), mediated by the atypical multifunctional DNA polymerase PfPrex, would require additional enzymatic functions for lagging strand processing. We identified an apicoplast-targeted, [4Fe-4S]-containing, FEN/Exo (PfExo) with a long LCR insertion and detected its interaction with PfPrex. Distinct from other known exonucleases across organisms, PfExo recognized a wide substrate range; it hydrolyzed 5'-flaps, processed dsDNA as a 5'-3' exonuclease, and was a bipolar nuclease on ssDNA and RNA-DNA hybrids. Comparison with the rodent P. berghei ortholog PbExo, which lacked the insertion and [4Fe-4S], revealed interspecies functional differences. The insertion-deleted PfExoΔins behaved like PbExo with a limited substrate repertoire because of compromised DNA binding. Introduction of the PfExo insertion into PbExo led to gain of activities that the latter initially lacked. Knockout of PbExo indicated essentiality of the enzyme for survival. Our results demonstrate the presence of a novel apicoplast exonuclease with a functional LCR that diversifies substrate recognition, and identify it as the candidate flap-endonuclease and RNaseH required for plDNA replication and maintenance.
PubMed: 38888125
DOI: 10.1093/nar/gkae512 -
Antimicrobial Agents and Chemotherapy Jun 2024The emergence of clinically drug-resistant malaria parasites requires the urgent development of new drugs. Mosquitoes are vectors of multiple pathogens and have...
The emergence of clinically drug-resistant malaria parasites requires the urgent development of new drugs. Mosquitoes are vectors of multiple pathogens and have developed resistance mechanisms against them, which often involve antimicrobial peptides (AMPs). An-cecB is an AMP of the malaria-transmitting mosquito genus , and we herein report its antimalarial activity against 3D7, the artemisinin-resistant strain 803, and the chloroquine-resistant strain Dd2 . We also demonstrate its anti-parasite activity , using the rodent malaria parasite (ANKA). We show that An-cecB displays potent antimalarial activity and that its mechanism of action may occur through direct killing of the parasite or through interaction with infected red blood cell membranes. Unfortunately, An-cecB was found to be cytotoxic to mammalian cells and had poor antimalarial activity . However, its truncated peptide An-cecB-1 retained most of its antimalarial activity and avoided its cytotoxicity . An-cecB-1 also showed better antimalarial activity . Mosquito-derived AMPs may provide new ideas for the development of antimalarial drugs against drug-resistant parasites, and An-cecB has potential use as a template for antimalarial peptides.
PubMed: 38874346
DOI: 10.1128/aac.00311-24 -
PLoS Neglected Tropical Diseases Jun 2024Malaria transmission-blocking vaccines (TBVs) aim to inhibit malaria parasite development in mosquitoes and prevent further transmission to the human host. The...
BACKGROUND
Malaria transmission-blocking vaccines (TBVs) aim to inhibit malaria parasite development in mosquitoes and prevent further transmission to the human host. The putative-secreted ookinete protein 25 (PSOP25), highly conserved in Plasmodium spp., is a promising TBV target. Here, we investigated PvPSOP25 from P. vivax as a TBV candidate using transgenic murine parasite P. berghei and clinical P. vivax isolates.
METHODS AND FINDINGS
A transgenic P. berghei line expressing PvPSOP25 (TrPvPSOP25Pb) was generated. Full-length PvPSOP25 was expressed in the yeast Pichia pastoris and used to immunize mice to obtain anti-rPvPSOP25 sera. The transmission-blocking activity of the anti-rPvPSOP25 sera was evaluated through in vitro assays and mosquito-feeding experiments. The antisera generated by immunization with rPvPSOP25 specifically recognized the native PvPSOP25 antigen expressed in TrPvPSOP25Pb ookinetes. In vitro assays showed that the immune sera significantly inhibited exflagellation and ookinete formation of the TrPvPSOP25Pb parasite. Mosquitoes feeding on mice infected with the transgenic parasite and passively transferred with the anti-rPvPSOP25 sera showed a 70.7% reduction in oocyst density compared to the control group. In a direct membrane feeding assay conducted with five clinical P. vivax isolates, the mouse anti-rPvPSOP25 antibodies significantly reduced the oocyst density while showing a negligible influence on mosquito infection prevalence.
CONCLUSIONS
This study supported the feasibility of transgenic murine malaria parasites expressing P. vivax antigens as a useful tool for evaluating P. vivax TBV candidates. Meanwhile, the moderate transmission-reducing activity of the generated anti-rPvPSOP25 sera necessitates further research to optimize its efficacy.
Topics: Animals; Mice; Plasmodium vivax; Malaria Vaccines; Plasmodium berghei; Protozoan Proteins; Humans; Malaria, Vivax; Female; Antigens, Protozoan; Antibodies, Protozoan; Malaria; Mice, Inbred BALB C
PubMed: 38865344
DOI: 10.1371/journal.pntd.0012231 -
Immunobiology Jul 2024Acute lung injury caused by severe malaria (SM) is triggered by a dysregulated immune response towards the infection with Plasmodium parasites. Postmortem analysis of...
Acute lung injury caused by severe malaria (SM) is triggered by a dysregulated immune response towards the infection with Plasmodium parasites. Postmortem analysis of human lungs shows diffuse alveolar damage (DAD), the presence of CD8 lymphocytes, neutrophils, and increased expression of Intercellular Adhesion Molecule 1 (ICAM-1). P. berghei ANKA (PbA) infection in C57BL/6 mice reproduces many SM features, including acute lung injury characterized by DAD, CD8 T lymphocytes and neutrophils in the lung parenchyma, and tissular expression of proinflammatory cytokines and adhesion molecules, such as IFNγ, TNFα, ICAM, and VCAM. Since this is related to a dysregulated immune response, immunomodulatory agents are proposed to reduce the complications of SM. The monocyte locomotion inhibitory factor (MLIF) is an immunomodulatory pentapeptide isolated from axenic cultures of Entamoeba hystolitica. Thus, we evaluated if the MLIF intraperitoneal (i.p.) treatment prevented SM-induced acute lung injury. The peptide prevented SM without a parasiticidal effect, indicating that its protective effect was related to modifications in the immune response. Furthermore, peripheral CD8 leukocytes and neutrophil proportions were higher in infected treated mice. However, the treatment prevented DAD, CD8 cell infiltration into the pulmonary tissue and downregulated IFNγ. Moreover, VCAM-1 expression was abrogated. These results indicate that the MLIF treatment downregulated adhesion molecule expression, impeding cell migration and proinflammatory cytokine tissular production, preventing acute lung injury induced by SM. Our findings represent a potential novel strategy to avoid this complication in various events where a dysregulated immune response triggers lung injury.
Topics: Animals; Acute Lung Injury; Mice; Disease Models, Animal; Malaria; Plasmodium berghei; Mice, Inbred C57BL; Neutrophils; CD8-Positive T-Lymphocytes; Cytokines; Lung; Humans; Female; Oligopeptides
PubMed: 38861873
DOI: 10.1016/j.imbio.2024.152823