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Infectious Disorders Drug Targets Mar 2024Malaria is still the deadliest parasitic disease caused by Plasmodium spp. Due to drug resistance and their unpleasant side effects, of conventional researchers are...
BACKGROUND
Malaria is still the deadliest parasitic disease caused by Plasmodium spp. Due to drug resistance and their unpleasant side effects, of conventional researchers are enormously seeking to achieve antimalarial drugs with more curative effective, less toxic and cost-affordable drugs using more advanced technology such as nanodrugs.
PURPOSE
The present study aimed to examine the antimalarial effects of a novel synthesized nonochloroquine-loaded curcumin relying on dendrimer G2 in susceptible mice.
METHODS
Antimalarial activity and toxicity of the nanocomposite were examined on BALB/C mice with microscopy, checking RBCs morphology and related enzymatic activity rate.
RESULTS
The maximum inhibitory effect of the nanocomposite was seen at 10 mg/kg, killing 98% of P. berghei compared to sole chloroquine, whereas ED50 was reported at 5.5 mg/kg. The safety of the synthesized nanocomposite was confirmed with biochemical tests with no detrimental effects on mice. The sustainability and longevity of the nanodrug increased significantly with the NDC-CQ assay compared to the control groups.
CONCLUSION
The study showed that nonochloroquine-loaded curcumin had a promising inhibitory effect on P. berghei growth in infected mice compared to standard drugs. However, further studies and clinical trials with large samples are recommended to study different aspects of using nanodrug.
PubMed: 38468520
DOI: 10.2174/0118715265276270240222070244 -
Bio-protocol Mar 2024The parasites that cause malaria undergo an obligate, asymptomatic developmental stage in the host liver before initiating the symptomatic blood-stage infection. The...
The parasites that cause malaria undergo an obligate, asymptomatic developmental stage in the host liver before initiating the symptomatic blood-stage infection. The parasite liver stage is a key intervention point for antimalarial chemoprophylaxis: successful targeting of liver-stage parasites prevents disease development in individuals and can help to reduce parasite transmission in populations, as the gametocyte forms that transmit infection to mosquitos are exclusively found in the blood stage. Antimalarial drugs that can target multiple parasite stages are thus highly desirable, and one emerging cellular target for such multistage active compounds is the process of protein synthesis or translation. Quantitative study of liver stage translation, and thus mechanistic evaluation of translation inhibitors against liver stage parasites, is not amenable to the methods allowing quantification of asexual blood stage translation, such as radiolabeled amino acid incorporation or lysate-based translation of reporter transcripts. Here, we present a method using o-propargyl puromycin (OPP) labeling of host and parasite nascent proteomes in the -HepG2 infection model, followed by automated confocal image acquisition and computational separation of vs. nascent proteome signals to allow simultaneous readout of the effects of translation inhibitors on both host and parasite. This protocol details our HepG2 cell culture and infected monolayer handling optimized for microscopy, our OPP labeling workflow, and our approach to automated confocal imaging, image processing, and data analysis. Key features • Uses the o-propargyl puromycin labeling technique developed by Liu et al. to quantitatively analyze protein synthesis in liver-stage parasites in actively translating hepatoma cells. • This quantitative approach should be adaptable for other puromycin-sensitive intracellular pathogens residing in actively translating host cells. • The -infected HepG2 recovery and reseeding protocol presented here is of use in applications beyond nascent proteome labeling and quantification.
PubMed: 38464937
DOI: 10.21769/BioProtoc.4952 -
Vaccine Apr 2024Malaria caused byPlasmodium vivaxis a pressing public health problem in tropical and subtropical areas.However, little progress has been made toward developing a P....
Malaria caused byPlasmodium vivaxis a pressing public health problem in tropical and subtropical areas.However, little progress has been made toward developing a P. vivaxvaccine, with only three candidates being tested in clinical studies. We previously reported that one chimeric recombinant protein (PvCSP-All epitopes) containing the conserved C-terminus of the P. vivax Circumsporozoite Protein (PvCSP), the three variant repeat domains, and aToll-like receptor-3 agonist,Poly(I:C), as an adjuvant (polyinosinic-polycytidylic acid, a dsRNA analog mimicking viral RNA), elicits strong antibody-mediated immune responses in mice to each of the three allelic forms of PvCSP. In the present study, a pre-clinical safety evaluation was performed to identify potential local and systemic toxic effects of the PvCSP-All epitopes combined with the Poly-ICLC (Poly I:C plus poly-L-lysine, Hiltonol®) or Poly-ICLC when subcutaneously injected into C57BL/6 mice and New Zealand White Rabbits followed by a 21-day recovery period. Overall, all observations were considered non-adverse and were consistent with the expected inflammatory response and immune stimulation following vaccine administration. High levels of vaccine-induced specific antibodies were detected both in mice and rabbits. Furthermore, mice that received the vaccine formulation were protected after the challenge with Plasmodium berghei sporozoites expressing CSP repeats from P. vivax sporozoites (Pb/Pv-VK210). In conclusion, in these non-clinical models, repeated dose administrations of the PvCSP-All epitopes vaccine adjuvanted with a Poly-ICLC were immunogenic, safe, and well tolerated.
Topics: Mice; Animals; Rabbits; Malaria, Vivax; Poly I-C; Polylysine; Plasmodium vivax; Protozoan Proteins; Malaria Vaccines; Mice, Inbred C57BL; Adjuvants, Immunologic; Recombinant Proteins; Epitopes; Antibodies, Protozoan; Carboxymethylcellulose Sodium
PubMed: 38448321
DOI: 10.1016/j.vaccine.2024.02.070 -
Parasites, Hosts and Diseases Feb 2024Antimalarial drugs are an urgently need and crucial tool in the campaign against malaria, which can threaten public health. In this study, we examined the cytotoxicity...
Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR mice.
Antimalarial drugs are an urgently need and crucial tool in the campaign against malaria, which can threaten public health. In this study, we examined the cytotoxicity of the 9 antimalarial compounds chemically synthesized using SKM13-2HCl. Except for SKM13-2HCl, the 5 newly synthesized compounds had a 50% cytotoxic concentration (CC50) > 100 µM, indicating that they would be less cytotoxic than SKM13-2HCl. Among the 5 compounds, only SAM13-2HCl outperformed SKM13-2HCl for antimalarial activity, showing a 3- and 1.3-fold greater selective index (SI) (CC50/IC50) than SKM13-2HCl in vitro against both chloroquine-sensitive (3D7) and chloroquine -resistant (K1) Plasmodium falciparum strains, respectively. Thus, the presence of morpholine amide may help to effectively suppress human-infectious P. falciparum parasites. However, the antimalarial activity of SAM13-2HCl was inferior to that of the SKM13-2HCl template compound in the P. berghei NK65-infected mouse model, possibly because SAM13-2HCl had a lower polarity and less efficient pharmacokinetics than SKM13-2HCl. SAM13-2HCl was more toxic in the rodent model. Consequently, SAM13-2HCl containing morpholine was selected from screening a combination of pharmacologically significant structures as being the most effective in vitro against human-infectious P. falciparum but was less efficient in vivo in a P. berghei-infected animal model when compared with SKM13-2HCl. Therefore, SAM13-2HCl containing morpholine could be considered a promising compound to treat chloroquine-resistant P. falciparum infections, although further optimization is crucial to maintain antimalarial activity while reducing toxicity in animals.
Topics: Mice; Animals; Humans; Antimalarials; Mice, Inbred ICR; Plasmodium berghei; Plasmodium falciparum; Chloroquine; Morpholines; Amides; Disease Models, Animal; Folic Acid Antagonists
PubMed: 38443769
DOI: 10.3347/PHD.23093 -
Parasitology International Aug 2024Malaria remains a major public health issue worldwide, with high rates of morbidity and mortality. The resistance of Plasmodium parasites to commonly used antimalarial...
Malaria remains a major public health issue worldwide, with high rates of morbidity and mortality. The resistance of Plasmodium parasites to commonly used antimalarial drugs has necessitated the development of novel drugs and targets for malaria treatment. Lycopene is a natural compound present in tomatoes and other red fruits and vegetables. This study aimed to evaluate the antimalarial activity of lycopene and its co-administration with chloroquine against chloroquine-resistant malaria, as well as to assess its impact on hematological abnormalities associated with malaria infection. The experimental animals for this study were infected with 10 NK65 Plasmodium berghei-infected red blood cells via intraperitoneal injection. The animals were then treated with artemether-lumefantrine, chloroquine, and varying doses of lycopene. The study evaluated percentage parasitemia, mean survival time, and various hematological parameters, including red blood cell count, hematocrit, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, red blood cell distribution width - coefficient of variation, red blood cell distribution width - standard deviation, white blood cell count, granulocyte count, lymphocyte count, monocyte count, and procalcitonin level. The study revealed that lycopene demonstrated significant (p < 0.05) antimalarial activity and the ability to ameliorate hematological abnormalities associated with acute malaria infection. The findings of this study highlight the potential of lycopene as a novel antimalarial agent. The results of this study may contribute to the development of new drugs for malaria treatment, particularly in low- and middle-income countries.
Topics: Lycopene; Animals; Antimalarials; Chloroquine; Mice; Malaria; Plasmodium berghei; Drug Resistance; Disease Models, Animal; Parasitemia; Male; Artemether, Lumefantrine Drug Combination
PubMed: 38428566
DOI: 10.1016/j.parint.2024.102873 -
ACS Infectious Diseases Apr 2024The O-fucosylation of the thrombospondin type I repeat (TSR) domain is important for TSR-containing proteins' optimal folding and stability. However, the importance of...
The O-fucosylation of the thrombospondin type I repeat (TSR) domain is important for TSR-containing proteins' optimal folding and stability. However, the importance of O-fucosyltransferase 2 (POFut2) remains unclear due to two different reports. Here, we disrupted the gene in and demonstrated that KO parasites develop normally in blood and mosquito stages but show reduced infectivity in mice. We found that the reduced infectivity of KO sporozoites was due to a diminished level of TRAP that affected the parasite gliding motility and hepatocyte infectivity. Using all-atom MD simulation, we also hypothesize that O-fucosylation impacts the TSR domain's stability more than its heparin binding capacity.
Topics: Animals; Mice; Fucosyltransferases; Plasmodium berghei; Sporozoites; Protozoan Proteins; Hepatocytes
PubMed: 38421807
DOI: 10.1021/acsinfecdis.3c00631 -
Journal of Natural Products Apr 2024Three new antiplasmodial compounds, named akedanones A (), B (), and C (), were discovered from the cultured material of sp. K20-0187 isolated from a soil sample...
Three new antiplasmodial compounds, named akedanones A (), B (), and C (), were discovered from the cultured material of sp. K20-0187 isolated from a soil sample collected at Takeda, Kofu, Yamanashi prefecture in Japan. The structures of compounds - were elucidated as new 2,3-dihydronaphthoquinones having prenyl and reverse prenyl groups by mass spectrometry and nuclear magnetic resonance analyses. Compound and the known furanonaphthoquinone I () showed potent antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant strains, with half-maximal inhibitory concentration values ranging from 0.06 to 0.3 μM. Compounds and also displayed potent antiplasmodial activity against drug-sensitive rodent malaria N strain, with inhibition rates of 47.6 and 43.1%, respectively, on intraperitoneal administration at a dose of 5 mg kg day for 4 days.
Topics: Antimalarials; Plasmodium falciparum; Streptomyces; Naphthoquinones; Molecular Structure; Plasmodium berghei; Animals; Japan; Mice; Chloroquine; Soil Microbiology
PubMed: 38421618
DOI: 10.1021/acs.jnatprod.3c01285 -
Molecular Microbiology May 2024Plasmodium is an obligate intracellular parasite that requires intense lipid synthesis for membrane biogenesis and survival. One of the principal membrane components is...
Plasmodium is an obligate intracellular parasite that requires intense lipid synthesis for membrane biogenesis and survival. One of the principal membrane components is oleic acid, which is needed to maintain the membrane's biophysical properties and fluidity. The malaria parasite can modify fatty acids, and stearoyl-CoA Δ9-desaturase (Scd) is an enzyme that catalyzes the synthesis of oleic acid by desaturation of stearic acid. Scd is dispensable in P. falciparum blood stages; however, its role in mosquito and liver stages remains unknown. We show that P. berghei Scd localizes to the ER in the blood and liver stages. Disruption of Scd in the rodent malaria parasite P. berghei did not affect parasite blood stage propagation, mosquito stage development, or early liver-stage development. However, when Scd KO sporozoites were inoculated intravenously or by mosquito bite into mice, they failed to initiate blood-stage infection. Immunofluorescence analysis revealed that organelle biogenesis was impaired and merozoite formation was abolished, which initiates blood-stage infections. Genetic complementation of the KO parasites restored merozoite formation to a level similar to that of WT parasites. Mice immunized with Scd KO sporozoites confer long-lasting sterile protection against infectious sporozoite challenge. Thus, the Scd KO parasite is an appealing candidate for inducing protective pre-erythrocytic immunity and hence its utility as a GAP.
Topics: Plasmodium berghei; Animals; Mice; Organelle Biogenesis; Liver; Merozoites; Malaria; Stearoyl-CoA Desaturase; Sporozoites; Protozoan Proteins; Anopheles; Female; Endoplasmic Reticulum
PubMed: 38419272
DOI: 10.1111/mmi.15246 -
MBio Apr 2024Neddylation is a type of posttranslational modification known to regulate a wide range of cellular processes by covalently conjugating the ubiquitin-like protein Nedd8...
Neddylation is a type of posttranslational modification known to regulate a wide range of cellular processes by covalently conjugating the ubiquitin-like protein Nedd8 to target proteins at lysine residues. However, the role of neddylation in malaria parasites has not been determined. Here, for the first time, we showed that neddylation plays an essential role in malaria transmission in . We found that disruption of Nedd8 did not affect blood-stage propagation, gametocyte development, gamete formation, or zygote formation while abolishing the formation of ookinetes and further transmission of the parasites in mosquitoes. These phenotypic defects in Nedd8 knockout parasites were complemented by reintroducing the gene that restored mosquito transmission to wild-type levels. Our data establish the role of Nedd8 in malaria parasite transmission.IMPORTANCENeddylation is a process by which Nedd8 is covalently attached to target proteins through three-step enzymatic cascades. The attachment of Nedd8 residues results in a range of diverse functions, such as cell cycle regulation, metabolism, immunity, and tumorigenesis. The potential neddylation substrates are cullin (CUL) family members, which are implicated in controlling the cell cycle. Cullin neddylation leads to the activation of cullin-RING ubiquitin ligases, which regulate a myriad of biological processes through target-specific ubiquitylation. Neddylation possibly regulates meiosis in zygotes, which subsequently develop into ookinetes. Our findings point to an essential function of this neddylation pathway and highlight its possible importance in designing novel intervention strategies.
Topics: Animals; Ubiquitins; Plasmodium berghei; Cullin Proteins; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 38411954
DOI: 10.1128/mbio.00232-24 -
Scientific Reports Feb 2024Malaria can have severe long-term effects. Even after treatment with antimalarial drugs eliminates the parasite, survivors of cerebral malaria may suffer from...
Malaria can have severe long-term effects. Even after treatment with antimalarial drugs eliminates the parasite, survivors of cerebral malaria may suffer from irreversible brain damage, leading to cognitive deficits. Angiotensin II, a natural human peptide hormone that regulates blood pressure, has been shown to be active against Plasmodium spp., the etiologic agent of malaria. Here, we tested two Ang II derivatives that do not elicit vasoconstriction in mice: VIPF, a linear tetrapeptide, which constitutes part of the hydrophobic portion of Ang II; and Ang II-SS, a disulfide-bridged derivative. The antiplasmodial potential of both peptides was evaluated with two mouse models: an experimental cerebral malaria model and a mouse model of non-cerebral malaria. The latter consisted of BALB/c mice infected with Plasmodium berghei ANKA. The peptides had no effect on mean blood pressure and significantly reduced parasitemia in both mouse models. Both peptides reduced the SHIRPA score, an assay used to assess murine health and behavior. However, only the constrained derivative (Ang II-SS), which was also resistant to proteolytic degradation, significantly increased mouse survival. Here, we show that synthetic peptides derived from Ang II are capable of conferring protection against severe manifestations of malaria in mouse models while overcoming the vasoconstrictive side effects of the parent peptide.
Topics: Animals; Mice; Humans; Malaria, Cerebral; Angiotensin II; Disease Models, Animal; Antimalarials; Peptides; Plasmodium berghei; Mice, Inbred C57BL
PubMed: 38409185
DOI: 10.1038/s41598-024-51267-5