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Pharmaceuticals (Basel, Switzerland) Dec 2023ANKA (PbA) infection in mice resembles several aspects of severe malaria in humans, such as cerebral malaria and acute respiratory distress syndrome. Herein, the...
ANKA (PbA) infection in mice resembles several aspects of severe malaria in humans, such as cerebral malaria and acute respiratory distress syndrome. Herein, the effects of -(coumarin-3-yl)cinnamamide (M220) against severe experimental malaria have been investigated. Treatment with M220 proved to protect cognitive abilities and lung function in PbA-infected mice, observed by an object recognition test and spirometry, respectively. In addition, treated mice demonstrated decreased levels of brain and lung inflammation. The production and accumulation of microglia, and immune cells that produce the inflammatory cytokines TNF and IFN-γ, decreased, while the production of the anti-inflammatory cytokine IL-10 by innate and adaptive immune cells was enhanced. Treatment with M220 promotes immunomodulatory, neuroprotective, and lung function-preserving effects during experimental severe malaria. Therefore, it may be an interesting therapeutic candidate to treat severe malaria effects.
PubMed: 38256880
DOI: 10.3390/ph17010046 -
ELife Jan 2024Gametocytes play key roles in the lifecycle. They are essential for sexual reproduction as precursors of the gametes. They also play an essential role in parasite...
Gametocytes play key roles in the lifecycle. They are essential for sexual reproduction as precursors of the gametes. They also play an essential role in parasite transmission to mosquitoes. Elucidation of the gene regulation at this stage is essential for understanding these two processes at the molecular level and for developing new strategies to break the parasite lifecycle. We identified a novel transcription factor (TF), designated as a partner of AP2-FG or PFG. In this article, we report that this TF regulates the gene expression in female gametocytes in concert with another female-specific TF AP2-FG. Upon the disruption of , majority of female-specific genes were significantly downregulated, and female gametocyte lost the ability to produce ookinetes. ChIP-seq analysis showed that it was located in the same position as AP2-FG, indicating that these two TFs form a complex. ChIP-seq analysis of PFG in -disrupted parasites and ChIP-seq analysis of AP2-FG in -disrupted parasites demonstrated that PFG mediates the binding of AP2-FG to a ten-base motif and that AP2-FG binds another motif, GCTCA, in the absence of PFG. In promoter assays, this five-base motif was identified as another female-specific -acting element. Genes under the control of the two forms of AP2-FG, with or without PFG, partly overlapped; however, each form had target preferences. These results suggested that combinations of these two forms generate various expression patterns among the extensive genes expressed in female gametocytes.
Topics: Animals; Female; Transcription Factors; Plasmodium; Transcription Factor AP-2; Biological Assay; Culicidae
PubMed: 38252559
DOI: 10.7554/eLife.88317 -
PLoS Pathogens Jan 2024Plasmodium parasites cause malaria, a global health disease that is responsible for more than 200 million clinical cases and 600 000 deaths each year. Most deaths are...
Plasmodium parasites cause malaria, a global health disease that is responsible for more than 200 million clinical cases and 600 000 deaths each year. Most deaths are caused by various complications, including malaria-associated acute respiratory distress syndrome (MA-ARDS). Despite the very rapid and efficient killing of parasites with antimalarial drugs, 15% of patients with complicated malaria succumb. This stresses the importance of investigating resolution mechanisms that are involved in the recovery from these complications once the parasite is killed. To study the resolution of MA-ARDS, P. berghei NK65-infected C57BL/6 mice were treated with antimalarial drugs after onset of symptoms, resulting in 80% survival. Micro-computed tomography revealed alterations of the lungs upon infection, with an increase in total and non-aerated lung volume due to edema. Whole body plethysmography confirmed a drastically altered lung ventilation, which was restored during resolution. Single-cell RNA sequencing indicated an increased inflammatory state in the lungs upon infection, which was accompanied by a drastic decrease in endothelial cells, consistent with CD8+ T cell-mediated killing. During resolution, anti-inflammatory pathways were upregulated and proliferation of endothelial cells was observed. MultiNicheNet interactome analysis identified important changes in the ligand-receptor interactions during disease resolution that warrant further exploration in order to develop new therapeutic strategies. In conclusion, our study provides insights in pro-resolving pathways that limit inflammation and promote endothelial cell proliferation in experimental MA-ARDS. This information may be useful for the design of adjunctive treatments to enhance resolution after Plasmodium parasite killing by antimalarial drugs.
Topics: Humans; Animals; Mice; Antimalarials; Endothelial Cells; X-Ray Microtomography; Mice, Inbred C57BL; Respiratory Distress Syndrome; Malaria; Sequence Analysis, RNA; Plasmodium berghei
PubMed: 38236930
DOI: 10.1371/journal.ppat.1011929 -
PloS One 2024The emergence and spread of antimalarial drug resistance have become a significant problem worldwide. The search for natural products to develop novel antimalarial drugs...
Assessment of antimalarial activity of crude extract of Chan-Ta-Lee-La and Pra-Sa-Chan-Dang formulations and their plant ingredients for new drug candidates of malaria treatment: In vitro and in vivo experiments.
The emergence and spread of antimalarial drug resistance have become a significant problem worldwide. The search for natural products to develop novel antimalarial drugs is challenging. Therefore, this study aimed to assess the antimalarial and toxicological effects of Chan-Ta-Lee-La (CTLL) and Pra-Sa-Chan-Dang (PSCD) formulations and their plant ingredients. The crude extracts of CTLL and PSCD formulations and their plant ingredients were evaluated for in vitro antimalarial activity using Plasmodium lactate dehydrogenase enzyme and toxicity to Vero and HepG2 cells using the tetrazolium salt method. An extract from the CTLL and PSCD formulations exhibiting the highest selectivity index value was selected for further investigation using Peter's 4-day suppressive test, curative test, prophylactic test, and acute oral toxicity in mice. The phytochemical constituents were characterized using gas chromatography-mass spectrometry (GC-MS). Results showed that ethanolic extracts of CTLL and PSCD formulations possessed high antimalarial activity (half maximal inhibitory concentration = 4.88, and 4.19 g/mL, respectively) with low cytotoxicity. Ethanolic extracts of the CTLL and PSCD formulations demonstrated a significant dose-dependent decrease in parasitemia in mice. The ethanolic CTLL extract showed the greatest suppressive effect after 4 days of suppressive (89.80%) and curative (35.94%) testing at a dose of 600 mg/kg. Moreover, ethanolic PSCD extract showed the highest suppressive effect in the prophylactic test (65.82%) at a dose of 600 mg/kg. There was no acute toxicity in mice treated with ethanolic CTLL and PSCD extracts at 2,000 mg/kg bodyweight. GC-MS analysis revealed that the most abundant compounds in the ethanolic CTLL extract were linderol, isoborneol, eudesmol, linoleic acid, and oleic acid, whereas ethyl 4-methoxycinnamate was the most commonly found compound in the ethanolic PSCD extract, followed by 3-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-4H-chromen-4-one, flamenol, oleic acid amide, linoleic acid, and oleic acid. In conclusions, ethanolic CTLL and PSCD extracts exhibited high antimalarial efficacy in vitro. The ethanolic CTLL extract at a dose of 600 mg/kg exhibited the highest antimalarial activity in the 4-day suppressive and curative tests, whereas the ethanolic PSCD extract at a dose of 600 mg/kg showed the highest antimalarial activity in the prophylactic test.
Topics: Animals; Mice; Antimalarials; Linoleic Acid; Oleic Acid; Plant Extracts; Malaria; Complex Mixtures; Plasmodium berghei
PubMed: 38206944
DOI: 10.1371/journal.pone.0296756 -
Malaria Journal Jan 2024Plasmodium lacks an mRNA export receptor ortholog, such as yeast Mex67. Yeast Mex67 contains a nuclear transport factor 2 (NTF2)-like domain, suggesting that NTF2-like...
BACKGROUND
Plasmodium lacks an mRNA export receptor ortholog, such as yeast Mex67. Yeast Mex67 contains a nuclear transport factor 2 (NTF2)-like domain, suggesting that NTF2-like domain-containing proteins might be associated with mRNA export in Plasmodium. In this study, the relationship between mRNA export and an NTF2-like domain-containing protein, PBANKA_1019700, was investigated using the ANKA strain of rodent malaria parasite Plasmodium berghei.
METHODS
The deletion mutant Δ1019700 was generated by introducing gene-targeting vectors into the P. berghei ANKA genome, and parasite growth and virulence were examined. To investigate whether PBANKA_1019700 is involved in mRNA export, live-cell fluorescence imaging and immunoprecipitation coupled to mass spectrometry (IP-MS) were performed using transgenic parasites expressing fusion proteins (1019700::mCherry).
RESULTS
Deletion of PBANKA_1019700 affected the sexual phase but not the asexual phase of malaria parasites. Live-cell fluorescence imaging showed that PBANKA_1019700 localizes to the cytoplasm. Moreover, IP-MS analysis of 1019700::mCherry indicated that PBANKA_1019700 interacts with ubiquitin-related proteins but not nuclear proteins.
CONCLUSIONS
PBANKA_1019700 is a noncanonical NTF2-like superfamily protein.
Topics: Humans; Plasmodium berghei; Active Transport, Cell Nucleus; Saccharomyces cerevisiae; Malaria; RNA, Messenger
PubMed: 38195464
DOI: 10.1186/s12936-024-04839-9 -
BMC Chemistry Jan 2024Pyrazole-bearing compounds are known for their diverse pharmacological effects including potent antileishmanial and antimalarial activities. Herein, some...
Pyrazole-bearing compounds are known for their diverse pharmacological effects including potent antileishmanial and antimalarial activities. Herein, some hydrazine-coupled pyrazoles were successfully synthesized and their structures were verified by employing elemental microanalysis, FTIR, and H NMR techniques. The in vitro antileishmanial and in vivo antimalarial activities of the synthesized pyrazole derivatives (9-15) were evaluated against Leishmania aethiopica clinical isolate and Plasmodium berghei infected mice, respectively. The result revealed that compound 13 displayed superior antipromastigote activity (IC = 0.018) that was 174- and 2.6-fold more active than the standard drugs miltefosine (IC = 3.130) and amphotericin B deoxycholate (IC = 0.047). The molecular docking study conducted on Lm-PTR1, complexed with Trimethoprim was acquired from the Protein Data Bank (PDB ID:2bfm), justified the better antileishmanial activity of compound 13. Furthermore, the target compounds 14 and 15 elicited better inhibition effects against Plasmodium berghei with 70.2% and 90.4% suppression, respectively. In conclusion, the hydrazine-coupled pyrazole derivatives may be considered potential pharmacophores for the preparation of safe and effective antileishmanial and antimalarial agents.
PubMed: 38191485
DOI: 10.1186/s13065-023-01111-0 -
Evidence-based Complementary and... 2023has been used to treat malaria in Ghana albeit without scientific evidence of antimalarial activity and safety. This work aimed to assess the antimalarial properties...
has been used to treat malaria in Ghana albeit without scientific evidence of antimalarial activity and safety. This work aimed to assess the antimalarial properties and acute toxicity of the aqueous leaf extract of in murine models. Aqueous extract of the plant was analysed for both suppressive and curative antimalarial properties in chloroquine-sensitive ANKA strains of rodent -infected mice. Acute toxicity evaluation was performed in rats according to the OECD 425 guidelines. The extract displayed antiplasmodial activity with ED of 117.49 ± 15.22 mg/kg and 144.84 ± 18.17 mg/kg in suppressive and curative studies, respectively. The highest % parasitaemia suppression exerted was 76.90 ± 0.64% and 61.50 ± 0.97%, respectively, in the suppressive and curative studies. Survival of infected mice treated with the extract was significantly prolonged. This was dependent on the dose of the extract but imperfectly related to the % parasitaemia suppression. Related antimalarial parameters including percentage hematocrit, changes in body weight, and temperature of experimental mice indicated alleviation of malarial symptoms of treated animals. The extract did not show toxicity in rats. L. has antimalarial properties, and was safe. It suppressed parasitaemia in both suppressive and curative studies, was not toxic to animals and prolonged the life of infected animals under treatment. This, therefore, justifies the traditional use of for the treatment of malaria in Ghana.
PubMed: 38161788
DOI: 10.1155/2023/5560711 -
Brain, Behavior, and Immunity Mar 2024Cerebral malaria (CM) is a fatal neuroinflammatory syndrome caused (in humans) by the protozoa Plasmodium (P.) falciparum. Glial cell activation is one of the mechanisms...
BACKGROUND
Cerebral malaria (CM) is a fatal neuroinflammatory syndrome caused (in humans) by the protozoa Plasmodium (P.) falciparum. Glial cell activation is one of the mechanisms that contributes to neuroinflammation in CM.
RESULT
By studying a mouse model of CM (caused by P. berghei ANKA), we describe that the induction of autophagy promoted p21-dependent senescence in astrocytes and that CXCL-10 was part of the senescence-associated secretory phenotype. Furthermore, p21 expression was observed in post-mortem brain and peripheral blood samples from patients with CM. Lastly, we found that the depletion of senescent astrocytes with senolytic drugs abrogated inflammation and protected mice from CM.
CONCLUSION
Our data provide evidence for a novel mechanism through which astrocytes could be involved in the neuropathophysiology of CM. p21 gene expression in blood cell and an elevated plasma CXCL-10 concentration could be valuable biomarkers of CM in humans. In the end, we believe senolytic drugs shall open up new avenues to develop newer treatment options.
Topics: Humans; Animals; Mice; Malaria, Cerebral; Neuroinflammatory Diseases; Astrocytes; Senotherapeutics; Autophagy
PubMed: 38157948
DOI: 10.1016/j.bbi.2023.12.030 -
Frontiers in Cellular and Infection... 2023Coronavirus disease 2019 (COVID-19) and malaria, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and parasites, respectively, share geographical...
Coronavirus disease 2019 (COVID-19) and malaria, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and parasites, respectively, share geographical distribution in regions where the latter disease is endemic, leading to the emergence of co-infections between the two pathogens. Thus far, epidemiologic studies and case reports have yielded insufficient data on the reciprocal impact of the two pathogens on either infection and related diseases. We established novel co-infection models to address this issue experimentally, employing either human angiotensin-converting enzyme 2 (hACE2)-expressing or wild-type mice, in combination with human- or mouse-infective variants of SARS-CoV-2, and the rodent malaria parasite. We now show that a primary infection by a viral variant that causes a severe disease phenotype partially impairs a subsequent liver infection by the malaria parasite. Additionally, exposure to an attenuated viral variant modulates subsequent immune responses and provides protection from severe malaria-associated outcomes when a blood stage infection was established. Our findings unveil a hitherto unknown host-mediated virus-parasite interaction that could have relevant implications for disease management and control in malaria-endemic regions. This work may contribute to the development of other models of concomitant infection between and respiratory viruses, expediting further research on co-infections that lead to complex disease presentations.
Topics: Humans; Mice; Animals; SARS-CoV-2; COVID-19; Rodentia; Coinfection; Malaria; Disease Models, Animal
PubMed: 38156320
DOI: 10.3389/fcimb.2023.1307553 -
Tropical Life Sciences Research Jun 2023Malaria still remains a life-threatening parasitic disease with universal targets set for control and elimination. This study aimed to evaluate the antimalarial...
Malaria still remains a life-threatening parasitic disease with universal targets set for control and elimination. This study aimed to evaluate the antimalarial susceptibility of isolates and to selected antimalarial agents and column chromatographic subfractions of leaves extract and FTIR and GCMS of SF8. Trager and Jensen as well as World Health Organisation (WHO) standardised micro-test system methods were used to determine susceptibility on the patients' blood samples; Column chromatographic procedure was carried out to obtain 11 pooled fractions; FTIR and GCMS were used to determine functional groups and phytochemicals respectively. anti-plasmodial activity against clinical isolates had IC range of 1.03 μg/mL-7.63 μg/mL while their IC against ranges from 4.32 μg/mL-7.89 μg/mL. Subfraction 8 (SF8) had the least IC of 4.32 μg/mL. The FTIR spectrum showed the presence of isoprenoid, alcohol, phenol, alkane, alkenes, ester, carboxylic acids, aromatics and nitro compounds while GCMS identified dodecanoic acid, methyl ester; carotol; hexadecanoic acid, methyl ester; 9-octadecenoic acid (Z)-, methyl ester (oleic acid); methyl stearate; heptadecanoic acid, 16-methyl-, methyl ester; all with their antimalarial reported activities. In conclusion, has a great potential for drug development against malaria parasite since it inhibited schizont growth and possesses phytocompounds with antimalarial report.
PubMed: 38144385
DOI: 10.21315/tlsr2023.34.2.14