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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 -
Journal of Ethnopharmacology Sep 2024Andrographis paniculata (AP) ((Burm f.) Wall. ex Nees) is a medicinal plant, documented for its folkloric use in the treatment of malaria.
Mechanism of antimalarial action and mitigation of infection-mediated mitochondrial dysfunction by phyto-constituents of Andrographis paniculata ((Burm f.) Wall. ex Nees) in Plasmodium berghei-infected mice.
ETHNOPHARMACOLOGICAL RELEVANCE
Andrographis paniculata (AP) ((Burm f.) Wall. ex Nees) is a medicinal plant, documented for its folkloric use in the treatment of malaria.
AIM
This study was designed to determine the potency of extract and fractions of A. paniculata (AP) as a curative, both for susceptible and resistant malaria and to also determine the plant's mechanism of action. This study was also designed to determine whether AP extract and its most potent fraction will mitigate infection-mediated mitochondrial dysfunction, and to assess the phytochemical constituents of the most potent fraction.
MATERIALS AND METHODS
n-Hexane, dichloromethane, ethylacetate and methanol were used to partition the methanol extract of A. paniculata. Graded doses of these extract and fractions were used to treat mice infected with chloroquine-sensitive strain of P. berghei in a curative model. The most potent fraction was used to treat mice infected with resistant (ANKA strain) P. berghei. Inhibition of hemozoin formation, reversal of mitochondrial dysfunction and antiinflammatory potentials were determined. A combination of ultraperformance liquid chromatography-quadrupole time of flight-mass spectrometry and nuclear magnetic resonance spectroscopy were used for chemical analysis.
RESULTS
Microscopy revealed that the dichloromethane fraction decreased the parasite burden the most, and inhibition of the hemozoin formation is one of its mechanisms of action. The dichloromethane fraction reversed parasite-induced mitochondrial pore opening in the host, enzyme-dependent ATP hydrolysis and peroxidation of host mitochondrial membrane phospholipids as well as its antiinflammatory potentials. The UPLC-qTOF-MS report and NMR fingerprints of the dichloromethane fraction of A. paniculata yielded fourteen compounds of which sibiricinone C was identified from the plant for the first time.
CONCLUSION
Fractions of A. paniculata possess antiplasmodial effects with the dichloromethane fraction having the highest potency. The potent effect of this fraction may be attributed to the phytochemicals present because it contains terpenes implicated with antimalarial and antiinflammatory activities.
Topics: Animals; Plasmodium berghei; Antimalarials; Malaria; Plant Extracts; Mice; Andrographis; Mitochondria; Male; Hemeproteins; Anti-Inflammatory Agents; Female
PubMed: 38670400
DOI: 10.1016/j.jep.2024.118241 -
Molecular and Biochemical Parasitology Sep 2023Cerebral Malaria (CM) is associated with the complex neurological syndrome, whose pathology is mediated by severe inflammatory processes following infection with...
Cerebral Malaria (CM) is associated with the complex neurological syndrome, whose pathology is mediated by severe inflammatory processes following infection with Plasmodium falciparum. Coenzyme-Q (Co-Q) is a potent anti-inflammatory, anti-oxidant, and anti-apoptotic agent with numerous clinical applications. The aim of this study was to elucidate the role of oral administration of Co-Q on the initiation or regulation of inflammatory immune response during experimental cerebral malaria (ECM). For this purpose, the pre-clinical effect of Co-Q was evaluated in C57BL/6 J mice infected with Plasmodium berghei ANKA (PbA). Treatment with Co-Q resulted in the reduction of infiltrating parasite load, greatly improved the survival rate of PbA-infected mice that occurred independent of parasitaemia and prevented PbA-induced disruption of the blood-brain barrier (BBB) integrity. Exposure to Co-Q resulted in the reduction of infiltration of effector CD8 + T cells in the brain and secretion of cytolytic Granzyme B molecules. Notably, Co-Q-treated mice had reduced levels of CD8 +T cell chemokines CXCR3, CCR2, and CCR5 in the brain following PbA-infection. Brain tissue analysis showed a reduction in the levels of inflammatory mediators TNF- α, CCL3, and RANTES in Co-Q administered mice. In addition, Co-Q modulated the differentiation and maturation of both splenic and brain dendritic cells and cross-presentation (CD8α+DCs) during ECM. Remarkably, Co-Q was very effective in decreasing levels of CD86, MHC-II, and CD40 in macrophages associated with ECM pathology. Exposure to Co-Q resulted in increased expression levels of Arginase-1 and Ym1/chitinase 3-like 3, which is linked to ECM protection. Furthermore, Co-Q supplementation prevented PbA-induced depletion of Arginase and CD206 mannose receptor levels. Co-Q abrogated PbA-driven elevation in pro-inflammatory cytokines IL-1β, IL-18, and IL-6 levels. In conclusion, the oral supplementation with Co-Q decelerates the occurrence of ECM by preventing lethal inflammatory immune responses and dampening genes associated with inflammation and immune-pathology during ECM, and offers an inimitable opening for developing an anti-inflammatory agent against cerebral malaria.
Topics: Mice; Animals; Malaria, Cerebral; Arginase; Disease Models, Animal; Mice, Inbred C57BL; Anti-Inflammatory Agents; Immunity; Plasmodium berghei
PubMed: 37385350
DOI: 10.1016/j.molbiopara.2023.111579 -
Malaria Journal Feb 2024The infection of the liver by Plasmodium parasites is an obligatory step leading to malaria disease. Following hepatocyte invasion, parasites differentiate into...
BACKGROUND
The infection of the liver by Plasmodium parasites is an obligatory step leading to malaria disease. Following hepatocyte invasion, parasites differentiate into replicative liver stage schizonts and, in the case of Plasmodium species causing relapsing malaria, into hypnozoites that can lie dormant for extended periods of time before activating. The liver stages of Plasmodium remain elusive because of technical challenges, including low infection rate. This has been hindering experimentations with well-established technologies, such as electron microscopy. A deeper understanding of hypnozoite biology could prove essential in the development of radical cure therapeutics against malaria.
RESULTS
The liver stages of the rodent parasite Plasmodium berghei, causing non-relapsing malaria, and the simian parasite Plasmodium cynomolgi, causing relapsing malaria, were characterized in human Huh7 cells or primary non-human primate hepatocytes using Correlative Light-Electron Microscopy (CLEM). Specifically, CLEM approaches that rely on GFP-expressing parasites (GFP-CLEM) or on an immunofluorescence assay (IFA-CLEM) were used for imaging liver stages. The results from P. berghei showed that host and parasite organelles can be identified and imaged at high resolution using both CLEM approaches. While IFA-CLEM was associated with more pronounced extraction of cellular content, samples' features were generally well preserved. Using IFA-CLEM, a collection of micrographs was acquired for P. cynomolgi liver stage schizonts and hypnozoites, demonstrating the potential of this approach for characterizing the liver stages of Plasmodium species causing relapsing malaria.
CONCLUSIONS
A CLEM approach that does not rely on parasites expressing genetically encoded tags was developed, therefore suitable for imaging the liver stages of Plasmodium species that lack established protocols to perform genetic engineering. This study also provides a dataset that characterizes the ultrastructural features of liver stage schizonts and hypnozoites from the simian parasite species P. cynomolgi.
Topics: Animals; Humans; Parasites; Liver; Malaria; Plasmodium berghei; Microscopy, Electron
PubMed: 38383417
DOI: 10.1186/s12936-024-04862-w -
Journal of Ethnopharmacology May 2024Novel drugs are needed to address the issue of malarial infection resistance; natural items can be a different source of these medications. Albizia malacophylla (A....
ETHNOPHARMACOLOGICAL RELEVANCE
Novel drugs are needed to address the issue of malarial infection resistance; natural items can be a different source of these medications. Albizia malacophylla (A. Rich.) Walp. (Leguminosae) is listed as one of the antimalarial medicinal plants in Ethiopian folk medicine. However, there are no reports regarding the biological activity or phytochemistry of the plant.
AIM OF THE STUDY
Thus, this study aimed to evaluate the A. malacophylla crude extract and solvent fractions' in vivo antimalarial activity utilizing 4-day suppressive, preventative, and curative tests in mice infected with P. berghei.
MATERIALS AND METHODS
The parasite Plasmodium berghei, which causes rodent malaria, was used to infect healthy male Swiss Albino mice, weighing 23-28 g and aged 6-8 weeks. Solvent fractions such as methanol, water, and chloroform were given in addition to an 80% methanolic extract at 100, 200, and 400 mg/kg doses. A Conventional test such as parasitemia, survival time, body weight, temperature, and packed cell capacity were employed to ascertain factors such as the suppressive, curative, and preventive tests.
RESULTS
Every test substance dramatically reduced the number of parasites in every experiment. Crude extract (with the highest percentage suppression of 67.78%) performs better antimalarial effect than the methanol fraction, which is the most efficient solvent fraction with a percentage suppression of 55.74%. With a suppression value of 64.83% parasitemia level, the therapeutic effects of 80% methanolic crude extract were greater than its curative and preventative effects in a four-day suppressive test. The survival period (17 days) was longer with the hydroalcoholic crude extract dose of 400 mg/kg than with other doses of the materials under investigation.
CONCLUSIONS
The results of this investigation validate the antimalarial characteristics of A. malacophylla leaf extract. The crude extract prevented weight loss, a decline in temperature, and a reduction in PCV. The results demonstrate that the plant has a promising antimalarial effect against P. berghei, hence supporting the traditional use of the plant. Therefore, it could serve as a foundation for the development of new antimalarial drugs.
PubMed: 38824975
DOI: 10.1016/j.jep.2024.118413 -
Scientific Reports Jul 2023Drug-resistant Plasmodium falciparum (Pf) infections are a major burden on the population and the healthcare system. The establishment of Pf resistance to most existing...
Drug-resistant Plasmodium falciparum (Pf) infections are a major burden on the population and the healthcare system. The establishment of Pf resistance to most existing antimalarial therapies has complicated the problem, and the emergence of resistance to artemisinin derivatives is even more concerning. It is increasingly difficult to cure malaria patients due to the limited availability of effective antimalarial drugs, resulting in an urgent need for more efficacious and affordable treatments to eradicate this disease. Herein, new nucleoside analogues including morpholino-nucleoside hybrids and thio-substituted nucleoside derivatives were prepared and evaluated for in vitro and in vivo antiparasitic activity that led a few hits especially nucleoside-thiopyranoside conjugates, which are highly effective against Pf3D7 and PfRKL-9 strains in submicromolar concentration. One adenosine derivative and four pyrimidine nucleoside analogues significantly reduced the parasite burden in mouse models infected with Plasmodium berghei ANKA. Importantly, no significant hemolysis and cytotoxicity towards human cell line (RAW) was observed for the hits, suggesting their safety profile. Preliminary research suggested that these thiosugar-nucleoside conjugates could be used to accelerate the antimalarial drug development pipeline and thus deserve further investigation.
Topics: Animals; Mice; Humans; Antimalarials; Nucleosides; Sugars; Plasmodium falciparum; Malaria; Malaria, Falciparum; Plasmodium berghei
PubMed: 37507429
DOI: 10.1038/s41598-023-39541-4 -
Frontiers in Cellular and Infection... 2023Malaria remains one of the most significant health issues worldwide, accounting for 2.6% of the total global disease burden, and efforts to eliminate this threat...
Malaria remains one of the most significant health issues worldwide, accounting for 2.6% of the total global disease burden, and efforts to eliminate this threat continue. The key focus is to develop an efficient and long-term immunity to this disease via vaccination or therapeutic approach, and innovative strategies would enable us to achieve this target. Previously, using a mouse co-infection disease model, cross-protection was illustrated between and . Hence, this study was planned to elucidate the impact of acute Peabody mjr and ANKA co-infection on the consequence of complicated malaria in the C57BL/6J mouse model of malaria. Furthermore, immune response and pathological features were analyzed, and the course of the disease was compared among experimental groups. Our study established that acute infection activated immunity which was otherwise suppressed by . The immunosuppressive tissue microenvironment was counteracted as evidenced by the enhanced immune cell population in co-infected mice, in contrast to -infected control mice. Parasite sequestration in the brain, liver, lung, and spleen of co-infected mice was significantly decreased and tissue injury was ameliorated. Meanwhile, the serum levels of IFN-γ, TNF-α, and IL-12p70 were reduced while the secretion of IL-10 was promoted in co-infected mice. Eventually, co-infected mice showed an extended rate of survival. Hereby, the principal cytokines associated with the severity of malaria by infection were TNF-α, IFN-γ, and IL-12p70. Moreover, it was evident from our flow cytometry results that innate immunity is crucial and macrophages are at the frontline of immunity against infection. Our study recommended further investigations to shed light on the effects of babesiosis in suppressing malaria with the goal of developing -based therapy against malaria.
Topics: Animals; Mice; Babesia microti; Plasmodium berghei; Tumor Necrosis Factor-alpha; Coinfection; Mice, Inbred C57BL; Malaria
PubMed: 37492527
DOI: 10.3389/fcimb.2023.1226088 -
Journal of Ethnopharmacology May 2024Phyllanthus muellerianus (Kunze) Exell, a member of the Phyllanthaceae family, is a medicinal plant widely distributed in Africa. Decoctions from the leaves are used in...
Evaluation of the antimalarial and CD4 T-cell modulatory effects of leaf methanol extract of Phyllanthus muellerianus (Kuntze) Exell (Phyllanthaceae) in Plasmodium berghei-infected mice.
ETHNOPHARMACOLOGICAL RELEVANCE
Phyllanthus muellerianus (Kunze) Exell, a member of the Phyllanthaceae family, is a medicinal plant widely distributed in Africa. Decoctions from the leaves are used in Nigeria to treat fevers, convulsions, some neurological disorders and malaria.
AIM OF THE STUDY
This study is to evaluate the anti-malarial properties of methanol extract of Phyllanthus muellerianus (MEPM) leaves and its ethyl acetate fraction using a murine malaria model infected with Plasmodium berghei. Additionally, we seek to investigate the potential modulatory effects of this extract and fraction on CD4 T-cell populations in the context of malaria infection.
MATERIALS AND METHODS
The anti-malarial effects of the leaf methanol extract of Phyllanthus muellerianus (MEPM) were screened using three established in vivo models of anti-plasmodial screening namely the curative, suppressive and prophylactic models. The methanol extract (MEPM) was afterwards fractionated into hexane (HFPM), ethyl acetate (EAFPM), and methanol (MFPM) fractions. In the pilot anti-malarial screening of the fractions, EAFPM exhibited the best antiparasitic activity. Subsequently, EAFPM was screened for anti-malarial activity using the three models above. The effects of the MEPM and EAFPM on haematological indices (Hb and PCV) of the inoculated animals were further screened and the mean survival time (MST) of the animals was monitored. CD4 T cells of various groups were counted before and after treatment using a flow cytometer. The EAFPM was further subjected to HPLC analysis for identification of its major compounds.
RESULTS
The EAFPM (100 and 200 mg/kg) elicited 88% and 93% cure respectively in the curative model, while artesunate (5 mg/kg,- the positive control) gave 87% protection. The MEPM and EAFPM also gave significant suppression of parasitemia in the suppressive model. The treated groups survived beyond 28 days as against 11 days by the control group (infected but not treated). The treated groups also prevented anaemia seen in the negative control. The EAFPM group significantly modulated the CD4 T cell. Compounds identified were Gallocatechin, Quercetin -3-O-gallate, Ellagic acid, and Methylellagic acid rhamnoside).
CONCLUSION
The study established that the leaf of Phyllanthus muellerianus possesses antimalarial activity, thus lending support to its use in the folkloric treatment of malaria.
Topics: Animals; Mice; Antimalarials; Plant Extracts; Methanol; Plasmodium berghei; Phyllanthus; T-Lymphocytes; Malaria; Plant Leaves; CD4-Positive T-Lymphocytes; Nigeria; Acetates; Ethanol; Ethylene Glycols; Fatty Acids
PubMed: 38382655
DOI: 10.1016/j.jep.2024.117936 -
Bioorganic & Medicinal Chemistry Letters Oct 2023Malaria continues to be a major burden on global health, responsible for 619,000 deaths in 2021. The causative agent of malaria is the eukaryotic parasite Plasmodium....
Malaria continues to be a major burden on global health, responsible for 619,000 deaths in 2021. The causative agent of malaria is the eukaryotic parasite Plasmodium. Resistance to artemisinin-based combination therapies (ACTs), the current first-line treatment for malaria, has emerged in Asia, South America, and more recently Africa, where >90% of all malaria-related deaths occur. This has necessitated the identification and investigation of novel parasite proteins and pathways as antimalarial targets, including components of the ubiquitin proteasome system. Here, we investigate Plasmodium falciparum deubiquitinase ubiquitin C-terminal hydrolase L3 (PfUCHL3) as one such target. We carried out a high-throughput screen with covalent fragments and identified seven scaffolds that selectively inhibit the plasmodial UCHL3, but not human UCHL3 or the closely related human UCHL1. After assessing toxicity in human cells, we identified four promising hits and demonstrated their efficacy against asexual P. falciparum blood stages and P. berghei sporozoite stages.
Topics: Antimalarials; Eukaryota; Folic Acid Antagonists; Plasmodium falciparum; Proteasome Endopeptidase Complex; Deubiquitinating Enzymes; Protozoan Proteins
PubMed: 37634761
DOI: 10.1016/j.bmcl.2023.129458 -
Trends in Parasitology Dec 2023Plasmodium ookinetes and sporozoites were discovered 125 years ago by MacCallum (J. Exp. Med. 1898;3:117-136) and Ross (Ind. Med. Gaz. 1899;34:1-3), respectively. While...
Plasmodium ookinetes and sporozoites were discovered 125 years ago by MacCallum (J. Exp. Med. 1898;3:117-136) and Ross (Ind. Med. Gaz. 1899;34:1-3), respectively. While the migration capacity of ookinetes was noted immediately, the movements of sporozoites remained enigmatic for decades. Today, we know many proteins involved in parasite migration and start to conceptualize a mechanistic understanding of motility.
Topics: Animals; Sporozoites; Plasmodium; Running; Plasmodium berghei; Protozoan Proteins
PubMed: 37865610
DOI: 10.1016/j.pt.2023.09.015