Browsing by Subject "malaria"

Now showing 1 - 6 of 6
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    Modeling the relationship between precipitation and malaria incidence in Mpumalanga, South Africa
    (BioMed Central Ltd, 2012) Silal, Sheetal
    Climatic or weather-driven factors such as rainfall have considerable impact on vector abundance and the extrinsic cycles that parasites undergo in mosquitoes. Climate models therefore allow for a better understanding of the dynamics of malaria transmission. While malaria seasons occur regularly between October and May in Mpumalanga, there is considerable variation in the starting point, peak and magnitude of the season. The relationship between rainfall and malaria incidence may be used to better model the variation in the malaria season. As a first step, this study seeks to explore the complex association between rainfall and malaria incidence through time series methods.
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    Mutation of GGMP Repeat Segments of Plasmodium falciparum Hsp70-1 Compromises Chaperone Function and Hop Co-Chaperone Binding
    (2021-02-23) Makumire, Stanley; Dongola, Tendamudzimu Harmfree; Chakafana, Graham; Tshikonwane, Lufuno; Chauke, Cecilia Tshikani; Maharaj, Tarushai; Zininga, Tawanda; Shonhai, Addmore
    Parasitic organisms especially those of the Apicomplexan phylum, harbour a cytosol localised canonical Hsp70 chaperone. One of the defining features of this protein is the presence of GGMP repeat residues sandwiched between α-helical lid and C-terminal EEVD motif. The role of the GGMP repeats of Hsp70s remains unknown. In the current study, we introduced GGMP mutations in the cytosol localised Hsp70-1 of Plasmodium falciparum (PfHsp70-1) and a chimeric protein (KPf), constituted by the ATPase domain of E. coli DnaK fused to the C-terminal substrate binding domain of PfHsp70-1. A complementation assay conducted using E. coli dnaK756 cells demonstrated that the GGMP motif was essential for chaperone function of the chimeric protein, KPf. Interestingly, insertion of GGMP motif of PfHsp70-1 into DnaK led to a lethal phenotype in E. coli dnaK756 cells exposed to elevated growth temperature. Using biochemical and biophysical assays, we established that the GGMP motif accounts for the elevated basal ATPase activity of PfHsp70-1. Furthermore, we demonstrated that this motif is important for interaction of the chaperone with peptide substrate and a co-chaperone, PfHop. Our findings suggest that the GGMP may account for both the specialised chaperone function and reportedly high catalytic efficiency of PfHsp70-1.
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    A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers
    (BioMed Central Ltd, 2011) Chilengi, Roma; Juma, Rashid; Abdallah, Ahmed; Bashraheil, Mahfudh; Lodenyo, Hudson; Nyakundi, Priscilla; Anabwani, Evelyn; Salim, Amina; Mwambingu, Gabriel; Wenwa, Ednah; Jemutai, Julie; Kipkeu, Chemtai; Oyoo, George; Muchohi, Simon; Kokwaro, Gilber
    BACKGROUND: Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. METHODS: Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. RESULTS: The mean age of participants was 23.9 +/- 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (Cmax) was 160-200 nM and after 6 hours, the effective concentration (Ceff) was <150 nM. CONCLUSION: Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceff of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.
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    Studies on in vitro antiplasmodial activity of cleome rutidosperma
    (2010) Bose, Anindya; Lategan, Carmen Abriette; Smith, Peter J; Gupta, Jayanta Kumar
    Malaria is a protozoal disease transmitted by the Anopheles mosquito, caused by minute parasitic protozoa of the genus Plasmodium, which infect human and insect hosts alternatively. It affects over 40% of the worldís population, with 120 million cases reported, and about 2 million deaths annually (1). The P. falciparum variety of the parasite accounts for 80% of cases and 90% of deaths caused by malaria. The declining efficacy of classical medication in relation to the rapid increase of parasite resistant strains, mainly of Plasmodium falciparum, as well as the greater resistance of vectors to insecticides, and the difficulty of creating efficient vaccines have led to an urgent need for new efficient antimalarial drugs (2, 3). Natural molecules may provide innovative strategies towards malarial control, hence active research groups are now working to develop new active compounds as an alternative to chloroquine, especially from artemisinin (4, 5), a plant-based antimalaria drug isolated from the Chinese plant Artemisia annua (6). Plants may well, therefore, prove to be the sources of new antimalarial in view of the success with the two important chemotherapeutic agents, quinine and artemisinin, both of which are derived from plants. Cleome rutidosperma (Capparidaceae) is a low-growing herb, up to 70 cm tall, found in waste grounds and grassy places with trifoliate leaves and small, violet-blue flowers, which turn pink as they age. The elongated capsules display the asymmetrical, dull black seeds. The plant is native to West Africa, although it has become naturalized in various parts of tropical America as well as Southeast Asia (7, 8). The diuretic, laxative, anthelmintic, antimicrobial, analgesic, anti-inflammatory, antipyretic, antioxidant and free radical scavenging activities of Cleome rutidosperma were reported earlier by the authors (9-13). The plant is used as antimalarial by the traditional healers in Cameroon and mild antiplasmodial activity of chloroform/methanol (1:1) extract of leaves of Cleome rutidosperma against chloroquine-sensitive (F32) laboratory strain of P. falciparum was reported earlier in Cameroon (14). The present study investigates the in vitro antiplasmodial activity of ethanolic extract and its fractions of aerial parts of Cleome rutidosperma against the chloroquine sensitive (CQS) D10 strain of the parasite, as well as their toxicity against a mammalian cell lines.
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    Synthesis of triazole-linked 2-trichloromethylquinazolines and exploration of their efficacy against P. falciparum
    (South African Chemical Institute, 2013) Hamann, A R; de Kock, C; Smith, P J; van Otterlo, W A; Blackie, M A
    Using 2-trichloromethylquinazoline as scaffold, seven novel triazole-linked compounds have been synthesized using CuAAC chemistry. The in vitrobiological activity of four of the compounds on the Plasmodium falciparumchloroquine-sensitive strain NF54 was then determined. The compounds which were tested showed moderate activity with 1.45 /iM as the lowest inhibitory concentration.
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    Transcriptional regulation in Plasmodium falciparum: characterisation of TBP-like protein
    (2025) Michowicz, Joanna; Oelgeschlger, Thomas
    Malaria persists as a devastating disease resulting in a high burden of morbidity and mortality worldwide. The most severe form of malaria is due to infection with Plasmodium falciparum, accounting for the overwhelming majority of malaria deaths. Despite extensive efforts to curb transmission, recent reports of drug resistance to front-line antimalarial treatments coupled with the continuing lack of effective vaccines implores the production of novel anti-malarials. Both parasite development and pathogenicity are tightly controlled by a highly regulated gene expression program. However, regulation at the level of transcription initiation is hitherto poorly understood. The TATA-binding protein (TBP) is a universal transcription factor required for transcription by RNA polymerase I, II and III. Multiple gene duplication events throughout eukaryotic evolution have resulted in many eukaryotes harbouring more than one TBP family protein. In metazoans, TBP paralogs have been shown to play important roles in cell-specific developmental gene expression programs. However, research into the roles of TBP paralogs in unicellular eukaryotes is extremely limited. Bioinformatic analyses have identified a P. falciparum putative TBP-like protein (PfTLP). Previous research in our laboratory demonstrated that PfTLP has DNA-binding activity and that it harbours two insertions, which are predicted intrinsically disordered regions (IDR1, IDR2), within its structurally conserved TBP DNA-binding domain. In recent years there has been mounting evidence that IDRs mediate liquid-liquid phase separation, a process which has transformed our understanding of cellular organisation and regulation of key cellular processes. The functional relevance of these IDRs is unknown. Therefore, to elucidate their role, this study was divided into three parts: (i) a bioinformatic analysis to investigate the prevalence of disordered regions within Apicomplexan TLPs, (ii) an investigation into the role of these regions in PfTLP DNA binding and (iii) an in-depth characterisation of phase separation by PfTLP IDRs and full-length PfTLP. This study highlights the prevalence of TLPs within Apicomplexa and, moreover, the presence of a conserved IDR2 in diverse Apicomplexan species. Both IDR1 and IDR2 were shown to bind to DNA and analysis of a panel of newly generated PfTLP deletion mutant protein constructs revealed that this DNA-binding activity stabilises PfTLP-DNA complexes. Finally, a systematic characterisation of the phase-separating properties of PfTLP IDRs and full-length PfTLP was carried out, using PfRBP1-CTD and PfTBP-IDR for comparison. It was found that PfTLP-IDR1 readily undergoes liquid-liquid phase separation (LLPS) at low protein concentrations, forming dynamic condensates that homogenously mix with dsDNA. In contrast, PfTLP-IDR2 does not self-assemble in the absence of phase-separating interaction partners. Interestingly, at a physiological protein concentration, full-length PfTLP was found to form clustered assemblies in isolation but formed separate, mixed condensates in the presence of dsDNA, suggesting a role of DNA in the regulation of PfTLP condensate formation. In addition, the interaction of PfTLP with DNA condensates was found to be independent of IDR1 and IDR2, consistent with the DNA-binding activity of the PfTLP structured domain. Thus, this study yields novel insights into the DNA-binding and phase-separating properties of PfTLP that may contribute to the assembly of the RNA polymerase II transcription initiation machinery of this divergent parasite.