Betulinic and ursolic acids from Nauclea latifolia roots mediate their antimalarial activities through docking with PfEMP-1 and PfPKG proteins.

BACKGROUND: Chemotherapies target the PfEMP-1 and PfPKG proteins in Plasmodium falciparum, the parasite that causes malaria, in an effort to prevent the disease's high fatality rate. This work identified the phytochemical components of Nauclea latifolia roots and docked the chemical compounds against target proteins, and examined the in vivo antiplasmodial effect of the roots on Plasmodium berghei-infected mice. METHODS: Standard protocols were followed for the collection of the plant's roots, cleaning, and drying of the roots, extraction and fraction preparation, assessment of the in vivo antiplasmodial activity, retrieval of the PfEMP-1 and PfPKG proteins, GCMS, ADME, and docking studies, chromatographic techniques were employed to separate the residual fraction's components, and the Swis-ADME program made it possible to estimate the drug's likeness and pharmacokinetic properties. The Auto Dock Vina 4.2 tool was utilized for molecular docking analysis. RESULTS: The residual fraction showed the best therapeutic response when compared favorably to amodiaquine (80.5%) and artesunate (85.1%). It also considerably reduced the number of parasites, with the % growth inhibition of the parasite at 42.8% (D2) and 83.4% (D5). Following purification, 25 compounds were isolated and characterized with GCMS. Based on their low molecular weights, non-permeation of the blood-brain barrier, non-inhibition of metabolizing enzymes, and non-violation of Lipinski's criteria, betulinic and ursolic acids were superior to chloroquine as the best phytochemicals. Hence, they are lead compounds. CONCLUSION: In addition to identifying the bioactive compounds, ADME, and docking data of the lead compounds as candidates for rational drug design processes as observed against Plasmodium falciparum target proteins (PfEMP-1 and PfPKG), which are implicated in the pathogenesis of malaria, the study has validated that the residual fraction of N. latifolia roots has the best antiplasmodial therapeutic index.

Pyrethroid insecticides susceptibility profiles and evaluation of L1014F kdr mutant alleles in Culex quinquefasciatus from lymphatic filariasis endemic communities.

This study investigated the dynamics in pyrethriod resistance and the presence/frequencies of L1014F knockdown resistance mutant allelles in Culex quinquefasciatus vector populations from Uruan Local Government Area of AkwaIbom State, Southern Nigeria between the months of March and November, 2021. Uruan LGA is among the endemic LGAs for lymphatic filariasis in AkwaIbomState. Female Anopheles mosquitoes from Eman Uruan, Ituk Mbang and Idu Uruan were exposed to permethrin, deltamethrin and alphacypermethrin in CDC insecticide coated bottles for susceptibility bioassay following standard protocols. The mosquitoes were obtained as aquatic forms from the study sites and reared under laboratory conditions to adults. The adult mosquitoes were used for this study. All the mosquitoes used for the insecticide susceptibility bioassay were morphologically identified. Standard Polymerase chain reaction (PCR) was used for authenticating the Culex quinquefasciatus species. A portion of the vgsc (917 bp) gene spanning the entire intron and the exon containing the L1014F mutation associated with knockdown resistance (kdr) in the vectorswere amplified using Allele-SPECIFIC POLYMERASE CHAIN REACTION (AS-PCR) in order to detect target site insensitivity in the vectors from the study sites. Results obtained revealed that vectors from all the study sites were resistant to permethrin insecticide (mortality rate: 18-23%). Suspected resistance (mortality rate: 90-93%) to deltamethrin and low resistance (mortality rate: 82-85%) to alphacypermethrin insecticides were detected. knockdown was more rapid with deltamethrin and alphacypermethrin than with permethrin across the study sites considering their KDT50 and KDT95. The frequency of the resistant phenotypes ranged from 35.14 to 55.3% across the study sites with a net of 45.1% resistant phenotype recorded in this study. The 1014F allelic frequency calculated from Hardy-Weinberg principle for vector populations across the study sites ranged from 0.500 (50.00%) to 0.7763 (77.63%). All populations witnessed significant (p < 0.05) deviations from Hardy-Weinberg equilibrium in the distribution of these alleles. The findings of this study show that there is a tendency to record an entire population of resistant vectors in this study area over time due to natural selection. The public health implication of these findings is that the use of pyrethroid based aerosols, coils, sprays, LLITNs and others for the purpose of controlling vectors of lymphatic filariasis and other diseases may be effort in futility.