Apicoplast-Resident Processes: Exploiting the Chink in the Armour of Plasmodium falciparum Parasites.

The discovery of a relict plastid, also known as an apicoplast (apicomplexan plastid), that houses housekeeping processes and metabolic pathways critical to Plasmodium parasites' survival has prompted increased research on identifying potent inhibitors that can impinge on apicoplast-localised processes. The apicoplast is absent in humans, yet it is proposed to originate from the eukaryote's secondary endosymbiosis of a primary symbiont. This symbiotic relationship provides a favourable microenvironment for metabolic processes such as haem biosynthesis, Fe-S cluster synthesis, isoprenoid biosynthesis, fatty acid synthesis, and housekeeping processes such as DNA replication, transcription, and translation, distinct from analogous mammalian processes. Recent advancements in comprehending the biology of the apicoplast reveal it as a vulnerable organelle for malaria parasites, offering numerous potential targets for effective antimalarial therapies. We provide an overview of the metabolic processes occurring in the apicoplast and discuss the organelle as a viable antimalarial target in light of current advances in drug discovery. We further highlighted the relevance of these metabolic processes to Plasmodium falciparum during the different stages of the lifecycle.

Mathematical modeling of malaria transmission dynamics in humans with mobility and control states.

Malaria importation is one of the hypothetical drivers of malaria transmission dynamics across the globe. Several studies on malaria importation focused on the effect of the use of conventional malaria control strategies as approved by the World Health Organization (WHO) on malaria transmission dynamics but did not capture the effect of the use of traditional malaria control strategies by vigilant humans. In order to handle the aforementioned situation, a novel system of Ordinary Differential Equations (ODEs) was developed comprising the human and the malaria vector compartments. Analysis of the system was carried out to assess its quantitative properties. The novel computational algorithm used to solve the developed system of ODEs was implemented and benchmarked with the existing Runge-Kutta numerical solution method. Furthermore, simulations of different vigilant conditions useful to control malaria were carried out. The novel system of malaria models was well-posed and epidemiologically meaningful based on its quantitative properties. The novel algorithm performed relatively better in terms of model simulation accuracy than Runge-Kutta. At the best model-fit condition of 98% vigilance to the use of conventional and traditional malaria control strategies, this study revealed that malaria importation has a persistent impact on malaria transmission dynamics. In lieu of this, this study opined that total vigilance to the use of the WHO-approved and traditional malaria management tools would be the most effective control strategy against malaria importation.

P53 Gene Expression and Nitric Oxide Levels after Artemisinin-Caffeine Treatment in Breast, Lungs and Liver of DMBA-Induced Tumorigenesis.

OBJECTIVE: With increasing incidence of cancers globally and limited resources in some affected countries, repurposing existing drugs for reducing tumorigenesis is highly important. Artemisinin and caffeine have potent anti-oxidative and anti-tumor properties but are therapies for other diseases. This study evaluated the biochemical and p53 gene modulatory effects of doses of artemisinin-caffeine combination on breast, lungs and liver tissues in rats induced with DMBA. METHODS: After due ethical approval, 30 animals were treated with 40mg/kg single dose of 7,12-dimethylbenzene anthracene (DMBA) as a model for DNA damage and induction of carcinogenesis. Five animals each received normal saline (normal), low dose artemisinin (Art; 4mg/kg), low dose caffeine (Caff; 25mg/kg), low dose combination of caff + art (25+4mg/kg), high dose combination of caff + art (50+8mg/kg) or no treatment (DMBA). All treatment doses were orally administered daily for two weeks post DMBA treatment. Nitric oxide levels and p53 relative gene expression was carried out using primer-specific RT-PCR, GAPDH was used as loading control and amplicons were resolved by gel electrophoresis. RESULTS: DMBA induced lesions in breast, liver, and lung tissues evident from histology analysis, compared to normal group. In all 3 tissues, caffeine (25mg/kg) and combination of caff + art (25+4mg/kg) significantly reduced p53 gene expression (p < 0.05), but there was significant increase in the group treated with low dose art (4mg/kg) and high dose caff + art, which were similar to DMBA group (p<0.05). In lungs, nitric oxide (NO) increased in all groups but not in caffeine, in the liver NO decreased with caffeine or its combination with art, compared to DMBA group. CONCLUSIONS: This study shows a dose-dependent synergistic anticancer effects of caffeine and artemisinin combination on p53 gene and nitric oxide regulation hence can mitigate tumor development.

In silico Structure Prediction, Molecular Docking, and Dynamic Simulation of Plasmodium falciparum AP2-I Transcription Factor.

Plasmodium falciparum Apicomplexan Apetala 2 Invasion (PfAP2-I) transcription factor (TF) is a protein that regulates the expression of a subset of gene families involved in P. falciparum red blood cell (RBC) invasion. Inhibiting PfAP2-I TF with small molecules represents a potential new antimalarial therapeutic target to combat drug resistance, which this study aims to achieve. The 3D model structure of PfAP2-I was predicted ab initio using ROBETTA prediction tool and was validated using Save server 6.0 and MolProbity. Computed Atlas of Surface Topography of proteins (CASTp) 3.0 was used to predict the active sites of the PfAP2-I modeled structure. Pharmacophore modeling of the control ligand and PfAP2-I modeled structure was carried out using the Pharmit server to obtain several compounds used for molecular docking analysis. Molecular docking and postdocking studies were conducted using AutoDock vina and Discovery studio. The designed ligands' toxicity predictions and in silico drug-likeness were performed using the SwissADME predictor and OSIRIS Property Explorer. The modeled protein structure from the ROBETTA showed a validation result of 96.827 for ERRAT, 90.2% of the amino acid residues in the most favored region for the Ramachandran plot, and MolProbity score of 1.30 in the 98th percentile. Five (5) best hit compounds from molecular docking analysis were selected based on their binding affinity (between -8.9 and -11.7 Kcal/mol) to the active site of PfAP2-I and were considered for postdocking studies. For the absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, compound MCULE-7146940834 had the highest drug score (0.63) and drug-likeness (6.76). MCULE-7146940834 maintained a stable conformation within the flexible protein's active site during simulation. The good, estimated binding energies, drug-likeness, drug score, and molecular dynamics simulation interaction observed for MCULE-7146940834 against PfAP2-I show that MCULE-7146940834 can be considered a lead candidate for PfAP2-I inhibition. Experimental validations should be carried out to ascertain the efficacy of these predicted best hit compounds.

Haptoglobin genotypes and malaria comorbidity in breast cancer and healthy Nigerian women.

Background: Breast cancer is the leading cause of mortality among women, with over a million cases recorded globally. Haptoglobin (Hp) protein and genotypes play important roles in cancer predisposition and progression, but studies have reported varying outcomes in populations. Aim: The association of Hp genotypes in breast cancer patients with malaria has not been investigated in Nigerians, which is the aim of our study. In healthy women (control; n = 279) and clinically diagnosed breast cancer patients (breast cancer; n = 70). Methods: Haptoglobin genotypes and Plasmodium falciparum cyclooxygenase III genes were detected by polymerase chain reaction (PCR). Proportions were compared, and the test of association was carried out with a significance level set at P < 0.05. Results: Overall, 311 of 349 (89%) individuals had malaria infection with similar proportions in breast cancer (63 of 70) and healthy control group (248 of 279); malaria incidence was, however, lower in Hp 2-2 breast cancer patients (P = 0.04). The prevalence of Hp genotypes was Hp 1-1 (78.2%), Hp 2-1 (7.2%), and 2-2 (14.6%). In breast cancer groups, Hp 2-2 genotype was significantly lower with 3 (4.2%) of 70 vs. 48 (17.2%) of 279 in control group (P = 0.006). Conclusions: The results of the study show low Hp 2-2 genotype relative to other genotypes in breast cancer patients; we conclude that low Hp 2-2 genotype is associated with lower malaria risk in breast cancer Nigerian women. It is important to further understand the roles malaria, Hp, and other genotypes play in the pathogenesis of aggressive breast cancer commonly seen in Nigerian women.

Résumé Contexte: Le cancer du sein est la principale cause de mortalité chez les femmes, avec plus d'un million de cas enregistrés dans le monde. La protéine et les génotypes de l'haptoglobine (Hp) jouent un rôle important dans la prédisposition et la progression du cancer, mais des études ont rapporté des résultats variables dans les populations. Objectif: L'association des génotypes d'haptoglobine chez les patientes atteintes d'un cancer du sein et atteintes de paludisme n'a pas été étudiée chez les Nigérians, ce qui est l'objectif de notre étude. Chez les femmes en bonne santé (témoin ; nombre = 279) et les patientes atteintes d'un cancer du sein diagnostiqué cliniquement (cancer du sein ; nombre = 70). Méthodologie: Les génotypes de l'haptoglobine et les gènes de la cyclooxygénase-III de Plasmodium falciparum ont été détectés par PCR. Les proportions ont été comparées et le test d'association a été réalisé avec un seuil de signification fixé à P < 0,05. Résultats: Dans l'ensemble, 311 personnes sur 349 (89 %) avaient une infection palustre avec des proportions similaires dans le groupe du cancer du sein (63 sur 70) et dans le groupe témoin sain (248 sur 279); l'incidence du paludisme était cependant plus faible chez les patientes atteintes d'un cancer du sein Hp 2-2 (p = 0,04). La prévalence des génotypes Hp était : Hp 1-1 (78,2 %), Hp 2-1 (7,2 %) et 2-2 (14,6 %). Dans les groupes de cancer du sein, le génotype Hp 2-2 était significativement plus faible avec 3 (4,2 %) sur 70 contre 48 (17,2 %) sur 279 dans le groupe témoin (p = 0,006). Conclusions: Les résultats de l'étude montrent un faible génotype Hp 2-2 par rapport aux autres génotypes chez les patientes atteintes d'un cancer du sein; nous concluons qu'un faible génotype Hp 2-2 est associé à un risque de paludisme plus faible chez les femmes nigérianes atteintes d'un cancer du sein. Il est important de mieux comprendre les rôles que jouent le paludisme, l'haptoglobine et d'autres génotypes dans la pathogenèse du cancer du sein agressif couramment observé chez les femmes nigérianes. Mots-clés: Cancer du sein, génotypes, haptoglobine, paludisme, Nigeria.

Effects of chronic exposure to paint fumes among artisans in Lagos State, Nigeria.

The chronic effects of automobile paint fumes and their volatile organic constituents form detrimental air pollution with hazardous consequences especially to paint industrial workers and the population within the vicinity. This study investigated the chronic effects of exposure to paint fumes in Mushin area of Lagos, Nigeria. Fifty artisans employed in automobile painting industries were compared with 50 control group whose work does not expose them to paint fumes. Five milliliters blood was collected and used for assessment of hematological and biochemical parameters. This was compared in artisan and unexposed control group and p value of < 0.05 indicates significant difference. In artisans, kidney function analysis showed a significant decrease in potassium (3.63 ± 0.1012 mEq/L) compared to healthy control (4.26 ± 0.1699 mEq/L, p = 0.0049), as well as bicarbonate ion concentration (23.89 ± 0.3795 vs 26.40 ± 0.3578 mmol/L respectively, p = 0.0011), however, a significant increase in creatinine level was recorded in artisans than control group (1.140 ± 0.1075 vs 0.76 ± 0.03578 mg/dL, p = 0.03); which is an indicator of renal function impairment. AST and ALT levels were significantly higher in artisans (11.44 ± 0.8190 and 8.78 ± 0.7558 U/L) compared to control group (6.83 ± 0.3086 and 6.67 ± 0.3354 U/L), respectively (p < 0.05), while ALP levels were similar. For oxidative stress parameters - CAT, MDA and protein, there was a significant increase in artisans while the corresponding GSH and SOD activities decreased significantly (p < 0.05). The results showed similar Zinc and Chromium levels in both groups but Lead was not detected in any participant. The findings of this study indicate that chronic exposure to paint fumes among automobile painting artisans may impair renal function, liver function and induce oxidative damages. Creating awareness of potential dangers and recommending use of personal protective equipment among automobile painting artisans can further decrease their exposure.ga1.

New Insights into the Link between Melanoma and Thyroid Cancer: Role of Nucleocytoplasmic Trafficking.

Cancer remains a major public health concern, mainly because of the incompletely understood dynamics of molecular mechanisms for progression and resistance to treatments. The link between melanoma and thyroid cancer (TC) has been noted in numerous patients. Nucleocytoplasmic transport of oncogenes and tumor suppressor proteins is a common mechanism in melanoma and TC that promotes tumorigenesis and tumor aggressiveness. However, this mechanism remains poorly understood. Papillary TC (PTC) patients have a 1.8-fold higher risk for developing cutaneous malignant melanoma than healthy patients. Our group and others showed that patients with melanoma have a 2.15 to 2.3-fold increased risk of being diagnosed with PTC. The BRAF V600E mutation has been reported as a biological marker for aggressiveness and a potential genetic link between malignant melanoma and TC. The main mechanistic factor in the connection between these two cancer types is the alteration of the RAS-RAF-MEK-ERK signaling pathway activation and translocation. The mechanisms of nucleocytoplasmic trafficking associated with RAS, RAF, and Wnt signaling pathways in melanoma and TC are reviewed. In addition, we discuss the roles of tumor suppressor proteins such as p53, p27, forkhead O transcription factors (FOXO), and NF-KB within the nuclear and cytoplasmic cellular compartments and their association with tumor aggressiveness. A meticulous English-language literature analysis was performed using the PubMed Central database. Search parameters included articles published up to 2021 with keyword search terms melanoma and thyroid cancer, BRAF mutation, and nucleocytoplasmic transport in cancer.

Hidden in plain sight: The effects of BCG vaccination in the COVID-19 pandemic.

To investigate the relationship between Bacille Calmette-Guérin (BCG) vaccination and SARS-CoV-2 by a bioinformatics approach, two datasets for the SARS-CoV-2 infection group and BCG-vaccinated group were downloaded. Differentially Expressed Genes were identified. Gene ontology and pathways were functionally enriched, and networking was constructed in NetworkAnalyst. Lastly, the correlation between post-BCG vaccination and COVID-19 transcriptome signatures was established. A total of 161 DEGs (113 upregulated DEGs and 48 downregulated genes) were identified in the SARS-CoV-2 group. In the pathway enrichment analysis, a cross-reference of upregulated Kyoto Encyclopedia of Genes and Genomes pathways in SARS-CoV-2 with downregulated counterparts in the BCG-vaccinated group, resulted in the intersection of 45 common pathways, accounting for 86.5% of SARS-CoV-2 upregulated pathways. Of these intersecting pathways, a vast majority were immune and inflammatory pathways with top significance in interleukin-17, tumor necrosis factor, NOD-like receptors, and nuclear factor-κB signaling pathways. Given the inverse relationship of the specific differentially expressed gene pathways highlighted in our results, the BCG-vaccine may play a protective role against COVID-19 by mounting a nonspecific immunological response and further investigation of this relationship is warranted.

Computational Identification of Metabolic Pathways of Plasmodium falciparum using the k-Shortest Path Algorithm.

Plasmodium falciparum, a malaria pathogen, has shown substantial resistance to treatment coupled with poor response to some vaccines thereby requiring urgent, holistic, and broad approach to prevent this endemic disease. Understanding the biology of the malaria parasite has been identified as a vital approach to overcome the threat of malaria. This study is aimed at identifying essential proteins unique to malaria parasites using a reconstructed iPfa genome-scale metabolic model (GEM) of the 3D7 strain of Plasmodium falciparum by filling gaps in the model with nineteen (19) metabolites and twenty-three (23) reactions obtained from the MetaCyc database. Twenty (20) currency metabolites were removed from the network because they have been identified to produce shortcuts that are biologically infeasible. The resulting modified iPfa GEM was a model using the k-shortest path algorithm to identify possible alternative metabolic pathways in glycolysis and pentose phosphate pathways of Plasmodium falciparum. Heuristic function was introduced for the optimal performance of the algorithm. To validate the prediction, the essentiality of the reactions in the reconstructed network was evaluated using betweenness centrality measure, which was applied to every reaction within the pathways considered in this study. Thirty-two (32) essential reactions were predicted among which our method validated fourteen (14) enzymes already predicted in the literature. The enzymatic proteins that catalyze these essential reactions were checked for homology with the host genome, and two (2) showed insignificant similarity, making them possible drug targets. In conclusion, the application of the intelligent search technique to the metabolic network of P. falciparum predicts potential biologically relevant alternative pathways using graph theory-based approach.

Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria.

BACKGROUND: The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies (ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria. METHODS: At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009-2010 and 2014-2015 and at 2-year interval in 2009-2010 and 2012-2015, respectively after deployment in 2005. RESULTS: Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009-2010 to 2014-2015 (P = 0.002 and P <  0.0001, respectively). Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55-1.64) to 1.9 days (95% CI, 1.9-2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P <  0.0001 for each). Enrolment parasitaemia > 75 000 µl- 1, haematocrit > 27% 1 day post-treatment initiation, treatment with artemether-lumefantrine and enrolment in 2014-2015 independently predicted APPD1. In parallel, Kaplan-Meier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P = 0.005) and from 9 to 15% (P = 0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3 h within 2 years (P <  0.0001). CONCLUSIONS: These data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children. TRIAL REGISTRATION: Pan African Clinical Trial Registration PACTR201508001188143 , 3 July 2015; PACTR201508001191898 , 7 July 2015 and PACTR201508001193368 , 8 July 2015 PACTR201510001189370 , 3 July 2015; PACTR201709002064150 , 1 March 2017; https://www.pactr.samrca.ac.za.

Asymptomatic malaria infections and Pfmdr1 mutations in an endemic area of Nigeria.

BACKGROUND: Malaria eradication globally is yet to be achieved and transmission is sustained in many endemic countries. Plasmodium falciparum continues to develop resistance to currently available anti-malarial drugs, posing great problems for malaria elimination. This study evaluates the frequencies of asymptomatic infection and multidrug resistance-1 (mdr-1) gene mutations in parasite isolates, which form the basis for understanding persistently high incidence in South West, Nigeria. METHODS: A total of 535 individuals aged from 6 months were screened during the epidemiological survey evaluating asymptomatic transmission. Parasite prevalence was determined by histidine-rich protein II rapid detection kit (RDT) in healthy individuals. Plasmodium falciparum mdr-1 gene mutations were detected by polymerase chain reaction (PCR) followed by restriction enzyme digest and electrophoresis to determine polymorphism in parasite isolates. Sequencing was done to confirm polymorphism. Proportions were compared using Chi-square test at p value < 0.05. RESULTS: Malaria parasites were detected by RDT in 204 (38.1%) individuals. Asymptomatic infection was detected in 117 (57.3%) and symptomatic malaria confirmed in 87 individuals (42.6%). Overall, individuals with detectable malaria by RDT was significantly higher in individuals with symptoms, 87 of 197 (44.2%), than asymptomatic persons; 117 of 338 (34.6%), p = 0.02. In a sub-set of 75 isolates, 18(24%) and 14 (18.6%) individuals had Pfmdr1 86Y and 1246Y mutations. CONCLUSIONS: There is still high malaria transmission rate in Nigeria with higher incidence of asymptomatic infections. These parasites harbour mutations on Pfmdr1 which contribute to artemisinin partner drug resistance; surveillance strategies to reduce the spread of drug resistance in endemic areas are needed to eliminate the reservoir of malaria parasites that can mitigate the eradication of malaria in Nigeria.

Cytotoxic Effects of Compounds Isolated from Ricinodendron heudelotii.

This study was designed to explore the in vitro anticancer effects of the bioactive compounds isolated from Ricinodendron heudelotii on selected cancer cell lines. The leaves of the plant were extracted with ethanol and partitioned in sequence with petroleum ether, ethyl acetate, and n-butanol. The ethyl acetate fraction was phytochemically studied using thin layer chromatography (TLC) and column chromatography (CC). Structural elucidation of pure compounds obtained from the ethyl acetate fraction was done using mass spectra, ¹H-NMR, and 13C-NMR analysis. The isolated compounds were subsequently screened using five different cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7, SW-480, and normal lung epithelial cell line, BEAS-2B, to assess their cytotoxic effects. Nine compounds were isolated and structurally elucidated as gallic acid, gallic acid ethyl ester, corilagin, quercetin-3-O-rhamnoside, myricetin-3-O-rhamnoside, 1,4,6-tri-O-galloyl glucose, 3,4,6-tri-O-galloyl glucose, 1,2,6-tri-O-galloyl glucose, and 4,6-di-O-galloyl glucose. Corilagin exhibited the most cytotoxic activity with an IC50 value of 33.18 µg/mL against MCF-7 cells, which were comparable to cisplatin with an IC50 value of 27.43 µg/mL. The result suggests that corilagin isolated from R. heudelotii has the potential to be developed as an effective therapeutic agent against the growth of breast cancer cells.

Dataset on analysis of quality of health and social insurance subscription in different socio-economic class of workers in selected areas in southwest Nigeria.

National social health insurance scheme aims to improve the health of citizens and provide equal access to health care across different income classes. This empirical datasets describes quality of health, insurance subscription, awareness, health care coverage and benefits in different socio-economic class of workers in Ota and Lagos, Nigeria. The perception of individual׳s state of health and level of satisfaction of accessed health care are reported and opinions on ways to meet the health needs of workers in a developing country such as Nigeria.

Cardiovascular Risk Factors in a Suburban Community in Nigeria.

The burden of hypertension, a silent killer, continues to increase in low- and middle-income countries. This study evaluated blood pressure (BP) in healthy adults to determine their risk of developing hypertension and to reduce associated morbidity of the disease. Overall, 182 subjects aged >16 years participated in the study. Systolic (SBP) and diastolic blood pressure (DBP) was measured after a resting period using mercury sphygmomanometer. Random blood glucose (RBG) concentration was also determined. Regression models were used to determine risk of high BP with p values < 0.05 indicating statistical difference. Prehypertension was present in 36.8% population and high BP in 31% individuals with hypertensive symptoms. DBP ≥ 90 mmHg was prevalent in the undiagnosed group, while diabetes comorbidity was detected in only 4 individuals. High BP or diabetes was not detected in those <20 year olds. Age > 35 years was an independent risk (likelihood ratio: 22.56, p < 0.0001); this increases to 26.48 (p < 0.0001) in the presence prediabetes and RBG > 100 mg/dl. Undiagnosed hypertension rate is high in the study area, and urgent interventions for large scale screening and management of the disease are required to reduce the burden of hypertension in Nigeria.