Computer-aided identification of potential inhibitors against Necator americanus glutathione S-transferase 3.

Hookworm infection is caused by the blood-feeding hookworm gastrointestinal nematodes. Its harmful effects include anemia and retarded growth and are common in the tropics. A current control method involves the mass drug administration of synthetic drugs, mainly albendazole and mebendazole. There are however concerns of low efficacy and drug resistance due to their repeated and excessive use. Although, Necator americanus glutathione S-transferase 3 (Na-GST-3) is a notable target, using natural product libraries for computational elucidation of promising leads is underexploited. This study sought to use pharmacoinformatics techniques to identify compounds of natural origins with the potential to be further optimized as promising inhibitors. A compendium of 3182 African natural products together with five known helminth GST inhibitors including Cibacron blue was screened against the active sites of the Na-GST-3 structure (PDB ID: 3W8S). The hit compounds were profiled to ascertain the mechanisms of binding, anthelmintic bioactivity, physicochemical and pharmacokinetic properties. The AutoDock Vina docking protocol was validated by obtaining 0.731 as the area under the curve calculated via the receiver operating characteristics curve. Four compounds comprising ZINC85999636, ZINC35418176, ZINC14825190, and Dammarane Triterpene13 were identified as potential lead compounds with binding energies less than -9.0 kcal/mol. Furthermore, the selected compounds formed key intermolecular interactions with critical residues Tyr95, Gly13 and Ala14. Notably, ZINC85999636, ZINC14825190, and dammarane triterpene13 were predicted as anthelmintics, whilst all the four molecules shared structural similarities with known inhibitors. Molecular modelling showed that the compounds had reasonably good binding free energies. More so, they had high binding affinities when screened against other variants of the Na-GST, namely Na-GST-1 and Na-GST-2. Ligand quality assessment using ligand efficiency dependent lipophilicity, ligand efficiency, ligand efficiency scale and fit quality scale showed the molecules are worthy candidates for further optimization. The inhibitory potentials of the molecules warrant in vitro studies to evaluate their effect on the heme regulation mechanisms.

In Vitro and In Vivo Toxicological Evaluation of Avicennia africana P: Beauv. (Avicenniaceae) Leaf Extract in a Rat Model.

Avicennia africana is an important ethnomedicinal plant that has long been used to treat malaria and several other diseases. Despite the plant's antimalarial and other therapeutic properties, there is limited evidence-based data on its potential toxicity. Hence, the purpose of the current study was to assess the safety of A. africana leaf ethanolic extract (AAE). The study was designed to ascertain the cytotoxic effects of the crude extract on red blood cells (RBCs) as well as the acute and subacute toxicity in Wistar albino rats in accordance with Organization for Economic Co-operation and Development (OECD) guidelines "Test No. 423" and CPMW/SWP/1042/99. The pulverized, shade-dried plant leaves were sequentially macerated with 70% ethanol to obtain the crude extract (AAE). The extract's cytotoxic activity (CC50) against the uninfected human red blood cells (RBCs) was determined using the 3-(4,5-Dimethylythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. For the acute toxicity studies, the rats (male and female) were divided randomly into six groups of five rats (n = 5) and dosed orally once with the following dose levels: 100, 300, 1000, 3000, and 5000 mgkg-1, p.o. of the extracted AAE, with the control group receiving only the vehicle. In the repeated dose toxicity studies, the rats (both sexes) were orally administered daily with AAE at 100, 300, and 1000 mgkg-1 for 14 days. Rat body weights were measured, and blood samples were tested for haematological and biochemical markers. Internal organs like the heart, kidney, liver, and spleen were collected, inspected, and weighed, and histological examinations were performed. The median lethal dose (LD50) value is greater than 5000 mgkg-1 body weight, with no significant change in bodyweight or relative organ weight (ROWs) of the extract-treated groups or control group. The extract showed greater cytotoxicity activity (CC50), which was >100 µg/mL, compared to the reference drug (artesunate).The dosage groups of 100 and 300 mgkg-1bwt had neutrophilia and lymphocytopenia (p < 0.05). However, changes in these haematological parameters may not be dose dependent and could be stress related. All the serum biochemical markers studied in rats given AAE did not show any significant change (p > 0.05). Histopathological examination of internal organs of AAE-treated rats did not show any significant abnormalities resulting from the extract treatment compared to the control group. Based on the findings in the present study, the LD50 value of AAE was found to exceed 5000 mgkg-1 in the acute toxicity test, while the no observed adverse effect level (NOAEL) in rats was 1000 mgkg-1 p.o. In the sub-acute toxicity tests. Histopathological analysis revealed no morphological abnormalities in the vital organs.

Dyslipidaemia Associated with Type 2 Diabetics with Micro and Macrovascular Complications among Ghanaians.

In this study, differences in lipid levels amongst diabetics with and without complications were assessed to determine lipid disorders that are associated with diabetic complications other than cardiovascular diseases. A Cross sectional study design was employed. The study included 288 diabetics and 108 non diabetics with different types of complications such as hypertension, nephropathy, neuropathy, and retinopathy. The mean serum total cholesterol was higher in patients with complications compared to those without complications and the non-diabetic controls. The normotensive diabetic patients had the lowest total cholesterol among the diabetic patients' groups (4.65 ± 0.17 mmol/l) compared to the diabetics with hypertension (6.051 ± 0.20 mmol/l), retinopathy (6.26 ± 0.29 mmol/l), neuropathy (5.80 ± 0.17 mmol/l) and nephropathy patients 5.74 ± 0.26 mmol/l (P < 0.05). The prevalence of dyslipidaemia among diabetic subjects was between 19.2 and 84.0%. The study shows that, in addition to macrovascular complications, dyslipidaemia is common in type 2 diabetes mellitus patients with microvascular complications.

Haptoglobin polymorphism and association with complications in ghanaian type 2 diabetic patients.

There is scanty information on the role of genetic factors, especially those relating to haptoglobin (Hp) phenotypes in the expression of complications among diabetes mellitus patients in Ghana. In this study, we investigated whether there is any association between Hp phenotypes and diabetic complications and to determine if association of the Hp phenotypes with diabetic complications in Ghanaian diabetics differ from those in Caucasians. A total of 398 participants were randomly recruited into the study. These comprised diabetic patients numbering 290 attending a diabetes Clinic in Ghana and 108 non-diabetic controls from the same community. Analyses of the results indicate that most of the diabetics with complications were of the Hp 2-2 (35%) and Hp 2-1 (23.9%) phenotypes. Fewer diabetics were found to be of the Hp 2-1 M phenotype. The controls were mostly of Hp 1-1 and Hp 2-1 M phenotypes. The odds ratio of having complications in a diabetic with an Hp 2-2 phenotype was 18.27 times greater than that for Hp 0-0. Hp 2-2 phenotype with its poor antioxidant activity may therefore be a useful predictor for the propensity of an individual to develop diabetes complications.