Identification of estrogen receptor agonists among hydroxylated polychlorinated biphenyls using classification-based quantitative structure-activity relationship models.

Identification of estrogen receptor (ER) agonists among environmental toxicants is essential for assessing the potential impact of toxicants on human health. Using 2D autocorrelation descriptors as predictor variables, two binary logistic regression models were developed to identify active ER agonists among hydroxylated polychlorinated biphenyls (OH-PCBs). The classifications made by the two models on the training set compounds resulted in accuracy, sensitivity and specificity of 95.9 %, 93.9 % and 97.6 % for ERα dataset and 91.9 %, 90.9 % and 92.7 % for ERß dataset. The areas under the ROC curves, constructed with the training set data, were found to be 0.985 and 0.987 for the two models. Predictions made by models I and II correctly classified 84.0 % and 88.0 % of the test set compounds and 89.8 % and 85.8% of the cross-validation set compounds respectively. The two classification-based QSAR models proposed in this paper are considered robust and reliable for rapid identification of ERα and ERß agonists among OH-PCB congeners.

Activity prediction, structure-based drug design, molecular docking, and pharmacokinetic studies of 1,4-dihydropyridines derivatives as α-amylase inhibitors.

Objectives: Diabetes places a substantial economic burden on countries worldwide. The costs associated with diabetes management, including healthcare services, medications, monitoring equipment, and productivity losses, are substantial. The International Diabetes Federation has estimated that global healthcare expenditures associated with diabetes and its complications exceed hundreds of billions of dollars annually. Therefore, a critical need exists to develop drugs that are highly effective, affordable, and easily accessible to society. Methods: This study explored the structural modification of 1,4-DHP derivatives to identify specific α-amylase inhibitors, with the aim of developing more effective and accessible drugs for diabetes. We evaluated the activity and binding ability of the designed compounds. In addition, we performed drug-likeness and pharmacokinetic studies on the modified compounds. Results: Equation (1) had the highest accuracy, on the basis of internal and external assessment parameters, including R2int = 0.852, R2adj = 0.803, Q2cv = 0.731, and R2ext = 0.884. Moreover, the five potent analogs identified through structure-based drug design demonstrated a more favorable interaction than observed for the template or acarbose. Additionally, comprehensive studies on the drug-like properties and pharmacokinetics of the designed compounds supported their oral safety and favorable pharmacokinetic profiles. Conclusions: The designed analogs show promise for developing new hypoglycemic agents. Their positive attributes and performance suggest that they may potentially serve as candidates for further research in improving treatments for high blood sugar-associated conditions.

Targeting CD20-expressing malignant melanoma cells augments BRAF inhibitor killing.

BACKGROUND: Mutant BRAF targeted therapies remain a standard of care for the treatment of metastatic malignant melanoma (MM); however, high initial response rates are tempered by the persistence of residual MM cells that eventually lead to disease recurrence and mortality. As MM recurrence during targeted therapy can present with the simultaneous occurrence of multiple tumour nodules at the original body sites, we hypothesized the presence of an intrinsically resistant MM cell subpopulation. OBJECTIVES: To identify an MM cell subpopulation that is intrinsically resistant to targeted therapy and possibly responsible for MM recurrence. METHODS: Using melanoma cell lines, we defined culture conditions for the reproducible three-dimensional growth of melanospheres to investigate putative cancer stem cell populations. We undertook RNA sequencing and bioinformatic analysis to characterize cell populations between adherent and nonadherent culture, and cells expressing or not expressing CD20. Furthermore, we defined an in vitro assay to evaluate the killing of melanoma cancer stem cells as a therapeutic test using combination therapies targeting driver mutation and CD20. RESULTS: We described the culture conditions that promote MM cells to form melanospheres with a reproducible colony-forming efficiency rate of 0.3-1.3%. RNA sequencing of melanosphere vs. conventional MM cell cultures (n = 6), irrespective of the BRAF mutation status, showed that melanosphere formation was associated with growth and differentiation transcriptional signatures resembling MM tumours. Importantly, melanosphere formation also led to the emergence of a CD20+ MM cell subpopulation, similar to that observed in primary human MM tumours. CD20+ MM cells were resistant to BRAF inhibitor therapy and, consistent with this finding, demonstrated a Forkhead box protein M1 transcriptomic profile (n = 6). Combining BRAF inhibitor and anti-CD20 antibody treatment led to the additional killing of previously resistant CD20+  BRAF mutant MM cells. CONCLUSIONS: In patients with MM that harbour a CD20+ subpopulation, combined therapy with BRAF inhibitor and anti-CD20 antibody could potentially kill residual MM cells and prevent disease recurrence.

Single-cell RNA seq analysis of erythroid cells reveals a specific sub-population of stress erythroid progenitors.

BACKGROUND: : Erythroid cells play important roles in hemostasis and disease. However, there is still significant knowledge gap regarding stress erythropoiesis. METHODS: : Two single-cell RNAseq datasets of erythroid cells on GEO with accession numbers GSE149938 and GSE184916 were obtained. The datasets from two sources, bone marrow and peripheral blood were analyzed using Seurat v4.1.1, and other tools in R. QC metrics were performed, data were normalized and scaled. Principal components that capture the variation of the data were determined. In clustering the cells, KNN graph was constructed and Louvain algorithm was applied to optimize the standard modularity function. Clusters were defined via differential expression of features. RESULTS: We identified 9 different cell types, with a particular cluster representing the stress erythroids. The clusters showed differentially expressed genes as observed from the gene signature plot. The stress erythroid cluster differentially expressed some genes including ALAS2, HEMGN, and GUK1. CONCLUSION: The erythroid population was found to be heterogeneous, with a distinct sub-cell type constituting the stress erythroids; this may have important implications for our knowledge of steady-state and stress erythropoiesis, and the markers found in this cluster may prove useful for future research into the dynamics of stress erythroid progenitor cell differentiation.

Rabies virus infection is associated with variations in calbindin D-28K and calretinin mRNA expression levels in mouse brain tissue.

Rabies virus (RABV) infection leads to a fatal neurological outcome in humans and animals and is associated with major alterations in cellular gene expression. In this study, we describe the effects of RABV infection on the mRNA expression levels of two genes, encoding the Ca2+-binding proteins (Ca-BPs) calbindin D-28K (Calb1) and calretinin (Calb2), in the brains of BALB/c mice. Sixty 4-week-old mice were divided into two test groups and one control group. Mice were inoculated intramuscularly with either a street rabies virus (SRV) strain or a challenge virus standard (CVS-11) strain and sacrificed at 3-day intervals up to day 18 postinfection. A direct fluorescent antibody test (DFAT) was used to verify the presence of RABV antigen in brain tissues, and real-time quantitative PCR (RT-PCR) was used to assess gene expression. Infection with both RABV strains resulted in significant (p < 0.05) increases in Calb1 and Calb2 expression in the test animals when compared with the controls at various time points in the study. Correlation analysis indicated very weak insignificant (p > 0.05) negative and positive relationships, respectively, between Calb1 expression (r = -0.04) and Calb2 expression (r = 0.08) with viral load (CVS-11 strain). Insignificant (p > 0.05) relationships were also observed Calb1 expression (r = -0.28) and Calb2 expression (r = 0.06) and viral load for the SRV strain.The observed alterations in Calb1 and Calb2 expression in this study indicate possible impairments in neuronal Ca2+ buffering and Ca2+ homeostasis as a result of RABV infection and, consequently, possible involvement of calbindin-D28K and calretinin in the neuropathogenesis of rabies.

Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential V600E-BRAF kinase inhibitors.

Objectives: V600E-BRAF kinase is an essential therapeutic target in melanoma and other types of tumors. Because of its resistance to known inhibitors and the adverse effects of some identified inhibitors, investigation of new potent inhibitors is necessary. Methods: In the present work, in silico strategies such as molecular docking simulation, pharmacokinetic evaluation, and density functional theory (DFT) computations were used to identify potential V600E-BRAF inhibitors from a set of 72 anticancer compounds in the PubChem database. Results: Five top-ranked molecules (12, 15, 30, 31, and 35) with excellent docking scores (MolDock score ≥90 kcal mol-1, Rerank score ≥60 kcal mol-1) were selected. Several potential binding interactions were discovered between the molecules and V600E-BRAF. The formation of H-bonds and hydrophobic interactions with essential residues of V600E-BRAF suggested the high stability of these complexes. The selected compounds had excellent pharmacological properties according to the drug likeness rules (bioavailability) and pharmacokinetic properties. Similarly, the energy for the frontier molecular orbitals, such as the HOMO, LUMO, energy gap, and other reactivity parameters, was computed with DFT. The frontier molecular orbital surfaces and electrostatic potentials were investigated to demonstrate the charge-density distributions potentially associated with anticancer activity. Conclusion: The identified compounds were found to be potent hit compounds for V600E-BRAF inhibition with superior pharmacokinetic properties; therefore, they may be promising cancer drug candidates.

New flavone-based arylamides as potential V600E-BRAF inhibitors: Molecular docking, DFT, and pharmacokinetic properties.

Objectives: The V600E-BRAF protein kinase is an attractive and essential therapeutic target in melanoma and other tumors. However, because of its resistance to the known inhibitors and side effects of some identified inhibitors, new potent inhibitors need to be identified. Methods: In the present work, in silico strategies such as the molecular docking simulation, DFT (Density-Functional-Theory) computations, and pharmacokinetic evaluation were used to determine potential V600E-BRAF inhibitors from a set of 31 synthesized novel flavone-based arylamides. Results: The docking result demonstrated that four compounds (10, 11, 28, and 31) had acceptable docking scores (MolDock score of -167.523 kcal mol-1, -158.168 kcal mol-1, -160.581 kcal mol-1,-162.302 kcal mol-1, and a Rerank score of -124.365, -129.365, -135.878 and -117.081, respectively) appeared as most active and potent V600E-BRAF inhibitors that topped vemurafenib (-158.139 and -118.607 kcal mol-1). The appearance of H-bonds and hydrophobic interactions with essential residues for V600E-BRAF proved the high stability of these complexes. The energy for the frontier molecular orbitals such as HOMO, LUMO, energy gap, and other reactivity parameters was computed using DFT. The frontier molecular-orbital surfaces and electrostatic potentials (EPs) were investigated to demonstrate the charge-density distributions that might be linked to anticancer activity. Similarly, the chosen compounds revealed superior pharmacological properties according to the drug-likeness rules (bioavailability) and pharmacokinetic properties. Conclusion: The chosen compounds were recognized as potent V600E-BRAF inhibitors with superior pharmacokinetic properties and could be promising cancer drug candidates.

In silico analysis of noscapine compounds as anti-tumor agents targeting the tubulin receptor.

Objective: This research aims to develop a mathematical model that relates the structural features of noscapine with anti-tumor activity, to explains the mode of binding between noscapine compounds and the target receptor tubulin by docking analysis. By considering the results of docking analysis and predictions of pharmacokinetic properties/drug likeness, we designed novel noscapine compounds as anti-tumor agents against pancreatic cancer. Methods: We used an in silico quantitative structure-activity relationship (QSAR) approach, molecular docking analysis and online tools for pharmacokinetics and drug likeness prediction to develop novel compounds. Results: A QSAR model with good validations parameters and quality of fit (R2 = 0.9731, Q2 CV = 0.9434, R2 adj = 0.9647 and R2 test set = 0.8343) was built utilizing 70% of the dataset as a training set and the remaining 30% as an external validation to ascertain its predictive capability. Three novel compounds were designed: D3, D4 and D6 with binding scores of -11.2, -10.2 and 10.6 kcal/mol, respectively, exhibiting high affinity towards the tubulin receptor than the template (parent compound) and the co-crystallized ligand (E∗) with a binding score of 9.2 kcal/mol. Conclusion: The QSAR approach and molecular docking analysis is an important approach for modern drug discovery. Pharmacokinetics studies of the selected novel compounds revealed good drug properties and can be used as candidate compounds for the development of anti-tumor agents for pancreatic cancer.

Removal of Antibiotic Resistance Genes, Class 1 Integrase Gene and Escherichia coli Indicator Gene in a Microalgae-Based Wastewater Treatment System.

Microalgae-based wastewater treatment systems (AWWTS) have recently shown promise in the mitigation of antibiotic resistance genes (ARGs) from municipal wastewater (MWW). However, due to the large number of ARGs that exist in MWW, the use of indirect conventional water quality parameters to monitor ARGs reduction in wastewater would make the process less burdensome and economically affordable. In order to establish a robust relationship between the ARGs and water quality parameters, the current study employed different microalgae strains in monoculture (CM2, KL10) and multi-species combinations (CK and WW) for the MWW treatment under outdoor environmental conditions. The studied genes were quantified in the MWW influents and effluents using real-time PCR. All the cultures substantially improved the physicochemical qualities of the MWW. Out of the 14 genes analyzed in this study, tetO, tetW, tetX and ermB were decreased beyond detection within the first 4 days of treatment in all the cultures. Other genes, including blaCTX, sul1, cmlA, aadA, int1 and uidA were also decreased beyond a 2 log reduction value (LRV). The mobile genetic element, int1, correlated positively with most of the ARGs, especially sul1 (r ≤ 0.99, p < 0.01) and aadA (r ≤ 0.97, p < 0.01). Similarly, the Escherichia coli indicator gene, uidA, correlated positively with the studied genes, especially with aadA, blaCTX, blaTEM and cmlA (r ≤ 0.99 for each, p < 0.01). Some of the studied genes also correlated positively with total dissolved solids (TDS) (r ≤ 0.98, p < 0.01), and/or negatively with total suspended solids (TSS) (r ≤ −0.98, p < 0.01) and pH (r ≤ −0.98, p < 0.01). Among the tested cultures, both monocultures, i.e., KL10 and CM2 were found to be more consistent in gene suppression than their multi-species counterparts. The findings revealed water quality parameters such as TDS, TSS and E. coli as reliable proxies for ARGs mitigation in AWWTS and further highlight the superiority of monocultures over multi-species cultures in terms of gene suppression from the MWW stream.

Novel microalgae strains from selected lower Himalayan aquatic habitats as potential sources of green products.

Microalgal biomass provides a renewable source of biofuels and other green products. However, in order to realize economically viable microalgal biorefinery, strategic identification and utilization of suitable microalgal feedstock is fundamental. Here, a multi-step suboptimal screening strategy was used to target promising microalgae strains from selected freshwaters of the study area. The resulting strains were found to be affiliated to seven closely-related genera of the family Scenedesmaceae, as revealed by both morphologic and molecular characterization. Following initial screening under upper psychrophilic to optimum mesophilic (irregular temperature of 14.1 to 35.9°C) cultivation conditions, superior strains were chosen for further studies. Further cultivation of the selected strains under moderate to extreme mesophilic cultivation conditions (irregular temperature of 25.7 to 42.2°C), yielded up to 74.12 mgL-1day-1, 19.96 mgL-1day-1, 48.56%, 3.34 µg/mL and 1.20 µg/mL, for biomass productivity, lipid productivity, carbohydrate content, pigments content and carotenoids content respectively. These performances were deemed promising compared with some previous, optimum conditions-based reports. Interestingly, the fatty acids profile and the high carotenoids content of the studied strains revealed possible tolerance to the stress caused by the changing suboptimal cultivation conditions. Overall, strains AY1, CM6, LY2 and KL10 were exceptional and may present sustainable, promising feedstock for utilization in large-scale generation of green products, including biodiesel, bioethanol, pigments and dietary supplements. The findings of this study, which exposed promising, eurythermal strains, would expand the current knowledge on the search for promising microalgae strains capable of performing under the largely uncontrolled large-scale cultivation settings.

A systematic review with meta-analysis on the antihypertensive efficacy of Nigerian medicinal plants.

ETHNOPHARMACOLOGICAL RELEVANCE: Despite the promising effects of herbal preparations in lowering blood pressure (BP), hypertension remains a major clinical challenge in Nigeria. The BP-lowering effects of medicinal plants are due to the presence of bioactive compounds. AIM OF THE STUDY: This meta-analysis presents a precise estimate of the therapeutic benefits of medicinal plants utilized in Nigeria for the management of hypertension in animals and humans. METHODS: A systematic literature search was performed through Cochrane, PubMed, Science Direct and Scopus databases from inception until February 28, 2021 using search terms related to randomized controlled trials of Nigerian medicinal plants for hypertension. Additional studies were identified through manual search. BP was the main outcome that was measured after the intervention. Meta-analysis was performed using the Review Manager and Meta-Essential. RESULTS: Nineteen trials comprising of 16 preclinical and 3 clinical studies were enrolled for the meta-analysis. A total number of 16 plants was identified of which H. sabdariffa was the highest reported plant. The plant extracts significantly lowered the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the hypertensive subjects compared to control. Weighted mean difference (WMD) for SBP (-43.60 mmHg, 95% CI: -63.18, -24.01; p<0.0001) and DBP (-29.50 mmHg, 95 CI: -43.66, -15.34; p<0.0001) was observed for the preclinical studies. For clinical trials, the WMD was -13.98 mmHg, 95 CI: -19.08, -8.88; p<0.00001 for SBP and -10.00 mmHg, 95 CI: -12.22, -7.78; p<0.00001 for DBP. High heterogeneity was observed for the outcome measures of preclinical studies, but not for the clinical studies. The observed substantial heterogeneity in preclinical studies may be linked to methodological shortcomings as evidenced by the results of the risk of bias assessment. There was no evidence of publication bias in animal trials for BP using the funnel plot and Egger's regression test (SBP, p=0.239 and DBP, p=0.112). CONCLUSIONS: This study provides evidence of medicinal preparations for the treatment of hypertension. A well-conducted trial with methodological rigour and a longer duration of follow-up is required for their effective clinical utilization.

Assessment of family needs of children with cerebral palsy in Northern-Nigeria: A cross-sectional study.

PURPOSE: This study aimed to identify the needs and priorities of parents of children with cerebral palsy (CP) in order to improve care by increasing family participation in rehabilitation programmes. METHODS: This cross-sectional questionnaire-based study was conducted between January to March 2019. Convenience sampling was used to recruit 43 family members (18 years and above) of children with CP who came to the physiotherapy departments for rehabilitation services for their children. Fisher's exact test was used to analyse the association between socio-demographic characteristics and each of the need items. RESULTS: Five different items were identified to be the family needs that were most frequently met: a) 'need for active involvement in the child's treatment and therapies' (n= 40; 93.0%), b) 'need for the provision of standard medical care (n= 39; 90.7%), c) 'need for questions to be answered honestly' (n= 38; 88.4%), d) 'need for healthcare professionals to respect the child's wishes' (n= 36; 83.7%), e) 'need for mothers to discuss their feelings (depression, stress etc.) with someone who has similar experience' (n= 36; 83.7%). Conversely, three items were the most unmet family needs: a) 'need to have professionals to consult whenever the child needs help' (n= 39; 90.7%), b) 'need to be informed about the child's prognosis' (n= 41; 95.3%), and c) 'need to have financial support to provide the child with adequate care' (n= 43; 100%). CONCLUSION: All participants overwhelmingly reported that their financial needs were their highest priority. The multiple needs of families of children with disabilities must be assessed and considered in rehabilitation services when treating children with CP.

Kinetic and thermodynamic studies of fenton oxidative decolorization of methylene blue.

The need for light intensity has made dye degradation very costly for industry. In this work, Fenton reagent was used for the efficient degradation of an aqueous solution of dye without the need for a light source. The influences of the pH of the media, the initial concentrations of Fe2+, H2O2, and methylene blue (MB) dye; in addition to temperature on the oxidation of MB dye were studied. The optimum amounts of the Fenton reagent were 4mM of Fe2+ and 70mM of H2O2 at 20 mg/L of dye. The optimum ratio of 0.05 of Fe2+/H2O2 was found to give the best result for the decolorization of dye. The Fenton process was effective at pH 3 with a maximum dye decolorization efficiency of 98.8% within 30 min of reaction, corresponding to a COD removal of 85%. The decolorization process was thermodynamically feasible, spontaneous, and endothermic. The activation energy (Ea) was 33.6 kJ/mol suggesting that the degradation reaction proceeded with a low energy barrier.

Potential biological activity of acacia honey.

Recent advances in functional foods-based research have increasingly become an area of major interest because it affects human health and activities. Functional foods are classes of foods with health promoting and disease preventing properties in addition to multiple nutritional values and of such type is honey. Acacia honey is a type of honey produced by bees (Apis mellifera) fed on Acacia flowers, hence the name. This review focuses on the potential biological activities of Acacia honey which includes quality, antioxidant, immuno-modulatory, antiproliferative and neurological properties at in vitro and in vivo levels. Based on our review, Acacia honey used from various researches is of high purity, contains some bioactive compounds ranging from vitamins, phenolics, flavonoids and fatty acids. It's highly nutritional with strong antioxidant and immuno-modulatory potentials which may therefore be considered a potential candidate for both cancer prevention and treatment. Neurologically, it may be considered as a viable therapeutic agent in the management of Alzheimer's disease.

Inhibitory effects of sodium arsenite and acacia honey on acetylcholinesterase in rats.

This study was conducted to investigate the effect of sodium arsenite and Acacia honey on acetylcholinesterase (AChE) activity and electrolytes in the brain and serum of Wistar rats. Male Wistar albino rats in four groups of five rats each were treated with distilled water, sodium arsenite (5 mg/kg body weight), Acacia honey (20% v/v), and sodium arsenite and Acacia honey, daily for one week. The sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the brain with the combined treatment being more potent. Furthermore, sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the serum. Strong correlation was observed between the sodium and calcium ion levels with acetylcholinesterase activity in the brain and serum. The gas chromatography mass spectrometry analysis of Acacia honey revealed the presence of a number of bioactive compounds such as phenolics, sugar derivatives, and fatty acids. These findings suggest that sodium arsenite and/or Acacia honey modulates acetylcholinesterase activities which may be explored in the management of Alzheimer's diseases but this might be counteracted by the hepatotoxicity induced by arsenics.

Ameliorative Effects of Acacia Honey against Sodium Arsenite-Induced Oxidative Stress in Some Viscera of Male Wistar Albino Rats.

Cancer is a leading cause of death worldwide and its development is frequently associated with oxidative stress-induced by carcinogens such as arsenicals. Most foods are basically health-promoting or disease-preventing and a typical example of such type is honey. This study was undertaken to investigate the ameliorative effects of Acacia honey on sodium arsenite-induced oxidative stress in the heart, lung and kidney tissues of male Wistar rats. Male Wistar albino rats divided into four groups of five rats each were administered distilled water, Acacia honey (20%), sodium arsenite (5 mg/kg body weight), Acacia honey, and sodium arsenite daily for one week. They were sacrificed anesthetically using 60 mg/kg sodium pentothal. The tissues were used for the assessment of glutathione peroxidase, catalase, and superoxide dismutase activities, protein content and lipid peroxidation. Sodium arsenite significantly (P < 0.05) suppressed the glutathione peroxidase, catalase, superoxide dismutase activities with simultaneous induction of lipid peroxidation. Administration of Acacia honey significantly increased (P < 0.05) glutathione peroxidase, catalase, and superoxide dismutase activities with concomitant suppression of lipid peroxidation as evident by the decrease in malondialdehyde level. From the results obtained, Acacia honey mitigates sodium arsenite induced-oxidative stress in male Wistar albino rats, which suggest that it may attenuate oxidative stress implicated in chemical carcinogenesis.

The effect of temperature on size and development in three species of benthic copepod.

The effect of temperature on the size and development times of three benthic cyclopoid copepods, Acanthocyclops viridis, A. vernalis and Macrocyclops albidus were investigated within the normal environmental temperature range (5°C-20°C). Adult weight decreased as temperature increased. All three species complete their development at 5°C and development times at all temperatures are presented as curvilinear logarithmic temperature functions. The duration of development decreases as temperature rises. The results are compared with those reported else-where for benthic and planktonic species and the ecological implications are discussed.