Ackee (Blighia sapida K.D. Koenig) Leaves and Arils Methanolic Extracts Ameliorate CdCl2-Induced Oxidative Stress Biomarkers in Drosophila melanogaster.

Different ethnomedical benefits have been documented on different parts of Ackee (Blighia sapida); however, their roles in ameliorating oxidative damages are not well established. CdCl2 inhibitory effects on some oxidative-stress biomarkers and ameliorative potentials of Ackee leaves (AL) and arils (AS) methanolic extracts were studied using Drosophila melanogaster as a model. One to 3-day-old D. melanogaster flies were orally exposed to different concentrations of CdCl2 in their diet for 7 days. The fly's survival profile and negative geotaxis assays were subsequently analysed. Methanolic extracts of AL and AS treatments showed negative geotaxis behaviour, and extracts were able to ameliorate the effect of Cd2+ on catalase and GST activities and increase total thiol and GSH levels, while it reduced the H2O2 generation (p ≤ 0.05) when compared to the control. Furthermore, Cd2+ exhibited noncompetitive and uncompetitive enzyme inhibition on catalase and GST activities, respectively, which may have resulted in the formation of Enzyme-substrate-Cd2+ transition complexes, thus inhibiting the conversion of substrate to product. This study, thus, suggests that the Cd2+ mechanism of toxicity was associated with oxidative damage, as evidenced by the alteration in the oxidative stress-antioxidant imbalance, and that the AL and AS extracts possess essential phytochemicals that could alleviate possibly deleterious oxidative damage effects of environmental pollutants such as CdCl2. Thus, Ackee plant parts possess essential phytonutrients which could serve as valuable resources in heavy metal toxicity management.

Hypoxia and the Kynurenine Pathway: Implications and Therapeutic Prospects in Alzheimer's Disease.

Neurodegenerative diseases (NDs) like Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease predominantly pose a significant socioeconomic burden. Characterized by progressive neural dysfunction coupled with motor or intellectual impairment, the pathogenesis of ND may result from contributions of certain environmental and molecular factors. One such condition is hypoxia, characterized by reduced organ/tissue exposure to oxygen. Reduced oxygen supply often occurs during the pathogenesis of ND and the aging process. Despite the well-established relationship between these two conditions (i.e., hypoxia and ND), the underlying molecular events or mechanisms connecting hypoxia to ND remain ill-defined. However, the relatedness may stem from the protective or deleterious effects of the transcription factor, hypoxia-inducible factor 1-alpha (HIF-1α). The upregulation of HIF-1α occurs in the pathogenesis of most NDs. The dual function of HIF-1α in acting as a "killer factor" or a "protective factor" depends on the prevailing local cellular condition. The kynurenine pathway is a metabolic pathway involved in the oxidative breakdown of tryptophan. It is essential in neurotransmission and immune function and, like hypoxia, associated with ND. Thus, a good understanding of factors, including hypoxia (i.e., the biochemical implication of HIF-1α) and kynurenine pathway activation in NDs, focusing on Alzheimer's disease could prove beneficial to new therapeutic approaches for this disease, thus the aim of this review.

Network analysis, sequence and structure dynamics of key proteins of coronavirus and human host, and molecular docking of selected phytochemicals of nine medicinal plants.

The novel coronavirus of 2019 (nCoV-19) has become a pandemic, affecting over 205 nations with over 7,410,000 confirmed cases which has resulted to over 418,000 deaths worldwide. This study aimed to identify potential therapeutic compounds and phytochemicals of medicinal plants that have potential to modulate the expression network of genes that are involve in SARS-CoV-2 pathology in human host and to understand the dynamics key proteins involved in the virus-host interactions. The method used include gene network analysis, molecular docking, and sequence and structure dynamics simulations. The results identified DNA-dependent protein kinase (DNA-PK) and Protein kinase CK2 as key players in SARS-CoV-2 lifecycle. Among the predicted drugs compounds, clemizole, monorden, spironolactone and tanespimycin showed high binding energies; among the studied repurposing compounds, remdesivir, simeprevir and valinomycin showed high binding energies; among the predicted acidic compounds, acetylursolic acid and hardwickiic acid gave high binding energies; while among the studied anthraquinones and glycosides compounds, ellagitannin and friedelanone showed high binding energies against 3-Chymotrypsin-like protease (3CLpro), Papain-like protease (PLpro), helicase (nsp13), RNA-dependent RNA polymerase (nsp12), 2'-O-ribose methyltransferase (nsp16) of SARS-CoV-2 and DNA-PK and CK2alpha in human. The order of affinity for CoV proteins is 5Y3E > 6NUS > 6JYT > 2XYR > 3VB6. Finally, medicinal plants with phytochemicals such as caffeine, ellagic acid, quercetin and their derivatives could possibly remediate COVID-19.Communicated by Ramaswamy H. Sarma.

Occurrence of chemical pollutants in major e-waste sites in West Africa and usefulness of cytotoxicity and induction of ethoxyresorufin-O-deethylase (EROD) in determining the effects of some detected brominated flame retardants and e-waste soil-derived extracts.

We investigated the occurrence of chemical pollutants in major e-waste sites in West Africa and usefulness of cytotoxicity and induction of ethoxyresorufin-O-deethylase (EROD) in determining the effects of some detected brominated flame retardants (BFRs) and e-waste soil-derived extracts. Analysis of the e-waste site samples using AAS and GC-MS techniques revealed the presence of a range of toxic metals as well as persistent and toxic organic pollutants, respectively, in the vicinity of the e-waste sites. As expected, the occurrence (%) of all the detected chemical pollutants in experimental soils significantly (P < 0.05) differs from occurrence (%) in control soil. The calculated LC50 values on RBL-2H3 cells of the detected tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD) were 3.75 µM and 4.2 µM, respectively. Tribromophenol (TBP), dibromobiphenyl (DBB), and decabromodiphenyl ether (DBDE) were remarkably less toxic on RBL-2H3 cells compared with TBBPA and HBCD as they did not reduce RBL-2H3 cell viability below 50% in the tested concentration range (0-20 µM). The study revealed that TBBPA and HBCD could induce significant RBL-2H3 cell death through caspase-dependent apoptosis. The study further shows that the cytotoxicity of some of these BFRs could increase synergistically when in mixtures and potentially activate inflammation through the stimulation of mast cell degranulation. The e-waste soil-derived extracts induced a concentration-dependent increase in EROD activity in the exposed RTG-W1 cells. Ultimately, nonpolar extracts had higher EROD-inducing potency compared with polar extracts and hence suggesting the presence in higher amounts of AhR agonists in nonpolar e-waste soil-derived extracts than polar extracts. Overall, there is urgent need for actions in order to improve the environmental quality of the e-waste sites.

In Silico Investigation of First-Pass Effect on Selected Small Molecule Excipients and Structural Dynamics of P-glycoprotein.

In this study, the interaction of selected pharmaceutical excipients on the function of P-glycoprotein (P-gp) and activity of 6 cytochrome P450 (CYP) isoforms were computationally investigated. At binding free energy cut-off value of -5.0 kcal/mol, the result showed possible modulatory or inhibitory effect by cethyl alcohol on CPY3A4 and P-gp; cetyltrimethyl-ammonium bromide (CTAB) on CYP1A2 and P-gp; dibutyl sebacate on CYP2C9, CYP2E1, and P-gp; sodium caprylate on CYP1A2 and CYP3A4; while most of the tested excipients have good interaction with the cytochromes and P-gp. The predicted pharmacokinetics provided possible inhibitors of the CYPs and P-gp and suggested that aspartame and acetyl tributyl citrate may not permeate blood-brain barrier and not act as P-gp substrates. Target prediction for CTAB showed 100% and 35% probability of target to dynamin-1 (UniProt ID: Q05193) and histamine H3 receptor (UniProt ID: Q9Y5N1), respectively, whereas tricaprylin showed 40% probability of target to 5 Protein kinase C (UniProt IDs: P17252, Q02156, Q04759, P24723, and P05129). This study shows that synergistic effect of some excipients present in a drug formulation and multiple drugs administration is possible through modulation of CYPs activities and P-gp function, and this is crucial for consideration to mitigate toxicity in pediatric and adult populations.

Molecular adaptation mechanisms employed by ethanologenic bacteria in response to lignocellulose-derived inhibitory compounds.

Current international interest in finding alternative sources of energy to the diminishing supplies of fossil fuels has encouraged research efforts in improving biofuel production technologies. In countries which lack sufficient food, the use of sustainable lignocellulosic feedstocks, for the production of bioethanol, is an attractive option. In the pre-treatment of lignocellulosic feedstocks for ethanol production, various chemicals and/or enzymatic processes are employed. These methods generally result in a range of fermentable sugars, which are subjected to microbial fermentation and distillation to produce bioethanol. However, these methods also produce compounds that are inhibitory to the microbial fermentation process. These compounds include products of sugar dehydration and lignin depolymerisation, such as organic acids, derivatised furaldehydes and phenolic acids. These compounds are known to have a severe negative impact on the ethanologenic microorganisms involved in the fermentation process by compromising the integrity of their cell membranes, inhibiting essential enzymes and negatively interact with their DNA/RNA. It is therefore important to understand the molecular mechanisms of these inhibitions, and the mechanisms by which these microorganisms show increased adaptation to such inhibitors. Presented here is a concise overview of the molecular adaptation mechanisms of ethanologenic bacteria in response to lignocellulose-derived inhibitory compounds. These include general stress response and tolerance mechanisms, which are typically those that maintain intracellular pH homeostasis and cell membrane integrity, activation/regulation of global stress responses and inhibitor substrate-specific degradation pathways. We anticipate that understanding these adaptation responses will be essential in the design of 'intelligent' metabolic engineering strategies for the generation of hyper-tolerant fermentation bacteria strains.

In silico analysis of cis-acting regulatory elements in 5' regulatory regions of sucrose transporter gene families in rice (Oryza sativa Japonica) and Arabidopsis thaliana.

The regulation of gene expression involves a multifarious regulatory system. Each gene contains a unique combination of cis-acting regulatory sequence elements in the 5' regulatory region that determines its temporal and spatial expression. Cis-acting regulatory elements are essential transcriptional gene regulatory units; they control many biological processes and stress responses. Thus a full understanding of the transcriptional gene regulation system will depend on successful functional analyses of cis-acting elements. Cis-acting regulatory elements present within the 5' regulatory region of the sucrose transporter gene families in rice (Oryza sativa Japonica cultivar-group) and Arabidopsis thaliana, were identified using a bioinformatics approach. The possible cis-acting regulatory elements were predicted by scanning 1.5kbp of 5' regulatory regions of the sucrose transporter genes translational start sites, using Plant CARE, PLACE and Genomatix Matinspector professional databases. Several cis-acting regulatory elements that are associated with plant development, plant hormonal regulation and stress response were identified, and were present in varying frequencies within the 1.5kbp of 5' regulatory region, among which are; A-box, RY, CAT, Pyrimidine-box, Sucrose-box, ABRE, ARF, ERE, GARE, Me-JA, ARE, DRE, GA-motif, GATA, GT-1, MYC, MYB, W-box, and I-box. This result reveals the probable cis-acting regulatory elements that possibly are involved in the expression and regulation of sucrose transporter gene families in rice and Arabidopsis thaliana during cellular development or environmental stress conditions.

Purification and properties of glucose 6-phosphate dehydrogenase from Aspergillus aculeatus.

Glucose 6-phosphate dehydrogenase (EC 1.1.1.49) was purified from Aspergillus aculeatus, a filamentous fungus previously isolated from infected tongue of a patient. The enzyme, apparently homogeneous, had a specific activity of 220 units mg(-1), a molecular weight of 105,000 +/- 5,000 Dal by gel filtration and subunit size of 52,000 +/- 1,100 Dal by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The substrate specificity was extremely strict, with glucose 6-phosphate (G6P) being oxidized by nicotinamide adenine dinucleotide phosphate (NADP) only. At assay pH of 7.5, the enzyme had K(m) values of 6 microM and 75 microM for NADP and G6P respectively. The k(cat) was 83 s(-1). Steady-state kinetics at pH 7.5 produced converging linear Lineweaver-Burk plots as expected for ternary-complex mechanism. The patterns of product and dead-end inhibition suggested that the enzyme can bind NADP and G6P separately to form a binary complex, indicating a random-order mechanism. The enzyme was irreversibly inactivated by heat in a linear fashion, with G6P providing a degree of protection. Phosphoenolpyruvate (PEP), adenosinetriphosphate (ATP), and fructose 6-phosphate (F6P), in decreasing order, are effective inhibitors. Zinc and Cobalt ions were effective inhibitors although cobalt ion was more potent; the two divalent metals were competitive inhibitors with respect to G6P, with Ki values of 6.6 microM and 4.7 microM respectively. It is proposed that inhibition by divalent metal ions, at low NADPH /NADP ratio, is another means of controlling pentosephosphate pathway.