Synergistic and Additive Effects of Menadione in Combination with Antibiotics on Multidrug-Resistant Staphylococcus aureus: Insights from Structure-Function Analysis of Naphthoquinones.

Antimicrobial resistance (AMR) interferes with the effective treatment of infections and increases the risk of microbial spread and infection-related illness and death. The synergistic activities of combinations of antimicrobial compounds offer satisfactory approaches to some extent. Structurally diverse naphthoquinones (NQs) including menadione (-CH3 group at C2) exhibit substantial antimicrobial activities against multidrug-resistant (MDR) pathogens. We explored the combinations of menadione with antibiotic ciprofloxacin or ampicillin against Staphylococcus aureus and its biofilms. We found an additive (0.590 %) were also observed. However, preformed biofilms were not affected. Dent formation was also evident in S. aureus treated with the test compounds. The structure-function relationship (SFR) of NQs was used to determine and predict their activity pattern against pathogens. Analysis of 10 structurally distinct NQs revealed that the compounds with -Cl, -Br, -CH3 , or -OH groups displayed the lowest MICs (32-256 µg/mL). Furthermore, 1,4-NQs possessing a halogen or -CH3 moiety showed elevated ROS activity, whereas molecules with an -OH group affected cell integrity. Improved activity of antimicrobial combinations and SFR approaches are significant in antimicrobial therapies.

Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases.

Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer's disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron-allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as APOE4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that HFE gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels.

Three-dimensional patterning in biomedicine: Importance and applications in neuropharmacology.

Nature manufactures biological systems in three dimensions with precisely controlled spatiotemporal profiles on hierarchical length and time scales. In this article, we review 3D patterning of biological systems on synthetic platforms for neuropharmacological applications. We briefly describe 3D versus 2D chemical and topographical patterning methods and their limitations. Subsequently, an overview of introducing a third dimension in neuropharmacological research with delineation of chemical and topographical roles is presented. Finally, toward the end of this article, an explanation of how 3D patterning has played a pivotal role in relevant fields of neuropharmacology to understand neurophysiology during development, normal health, and disease conditions is described. The future prospects of organs-on-a--like devices to mimic patterned blood-brain barrier in the context of neurotherapeutic discovery and development for the prioritization of lead candidates, membrane potential, and toxicity testing are also described. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1369-1382, 2018.