A previous study for the identification of acetylcholinesterase (AChE) inhibitors demonstrated that the hybrid between tyrosol, the 1,2,3-triazole nucleus, and the coumarin group, namely ...7-({1-2-(4-hydroxyphenyl)ethyl-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (10), has a high enzyme inhibitory activity. Here, we synthesized analogues of 10 via triazole with pharmacophoric groups represented by tyrosine, phenylalanine, tryptophan, and glycine in addition to evaluating the impact of coumarin-linked amino acids on AChE inhibition. We obtained eight triazoles, six of which are undescribed. In general, the presence of carboxylic acid decreased the inhibitory activity, while aromatic amino acids increased enzymatic inhibition compared to glycine. The derivative containing tyrosine, structurally most similar to 10, presented the lowest inhibition percentage, indicating that phenolic hydroxyl is not the preponderant factor for inhibition. Molecular docking was not enough to explain in vitro experiments. On the other hand, MlogP (logP calculated by the Moriguchi method) was related positively to enzymatic inhibition. To increase the hydrophobicity of the molecules, we tested the esterified triazole derivatives comparatively with the enzyme. The compound ethyl 2-(4-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetate (6) presented an increment of inhibitory activity of 46.97 ± 1.75% at 100 μmol L-1. We also associated the best activity with the lowest van der Waals volume and molar mass values.
Display omitted
•Amides derived from sclareolide showed enzymatic inhibition of 65.2% to 78.2%.•All BuChE inhibitors were more potent than positive control galantamine.•Docking studies showed ...important structural portion for AChE and BuChE inhibition.•Compound 15 (Ki 1.71; EC50 > 30 μM) is a lead to treat Alzheimer’s disease.•New lead for the development of new drug to treat Alzheimer’s disease is reported.
A series of 25 amides (15 new) derived from (3aR)-(+)-sclareolide were prepared and subjected to Ellman’s assay to determine their efficacies as inhibitors for AChE or BuChE. Five amides (9, 13, 14, 15 and 17) caused inhibition of one of the enzymes greater than 60%; thereby those that inhibited BuChE were more active than positive control galantamine, and they showed better Ki values (1.07 to 8.49). In general, it was found that molecules holding a meta-substituted phenyl group showed a higher percentage of enzymatic inhibition. Molecular modelling calculations indicated the putative interactions of compounds with the amino acids residues of both enzymes AChE and BuChE. The cytotoxicity of compounds 9, 13, 14, 15 and 17 was evaluated against a non-malignant murine embryonic fibroblast cell line (NIH 3T3). Of special note is compound 15, as it presented the second-best Ki value for BuChE (1.71), was not cytotoxic (EC50 > 30 μM). Compound 15 also does not violate Lipinski rules, and showed permeability in the blood brain barrier, indicating that it can be considered a lead for the development of new drugs to treat Alzheimer’s disease.
This work describes the synthesis, characterization and in vitro anticancer activity of two platinum(II) complexes of the type Pt(L1)2(1,10-phen) 1 and Pt(L2)2(1,10-phen) 2, where ...L1 = 5-heptyl-1,3,4-oxadiazole-2-(3H)-thione, L2 = 5-nonyl-1,3,4-oxadiazole-2-(3H)-thione and 1,10-phen = 1,10-phenanthroline. As to the structure of these complexes, the X-ray structural analysis of 1 indicates that the geometry around the platinum(II) ion is distorted square-planar, where two 5-alkyl-1,3,4-oxadiazol-2-thione derivatives coordinate a platinum(II) ion through the sulfur atom. A chelating bidentate phenanthroline molecule completes the coordination sphere. We tested these complexes in two breast cancer cell lines, namely, MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). In both cells, the most lipophilic platinum compound, complex 2, was more active than cisplatin, one of the most widely used anticancer drugs nowadays. DNA binding studies indicated that such complexes are able to bind to ct-DNA with Kb values of 104 M−1. According to data from dichroism circular and fluorescence spectroscopy, these complexes appear to bind to the DNA in a non-intercalative, probably via minor groove. Molecular docking followed by semiempirical simulations indicated that these complexes showed favorable interactions with the minor groove of the double helix of ct-DNA in an A-T rich region. Thereafter, flow cytometry analysis showed that complex 2 induced apoptosis and necrosis in MCF-7 cells.
Two platinum(II) complexes with 5-alkyl-1,3,4-oxadiazol-2(3H)-thione derivatives were active against two tumor cell lines and induced apoptosis and necrosis in MCF-7 cells. Display omitted
•New Pt(II) complexes with 5-alkyl-1,3,4-oxadiazol-2(3H)-thione derivatives were prepared.•They were active against two tumor cell lines.•\Both complexes bind to ct-DNA with Kb values in the range of 104 M−1.•Molecular docking studies suggest that these complexes bind to the minor groove of DNA.•The most active complex induced apoptosis and necrosis in MCF-7 cells.
Summary
This article proposes a comparison between mathematical modeling and experimental results of the electric interactions of a synchronous and an induction generator. The electric system is ...composed by a synchronous generator operating in parallel with the induction generator, both through a common bus, connected to nonlinear loads. Measurements are made at several points for different system configurations presenting the repowering effect. The analysis of the harmonic flow and the sensitivity of the system parameters are performed. To make predictions in the system, a validated computational model with experimental data is proposed. The results obtained comparing the mathematical modeling and experimental tests show the increase of the active power by the induction generator, as well as the circulation of harmonic currents in the common bus. The results obtained through the computational model present predictions of load unbalance and increase in the system harmonic distortions. The sensitivity analysis confirms the induction generator influences on the system harmonic flow.
The human respiratory syncytial virus (hRSV) is the major cause of lower respiratory tract infection in children and elderly people worldwide. Its genome encodes 11 proteins including SH protein, ...whose functions are not well known. Studies show that SH protein increases RSV virulence degree and permeability to small compounds, suggesting it is involved in the formation of ion channels. The knowledge of SH structure and function is fundamental for a better understanding of its infection mechanism. The aim of this study was to model, characterize, and analyze the structural behavior of SH protein in the phospholipids bilayer environment. Molecular modeling of SH pentameric structure was performed, followed by traditional molecular dynamics (MD) simulations of the protein immersed in the lipid bilayer. Molecular dynamics with excited normal modes (MDeNM) was applied in the resulting system in order to investigate long time scale pore dynamics. MD simulations support that SH protein is stable in its pentameric form. Simulations also showed the presence of water molecules within the bilayer by density distribution, thus confirming that SH protein is a viroporin. This water transport was also observed in MDeNM studies with histidine residues of five chains (His22 and His51), playing a key role in pore permeability. The combination of traditional MD and MDeNM was a very efficient protocol to investigate functional conformational changes of transmembrane proteins that act as molecular channels. This protocol can support future investigations of drug candidates by acting on SH protein to inhibit viral infection.
Graphical Abstract
The ion channel of the human respiratory syncytial virus (hRSV) small hydrophobic protein (SH) transmembrane domainᅟ
Abstract
Background
This is the first study in Brazil that evaluates the prevalence of low renal function in the Brazilian population and associated factors, using biochemical measures.
Methods
This ...is a cross-sectional household-based epidemiological survey, the National Health Survey (PNS), conducted in 2014 and 2015. The explanatory variables were: sociodemographic characteristics, lifestyles, chronic diseases, anthropometry. The prevalence of kidney filtration rate (KFR) <60 ml / min / 1.73m2 was estimated, using Poisson regression to calculate the Prevalence Ratio Adjusted (RPaj) by age and gender.
Results
The prevalence of low renal function was 6.48% (95% CI 5.88-7.09). After adjusting remained associated: female (RPaj 1.4 CI (95% 1.16-1.68), age 45-59 years was RPaj = 7.3 (95% CI 3.8-14.1), 60 years or older RPaj = 33.6 (95% CI 17.8- 63.4), obesity RP 1.32 (95% CI 1.1-1.7), diabetes PR = 1.4 (95% CI 1.2-1.8), poor / very poor self-rated health PR = 1.5 (95% CI 1.2-1.9).
Conclusions
Renal function <60 ml / min / 1.73m2 was higher in females, increased with age, was associated with obesity, diabetes and poorer health assessment. CKD through biochemical tests and risk and protection factors are essential to support public health policies.
Key messages
The prevalence with laboratory data was 4 times higher than self-reported studies, showing the underreporting of low renal function in Brazil population. The primary care team should request simple biochemical tests, such as creatinine, routinely in the target population, especially the elderly, for prevention and early management of kidney diseases.
The β-glucosidases are enzymes essential for several industrial applications, especially in the field of plant structural polysaccharides conversion into bioenergy and bioproducts. In a recent study, ...we have provided a biochemical characterization of two hyperthermostable β-glucosidases from
Thermotoga petrophila
belonging to the families GH1 (
Tp
BGL1) and GH3 (
Tp
BGL3). Here, as part of a continuing investigation, the oligomeric state, the net charge, and the structural stability, at acidic pH, of the
Tp
BGL1 and
Tp
BGL3 were characterized and compared. Enzymatic activity is directly related to the balance between protonation and conformational changes. Interestingly, our results indicated that there were no significant changes in the secondary, tertiary and quaternary structures of the β-glucosidases at temperatures below 80 °C. Furthermore, the results indicated that both the enzymes are stable homodimers in solution. Therefore, the observed changes in the enzymatic activities are due to variations in pH that modify protonation of the enzymes residues and the net charge, directly affecting the interactions with ligands. Finally, the results showed that the two β-glucosidases displayed different pH dependence of thermostability at temperatures above 80 °C.
Tp
BGL1 showed higher stability at pH 6 than at pH 4, while
Tp
BGL3 showed similar stability at both pH values. This study provides a useful comparison of the structural stability, at acidic pH, of two different hyperthermostable β-glucosidases and how it correlates with the activity of the enzymes. The information described here can be useful for biotechnological applications in the biofuel and food industries.
Economic viability and eco-friendliness are important characteristics that make implants available to the population in a sustainable way. In this work, we evaluate the performance of a low-cost, ...widely available, and eco-friendly material (talc from soapstone) relative to reduced graphene oxide as reinforcement to brittle hydroxyapatite coatings. We employ a low-cost and straightforward technique, electrodeposition, to deposit the composite coatings on the titanium substrate. Corrosion, wear, and biocompatibility tests indicate that the reduced graphene oxide can be effectively replaced by talc without reducing the mechanical, anticorrosion, and biocompatible composite coatings properties. Our results indicate that talc from soapstone is a promising material for biomedical applications.
Display omitted
•We have employed a simple and cheap technique to produce biocomposite coatings.•HA/talc and HA/rGO coatings present improved mechanical properties.•HA/talc and HA/rGO coatings are biocompatible and induce bone maturation.•RGO can be successfully replaced by the low-cost talc from soapstone.
The Atlantic goliath grouper, Epinephelus itajara , is a critically endangered species, threatened by illegal fishing and the destruction of its habitats. A number of other closely related grouper ...species found in the western Atlantic are also fished intensively. While some countries apply rigorous legislation, illegal harvesting followed by the falsification of fish products, which impedes the correct identification of the species, is a common practice, allowing the catch to be marketed as a different grouper species. In this case, molecular techniques represent an important tool for the monitoring and regulation of fishery practices, and are essential for the forensic identification of a number of different species. In the present study, species-specific primers were developed for the Cytochrome Oxidase subunit I gene, which were applied in a multiplex PCR for the simultaneous identification of nine different species of Epinephelidae: Epinephelus itajara , E. quinquefasciatus , E. morio , Hyporthodus flavolimbatus , H. niveatus , Mycteroperca acutirostris , M. bonaci , M. marginata , and M. microlepis . Multiplex PCR is a rapid, reliable and cost-effective procedure for the identification of commercially-valuable endangered fish species, and may represent a valuable tool for the regulation and sustainable management of fishery resources.
The beta-glucosidases are enzymes essential for several industrial applications, especially in the field of plant structural polysaccharides conversion into bioenergy and bioproducts. In a recent ...study, we have provided a biochemical characterization of two hyperthermostable beta-glucosidases from Thermotoga petrophila belonging to the families GH1 (TpBGL1) and GH3 (TpBGL3). Here, as part of a continuing investigation, the oligomeric state, the net charge, and the structural stability, at acidic pH, of the TpBGL1 and TpBGL3 were characterized and compared. Enzymatic activity is directly related to the balance between protonation and conformational changes. Interestingly, our results indicated that there were no significant changes in the secondary, tertiary and quaternary structures of the beta-glucosidases at temperatures below 80 °C. Furthermore, the results indicated that both the enzymes are stable homodimers in solution. Therefore, the observed changes in the enzymatic activities are due to variations in pH that modify protonation of the enzymes residues and the net charge, directly affecting the interactions with ligands. Finally, the results showed that the two beta-glucosidases displayed different pH dependence of thermostability at temperatures above 80 °C. TpBGL1 showed higher stability at pH 6 than at pH 4, while TpBGL3 showed similar stability at both pH values. This study provides a useful comparison of the structural stability, at acidic pH, of two different hyperthermostable beta-glucosidases and how it correlates with the activity of the enzymes. The information described here can be useful for biotechnological applications in the biofuel and food industries.
PDF
