A novel cardenolide glycoside isolated from Xysmalobium undulatum reduces levels of the Alzheimer’s disease-associated β-amyloid peptides aβ42 in vitro

Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high risk of Alzheimer’s disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins from APPs, we previously screened a library of plant extracts and identified Xysmalobium undulaum (Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and identification of the active principles from the plant species using a bioassay-guided fractionation. Fractions and resulting pure compounds from the purification process of the extract of X. undulatum were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated glycosydated crotoxogenin (1), xysmalogenin-3, β-D-glucopyranoside (2), and crotoxigenin 3-Oglucopyranoside (3), were subsequently isolated and their structures elucidated using NMR and mass spectrometry. Compound 1, a novel cardenolide, and 2 significantly decreased the Aβ42 levels in a dose-dependent manner while compound 3 was inactive. In silico investigations identified the AD’s β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside moiety being of significance in binding to the enzyme active site. Our study provides the first report of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD treatment drugs.The University of Pretoria Post Graduate Research Support Bursary, South Africa; the Bio-Synergy Research Project; the Bio & Medical Technology Development Program of the Ministry of Science, ICT, and Future Planning through the National Research Foundation, Korea.http://www.mdpi.com/journal/pharmaceuticalspm2022BiochemistryChemistryGeneticsMicrobiology and Plant Patholog

Recreational fish-finders - an inexpensive alternative to scientific echo-sounders for unravelling the links between marine top predators and their prey

Studies investigating how mobile marine predators respond to their prey are limited due to the challenging nature of the environment. While marine top predators are increasingly easy to study thanks to developments in bio-logging technology, typically there is scant information on the distribution and abundance of their prey, largely due to the specialised nature of acquiring this information. We explore the potential of using single-beam recreational fish-finders (RFF) to quantify relative forage fish abundance and draw inferences of the prey distribution at a fine spatial scale. We compared fish school characteristics as inferred from the RFF with that of a calibrated scientific split-beam echo-sounder (SES) by simultaneously operating both systems from the same vessel in Algoa Bay, South Africa. Customized open-source software was developed to extract fish school information from the echo returns of the RFF. For schools insonified by both systems, there was close correspondence between estimates of mean school depth (R 2 = 0.98) and school area (R 2 = 0.70). Estimates of relative school density (mean volume backscattering strength; S v ) measured by the RFF were negatively biased through saturation of this system given its smaller dynamic range. A correction factor applied to the RFF-derived density estimates improved the comparability between the two systems. Relative abundance estimates using all schools from both systems were congruent at scales from 0.5 km to 18 km with a strong positive linear trend in model fit estimates with increasing scale. Although absolute estimates of fish abundance cannot be derived from these systems, they are effective at describing prey school characteristics and have good potential for mapping forage fish distribution and relative abundance. Using such relatively inexpensive systems could greatly enhance our understanding of predator-prey interactions

A cytotoxic bis(1,2,3-triazol-5-ylidene)carbazolide gold(III) complex targets DNA by partial intercalation

Abstract The syntheses of bis(triazolium)carbazole precursors and their corresponding coinage metal (Au, Ag) complexes are reported. For alkylated triazolium salts, di- or tetranuclear complexes with bridging ligands were isolated, while the bis(aryl) analogue afforded a bis(carbene) AuI-CNC pincer complex suitable for oxidation to the redox-stable [AuIII(CNC)Cl]⁺ cation. Although the ligand salt and the [AuIII(CNC)Cl]⁺ complex were both notably cytotoxic toward the breast cancer cell line MDA-MB-231, the AuIII complex was somewhat more selective. Electrophoresis, viscometry, UV-vis, CD and LD spectroscopy suggest the cytotoxic [AuIII(CNC)Cl]⁺ complex behaves as a partial DNA intercalator. In silico screening indicated that the [AuIII(CNC)Cl]⁺ complex can target DNA three-way junctions with good specificity, several other regular B-DNA forms, and Z-DNA. Multiple hydrophobic π-type interactions involving T and A bases appear to be important for B-form DNA binding, while phosphate O⋅⋅⋅Au interactions evidently underpin Z-DNA binding. The CNC ligand effectively stabilizes the AuIII ion, preventing reduction in the presence of glutathione. Both the redox stability and DNA affinity of the hit compound might be key factors underpinning its cytotoxicity in vitro

Plots for three scenarios, 1–3, representing three schools selected from the recreational fish-finder (RFF) outputs with different pixel skewness values: a) 2D scatter plots showing the influence of different combinations of mean volume backscattering strength (Sv) starting values and colour step values on the difference in Sv values (Sv diff) between the RFF and the scientific echosounder (SES) outputs (colour scale bar—low values indicate optimal estimates), cross-hatch denotes optimal colour step values at starting values of -65 dB; b) least-squares regressions between volume backscattering coefficients (sv¯) of the SES (transformed) and RFF outputs of the 36 matched schools using starting and colour step values for the RFF outputs as determined by the 2D scatter plot analyses, coefficients are given at the top of each plot and shaded areas denote the 95% confidence intervals; c) histograms showing the frequency of schools in 4 dB S_v bins for the SES-derived schools, the

<p>Plots for three scenarios, 1–3, representing three schools selected from the recreational fish-finder (RFF) outputs with different pixel skewness values: a) 2D scatter plots showing the influence of different combinations of mean volume backscattering strength (Sv) starting values and colour step values on the difference in Sv values (Sv diff) between the RFF and the scientific echosounder (SES) outputs (colour scale bar—low values indicate optimal estimates), cross-hatch denotes optimal colour step values at starting values of -65 dB; b) least-squares regressions between volume backscattering coefficients (<math><mrow><msub><mrow><mi>s</mi></mrow><mrow><mi>v</mi></mrow></msub></mrow><mo>¯</mo></math>) of the SES (transformed) and RFF outputs of the 36 matched schools using starting and colour step values for the RFF outputs as determined by the 2D scatter plot analyses, coefficients are given at the top of each plot and shaded areas denote the 95% confidence intervals; c) histograms showing the frequency of schools in 4 dB S_v bins for the SES-derived schools, the RFF-derived schools before application of a correction factor as predicted by the linear regression models (b), and the RFF-derived schools with this correction factor applied (RFF corr).</p

Flow diagram illustrating the workflow of FISH software showing the different steps in the processing phase (steps 1–3) and the review phase (step 4).

<p>Flow diagram illustrating the workflow of FISH software showing the different steps in the processing phase (steps 1–3) and the review phase (step 4).</p

Frequency of fish school encounter scenarios of the recreational fish-finder (RFF) and the scientific echo-sounder (SES) quantified by 500 m Elementary Distance Sampling Units (EDSU).

<p>Frequency of fish school encounter scenarios of the recreational fish-finder (RFF) and the scientific echo-sounder (SES) quantified by 500 m Elementary Distance Sampling Units (EDSU).</p

Least squares linear regressions showing the relationship between volume backscattering coefficients (sv¯) and mean school depth for the 36 matched schools insonified by the recreational fish-finder (RFF) and the scientific echosounder (SES).

<p>Shaded areas denote 95% confidence intervals.</p