Biology subjects

Serpell, C.

Publications and source records attributed to Serpell, C..

4 recordsLinked to original sources

bioRxiv2025

Identification of molecular pathways involved in the anti-liver cancer activity of madecassic acid

Natural products are a time-tested source of medicinal compounds, and there is huge interest in discovery of new drugs from plant sources. However, in many cases the effects are not as well understood, strong, or selective, as would be hoped. An example of this is madecassic acid (MA), which has promising activity against liver cancer, activity which can be improved through chemical modifications, although a molecular understanding of its mechanism of action is unknown. In this report we have used chemical proteomics to identify the proteins with which madecassic interacts in liver cancer cells, and used RNAseq to support those findings, as well as showing more precisely how chemical modifications can focus and amplify MA activity. Our results show that madecassic acid interacts with a number of proteins relating to metabolism, nucleic acid processing, and protein folding, which have been previously identified as linked to liver cancer. This provides a route from phenotypic- to target based-drug discovery and develop new potential treatments for a globally challenging disease.

pharmacology and toxicology↗

bioRxiv2025

Regioselectively Acetylated Silybin Derivatives and their Cytotoxic Activity in Liver Cancer Cells

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=48 SRC="FIGDIR/small/638106v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@13744c8org.highwire.dtl.DTLVardef@184bb9borg.highwire.dtl.DTLVardef@138f442org.highwire.dtl.DTLVardef@2c45ca_HPS_FORMAT_FIGEXP M_FIG C_FIG Natural products continue to serve as a valuable source of starting points for therapeutic agents. Six silybin derivatives have been synthesized and tested in vitro for their cytotoxic effect on the human hepatocellular carcinoma line HepG2 using the MTT assay. Results indicate that the 3,5,7,20,23-penta-O-acetyl-2,3-dehydrosilybin possesses a stronger cytotoxic effect than that of the parent silybin by a factor of 12. This compound was further evaluated for its cytotoxic activity on Hep3B, Huh7, and Huh7R hepatocellular carcinoma cell lines, giving similar potencies, arresting the cell cycle at S phase and causing apoptosis. These results illustrate the potential of silybin derivatives as therapeutics against liver cancer.

pharmacology and toxicology↗

bioRxiv2020

Three-dimensional reconstruction of individual helical nano-filament structures from atomic force microscopy topographs

Atomic force microscopy, AFM, is a powerful tool that can produce detailed topographical images of individual nano-structures with a high signal-to-noise ratio without the need for ensemble averaging. However, the application of AFM in structural biology has been hampered by the tip-sample convolution effect, which distorts images of nano-structures, particularly those that are of similar dimensions to the cantilever probe tips used in AFM. Here we show that the tip-sample convolution results in a feature-dependent and non-uniform distribution of image resolution on AFM topographs. We show how this effect can be utilised in structural studies of nano-sized upward convex objects such as spherical or filamentous molecular assemblies deposited on a flat surface, because it causes magnification of such objects in AFM topographs. Subsequently, this enhancement effect is harnessed through contact-point based deconvolution of AFM topographs. Here, the application of this approach is demonstrated through the 3D reconstruction of the surface envelope of individual helical amyloid filaments without the need of cross-particle averaging using the contact-deconvoluted AFM topographs. Resolving the structural variations of individual macromolecular assemblies within inherently heterogeneous populations is paramount for mechanistic understanding of many biological phenomena such as amyloid toxicity and prion strains. The approach presented here will also facilitate the use of AFM for high-resolution structural studies and integrative structural biology analysis of single molecular assemblies.

biophysics↗

bioRxiv2020

Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly

Amyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-curve based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.

biophysics↗