Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

Alzheimer's disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H-NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains

Anti-multiple myeloma potential of secondary metabolites from Hibiscus sabdariffa

Multiple myeloma (MM) belongs to hematological cancers and its incidence is increasing worldwide. Despite recent advances in its therapy, MM still causes many deaths every year. In fact, current therapies sometimes fail and are associated with severe adverse eects, including neurotoxicity. As a part of our ongoing efforts to discover new potential therapies against MM, we prepared Hibiscus sabdariffa extracts obtained by a microwave-assisted solvent extraction and investigate their activity by in vitro assays on the RPMI-8226 cell line. The bioguided fractionation of the crude ethanolic extract allowed the identification of HsFC as the most effective extract. We assessed cell viability (MTT and Tripan blue test), cell migration (Boyden chamber assay), and neurotoxicity (DRG neurotoxicity assay). The promising results prompted us to further fractionate HsFC and we obtained two molecules effective against RPMI-8226 cells without neurotoxic effects at their active concentrations. Moreover, both compounds are able to significantly reduce cell migration

Metaphors as Knowledge Activators in Data Visualizations: the case of the Archipelago of Calvino's literary works.

In this paper we present the outcomes of a collaboration between scholars and designers aimed at exploring the potentials of data visualization in support to the creation of literary critique. By exploiting action research, we envisioned a methodological integration between data visualization, design and literary critique aimed at the representation of humanistic data and knowledge. In our work we made an extensive use of the visual metaphors (the natural landscape), with the aim of activating domain experts’ knowledge and externalizing inconsistent and ill-defined information. In conclusion we argue that similar methodological integrations are important contributions that communication designers can bring to the field of Digital Humanities

New insight into pectin effects on mesophyll conductance in four species of deciduous Forest

The amount of pectin in the cell wall is considered a critical element regulating cell wall porosity. Thus, it is likely to influence the diffusional processes particularly that from the substomatal cavities to the carboxylation sites in the chloroplast stroma (i.e. mesophyll conductance, gm). We analyzed in four deciduous species (Acer campestre, Crateaugus monogyna, Corylus avellana, Quercus robur) the correlation between pectin and g m in two phase of leaves development (i.e. mature green leaves and senescent leaves). Results showed that in A. campestre, C. monogyna and Q. robur to higher value of pectin in mature green leaves corresponded the higher g m value. Taking into account this result, we can assume that a higher amount of pectins is associated to an increased cell wall hydrophilicity and elasticity, thus increasing gm because CO2 molecules cross the wall dissolved in water. An opposite behavior was observed in C. avellana

Secondary metabolites profile and physiological leaf traits in wild and cultivated Corylus avellana under different nutritional status

Leaf secondary metabolites production and physiological leaf traits were analyzed in Corylus avellana wild type (WT) and cultivar (cv. ‘Tonda Gentile Trilobata’, TGT) under different nutrient supplies. Three treatments were applied: control treatment with no fertilizer supply (WTC and TGTC), low nutrient treatment (WTLN and TGTLN) and high nutrient treatment (WTHN and TGTHN). The analysis of leaf extracts showed a higher concentration of Quercitrin and Myricitrin, with the highest concentrations of both the compounds in WT than TGT. This result can be related to the ecological role of flavonoids, including also antimicrobial properties, which resulted more useful in the understory forest form which hazelnut wild type originates. Therefore, their lower concentration in TGT can be relate to the genetic background of TGT cultivar with a lesser intrinsic need to produce such compounds and justified by a usual growth under more controlled environmental conditions, including also pest and disease control

Anti-multiple myeloma potential of secondary metabolites from hibiscus sabdariffa—part 2

Multiple Myeloma (MM) is an aggressive tumor causing millions of deaths every year and currently available therapies are often unsuccessful or correlated with severe side effects. In our previous work we demonstrated that the Hibiscus sabdariffa hydroalcoholic extract inhibits the growth of the MM cell line and we isolated two metabolites responsible for the activity: Hib-ester and Hib-carbaldehyde. Herein we report their interaction with proteasome, one of the main targets in the fight against MM. The molecular modelling study outlined a good interaction of both compounds with the target and these results prompted us to investigate their potential to inhibit proteasome. Metabolites were then isolated from the calyces and an extract with a high content of Hib-ester and Hib-carbaldehyde was prepared. An anticancer profile was drawn, evaluating apoptosis, autophagy and proteasome inhibition, with the anticancer properties being mainly attributed to the Hib-ester and Hib-carbaldehyde, while the proteasome inhibition of the extract could also be ascribed to the presence of anthocyanins, a class of secondary metabolites already known for their proteasome inhibitory activity

Anti-multiple myeloma potential of secondary metabolites from Hibiscus sabdariffa

Multiple myeloma (MM) belongs to hematological cancers and its incidence is increasing worldwide. Despite recent advances in its therapy, MM still causes many deaths every year. In fact, current therapies sometimes fail and are associated with severe adverse effects, including neurotoxicity. As a part of our ongoing efforts to discover new potential therapies against MM, we prepared Hibiscus sabdariffa extracts obtained by a microwave-assisted solvent extraction and investigate their activity by in vitro assays on the RPMI-8226 cell line. The bioguided fractionation of the crude ethanolic extract allowed the identification of HsFC as the most effective extract. We assessed cell viability (MTT and Tripan blue test), cell migration (Boyden chamber assay), and neurotoxicity (DRG neurotoxicity assay). The promising results prompted us to further fractionate HsFC and we obtained two molecules effective against RPMI-8226 cells without neurotoxic effects at their active concentrations. Moreover, both compounds are able to significantly reduce cell migration