A combined fragment-based virtual screening and STD-NMR approach for the identification of E-cadherin ligands

Cadherins promote cell-cell adhesion by forming homophilic interactions via their N-terminal extracellular domains. Hence, they have broad-ranging physiological effects on tissue organization and homeostasis. When dysregulated, cadherins contribute to different aspects of cancer progression and metastasis; therefore, targeting the cadherin adhesive interface with small-molecule antagonists is expected to have potential therapeutic and diagnostic value. Here, we used molecular docking simulations to evaluate the propensity of three different libraries of commercially available drug-like fragments (nearly 18,000 compounds) to accommodate into the Trp2 binding pocket of E-cadherin, a crucial site for the orchestration of the protein’s dimerization mechanism. Top-ranked fragments featuring five different aromatic chemotypes were expanded by means of a similarity search on the PubChem database (Tanimoto index >90%). Of this set, seven fragments containing an aromatic scaffold linked to an aliphatic chain bearing at least one amine group were finally selected for further analysis. Ligand-based NMR data (Saturation Transfer Difference, STD) and molecular dynamics simulations suggest that these fragments can bind E-cadherin mostly through their aromatic moiety, while their aliphatic portions may also diversely engage with the mobile regions of the binding site. A tetrahydro-β-carboline scaffold functionalized with an ethylamine emerged as the most promising fragment

Aromatic profile of white sweet semi-sparkling wine from Malvasia di Candia aromatica grapes

Malvasia di Candia aromatica is an aromatic white grape (Vitis vinifera L.) cultivar that grows in the Emilia-Romagna and Lombardy regions and is used for manufacturing sweet and dry white wines. A study of the gas chromatography analysis of the aromatic profile was carried out during the winemaking process for the production of a sweet semi-sparkling wine. At the end of the monitoring period, free monoterpenic and fermentative compounds characterised the aromatic profile of the wine. Linalool and nerol had a similar concentration, while the main fermentative compounds were the isoamyl alcohols, 2-phenylethanol, medium-chain fatty acids and their corresponding ethyl esters, and isoamyl acetate. All these compounds showed increasing trends during the fermentation process. The amount of linalool at the end of the monitoring period exceeded the threshold of perception, hence contributing to the floral scent of the wine. The higher alcohols (concentration up to 200 mg/L) and their esters also made a pleasant contribution to the aroma definition. Finally, the low temperature of fermentation helped to preserve the varietal aroma and enhanced the production of fermentative compounds, with a corresponding restraint of higher alcohols. This work is a first approach to a study of the sweet semi-sparkling wine (vino frizzante) obtained from Malvasia di Candia aromatica grapes. A more detailed investigation is required to understand how to improve the varietal and fermentative aromas of the wine

Pt-WOx/C Catalysts for α, β-Unsaturated Aldehydes Hydrogenation: An NMR Study of the Effect of the Reactant Adsorption on Activity and Selectivity

The selective hydrogenation of alpha,beta-unsaturated aldehydes is an ideal case for studying the structure-activity relationships in heterogeneous catalysis. In particular, cinnamaldehyde can be used as probe molecule for revealing the competition between hydrogenation of C=C and C=O bond. Here, we investigated the effect of the modification of some Pt supported on carbon catalysts by WOx species in cinnamaldehyde hydrogenation, as WOx species are reported to increase the adsorption and activation of the C=O group of alpha, beta-unsaturated aldehydes. Classical techniques used for correlating the catalyst activity and the selectivity to the characteristic of the materials (XRD, HAADF-STEM, XEDS mapping and XPS) have been coupled with NMR relaxometry, as innovative application, to disclose how the molecule approaches the catalyst surface. This indeed constitutes a crucial aspect that rule the catalytic activity. Therefore, an innovative, holistic approach has been used to consider the whole catalytic system

Aromatic Characterisation of Malvasia Odorosissima Grapevines and Comparison with Malvasia di Candia Aromatica

Malvasia odorosissima is an aromatic grapevine (Vitis vinifera L., 1753) variety that is often confused with Malvasia di Candia aromatica (Vitis vinifera L., 1753), despite the genetic information now available on the pedigree and genetic relationships linking the two varieties. In an effort to offer a contribution to fill this gap, also from an aromatic point of view, free and glycosylated aroma compounds were determined using the SPE extraction method, followed by GC-MS analysis in two consecutive vintages. The results have for the first time provided the aromatic characterisation of Malvasia odorosissima. Geraniol and its derivatives were the most abundant set of volatiles. In contrast to Malvasia di Candia aromatica and the other aromatic varieties, Malvasia odorosissima showed a very small amount of glycosylated volatiles, thus expressing its aromatic potential almost completely. The abundance of free terpenoids in the aromatic profile of Malvasia odorosissima, even higher than in Malvasia di Candia aromatica, is a main feature for the oenological exploitation of this variety, which is on the brink of extinction. In addition, the presence of rose oxides, found solely in Malvasia odorosissima, renders its aromatic profile more similar to that of White Muscat. This result is consistent with the parent-offspring relationship linking the two varieties that was recently ascertained

Determination of the binding epitope of RGD-peptidomimetics to \u3b1v\u3b23 and \u3b1IIb\u3b23 integrin-rich intact cells by NMR and computational studies

NMR experiments (transferred NOE and Saturation Transfer Difference) were used to shed light on the binding epitope of RGD peptidomimetics 1-3 with integrins \u3b1v\u3b23 and \u3b1IIb\u3b23, expressed on the membrane of ECV304 bladder cancer cells and human platelets, respectively. The NMR results were supported by docking calculations in the active sites of \u3b1v\u3b23 and \u3b1IIb\u3b23 integrin receptors and were compared to the results of competitive \u3b1v\u3b23 receptor binding assays and competitive ECV304 cell adhesion experiments. While cis RGD ligand 1 interacts mainly with the \u3b1 integrin subunit through its basic guanidine group, trans RGD ligands 2 and 3 are able to interact with both the \u3b1 and \u3b2 integrin subunits via an electrostatic clam

Biological Aspects, Advancements and Techno-Economical Evaluation of Biological Methanation for the Recycling and Valorization of CO2

Nowadays, sustainable and renewable energy production is a global priority. Over the past decade, several Power-to-X (PtX) technologies have been proposed to store and convert the surplus of renewable energies into chemical bonds of chemicals produced by different processes. CO2 is a major contributor to climate change, yet it is also an undervalued source of carbon that could be recycled and represents an opportunity to generate renewable energy. In this context, PtX technologies would allow for CO2 valorization into renewable fuels while reducing greenhouse gas (GHG) emissions. With this work we want to provide an up-to-date overview of biomethanation as a PtX technology by considering the biological aspects and the main parameters affecting its application and scalability at an industrial level. Particular attention will be paid to the concept of CO2-streams valorization and to the integration of the process with renewable energies. Aspects related to new promising technologies such as in situ, ex situ, hybrid biomethanation and the concept of underground methanation will be discussed, also in connection with recent application cases. Furthermore, the technical and economic feasibility will be critically analyzed to highlight current options and limitations for implementing a sustainable process

Ultrasound elastography assessment of skin involvement in systemic sclerosis: Lights and shadows

Objective. To assess skin elasticity in systemic sclerosis (SSc) by using a new imaging modality, ultrasound elastography (UE). Methods. Our study included 18 consecutive patients with SSc and 15 healthy controls. Modified Rodnan skin score, physical examination, and assessment of organ involvement were performed. UE was carried out on the middle forearm and on the fingers of the dominant arm. The echo signals recorded in real time during freehand operations of probe compression and relaxation produced images representing tissue elasticity, consisting of translucent colored bands superimposed on the B-mode ultrasonographic images. The color scale varied within a large band spectrum from red, indicative of soft and highly elastic tissue, to blue, which denoted hard and barely elastic tissue. Results. On the forearm of all patients, UE showed a homogeneous blue area corresponding to the dermis visualized in a B-mode ultrasonographic image; in controls, a blue pattern was never detected and a predominance of green with sporadic areas of pale blue was observed. At sequential evaluations, UE of fingers produced inconstant and changeable colored areas. Conclusion. The imaging pattern observed in the forearm of patients with SSc may represent the reduction of strain in the dermis clue to loss of elasticity. The variable pattern obtained by finger evaluation demonstrated that UE can assess skin involvement in SSc only in those areas where the dermis is known to be thicker and where the bone hyperreflection is minimal. Further studies are needed to confirm our results and determine the validity of this new imaging modality. (First Release June 15 2010; J Rheumatol 2010;37: 1688-91: doi:10.3899/jrheum.090974

Luminescence Lifetime-Based Sensing Platform Based on Cyclometalated Iridium(III) Complexes for the Detection of Perfluorooctanoic Acid in Aqueous Samples

Luminescence lifetimes are an attractive analytical method for detection due to its high sensitivity and stability. Iridium probes exhibit luminescence with long excited-state lifetimes, which are sensitive to the local environment. Perfluorooctanoic acid (PFOA) is listed as a chemical of high concern regarding its toxicity and is classified as a "forever chemical". In addition to strict limits on the presence of PFOA in drinking water, environmental contamination from industrial effluent or chemical spills requires rapid, simple, accurate, and cost-effective analysis in order to aid containment. Herein, we report the fabrication and function of a novel and facile luminescence sensor for PFOA based on iridium modified on gold surfaces. These surfaces were modified with lipophilic iridium complexes bearing alkyl chains, namely, IrC6 and IrC12, and Zonyl-FSA surfactant. Upon addition of PFOA, the modified surfaces IrC6-FSA@Au and IrC12-FSA @Au show the largest change in the red luminescence signal with changes in the luminescence lifetime that allow monitoring of PFOA concentrations in aqueous solutions. The platform was tested for the measurement of PFOA in aqueous samples spiked with known concentrations of PFOA and demonstrated the capacity to determine PFOA at concentrations &gt;100 μg/L (240 nM).</p

Exploration of ligand binding modes towards the identification of compounds targeting HuR : a combined STD-NMR and Molecular Modelling approach

Post-transcriptional processes have been recognised as pivotal in the control of gene expression, and impairments in RNA processing are reported in several pathologies (i.e., cancer and neurodegeneration). Focusing on RNA-binding proteins (RBPs), the involvement of Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs in the aetiology of various dysfunctions, has suggested the great potential of compounds able to interfere with the complex stability as an innovative pharmacological strategy for the treatment of numerous diseases. Here, we present a rational follow-up investigation of the interaction between ELAV isoform HuR and structurally-related compounds (i.e., favonoids and coumarins), naturally decorated with diferent functional groups, by means of STD-NMR and Molecular Modelling. Our results represent the foundation for the development of potent and selective ligands able to interfere with ELAV–RNA complexes