Impact of a Water-Soluble Gallic Acid-Based Dendrimer on the Color-Stabilizing Mechanisms of Anthocyanins

project grant (PTDC/OCE-ETA/31250/2017) with financial support from FCT/MCTES through national funds and co-financed by FEDER, under the Partnership Agreement PT2020 (UID/QUI/50006/2019-POCI/01/0145/FEDER/007265). Financial support was also obtained from the Spanish Ministry of Science, Innovation and Universities (CTQ2015-69021-R and RTI2018-102212-B-I00), the Xunta de Galicia (GRC2014/040, ED431C 2018/30, and Centro Singular de Investigacion de Galicia Accreditation 2016-2019, ED431G/09) and the European Union (European Regional Development Fund-ERDF).The interaction of two anthocyanins with a water-soluble polyanionic dendrimer was studied through UV/Vis, stopped-flow, and NMR spectroscopy. Cyanidin-3-glucoside (cy3glc) revealed a stronger interaction than malvidin-3-glucoside (mv3glc) at pH 1 according to their apparent association constants. A higher color increased was also obtained for cy3glc at pH 3.5 as a result of this stronger interaction. A high-frequency chemical shift of the cy3glc aromatic protons suggest the formation of ionic pairs. The interaction parameters (K≈700 m−1, n≈295) indicated the binding of approximately two anthocyanin molecules by each sulfate group. The equilibrium and rate constants of cy3glc in the presence of dendrimer showed an increased stability of the flavylium cation and a higher protection of this species from hydration (pK′a and pKh increased almost one pH unit). The tuning and color stabilization of anthocyanins by using this dendrimer allow novel applications as colorimetric sensors for food packaging.authorsversionpublishe

Functional gallic acid-based dendrimers as synthetic nanotools to remodel amyloid-β-42 into noncytotoxic forms

The self-assembly of amyloid-β (Aβ) generates cytotoxic oligomers linked to the onset and progression of Alzheimer’s disease (AD). As many fundamental molecular pathways that control Aβ aggregation are yet to be unraveled, an important strategy to control Aβ cytotoxicity is the development of bioactive synthetic nanotools capable of interacting with the heterogeneous ensemble of Aβ species and remodel them into noncytotoxic forms. Herein, the synthesis of nanosized, functional gallic acid (Ga)-based dendrimers with a precise number of Ga at their surface is described. It is shown that these Ga-terminated dendrimers interact by H-bonding with monomeric/oligomeric Aβ species at their Glu, Ala, and Asp residues, promoting their remodeling into noncytotoxic aggregates in a process controlled by the Ga units. The multivalent presentation of Ga on the dendrimer surface enhances their ability to interact with Aβ, inhibiting the primary and secondary nucleation of Aβ fibrillization and disrupting the Aβ preformed fibrils.The authors acknowledge the financial support from the EC (FORECAST-668983), “Programa Operacional Regional do Norte”, “Fundo Social Europeu”, Norte2020 TERM&SC, for the PhD grant NORTE-08-5369-FSE-000044, the Spanish Ministry of Science and Innovation (RTI2018-102212-B-I00), the Xunta de Galicia (ED431C 2018/30; Centro singular de investigación de Galicia accreditation 2019−2022, ED431G 2019/03), European Regional Development Fund-ERDF, and the Galician Supercomputing Centre (CESGA) and the MAT2016-80266-R of the Spanish Ministry of Science and Innovation

Liver X Receptor Activation with an Intranasal Polymer Therapeutic Prevents Cognitive Decline without Altering Lipid Levels

The progressive accumulation of amyloid-beta (Aβ) in specific areas of the brain is a common prelude to late-onset of Alzheimer's disease (AD). Although activation of liver X receptors (LXR) with agonists decreases Aβ levels and ameliorates contextual memory deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits their clinical application. DMHCA (N,N-dimethyl-3β-hydroxycholenamide) is an LXR partial agonist that, despite inducing the expression of apolipoprotein E (main responsible of Aβ drainage from the brain) without increasing cholesterol/triglyceride levels, shows nil activity in vivo because of a low solubility and inability to cross the blood brain barrier. Herein, we describe a polymer therapeutic for the delivery of DMHCA. The covalent incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate esters produces an amphiphilic copolymer that efficiently self-assembles into nanometric micelles that exert a biological effect in primary cultures of the central nervous system (CNS) and experimental animals using the intranasal route. After CNS biodistribution and effective doses of DMHCA micelles were determined in nontransgenic mice, a transgenic AD-like mouse model of cerebral amyloidosis was treated with the micelles for 21 days. The benefits of the treatment included prevention of memory deterioration and a significant reduction of hippocampal Aβ oligomers without affecting plasma lipid levels. These results represent a proof of principle for further clinical developments of DMHCA delivery systems.Fil: Navas Guimaraes, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; ArgentinaFil: Lopez Blanco, Roi. Universidad de Santiago de Compostela; EspañaFil: Correa, Juan. Universidad de Santiago de Compostela; EspañaFil: Fernandez Villamarin, Marcos. Universidad de Santiago de Compostela; EspañaFil: Bistue Millon, Maria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; ArgentinaFil: Martino Adami, Pamela Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Kumar, Vijay. University of Colorado; Estados UnidosFil: Wempe, Michael F.. University of Colorado; Estados UnidosFil: Cuello, A. C.. McGill University; CanadáFil: Fernandez Megia, Eduardo. Universidad de Santiago de Compostela; EspañaFil: Bruno, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; Argentin

Unveiling an NMR-invisible fraction of polymers in solution by saturation transfer difference

The observation of signals in solution NMR requires nuclei with sufficiently large transverse relaxation times (T2). Otherwise, broad signals embedded in the baseline afford an invisible fraction of nuclei (IF). Based on the STD (saturation transfer difference) sequence, IF-STD is presented as a quick tool to unveil IF in the 1H NMR spectra of polymers. The saturation of a polymer in a region of the NMR spectrum with IF (very short 1H T2) results in an efficient propagation of the magnetization by spin diffusion through the network of protons to a visible–invisible interphase with larger 1H T2 (STDon). Subtracting this spectrum from one recorded without saturation (STDoff) produces a difference spectrum (STDoff-on), with the nuclei at the visible–invisible interphase, that confirms the presence of an IF. Analysis of a wide collection of polymers by IF-STD reveals IF more common than previously thought, with relevant IF figures when STD > 0.4% at 750 MHz. A fundamental property of the IF-STD experiment is that the signal is generated within a single state comprising polymer domains with different dynamics, as opposed to several states in exchange with different degrees of aggregation. Contrary to a reductionist visible–invisible dichotomy, our results confirm a continuous distribution of nuclei with diverse dynamics. Since nuclei observed (edited) by IF-STD at the visible–invisible interphase are in close spatial proximity to the IF (tunable with the saturation time), they emerge as a privileged platform from which gaining an insight into the IF itselfThis work was supported by the Spanish Ministry of Science and Innovation (RTI2018-102212-B-I00), the Xunta de Galicia (ED431C 2018/30, and Centro singular de investigación de Galicia accreditation 2019–2022, ED431G2019/03), Axencia Galega de Innovación (IN845D 2020/09), and the European Union (European Regional Development Fund-ERDF)S

Filtering the NMR Spectra of Mixtures by Coordination to Paramagnetic Cu2+

The paramagnetic spin relaxation (PSR) filter allows the selective NMR signal suppression of components in mixtures according to their complexation ability to a paramagnetic ion. It relies on the faster relaxation of nuclei in paramagnetic environments and thus is complementary to classical diffusion and relaxation filters. So far, the PSR filter has established Gd3+ as the sole PSR agent, restricting the paramagnetic filtering repertoire. Herein, we present Cu2+ as a robust PSR agent with characteristic filtering properties. While Gd3+ depends on unspecific ion-pair interactions with anionic components, Cu2+ stands out for filtering species via ordered coordination complexes. An evaluation of the paramagnetic effect of Cu2+ over more than 50 small molecules and polymers has unveiled different sensitivities to Cu2+ (especially high for pyridines, diamines, polyamines, and amino alcohols) and precise filtering conditions for mixtures (1H, COSY, and HMQC) that were challenged with a test bed of commercial drugs. The advantage of integrating Cu2+ and Gd3+ for the stepwise PSR filtering of complex mixtures is also shownThis work was supported by the Spanish Ministry of Science and Innovation (and PID2021-127684OB-I00), the Xunta de Galicia (ED431C 2018/30, and Centro singular de investigación de Galicia accreditation 2019–2022, ED431G2019/03), Axencia Galega de Innovación (IN845D 2020/09), and the European Union (European Regional Development Fund-ERDF).S

Studies towards the synthesis of the C29-C51 fragment of altohyrtin A

The synthesis of the highly substituted E and F pyran fragment 23 of altohyrtin A 1 from tri-O-benzyl-d-glucal 5 is described. The synthesis of a model compound 31 containing the altohyrtin A triene side-chain outlines the proposed strategy for the elaboration of the F pyran