Pomegranate's Neuroprotective Effects against Alzheimer's Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites.

Pomegranate shows neuroprotective effects against Alzheimer's disease (AD) in several reported animal studies. However, whether its constituent ellagitannins and/or their physiologically relevant gut microbiota-derived metabolites, namely, urolithins (6H-dibenzo[b,d]pyran-6-one derivatives), are the responsible bioactive constituents is unknown. Therefore, from a pomegranate extract (PE), previously reported by our group to have anti-AD effects in vivo, 21 constituents, which were primarily ellagitannins, were isolated and identified (by HPLC, NMR, and HRESIMS). In silico computational studies, used to predict blood-brain barrier permeability, revealed that none of the PE constituents, but the urolithins, fulfilled criteria required for penetration. Urolithins prevented ß-amyloid fibrillation in vitro and methyl-urolithin B (3-methoxy-6H-dibenzo[b,d]pyran-6-one), but not PE or its predominant ellagitannins, had a protective effect in Caenorhabditis elegans post induction of amyloid ß(1-42) induced neurotoxicity and paralysis. Therefore, urolithins are the possible brain absorbable compounds which contribute to pomegranate's anti-AD effects warranting further in vivo studies on these compounds.

Phenolic constituents of Carex vulpinoidea seeds and their tyrosinase inhibitory activities.

Two new phenolics, a stilbenoid, vulpinoideol A (1), and a chalcone, vulpinoideol B (2), along with ten known compounds (3-12) were isolated from Carex vulpinoidea Michx. seeds. The structures of compounds 1-12 were elucidated based on spectrometric and spectroscopic analyses including HRESIMS, 1D and 2D NMR data. All compounds were evaluated for their tyrosinase enzyme inhibitory activities.

Structure Activity Related, Mechanistic, and Modeling Studies of Gallotannins containing a Glucitol-Core and α-Glucosidase.

Gallotannins containing a glucitol core, which are only produced by members of the maple (Acer) genus, are more potent α-glucosidase inhibitors than the clinical drug, acarbose. While this activity is influenced by the number of substituents on the glucitol core (e.g. more galloyl groups leads to increased activity), the mechanisms of inhibitory action are not known. Herein, we investigated ligand-enzyme interactions and binding mechanisms of a series of 'glucitol-core containing gallotannins (GCGs)' against the α-glucosidase enzyme. The GCGs included ginnalins A, B and C (containing two, one, and one galloyl/s, respectively), maplexin F (containing 3 galloyls) and maplexin J (containing 4 galloyls). All of the GCGs were noncompetitive inhibitors of α-glucosidase and their interactions with the enzyme were further explored using biophysical and spectroscopic measurements. Thermodynamic parameters (by isothermal titration calorimetry) revealed a 1:1 binding ratio between GCGs and α-glucosidase. The binding regions between the GCGs and α-glucosidase, probed by a fluorescent tag, 1,1'-bis(4-anilino-5-napththalenesulfonic acid, revealed that the GCGs decreased the hydrophobic surface of the enzyme. In addition, circular dichroism analyses showed that the GCGs bind to α-glucosidase and lead to loss of the secondary α-helix structure of the protein. Also, molecular modeling was used to predict the binding site between the GCGs and the α-glucosidase enzyme. This is the first study to evaluate the mechanisms of inhibitory activities of gallotannins containing a glucitol core on α-glucosidase.

New Gallotannin and other Phytochemicals from Sycamore Maple (Acer pseudoplatanus) Leaves.

The maple (Acer) genus is a reported source of bioactive (poly)phenols, including gallotannins, but several of its members, such as the sycamore maple (A. pseudoplatanus), remain uninvestigated. Herein, thirty-nine compounds, including a new gallotannin, 1,2,3-tri-O-galloyl-6-O-(p-hydroxybenzoyl)-ß-D- glucopyranoside (1), and thirty-eight (2-39) known compounds, consisting of four gallotannins, one ellagitannin, thirteen flavonoids, eight hydroxycinnamic acids, ten benzoic acid derivatives, and two sesquiterpenoids, were isolated from sycamore maple leaves. Their structures were determined based on NMR and mass spectral analyses. The isolates were evaluated for α-glucosidase inhibitory and antioxidant activities. Among the isolates, the gallotannins were the most potent α-glucosidase inhibitors with thirteen-fold more potent activity compared with the clinical drug, acarbose (IC50 = 16-31 vs. 218 µM). Similarly, the gallotannins showed the highest antioxidant activities, followed by the other phenolic sub-classes, while the sesquiterpenoids were inactive.

A comparative study of hollow copper sulfide nanoparticles and hollow gold nanospheres on degradability and toxicity.

Gold and copper nanoparticles have been widely investigated for photothermal therapy of cancer. However, degradability and toxicity of these nanoparticles remain concerns. Here, we compare hollow CuS nanoparticles (HCuSNPs) with hollow gold nanospheres (HAuNS) in similar particle sizes and morphology following intravenous administration to mice. The injected pegylated HCuSNPs (PEG-HCuSNPs) are eliminated through both hepatobiliary (67 percentage of injected dose, %ID) and renal (23 %ID) excretion within one month postinjection. By contrast, 3.98 %ID of Au is excreted from liver and kidney within one month after iv injection of pegylated HAuNS (PEG-HAuNS). Comparatively, PEG-HAuNS are almost nonmetabolizable, while PEG-HCuSNPs are considered biodegradable nanoparticles. PEG-HCuSNPs do not show significant toxicity by histological or blood chemistry analysis. Principal component analysis and 2-D peak distribution plots of data from matrix-assisted laser desorption ionization-time-of-flight imaging mass spectrometry (MALDI-TOF IMS) of liver tissues demonstrated a reversible change in the proteomic profile in mice receiving PEG-HCuSNPs. This is attributed to slow dissociation of Cu ion from CuS nanoparticles along with effective Cu elimination for maintaining homeostasis. Nonetheless, an irreversible change in the proteomic profile is observed in the liver from mice receiving PEG-HAuNS by analysis of MALDI-TOF IMS data, probably due to the nonmetabolizability of Au. This finding correlates with the elevated serum lactate dehydrogenase at 3 months after PEG-HAuNS injection, indicating potential long-term toxicity. The comparative results between the two types of nanoparticles will advance the development of HCuSNPs as a new class of biodegradable inorganic nanomaterials for photothermal therapy.