Brain-Targeted Proanthocyanidin Metabolites for Alzheimer's Disease Treatment

While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as limited knowledge regarding their bioavailability, metabolism and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer’s disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric (Po) forms. In this study we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ~400 nM. Most importantly we report for the first time that a biosynthetic epicatechin metabolite, 3’-O-methyl-epicatechin-5-O-β-glucuronide (3’-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3’-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in Alzheimer’s disease and other forms of dementia

Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota

Gut microbiota-related metabolites are potential clinical biomarkers for cardiovascular disease (CVD). Circulating succinate, a metabolite produced by both microbiota and the host, is increased in hypertension, ischemic heart disease, and type 2 diabetes. We aimed to analyze systemic levels of succinate in obesity, a major risk factor for CVD, and its relationship with gut microbiome. We explored the association of circulating succinate with specific metagenomic signatures in cross-sectional and prospective cohorts of Caucasian Spanish subjects. Obesity was associated with elevated levels of circulating succinate concomitant with impaired glucose metabolism. This increase was associated with specific changes in gut microbiota related to succinate metabolism: a higher relative abundance of succinate-producing Prevotellaceae (P) and Veillonellaceae (V), and a lower relative abundance of succinate-consuming Odoribacteraceae (O) and Clostridaceae (C) in obese individuals, with the (P + V/O + C) ratio being a main determinant of plasma succinate. Weight loss intervention decreased (P + V/O + C) ratio coincident with the reduction in circulating succinate. In the spontaneous evolution after good dietary advice, alterations in circulating succinate levels were linked to specific metagenomic signatures associated with carbohydrate metabolism and energy production with independence of body weight change. Our data support the importance of microbe-microbe interactions for the metabolite signature of gut microbiome and uncover succinate as a potential microbiota-derived metabolite related to CVD risk

Combining nuclear magnetic resonance spectroscopy and mass spectrometry in biomarker discovery

Metabolic profiling of biological specimens is emerging as a promising approach for discovering specific biomarkers in the diagnosis of a number of diseases. Amongst many analytical techniques, nuclear magnetic resonance spectroscopy and mass spectrometry are the most information-rich tools that enable high-throughput and global analysis of hundreds of metabolites in a single step. Although only one of the two techniques is utilized in a majority of metabolomics applications, there is a growing interest in combining the data from the two methods to effectively unravel the mammoth complexity of biological samples. In this article, current developments in nuclear magnetic resonance, mass spectrometry and multivariate statistical analysis methods are described. While some general applications that utilize the combination of the two analytical methods are presented briefly, the emphasis is laid on the recent applications of nuclear magnetic resonance and mass spectrometry methods in the studies of hepatopancreatobiliary and gastrointestinal malignancies. </jats:p

Condensed heterotricycles: potential metabolites of dibenz[b,f][I,4]oxazepine antidepressant, sintamil

The synthesis of several potential metabolites of the antidepressant, Sintamil (1) is described. Nitrolactams 3, 6 and 10, aminolactams 4, 7 and 11, and the aminoalkyl derivatives 8, 9, 12 and 13 have been described before [Indian J. Chem., 12 (T974), 227]. Treatment of 1 with H2O2 gave the N-oxide 2. Several syntheses of the desmethyl derivative 5 have been achieved : alkylation of 3 with N-(3-chloropropyl)-N-methylformamide followed by hydrolysis; demethylation of 1 with CNBr, followed by acid cleavage of the cyano group in 15 and with ethyl chloroformate, followed by treatment with HBr in acetic acid. Treatment of the intermediate urethane 16 from the last reaction with alcoholic alkali afforded the ring cleaved product 17. The methylaminopropyl lactam 5 was converted into the acetate 18 and urea 19. It was also reduced to the diamine 20. . Treatment of the chlorolactam 14 with the sodium salt of p-toluenesulphonamide led to thV derivative 21. Alkali-catalysed addition of lactam 3 to acrylonitrile gave 22; addition to methyl acrylate gave the ester 23 which was hydrolysed to the acid 24 on the one hand and reduced to the amino ester 28 on the other. Propionitrile 25 and propionic ester 26 were similarly prepared. N-(2-Chloro-5-nitrobenzoyl)-4-benzyloxy-2-hydroxyaniline (30) was cyclized to the lactam 31, which was aminoalkylated to 32. Treatment of 32 with hot acid cleaved the benzyl group to afford the phenolic lactam 33

Induced Amphotropic and Thermotropic Ionic Liquid Crystallinity in Phosphonium Halides: “Lubrication” by Hydroxyl Groups

The influence of covalently attaching hydroxymethylene to the methyl groups of methyl-tri-n-alkylphosphonium halides (where the alkyl chains are decyl, tetradecyl, or octadecyl and the halide is chloride or bromide) or adding methanol as a solute to the salts on their solid, liquid-crystalline (smectic A2), and isotropic phases has been investigated using a variety of experimental techniques. These structural and compositional changes are found to induce liquid crystallinity in some cases and to enhance the temperature range and lower the onset temperature of the liquid-crystalline phases in some others. The results are interpreted in terms of the lengths of the three n-alkyl chains attached to the phosphorus cation, the nature of the halide anion, the influence of H-bonding interactions at the head group regions of the layered phases, and other solvent−solute interactions. The fact that at least 1 molar equiv of methanol must be added to effect complete (isothermal) conversion of a solid methyl-tri-n-alkylphosphonium salt to a liquid crystal demonstrates a direct and strong association between individual methanol molecules and the phosphonium salts. Possible applications of such systems are suggested