5-(3′,4′-Dihydroxyphenyl)-γ-Valerolactone Is a Substrate for Human Paraoxonase: A Novel Pathway in Flavan-3-ol Metabolism

Scope

Dietary flavan-3-ols are known to mediate cardiovascular benefits. Currently, it is assumed that the levels of flavan-3-ol catabolites detected in humans, 5-(3ʹ,4ʹ-dihydroxyphenyl)-γ-valerolactone (γVL) and 5-(3ʹ,4ʹ-dihydroxyphenyl)-γ-valeric acid (γVA), and their corresponding phase II metabolites, are determined exclusively by the action of the gut microbiome. However, a family of human proteins, paraoxonase (PON), can theoretically hydrolyze γVL metabolites into the corresponding γVAs. This study aims to determine if PON is involved in γVL and γVA metabolism in humans.

Methods and results

A rapid conversion of γVL into γVA is detected in serum ex vivo (half-life = 9.8 ± 0.3 min) that is catalyzed by PON1 and PON3 isoforms. Phase II metabolites of γVL are also reacted with PON in serum. Following an intake of flavan-3-ol in healthy males (n = 13), the profile of γVA metabolites detected is consistent with that predicted from the reactivity of γVL metabolites with PON in serum. Furthermore, common PON polymorphisms are evaluated to assess the use of γVL metabolites as biomarkers of flavan-3-ol intake.

Conclusion

PONs are involved in flavan-3-ol metabolic pathway in humans. PON polymorphisms have a minor contribution to inter-individual differences in the levels of γVL metabolites, without affecting their use as a nutritional biomarker.     

Nutritional biomarkers for objective dietary assessment

The accurate assessment of dietary exposure is important in investigating associations between diet and disease. Research in nutritional epidemiology, which has resulted in a large amount of information on associations between diet and chronic diseases in the last decade, relies on accurate assessment methods to identify these associations. However, most dietary assessment instruments rely to some extent on self-reporting, which is prone to systematic bias affected by factors such as age, gender, social desirability and approval. Nutritional biomarkers are not affected by these and therefore provide an additional, alternative method to estimate intake. However, there are also some limitations in their application: they are affected by inter-individual variations in metabolism and other physiological factors, and they are often limited to estimating intake of specific compounds and not entire foods. It is therefore important to validate nutritional biomarkers to determine specific strengths and limitations. In this perspective paper, criteria for the validation of nutritional markers and future developments are discussed.     

A Simple Route to 4-aryl and 4-hetaryl substituted 6-methyl-2,2-difluoro-1,3,2-(2H)-dioxaborines

4-(Het)aryl-2,2-difluoro-6-methyl-1,3,2-(2H)-dioxaborines 3a-3i, 6a-6c, 8 were prepared in a one-pot reaction from donor substituted arenes and hetarenes 2a-2i, 5a-5c, 7 , resp., by a boron trifluoride mediated acetoacetylation. With resorcinol dimethylether ( 11 ), diphenyl ether ( 13a ), and 1,3-phenoxy-propane ( 13b ) this acetoacetylation gives rise to the formation of bis-1,3,2-(2H)-dioxaborines 12, 14a , and 14b , respectively. From triphenylamine ( 9 ) a tris-1,3,2-(2H)-dioxaborine 10 has been obtained. Phloroglucinol trimethylether ( 15a ) is demethylated as well as acetylated and acetoacetylated at once to give a bis-1,3,2-(2H)-dioxaborine derivative 17 .     

Analysis of defect mechanisms in nonstoichiometric ceria–zirconia by the microwave cavity perturbation method

In this microwave study, the defect chemistry of ceria–zirconia solid solutions (CZO, Ce_1−yZr_yO_2−δ) was investigated at high temperatures by a resonant microwave method. Specifically, the effects of temperature and Zr content on the dielectric properties and defect chemistry mechanisms in CZO were analyzed. Experiments were performed on a series of different CZO powders (y = 0.2, 0.33, 0.50, 0.67). Measurements at 600°C and different oxygen partial pressures (p_O2 = 10⁻²⁶–0.2 bar) confirm a dominant n-type conduction of small-polarons in CZO due to the preferred formation of oxygen vacancies, which is also supported by a multimodal analysis. Polarization losses were found to be negligible in the GHz range. Furthermore, an increased relative permittivity was observed in CZO, which correlates with the concentration of oxygen vacancies in CZO. Our microwave study is the first to provide a comprehensive data set for the dielectric properties of CZO powder sample in a wide range of different conditions. In addition, the connection of dielectric properties to CZO defect chemistry mechanisms is presented. The results are in good agreement with findings in the literature and may contribute to a better understanding of microwave-based state diagnosis of CZO-based materials, as it discussed for three-way catalysts.     

Quantitative Standards of 4-O-Acetyl- and 9-O-Acetyl-N-Acetylneuraminic Acid for the Analysis of Plasma and Serum

N-Acetylneuraminic acid (sialic acid, Neu5Ac) is one of a large, diverse family of nine-carbon monosaccharides that play roles in many biological functions such as immune response. Neu5Ac has previously been identified as a potential biomarker for the presence and pathogenesis of cardiovascular disease (CVD), diabetes and cancer. More recent research has highlighted acetylated sialic acid derivatives, specifically Neu5,9Ac₂, as biomarkers for oral and breast cancers, but advances in analysis have been hampered due to a lack of commercially available quantitative standards. We report here the synthesis of 9-O- and 4-O-acetylated sialic acids (Neu5,9Ac₂ and Neu4,5Ac₂) with optimisation of previously reported synthetic routes. Neu5,9Ac₂ was synthesised in 1 step in 68 % yield. Neu4,5Ac₂ was synthesised in 4 steps in 39 % overall yield. Synthesis was followed by analysis of these standards via quantitative NMR (qNMR) spectroscopy. Their utilisation for the identification and quantification of specific acetylated sialic acid derivatives in biological samples is also demonstrated.