Transacylation and hydrolysis of the acyl glucuronides of ibuprofen and its α-methyl-substituted analogues investigated by H NMR spectroscopy and computational chemistry: Implications for drug design.

Drugs and drug metabolites containing a carboxylic-acid moiety can undergo in vivo conjugation to form 1-β-O-acyl-glucuronides (1-β-O-AGs). In addition to hydrolysis, these conjugates can undergo spontaneous acyl migration, and anomerisation reactions, resulting in a range of positional isomers. Facile transacylation has been suggested as a mechanism contributing to the toxicity of acyl glucuronides, with the kinetics of these processes thought to be a factor.

Lifestyle and socioeconomic determinants of diabetes: Evidence from country-level data.

Objective: The objectives of the study is to investigate the global socioeconomic risk factors associated with diabetes prevalence using evidence from available country-level data.

Design: A cross-sectional study based on (2010 & 2019) countrywide Health Nutrition and Population Statistics data.

Population: People ages 20-79 who have diabetes.

Kinetic modelling of acyl glucuronide and glucoside reactivity and development of structure-property relationships.

Acyl glucuronide metabolites have been implicated in the toxicity of several carboxylic acid-containing drugs, and the rate of their degradation via intramolecular transacylation and hydrolysis has been associated with the degree of protein adduct formation. Although not yet proven, the formation of protein adducts in vivo - and subsequent downstream effects - has been proposed as a mechanism of toxicity for carboxylic acid-containing xenobiotics capable of forming acyl glucuronides. A structurally-related series of metabolites, the acyl glucosides, have also been shown to undergo similar degradation reactions and consequently the potential to display a similar mode of toxicity.

Metabolic phenotype modulation by caloric restriction in a lifelong dog study.

Modeling aging and age-related pathologies presents a substantial analytical challenge given the complexity of gene-environment influences and interactions operating on an individual. A top-down systems approach is used to model the effects of lifelong caloric restriction, which is known to extend life span in several animal models. The metabolic phenotypes of caloric-restricted (CR; n = 24) and pair-housed control-fed (CF; n = 24) Labrador Retriever dogs were investigated by use of orthogonal projection to latent structures discriminant analysis (OPLS-DA) to model both generic and age-specific responses to caloric restriction from the ¹H NMR blood serum profiles of young and older dogs.

Colonization-induced host-gut microbial metabolic interaction.

Unlabelled: The gut microbiota enhances the host's metabolic capacity for processing nutrients and drugs and modulate the activities of multiple pathways in a variety of organ systems. We have probed the systemic metabolic adaptation to gut colonization for 20 days following exposure of axenic mice (n = 35) to a typical environmental microbial background using high-resolution (1)H nuclear magnetic resonance (NMR) spectroscopy to analyze urine, plasma, liver, kidney, and colon (5 time points) metabolic profiles. Acquisition of the gut microbiota was associated with rapid increase in body weight (4%) over the first 5 days of colonization with parallel changes in multiple pathways in all compartments analyzed.

Synthesis of a series of phenylacetic acid 1-β-O-acyl glucosides and comparison of their acyl migration and hydrolysis kinetics with the corresponding acyl glucuronides.

We report the synthesis of the 1-β-O-acyl glucoside conjugates of phenylacetic acid (PAA), R- and S-α-methyl-PAA and α,α'-dimethyl-PAA, and measurement of their transacylation and hydrolysis reactivity by NMR methods. These are analogues of acyl glucuronides, the transacylation kinetics of which could be important in adverse drug effects. One aim of this work was to investigate whether, as previously postulated, the free carboxylate group of the acyl glucuronides plays a part in the mechanism of the internal acyl migration.

Self-modeling curve resolution recovery of temporal metabolite signal modulation in NMR spectroscopic data sets: application to a life-long caloric restriction study in dogs.

A novel model-free statistical approach (self modeling curve resolution, SMCR) has been applied to recover biochemical information from complex overlapping signals in (1)H NMR spectra of blood serum in a long-term study of caloric restriction (CR) in the dog (n = 24 control fed (CF) and n = 24 CR animals). A new statistical spectroscopic construct, the spectrotype, is proposed which is a spectroscopic subset description or component of a metabolic phenotype. Characterization of the (1)H NMR profiles according to their evolutionary contribution of each spectrotype gives clues to the kinetics of the macro-biochemical response profiles and the identity of the underlying biochemical constituents, governing the evolutionary global response to an intervention.