Metabolomic profiling of brain from infants who died from Sudden Infant Death Syndrome reveals novel predictive biomarkers.

OBJECTIVE: Sudden Infant Death Syndrome (SIDS) is defined as the sudden death of an infant <1 year of age that cannot be explained following a thorough investigation. Currently, no reliable clinical biomarkers are available for the prediction of infants who will die of SIDS. STUDY DESIGN: This study aimed to profile the medulla oblongata from postmortem human brain from SIDS victims (n=16) and compare their profiles with that of age-matched controls (n=7). RESULTS: Using LC-Orbitrap-MS, we detected 12 710 features in electrospray ionization positive (ESI+) mode and 8243 in ESI- mode from polar extracts of brain. Five features acquired in ESI+ mode produced a predictive model for SIDS with an area under the receiver operating characteristic curve (AUC) of 1 (confidence interval (CI): 0.995-1) and a predictive power of 97.4%. Three biomarkers acquired in ESI- mode produced a predictive model with an AUC of 0.866 (CI: 0.767-0.942) and a predictive power of 77.6%. We confidently identified 5 of these features (l-(+)-ergothioneine, nicotinic acid, succinic acid, adenosine monophosphate and azelaic acid) and putatively identify another 4 out of the 15 in total. CONCLUSIONS: This study underscores the potential value of metabolomics for studying SIDS. Further characterization of the metabolome of postmortem SIDS brains could lead to the identification of potential antemortem biomarkers for novel prevention strategies for SIDS.

Metabolomics reveals novel biomarkers of illegal 5-nitromimidazole treatment in pigs. Further evidence of drug toxicity uncovered.

The aim of the study was to investigate the potential of a metabolomics platform to distinguish between pigs treated with ronidazole, dimetridazole and metronidazole and non-medicated animals (controls), at two withdrawal periods (day 0 and 5). Livers from each animal were biochemically profiled using UHPLC-QTof-MS in ESI+ mode of acquisition. Several Orthogonal Partial Least Squares-Discriminant Analysis models were generated from the acquired mass spectrometry data. The models classified the two groups control and treated animals. A total of 42 ions of interest explained the variation in ESI+. It was possible to find the identity of 3 of the ions and to positively classify 4 of the ionic features, which can be used as potential biomarkers of illicit 5-nitroimidazole abuse. Further evidence of the toxic mechanisms of 5-nitroimidazole drugs has been revealed, which may be of substantial importance as metronidazole is widely used in human medicine.

New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish.

Azaspiracid (AZA) poisoning was unknown until 1995 when shellfish harvested in Ireland caused illness manifesting by vomiting and diarrhoea. Further in vivo/vitro studies showed neurotoxicity linked with AZA exposure. However, the biological target of the toxin which will help explain such potent neurological activity is still unknown. A region of Irish coastline was selected and shellfish were sampled and tested for AZA using mass spectrometry. An outbreak was identified in 2010 and samples collected before and after the contamination episode were compared for their metabolite profile using high resolution mass spectrometry. Twenty eight ions were identified at higher concentration in the contaminated samples. Stringent bioinformatic analysis revealed putative identifications for seven compounds including, glutarylcarnitine, a glutaric acid metabolite. Glutaric acid, the parent compound linked with human neurological manifestations was subjected to toxicological investigations but was found to have no specific effect on the sodium channel (as was the case with AZA). However in combination, glutaric acid (1 mM) and azaspiracid (50 nM) inhibited the activity of the sodium channel by over 50%. Glutaric acid was subsequently detected in all shellfish employed in the study. For the first time a viable mechanism for how AZA manifests itself as a toxin is presented.

Chronic treatment with a stable obestatin analog significantly alters plasma triglyceride levels but fails to influence food intake; fluid intake; body weight; or body composition in rats.

Obestatin (OB(1-23) is a 23 amino acid peptide encoded on the preproghrelin gene, originally reported to have metabolic actions related to food intake, gastric emptying and body weight. The biological instability of OB(1-23) has recently been highlighted by studies demonstrating its rapid enzymatic cleavage in a number of biological matrices. We assessed the stability of both OB(1-23) and an N-terminally PEGylated analog (PEG-OB(1-23)) before conducting chronic in vivo studies. Peptides were incubated in rat liver homogenate and degradation monitored by LC-MS. PEG-OB(1-23) was approximately 3-times more stable than OB(1-23). Following a 14 day infusion of Sprague-Dawley rats with 50 nmol/kg/day of OB(1-23) or a N-terminally PEGylated analog (PEG-OB(1-23)), we found no changes in food/fluid intake, body weight and plasma glucose or cholesterol between groups. Furthermore, morphometric liver, muscle and white adipose tissue (WAT) weights and tissue triglyceride concentrations remained unaltered between groups. However, with stabilized PEG-OB(1-23) we observed a 40% reduction in plasma triglycerides. These findings indicate that PEG-OB(1-23) is an OB(1-23) analog with significantly enhanced stability and suggest that obestatin could play a role in modulating physiological lipid metabolism, although it does not appear to be involved in regulation of food/fluid intake, body weight or fat deposition.

Investigation of acetyl migrations in furanosides.

Standard reaction conditions for the desilylation of acetylated furanoside (riboside, arabinoside and xyloside) derivatives facilitate acyl migration. Conditions which favour intramolecular and intermolecular mechanisms have been identified with intermolecular transesterifications taking place under mild basic conditions when intramolecular orthoester formations are disfavoured. In acetyl ribosides, acyl migration could be prevented when desilylation was catalysed by cerium ammonium nitrate.