Maximum entropy modeling of metabolic networks by constraining growth-rate moments predicts coexistence of phenotypes.

In this work maximum entropy distributions in the space of steady states of metabolic networks are considered upon constraining the first and second moments of the growth rate. Coexistence of fast and slow phenotypes, with bimodal flux distributions, emerges upon considering control on the average growth (optimization) and its fluctuations (heterogeneity). This is applied to the carbon catabolic core of Escherichia coli where it quantifies the metabolic activity of slow growing phenotypes and it provides a quantitative map with metabolic fluxes, opening the possibility to detect coexistence from flux data. A preliminary analysis on data for E. coli cultures in standard conditions shows degeneracy for the inferred parameters that extend in the coexistence region.

Acetyl L-carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: An in vivo assessment.

Verapamil is a Ca2+ channel blocker and is highly prescribed as an anti-anginal, antiarrhythmic and antihypertensive drug. Ketamine, an antagonist of the Ca2+ -permeable N-methyl-d-aspartate-type glutamate receptors, is a pediatric anesthetic. Previously we have shown that acetyl l-carnitine (ALCAR) reverses ketamine-induced attenuation of heart rate and neurotoxicity in zebrafish embryos. Here, we used 48 h post-fertilization zebrafish embryos that were exposed to relevant drugs for 2 or 4 h. Heart beat and overall development were monitored in vivo. In 48 h post-fertilization embryos, 2 mm ketamine reduced heart rate in a 2 or 4 h exposure and 0.5 mm ALCAR neutralized this effect. ALCAR could reverse ketamine's effect, possibly through a compensatory mechanism involving extracellular Ca2+ entry through L-type Ca2+ channels that ALCAR is known to activate. Hence, we used verapamil to block the L-type Ca2+ channels. Verapamil was more potent in attenuating heart rate and inducing morphological defects in the embryos compared to ketamine at specific times of exposure. ALCAR reversed cardiotoxicity and developmental toxicity in the embryos exposed to verapamil or verapamil plus ketamine, even in the presence of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester, an inhibitor of intracellular Ca2+ release suggesting that ALCAR acts via effectors downstream of Ca2+ . In fact, ALCAR's protective effect was blunted by oligomycin A, an inhibitor of adenosine triphosphate synthase that acts downstream of Ca2+ during adenosine triphosphate generation. We have identified, for the first time, using in vivo studies, a downstream effector of ALCAR that is critical in abrogating ketamine- and verapamil-induced developmental toxicities. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Energy expenditure and oxygen consumption as novel biomarkers of obesity-induced cardiac disease in rats.

The purpose of the present study was to determine calorimetric parameters to predict obesity adverse effects on oxidative stress and cardiac energy metabolism. Male Wistar 24 rats were divided into three groups (n = 8): given standard chow and water (C), receiving standard chow and 30% sucrose in its drinking water (S), and given sucrose-rich diet and water (SRD). After 45 days, both S and SRD rats had obesity, serum oxidative stress, and dyslipidemic profile, but the body weight gain and feed efficiency (FE) were higher in SRD than in S, whereas the obesity-related oxidative stress, myocardial triacylglycerol accumulation, and enhanced cardiac lactate dehydrogenase (LDH) activity were higher in S than in SRD rats. Myocardial beta-hydroxyacyl coenzyme-A-dehydrogenase was lower in SRD and in S than in C, whereas glycogen was only depleted in S rats. Myocardial pyruvate dehydrogenase (PDH) was lowest in S rats indicating depressed glucose oxidation. There was higher myocardial LDH/citrate synthase (CS) ratio and lower adenosine triphosphate (ATP)-synthetase indicating delayed aerobic metabolism in S rats than in the others. Cardiac ATP-synthetase was positively correlated with energy expenditure, namely resting metabolic rate (RMR), and with oxygen consumption per body weight (VO(2)/body weight). Myocardial lipid hydroperoxide (LH)/ total antioxidant substances (TAS) ratio and triacylglycerol accumulation were negatively correlated with RMR and with VO(2)/body weight. In conclusion, the present study brought new insights into obesity because the study demonstrated for the first time that reduced energy expenditure and oxygen consumption may provide novel risk factors of obesity-induced reduced energy generation for myocardial contractile function. The results serve to highlight the role of calorimetric changes as novel biomarkers of risk to obesity-induced cardiac effects.