Effect of body fat distribution on the transcription response to dietary fat interventions

Combination of decreased energy expenditure and increased food intake results in fat accumulation either in the abdominal site (upper body obesity, UBO) or on the hips (lower body obesity, LBO). In this study, we used microarray gene expression profiling of adipose tissue biopsies to investigate the effect of body fat distribution on the physiological response to two dietary fat interventions. Mildly obese UBO and LBO male subjects (n = 12, waist-to-hip ratio range 0.93–1.12) were subjected to consumption of diets containing predominantly either long-chain fatty acids (PUFA) or medium-chain fatty acids (MCT). The results revealed (1) a large variation in transcription response to MCT and PUFA diets between UBO and LBO subjects, (2) higher sensitivity of UBO subjects to MCT/PUFA dietary intervention and (3) the upregulation of immune and apoptotic pathways and downregulation of metabolic pathways (oxidative, lipid, carbohydrate and amino acid metabolism) in UBO subjects when consuming MCT compared with PUFA diet. In conclusion, we report that despite the recommendation of MCT-based diet for improving obesity phenotype, this diet may have adverse effect on inflammatory and metabolic status of UBO subjects. The body fat distribution is, therefore, an important parameter to consider when providing personalized dietary recommendation

Short-term fatty acid intervention elicits differential gene expression responses in adipose tissue from lean and overweight men

The goal of this study was to investigate the effect of a short-term nutritional intervention on gene expression in adipose tissue from lean and overweight subjects. Gene expression profiles were measured after consumption of an intervention spread (increased levels of polyunsaturated fatty acids, conjugated linoleic acid and medium chain triglycerides) and a control spread (40 g of fat daily) for 9 days. Adipose tissue gene expression profiles of lean and overweight subjects were distinctly different, mainly with respect to defense response and metabolism. The intervention resulted in lower expression of genes related to energy metabolism in lean subjects, whereas expression of inflammatory genes was down-regulated and expression of lipid metabolism genes was up-regulated in the majority of overweight subjects. Individual responses in overweight subjects were variable and these correlated better to waist–hip ratio and fat percentage than BMI

Proteomics of human liver membrane transporters: a focus on fetuses and newborn infants

Background: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples. Methods: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age (gestational age [GA], postnatal age [PNA], and postmenstrual age); between protein and mRNA expression; and between protein expression and genotype. Results: We analyzed 36 fetal (median GA 23.4 weeks [range 15.3–41.3]), 12 premature newborn (GA 30.2 weeks [24.9–36.7], PNA 1.0 weeks [0.14–11.4]), 10 term newborn (GA 40.0 weeks [39.7–41.3], PNA 3.9 weeks [0.3–18.1]), 4 pediatric (PNA 4.1 years [1.1–7.4]) and 8 adult liver samples. A relationship with age was found for BCRP, BSEP, GLUT1, MDR1, MRP1, MRP2, MRP3, NTCP, OATP1B1 and OCT1, with the strongest relationship for postmenstrual age. For most transporters mRNA and protein expression were not correlated. No genotype-protein expression relationship was detected. Discussion and conclusion: Various developmental patterns of protein expression of hepatic transporters emerged in fetuses and newborns up to four months of age. Postmenstrual age was the most robust factor predicting transporter expression in this cohort. Our data fill an important gap in current pediatric transporter ontogeny knowledge

Effect of normobaric hyperoxia on antioxidant defenses of hela and CHO cells

The effect of increased intracellular oxygen activation on cellular antioxidant defenses in CHO and HeLa cells was studied. In both cell types, hyperoxic exposure (up to 4 days, 600-700 mm Hg O2) and in CHO cells menadione (up to 3 days, 15 μM) failed to affect the enzymatic antioxidant defenses Mn-containing superoxide dismutase (Mn-SOD), CuZn-SOD, catalase and glutathione peroxidase. The markedly increased antioxidant enzyme activities observed in a recently obtained oxygen-tolerant CHO variant persisted under normoxia. These data suggest that the synthesis of antioxidant enzymes is constitutive. Glutathione levels of HeLa cells did not respond to hyperoxia whereas in CHO cells hyperoxia and menadione exposure resulted in a 2- and 7-fold increase in glutathione contents, respectively. However, considering the large variations in glutathione contents observed under normal culture conditions, it is uncertain whether this increase is to be considered as a true adaptive response

Nutrient-induced glucagon like peptide-1 release is modulated by serotonin

Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists.Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50 mM) and rebaudioside A (12.5 mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release.Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155 μM) further enhanced casein and safflower oil induced-serotonin release.Exposure of ileal tissue segments to serotonin (30 μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100 μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10 μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process.</p

A Proof-of-Concept System Dynamics Simulation Model of the Development of Burnout and Recovery Using Retrospective Case Data

The phenomenon of burnout is a complex issue, which despite major efforts from researchers and organizations remains hard to prevent. The current literature highlights an increasing global prevalence of employees that are dealing with burnout. What has been largely missing is a more systemic, dynamic, and personal perspective on the interactions of the key determinants of burnout. Burnout can be seen as the outcome of a complex system involving feedback loops between individual mental models, individual behavior, and external social influences. Understanding the feedback loops involved may enable employees and organizations to intervene in burnout trajectories early and effectively. System dynamics (SD) modeling is a methodology that can describe the structure and behavior of a complex system. The current paper describes the development of an SD model of burnout. First, an expert- and literature-informed causal loop diagram (CLD) of burnout is developed. Then, a novel approach is developed to collect personal retrospective scenario data. Finally, the CLD and data are translated into a quantitative SD model. The potential of the SD model is illustrated by simulating the behavior of three realistic personas during the onset of and recovery from burnout. The process of development of an SD model of burnout is presented and the strengths and limitations of the approach are discussed

The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir.

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed

The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed.status: publishe

The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir.

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed

Regional expression levels of drug transporters and metabolizing enzymes along the pig and human intestinal tract and comparison with Caco-2 cells

Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to better characterize available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine intestine, human intestine and Caco-2 cells. We therefore determined the absolute protein expression of 19 drug transporters and the mRNA expression of 12 metabolic enzymes along the pig intestinal tract (duodenum, jejunum, ileum; N=4), in human intestine (jejunum; N=9) and Caco-2 cells. Expression of the included transporters and enzymes was in general well comparable between porcine and human intestinal tissue, though BCRP, MCT5, MDR1, MRP1, MRP3 (~2-fold) and OATP4A1 (~6-fold) was higher expressed in pig compared to human jejunum. Alternatively, expression level of relevant transporter proteins (GLUT1, OATP4A1, MRP2, MRP1 and OATP2B1) was significantly higher (3- to 130-fold) in Caco-2 cells compared to human jejunum. Moreover, all examined CYPs showed at least a five-fold lower gene expression in Caco-2 cells compared to human jejunum, with the smallest differences for CYP1A1 and CYP3A5 and the largest difference for CYP3A4 (871-fold higher expression in human jejunum compared to Caco-2 cells). In conclusion, a comprehensive overview is provided of the expression levels of clinically relevant transporter proteins and metabolic enzymes in porcine and human intestinal tissue, and Caco-2 cells, which may assist in deciding upon the most suitable model to further improve our understanding of processes that determine intestinal absorption of compounds