Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life.

Human hepatic membrane-embedded transporter proteins are involved in trafficking endogenous and exogenous substrates. Even though impact of transporters on pharmacokinetics is recognized, little is known on maturation of transporter protein expression levels, especially during early life. We aimed to study the protein expression of 10 transporters in liver tissue from fetuses, infants, and adults.

Ontogeny of human hepatic and intestinal transporter gene expression during childhood: age matters.

Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane-bound proteins that mediate the cellular uptake or efflux of drugs and are important to drug absorption and elimination. Very limited data are available on the effect of age on transporter expression.

In vitro gastrointestinal model (TIM) with predictive power, even for infants and children?

There is a need for information on the bioavailability in pediatric patients of drugs from manipulated dosage forms when applied in combination with food and/or co-medication under realistic daily practice circumstances. We describe the development, validation and application of a dynamic, computer-controlled in vitro system mimicking the conditions in the upper gastrointestinal tract of neonates, infants and toddlers: TIMpediatric. Paracetamol and diclofenac in age-related food matrices and with esomeprazole co-medication were tested.

Ontogeny of oral drug absorption processes in children.

Introduction: A large proportion of prescribed drugs to children are administered orally. Age-related change in factors affecting oral absorption can have consequences for drug dosing.

Areas Covered: For each process affecting oral drug absorption, a systematic search has been performed using Medline to identify relevant articles (from inception till February 2012) in humans.

Threonine metabolism in the intestine of mice: loss of mucin 2 induces the threonine catabolic pathway.

Objectives: Previous studies have shown that the intestine uses a major part of the dietary threonine intake for the synthesis of the structural component of the protective intestinal mucus layer, the secretory mucin Muc2. In this context, the high intestinal demand for dietary threonine probably results from its incorporation into secretory mucins rich in threonine residues. Therefore, we compared threonine utilization in the colon of Muc2 knockout (Muc2-/-) and wild-type (Muc2+/+) mice to investigate the intestinal dietary threonine metabolism in the absence of Muc2, which results in inflammation of the colon.

Chemotherapy does not influence intestinal amino acid uptake in children.

Chemotherapy will frequently induce intestinal damage (mucositis). Enteral nutrition is then often withheld for fear of impaired intestinal absorption as shown in animal models. There is no clinical evidence, however, that absorption is indeed compromised during chemotherapy-induced mucositis.

Alterations in epithelial and mesenchymal intestinal gene expression during doxorubicin-induced mucositis in mice.

In the current study we aimed to gain insight into epithelial-mesenchymal cross-talk and progenitor compartment modulation during doxorubicin (DOX)-induced mucositis in mice. Intestinal segments were collected on various days after DOX treatment. DOX-induced damage at day 1-2 was characterized by increased epithelial proliferation and apoptosis and a decrease in the expression of epithelial differentiation markers.

Methotrexate-induced mucositis in mucin 2-deficient mice.

The mucin Muc2 or Mycin2 (Muc2), which is the main structural component of the protective mucus layer, has shown to be upregulated during chemotherapy-induced mucositis. As Muc2 has shown to have protective capacities, upregulation of Muc2 may be a counter reaction of the intestine protecting against mucositis. Therefore, increasing Muc2 protein levels could be a therapeutic target in mucositis prevention or reduction.

Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection.

Background & Aims: Expression of mucin MUC2, the structural component of the colonic mucus layer, is lowered in inflammatory bowel disease. Our aim was to obtain insight in the role of Muc2 in epithelial protection.

Methods: Muc2 knockout (Muc2(-/-)) and Muc2 heterozygous (Muc2(+/-)) mice were characterized and challenged by a colitis-inducing agent, dextran sulfate sodium (DSS).

Protection against chemotherapy induced mucositis by TGF-beta(2) in childhood cancer patients: results from a randomized cross-over study.

Background: Mucositis is one of the most frequent and severe side-effect of chemotherapy in childhood-cancer patients for which there is no prophylaxis available. The efficacy and feasibility of a TGF-beta(2)-enriched feeding for preventing oral and gastro-intestinal-mucositis in childhood-cancer patients were studied.

Procedure: The study was designed as a two-period cross-over, randomized, double-blinded, placebo, controlled trial.

Contributions of mucosal immune cells to methotrexate-induced mucositis.

The use of high doses of the anti-cancer drug methotrexate (MTX) is associated with intestinal damage. As a result, mucosal immune cells become increasingly exposed to a vast amount of microbial stimuli. We aimed at determining whether these cells are still functional during MTX treatment.

The effect of cytostatic drug treatment on intestine-specific transcription factors Cdx2, GATA-4 and HNF-1alpha in mice.

Chemotherapy-induced intestinal damage is a very important dose-limiting side effect for which there is no definitive prophylaxis or treatment. This is in part due to the lack of understanding of its pathophysiology and impact on intestinal differentiation. The objective of this study was to investigate the gene expression of the small intestinal transcription factors HNF-1alpha, Cdx2, GATA-4 in an experimental model of methotrexate (MTX)-induced intestinal damage, and to correlate these alterations with histological damage, epithelial proliferation and differentiation.

Validation of the direct nasopharyngeal sampling method for collection of expired air in preterm neonates.

In clinical studies, the oxidation of 13C-labeled substrates to 13CO2 and the measurement of the appearance of excess 13CO2 in expiratory air has progressed to an increasingly common method as it is noninvasive and lacks the radiation exposure associated with the use of 14C. The collection of respiratory CO2 currently used occurs via trapping of CO2 in sodium hydroxide (trapping method), sometimes in conjunction with indirect calorimetry. The aim of the present study was to determine the accuracy of our direct nasopharyngeal sampling method for the collection of breath samples in preterm infants compared with the currently used trapping method.