Dataset Information

Effect of Ketoprofen and ATB-352 on the Immature Human Intestine: Identification of Responders and Non-responders.

ABSTRACT:

Background and objective

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of life-threatening adverse effects on the immature gastrointestinal tract. NSAID derivatives exploiting the beneficial effects of biologically active gases, such as hydrogen sulfide (H2S), have been developed. Herein, we determined the effects of ketoprofen and ATB-352, a H2S-releasing ketoprofen derivative, on selected metabolic pathways previously identified to be significantly altered by indomethacin in the human immature intestine.

Methods

Ketoprofen and ATB-352 were tested on human mid-gestation small intestinal explants maintained in a serum-free organ culture system for 48 hours. The expression levels of the representative genes involved in selected metabolic pathways were measured by real-time PCR after a treatment of 48 hours.

Results

Tested at a concentration that allows more than 80% inhibition of PGE2 production, ketoprofen was found to be less damaging than indomethacin at an equivalent dosage. However, based on the inducibility of cyclooxygenase-2 transcript expression, we were able to discriminate between responder individuals in which the deleterious effects observed with indomethacin were attenuated, and non-responder specimens in which the effects were similar to those observed with indomethacin. ATB-352 did not induce significant changes compared to ketoprofen on these metabolic pathways.

Conclusions

These results show less damaging effects of ketoprofen compared to indomethacin on the immature intestine and indicate that the intestinal response to this NSAID significantly varies between individuals. However, the results did not allow us to demonstrate a specific beneficial effect of H2S release in organ culture.

SUBMITTER: Thibault MP

PROVIDER: S-EPMC6510328 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of Ketoprofen and ATB-352 on the Immature Human Intestine: Identification of Responders and Non-responders.

Thibault Marie-Pier MP Tremblay Éric É Wallace John L JL Beaulieu Jean-François JF

Journal of pediatric gastroenterology and nutrition 20190501 5

<h4>Background and objective</h4>The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of life-threatening adverse effects on the immature gastrointestinal tract. NSAID derivatives exploiting the beneficial effects of biologically active gases, such as hydrogen sulfide (H2S), have been developed. Herein, we determined the effects of ketoprofen and ATB-352, a H2S-releasing ketoprofen derivative, on selected metabolic pathways previously identified to be sign ...[more]

PMID: 31022092

Similar Datasets

Project description:BackgroundFaced with an increasing number of choices for biologic therapies, rheumatologists have a critical need for better tools to inform rheumatoid arthritis (RA) disease management. The ability to identify patients who are unlikely to respond to first-line biologic anti-TNF therapies prior to their treatment would allow these patients to seek alternative therapies, providing faster relief and avoiding complications of disease.MethodsWe identified a gene expression classifier to predict, pre-treatment, which RA patients are unlikely to respond to the anti-TNF infliximab. The classifier was trained and independently evaluated using four published whole blood gene expression data sets, in which RA patients (n = 116 = 44 + 15 + 30 + 27) were treated with infliximab, and their response assessed 14-16 months post treatment according to the European League Against Rheumatism (EULAR) response criteria. For each patient, prior knowledge was used to group gene expression measurements into disease-relevant biological signaling mechanisms that were used as the input features for regularized logistic regression.ResultsThe classifier produced a substantial enrichment of non-responders (59 %, given by the cross validated test precision) compared to the full population (27 % non-responders), while identifying nearly a third of non-responders. Given this classifier performance, treatment of predicted non-responders with alternative biologics would decrease their chance of non-response by between a third and a half, substantially improving their odds of effective treatment and stemming further disease progression. The classifier consisted of 18 signaling mechanisms, which together indicated that higher inflammatory signaling mediated by TNF and other cytokines was present pre-treatment in the blood of patients who responded to infliximab treatment. In contrast, non-responders were classified by relatively higher levels of specific metabolic activities in the blood prior to treatment.ConclusionsWe were able to successfully produce a classifier to identify a population of RA patients significantly enriched in anti-TNF non-responders across four different patient cohorts. Additional prospective studies are needed to validate and refine the classifier for clinical use.

Project description:Paneth cells were first described in the late 19th century by Gustav Schwalbe and Josef Paneth as columnar epithelial cells possessing prominent eosinophilic granules in their cytoplasm. Decades later there is continued interest in Paneth cells as they play an integral role in maintaining intestinal homeostasis and modulating the physiology of the small intestine and its associated microbial flora. Paneth cells are highly specialized secretory epithelial cells located in the small intestinal crypts of Lieberkühn. The dense granules produced by Paneth cells contain an abundance of antimicrobial peptides and immunomodulating proteins that function to regulate the composition of the intestinal flora. This in turn plays a significant role in secondary regulation of the host microvasculature, the normal injury and repair mechanisms of the intestinal epithelial layer, and the levels of intestinal inflammation. These critical functions may have even more importance in the immature intestine of premature infants. While Paneth cells begin to develop in the middle of human gestation, they do not become immune competent or reach their adult density until closer to term gestation. This leaves preterm infants deficient in normal Paneth cell biology during the greatest window of susceptibility to develop intestinal pathology such as necrotizing enterocolitis (NEC). As 10% of infants worldwide are currently born prematurely, there is a significant population of infants contending with an inadequate cohort of Paneth cells. Infants who have developed NEC have decreased Paneth cell numbers compared to age-matched controls, and ablation of murine Paneth cells results in a NEC-like phenotype suggesting again that Paneth cell function is critical to homeostasis to the immature intestine. This review will provide an up to date and comprehensive look at Paneth cell ontogeny, the impact Paneth cells have on the host-microbial axis in the immature intestine, and the repercussions of Paneth cell dysfunction or loss on injury and repair mechanisms in the immature gut.

Dataset Information

Effect of Ketoprofen and ATB-352 on the Immature Human Intestine: Identification of Responders and Non-responders.

Background and objective

Methods

Results

Conclusions

Publications

Effect of Ketoprofen and ATB-352 on the Immature Human Intestine: Identification of Responders and Non-responders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets