Researchers from the Faculty of Science helped find substances to improve the treatment of inflammatory bowel diseases

Reproduction: Žurnál UP
tuesday 14. april 2020, 9:04 – Text: Šárka Chovancová

In the future, the results of an international study on a special receptor within cells, which involved experts from the Department of Cell Biology and Genetics of the UP Faculty of Science, could be used in the effective treatment of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

Researchers have synthesized and characterized substances that correctly activate the pregnane X receptor and thanks to that have an anti-inflammatory effect. The results were published by the prestigious journal EMBO Molecular Medicine. Its front page was also dedicated to this international study. Other leading journals have treated this discovery in editorials.

The pregnane X receptor (PXR), discovered in the mid-1990s, has hitherto been considered as the steroid and xenobiotic-sensing nuclear receptor (XSR) and a key regulator of drug metabolism, whose activation is highly undesirable in terms of drug-drug interactions and interactions between food components and drugs.

However, experts have now demonstrated that correct endogenous activation of PXR by common metabolites is desirable for a variety of physiological processes within the organism. In contrast, insufficient endogenous PXR activation or its excessive activation by foreign compounds results in a number of pathological conditions such as inflammatory bowel disease, fatty liver disease, diabetes or Alzheimer’s disease. “It therefore follows that PXR is a potential target in the therapy of these diseases. In our work, we dealt with the role and therapeutic targeting of PXR in inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. We found inspiration in the microbial world, specifically in substances produced by the human intestinal microbiome,” said Zdeněk Dvořák from the Department of Cell Biology and Genetics.

The international team of researchers based the study on earlier observations of Prof Mani’s team from Albert Einstein College of Medicine in New York. “Their observations suggest that indole and indole-3-propionic acid (IPA), produced by the intestinal microflora, act in mice against intestinal inflammation through the PXR. If this signalling is insufficient, these pathological conditions start developing,” said Dvořák, describing the mechanism of PXR influence on inflammatory processes in the body.

Scientists have therefore prepared substances that mimic microbial indole catabolites and have the potential to correctly activate the PXR. “We have proven that our substances based on the concept of microbial metabolite mimicry, which contain indole and IPA in their structure, have a high ability to activate PXR. These substances show anti-inflammatory activity in the human intestinal lining, human intestinal organoids and in mice after experimentally induced colitis,” noted Dvořák.

In the United States, patent proceedings were already initiated in 2018 for the results of the international study on the effects of test substances on the functioning of PXR. “The subject of protection is the potential use of our substances in the treatment of inflammatory bowel diseases,” added Dvořák.

The study was the joint effort of scientists from 17 research institutions in the USA, Canada, Italy, India, Slovakia and the Czech Republic. “The Department of Cell Biology and Genetics played a major role in the study. Scientists from the UP Faculty of Science hold shared first authorship as well as the position of corresponding author. It is one result of long-term and profound scientific-pedagogical cooperation between the Department of Cell Biology and Genetics and the Albert Einstein College of Medicine in New York,” added Dvořák.

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