Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol's metabolite KH176m.

Increased prostaglandin E2 (PGE2) levels were detected in mitochondrial disease patient cells harboring nuclear gene mutations in structural subunits of complex I, using a metabolomics screening approach. The increased levels of this principal inflammation mediator normalized following exposure of KH176m, an active redox-modulator metabolite of sonlicromanol (KH176). We next demonstrated that KH176m selectively inhibited lipopolysaccharide (LPS) or interleukin-1ß (IL-1ß)-induced PGE2 production in control skin fibroblasts. Comparable results were obtained in the mouse macrophage-like cell line RAW264.7. KH176m selectively inhibited mPGES-1 activity, as well as the inflammation-induced expression of mPGES-1. Finally, we showed that the effect of KH176m on mPGES-1 expression is due to the inhibition of a PGE2-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Based on the results obtained we discuss potential new therapeutic applications of KH176m and its clinical stage parent drug candidate sonlicromanol in mitochondrial disease and beyond.

Dietary patterns, beliefs and behaviours among individuals with inflammatory bowel disease: a cross-sectional study.

BACKGROUND: Inflammatory bowel disease (IBD) refers to a group of incurable gastrointestinal diseases that are common among young adults. The present study aimed to describe dietary intake, self-modifications and beliefs among adults aged 18-35 years with IBD and to compare those with active versus inactive disease. National guidelines for daily intake include: 34 g of fibre for males and 28 g of fibre for females, 3 oz of whole grains, 1000 mg of calcium, <10% of added sugars, three cups of dairy, 2.5 cups of vegetables and two cups of fruit. METHODS: Individuals with a diagnosis of IBD were recruited online using convenience sampling (n = 147). Data included a dietary screening questionnaire, self-directed diet modifications, dietary beliefs questionnaire and demographics. Chi-squared and t-tests were used to compare those with active versus inactive disease. RESULTS: The sample was predominantly female (90%) and diagnosed with Crohn's disease (64%). Daily intake for females was 9.7 g of fibre, 0.3 oz of whole grains, 683.8 g of calcium, 1.1 of cups vegetables and 0.5 of cups fruit. Daily intake for males was 14.2 g of fibre, 0.4 oz of whole grains, 882.9 g of calcium, 1.4 cups of vegetables and 0.5 cups of fruit. Participants most often modified fibre (73%), fruits and vegetables (71%), grains (67%), and dairy (66%) as a result of their IBD. Eighty-three percent believed that modifying their diet could reduce IBD symptoms. CONCLUSIONS: Both men and women with IBD struggle to meet the national guidelines for intake of fibre, whole grains, fruits and vegetables. The majority reported modifying their dietary intake as a result of IBD and expressed belief that diet could reduce symptoms.

The production of intrinsically labeled milk and meat protein is feasible and provides functional tools for human nutrition research.

Administration of labeled, free amino acids does not allow direct assessment of in vivo dietary protein digestion and absorption kinetics. Consequently, dietary protein sources with labeled amino acids incorporated within their protein matrix are required. The aim of the present study was to produce intrinsically L-[1-(13)C]phenylalanine-labeled milk and meat protein that would permit in vivo assessment of postprandial protein digestion and absorption kinetics in humans. One lactating dairy cow was continuously infused with 420 µmol of L-[1-(13)C]phenylalanine/min for 96 h, with plasma and milk being collected before, during, and after isotope infusion. Twenty-four hours after infusion, the cow was slaughtered to produce intrinsically labeled meat. Levels of L-[1-(13)C]phenylalanine enrichment as high as 40 mole percent excess (MPE) in milk and 1.5 MPE in meat protein were achieved. In a subsequent human proof-of-principle experiment, 2 healthy young males (25±1 yr; 66.2±5.2 kg) each ingested 135 g of L-[1-(13)C]phenylalanine intrinsically labeled minced beef, after which plasma samples were collected at regular time intervals. Plasma L-[1-(13)C]phenylalanine enrichments increased during the first 90 min following beef ingestion, reaching peak plasma enrichment levels of 0.61±0.04 MPE. Whole-body net protein balance, assessed by continuous infusion of L-[ring-(2)H(5)]phenylalanine and L-[ring-(2)H(2)]tyrosine, was higher in the postprandial period compared with basal values (6.4±0.1 vs. -4.5±0.1 µmol/kg per h). In conclusion, the production of intrinsically L-[1-(13)C]phenylalanine-labeled milk and meat protein is feasible and provides functional tools to investigate in vivo protein digestion and absorption kinetics in humans.

The induction of epidermal ornithine decarboxylase following UV-B irradiation is inhibited by estriol.

The induction of epidermal ornithine decarboxylase (ODC) can be partially blocked by corticosteroids, retinoic acid or active vitamin D3. The influence of the other members of this so-called "steroid hormone receptor superfamily", namely the sex-steroids and thyroid hormone, is unknown in epidermis, but they enhance ODC induction in certain other tissues. Here we investigated whether topical estriol leads to a spontaneous and/or enhanced epidermal ODC induction 8 h after UV-B irradiation of 6 postmenopausal women. Contrary to expectation, estriol did not stimulate induction but reduced induction by 44%. This observation raises the possibility that all members of the steroid hormone receptor superfamily may share a common AP-1 binding site.

The induction of ornithine decarboxylase in human epidermis is independent of lipoxygenase and cyclo-oxygenase pathways.

In vivo studies in rodents suggest that prostaglandins and/or leukotrienes are involved in the epidermal induction of ornithine decarboxylase (ODC). Recently, we have shown that, in human epidermis, prostaglandins are not involved in this process. Here we report the role of leukotrienes in epidermal ODC induction in human skin. Topical flufenamic acid (Dignodolin), vehicle, or nothing was applied under plastic occlusion to three sites on the backs of healthy volunteers. This was followed 1 h later by Sellotape stripping. After renewed application and occlusion for 8 h, biopsies were carried out for the estimation of ODC levels. There were no significant differences in the levels of ODC between the flufenamic acid treated and control sites. To confirm this finding, test sites were irradiated with 3 MED of UVB. This was immediately followed by the application of flufenamic acid, vehicle, or nothing to the three irradiated sites. After 8 h, biopsies were taken, and the levels of ODC were again similar in the flufenamic acid- and the vehicle-treated sites. The data indicate that, following Sellotape stripping or UVB irradiation, neither lipoxygenase not cyclooxygenase products contribute to the in vivo induction of ODC in human epidermis.