32 research outputs found
Celiac Disease: Role of the Epithelial Barrier
In celiac disease (CD) a T-cell–mediated response to gluten is mounted in
genetically predisposed individuals, resulting in a malabsorptive enteropathy
histologically highlighted by villous atrophy and crypt hyperplasia. Recent
data point to the epithelial layer as an under-rated hot spot in celiac
pathophysiology to date. This overview summarizes current functional and
genetic evidence on the role of the epithelial barrier in CD, consisting of
the cell membranes and the apical junctional complex comprising sealing as
well as ion and water channel-forming tight junction proteins and the adherens
junction. Moreover, the underlying mechanisms are discussed, including
apoptosis of intestinal epithelial cells, biology of intestinal stem cells,
alterations in the apical junctional complex, transcytotic uptake of gluten
peptides, and possible implications of a defective epithelial polarity.
Current research is directed toward new treatment options for CD that are
alternatives or complementary therapeutics to a gluten-free diet. Thus,
strategies to target an altered epithelial barrier therapeutically also are
discussed
The structural basis of Edc3- and Scd6-mediated activation of the Dcp1:Dcp2 mRNA decapping complex
Content of Adenine Nucleotides and Orthophosphate in Exporting and Importing Mature Maize Leaves
The expression of human tight junction proteins Occludin and Claudin-2 is differentially regulated in distinct epithelial cell types and affected by proinflammatory cytokines
The plant-derived glucocorticoid receptor agonist Endiandrin A acts as co-stimulator of colonic epithelial sodium channels (ENaC) via SGK-1 and MAPKs.
In a search for secondary plant compounds that bind to the glucocorticoid receptor (GR), the cyclobutane lignan endiandrin A was discovered from the rainforest tree Endiandra anthropophagorum Domin. Our present study aims to characterize the effect of endiandrin A on GR-dependent induction of colonic sodium transport. The effect of endiandrin A was analyzed in GR-expressing colonic HT-29/B6 cells (HT-29/B6-GR). GR transactivation and subcellular localization were investigated by reporter gene assay and immunofluorescence. Epithelial sodium channel (ENaC) was analyzed by qRT-PCR and by measuring amiloride-sensitive short-circuit current (I(sc)) in Ussing chambers. Endiandrin A (End A) has been identified as GR receptor binder. However, it did not cause significant GR transactivation as pGRE-luciferase activity was only 7% of that of the maximum effect of dexamethasone. Interestingly, endiandrin A had a significant impact on dexamethasone-dependent sodium absorption in cells co-exposed to tumor necrosis factor (TNF)-α. This was in part due to up-regulation of β- and γ-ENaC subunit expression. Endiandrin A potentiated GR-mediated transcription by increasing GR protein expression and phosphorylation. It inhibited c-Jun N-terminal kinase (JNK) activation induced by dexamethasone and/or TNF-α and increased levels of GR localized to the nucleus. Additionally, endiandrin A increased the serum- and glucocorticoid-induced kinase (sgk)-1 via activation of p38. Finally, the regulation of ENaC function by endiandrin A was confirmed in rat native colon. In conclusion, endiandrin A potentiates glucocorticoid-driven activation of colonic epithelial sodium channels via JNK inhibition and p38 activation due to transcriptional up-regulation of β- and γ-ENaC-subunits along with induction of sgk-1