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Background and Purpose: Chymotrypsin is a pancreatic protease secreted into the lumen of the small intestine to digest food proteins. We hypothesized that chymotrypsin activity may be found close to epithelial cells and that chymotrypsin signals to them via protease‐activated receptors (PARs). We deciphered molecular pharmacological mechanisms and gene expression regulation for chymotrypsin signalling in intestinal epithelial cells. Experimental Approach: The presence and activity of chymotrypsin were evaluated by Western blot and enzymatic activity tests in the luminal and mucosal compartments of murine and human gut samples. The ability of chymotrypsin to cleave the extracellular domain of PAR1 or PAR2 was assessed using cell lines expressing N‐terminally tagged receptors. The cleavage site of chymotrypsin on PAR1 and PAR2 was determined by HPLC–MS analysis. The chymotrypsin signalling mechanism was investigated in CMT93 intestinal epithelial cells by calcium mobilization assays and Western blot analyses of (ERK1/2) phosphorylation. The transcriptional consequences of chymotrypsin signalling were analysed on colonic organoids. Key Results: We found that chymotrypsin was present and active in the vicinity of the colonic epithelium. Molecular pharmacological studies have shown that chymotrypsin cleaves both PAR1 and PAR2 receptors. Chymotrypsin activated calcium and ERK1/2 signalling pathways through PAR2, and this pathway promoted interleukin‐10 (IL‐10) up‐regulation in colonic organoids. In contrast, chymotrypsin disarmed PAR1, preventing further activation by its canonical agonist, thrombin. Conclusion and Implications: Our results highlight the ability of chymotrypsin to signal to intestinal epithelial cells via PARs, which may have important physiological consequences in gut homeostasis. [ABSTRACT FROM AUTHOR]

Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiovascular function and dysfunction has advanced from the assumption that it is a single layer of cells that serves as a barrier between the blood stream and vascular smooth muscle to an understanding of its role as an essential endocrine-like organ. In terms of historical contributions, we pay particular credit to (1) the Canadian scientist Dr. Rudolf Altschul who, based on pathological changes in the appearance of the endothelium, advanced the argument in 1954 that 'one is only as old as one's endothelium' and (2) the American scientist Dr. Robert Furchgott, a 1998 Nobel Prize winner in Physiology or Medicine, who identified the importance of the endothelium in the regulation of blood flow. This review provides a brief history of how our knowledge of endothelial function has advanced and now recognize that the endothelium produces a plethora of signaling molecules possessing paracrine, autocrine, and, arguably, systemic hormone functions. In addition, the endothelium is a therapeutic target for the anti-diabetic drugs metformin, glucagon-like peptide I (GLP-1) receptor agonists, and inhibitors of the sodium-glucose cotransporter 2 (SGLT2) that offset the vascular disease associated with diabetes. Key words: endothelium, endothelial dysfunction, diabetes, hyperglycaemia, metformin, GLP-1 agonists, SGLT2 inhibitors. Au cours des 66 dernieres annees, notre connaissance du role de l'endothelium sur la regulation du fonctionnement et des dysfonctionnements du systeme cardiovasculaire a fait des progres a partir de la presomption qu'il s'agirait d'une couche monocellulaire servant de barriere entre la circulation sanguine et le muscle lisse vasculaire, pour parvenir a la comprehension de son role s'apparentant a celui d'un organe endocrinien essentiel. Nous rendons hommage aux personnes suivantes pour leurs contributions historiques : (1) le docteur Rudolf Altschul, scientifique canadien qui s'est base sur des variations pathologiques dans l'apparence de l'endothelium pour avancer en 1954 l'argument selon lequel on n'a guere plus que l'age de son endothelium (<< one is only as old as one's endothelium >>) et (2) le docteur Robert Furchgott, scientifique americain laureat du prix Nobel de physiologie ou de medecine de 1998, qui a etabli l'importance de l'endothelium dans la regulation de la circulation sanguine. Cet article de synthese comporte un bref historique sur la maniere dont notre connaissance du fonctionnement de l'endothelium s'est accrue et reconnait maintenant que l'endothelium produit une plethore de molecules de signalisation avec des fonctions hormonales paracrines, autocrines et sans doute generales. De plus, l'endothelium est une cible therapeutique pour des medicaments antidiabetiques comme la metformine, les agonistes des recepteurs du peptide 1 de type glucagon (GLP-1) et les inhibiteurs du co-transporteur 2 sodium-glucose (SGLT2), qui permettent d'eloigner les patients de la maladie vasculaire associee au diabete. Mots-des : endothelium, dysfonctionnement endothelial, diabete, hyperglycemie, metformine, agonistes des recepteurs du GLP-1, inhibiteur du SGLT2., Introduction: why the endothelium? When asking the question 'why the endothelium?', one immediately thinks of the landmark paper published in Nature in 1980 by Furchgott and Zawadzki that first described [...]