The abnormal expression of various estrogen receptors in the colon of patients with UC was not completely the same, suggesting estrogen receptor mediated the effect of estrogen in colitis through a specific signaling pathway ( Jacenik et al., 2019b). Modulation of ERS and UPR is a potential therapeutic target for UC, and its protective effect upon the epithelial cell is worthwhile ( Wu et al., 2010 Bernstein, 2015 Désir-Vignéet al., 2018).Įstrogen plays a crucial role in UC by binding to specific estrogen receptors, the classic nuclear estrogen receptor and membrane estrogen receptor ( Harnish et al., 2004 Bábíčková et al., 2015 Jacenik et al., 2019b). Conversely, prolonged and unmitigated ERS causes mucosal inflammation in UC via multiple mechanisms, such as increased colonic epithelium apoptosis, decreased mucin secretion of goblet cells, and injury of intestinal epithelial stemness and, consequently, impairs mucosal barrier function and mucosal innate immunity ( McGuckin et al., 2010 Cao, 2016 Liu et al., 2018). Physiologic activation of UPR is an adaptive response for mammalian animals to restore ER homeostasis and maintain epithelial homeostasis ( Kaser and Blumberg, 2010).
ERS means the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen, which dissociates glucose-regulating peptide 78 (GRP78) from ER-localized transmembrane protein sensors-inositol requiring enzyme 1 (IRE1), double-stranded RNA-dependent protein kinase–like ER kinase (PERK), and activating transcription factor 6 (ATF6)-thereby activating the unfolded protein response (UPR) ( McGuckin et al., 2010). Growing evidence links endoplasmic reticulum stress (ERS) and UC ( McGuckin et al., 2010 Bogaert et al., 2011). In addition to anti-inflammatory and immunomodulatory therapies, mucosal healing, which is closely related to long-term remission and prevention of recurrence, might be another goal of IBD therapy ( Bernstein, 2015). The incidence rate was also accelerating in the newly industrialized countries of Asia, South America, and Africa in the 21st century ( Ng et al., 2018). A paper published in 2018 showed that the highest reported prevalence values of UC were in Europe (5.05 per 100,000 in Norway) and North America (2.86 per 100,000 in the United States). Ulcerative colitis (UC) is one of two major types of inflammatory bowel disease (IBD), which leads to chronic, recurrent, and intermittent inflammatory mucosal lesions of the distal colon, characterized by hematochezia, diarrhea, weight loss, and abdominal pain ( Adams and Bornemann, 2013). These findings demonstrate that GPER activation prevents colitis by protecting the colonic crypt cells, which are associated with inhibition of endoplasmic reticulum stress. In cultured CCD841 cells, G-1 treatment fought against cell injury induced by endoplasmic reticulum stress. G-1 therapy inhibited the increase of cleavage caspase-3– and TUNEL-positive cells in colonic crypts in the colitis model, increased the number of Ki67- and bromodeoxyuridine-positive cells in crypts, and reversed the decrease of cyclin D1 and cyclin B1 expression in colitis, indicating its protective effect on crypt cells.
GPER activation reduced expression of glucose-regulating peptide-78 and anti-CCAAT/enhancer-binding protein homologous protein and attenuated the three arms of the unfolded protein response in colitis. G-1 administration prevented the dysfunction of tight junction protein expression and goblet cells in colitis model and thus inhibited the increase of mucosal permeability in colitis-suffering mice significantly. All of these effects were prevented by a selective GPER blocker.
The selective GPER agonist G-1 inhibited weight loss and colon shortening and decreased the disease activity index for colitis and histologic damage in mice with colitis. We used male C57BL/6 mice to establish the acute colitis model with administration of dextran sulfate sodium and explored the effect of GPER on acute colitis and its possible mechanism. G protein–coupled estrogen receptor (GPER) might be involved in ulcerative colitis (UC), but the direct effect of GPER on UC is still unclear.
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