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  • ER redox imbalance leads to

    2019-10-08

    ER redox imbalance leads to the accumulation of misfolded proteins, which might trigger the unfolded protein response (UPR) [17]. In the initiation of UPR, GRP78 preferentially binds to unfolded proteins, shifting the binding equilibrium away from IRE-1, PERK, and ATF-6, the initiators of UPR [18]. In these involved signaling cascades, IRE-1 and ATF-6 rectify and re-establish ER homeostasis, while PERK eliminate misfolded proteins to elicit pro-apoptotic effects in case the ER homeostasis is not reinstated [19], [20]. Activated PERK can phosphorylate eIF2a to selectively increase ATF-4, resulting in the transcriptional induction of CHOP. CHOP plays a convergent role in UPR, which has been identified as one of the most important mediators in ER stress-induced apoptosis [21], [22]. Farrukh et al. have declared that UVB irradiation induces ER stress and PERK-eIF2a pathway only in Hs68 fibroblasts but not in HaCaT cells [8]. However, the studies from Lu et al. was in contrast with these findings and showed that eIF2a, the downstream factor of PERK, could be phosphorylated by UVB irradiation in HaCaT cells [23], [24]. Therefore, further in-depth studies are still needed to clarify the association between UVB irradiation and ER stress-induced PERK-eIF2a pathway activation in the HaCaT cells.
    Disclosures
    Introduction The presence of the neuropeptide oxytocin (OT) in milk and its role in milk letdown are well known. Less known is the role of OT delivered in mothers\' milk on newborn gut development. Recent in vivo studies in rodent gut have demonstrated multiple important effects of OT/OT receptor (OTR) signaling on enteric neurons (1). Other experiments have shown that OT in combination with secretin is anti-inflammatory in animal models of colitis (2) and OTR deficient mice have altered gastrointestinal structure, motility, macromolecular permeability, mucosal maintenance and inflammatory responses [1]. OT appears to play an important role in early gut function and development. For instance, OTR expression is developmentally regulated during the milk-suckling period, and toward the end of the suckling period, OTR expression appears to migrate toward stem cells in the crypts [4]. There are several stressors to the newborn gut. These include temporary starvation, particularly of essential DHAP prior to first feed [2]. The first feeding of colostrum exposes the gut to high concentrations of foreign microbiota [3], [4], as well as the anti-inflammatory OT [5], [6], [7]. Another stressor includes early colonization by microbiota. In vitro experiments utilizing lipopolysaccharide (LPS) to mimic exposure of the newborn gut to bacterial endotoxin have shown that inflammatory signaling in enterocytes may be attenuated by OT to reduce cellular stress [ [8]. Other studies in gut cells support this hypothesis. OT downregulates the PI3K/Akt/mTORC protein synthesis pathway [9], a pathway dysregulated in autism and linked to mRNA translation and [12]. OT also modulates central sensors of the unfolded protein response (UPR) [10], a transcriptional program that strictly limits mRNA translation and clears unfolded proteins to resolve endoplasmic reticulum (ER) stress [14]. LPS activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB), which is a transcription factor that regulates the expression of ∼150 genes, including pro-inflammatory proteins that are normally downregulated by NF-KB inhibitor, IKB [11]. Phosphorylated IKB (pIKB) releases NF-KB, which translocates to the nucleus to serve as an active transcription factor [12], [13]. Collectively, these studies show that exposure to OT suppresses activation of the inflammatory pathway and stimulates the UPR. In the present study, we tested the impact of colostrum OT on markers of cellular stress and inflammation signaling in early postnatal villus tissue. We also measured LC3A, a marker of autophagy, to test whether amino acid insufficiency stress stimulates or inhibits inflammation during the interval between birth and first feeding before villus tissue is exposed to colostrum [14]. We examined protein expression in harvested villi that were unprimed (prior to first feed) and in vivo primed (subsequent to first feed). We exposed in vivo unprimed and colostrum primed tissue at a subsequent ex vivo stage to vehicle alone, LPS, exogenous OT or OTR antagonist (OTA). In a second protocol, we compared ex vivo the effects of vehicle versus colostrum in the presence and absence of OTA on villi obtained from unprimed rats using extracted colostrum. Our results suggest that colostrum OT plays a pivotal anti-inflammatory role that includes autophagy in the newborn rat gut villi.