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  • The IRE pathway was not

    2019-07-24

    The IRE1 pathway was not modified by ANP or cerulein-induced AP. IRE1 has kinase and endoribonuclease activities in its cytosolic region and uses a nonconventional mRNA splicing mechanism and/or post-transcriptional modifications of diverse substrates through RIDD to transmit UPR signaling [19,20,41]. ER stress induces oligomerization and autophosphorylation of IRE1 leading to its activation. Stimulation of IRE1 endoribonuclease domain induces the splicing of XBP1 mRNA, to yield a potent transcriptional factor, sXBP1, which also plays a critical role in normal pancreatic development [42]. sXBP1 translocates to the nucleus and enhances the transcription of genes that increase the ER size and function [42]. The observation that sXBP1 expression was unchanged in AP in the presence or absence of ANP suggests that at this point IRE1 signaling is likely turned off. In accordance, it was shown that IRE1 signaling attenuates upon sustained ER stress [43]. Furthermore, a previous study showing the time course of sXBP1 expression showed that cerulein-induced AP causes a significant increase in sXBP1 at 1 and 2 h following the first cerulein injection, but no changes are observed at 4 h [8]. IRE1 is also involved in caspase 2 activation. Under conditions of sustained ER stress, IRE1 promotes the rapid degradation of microRNAs that target caspase-2 mRNA which in turn causes rapid caspase 2 activation which contributes to apoptosis [21,44]. In addition, caspase 2 activation also ameliorates oxidative stress [45]. Caspase 2 is a highly evolutionary conserved member of the caspase family, although its role is poorly understood and controversial. Several reports suggest that caspase 2 may act as an effector or initiator caspase, although other studies suggest that it would be implicated in a complex cellular signaling pathway that leads Nocodazole to initiate apoptosis as the last resort [44]. Present findings show that ANP stimulates caspase 2 activation, although in AP its activation was diminished. A previous study showed that in cerulein-induced pancreatitis neutrophils do not affect the mitochondrial pathway of apoptosis but limit apoptosis by p53-induced caspase 2 inhibition thus favoring pancreatic necrosis [46]. We previously reported that ANP reduces neutrophil infiltration and necrosis in AP, which may account for present findings regarding caspase 2 activity [15]. A cross-talk between ER stress and inflammation has been proposed. In fact, the three signaling pathways of the UPR may activate NF-kB [6]. In AP activation of NF-κB triggers the inflammatory response mediated by a plethora of proinflammatory cytokines as well as enzymes like COX2 and inducible nitric oxide synthase. However, it was reported that CHOP activation induced by PERK/eIF2α plays a negative regulatory role in inflammation [7]. In a previous study we showed that ANP reduced NF-κB activation and reduced proinflammatory cytokines. The anti-inflammatory role of ANP is further confirmed in the present work by enhanced CHOP activation. An interplay between autophagy and apoptosis where Beclin-1 plays a major role has been reported [23]. Silencing of Beclin-1 leads to apoptosis and reduction of autophagy sensitizes cells to programmed cell death [47,48]. We here show that Beclin-1 expression was increased in AP but decreased by ANP suggesting reduced autophagy. It was reported that enhanced Bax expression reduces autophagy by inducing Beclin-1 cleavage by caspases. In particular, it was shown that caspase 3 cleaves Beclin-1 at Asp 149 thus inhibiting autophagosome synthesis [49]. In accordance, we previously reported that ANP enhances caspase 3 activity and expression and here we show that the atrial peptide enhances Bax expression.
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    Introduction Obesity is recognized as a growing risk for global health. According to the World Health Organization, in 2016 13% of all adults worldwide were obese [1]. Obesity is associated with pathological conditions such as hepatic steatosis, type 2 diabetes and cardiovascular disease [2]. However the underlying etiology that links obesity with these pathologies remains to be elucidated. Proteoglycan 4 (Prg4) has emerged from human association studies, on both transcriptional and protein levels, as a possible factor contributing to weight gain, dyslipidemia and insulin resistance [[3], [4], [5]]. Furthermore, Prg4 is differentially expressed in delta and pancreatic polypeptide cell subsets located in the islets of Langerhans of type 2 diabetes patients, further associating this proteoglycan with this disease [6].