KB1 and/or CaMKK, related to oxidative pressure and ER stress, respectively, can regulate activation of AMPK (Carling et al., 2008, Willows et al., 2017). As a result, inhibition of LKB1 in hPACs treated with EtOH, acetaldehyde and FAEEs as discovered in this study could also contribute towards the inactivation of AMPK. On the other hand, an upregulation of CaMKK as observed only in hPACs treated with FAEEs can be a important discovering and warrants further investigations within the context of FAEE-induced ER tension (Ozcan and Tabas, 2010) and calcium metabolism (Tokumitsu et al., 2000, Tokumitsu et al., 2001). Of importance, FAEEs have been shown to bring about calcium toxicity linked towards the sequestration of calcium in the ER membrane in pancreatic acinar cells (Criddle et al., 2004, Criddle et al., 2006). Thus, an elevated expression of CaMKK in hPACs treated with FAEEs, only, may very well be caused by an elevated cytosolic calcium and ER strain suggesting a differential regulation of AMPK by EtOH and its metabolites. Since a putative hyperlink has been discovered in between AMPK inactivation and ER/oxidative AMPK Activator Accession stress in relation to EtOH-induced pancreatic acinar cell injury (Srinivasan et al., 2020), a systemic response to ER anxiety observed in hPACs treated with EtOH, acetaldehyde and FAEEs could possibly be interrelated. Additionally, a reduced expression of sXBP1 collectively with enhanced expression for PERK/CHOP arm of UPR in hPACs treated with EtOH, acetaldehyde and FAEEs suggests a lack of adaptive UPR to retain ER homeostasis commonly observed in subjects with alcoholic chronic pancreatitis (Sah et al., 2014, Lugea et al., 2017a). Furthermore, regardless of enhanced phosphorylation of IRE1, downregulation of sXBP1 in hPACs treated with EtOH, acetaldehyde / FAEEs is supported by enhanced levels of uXBP1. sXBP1 is an essential translational and transcriptional regulator involved in homeostasis of ER membrane, but a precise molecular mechanism underlying EtOH and its metabolites induced downregulation of sXBP1 is largely unknown. Several components like decreased zymogen granules, degradation of sXBP1, and inhibition of IRE1-RNASE activity and post translational regulatory mechanism of XBP1 could contribute towards downregulation of sXBP1 in cells undergoing prolonged ER tension (Yoshida et al., 2006, Lugea et al., 2017a,Author Manuscript Author Manuscript Author Manuscript Author ManuscriptAlcohol Clin Exp Res. Author manuscript; readily available in PMC 2022 May 01.Srinivasan et al.PageSun et al., 2019). Hence, additional studies to know the underlying mechanism of EtOH-induced gene regulation of XBP1 can open new avenues for therapeutics of ACP. Improved levels of inflammatory cytokines and chemokines happen to be reported in individuals with serious acute pancreatitis and animal models of acute pancreatitis (Gukovskaya et al., 1997, Brivet et al., 1999, Hirota et al., 2000, Yang et al., 2000, Regner et al., 2008, Aoun et al., 2009). Nevertheless, EtOH and its metabolites can regulate transcription aspects and cytokines either positively or negatively according to the effect of oxidative or nonoxidative VEGFR3/Flt-4 review metabolic pathways (Gukovskaya et al., 2002). A concentration-dependent activation of three main classes of MAPKs as identified in hPACs treated with EtOH, acetaldehyde, or FAEEs may also mediate the production of pro-inflammatory cytokines and chemokines involved within the improvement of pancreatitis (Dabrowski et al., 2000, Irrera et al., 2014) and support our findings of an increased expression of inflammatory cyt
