Melatonin attenuates the inflammatory response via�inhibiting the C/EBP homologous protein-mediated pathway in taurocholate-induced acute pancreatitis

Abstract

Acute pancreatitis (AP) is a serious disease characterized by the activation of trypsin, autodigestion, edemas, hemorrhages and necrosis. However, the mechanisms of regulating the apoptosis and inflammation of acinar cells in AP remain unclear. The endoplasmic reticulum (ER) stress-related molecule, c/EBP homologous protein (cHOP), has pro-apoptotic and pro-inflammatory properties, in addition to regulating ER stress responses. In the present study, a lentivirus-mediated RNA interference (RNAi) approach was used to specifically knockdown the expression of cHOP in the pancreatic tissue of Sprague-dawley rats to investigate the potential role of cHOP during AP, which was induced by the retrograde injection of 5% taurocholate into the biliopancreatic duct of rats. Pre-treatment with melatonin was further used to identify the potential anti-inflammatory mechanisms in AP. Pancreatic tissues were procured for western blot analysis, histological examination, reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining. ER stress was rapidly activated in the early stage and increased over time in the rat AP model. However, the silencing of cHOP expression markedly inhibited apoptosis and ER stress, reducing the activation of nuclear factor-κB and inflammation injury in AP. Melatonin also exhibited anti-inflammatory and apoptotic effects, and significantly decreased the expression of cHOP. Thus, it can be concluded that the cHOP-mediated pathway serves an important role in the development of AP, and that melatonin can reduce pancreatic damage via the inhibition of cHOP expression.

Potential utility of melatonin in deadly infectious diseases related to the overreaction of innate immune response and destructive inflammation: focus on COVID-19

“…In the follow-up studies, the group also observed that melatonin not only suppresses the non-specific local but also the systemic inflammations induced by zymosan in rats (101,102). Thereafter, the anti-inflammatory activity of melatonin in different inducers, animal models and even in human clinical trials has been documented (103)(104)(105)(106). Inflammation is always manifested by neutrophil infiltration, increased microvascular leakage, tissue swelling and fever.…”

Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

“…In a rat model for intracerebral hemorrhage, melatonin has been shown to exert neuroprotective effects via the suppression of the ATF6 pathway 233 . Melatonin was also shown to attenuate inflammation in LPS-induced AP in AR42J cells and in taurocholate-induced AP in rats 234,235 . Interestingly, pharmacologic ATF6 activation has also been shown to be protective in many diseases, including ischemic heart disease, and diabetes and neurodegenerative disorders [236][237][238][239][240] .…”

Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

“…Through reporter-based assays, Bix, compound 147 (AA 147) and 263 (AA 263) have been identified and both specifically activate the ATF6 arm of the UPR [ 214 , 249 , 250 ]. Bix has been shown to exert beneficial effects in experimental models for multiple disease conditions, such as stroke and kidney injury [ 214 , 215 ]. In a mouse model of ischemic heart disease, AA 147 was shown to exert a protective effect in multiple tissues, including heart, brain, kidney and liver [ 216 ].…”