N‐(3′,4′‐dimethoxycinnamonyl) anthranilic acid alleviates severe acute pancreatitis by inhibiting intestinal barrier dysfunction and NF‐κB activation

Abstract

Severe acute pancreatitis (SAP) can affect intestinal barrier with a high mortality. To date, effective therapies for SAP are still in urgently need. The purpose of this study was to investigate the role of anthranilic acid active synthetic derivative, N‐(3′,4′‐dimethoxycinnamonyl) anthranilic acid (3,4‐DAA), in intestinal barrier dysfunction of SAP. In this study, SAP mice model was induced by caerulein combined with lipopolysaccharide (LPS). SAP mice were pretreated with 3,4‐DAA orally. Histological structures of pancreatic and intestinal tissues were observed via hematoxylin–eosin (H&E) staining. Pancreas myeloperoxidase (MPO), serum lipase, and amylase were detected using corresponding kits. Western blot analysis and reverse transcription and quantitative PCR (RT‐qPCR) were employed to determine the levels of inflammatory factors in both pancreatic and intestinal tissues. Moreover, the levels of intestinal barrier‐related proteins, NLRP3 inflammasome and NF‐κB pathway were examined by western blot analysis. Result revealed that 3,4‐DAA significantly attenuated pancreas and intestine damage, inhibited the release of inflammatory factors and intestinal barrier dysfunction. Moreover, the expression of NLRP3 and phospho‐NF‐κB p65 in pancreatic and intestinal tissues was notably suppressed by 3,4‐DAA. To sum up, these results demonstrated that 3,4‐DAA could ameliorate SAP, partly attributing to the inhibition of intestinal barrier dysfunction and the release of inflammatory factors. These findings may provide a new mechanism support for 3,4‐DAA application in the clinical treatment of SAP.

The trigger for pancreatic disease: NLRP3 inflammasome

“…Some other substances can also affect the formation of NLRP3 inflammasome in pancreatitis. For example, the bile acid receptor agonist INT-777 effectively relieves inflammation and pancreatic acinar cell damage by blocking the ROS/NLRP3 pathway; ABX combination therapy (vancomycin, neomycin, and polymyxin b) attenuated the activation of TLR4 and NLRP3 by inhibiting the translocation of gut bacteria to the pancreas, thereby suppressing uncontrolled diffuse inflammation in the pancreas and adjacent organs during AP; β-hydroxybutyric acid can reduce the activity of caspase-1 and inhibit the maturation of IL-1β, thereby inhibiting NLRP3 inflammasome [ 55 ]; 3,4-DAA and Butyrate have also been found to affect the formation of NLRP3 inflammasomes through different pathways [ 56 , 57 ].…”