Da-Cheng-Qi decoction attenuates inflammatory edema and endoplasmic reticulum stress in acute pancreatitis via suppressing NF-κB pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Da-Cheng-Qi Decoction (DCQD) is clinically used for acute pancreatitis (AP). AP is an inflammatory disorder, characterized by inflammatory edema (IE) and endoplasmic reticulum stress (ERS). AIM OF THE STUDY: This study aims to investigate whether DCQD attenuates IE and ERS in AP via nuclear factor κB (NF-κB) pathway. MATERIALS AND METHODS: In vivo, an AP model was established in Balb/c mice via L-arginine intraperitoneal injection (24 h); in vitro, an AP model was induced in rat pancreatic exocrine cells (AR42J) using cerulein (24 h). Mice were treated with DCQD (18 g/kg, 9 g/kg, and 4.5 g/kg); cells received DCQD-containing serum (5%, 2.5% and 1.25%). Network pharmacology, transcriptomics and non-targeted metabolomics were performed to predict core pathway. Pharmacological modulation employed NF-κB agonist and inhibitor. Docking and molecular dynamics (MD) validated interactions between core DCQD compound and proteins. Several pharmacological indicators tests and molecular biological assessments were conducted. RESULTS: Network pharmacology identified 138 DCQD targets overlapping with AP, with NF-κB pathway as a core pathway. Docking/MD demonstrated strong binding affinity between rhein and NF-κB. In vivo, DCQD (9 g/kg or 2.5% drug-containing serum) significantly lowered pancreas coefficient, decreased serum α-amylase and interleukin-6 (IL-6), and attenuated pancreatic Na accumulation and Cadepletion. In vitro, DCQD-containing serum increased cell viability, suppressed IL-6, and modulated ion imbalance. Mechanistically, DCQD down-regulated NF-κB, IE-related proteins and ERS-related proteins. The NF-κB inhibitor enhanced DCQD's protective effects, while the NF-κB agonist counteracted them. CONCLUSION: DCQD ameliorates IE and ERS in AP, primarily through suppressing NF-κB pathway.