Transcriptomics and Network Pharmacology Reveal the Protective Effect of Chaiqin Chengqi Decoction on Obesity-Related Alcohol-Induced Acute Pancreatitis via Oxidative Stress and PI3K/Akt Signaling Pathway

Abstract

Obesity-related acute pancreatitis (AP) is characterized by increasing prevalence worldwide and worse clinical outcomes compared to AP of other etiologies. Chaiqin chengqi decoction (CQCQD), a Chinese herbal formula, has long been used for the clinical management of AP but its therapeutic actions and the underlying mechanisms have not been fully elucidated. This study has investigated the pharmacological mechanisms of CQCQD in a novel mouse model of obesity-related alcohol-induced AP (OA-AP). The mouse OA-AP model was induced by a high-fat diet for 12 weeks and subsequently two intraperitoneal injections of ethanol, CQCQD was administered 2 h after the first injection of ethanol. The severity of OA-AP was assessed and correlated with changes in transcriptomic profiles and network pharmacology in the pancreatic and adipose tissues, and further docking analysis modeled the interactions between compounds of CQCQD and their key targets. The results showed that CQCQD significantly reduced pancreatic necrosis, alleviated systemic inflammation, and decreased the parameters associated with multi-organ dysfunction. Transcriptomics and network pharmacology analysis, as well as further experimental validation, have shown that CQCQD induced Nrf2/HO-1 antioxidant protein response and decreased Akt phosphorylation in the pancreatic and adipose tissues. In vitro, CQCQD protected freshly isolated pancreatic acinar cells from H2O2-elicited oxidative stress and necrotic cell death. The docking results of AKT1 and the active compounds related to AKT1 in CQCQD showed high binding affinity. In conclusion, CQCQD ameliorates the severity of OA-AP by activating of the antioxidant protein response and down-regulating of the PI3K/Akt signaling pathway in the pancreas and visceral adipose tissue.

High-density lipoprotein cholesterol level as an independent protective factor against aggravation of acute pancreatitis: a case–control study

“…Therefore, HDL may alleviate acute pancreatitis by activating the NRF2/HO-1-mediated ferroptosis pathway. Studies have shown that the severity of acute pancreatitis can be improved by inhibiting the PI3K/Akt pathway ( 35 ). Inhibiting scavenger receptor class B type I (SR-BI) is sufficient to cause apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling ( 36 ).…”

AGI grade-guided chaiqin chengqi decoction treatment for predicted moderately severe and severe acute pancreatitis (CAP trial): study protocol of a randomised, double-blind, placebo-controlled, parallel-group, pragmatic clinical trial

“…Over the past 30 years, the Chinese herbal formula CQCQD has been widely used as an adjunctive therapy of conventional comprehensive treatment for AP in our hospital. A plethora of basic research studies from our group have revealed that CQCQD reduced pro-inflammatory indices and improved pancreatic and multiple organ injuries in experimental AP models [23,[49][50][51][52][53]. However, high-quality evidence from clinical studies to demonstrate its efficacy in AP patients is still lacking.…”

Targeting PI3K/AKT signaling pathway in obesity

“…Moreover, in a mouse model of obesity-related alcohol-induced acute pancreatitis chaiqin chengqi decoction (CQCQD) alleviated induced multi-organ dysfunction by decrease of AKT phosphorylation in pancreatic and adipose tissues. The network pharmacology analysis of all quality markers from the CQCQD revealed that six of them, among which is honokiol, possess high-affinity binding to AKT1 [138]. In a recent investigation, honokiol has stimulated adipocyte differentiation in murine adipocytes through SIRT3 activation.…”