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

Xinmin Yang; Linbo Yao; Mei Yuan; Xiaoying Zhang; Monika A Jakubowska; Pawel E Ferdek; Lei Dai; Jingyu Yang; Tao Jin; Lihui Deng; Xianghui Fu; Dan Du; Tingting Liu; David N Criddle; Robert Sutton; Wei Huang; Qing Xia

doi:10.3389/fphar.2022.896523

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

Front Pharmacol. 2022 Jun 8:13:896523. doi: 10.3389/fphar.2022.896523. eCollection 2022.

Authors

Xinmin Yang¹, Linbo Yao¹, Mei Yuan¹, Xiaoying Zhang¹, Monika A Jakubowska², Pawel E Ferdek³, Lei Dai⁴, Jingyu Yang¹, Tao Jin¹, Lihui Deng¹, Xianghui Fu⁴, Dan Du⁵, Tingting Liu¹, David N Criddle⁶, Robert Sutton⁷, Wei Huang^{1

8}, Qing Xia¹

Affiliations

¹ Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China.
² Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
³ Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
⁴ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
⁵ Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
⁶ Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
⁷ Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
⁸ Institutes for Systems Genetics & Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.

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.

Keywords: Chaiqin chengqi decoction; PI3K/Akt pathway; antioxidant protein response; obesity-related acute pancreatitis; pharmacology network analysis; transcriptomics.