Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2022; 28(29): 3825-3837
Published online Aug 7, 2022. doi: 10.3748/wjg.v28.i29.3825
Qingyi decoction attenuates intestinal epithelial cell injury via the calcineurin/nuclear factor of activated T-cells pathway
Guan-Yu Wang, Dong Shang, Gui-Xin Zhang, Hui-Yi Song, Nan Jiang, Huan-Huan Liu, Hai-Long Chen
Guan-Yu Wang, Dong Shang, Gui-Xin Zhang, Hai-Long Chen, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Guan-Yu Wang, Dong Shang, Gui-Xin Zhang, Nan Jiang, Huan-Huan Liu, Hai-Long Chen, Institute of Integrative Medicine of Dalian Medical University, Dalian 116044, Liaoning Province, China
Hui-Yi Song, Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Author contributions: Wang GY, Shang D, and Chen HL designed the research; Wang GY, Jiang N, and Liu HH performed the research; Song HY, Wang GY and Zhang GX analyzed the data; Wang GY and Chen HL wrote the paper.
Supported by the National Key R and D Program of China, No. 2019YFE0119300; National Natural Science Foundation of China, No. 82074158; Project funded by China Postdoctoral Science Foundation, No. 2018M631793; Natural Science Foundation of Liaoning Province, No. 2019-ZD-0624; and Dalian Traditional Chinese Medicine-Related Scientific Research Project, No. 18Z2002.
Institutional animal care and use committee statement: This study was approved by the Animal Experimental Ethics Committee of Dalian Medical University (No. AEE19003).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hai-Long Chen, PhD, Chief Physician, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, Liaoning Province, China. hailongchen2014@yeah.net
Received: September 18, 2021
Peer-review started: September 18, 2021
First decision: December 4, 2021
Revised: December 15, 2021
Accepted: July 8, 2022
Article in press: July 8, 2022
Published online: August 7, 2022
Processing time: 319 Days and 6.4 Hours
Abstract
BACKGROUND

Recent studies have demonstrated that dysfunction of the intestinal barrier is a significant contributing factor to the development of severe acute pancreatitis (SAP). A stable intestinal mucosa barrier functions as a major anatomic and functional barrier, owing to the balance between intestinal epithelial cell (IEC) proliferation and apoptosis. There is some evidence that calcium overload may trigger IEC apoptosis and that calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling might play an important role in calcium-mediated apoptosis.

AIM

To investigate the potential mechanisms underlying the therapeutic effect of Qingyi decoction (QYD) in SAP.

METHODS

A rat model of SAP was created via retrograde infusion of sodium deoxycholate. Serum levels of amylase, tumor necrosis factor (TNF-α), interleukin (IL)-6, D-lactic acid, and diamine oxidase (DAO); histological changes; and apoptosis of IECs were examined in rats with or without QYD treatment. The expression of the two subunits of CaN and NFAT in intestinal tissue was measured via quantitative real-time polymerase chain reaction and western blotting. For in vitro studies, Caco-2 cells were treated with lipopolysaccharide (LPS) and QYD serum, and then cell viability and intracellular calcium levels were detected.

RESULTS

Retrograde infusion of sodium deoxycholate increased the severity of pancreatic and intestinal pathology and the levels of serum amylase, TNF-α, and IL-6. Both the indicators of intestinal mucosa damage (D-lactic acid and DAO) and the levels of IEC apoptosis were elevated in the SAP group. QYD treatment reduced the serum levels of amylase, TNF-α, IL-6, D-lactic acid, and DAO and attenuated the histological findings. IEC apoptosis associated with SAP was ameliorated under QYD treatment. In addition, the protein expression levels of the two subunits of CaN were remarkably elevated in the SAP group, and the NFATc3 gene was significantly upregulated at both the transcript and protein levels in the SAP group compared with the control group. QYD significantly restrained CaN and NFATc3 gene expression in the intestine, which was upregulated in the SAP group. Furthermore, QYD serum significantly decreased the LPS-induced elevation in intracellular free Ca2+ levels and inhibited cell death.

CONCLUSION

QYD can exert protective effects against intestinal mucosa damage caused by SAP and the protective effects are mediated, at least partially, by restraining IEC apoptosis via the CaN/NFATc3 pathway.

Keywords: Severe acute pancreatitis; Intestinal epithelial cell; Apoptosis; Calcineurin/nuclear factor of activated T-cells pathway; Qingyi decoction

Core Tip: This manuscript investigated the role of the calcineurin (CaN)/nuclear factor of activated T-cells (NFATc3) pathway in the apoptosis of intestinal epithelial cells (IECs) in severe acute pancreatitis (SAP) and the potential mechanisms underlying the therapeutic effect of Qingyi decoction (QYD). QYD significantly restrained CaN and NFATc3 gene expression in the intestine, ameliorated IEC apoptosis associated with SAP, and decreased the lipopolysaccharide-induced elevation in intracellular free Ca2+ levels and cell death. These findings suggest that the protective effects of QYD might be mediated, at least partially, by downregulating IEC apoptosis via the CaN/NFATc3 pathway.