Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2022; 28(32): 4635-4648
Published online Aug 28, 2022. doi: 10.3748/wjg.v28.i32.4635
The mechanism of Yinchenhao decoction in treating obstructive-jaundice-induced liver injury based on Nrf2 signaling pathway
Jun-Jian Liu, Yan Xu, Shuai Chen, Cheng-Fei Hao, Jing Liang, Zhong-Lian Li
Jun-Jian Liu, Cheng-Fei Hao, Zhong-Lian Li, The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
Yan Xu, Graduate School, Tianjin Medical University, Tianjin 3000070, China
Shuai Chen, Department of Thoracic Surgery, Xuzhou City Hospital of Traditional Chinese Medicine, Xuzhou 221000, Jiangsu Province, China
Jing Liang, School of Foreign Languages, Chengdu University of Traditional Chinese Medicine, Chengdu 610000, Sichuan Province, China
Author contributions: Liu JJ, Xu Y, and Li ZL designed and coordinated the study; Liu JJ, Xu Y, and Chen S performed the experiments and acquired the data; Xu Y, Chen S, and Hao CF analyzed the data; Liu JJ, and Xu Y wrote the manuscript; Liang J proofread the manuscript; and All authors approved the final version of the article.
Supported by the Scientific and Technological Project in Key Areas of Traditional Chinese Medicine of Tianjin Municipal Health and Health Committee, China, No. 2019003; and the Integrated Traditional Chinese and Western Medicine Project of Tianjin Municipal Health and Health Committee, China, No. 2021042.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Tianjin Medical University Nankai Hospital.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (license No. SCXK Jin 2020-0008). The experimental protocol was approved by the Animal Research Committee of Tianjin Medical University Nankai Hospital (approval No. NKYY-DWLL-2021-102).
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
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 NonCommercial (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: Zhong-Lian Li, MD, PhD, Chief Doctor, Doctor, Professor, Surgeon, The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, No. 6 Changjiang Street, Nankai District, Tianjin 300102, China. nkyylzl@163.com
Received: March 24, 2022
Peer-review started: March 24, 2022
First decision: May 30, 2022
Revised: June 8, 2022
Accepted: June 24, 2022
Article in press: June 24, 2022
Published online: August 28, 2022
Processing time: 155 Days and 0.1 Hours
Abstract
BACKGROUND

Obstructive jaundice (OJ) is caused by bile excretion disorder after partial or complete bile duct obstruction. It may cause liver injury through various mechanisms. Traditional Chinese medicine (TCM) has a lot of advantages in treating OJ. The recovery of liver function can be accelerated by combining Chinese medicine treatment with existing clinical practice. Yinchenhao decoction (YCHD), a TCM formula, has been used to treat jaundice. Although much progress has been made in recent years in understanding the mechanism of YCHD in treating OJ-induced liver injury, it is still not clear.

AIM

To investigate chemical components of YCHD that are effective in the treatment of OJ and predict the mechanism of YCHD.

METHODS

The active components and putative targets of YCHD were predicted using a network pharmacology approach. Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes path enrichment analysis were carried out by cluster profile. We predicted the biological processes, possible targets, and associated signaling pathways that YCHD may involve in the treatment of OJ. Thirty male Sprague–Dawley rats were randomly divided into three groups, each consisting of 10 rats: the sham group (Group S), the OJ model group (Group M), and the YCHD-treated group (Group Y). The sham group only received laparotomy. The OJ model was established by ligating the common bile duct twice in Groups M and Y. For 1 wk, rats in Group Y were given a gavage of YCHD (3.6 mL/kg) twice daily, whereas rats in Groups S and M were given the same amount of physiological saline after intragastric administration daily. After 7 d, all rats were killed, and the liver and blood samples were collected for histopathological and biochemical examinations. Total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), and aspartate transaminase (AST) levels in the blood samples were detected. The gene expression levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), and the nucleus positive rate of NF-E2 related factor 2 (Nrf2) protein were measured. Western blot analyses were used to detect the protein and gene expression levels of Nrf2, Kelch-like ECH-associated protein 1, NAD(P)H quinone dehydrogenase 1 (NQO1), and glutathione-S-transferase (GST) in the liver tissues. One-way analysis of variance was used to evaluate the statistical differences using the statistical package for the social sciences 23.0 software. Intergroup comparisons were followed by the least significant difference test and Dunnett’s test.

RESULTS

The effects of YCHD on OJ involve biological processes such as DNA transcription factor binding, RNA polymerase II specific regulation, DNA binding transcriptional activator activity, and nuclear receptor activity. The protective effects of YCHD against OJ were closely related to 20 pathways, including the hepatitis-B, the mitogen-activated protein kinase, the phosphatidylinositol 3-kinase/protein kinase B, and tumor necrosis factor signaling pathways. YCHD alleviated the swelling and necrosis of hepatocytes. Following YCHD treatment, the serum levels of TBIL (176.39 ± 17.03 μmol/L vs 132.23 ± 13.88 μmol/L, P < 0.01), DBIL (141.41 ± 14.66 μmol/L vs 106.43 ± 10.88 μmol/L, P < 0.01), ALT (332.07 ± 34.34 U/L vs 269.97 ± 24.78 U/L, P < 0.05), and AST (411.44 ± 47.64 U/L vs 305.47 ± 29.36 U/L, P < 0.01) decreased. YCHD promoted the translocation of Nrf2 into the nucleus (12.78 ± 0.99 % vs 60.77 ± 1.90 %, P < 0.001). After YCHD treatment, we found a decrease in iNOS (0.30 ± 0.02 vs 0.20 ± 0.02, P < 0.001) and an increase in eNOS (0.18 ± 0.02 vs 0.32 ± 0.02, P < 0.001). Meanwhile, in OJ rats, YCHD increased the expressions of Nrf2 (0.57 ± 0.03 vs 1.18 ± 0.10, P < 0.001), NQO1 (0.13 ± 0.09 vs 1.19 ± 0.07, P < 0.001), and GST (0.12 ± 0.02 vs 0.50 ± 0.05, P < 0.001), implying that the potential mechanism of YCHD against OJ-induced liver injury was the upregulation of the Nrf2 signaling pathway.

CONCLUSION

OJ-induced liver injury is associated with the Nrf2 signaling pathway. YCHD can reduce liver injury and oxidative damage by upregulating the Nrf2 pathway.

Keywords: Yinchenhao decoction; Obstructive jaundice; Network pharmacology; Liver injury; Animal models; Oxidative stress

Core tip: Obstructive Jaundice (OJ) may cause liver injury through various mechanisms. Traditional Chinese medicine has lots of advantages in treating OJ. The mechanism of Yinchenhao decoction (YCHD) for treating OJ-induced liver injury has made significant progress in recent years, but it is still unclear. We used the network pharmacology approach to predict the active components and putative targets of YCHD. We created the OJ rat models and through randomized controlled trials, concluded that YCHD could alleviate liver injury and oxidative damage, thereby promoting the translocation of NF-E2 related factor 2 (Nrf2) to the nucleus, and upregulating the Nrf2 signaling pathway.