https://orcid.org/0000-0001-8451-6335
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Abstract
Background
Acute-on-chronic liver failure (ACLF) is a severe, complicated human disease. E2F1-mediated apoptosis plays an important role in ACLF development. Jieduan-Niwan (JDNW) formula, a traditional Chinese medicine (TCM), has shown remarkable clinical efficacy in ACLF treatment. However, the hepatoprotective mechanisms of the formula are barely understood.
Purpose
This study aimed to investigate the mechanisms of JDNW formula in ACLF treatment by specifically regulating E2F1-mediated apoptotic signaling pathways in rats.
Methods
The JDNW components were determined by high-performance liquid chromatography (HPLC) analysis. The ACLF rat model was established using human serum albumin immune-induced liver cirrhosis, followed by D-galactosamine and lipopolysaccharide joint acute attacks. The ACLF rat was treated with JDNW formula. Prothrombin time activity was measured to investigate the coagulation function. Liver pathological injury was observed by hematoxylin-eosin (HE) and reticular fiber staining. The hepatocyte apoptosis index and apoptosis rate were determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and flow cytometry, respectively. Additionally, the expression of key genes and proteins that regulate E2F1-mediated apoptosis was analyzed by quantitative real-time PCR and Western blot.
Results
Seven major components of JDNW formula were detected. The formula ameliorated the coagulation function, decreased the hepatocyte apoptosis index and apoptosis rate, and alleviated liver pathological damage in ACLF rats. The down-regulation of the expression of genes and proteins from p53-dependent and non-p53-dependent apoptosis pathways and the up-regulation of the expression of genes from blocking anti-apoptotic signaling pathways indicated that JDNW formula inhibited excessive hepatocyte apoptosis in ACLF rats via E2F1-mediated apoptosis signaling pathways.
Conclusion
The findings indicate that JDNW formula protects livers of ACLF rats by inhibiting E2F1-mediated apoptotic signaling pathways, implying that these pathways might be a potential therapeutic target for ACLF treatment.
Acknowledgments
This work was supported by the National Natural Science Foundation of China [grant number 81573767], and the National Key Research and Development Program of China – Research on Inheritance and Innovation of Experience (Integration of Tao and Shu) of Illustrious Senior Traditional Chinese Medicine Practitioners by adopting Multiple Research Methods [grant number 2018YFC1704100] and its subproject-Research on the Academic Viewpoints, Unique Diagnostic and Treatment Methods and Major Diseases Prevention and Treatment Experience of Illustrious Senior Traditional Chinese Medicine Practitioners in Eastern China [grant number 2018YFC1704102]. We gratefully acknowledge the contributions of Dr Weina Hou (Department of Biology, University of Minho, Portugal) for providing language assistance, including writing assistance, organizing, reading, correcting and vetting the manuscript.
Ethical Approval
All animal experiments were approved by the Animal Ethics Committee of the Capital Medical University (approval ID: AEEI-2015-187) and performed in accordance with the Guide for the Care and Use of Laboratory Animals of the Beijing Municipal Government.
Disclosure
The authors report no conflicts of interest in relation to this work.