Drug Design, Development and Therapy (Sep 2021)
The Jieduan-Niwan (JDNW) Formula Ameliorates Hepatocyte Apoptosis: A Study of the Inhibition of E2F1-Mediated Apoptosis Signaling Pathways in Acute-on-Chronic Liver Failure (ACLF) Using Rats
Abstract
Weixin Hou,1– 4 Yulin Hao,1,2 Wenlong Yang,1,2 Tian Tian,1,2 Peng Fang,1,2 Yuqiong Du,1,2 Lianyin Gao,1,2 Yanbin Gao,3,4 Qiuyun Zhang1,2 1Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People’s Republic of China; 3Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 4Department of Endocrinology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Qiuyun ZhangDepartment of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, No. 10 You An Men Wai, Xi Tou Tiao, Feng Tai District, Beijing, 100069, People’s Republic of ChinaTel +86 10 8391 1638Email [email protected] GaoDepartment of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, No. 10 You An Men Wai, Xi Tou Tiao, Feng Tai District, Beijing, 100069, People’s Republic of ChinaTel +86 10 8391 1720Email [email protected]: 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.Keywords: traditional Chinese medicine, apoptosis, Jieduan-Niwan formula, acute-on-chronic liver failure rat model, E2F1, pharmacological effect
