Jieduan-Niwan Formula Reduces Liver Apoptosis in a Rat Model of Acute-on-Chronic Liver Failure by Regulating the E2F1-Mediated Intrinsic Apoptosis Pathway

Abstract

Acute-on-chronic liver failure (ACLF) is a serious and complicated disease that threatens human health because its pathogenesis is unclear, and the outcome of the current therapies has been less than satisfactory. A national famous doctor of traditional Chinese medicine, Qian Ying, created the Jieduan-Niwan Formula (JDNW), based on his long-term clinical experience. However, despite the good clinical outcome, the biological mechanism by which it works is unknown. In the current study, we established an ACLF rat model by administering human serum albumin (HSA) combined with D-galactosamine (D-GalN) and lipopolysaccharide (LPS) to explore the potential mechanism of JDNW in treating ACLF. The rats were treated with JDNW by administration of the model substances and sacrificed after 4, 8, and 12 h. Then we divided the rats into normal group, model at 4 h, model at 8 h, model at 12 h, JDNW at 4 h, JDNW at 8 h, and JDNW at 12 h. Biochemical and histopathological examinations were performed to compare the rats in different groups. Compared with the ACLF model group, expression levels of alanine transaminase, aspartate aminotransferase, total bilirubin, and TNF-α and IL-6 proteins were reduced in the JDNW group at the corresponding time points, the survival rates of rats were increased, and the pathological condition of the liver was improved. In addition, JDNW treatment improved the ultrastructure of hepatocytes and mitochondria and decreased the hepatocyte apoptosis index. E2F1, P53, P73, Apaf-1, p14ARF, caspase-3, caspase-6, and caspase-7 levels in the JDNW group were distinctly lower than those in the untreated rats. Moreover, Bcl-2 and Mcl-1 levels increased. Thus, JDNW decreases ACLF-induced mortality in rats by modulating the E2F1-mediated intrinsic apoptotic pathway.

Network Pharmacology Approach to Explore the Potential Mechanisms of Jieduan‐Niwan Formula Treating Acute‐on‐Chronic Liver Failure

“…The level of TNF is related to the severity and prognosis of ACLF [ 41 ]. In our previous study, it has been confirmed that JDNW Formula can reduce inflammatory factors such as TNF- α and IL-6 [ 10 ]. By regulating the pathways or related targets like PI3K/Akt pathway, GSK3, JNK, and AMPK, the cAMP signaling pathway is involved in hepatic physiological and pathological processes, including lipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and hepatocyte apoptosis [ 42 ].…”

“…According to the network, targets of JDNW Formula for treating ACLF are involved in the responses to oxidative stress, responses to the pathogen-associated molecular pattern (PAMP), regulation of inflammatory responses, apoptotic pathways, and cell proliferation. In fact, our previous study has proved that JDNW Formula can alleviate ACLF by regulating JNK-induced mitochondrial apoptotic pathway and E2F1-mediated intrinsic apoptosis pathway in vivo [ 9 , 10 ].…”

“…Rats were adaptively housed for 5 days before the experiment. As described in previous studies [ 10 ], rats were induced into immunological hepatic fibrosis using HSA. 6 weeks later, rats were given coadministration of 400 mg/kg D-GalN and 100 μ g/kg LPS intraperitoneal injection for the acute attack to construct the ACLF model.…”

“…Through the clinical observation of the efficacy of patients with ACLF, it is found that the comprehensive curative effect of JDNW Formula combined with the western medicine treatment group has an advantage compared with the western medicine treatment group [ 8 ]. Our previous studies have demonstrated that JDNW Formula increased the survival ratio of ACLF rats, improved liver function, downregulated the expression of inflammatory factors, and inhibited hepatocytes apoptosis by regulating mitochondrial apoptosis pathway mediated by E2F1 and JNK [ 9 , 10 ]. However, the effective compounds and potential mechanisms of JDNW Formula in the treatment of ACLF still needed to be further explored.…”

Uncovering bioactive compounds and potential mechanisms of Jieduan-Niwan Formula against liver failure

“…Future studies should discuss therapeutic potential against these diseases before clinical usage. Our previously published data showed that JDNW formula protected liver tissue against human serum albumin (HSA) combined with D-galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced liver failure, decreased mortality and inhibited hepatocyte apoptosis [20]. Therefore, the present study aimed at understanding the biological mechanisms of JDNW formula against liver failure and identi cation of important ingredients of this formula.…”