Hepatocyte necrosis plays an important role in the progression of ALF. 4 In the future, if a novel therapy can effectively reduce the hepatocyte damage and reduce the local and systemic inflammatory response of the liver, it will greatly reduce the fatality rate of ALF and buy time for liver transplantation. 3 Scarcity of liver donors, concurrent systemic inflammatory response syndrome (SIRS), and sepsis often lead to premature death of ALF patients before liver transplantation. Despite the progress in treatment methods, ALF mortality has not been significantly improved for a long time, and studies have shown that ALF mortality without liver transplantation is still close to 90%. 2 Clinical treatment of ALF mainly includes internal medical treatment, artificial liver support therapy, stem cell transplantation, etc. 1 Hepatotropic viruses infection and drug-induced liver injury contribute to the majority of ALF cases. The main clinical manifestations of ALF are jaundice and coagulopathy (international normalized ratio ≥1.5), which rapidly progresses to hepatic encephalopathy. ALF is defined as the rapid loss of liver function caused by severe acute liver injury in the absence of known underlying chronic liver disease. The concept of fulminant hepatitis and fulminant liver failure was introduced by Roger Williams et al in 1993 and is often used as a related surrogate term for ALF.
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Keywords: acute liver failure, Sini Decoction plus Ginseng Soup, PPARα, necroptosis, damage-associated molecular patterns, proinflammatory
The expression of CPT1A, a key enzyme involved in fatty acid β-oxidation, was found to be significantly up-regulated in the SNRS treated group, accompanied by an increased adenosine-triphosphate (ATP) level, which may be the relevant mechanism by which SNRS reduces necroptosis.Ĭonclusion: The potential therapeutic effect of SNRS on ALF may be through promoting the expression of PPARα and increasing the level of ATP in liver tissue, thereby inhibiting necroptosis of hepatocytes, reducing hepatocyte damage, and improving liver function. Reduced necroptosis resulted in decreased HMGB1 release, which in turn inhibited the activation of TLR4-JNK and NLRP3 inflammasome signaling pathways and the expression of NF-κB protein induced by LPS/D-GalN.
Further mechanism studies showed that SNRS significantly promoted the protein expression of PPARα and decreased the expression of necroptosis proteins (RIP3, MLKL, p-MLKL) in ALF mice. The survival rate of ALF mice treated with SNRS was significantly increased. Results: The protective effect of SNRS on the ALF model is mainly reflected in the reduction of serum alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) as well as the ameliorated pathology of the liver tissue. The animals are grouped as follows: Control group (vehicle-treated), Model group (LPS/D-GalN+DMSO), SNRS group (LPS/D-GalN+SNRS+DMSO), Inhibitor group (LPS/D-GalN+GW6471), Agonist group (LPS/D-GalN+WY14643), and Inhibitor+SNRS group (LPS/D-GalN+GW6471+SNRS). On this basis, the peroxisome proliferator-activated receptor (PPAR) α agonist (WY14643) and inhibitor (GW6471) were added to verify whether the therapeutic mechanism of SNRS is related to its promoting effect on PPARα. Methods: To study the protective effect of SNRS on ALF mice, the ICR mice were firstly divided into 4 groups: Control group (vehicle-treated), Model group (LPS/D-GalN), SNRS group (LPS/D-GalN+SNRS), and Silymarin group (LPS/D-GalN+Silymarin), the therapeutic drug was administered by gavage 48h, 24h before, and 10 min after LPS/D-GalN injection.
Purpose: This study aimed to investigate the improvement effect of Sini Decoction plus Ginseng Soup (SNRS) on the LPS/D-GalN-induced acute liver failure (ALF) mouse model and the molecular mechanism of the SNRS effect. *These authors contributed equally to this workĬorrespondence: Xiaoyu Hu, Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, No. Ying He, 1, 2, * Yang Zhang, 3, * Junli Zhang, 2 Xiaoyu Hu 3ġDepartment of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, People’s Republic of China 2Department of College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China 3Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
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