Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease

Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we evaluated the effects of pharmacological A2AR and A1R activation. The A2AR agonist CGS21680 protected the primary steatotic murine hepatocyte from IR damage and the activation of ASK1 and JNK. Such an effect was attributed to a phosphatidylinositol-3-kinase (PI3K)/Akt-dependent inhibition of ASK1. By contrast, the A1R agonist CCPA enhanced IR damage, intracellular steatosis and oxidative species (OS) production, thereby further increasing the lipid/OS-dependent ASK1-JNK stimulation. The CGS2680 and CCPA effects were nullified by a genetic ASK1 downregulation in steatotic hepatoma C1C7 cells. In steatotic mice livers, CGS21680 protected against hepatic IRI and ASK1/JNK activation whereas CCPA aggravated hepatic steatosis and IRI, and enhanced ASK1 and JNK stimulation. These results evidence a novel mechanism of CGS21680-mediated hepatoprotection, i.e., the PI3K/AKT-dependent inhibition of ASK1, and they show that CGS21680 and CCPA reduces and enhances the IRI of fatty liver, respectively, by preventing or increasing the activation of the cytotoxic ASK1/JNK axis. They also indicate the selective employment of A2AR agonists as an effective therapeutic strategy to prevent IRI in human fatty liver surgery.

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A Review of Research Progress on Agathis dammara and Its Application Prospects for Cardiovascular Diseases and Fatty Liver Disease

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666201117110834 ◽

2020 ◽

Vol 20 ◽

Author(s):

Anyi Wang ◽

Shanshan Yue ◽

Ankang Peng ◽

Rong Qi

Keyword(s):

Liver Disease ◽

Cardiovascular Diseases ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Modern Society ◽

Research Progress ◽

Myocardial Ischemia Reperfusion ◽

Application Prospects

: Cardiovascular diseases and fatty liver disease have become the leading causes of death in modern society. However, currently existing drugs do not solve all issues related to these diseases; thus, it is expected that more potential drugs for clinical use will be developed. Undeniably, natural products have attracted increasing attention. It is of great significance to identify effective active monomer components for drug discovery and disease prevention. As a pure natural product, Agathis dammara (AD) has antioxidant, hypolipidemic, hypoglycemic, antitumor and anti-inflammatory activities. However, at present, there are few reports regarding the effects of AD on chronic inflammatory cardiovascular diseases such as aneurysm, atherosclerosis, myocardial ischemia-reperfusion injury, and cardiac hypertrophy and liver diseases such as fatty liver disease. AD and products derived from it have very broad application prospects for cardiovascular diseases and fatty liver disease.

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