Abstract
Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 μM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl4). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl4 through the intraperitoneal injection of 1 mL/kg CCl4 and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl4-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl4 and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl4 to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl4 treatment. Furthermore, the apoptotic response induced by CCl4 treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl4.
Highlights
Liver is the major organ where chemicals and drugs are processed and metabolized [1].Damage to the liver poses a serious and fatal risk
We evaluated the toxicity of CCl4 on HepG2 cells in a time-dependent and dosedependent manner
In order to enumerate whether CCl4 administration to mice would trigger apoptosis, we evaluated the expression of apoptosis-associated markers
Summary
Liver is the major organ where chemicals and drugs are processed and metabolized [1]. Damage to the liver poses a serious and fatal risk. Liver fibrosis has been one of the critical issues in the medical community because of the significant cases of morbidity and mortality worldwide. Medical negligence associated with these alterations leads to fibrosis, progressing to cirrhosis, carcinoma, liver failure, and death. The major causes of liver fibrosis include chronic ethanol consumption, non-alcoholic steatohepatitis, viral infections such as hepatitis B and hepatitis C, helminthes infection, excessive amount of iron and copper in the body, obstruction to the bile ducts, and drug-induced liver damage [2,3]. A fibrotic liver is distinguished by the excessive deposition of extracellular matrix (ECM)
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