bicyclol and Liver-Cirrhosis

Topics: Animals; Biphenyl Compounds; Drugs, Chinese Herbal; Genetic Therapy; Hepatocyte Growth Factor; Hepatocytes; Humans; Liver Cirrhosis; Plants, Medicinal; Ursodeoxycholic Acid

Bicyclol, a synthetic hepatoprotective and anti-inflammatory agent approved in China, was widely used to treat various hepatitis accompanied by elevated serum aminotransferases. However, the pharmacological effects and mechanisms of bicyclol on advanced liver diseases, such as fibrosis/cirrhosis and hepatocellular carcinoma (HCC), remain to be explored. Here, we revealed that bicyclol prevents from formatting severe fibrosis, slows the progression of moderate liver fibrosis, accelerates the regression of moderate liver fibrosis, decreases the malignancy of HCC in rat models induced by diethylnitrosamine (DEN), and also blocks steatohepatitis to HCC in mice induced by western diet plus carbon tetrachloride and DEN. The detailed pharmacological mechanism showed that bicyclol alleviates chronic progressive liver diseases by inhibiting the levels of IL-6 and subsequent phosphorylated STAT3. Conclusion: Bicyclol plays significant protective roles in multiply stages of fibrosis/cirrhosis-HCC and nonalcoholic fatty liver disease-related HCC via inhibiting IL-6/STAT3 signaling pathway. Therefore, bicyclol might be a promising therapeutic strategy for treating advanced liver diseases.

Topics: Animals; Biphenyl Compounds; Carcinoma, Hepatocellular; Disease Models, Animal; Interleukin-6; Liver; Liver Cirrhosis; Liver Neoplasms; Mice; Rats; Signal Transduction

Liver fibrosis results from chronic liver injury in conjunction with the accumulation of extracellular matrix proteins. The present study was performed to estimate the effect of bicyclol on bovine serum albumin (BSA)-induced immunological liver fibrosis in rats. Bicyclol (1) (100, 200, and 300 mg/kg) was given to rats by oral administration once a day for 5 weeks from the fourth week of intravenous injection of BSA. Blood and liver tissues were collected for the measurement of hydroxyproline (Hyp), procollagen type III (PIIIP), hyaluronic acid (HA), and transforming growth factor beta-1 (TGF-beta1) levels and liver pathological changes. The mRNA and protein expressions of hepatic TGF-beta1, interleukin-1 (IL-1), IL-10, MMP-2, TIMP-1, phosphorylated p38 (Pp38), and Smad2/3 were detected by reverse transcription polymerase chain reaction and Western blot. As a result, bicyclol significantly protected against BSA-induced liver fibrosis as evidenced by the reduction of elevated serum HA, PIIIP, and hepatic Hyp in rats, while liver pathological changes were also alleviated. The overexpressions of hepatic TGF-beta1, IL-1beta, IL-10, MMP-2, and TIMP-1 were suppressed by bicyclol in BSA-treated rats. The phosphorylations of Pp38 and Smad2/3 were also inhibited after bicyclol treatment. The hepatoprotection of bicyclol was mainly due to the modulation on the expression of inflammatory/anti-inflammatory cytokines, downregulation of hepatic TGF-beta1, and inhibition of hepatic collagen synthesis.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biphenyl Compounds; Dose-Response Relationship, Drug; Liver; Liver Cirrhosis; Male; Matrix Metalloproteinase 2; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sequence Homology, Nucleic Acid; Serum Albumin, Bovine; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta1