title: Antifibrotic effects of tanshinol in experimental hepatic fibrosis by targeting PI3K/AKT/mTOR/p70S6K1 signaling pathways.
abstract: Tanshinol is a water-soluble bioactive monomer purified from the dried root of Salvia miltiorrhiza and has been reported to exert hepatoprotective efficacy in rodents. However, detailed knowledge remains limited about tanshinol's effects on hepatic stellate cells (HSC) functions, which play an essential role in the progression of hepatic fibrosis. Our research primarily focused on the effects of tanshinol on activation and apoptosis of HSC and further investigated PI3K/AKT/mTOR/p70S6K1 signaling pathways' participation in the pathogenesis of hepatic fibrosis in carbon tetrachloride (CCl4)-induced hepatic fibrosis.
  
  
  
  The antifibrotic effects of tanshinol on the development of fibrosis were established through CCl4-induced rat models. 48 male Sprague-Dawley (SD) rats were randomized to the normal group, CCl4 model group, and two tanshinol treatment groups, including a lower dosage group as well as a higher dosage group.
  
  
  
  Tanshinol prominently mitigated liver fibrosis and reduced levels of alanine aminotransferase (ALT), aspartate transaminase (AST), hydroxyproline content, and other serum markers of liver fibrosis. Concomitantly, tanshinol regulated the degradation of extracellular matrix as well as hepatic sinusoid and inhibited the expression of inflammation-related genes. Tanshinol promoted apoptosis of the activated HSC and increased cleaved caspase 3 levels and the number of TUNEL-positive HSC in two tanshinol-administered groups. In addition, tanshinol significantly inhibited the expression of phosphorylated AKT, phosphorylated mTOR, and phosphorylated p70S6K1 proteins.
  
  
  
  This study demonstrates that tanshinol exerts antifibrotic effects through targeting multiple mechanisms correlated with PI3K/AKT/mTOR/p70S6K1 signaling pathways, and has the prospect of becoming a new treatment strategy for hepatic fibrosis.
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ruqin
authors.initials: R
authors.lastname: Peng
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shaozhan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Yuan
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015153:Blotting, Western; D002109:Caffeic Acids / Q000627:therapeutic use*; D002251:Carbon Tetrachloride / Q000633:toxicity; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D002109:Caffeic Acids; D002251:Carbon Tetrachloride; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C585969:tanshinol