title: Didymin Alleviates Hepatic Fibrosis Through Inhibiting ERK and PI3K/Akt Pathways via Regulation of Raf Kinase Inhibitor Protein.
abstract: BACKGROUND
  Didymin has been reported to have anti-cancer potential. However, the effect of didymin on liver fibrosis remains illdefined.
  
  
  METHODS
  Hepatic fibrosis was induced by CCl4 in rats. The effects of didymin on liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminases activities and collagen-related indicators levels were determined by commercially available kits. Moreover, the effects of didymin on hepatic stellate cell apoptosis and cell cycle were analyzed by flow cytometry. Mitochondrial membrane potential was detected by using rhodamine-123 dye. The expression of Raf kinase inhibitor protein (RKIP) and the phosphorylation of the ERK/MAPK and PI3K/Akt pathways were assessed by Western blot.
  
  
  RESULTS
  Didymin significantly ameliorated chronic liver injury and collagen deposition. It strongly inhibited hepatic stellate cells proliferation, induced apoptosis and caused cell cycle arrest in G2/M phase. Moreover, didymin notably attenuated mitochondrial membrane potential, accompanied by release of cytochrome C. Didymin significantly inhibited the ERK/MAPK and PI3K/Akt pathways. The effects of didymin on the collagen accumulation in rats and on the biological behaviors of hepatic stellate cells were largely abolished by the specific RKIP inhibitor locostatin.
  
  
  CONCLUSIONS
  Didymin alleviates hepatic fibrosis by inhibiting ERK/MAPK and PI3K/Akt pathways via regulation of RKIP expression.
authors.affiliation: Guangxi Medical University, Nanning, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Lin
authors.forename: Faicheng
authors.initials: F
authors.lastname: Bai
authors.forename: Jinlan
authors.initials: J
authors.lastname: Nie
authors.forename: Shengjuan
authors.initials: S
authors.lastname: Lu
authors.forename: Chunyuang
authors.initials: C
authors.lastname: Lu
authors.forename: Xunshuai
authors.initials: X
authors.lastname: Zhu
authors.forename: Jinbin
authors.initials: J
authors.lastname: Wei
authors.forename: Zhongpeng
authors.initials: Z
authors.lastname: Lu
authors.forename: Quanfang
authors.initials: Q
authors.lastname: Huang
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D006027:Glycosides / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D020169:Caspases; D018797:Cell Cycle Proteins; D003094:Collagen; D045304:Cytochromes c; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D006027:Glycosides; D049488:Phosphatidylethanolamine Binding Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; C550693:PEBP1 protein, rat; C552234:didymin