title: Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats via inhibiting MMP2/9, TIMP1/2 and the TGF-β/Smad signaling pathways.
abstract: OBJECTIVE
  Chinese medicine CGA formula consists of polysaccharide from Cordyceps sinensis mycelia (CS-PS), gypenosides and amygdalin, which is derived from Fuzheng Huayu (FZHY) capsule for treating liver fibrosis. In this study we attempted to confirm the therapeutic effects of CGA formula in dimethylnitrosamine (DMN)-induced liver fibrosis in rats, and to identify the mechanisms of anti-fibrotic actions.
  
  
  METHODS
  Rats were injected with DMN (10 mg·kg(-1)·d(-1), ip) for 3 consecutive days per week over a 4-week period. The rats then were orally administered with CGA formula (CS-PS 60 mg·kg(-1)·d(-1), gypenosides 50 mg·kg(-1)·d(-1) and amygdalin 80 mg·kg(-1)·d(-1)) daily in the next 2 weeks. CS-PS, gypenosides or amygdalin alone were administered as individual component controls, whereas colchicine and FZHY were used as positive controls. Serum biomarkers were measured. Hepatic injury, collagen deposition and stellate cell activation were examined. The MMP activities, expression of TIMP protein and proteins involved in the TGF-β1/Smad signaling pathways in liver tissues were assayed.
  
  
  RESULTS
  In DMN-treated rats, administration of CGA formula significantly decreased serum ALT, AST and total bilirubin and hepatic hydroxyproline levels, increased serum albumin level, and attenuated liver fibrosis as shown by histological examination. Furthermore, these effects were comparable to those caused by administration of FZHY, and superior to those caused by administration of colchicine or the individual components of CGA formula. Moreover, administration of CGA formula significantly decreased the protein levels of α-SMA, TGF-β1, TGF-β1 receptor (TβR-I), p-TβR-I, p-TβR-II, p-Smad2, p-Smad3, TIMP1 and TIMP2, as well as MMP2 and MMP9 activities in liver tissues of DMN-treated rats.
  
  
  CONCLUSIONS
  Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats, and this effect was likely associated with the down-regulation of MMP2/9 activities, TIMP1/2 protein expression and the TGF-β1/Smad signaling pathways in the liver.
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Li
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai 201203, China.|Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Peng
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhao-Lin
authors.initials: ZL
authors.lastname: Sun
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Hua-Jie
authors.initials: HJ
authors.lastname: Tian
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Duan
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai 201203, China.|Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|E-Institute of TCM Internal Medicine, Shanghai Municipal Education Commission, Shanghai 201203, China.|Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai 201203, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|E-Institute of TCM Internal Medicine, Shanghai Municipal Education Commission, Shanghai 201203, China.|Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai 201203, China.
authors.forename: Yi-Yang
authors.initials: YY
authors.lastname: Hu
mesh_terms: D000678:Amygdalin / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D032661:Cordyceps / Q000737:chemistry; D004128:Dimethylnitrosamine; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000627:therapeutic use*; D029774:Gynostemma / Q000737:chemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D051785:Smad Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; C532829:fuzheng huayu; C474918:gypenoside; D019716:Tissue Inhibitor of Metalloproteinase-2; D000678:Amygdalin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004128:Dimethylnitrosamine