title: N-methyl-4-isoleucine cyclosporine attenuates CCl -induced liver fibrosis in rats by interacting with cyclophilin B and D.
abstract: OBJECTIVE
  N-methyl-4-isoleucine cyclosporine (NIM811), a new analogue of cyclosporine A, can inhibit collagen deposition in vitro and reduce liver necrosis in a bile-duct-ligation animal model. However, whether NIM811 effects on CCl(4) -induced rat liver fibrosis, and the related mechanism has not been determined.
  
  
  METHODS
  A liver fibrosis model was induced in Wistar rats using CCl(4) for 6 weeks. Meanwhile, two different doses of NIM811 (low-dose 10 mg/kg and high-dose 20 mg/kg) were given to the CCl(4) -treated rats. Liver fibrosis was then evaluated according to histopathological scoring and liver hydroxyproline content. Serum alanine aminotransferase, aspartate aminotransferase and albumin levels, expression of matrix metalloproteinase-13, tissue inhibitor of metalloproteinase-1, α-smooth muscle actin and cyclophilin B and D in liver tissue were determined. Cyclophilin B and D were also studied in an hepatic stellate cell line.
  
  
  RESULTS
  Hydroxyproline content was decreased in both NIM811 groups compared with the model (P < 0.05). Liver necrosis and fibrosis were also attenuated in the NIM811 groups. NIM811 suppressed the expression of tissue inhibitor of metalloproteinase-1, transforming growth factor beta mRNA and α-smooth muscle actin protein in liver tissue. Expression of cyclophilin B in the fibrosis model was increased compared with the normal group (P < 0.05), and was decreased significantly in the low-dose NIM811 treatment group (P < 0.05), which indicated that cyclophilin B might have a profibrotic effect. In vitro studies revealed that cyclophilin B and/or D knockout were associated with collagen inhibition.
  
  
  CONCLUSIONS
  NIM811 attenuates liver fibrosis in a CCl(4)-induced rat liver fibrosis model, which may be related to binding with cyclophilin B and D.
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tailing
authors.initials: T
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: You
authors.forename: Jidong
authors.initials: J
authors.lastname: Jia
mesh_terms: D000199:Actins / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride; D002460:Cell Line; D024061:Collagen Type III / Q000235:genetics; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D002251:Carbon Tetrachloride; D024061:Collagen Type III; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D016572:Cyclosporine; D006909:Hydroxyproline; D053509:Matrix Metalloproteinase 13; D012333:RNA, Messenger; D012709:Serum Albumin; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; C498862:Acta2 protein, rat; C081786:cyclophilin B; C090438:(melle-4)cyclosporin; C507083:Mmp13 protein, rat