title: Cepharanthin, a biscoclaurine alkaloid, prevents destruction of acinar tissues in murine Sjögren's syndrome.
abstract: OBJECTIVE
  Our previous study suggested that suppression by cepharanthin of tumor necrosis factor-a (TNF-a)-induced matrix metalloproteinase-9 (MMP-9) could prevent destruction of the acinar structure in the salivary glands of patients with Sjögren's syndrome (SS). In this study, we observed that in vivo administration of cepharanthin prevented severe damage to acinar tissues in the murine model of human SS.
  
  
  METHODS
  Cepharanthin was intraperitoneally administered to thymectomized female NFS/sld mice. Inflammatory lesions in the salivary and lacrimal glands were then examined histologically. Expression of phosphorylated IkB-a, MMP-9, and type IV collagen was analyzed immunohistochemically. The apoptotic cell death of acinar cells was determined.
  
  
  RESULTS
  Although extensive mononuclear cell infiltration and destruction of acinar tissue in salivary and lacrimal glands were observed in control mice, significant improvement of these lesions was evident in mice treated with cepharanthin. Immunohistochemical analysis revealed that p65, phosphorylated IkB-a, and MMP-9 were more strongly stained in the acinar cells of control mice than in cepharanthin-treated mice. Although no staining for type IV collagen was observed in the acinar tissues of control mice, continuity of staining for type IV collagen was observed in acinar tissues of cepharanthin-treated mice. Destruction of acinar tissues was attributed to the induction of apoptosis, suggesting that cepharanthin inhibits apoptosis by suppressing phosphorylation of IkB-a, followed by prevention of MMP-9 activation.
  
  
  CONCLUSIONS
  Our findings suggest that cepharanthin may be a promising agent for use in preventing destruction of acinar tissues in murine SS.
authors.affiliation: Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Tokushima, Japan. azumasa@dent.tokushima-u.ac.jp
authors.forename: Masayuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ashida
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tamatani
authors.forename: Katsumi
authors.initials: K
authors.lastname: Motegi
authors.forename: Natsumi
authors.initials: N
authors.lastname: Takamaru
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Sato
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D044182:Benzylisoquinolines; D002352:Carrier Proteins / Q000032:analysis; D024141:Collagen Type IV / Q000032:analysis; D005260:Female; D020672:I-kappa B Proteins / Q000032:analysis; D007150:Immunohistochemistry; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008817:Mice, Mutant Strains; D000072000:NF-KappaB Inhibitor alpha; D009363:Neoplasm Proteins / Q000032:analysis; D012469:Salivary Glands / Q000737:chemistry / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D012859:Sjogren's Syndrome / Q000188:drug therapy / Q000473:pathology*; D051996:Transcription Factor RelA; D052117:Benzodioxoles
chemical_list: D000470:Alkaloids; D044182:Benzylisoquinolines; D002352:Carrier Proteins; D024141:Collagen Type IV; D020672:I-kappa B Proteins; D020780:Matrix Metalloproteinase 9; D000072000:NF-KappaB Inhibitor alpha; D009363:Neoplasm Proteins; D051996:Transcription Factor RelA; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; C006947:cepharanthine; D052117:Benzodioxoles