title: Rhus vernicifluaStokes attenuates cholestatic liver cirrhosis-induced interstitial fibrosis via Smad3 down-regulation and Smad7 up-regulation.
abstract: Cholestatic liver cirrhosis (CLC) eventually proceeds to end-stage liver failure by mediating overwhelming deposition of collagen, which is produced by activated interstitial myofibroblasts. Although the beneficial effects ofRhus vernicifluaStokes (RVS) on various diseases are well-known, its therapeutic effect and possible underlying mechanism on interstitial fibrosis associated with CLC are not elucidated. This study was designed to assess the protective effects of RVS and its possible underlying mechanisms in rat models of CLC established by bile duct ligation (BDL). We demonstrated that BDL markedly elevated the serological parameters such as aspartate aminotransferase, alanine transaminase, total bilirubin, and direct bilirubin, all of which were significantly attenuated by the daily uptake of RVS (2 mg/kg/day) for 28 days (14 days before and after operation) via intragastric route. We observed that BDL drastically induced the deterioration of liver histoarchitecture and excessive deposition of extracellular matrix (ECM), both of which were significantly attenuated by RVS. In addition, we revealed that RVS inhibited BDL-induced proliferation and activation of interstitial myofibroblasts, a highly suggestive cell type for ECM production, as shown by immunohistochemical and semi-quantitative detection of α-smooth muscle actin and vimentin. Finally, we demonstrated that the anti-fibrotic effect of RVS was associated with the inactivation of Smad3, the key downstream target of a major fibrogenic cytokine, i.e., transforming growth factor β (TGF-β). Simultaneously, we also found that RVS reciprocally increased the expression of Smad7, a negative regulatory protein of the TGF-β/Smad3 pathway. Taken together, these results suggested that RVS has a therapeutic effect on CLC, and these effects are, at least partly, due to the inhibition of liver fibrosis by the downregulation of Smad3 and upregulation of Smad7.
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Mi Na
authors.initials: MN
authors.lastname: Gil
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Du Ri
authors.initials: DR
authors.lastname: Choi
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Yu
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Ji Heun
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Dermatology, Chung-Ang University R&D Center, Seoul, Korea.
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Bak
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Do-Kyung
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Nam-Seob
authors.initials: NS
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Je-Hun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Young-Gil
authors.initials: YG
authors.lastname: Jeong
authors.affiliation: Lifetree Co., Ltd., Suwon, Korea.
authors.forename: Chun Soo
authors.initials: CS
authors.lastname: Na
authors.affiliation: Lifetree Co., Ltd., Suwon, Korea.
authors.forename: Dae Seung
authors.initials: DS
authors.lastname: Na
authors.affiliation: Department of Gastroenterology and Hepatology, Konyang University Hospital, Daejeon, Korea.
authors.forename: Ki-Hyun
authors.initials: KH
authors.lastname: Ryu
authors.affiliation: Department of Anatomy, Konyang University College of Medicine, Daejeon, Korea.; Myunggok Research Institute, Konyang University College of Medicine, Daejeon, Korea.
authors.forename: Seung Yun
authors.initials: SY
authors.lastname: Han
keywords: Bile duct ligation; Cholestatic liver cirrhosis; Rhus verniciflua Stokes