کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6119207 | 1592286 | 2015 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease
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کلمات کلیدی
TGF-β pathwayHSCsECMCBDLALK5qPCRCTHRC1FBSDMEMTGF-βphosphorylated Smadα-SMAactivin receptor-like kinase 5ddC - DDCDulbecco's modified Eagle Medium - Eagle Medium اصلاح شده DulbeccoH&E - H & EAdenovirus - آدنوویروسalpha smooth muscle actin - آلفا آکتیو عضله صافchromatin immunoprecipitation - ایمن سازی کروماتینImmunoblot - ایمونوبولتtransforming growth factor-β - تبدیل فاکتور رشد βfetal bovine serum - سرم جنین گاوHepatic stellate cell - سلول ستاره ای کبدیHepatic stellate cells - سلولهای ستارهای کبدیCo-IP - شرکت-IPHepatic fibrosis - فیبروز کبدیExtracellular matrix - ماتریکس خارج سلولیCo-Immunoprecipitation - هم ایمن زداییHematoxylin & Eosin - هماتوکسیلین و ائوزینquantitative real-time polymerase chain reaction - واکنش زنجیره ای پلیمراز کمی زمان واقعی استcommon bile duct ligation - پیوند مجرای صفراوی مشترکCHiP - چیپ
موضوعات مرتبط
علوم زیستی و بیوفناوری
ایمنی شناسی و میکروب شناسی
ایمونولوژی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Collagen triple helix repeat containing-1 (Cthrc1) is a documented specific inhibitor of TGF-β signaling. Based on this observation, we developed the hypothesis that knocking in/knocking out the Cthrc1 gene in murine models of cholestasis would alter the natural history of cholestatic fibrosis. To study this thesis, we studied two murine models of fibrosis, first, common bile duct ligation (CBDL) and second, feeding of 3, 5-diethoxy-carbonyl-1, 4-dihydrocollidine (DDC). In both models, we administered well-defined adenoviral vectors that expressed either Cthrc1 or, alternatively, a short hairpin RNA (shRNA)-targeting Cthrc1 either before or after establishment of fibrosis. Importantly, when Cthrc1 gene expression was enhanced, we noted a significant improvement of hepatic fibrosis, both microscopically and by analysis of fibrotic gene expression. In contrast, when Cthrc1 gene expression was deleted, there was a significant exacerbation of fibrosis. To identify the mechanism of action of these significant effects produced by knocking in/knocking out Cthrc gene expression, we thence studied the interaction of Cthrc1 gene expression using hepatic stellate cells (HSCs) and human LX-2 cells. Importantly, we demonstrate that Cthrc1 is induced by TGF-β1 via phospho-Smad3 binding to the promoter with subsequent transcription activation. In addition, we demonstrate that Cthrc1 inhibits TGF-β signaling by accelerating degradation of phospho-Smad3 through a proteosomal pathway. Importantly, the anti-fibrotic effects can be recapitulated with a truncated fragment of Cthrc1. In conclusion, our findings uncover a critical negative feedback regulatory loop in which TGF-β1 induces Cthrc1, which can attenuate fibrosis by accelerating degradation of phospho-Smad3.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Autoimmunity - Volume 63, September 2015, Pages 76-87
Journal: Journal of Autoimmunity - Volume 63, September 2015, Pages 76-87
نویسندگان
Zhaolian Bian, Qi Miao, Wei Zhong, Haiyan Zhang, Qixia Wang, Yanshen Peng, Xiaoyu Chen, Canjie Guo, Li Shen, Fan Yang, Jie Xu, Dekai Qiu, Jingyuan Fang, Scott Friedman, Ruqi Tang, M. Eric Gershwin, Xiong Ma,