| N1-acetyl substituted pyrrolidine derivative CIP-A5: A novel compound that could ameliorate liver cirrhosis through modulation of hepatic stellate cell activity. | |
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MedLine Citation:
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PMID: 21349324 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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(2S,4R)-methyl 1-acetyl-4-(N-(4-bromophenyl)sulfamoyloxy)pyrrolidine-2-carboxylate (CIP-A5) is the N1-acetyl substituted pyrrolidine derivative which was designed against the structure of matrix metalloproteinase (MMP-2) and MMP-9. CIP-A5 has been considered as a candidate compound for treatment of liver cirrhosis. In this study, we evaluated the efficacy of CIP-A5 on the activity of hepatic stellate cells. CIP-A5 prevented the transforming growth factor β (TGF-β)-induced proliferation of hepatic stellate HSC-T6 cells as estimated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. CIP-A5 stimulated MMPs activity as evidenced by an increase of degradation of succinylated gelatin. Gelatin zymography analysis showed that CIP-A5 stimulated the secretion and activity of MMP-2 and MMP-9 in HSC-T6 cells. This stimulatory effect on MMPs was verified by the observation of increased expression of MMP-2 and MMP-9 as evaluated by Western blot assay. At the same time, a significant decrease of the expression of tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) was observed, suggesting a modulation of the balance of MMPs/TIMPs in hepatic stellate cells. CIP-A5 treatment also resulted in suppression of the profibrogenic cytokines, such as TGF-β, tumor necrosis factor alpha (TNF-α) and connective tissue growth factor (CTGF) in HSC-T6 cells. CIP-A5 did not have cytotoxicity to human normal hepatic cells. These results implied that CIP-A5 could selectively ameliorate the process of liver cirrhosis through modulation of activated hepatic stellate cell activity, which offers hope for prevention and treatment of this devastating end-stage liver disease. |
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Authors:
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Xiao-Dan Wang; Zu-Hua Gao; Xia Xue; Yan-Na Cheng; Pan Yue; Xu-Wen Fang; Xian-Jun Qu |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-2-21 |
Journal Detail:
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Title: Toxicology in vitro : an international journal published in association with BIBRA Volume: - ISSN: 1879-3177 ISO Abbreviation: - Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-2-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8712158 Medline TA: Toxicol In Vitro Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier Ltd. |
Affiliation:
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Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China; Department of Pharmacology, School of Pharmaceutical Sciences, Taishan Medical College, Taian, Shandong, China. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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