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Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats

Title
 Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats
Authors
 Do Young Kim; Sook In Chung; Kwang-Hyub Han; Hee Dong Park; Jung Gyu Park; Kwan Sik Lee; Young Nyun Park; Min Goo Lee; Man Kil Jung; Jung Il Lee; Yong Han Paik; Simon Weonsang Ro
Issue Date
2013
Journal Title
 Apoptosis
ISSN
 1360-8185
Citation
 Apoptosis, Vol.18(12) : 1481~1491, 2013
Abstract
We sought to determine the hepatic fibrosis-reversal effects upon simultaneous administration of lithospermate B (LAB), an anti-oxidant, and nivocasan, a caspase inhibitor, to rats compared with each compound alone. Liver fibrosis was induced in Sprague–Dawley rats by thioacetamide (TAA). Rats were treated with TAA and then given LAB and (or) nivocasan. Fibrotic areas were evaluated quantitatively by computerized morphometry. Apoptosis was assessed using a TUNEL assay, and immunohistochemical staining for malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE) was performed to assess oxidative stress levels. Real-time quantitative PCR was used to quantify expression of fibrosis-related genes. The degree of hepatic fibrosis was significantly reduced in rats treated with LAB and nivocasan compared to either treatment alone (P < 0.001). Treatment with each compound significantly decreased expression of fibrosis-related genes, such as type I collagen α1 (col1α1), α-SMA and TGF-β1 (P < 0.05). Co-treatment with LAB and nivocasan further reduced col1α1 expression compared to treatment with either compound. A TUNEL assay revealed that hepatocyte apoptosis was significantly decreased in the group treated with nivocasan compared to other groups (P < 0.01). Immunohistochemistry showed a decrease in MDA and 4HNE, reflecting amelioration of oxidative stress, when LAB or LAB+nivocasan was administered compared to nivocasan alone (P < 0.01). Nivocasan was found to inhibit caspase-1, -3, -7, -9 and gliotoxin-induced death of rat-derived hepatic stellate cells was inhibited by nivocasan administration without overexpression of α-SMA. Conclusions: Co-incidental administration of LAB and nivocasan suppressed oxidative stress and apoptosis, resulting in enhanced reversal of hepatic fibrosis in rat.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/88460
DOI
10.1007/s10495-013-0896-5
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Internal Medicine
1. 연구논문 > 1. College of Medicine > Dept. of Pathology
1. 연구논문 > 1. College of Medicine > Dept. of Pharmacology
1. 연구논문 > 5. Research Institutes > Liver Cirrhosis Clinical Research Center
1. 연구논문 > 1. College of Medicine > Yonsei Biomedical Research Center
Yonsei Authors
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Link
 http://link.springer.com/article/10.1007%2Fs10495-013-0896-5
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