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

Authors
 Do Young Kim  ;  Sook In Chung  ;  Simon Weonsang Ro  ;  Yong Han Paik  ;  Jung Il Lee  ;  Man Kil Jung  ;  Min Goo Lee  ;  Young Nyun Park  ;  Kwan Sik Lee  ;  Jung Gyu Park  ;  Hee Dong Park  ;  Kwang-Hyub Han 
Citation
 APOPTOSIS, Vol.18(12) : 1481-1491, 2013 
Journal Title
 APOPTOSIS 
ISSN
 1360-8185 
Issue Date
2013
MeSH
Animals ; Antioxidants/administration & dosage* ; Apoptosis/drug effects* ; Caspase Inhibitors/administration & dosage* ; Caspases/genetics ; Caspases/metabolism ; Collagen Type I/genetics ; Collagen Type I/metabolism ; Drug Therapy, Combination ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Liver Cirrhosis/drug therapy* ; Liver Cirrhosis/genetics ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/physiopathology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism
Keywords
Animals ; Antioxidants/administration & dosage* ; Apoptosis/drug effects* ; Caspase Inhibitors/administration & dosage* ; Caspases/genetics ; Caspases/metabolism ; Collagen Type I/genetics ; Collagen Type I/metabolism ; Drug Therapy, Combination ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Liver Cirrhosis/drug therapy* ; Liver Cirrhosis/genetics ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/physiopathology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism
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.
Full Text
http://link.springer.com/article/10.1007%2Fs10495-013-0896-5
DOI
10.1007/s10495-013-0896-5
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Liver Cirrhosis Clinical Research Center (간경변증임상연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영)
Ro, Simon Weonsang(노원상) ORCID logo https://orcid.org/0000-0003-2187-3698
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Lee, Kwan Sik(이관식) ORCID logo https://orcid.org/0000-0002-3672-1198
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lee, Jung Il(이정일) ORCID logo https://orcid.org/0000-0002-0142-1398
Chung, Sook In(정숙인) ORCID logo https://orcid.org/0000-0002-7915-9203
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/88460
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