Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats
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- 作者：Do Young Kim (1) (4)
Sook In Chung (4) (7)
Simon Weonsang Ro (1) (4)
Yong Han Paik (5)
Jung Il Lee (1) (4)
Man Kil Jung (6)
Min Goo Lee (2)
Young Nyun Park (3) (4)
Kwan Sik Lee (1) (4)
Jung Gyu Park (8)
Hee Dong Park (8)
Kwang-Hyub Han (1) (4) - 关键词：Hepatic fibrosis ; Caspase inhibitor ; Antioxidant ; Rat
- 刊名：Apoptosis
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：18
- 期：12
- 页码：1481-1491
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- 作者单位：Do Young Kim (1) (4)
Sook In Chung (4) (7)
Simon Weonsang Ro (1) (4)
Yong Han Paik (5)
Jung Il Lee (1) (4)
Man Kil Jung (6)
Min Goo Lee (2)
Young Nyun Park (3) (4)
Kwan Sik Lee (1) (4)
Jung Gyu Park (8)
Hee Dong Park (8)
Kwang-Hyub Han (1) (4)
1. Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
4. Liver Cirrhosis Clinical Research Center, Seoul, Korea
7. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
5. Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
6. Department of Chemistry, Yonsei University College of Science, Seoul, Korea
2. Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
3. Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
8. LG Life Sciences, Ltd., Daejeon, Korea - ISSN：1573-675X
文摘
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 Spragueawley 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 (col1), SMA and TGF- (P<0.05). Co-treatment with LAB and nivocasan further reduced col1 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 SMA. Conclusions: Co-incidental administration of LAB and nivocasan suppressed oxidative stress and apoptosis, resulting in enhanced reversal of hepatic fibrosis in rat.