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

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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.

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Acknowledgments

This study was funded in part by a Korea Healthcare Technology R&D Project from the Ministry for Health and Welfare, Republic of Korea (HI10C2020), and supported in part by a faculty research grant of Yonsei University College of Medicine for 2010 (6-2010-0032).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea

    Do Young Kim, Simon Weonsang Ro, Jung Il Lee, Kwan Sik Lee & Kwang-Hyub Han

  2. Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea

    Min Goo Lee

  3. Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

    Young Nyun Park

  4. Liver Cirrhosis Clinical Research Center, Seoul, Korea

    Do Young Kim, Sook In Chung, Simon Weonsang Ro, Jung Il Lee, Young Nyun Park, Kwan Sik Lee & Kwang-Hyub Han

  5. Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea

    Yong Han Paik

  6. Department of Chemistry, Yonsei University College of Science, Seoul, Korea

    Man Kil Jung

  7. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

    Sook In Chung

  8. LG Life Sciences, Ltd., Daejeon, Korea

    Jung Gyu Park & Hee Dong Park

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  1. Do Young Kim
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Corresponding author

Correspondence to Kwang-Hyub Han.

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Do Young Kim and Sook In Chung contributed equally to this work.

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Kim, D.Y., Chung, S.I., Ro, S.W. et al. Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats. Apoptosis 18, 1481–1491 (2013). https://doi.org/10.1007/s10495-013-0896-5

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  • DOI: https://doi.org/10.1007/s10495-013-0896-5

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