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

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

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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.

Original languageEnglish
Pages (from-to)1481-1491
Number of pages11
JournalApoptosis
Volume18
Issue number12
DOIs
Publication statusPublished - 2013 Dec 1

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All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

Cite this

Kim, D. Y., Chung, S. I., Ro, S. W., Paik, Y. H., Lee, J. I., Jung, M. K., Lee, M. G., Park, Y. N., Lee, K. S., Park, J. G., Park, H. D., & Han, K. H. (2013). Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats. Apoptosis, 18(12), 1481-1491. https://doi.org/10.1007/s10495-013-0896-5