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

doyoung 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, KwangHyub Han

Research output: Contribution to journalArticle

12 Citations (Scopus)

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

Fingerprint

Caspase Inhibitors
Rats
Fibrosis
Antioxidants
Liver
Oxidative stress
Thioacetamide
Oxidative Stress
In Situ Nick-End Labeling
Apoptosis
Malondialdehyde
Assays
Gliotoxin
Genes
Caspase 1
Hepatic Stellate Cells
Therapeutics
Collagen Type I
lithospermate B
Oxidants

All Science Journal Classification (ASJC) codes

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

Cite this

kim, doyoung ; Chung, Sook In ; Ro, Simon Weonsang ; Paik, Yong Han ; Lee, Jung Il ; Jung, Man Kil ; Lee, Min Goo ; Park, Young Nyun ; Lee, Kwan Sik ; Park, Jung Gyu ; Park, Hee Dong ; Han, KwangHyub. / Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats. In: Apoptosis. 2013 ; Vol. 18, No. 12. pp. 1481-1491.
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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.",
author = "doyoung kim and Chung, {Sook In} and Ro, {Simon Weonsang} and Paik, {Yong Han} and Lee, {Jung Il} and Jung, {Man Kil} and Lee, {Min Goo} and Park, {Young Nyun} and Lee, {Kwan Sik} and Park, {Jung Gyu} and Park, {Hee Dong} and KwangHyub Han",
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kim, D, Chung, SI, Ro, SW, Paik, YH, Lee, JI, Jung, MK, Lee, MG, Park, YN, Lee, KS, Park, JG, Park, HD & Han, K 2013, 'Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats', Apoptosis, vol. 18, no. 12, pp. 1481-1491. https://doi.org/10.1007/s10495-013-0896-5

Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats. / kim, doyoung; Chung, Sook In; Ro, Simon Weonsang; Paik, Yong Han; Lee, Jung Il; Jung, Man Kil; Lee, Min Goo; Park, Young Nyun; Lee, Kwan Sik; Park, Jung Gyu; Park, Hee Dong; Han, KwangHyub.

In: Apoptosis, Vol. 18, No. 12, 01.12.2013, p. 1481-1491.

Research output: Contribution to journalArticle

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T1 - Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats

AU - kim, doyoung

AU - Chung, Sook In

AU - Ro, Simon Weonsang

AU - Paik, Yong Han

AU - Lee, Jung Il

AU - Jung, Man Kil

AU - Lee, Min Goo

AU - Park, Young Nyun

AU - Lee, Kwan Sik

AU - Park, Jung Gyu

AU - Park, Hee Dong

AU - Han, KwangHyub

PY - 2013/12/1

Y1 - 2013/12/1

N2 - 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.

AB - 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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