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Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models
BACKGROUND/AIMS: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treat...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Association of Internal Medicine
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271712/ https://www.ncbi.nlm.nih.gov/pubmed/35811365 http://dx.doi.org/10.3904/kjim.2021.138 |
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author | Kang, Seong Hee Yim, Hyung Joon Hwang, Ji-won Kim, Mi-jung Lee, Young-Sun Jung, Young Kul Yim, Hyungshin Kim, Baek-Hui Park, Hae-Chul Seo, Yeon Seok Kim, Ji Hoon Yeon, Jong Eun Um, Soon Ho Byun, Kwan Soo |
author_facet | Kang, Seong Hee Yim, Hyung Joon Hwang, Ji-won Kim, Mi-jung Lee, Young-Sun Jung, Young Kul Yim, Hyungshin Kim, Baek-Hui Park, Hae-Chul Seo, Yeon Seok Kim, Ji Hoon Yeon, Jong Eun Um, Soon Ho Byun, Kwan Soo |
author_sort | Kang, Seong Hee |
collection | PubMed |
description | BACKGROUND/AIMS: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. METHODS: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. RESULTS: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. CONCLUSIONS: The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis. |
format | Online Article Text |
id | pubmed-9271712 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Korean Association of Internal Medicine |
record_format | MEDLINE/PubMed |
spelling | pubmed-92717122022-07-13 Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models Kang, Seong Hee Yim, Hyung Joon Hwang, Ji-won Kim, Mi-jung Lee, Young-Sun Jung, Young Kul Yim, Hyungshin Kim, Baek-Hui Park, Hae-Chul Seo, Yeon Seok Kim, Ji Hoon Yeon, Jong Eun Um, Soon Ho Byun, Kwan Soo Korean J Intern Med Original Article BACKGROUND/AIMS: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. METHODS: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. RESULTS: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. CONCLUSIONS: The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis. Korean Association of Internal Medicine 2022-07 2022-06-08 /pmc/articles/PMC9271712/ /pubmed/35811365 http://dx.doi.org/10.3904/kjim.2021.138 Text en Copyright © 2022 The Korean Association of Internal Medicine https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Kang, Seong Hee Yim, Hyung Joon Hwang, Ji-won Kim, Mi-jung Lee, Young-Sun Jung, Young Kul Yim, Hyungshin Kim, Baek-Hui Park, Hae-Chul Seo, Yeon Seok Kim, Ji Hoon Yeon, Jong Eun Um, Soon Ho Byun, Kwan Soo Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models |
title | Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models |
title_full | Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models |
title_fullStr | Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models |
title_full_unstemmed | Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models |
title_short | Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models |
title_sort | improved anti-fibrotic effects by combined treatments of simvastatin and ns-398 in experimental liver fibrosis models |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271712/ https://www.ncbi.nlm.nih.gov/pubmed/35811365 http://dx.doi.org/10.3904/kjim.2021.138 |
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