{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T02:16:13Z","timestamp":1767838573082,"version":"3.49.0"},"reference-count":36,"publisher":"Korean Association of Internal Medicine","issue":"4","license":[{"start":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T00:00:00Z","timestamp":1654646400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/"}],"content-domain":{"domain":["kjim.org"],"crossmark-restriction":true},"short-container-title":["Korean J Intern Med"],"published-print":{"date-parts":[[2022,7,1]]},"abstract":"<jats:p>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-\u03b2 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.<\/jats:p>","DOI":"10.3904\/kjim.2021.138","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T00:42:59Z","timestamp":1656463379000},"page":"745-756","update-policy":"https:\/\/doi.org\/10.3904\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models"],"prefix":"10.3904","volume":"37","author":[{"given":"Seong Hee","family":"Kang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6036-2754","authenticated-orcid":true,"given":"Hyung 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