{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:35:43Z","timestamp":1790012143248,"version":"4.0.1"},"reference-count":58,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bio &amp; Medical Technology Development Program of the National Research Foundation (NRF)","award":["#2021M3A9E4081652"],"award-info":[{"award-number":["#2021M3A9E4081652"]}]},{"name":"Bio &amp; Medical Technology Development Program of the National Research Foundation (NRF)","award":["#NRF-2017M3A9E9032772"],"award-info":[{"award-number":["#NRF-2017M3A9E9032772"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Lettuce (Lactuca sativa L.) contains various bioactive compounds that can reduce the severity of inflammatory diseases. This study aimed to identify therapeutic effects and underlying mechanisms of fermented lettuce extract (FLE) containing stable nitric oxide (NO) on collagen-induced arthritis (CIA) in mice and fibroblast-like synoviocytes (MH7A line) from patients with rheumatoid arthritis (RA). DBA\/1 mice were immunized with bovine type II collagen and orally administered FLE for 14 days. On day 36, mouse sera and ankle joints were collected for serological and histological analysis, respectively. Consuming FLE inhibited RA development, suppressing pro-inflammatory cytokine productions, synovial inflammation, and cartilage degradation. The therapeutic effects of FLE in CIA mice were similar to those of methotrexate (MTX), which is typically used to treat RA. In vitro, FLE suppressed the transforming growth factor-\u03b2 (TGF-\u03b2)\/Smad signaling pathway in MH7A cells. We also demonstrated that FLE inhibited TGF-\u03b2-induced cell migration, suppressed MMP-2\/9 expression, inhibited MH7A cell proliferation, and increased the expression of autophagy markers LC3B and p62 in a dose-dependent manner. Our data suggest that FLE could induce autophagosome formations in the early of stages of autophagy while inhibiting their degradation in the later stages. In conclusion, FLE is a potential therapeutic agent for RA.<\/jats:p>","DOI":"10.3390\/nu15051106","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T01:31:06Z","timestamp":1677115866000},"page":"1106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Fermented Lettuce Extract Containing Nitric Oxide Metabolites Attenuates Inflammatory Parameters in Model Mice and in Human Fibroblast-Like Synoviocytes"],"prefix":"10.3390","volume":"15","author":[{"given":"Jisu","family":"Park","sequence":"first","affiliation":[{"name":"Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0342-3108","authenticated-orcid":false,"given":"Ji Hyeon","family":"Ryu","sequence":"additional","affiliation":[{"name":"Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo-Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Soo","family":"Chun","sequence":"additional","affiliation":[{"name":"HumanEnos LLC., Wanju 55347, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Sun","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Nitric Oxide Metabolite, Wonkwang University, Iksan 54538, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7894-0930","authenticated-orcid":false,"given":"Yong-Il","family":"Shin","sequence":"additional","affiliation":[{"name":"Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea"},{"name":"Department of Rehabilitation Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"108911","DOI":"10.1016\/j.biopha.2019.108911","article-title":"Triptolide suppresses human synoviocyte MH7A cells mobility and maintains redox balance by inhibiting autophagy","volume":"115","author":"Xie","year":"2019","journal-title":"Biomed Pharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s12026-021-09173-9","article-title":"Effect of interleukin-6, -17, -21, -22, and -23 and STAT3 on signal transduction pathways and their inhibition in autoimmune arthritis","volume":"69","author":"Tabarkiewicz","year":"2021","journal-title":"Immunol. 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