{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T14:00:14Z","timestamp":1776952814523,"version":"3.51.4"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,5,27]],"date-time":"2019-05-27T00:00:00Z","timestamp":1558915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017R1A2B4008163"],"award-info":[{"award-number":["2017R1A2B4008163"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is a major inflammatory lung disease characterized by irreversible and progressive airflow obstruction. Although corticosteroids are often used to reduce inflammation, steroid therapies are insufficient in patients with refractory COPD. Both serum amyloid A (SAA) and IL-33 have been implicated in the pathology of steroid-resistant lung inflammation. Picroside II isolated from Pseudolysimachion rotundum var. subintegrum (Plantaginaceae) is a major bioactive component of YPL-001, which has completed phase-2a clinical trials in chronic obstructive pulmonary disease patients. In this study, we investigated whether picroside II is effective in treating steroid refractory lung inflammation via the inhibition of the SAA-IL-33 axis. Picroside II inhibited LPS-induced SAA1 expression in human monocytes, which are resistant to steroids. SAA induced the secretion of IL-33 without involving cell necrosis. Picroside II, but not dexamethasone effectively inhibited SAA-induced IL-33 expression and secretion. The inhibitory effect by picroside II was mediated by suppressing the mitogen-activated protein kinase (MAPK) p38, ERK1\/2, and nuclear factor-\u03baB pathways. Our results suggest that picroside II negatively modulates the SAA-IL-33 axis that has been implicated in steroid-resistant lung inflammation. These findings provide valuable information for the development of picroside II as an alternative therapeutic agent against steroid refractory lung inflammation in COPD.<\/jats:p>","DOI":"10.3390\/molecules24102020","type":"journal-article","created":{"date-parts":[[2019,5,27]],"date-time":"2019-05-27T11:19:27Z","timestamp":1558955967000},"page":"2020","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Picroside II Isolated from Pseudolysimachion rotundum var. subintegrum Inhibits Glucocorticoid Refractory Serum Amyloid A (SAA) Expression and SAA-induced IL-33 Secretion"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1680-616X","authenticated-orcid":false,"given":"Kiram","family":"Lee","sequence":"first","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju, Chungbuk 28116, Korea"},{"name":"Department of Biomolecular Science, University of Science &amp; Technology (UST), Daejeon 341113, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Choi","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju, Chungbuk 28116, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo Kyong","family":"Choi","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju, Chungbuk 28116, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young-Mi","family":"Gu","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju, Chungbuk 28116, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyung Won","family":"Ryu","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju, Chungbuk 28116, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sei-Ryang","family":"Oh","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju, Chungbuk 28116, Korea"},{"name":"Department of Biomolecular Science, University of Science &amp; Technology (UST), Daejeon 341113, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1293-6159","authenticated-orcid":false,"given":"Hyun-Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju, Chungbuk 28116, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(04)16855-4","article-title":"Burden and clinical features of chronic obstructive pulmonary disease (COPD)","volume":"364","author":"Pauwels","year":"2004","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1164\/rccm.200703-456SO","article-title":"Global Initiative for Chronic Obstructive Lung, D., Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary","volume":"176","author":"Rabe","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1183\/09031936.00142414","article-title":"Global and regional trends in COPD mortality, 1990-2010","volume":"45","author":"Burney","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nrd4025","article-title":"New anti-inflammatory targets for chronic obstructive pulmonary disease","volume":"12","author":"Barnes","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1016\/S0140-6736(09)60326-3","article-title":"Glucocorticoid resistance in inflammatory diseases","volume":"373","author":"Barnes","year":"2009","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1073\/pnas.1109382109","article-title":"Serum amyloid A opposes lipoxin A(4) to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease","volume":"109","author":"Bozinovski","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1189\/jlb.3VMR0315-080R","article-title":"Emerging functions of serum amyloid A in inflammation","volume":"98","author":"Ye","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1164\/rccm.200506-859OC","article-title":"Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations","volume":"173","author":"Papi","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1164\/rccm.200705-678OC","article-title":"Serum amyloid a is a biomarker of acute exacerbations of chronic obstructive pulmonary disease","volume":"177","author":"Bozinovski","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1164\/rccm.200505-704OC","article-title":"Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease","volume":"173","author":"Hurst","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4072","DOI":"10.4049\/jimmunol.177.6.4072","article-title":"Serum amyloid A is an endogenous ligand that differentially induces IL-12 and IL-23","volume":"177","author":"He","year":"2006","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Migita, K., Izumi, Y., Jiuchi, Y., Kozuru, H., Kawahara, C., Nakamura, M., Nakamura, T., Agematsu, K., Masumoto, J., and Yasunami, M. (2014). Serum amyloid A induces NLRP-3-mediated IL-1beta secretion in neutrophils. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096703"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1182\/blood-2002-05-1431","article-title":"Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1\/LXA4R","volume":"101","author":"He","year":"2003","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3967","DOI":"10.1172\/JCI65570","article-title":"Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease","volume":"123","author":"Byers","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.jaci.2013.04.012","article-title":"IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma","volume":"132","author":"Saglani","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/j.intimp.2006.01.010","article-title":"Suppressive effect of verproside isolated from Pseudolysimachion longifolium on airway inflammation in a mouse model of allergic asthma","volume":"6","author":"Oh","year":"2006","journal-title":"Int. Immunopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.cyto.2015.08.262","article-title":"Verproside inhibits TNF-alpha-induced MUC5AC expression through suppression of the TNF-alpha\/NF-kappaB pathway in human airway epithelial cells","volume":"77","author":"Lee","year":"2016","journal-title":"Cytokine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11990","DOI":"10.3390\/molecules171011990","article-title":"In vitro and in vivo metabolism of verproside in rats","volume":"17","author":"Kim","year":"2012","journal-title":"Molecules"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Choi, J., Choi, B.K., Kim, J.S., Lee, J.W., Park, H.A., Ryu, H.W., Lee, S.U., Hwang, K.W., Yun, W.K., and Kim, H.C. (2016). Picroside II Attenuates Airway Inflammation by Downregulating the Transcription Factor GATA3 and Th2-Related Cytokines in a Mouse Model of HDM-Induced Allergic Asthma. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167098"},{"key":"ref_20","first-page":"650","article-title":"Human serum amyloid A genes are expressed in monocyte\/macrophage cell lines","volume":"145","author":"Meek","year":"1994","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.immuni.2009.06.011","article-title":"IL-33 raises alarm","volume":"31","author":"Lamkanfi","year":"2009","journal-title":"Immunity"},{"key":"ref_22","first-page":"137","article-title":"Emerging role of MAP kinase pathways as therapeutic targets in COPD","volume":"1","author":"Mercer","year":"2006","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.jaci.2008.02.004","article-title":"Cell-specific activation profile of extracellular signal-regulated kinase 1\/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic airways","volume":"121","author":"Liu","year":"2008","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"22","DOI":"10.4049\/jimmunol.181.1.22","article-title":"Cutting edge: TLR2 is a functional receptor for acute-phase serum amyloid A","volume":"181","author":"Cheng","year":"2008","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1189\/jlb.0407203","article-title":"Is serum amyloid A an endogenous TLR4 agonist?","volume":"83","author":"Sandri","year":"2008","journal-title":"J. Leukoc. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6119","DOI":"10.4049\/jimmunol.1002843","article-title":"Serum amyloid A activates the NLRP3 inflammasome via P2 \u00d7 7 receptor and a cathepsin B-sensitive pathway","volume":"186","author":"Niemi","year":"2011","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1002\/eji.201344310","article-title":"Serum amyloid A induces interleukin-33 expression through an IRF7-dependent pathway","volume":"44","author":"Sun","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Moussion, C., Ortega, N., and Girard, J.P. (2008). The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: A novel \u2018alarmin\u2019?. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003331"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1016\/j.jaci.2015.10.003","article-title":"Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses","volume":"137","author":"Hristova","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jaci.2012.02.013","article-title":"A critical role of IL-33 in experimental allergic rhinitis","volume":"130","author":"Haenuki","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4032","DOI":"10.4049\/jimmunol.1400110","article-title":"Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa","volume":"192","author":"Hara","year":"2014","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1615\/CritRevImmunol.v32.i4.40","article-title":"Immune functions of serum amyloid A","volume":"32","author":"Eklund","year":"2012","journal-title":"Crit. Rev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1165\/rcmb.2003-0438OC","article-title":"A20 inhibits toll-like receptor 2- and 4-mediated interleukin-8 synthesis in airway epithelial cells","volume":"31","author":"Gon","year":"2004","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pharmthera.2008.09.003","article-title":"Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease","volume":"121","author":"Edwards","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nri.2016.95","article-title":"Interleukin-33 in health and disease","volume":"16","author":"Liew","year":"2016","journal-title":"Nat. Rev. Immunol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/10\/2020\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:55:20Z","timestamp":1760187320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/10\/2020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,27]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["molecules24102020"],"URL":"https:\/\/doi.org\/10.3390\/molecules24102020","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,27]]}}}