{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T19:06:25Z","timestamp":1788375985163,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T00:00:00Z","timestamp":1598313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education","award":["NRF-2016R1A6A1A03011325"],"award-info":[{"award-number":["NRF-2016R1A6A1A03011325"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Osteoarthritis (OA) is a common joint degenerative disease induced by oxidative stress in chondrocytes. Although induced-heme oxygenase-1 (HO-1) has been found to protect cells against oxygen radical damage, little information is available regarding the use of bioactive compounds from natural sources for regulating the HO-1 pathway to treat OA. In this study, we explored the inhibitory effects of cudratricusxanthone O (CTO) isolated from the Maclura tricuspidata Bureau (Moraceae) on H2O2-induced damage of SW1353 chondrocytes via regulation of the HO-1 pathway. CTO promoted HO-1 expression by enhancing the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus without inducing toxicity. Pretreatment with CTO-regulated reactive oxygen species (ROS) production by inducing expression of antioxidant enzymes in H2O2-treated cells and maintained the functions of H2O2-damaged chondrocytes. Furthermore, CTO prevented H2O2-induced apoptosis by regulating the expression of anti-apoptotic proteins. Treatment with the HO-1 inhibitor tin-protoporphyrin IX revealed that these protective effects were exerted due to an increase in HO-1 expression induced by CTO. In conclusion, CTO protects chondrocytes from H2O2-induced damages\u2014including ROS accumulation, dysfunction, and apoptosis through activation of the Nrf2\/HO-1 signaling pathway in chondrocytes and, therefore, is a potential therapeutic agent for OA treatment.<\/jats:p>","DOI":"10.3390\/antiox9090788","type":"journal-article","created":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T10:48:24Z","timestamp":1598352504000},"page":"788","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Cudratricusxanthone O Inhibits H2O2-Induced Cell Damage by Activating Nrf2\/HO-1 Pathway in Human Chondrocytes"],"prefix":"10.3390","volume":"9","author":[{"given":"Eun-Nam","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Su","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil-Saeng","family":"Jeong","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16044","DOI":"10.1038\/boneres.2016.44","article-title":"Osteoarthritis: Toward a comprehensive understanding of pathological mechanism","volume":"5","author":"Chen","year":"2017","journal-title":"Bone Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1002\/art.1780300811","article-title":"The prevalence of knee osteoarthritis in the elderly. The framingham osteoarthritis study","volume":"30","author":"Felson","year":"1987","journal-title":"Arthritis Rheum."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of proinflammatory cytokines in the pathophysiology of osteoarthritis","volume":"7","author":"Kapoor","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_4","first-page":"2207","article-title":"Expression of the cartilage derived anti-angiogenic factor chondromodulin-I decreases in the early stage of experimental osteoarthritis","volume":"30","author":"Hayami","year":"2003","journal-title":"J. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3109\/03008200009005288","article-title":"Development of articular cartilage: What do we know about it and how may it occur?","volume":"41","author":"Pacifici","year":"2000","journal-title":"Connect Tissue Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1080\/09629350120080401","article-title":"Diphenyleneiodonium inhibits NF-kappaB activation and iNOS expression induced by IL-1beta: Involvement of reactive oxygen species","volume":"10","author":"Mendes","year":"2001","journal-title":"Mediators Inflamm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.2174\/1381612823666170113153818","article-title":"Synergistic interaction between heme oxygenase (HO) and nuclear-factor E2-related factor-2 (Nrf2) against oxidative stress in cardiovascular related diseases","volume":"23","author":"Ndisang","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"91","DOI":"10.5483\/BMBRep.2017.50.2.188","article-title":"The hypertension drug, verapamil, activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity","volume":"50","author":"Lee","year":"2017","journal-title":"BMB Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1101\/gad.225680.113","article-title":"The emerging role of the Nrf2-Keap1 signaling pathway in cancer","volume":"27","author":"Jaramillo","year":"2013","journal-title":"Genes Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0891-5849(99)00223-3","article-title":"The heme synthesis and degradation pathways: Role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties","volume":"28","author":"Ryter","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.2174\/0929867043365080","article-title":"Heme oxygenase-1: A novel therapeutic target in oxidative tissue injuries","volume":"11","author":"Takahashi","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1164\/rccm.200311-1607OC","article-title":"Heme oxygenase-1 expression in human lungs with cystic fibrosis and cytoprotective effects against Pseudomonas aeruginosa in vitro","volume":"170","author":"Zhou","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.phytochem.2014.10.021","article-title":"Isoflavones with neuroprotective activities from fruits of Cudrania tricuspidata","volume":"111","author":"Hiep","year":"2015","journal-title":"Phytochemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/ptr.3577","article-title":"The fruits of Cudrania tricuspidata suppress development of atopic dermatitis in NC\/Nga mice","volume":"26","author":"Lee","year":"2012","journal-title":"Phytother. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1021\/np800418j","article-title":"Prenylated and benzylated flavonoids from the fruits of Cudrania tricuspidata","volume":"72","author":"Han","year":"2008","journal-title":"J. Nat. Prod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/BF02975134","article-title":"Hepatoprotective constituents of Cudrania tricuspidata","volume":"28","author":"Tian","year":"2005","journal-title":"Arch. Pharm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1055\/s-2008-1081315","article-title":"Cudratricusxanthone A protects mouse hippocampal cells against glutamate-induced neurotoxicity via the induction of heme oxygenase-1","volume":"74","author":"Jeong","year":"2008","journal-title":"Planta Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11173","DOI":"10.3390\/molecules200611173","article-title":"Protein tyrosine phosphatase 1B inhibitors from the roots of Cudrania tricuspidata","volume":"20","author":"Quang","year":"2015","journal-title":"Molecules"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.intimp.2008.11.008","article-title":"Cudratricusxanthone A from Cudrania Tricuspidata suppresses pro-Inflammatory mediators through expression of anti-inflammatory Heme oxygenase-1 in RAW264.7 macrophages","volume":"9","author":"Jeong","year":"2009","journal-title":"Int. Immunopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.2147\/DDDT.S244059","article-title":"Resveratrol Exerts Anti-Osteoarthritic Effect by Inhibiting TLR4\/NF-\u03baB Signaling Pathway via the TLR4\/Akt\/FoxO1 Axis in IL-1\u03b2-Stimulated SW1353 Cells","volume":"14","author":"Xiaolei","year":"2020","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Huang, T.C., Chang, W.T., Hu, Y.C., Hsieh, B.S., Cheng, H.L., Yen, J.H., Chiu, P.R., and Chang, K.L. (2018). Zinc Protects Articular Chondrocytes through Changes in Nrf2-Mediated Antioxidants, Cytokines and Matrix Metalloproteinases. Nutrients, 10.","DOI":"10.3390\/nu10040471"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Park, C., Jeong, J.W., Lee, D.S., Yim, M.J., Lee, J.M., Han, M.H., Kim, S., Kim, H.S., Kim, G.Y., and Park, E.K. (2018). Sargassum serratifolium Extract Attenuates Interleukin-1_-Induced Oxidative Stress and Inflammatory Response in Chondrocytes by Suppressing the Activation of NF-kB, p38 MAPK, and PI3K\/Akt. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082308"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hong, G.U., Lee, J.Y., Kang, H., Kim, T.Y., Park, J.Y., Hong, E.Y., Shin, Y.H., Jung, S.H., Chang, H.B., and Kim, Y.H. (2018). Inhibition of Osteoarthritis-RelatedMolecules by Isomucronulatol 7-O-\u03b2-D-glucoside and Ecliptasaponin A in IL-1\u03b2-Stimulated Chondrosarcoma Cell Model. Molecules, 23.","DOI":"10.3390\/molecules23112807"},{"key":"ref_24","unstructured":"Lee, W.H., Ku, S.K., Kim, T.I., Kim, E.N., Park, E.K., Jeong, G.S., and Bae, J.S. (2019). Inhibitory effects of cudratricusxanthone O on particulate matter-induced pulmonary injury. Int. J. Environ. Health Res., 1\u201314."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1186\/s13075-015-0774-3","article-title":"Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis","volume":"17","author":"Cai","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1186\/s13075-015-0792-1","article-title":"Bach1 deficiency reduces severity of osteoarthritis through upregulation of heme oxygenase-1","volume":"17","author":"Takada","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_27","first-page":"541","article-title":"The role of free radicals, oxidative stress and antioxidant systems in diabetic vascular disease","volume":"101","author":"Jakus","year":"2000","journal-title":"Bratislavsk\u00e9 Lek\u00e1rske Listy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1089\/ars.2005.7.1664","article-title":"Molecular mechanism of Nrf2 activation by oxidative stress","volume":"7","author":"Kang","year":"2005","journal-title":"Antioxid. Redox. Sign."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wu, P.S., Yen, J.H., Kou, M.C., and Wu, M.J. (2015). \u201cLuteolin and apigenin attenuate 4-hydroxy-2-nonenal-mediated cell death through modulation of UPR, Nrf2-ARE and MAPK pathways in PC12 cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130599"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19989","DOI":"10.1074\/jbc.M101169200","article-title":"Different regulatory mechanisms modulate the expression of a dinoflagellate iron-superoxide dismutase","volume":"276","author":"Okamoto","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1136\/ard.61.suppl_2.ii78","article-title":"Type II collagen degradation and its regulation in articular cartilage in osteoarthritis","volume":"61","author":"Poole","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s12291-009-0007-0","article-title":"Multiple matrix metalloproteinases in type II collagen induced arthritis","volume":"24","author":"Sandya","year":"2009","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.vaa.2016.04.004","article-title":"Effects of xylazine and dexmedetomidine on equine articular chondrocytes in vitro","volume":"44","author":"Mancini","year":"2017","journal-title":"Vet. Anaesth. Analg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1073\/pnas.241655498","article-title":"Cytochrome c release from mitochondria proceeds by a two-step process","volume":"99","author":"Ott","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.bbabio.2006.03.016","article-title":"Multiple pathways of cytochrome c release from mitochondria in apoptosis","volume":"1757","author":"Gogvadze","year":"2006","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8471","DOI":"10.1007\/s13277-016-5035-9","article-title":"Major apoptotic mechanisms and genes involved in apoptosis","volume":"37","author":"Kiraz","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"385","DOI":"10.2741\/4395","article-title":"Hypoxia increases Nrf2-induced HO-1 expression via the PI3K\/Akt pathway","volume":"21","author":"Zhao","year":"2016","journal-title":"Front. Biosci."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/9\/788\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:06:33Z","timestamp":1760177193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/9\/788"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,25]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["antiox9090788"],"URL":"https:\/\/doi.org\/10.3390\/antiox9090788","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,25]]}}}