{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:57:45Z","timestamp":1788969465057,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,11]],"date-time":"2020-01-11T00:00:00Z","timestamp":1578700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["HI12C1821"],"award-info":[{"award-number":["HI12C1821"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are accessible, available in abundance, and have been shown to be a promising source that can regenerate cartilage in patients with osteoarthritis or other orthopedic diseases. Recently, a three-dimensional (3D) cell culture system was developed to mimic the naive tissue microenvironment. However, the efficacy of cells generated from the 3D spheroid culture system has not yet been elucidated. In the present study, we demonstrate the changes in superoxide dismutase 2 (SOD2) gene expression, an indicator of oxidative stress, on 3D spheroid MSCs. Moreover, siRNA transfection and neutralizing antibody investigations were performed to confirm the function of SOD2 and E-cadherin. Overall, we found that SOD2 siRNA transfection in the spheroid form of MSCs increases the expression of apoptotic genes and decreases the clearance of mitochondrial reactive oxygen species (ROS). As a result, we confirm that 3D spheroid formation increases E-cadherin and SOD2 expression, ultimately regulating the phosphoinositide 3-kinase (PI3K\/pAkt\/pNrf2 and pERK\/pNrf2 signaling pathway. Additionally, we show that SOD2 expression on 3D spheroid MSCs affects the regeneration rates of destructive cartilage in an osteoarthritic model. We postulate that the impact of SOD2 expression on 3D spheroid MSCs reduces oxidative stress and apoptosis, and also promotes cartilage regeneration.<\/jats:p>","DOI":"10.3390\/antiox9010066","type":"journal-article","created":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T04:05:51Z","timestamp":1578888351000},"page":"66","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Up-Regulation of Superoxide Dismutase 2 in 3D Spheroid Formation Promotes Therapeutic Potency of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells"],"prefix":"10.3390","volume":"9","author":[{"given":"Miyoung","family":"Lee","sequence":"first","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo Ram","family":"Song","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jueun","family":"Ha","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minju","family":"Lee","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Jin","family":"Choi","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonil","family":"Oh","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0034-114X","authenticated-orcid":false,"given":"Soyoun","family":"Um","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Jin","family":"Jin","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nbt.2816","article-title":"Mesenchymal stem cells: Immune evasive, not immune privileged","volume":"32","author":"Ankrum","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6940283","DOI":"10.1155\/2016\/6940283","article-title":"Stem Cells Applications in Regenerative Medicine and Disease Therapeutics","volume":"2016","author":"Mahla","year":"2016","journal-title":"Int. J. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jconrel.2019.04.002","article-title":"Intra-articular delivery of synovium-resident mesenchymal stem cells via BMP-7-loaded fibrous PLGA scaffolds for cartilage repair","volume":"302","author":"Kim","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s10875-017-0457-8","article-title":"Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis","volume":"38","author":"Liu","year":"2018","journal-title":"J. Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6425","DOI":"10.1016\/j.biomaterials.2011.05.033","article-title":"Enhanced MSC chondrogenesis following delivery of TGF-beta3 from alginate microspheres within hyaluronic acid hydrogels in vitro and in vivo","volume":"32","author":"Bian","year":"2011","journal-title":"Biomaterials"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1126\/science.1222454","article-title":"Unlike bone, cartilage regeneration remains elusive","volume":"338","author":"Huey","year":"2012","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.berh.2014.08.002","article-title":"Burden of disability due to musculoskeletal (MSK) disorders","volume":"28","author":"March","year":"2014","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"392","author":"James","year":"2018","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"32786","DOI":"10.1038\/srep32786","article-title":"Chondrogenic commitment of human umbilical cord blood-derived mesenchymal stem cells in collagen matrices for cartilage engineering","volume":"6","author":"Hervieu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"331","DOI":"10.3727\/096368912X657648","article-title":"Chondrogenically tuned expansion enhances the cartilaginous matrix-forming capabilities of primary, adult, leporine chondrocytes","volume":"22","author":"Huey","year":"2013","journal-title":"Cell Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1007\/s10529-010-0293-x","article-title":"Chondrogenic differentiation of human mesenchymal stem cells: A comparison between micromass and pellet culture systems","volume":"32","author":"Zhang","year":"2010","journal-title":"Biotechnol. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1126\/science.1215157","article-title":"A stem cell-based approach to cartilage repair","volume":"336","author":"Johnson","year":"2012","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ceb.2015.07.002","article-title":"Integration of cell-cell and cell-ECM adhesion in vertebrate morphogenesis","volume":"36","author":"McMillen","year":"2015","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.tice.2010.12.004","article-title":"A scaffold-free in vitro model for osteogenesis of human mesenchymal stem cells","volume":"43","author":"Hildebrandt","year":"2011","journal-title":"Tissue Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/j.biomaterials.2011.11.049","article-title":"The influence of spheroid formation of human adipose-derived stem cells on chitosan films on stemness and differentiation capabilities","volume":"33","author":"Cheng","year":"2012","journal-title":"Biomaterials"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1111\/jcmm.12336","article-title":"Epigenetic changes of mesenchymal stem cells in three-dimensional (3D) spheroids","volume":"18","author":"Guo","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1089\/ten.tea.2011.0640","article-title":"Transplantation of cord blood mesenchymal stem cells as spheroids enhances vascularization","volume":"18","author":"Bhang","year":"2012","journal-title":"Tissue Eng. Part A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9176357","DOI":"10.1155\/2016\/9176357","article-title":"Spheroid Culture of Mesenchymal Stem Cells","volume":"2016","author":"Cesarz","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13287-017-0558-6","article-title":"The therapeutic potential of three-dimensional multipotent mesenchymal stromal cell spheroids","volume":"8","author":"Petrenko","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1002\/stem.1499","article-title":"Dynamic compaction of human mesenchymal stem\/precursor cells into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1)","volume":"31","author":"Bartosh","year":"2013","journal-title":"Stem Cells"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1159\/000332045","article-title":"Spheroid formation and neural induction in human adipose-derived stem cells on a chitosan-coated surface","volume":"196","author":"Hsueh","year":"2012","journal-title":"Cells Tissues Organs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1089\/ten.tea.2016.0315","article-title":"In Situ Release of VEGF Enhances Osteogenesis in 3D Porous Scaffolds Engineered with Osterix-Modified Adipose-Derived Stem Cells","volume":"23","author":"Xu","year":"2017","journal-title":"Tissue Eng. Part A"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sridharan, B., Lin, S.M., Hwu, A.T., Laflin, A.D., and Detamore, M.S. (2015). Stem Cells in Aggregate Form to Enhance Chondrogenesis in Hydrogels. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141479"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/art.10767","article-title":"Cartilage-like gene expression in differentiated human stem cell spheroids: A comparison of bone marrow-derived and adipose tissue-derived stromal cells","volume":"48","author":"Winter","year":"2003","journal-title":"Arthritis Rheumatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1089\/ten.tea.2011.0647","article-title":"Enhanced cartilage formation via three-dimensional cell engineering of human adipose-derived stem cells","volume":"18","author":"Yoon","year":"2012","journal-title":"Tissue Eng. Part A"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Baptista, L.S., Kronemberger, G.S., Cortes, I., Charelli, L.E., Matsui, R.A.M., Palhares, T.N., Sohier, J., Rossi, A.M., and Granjeiro, J.M. (2018). Adult Stem Cells Spheroids to Optimize Cell Colonization in Scaffolds for Cartilage and Bone Tissue Engineering. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051285"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s00441-014-2055-x","article-title":"Three-dimensional spheroid culture of human umbilical cord mesenchymal stem cells promotes cell yield and stemness maintenance","volume":"360","author":"Li","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_28","first-page":"188","article-title":"An in vitro model for hepatocyte-like cell differentiation from Wharton\u2019s jelly derived-mesenchymal stem cells by cell-base aggregates","volume":"8","author":"Ayatollahi","year":"2015","journal-title":"Gastroenterol. Hepatol. Bed Bench"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/mt.2012.58","article-title":"Spherical bullet formation via E-cadherin promotes therapeutic potency of mesenchymal stem cells derived from human umbilical cord blood for myocardial infarction","volume":"20","author":"Lee","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1038\/s41598-018-20975-0","article-title":"Spheroid-cultured human umbilical cord-derived mesenchymal stem cells attenuate hepatic ischemia-reperfusion injury in rats","volume":"8","author":"Sun","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13294","DOI":"10.1074\/jbc.M208670200","article-title":"Differential effects of superoxide dismutase isoform expression on hydroperoxide-induced apoptosis in PC-12 cells","volume":"278","author":"Pias","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.freeradbiomed.2014.08.026","article-title":"Manganese superoxide dismutase in breast cancer: From molecular mechanisms of gene regulation to biological and clinical significance","volume":"77","author":"Becuwe","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7953","DOI":"10.1038\/s41598-017-08537-2","article-title":"Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G1-induced lung adenocarcinoma","volume":"7","author":"Yi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kwon, J.H., Kim, M., Bae, Y.K., Kim, G.H., Choi, S.J., Oh, W., Um, S., and Jin, H.J. (2019). Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194815"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Smyrek, I., Mathew, B., Fischer, S.C., Lissek, S.M., Becker, S., and Stelzer, E.H.K. (2019). E-cadherin, actin, microtubules and FAK dominate different spheroid formation phases and important elements of tissue integrity. Biol. Open, 8.","DOI":"10.1242\/bio.037051"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1038\/labinvest.2017.89","article-title":"Correlation between E-cadherin interactions, survivin expression, and apoptosis in MDCK and ts-Src MDCK cell culture models","volume":"97","author":"Capra","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1089\/scd.2011.0252","article-title":"Three-dimensional spheroid culture of human gingiva-derived mesenchymal stem cells enhances mitigation of chemotherapy-induced oral mucositis","volume":"21","author":"Zhang","year":"2012","journal-title":"Stem Cells Dev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13724","DOI":"10.1073\/pnas.1008117107","article-title":"Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties","volume":"107","author":"Bartosh","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"121","DOI":"10.22203\/eCM.v033a09","article-title":"Cell aggregation enhances bone formation by human mesenchymal stromal cells","volume":"33","author":"Chatterjea","year":"2017","journal-title":"Eur. Cell Mater."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1634\/stemcells.2007-0022","article-title":"Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro","volume":"25","author":"Potapova","year":"2007","journal-title":"Stem Cells"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1089\/scd.2015.0278","article-title":"Spheroid Mesenchymal Stem Cells and Mesenchymal Stem Cell-Derived Microvesicles: Two Potential Therapeutic Strategies","volume":"25","author":"Xie","year":"2016","journal-title":"Stem Cells Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1089\/ars.2013.5305","article-title":"MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx","volume":"20","author":"Candas","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.freeradbiomed.2009.12.024","article-title":"Mitochondrial superoxide dismutase SOD2, but not cytosolic SOD1, plays a critical role in protection against glutamate-induced oxidative stress and cell death in HT22 neuronal cells","volume":"48","author":"Fukui","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.lfs.2018.10.020","article-title":"Protective effects of SOD2 overexpression in human umbilical cord mesenchymal stem cells on lung injury induced by acute paraquat poisoning in rats","volume":"214","author":"Zhang","year":"2018","journal-title":"Life Sci."},{"key":"ref_45","first-page":"439","article-title":"Anti-inflammatory effect of recombinant human superoxide dismutase in rats and mice and its mechanism","volume":"23","author":"Zhang","year":"2002","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1177\/0960327114533808","article-title":"The relation between oxidative stress, inflammation, and neopterin in the paraquat-induced lung toxicity","volume":"34","author":"Toygar","year":"2015","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1146\/annurev-immunol-042617-053010","article-title":"Apoptosis and Clearance of Apoptotic Cells","volume":"36","author":"Nagata","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3756","DOI":"10.1007\/s00018-008-8281-1","article-title":"The cell-cell adhesion molecule E-cadherin","volume":"65","author":"Berx","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1158\/0008-5472.CAN-07-2938","article-title":"Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways","volume":"68","author":"Onder","year":"2008","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1002\/1529-0131(200106)44:6<1304::AID-ART222>3.0.CO;2-T","article-title":"Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: A study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage","volume":"44","author":"Aigner","year":"2001","journal-title":"Arthritis Rheumatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"333","DOI":"10.2174\/138945007779940025","article-title":"Cell death and apoptosis in osteoarthritic cartilage","volume":"8","author":"Kim","year":"2007","journal-title":"Curr. Drug Targets"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1136\/ard.2009.119966","article-title":"Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease","volume":"69","author":"Scott","year":"2010","journal-title":"Ann. Rheum Dis."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Chung, Y.P., Chen, Y.W., Weng, T.I., Yang, R.S., and Liu, S.H. (2019). Arsenic induces human chondrocyte senescence and accelerates rat articular cartilage aging. Arch. Toxicol.","DOI":"10.1007\/s00204-019-02607-2"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1023\/A:1020185404126","article-title":"Aging, articular cartilage chondrocyte senescence and osteoarthritis","volume":"3","author":"Martin","year":"2002","journal-title":"Biogerontology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"11722","DOI":"10.1038\/srep11722","article-title":"Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration","volume":"5","author":"Koike","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1074\/mcp.M800292-MCP200","article-title":"Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: A decrease in mitochondrial superoxide dismutase points to a redox imbalance","volume":"8","author":"Calamia","year":"2009","journal-title":"Mol. Cell. Proteom."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Coleman, M.C., Brouillette, M.J., Andresen, N.S., Oberley-Deegan, R.E., and Martin, J.M. (2017). Differential Effects of Superoxide Dismutase Mimetics after Mechanical Overload of Articular Cartilage. Antioxidants, 6.","DOI":"10.3390\/antiox6040098"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.molmed.2004.09.003","article-title":"Nrf2-Keap1 defines a physiologically important stress response mechanism","volume":"10","author":"Motohashi","year":"2004","journal-title":"Trends Mol. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.freeradbiomed.2015.06.044","article-title":"Beyond antioxidant genes in the ancient Nrf2 regulatory network","volume":"88","author":"Lacher","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.2147\/DMSO.S228351","article-title":"Protective Effects Of Astragalus Polysaccharides On Oxidative Stress In High Glucose-Induced Or SOD2-Silenced H9C2 Cells Based On PCR Array Analysis","volume":"12","author":"Sun","year":"2019","journal-title":"Diabetes Metab. Syndr. Obes."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/1\/66\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:04:29Z","timestamp":1760364269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/1\/66"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,11]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["antiox9010066"],"URL":"https:\/\/doi.org\/10.3390\/antiox9010066","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,11]]}}}