{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T16:03:13Z","timestamp":1792857793025,"version":"4.5.0"},"reference-count":31,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016808","name":"Natural Science Foundation of Xiamen, China","doi-asserted-by":"publisher","award":["3502Z202573097"],"award-info":[{"award-number":["3502Z202573097"]}],"id":[{"id":"10.13039\/100016808","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Third Institute of Oceanography","award":["2025021"],"award-info":[{"award-number":["2025021"]}]},{"award":["2025021"],"award-info":[{"award-number":["2025021"]}],"id":[{"id":"https:\/\/ror.org\/00w6b9958","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005270","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2025J01242"],"award-info":[{"award-number":["2025J01242"]}],"id":[{"id":"10.13039\/501100005270","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Technology Innovation Center for Exploitation of Marine Biological Resources, Ministry of Natural Resources, P. R. China","award":["TICMBR202403"],"award-info":[{"award-number":["TICMBR202403"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) is a prevalent chronic joint disease lacking disease-modifying drugs. Animal models with distinct pathogenic mechanisms\u2014monosodium iodoacetate (MIA) for metabolic toxicity and collagenase-induced osteoarthritis (CIOA) for matrix degradation\u2014are essential for therapeutic evaluation. In this study, topical application of neoagarohexaose (NA6) at 5 and 10 mg\/kg twice daily was assessed in MIA- and CIOA-induced mouse OA models. NA6 at both doses reduced paw swelling, improved serum oxidative stress markers (catalase (CAT), malondialdehyde (MDA), myeloperoxidase (MPO)), ameliorated cartilage damage and Osteoarthritis Research Society International (OARSI) scores, and decreased inflammatory cell infiltration. Immunohistochemistry showed that NA6 downregulated interleukin-1\u03b2 (IL-1\u03b2) and interleukin-6 (IL-6), upregulated NAD(P)H:quinone oxidoreductase 1 (NQO1), and restored the compensatorily elevated heme oxygenase-1 (HO-1) toward baseline levels. The high-dose NA6 (10 mg\/kg) showed comparable or favorable efficacy at the tested doses relative to the positive control diclofenac. These results demonstrate that NA6 exerts anti-inflammatory, antioxidant, and chondroprotective effects in both OA models, supporting its potential as a topical therapeutic candidate for OA symptom management and structural protection.<\/jats:p>","DOI":"10.3390\/ijms27146162","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T11:43:34Z","timestamp":1783683814000},"page":"6162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neoagarohexaose Attenuates Inflammatory and Oxidative Joint Injury in MIA\/CIOA Mouse Models of Osteoarthritis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5594-5042","authenticated-orcid":false,"given":"Nan","family":"Wu","sequence":"first","affiliation":[{"name":"Technology Innovation Center for Exploitation of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4764-9865","authenticated-orcid":false,"given":"Yating","family":"Du","sequence":"additional","affiliation":[{"name":"Technology Innovation Center for Exploitation of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaocheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Technology Innovation Center for Exploitation of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuhua","family":"Chan","sequence":"additional","affiliation":[{"name":"Technology Innovation Center for Exploitation of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8134-1944","authenticated-orcid":false,"given":"Runying","family":"Zeng","sequence":"additional","affiliation":[{"name":"Technology Innovation Center for Exploitation of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s13075-025-03658-w","article-title":"Epidemiological trends of osteoarthritis at the global, regional, and national levels from 1990 to 2021 and projections to 2050","volume":"27","author":"Qiao","year":"2025","journal-title":"Arthritis Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1759720X241273009","DOI":"10.1177\/1759720X241273009","article-title":"Knee osteoarthritis: Disease burden, available treatments, and emerging options","volume":"16","author":"Langworthy","year":"2024","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.joca.2023.05.004","article-title":"Age and oxidative stress regulate Nrf2 homeostasis in human articular chondrocytes","volume":"31","author":"Taylor","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cofs.2016.02.002","article-title":"Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects","volume":"8","author":"Zhang","year":"2016","journal-title":"Curr. Opin. Food Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.17305\/bb.2024.11437","article-title":"Alleviating the IL-1\u03b2-stimulated extracellular matrix degradation in osteoarthritis, and chondrocyte inflammation by Morinda officinalis polysaccharide via the SIRT6\/NF-\u03baB pathway","volume":"25","author":"Zhao","year":"2025","journal-title":"Biomol. Biomed."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s42358-024-00427-2","article-title":"Hck promotes IL-1\u03b2-induced extracellular matrix degradation, inflammation, and apoptosis in osteoarthritis via activation of the JAK-STAT3 signaling pathway","volume":"64","author":"Yan","year":"2024","journal-title":"Adv. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kim, S.K., Kim, B., Choe, J.Y., Kim, J.W., and Park, K.Y. (2024). Interleukin-37 Inhibits Interleukin-1\u03b2-Induced Articular Chondrocyte Apoptosis by Suppressing Reactive Oxygen Species. Biomedicines, 12.","DOI":"10.3390\/biomedicines12092025"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5581346","DOI":"10.1155\/2022\/5581346","article-title":"Emodin Attenuates the ECM Degradation and Oxidative Stress of Chondrocytes through the Nrf2\/NQO1\/HO-1 Pathway to Ameliorate Rat Osteoarthritis","volume":"2022","author":"Ma","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107382","DOI":"10.1016\/j.foodhyd.2021.107382","article-title":"Antioxidant neoagarooligosaccharides (NAOs) and dietary fiber production from red algae Gracilariopsis lemaneiformis using enzyme assisted one-step process","volume":"125","author":"Song","year":"2022","journal-title":"Food Hydrocoll."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"118076","DOI":"10.1016\/j.carbpol.2021.118076","article-title":"Agar oligosaccharides: A review of preparation, structures, bioactivities and application","volume":"265","author":"Chen","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110408","DOI":"10.1016\/j.foodres.2021.110408","article-title":"Advances in agaro-oligosaccharides preparation and bioactivities for revealing the structure-function relationship","volume":"145","author":"Jiang","year":"2021","journal-title":"Food Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jo, E., Gajanayaka, N.D., Bandara, M.S., Marasinghe, S.D., Park, G.H., Lee, S.J., Oh, C., and Lee, Y. (2024). Odd-Numbered Agaro-Oligosaccharides Produced by \u03b1-Neoagaro-Oligosaccharide Hydrolase Exert Antioxidant Activity in Human Dermal Fibroblasts. Mar. Drugs, 22.","DOI":"10.3390\/md22110495"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"106737","DOI":"10.1016\/j.jff.2025.106737","article-title":"Neoagarooligosaccharides improve non-alcoholic fatty liver disease by modulating lipid metabolism and Nrf2-related pathways","volume":"127","author":"Bae","year":"2025","journal-title":"J. Funct. Foods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12938-021-00917-0","article-title":"Aldehyde dehydrogenase 2 alleviates monosodium iodoacetate-induced oxidative stress, inflammation and apoptosis in chondrocytes via inhibiting aquaporin 4 expression","volume":"20","author":"Pan","year":"2021","journal-title":"Biomed. Eng. Online"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40169-018-0215-4","article-title":"Pros and cons of mouse models for studying osteoarthritis","volume":"7","author":"Bapat","year":"2018","journal-title":"Clin. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hong, J.I., Park, I.Y., and Kim, H.A. (2020). Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020533"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, L., Huang, X., Xiong, H., and Yang, L. (2026). The Nrf2\/HO-1 signaling pathway in arthritis: From molecular mechanisms to therapeutic potential. Front. Cell Dev. Biol., 14.","DOI":"10.3389\/fcell.2026.1728679"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/j.joca.2025.08.003","article-title":"Temporal profiling of lipid mediators in synovium and tibial plateau during joint inflammation in a collagenase-induced mouse model of osteoarthritis","volume":"33","author":"Zhou","year":"2025","journal-title":"Osteoarthr. Cartil."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1080\/03008207.2025.2500530","article-title":"Cross-regulation of inflammation and metabolic mechanisms in osteoarthritis: Recent advances bridging the gap to novel treatments","volume":"66","year":"2025","journal-title":"Connect. Tissue Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s40744-020-00196-6","article-title":"Topical Diclofenac, an Efficacious Treatment for Osteoarthritis: A Narrative Review","volume":"7","author":"Fayet","year":"2020","journal-title":"Rheumatol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13203","DOI":"10.1038\/s41598-026-43064-z","article-title":"Cycloastragenol attenuates osteoarthritis by restoring chondrocyte senescence via the NRF2\/NF-\u03baB signaling axis","volume":"16","author":"Zhang","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ryter, S.W. (2022). Heme Oxygenase-1: An Anti-Inflammatory Effector in Cardiovascular, Lung, and Related Metabolic Disorders. Antioxidants, 11.","DOI":"10.3390\/antiox11030555"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gao, W., Guo, L., Yang, Y., Wang, Y., Xia, S., Gong, H., Zhang, B.K., and Yan, M. (2021). Dissecting the Crosstalk Between Nrf2 and NF-\u03baB Response Pathways in Drug-Induced Toxicity. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.809952"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hsieh, T.H., Ho, J.Y., Wang, C.C., Liu, F.C., Lee, C.H., Lee, H.S., and Peng, Y.J. (2025). Fucoidan Modulates Osteoarthritis Progression Through miR-22\/HO-1 Pathway. Cells, 14.","DOI":"10.3390\/cells14151208"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6187","DOI":"10.2147\/IJN.S503829","article-title":"Chitosan Nanoparticles as an Alternative Therapeutic Approach for Knee Osteoarthritis Treatment: A Systematic Review","volume":"20","author":"Novy","year":"2025","journal-title":"Int. J. Nanomed."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.foodchem.2019.05.132","article-title":"Characterization of a novel alkaline beta-agarase and its hydrolysates of agar","volume":"295","author":"Chen","year":"2019","journal-title":"Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.1038\/s41598-023-29976-0","article-title":"Protective effects of Pudilan Tablets against osteoarthritis in mice induced by monosodium iodoacetate","volume":"13","author":"Fang","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Barry, F., Chai, F., Chijcheapaza-Flores, H., Garcia-Fernandez, M.J., Blanchemain, N., and Nicot, R. (2023). Comparison of chemical-induced temporomandibular osteoarthritis rat models (monosodium iodoacetate versus collagenase type II) for the study of prolonged drug delivery systems. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0281135"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s13075-025-03507-w","article-title":"Longitudinal assessment of structural and locomotor deficits as a prediction of severity in the collagenase-induced mouse model of osteoarthritis","volume":"27","author":"Toupet","year":"2025","journal-title":"Arthritis Res. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Horv\u00e1th, \u00c1.I., B\u00f6lcskei, K., Szentes, N., Borb\u00e9ly, \u00c9., T\u00e9kus, V., Botz, B., Ruszn\u00e1k, K., Fut\u00e1csi, A., Cz\u00e9h, B., and M\u00e1tyus, P. (2024). Novel multitarget analgesic candidate SZV-1287 demonstrates potential disease-modifying effects in the monoiodoacetate-induced osteoarthritis mouse model. Front. Pharmacol., 15, Erratum in Front. Pharmacol.\u00a02025, 16, 1646562.","DOI":"10.3389\/fphar.2024.1377081"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.joca.2021.01.006","article-title":"Optimization of histologic grading schemes in spontaneous and surgically-induced murine models of osteoarthritis","volume":"29","author":"Armstrong","year":"2021","journal-title":"Osteoarthr. Cartil."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T11:46:01Z","timestamp":1783683961000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,10]]},"references-count":31,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146162"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146162","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,10]]}}}