{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T22:42:40Z","timestamp":1788302560110,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea Ministry of Science and ICT","award":["2018R1C1B6007038"],"award-info":[{"award-number":["2018R1C1B6007038"]}]},{"name":"National Research Foundation of Korea Ministry of Science and ICT","award":["2019R1I1A3A01061034"],"award-info":[{"award-number":["2019R1I1A3A01061034"]}]},{"name":"Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT &amp; Future Planning","award":["NSN2011380"],"award-info":[{"award-number":["NSN2011380"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Although safflower seed extract exhibits pharmacological activity against various diseases, the effects of its individual compounds on osteoarthritis (OA) have not been elucidated. Here, we evaluated the effects of these extracts and their single compounds on OA. N-(p-Coumaroyl) serotonin and N-feruloyl serotonin, main components of safflower seed extract, were isolated by high-performance liquid chromatography. Under in vitro OA mimic conditions, the expression of the matrix metalloproteinases (MMPs) MMP3\/13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) ADAMTS5 were reduced in mouse chondrocytes treated with safflower seed extract. Furthermore, the oral administration of safflower seed extract attenuated cartilage destruction in a mouse OA model induced by destabilization of the medial meniscus. N-(p-Coumaroyl) serotonin and N-feruloyl serotonin, but not serotonin, reduced MMP3, MMP13, and ADAMTS5 expression in IL-1\u03b2-treated chondrocytes. Additionally, they significantly blocked the nuclear factor-\u03baB (NF-\u03baB) pathway by inhibiting I\u03baB degradation and p65 phosphorylation. Our results suggest that safflower seed extract and its single compounds can attenuate cartilage destruction by suppressing MMP and ADMATS5 expression. The anti-arthritic effects are mediated by NF-\u03baB signaling and involve the inhibition of I\u03baB degradation and p65 phosphorylation. These results indicate that safflower seed extract may serve as a novel therapeutic agent against OA.<\/jats:p>","DOI":"10.3390\/ph14030258","type":"journal-article","created":{"date-parts":[[2021,3,14]],"date-time":"2021-03-14T23:52:06Z","timestamp":1615765926000},"page":"258","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Safflower Seed Extract Attenuates the Development of Osteoarthritis by Blocking NF-\u03baB Signaling"],"prefix":"10.3390","volume":"14","author":[{"given":"Seong Jae","family":"Han","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"},{"name":"Department of Pharmacology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Degenerative InterDiseases Research Center, Ajou University School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Ju","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"},{"name":"Department of Pharmacology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Degenerative InterDiseases Research Center, Ajou University School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7691-5686","authenticated-orcid":false,"given":"Kwang Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Life Science and Environmental Biochemistry, Pusan National University, Miryang 50463, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunjeong","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"},{"name":"Department of Pharmacology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Degenerative InterDiseases Research Center, Ajou University School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Su","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Medicinal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong 369-873, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seokho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2180-4860","authenticated-orcid":false,"given":"Joong Sun","family":"Kim","sequence":"additional","affiliation":[{"name":"Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju-si, Jeollanam-do 58245, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Pil","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Convergence Medical Science, Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 52727, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Jung","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"},{"name":"Department of Pharmacology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Degenerative InterDiseases Research Center, Ajou University School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"ref_1","first-page":"507","article-title":"Osteoarthritis: Value of imaging and biomarkers","volume":"69","author":"Richette","year":"2019","journal-title":"La Rev. Du Prat."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"116786","DOI":"10.1016\/j.lfs.2019.116786","article-title":"The role of matrix metalloproteinases in osteoarthritis pathogenesis: An updated review","volume":"234","author":"Mehana","year":"2019","journal-title":"Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.biopha.2017.12.050","article-title":"Ghrelin prevents articular cartilage matrix destruction in human chondrocytes","volume":"98","author":"Liu","year":"2017","journal-title":"Biomed. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.omtm.2018.02.006","article-title":"Isoliquiritigenin Inhibits IL-1\u03b2-Induced Production of Matrix Metalloproteinase in Articular Chondrocytes","volume":"9","author":"Zhang","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fphar.2017.00282","article-title":"Revisiting the role of interleukin-1 pathway in osteoarthritis: Interleukin-1\u03b1 and-1\u03b2, and NLRP3 inflammasome are not involved in the pathological features of the murine menisectomy model of osteoarthritis","volume":"8","author":"Nasi","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Choi, M.C., Jo, J., Park, J., Kang, H.K., and Park, Y. (2019). NF-\u03baB Signaling Pathways in Osteoarthritic Cartilage Destruction. Cells, 8.","DOI":"10.3390\/cells8070734"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/bs.ircmb.2017.07.007","article-title":"NF-\u03baB and the Transcriptional Control of Inflammation","volume":"335","author":"Mitchell","year":"2018","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/s13287-019-1252-7","article-title":"Effect of canonical NF-\u03baB signaling pathway on the differentiation of rat dental epithelial stem cells","volume":"10","author":"Liang","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13075-017-1296-y","article-title":"Molecular mechanisms underlying osteoarthritis development: Notch and NF-\u03baB","volume":"15","author":"Saito","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4564","DOI":"10.1038\/s41467-018-07022-2","article-title":"Reciprocal inhibition of YAP\/TAZ and NF-\u03baB regulates osteoarthritic cartilage degradation","volume":"1","author":"Deng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2147\/JIR.S140188","article-title":"Mechanisms of NF-\u03baB p65 and strategies for therapeutic manipulation","volume":"11","author":"Giridharan","year":"2018","journal-title":"J. Inflamm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/978-981-13-9367-9_10","article-title":"NF-\u03baB, I\u03baB, and IKK: Integral Components of Immune System Signaling","volume":"1172","author":"Mulero","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.freeradbiomed.2018.09.025","article-title":"Redox and NF-\u03baB signaling in osteoarthritis","volume":"132","author":"Lepetsos","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"(2020). The Role of Inflammation in the Pathogenesis of Osteoarthritis. Mediat. Inflamm., 2020, 8293921.","DOI":"10.1155\/2020\/8293921"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8126","DOI":"10.1111\/jcmm.15471","article-title":"Seomae mugwort and jaceosidin attenuate osteoarthritic cartilage damage by blocking I\u03baB degradation in mice","volume":"24","author":"Lee","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/s11926-018-0782-9","article-title":"Natural products for promoting joint health and managing osteoarthritis","volume":"20","author":"Henrotin","year":"2018","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"503","DOI":"10.4062\/biomolther.2019.139","article-title":"Natural products as sources of novel drug candidates for the pharmacological management of osteoarthritis: A narrative review","volume":"27","author":"Kang","year":"2019","journal-title":"Biomol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bacchetti, T., Morresi, C., Bellachioma, L., and Ferretti, G. (2020). Antioxidant and Pro-Oxidant Properties of Carthamus tinctorius, Hydroxy Safflor Yellow A, and Safflor Yellow A. Antioxidants, 9.","DOI":"10.3390\/antiox9020119"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1142\/S0192415X1850009X","article-title":"Protective Effect of Safflower Seed on Cisplatin-Induced Renal Damage in Mice via Oxidative Stress and Apoptosis-Mediated Pathways","volume":"46","author":"Park","year":"2018","journal-title":"Am. J. Chin. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"104654","DOI":"10.1016\/j.phrs.2020.104654","article-title":"Pharmacological potential of the combination of Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua) for diabetes mellitus and its cardiovascular complications","volume":"153","author":"Orgah","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ibrahim, F.Y., El-Khateeb, A.Y., and Mohamed, A.H. (2019). Rhus and Safflower Extracts as Potential Novel Food Antioxidant, Anticancer, and Antimicrobial Agents Using Nanotechnology. Foods, 8.","DOI":"10.3390\/foods8040139"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"383","DOI":"10.3923\/pjbs.2019.383.392","article-title":"In vitro Anticancer Activity of Quinoa and Safflower Seeds and Their Preventive Effects on Non-alcoholic Fatty Liver","volume":"22","author":"Mohamed","year":"2019","journal-title":"Pak. J. Biol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.phrs.2018.06.015","article-title":"Beyond a neurotransmitter: The role of serotonin in inflammation and immunity","volume":"140","author":"Wu","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s11060-017-2382-3","article-title":"N-(p-coumaroyl) serotonin inhibits glioblastoma cells growth through triggering S-phase arrest and apoptosis","volume":"132","author":"Lazari","year":"2017","journal-title":"J. Neuro-Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1142\/S0192415X16500130","article-title":"Phytochemistry and Pharmacology of Carthamus tinctorius L.","volume":"44","author":"Zhang","year":"2016","journal-title":"Am. J. Chin. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.phrs.2018.05.012","article-title":"Oral hydroxysafflor yellow A reduces obesity in mice by modulating the gut microbiota and serum metabolism","volume":"134","author":"Liu","year":"2018","journal-title":"Pharm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1142\/S0192415X19500186","article-title":"Protective effects of serotonin and its derivatives, N-feruloylserotonin and N-(p-coumaroyl) serotonin, against cisplatin-induced renal damage in mice","volume":"47","author":"Park","year":"2019","journal-title":"Am. J. Chin. Med."},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"112261","DOI":"10.1016\/j.jep.2019.112261","article-title":"Loganin ameliorates cartilage degeneration and osteoarthritis development in an osteoarthritis mouse model through inhibition of NF-\u03baB activity and pyroptosis in chondrocytes","volume":"247","author":"Hu","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5369","DOI":"10.1111\/jcmm.14418","article-title":"Cirsium japonicum var. maackii and apigenin block Hif-2\u03b1-induced osteoarthritic cartilage destruction","volume":"23","author":"Cho","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6093","DOI":"10.3390\/ijms16036093","article-title":"Osteoarthritis in the XXIst century: Risk factors and behaviours that influence disease onset and progression","volume":"16","author":"Musumeci","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/nm.2153","article-title":"Hypoxia-inducible factor-2\u03b1 is a catabolic regulator of osteoarthritic cartilage destruction","volume":"16","author":"Yang","year":"2010","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15040","DOI":"10.1038\/boneres.2015.40","article-title":"Current research on pharmacologic and regenerative therapies for osteoarthritis","volume":"4","author":"Zhang","year":"2016","journal-title":"Bone Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1089\/jmf.2016.3705","article-title":"Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials","volume":"19","author":"Daily","year":"2016","journal-title":"J. Med. Food"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"328","DOI":"10.5582\/ddt.2019.01086","article-title":"Safflower seed extract synergizes the therapeutic effect of cisplatin-induced nephrotoxicity in human colorectal carcinoma RKO cells and RKO-transplanted mice","volume":"13","author":"Park","year":"2019","journal-title":"Drug Discov. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3650","DOI":"10.1039\/C9FO00615J","article-title":"Saffloer (Carthamus tinctorius L.) seed attenuates memory impairment induced by scopolamine in mice via regulation of cholinergic dysfunction and oxidative stress","volume":"10","author":"Kim","year":"2019","journal-title":"Food Funct."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00217-019-03414-w","article-title":"Profiling of the bioactive components of safflower seeds and seed oil: Cultivated (Carthamus tinctorius L.) vs. wild (Carthamus oxyacantha M. Bieb.)","volume":"246","author":"Chakradhar","year":"2020","journal-title":"Eur. Food Res. Technol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1111\/bcp.12923","article-title":"Antioxidant and antiplatelet activity by polyphenol-rich nutrients: Focus on extra virgin olive oil and cocoa","volume":"83","author":"Loffredo","year":"2017","journal-title":"Br. J. Clin. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Serino, A., and Salazar, G. (2018). Protective Role of Polyphenols against Vascular Inflammation, Aging and Cardiovascular Disease. Nutrients, 11.","DOI":"10.3390\/nu11010053"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.cellsig.2018.10.005","article-title":"Interleukin-1\u03b2 signaling in osteoarthritis\u2013chondrocytes in focus","volume":"53","author":"Meurer","year":"2019","journal-title":"Cell. Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41598-018-36500-2","article-title":"Identification of Chondrocyte Genes and Signaling Pathways in Response to Acute Joint Inflammation","volume":"9","author":"Lv","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10499","DOI":"10.18632\/aging.102472","article-title":"Melatonin modulates IL-1\u03b2-induced extracellular matrix remodeling in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration and inflammation","volume":"11","author":"Zhang","year":"2019","journal-title":"Aging"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.3892\/mmr.2017.6312","article-title":"Icariin inhibits MMP-1, MMP-3 and MMP-13 expression through MAPK pathways in IL-1\u03b2-stimulated SW1353 chondrosarcoma cells","volume":"15","author":"Zeng","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Sirikaew, N., Chomdej, S., Tangyuenyong, S., Tangjitjaroen, W., Somgird, C., Thitaram, C., and Ongchai, S. (2019). Proinflammatory cytokines and lipopolysaccharides up regulate MMP-3 and MMP-13 production in Asian elephant (Elephas maximus) chondrocytes: Attenuation by anti-arthritic agents. BMC Vet. Res., 15.","DOI":"10.1186\/s12917-019-2170-8"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"221","DOI":"10.4196\/kjpp.2016.20.2.221","article-title":"Effects of prunetin on the proteolytic activity, secretion and gene expression of MMP-3 in vitro and production of MMP-3 in vivo","volume":"20","author":"Nam","year":"2016","journal-title":"Korean J. Physiol. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.4049\/jimmunol.1800486","article-title":"Activation of NF-\u03baB in synovium versus cartilage from patients with advanced knee osteoarthritis: A potential contributor to inflammatory aspects of disease progression","volume":"201","author":"Ahmed","year":"2018","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/wsbm.1331","article-title":"Signaling via the NF-\u03baB system","volume":"8","author":"Mitchell","year":"2016","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.biocel.2017.09.021","article-title":"FBXO32 activates NF-\u03baB through I\u03baB\u03b1 degradation in inflammatory and genotoxic stress","volume":"92","author":"Meshram","year":"2017","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s13018-015-0296-3","article-title":"IL-1\u03b2 promotes ADAMTS enzyme-mediated aggrecan degradation through NF-\u03baB in human intervertebral disc","volume":"10","author":"Sun","year":"2015","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1159\/000481645","article-title":"Licochalcone A Inhibits MMPs and ADAMTSs via the NF-\u03baB and Wnt\/\u03b2-Catenin Signaling Pathways in Rat Chondrocytes","volume":"43","author":"Chen","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.joca.2007.03.006","article-title":"The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129\/SvEv mouse","volume":"15","author":"Glasson","year":"2007","journal-title":"Osteoarthr. Cart."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Samvelyan, H.J., Hughes, D., Stevens, C., and Staines, K.A. (2020). Models of Osteoarthritis: Relevance and New insight. Calcif. Tissue Int.","DOI":"10.1007\/s00223-020-00670-x"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/3\/258\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:54Z","timestamp":1760160894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/3\/258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ph14030258"],"URL":"https:\/\/doi.org\/10.3390\/ph14030258","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]}}}