{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:03:03Z","timestamp":1783051383563,"version":"3.54.6"},"reference-count":63,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"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":"crossref","award":["2022R1C1C1003491"],"award-info":[{"award-number":["2022R1C1C1003491"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoclast differentiation inhibition is a viable treatment strategy for osteoporosis because osteoclasts play a vital role in disease progression. Rhusflavone (Rhus), a biflavonoid, exhibits a sedative\u2013hypnotic effect via the positive allosteric modulation of GABA(A) receptors. Although several biflavonoids possess activities that help prevent bone loss, the potential effects of Rhus on osteoclastogenesis have not been reported yet. In this study, we investigated the effects and underlying biological mechanisms of Rhus isolated from the dried roots of Rhus succedanea on osteoclastogenesis in primary cultured bone marrow-derived macrophages. No cytotoxicity was observed in bone marrow macrophages (BMMs) or during osteoclast differentiation. However, Rhus reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts during receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis. The results of F-actin ring formation demonstrated that Rhus suppresses the bone resorption activity of osteoclasts. Additionally, Rhus inhibits the expression of osteoclast differentiation marker proteins, specifically c-Fos and NF-ATc1. Western blot analysis revealed that Rhus primarily attenuated RANKL-mediated key signaling pathways, particularly the AKT signaling pathway. Furthermore, we found that the AKT activator and inhibitor pharmacologically abolished and enhanced the inhibitory effects of Rhus on osteoclast differentiation, respectively. Taken together, our findings provide evidence that Rhus is a promising biologically active compound that regulates osteoclast differentiation by inhibiting the AKT signaling pathway, which may contribute to future drug development.<\/jats:p>","DOI":"10.3390\/ijms26073025","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T06:58:43Z","timestamp":1742972323000},"page":"3025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Rhusflavone Modulates Osteoclastogenesis Through RANKL-Induced AKT Signaling in Bone Marrow-Derived Macrophages"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6504-1610","authenticated-orcid":false,"given":"Hyung-Mun","family":"Yun","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bomi","family":"Kim","sequence":"additional","affiliation":[{"name":"National Institute for Korean Medicine Development, Gyeongsan 38540, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eonmi","family":"Kim","sequence":"additional","affiliation":[{"name":"National Institute for Korean Medicine Development, Gyeongsan 38540, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Ran","family":"Park","sequence":"additional","affiliation":[{"name":"Honam Regional Center, Korea Basic Science Institute (KBSI), Gwangju 61751, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"ref_1","first-page":"17455057231176655","article-title":"An overview of the management of osteoporosis in the aging female population","volume":"19","author":"Amin","year":"2023","journal-title":"Womens Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5152\/eurjrheum.2016.048","article-title":"An overview and management of osteoporosis","volume":"4","author":"Sozen","year":"2017","journal-title":"Eur. J. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/nrg1122","article-title":"Genetic regulation of osteoclast development and function","volume":"4","author":"Teitelbaum","year":"2003","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","first-page":"6605","article-title":"TNF-alpha and RANKL promote osteoclastogenesis by upregulating RANK via the NF-kappaB pathway","volume":"17","author":"Luo","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.molmed.2005.11.007","article-title":"RANKL-RANK signaling in osteoclastogenesis and bone disease","volume":"12","author":"Wada","year":"2006","journal-title":"Trends Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1080\/15216540500137669","article-title":"RANKing intracellular signaling in osteoclasts","volume":"57","author":"Feng","year":"2005","journal-title":"IUBMB Life"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"706","DOI":"10.14348\/molcells.2017.0225","article-title":"Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation","volume":"40","author":"Park","year":"2017","journal-title":"Mol. Cells"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1096\/fba.2020-00058","article-title":"Current advances in regulation of bone homeostasis","volume":"2","year":"2020","journal-title":"FASEB Bioadv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1359\/JBMR.041114","article-title":"Drugs used to treat osteoporosis: The critical need for a uniform nomenclature based on their action on bone remodeling","volume":"20","author":"Riggs","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"h3783","DOI":"10.1136\/bmj.h3783","article-title":"Bisphosphonates for the prevention and treatment of osteoporosis","volume":"351","author":"Maraka","year":"2015","journal-title":"BMJ"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ejendo\/lvad168","article-title":"Breast cancer risk association with postmenopausal hormone therapy: Health Insurance Database in South Korea-based cohort study","volume":"190","author":"Yuk","year":"2024","journal-title":"Eur. J. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1007\/s10147-023-02405-y","article-title":"Advantages and limitations of estrogen replacement therapy on hypogonadal survivors of childhood cancer","volume":"28","author":"Nakamura","year":"2023","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1111\/odi.12333","article-title":"Management of bisphosphonate-related osteonecrosis of the jaw: A literature review","volume":"21","author":"Spanou","year":"2015","journal-title":"Oral Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.5713\/ajas.18.0045","article-title":"In vitro evaluation of Rhus succedanea extracts for ruminants","volume":"31","author":"Kim","year":"2018","journal-title":"Asian-Australas J. Anim. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4376","DOI":"10.1080\/07391102.2020.1858165","article-title":"Biflavonoids from Rhus succedanea as probable natural inhibitors against SARS-CoV-2: A molecular docking and molecular dynamics approach","volume":"40","author":"Lokhande","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1055\/s-2006-961914","article-title":"Hinokiflavone, a cytotoxic principle from Rhus succedanea and the cytotoxicity of the related biflavonoids","volume":"55","author":"Lin","year":"1989","journal-title":"Planta Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.jep.2012.04.047","article-title":"Rhus parviflora and its biflavonoid constituent, rhusflavone, induce sleep through the positive allosteric modulation of GABA(A)-benzodiazepine receptors","volume":"142","author":"Shrestha","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e17722","DOI":"10.7717\/peerj.17722","article-title":"Ginkgetin attenuates bone loss in OVX mice by inhibiting the NF-kappaB\/IkappaBalpha signaling pathway","volume":"12","author":"Wei","year":"2024","journal-title":"PeerJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1055\/s-0043-124594","article-title":"Amentoflavone Inhibits Osteoclastogenesis and Wear Debris-Induced Osteolysis via Suppressing NF-kappaB and MAPKs Signaling Pathways","volume":"84","author":"Zhang","year":"2018","journal-title":"Planta Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.intimp.2017.05.029","article-title":"Sciadopitysin suppresses RANKL-mediated osteoclastogenesis and prevents bone loss in LPS-treated mice","volume":"49","author":"Cao","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1007\/s11914-011-0078-8","article-title":"Bone development: Overview of bone cells and signaling","volume":"9","author":"Teti","year":"2011","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1172\/JCI36809","article-title":"Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice","volume":"119","author":"Kim","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1172\/JCI22513","article-title":"A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss","volume":"116","author":"Aoki","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3097","DOI":"10.1007\/s40520-023-02614-5","article-title":"Do lifestyle, anthropometric and demographic factors associated with muscle strength differ in a UK and Japanese cohort? An exploratory analysis","volume":"35","author":"Dennison","year":"2023","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wang, C., Shu, X., Tao, J., Zhang, Y., Yuan, Y., and Wu, C. (2021). Seasonal Variation and Global Public Interest in the Internet Searches for Osteoporosis. Biomed. Res. Int., 2021.","DOI":"10.1155\/2021\/6663559"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s00198-020-05736-y","article-title":"Contribution of elevation and residential proximity to the coast in explaining geographic variations in hip fracture incidence. A Norwegian Epidemiologic Osteoporosis Studies (NOREPOS) study","volume":"32","author":"Dahl","year":"2021","journal-title":"Osteoporos. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s11657-017-0407-3","article-title":"Seasonal variation of serum vitamin D levels in Romania","volume":"12","author":"Niculescu","year":"2017","journal-title":"Arch. Osteoporos."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/pr.2015.206","article-title":"Seasonal variations in growth and body composition of 8-11-y-old Danish children","volume":"79","author":"Dalskov","year":"2016","journal-title":"Pediatr. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/s12276-024-01157-7","article-title":"Unraveling the intricacies of osteoclast differentiation and maturation: Insight into novel therapeutic strategies for bone-destructive diseases","volume":"56","author":"Takegahara","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.mod.2012.04.003","article-title":"Role of tartrate-resistant acid phosphatase (TRAP) in long bone development","volume":"129","author":"Blumer","year":"2012","journal-title":"Mech. Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1002\/jcb.20835","article-title":"Secretion of tartrate-resistant acid phosphatase by osteoclasts correlates with resorptive behavior","volume":"98","author":"Kirstein","year":"2006","journal-title":"J. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/nm1593","article-title":"Skeletal remodeling in health and disease","volume":"13","author":"Zaidi","year":"2007","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3087","DOI":"10.7150\/thno.24426","article-title":"Dysregulation of 5-hydroxytryptamine 6 receptor accelerates maturation of bone-resorbing osteoclasts and induces bone loss","volume":"8","author":"Park","year":"2018","journal-title":"Theranostics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"118060","DOI":"10.1016\/j.jep.2024.118060","article-title":"Orcinol gentiobioside inhibits RANKL-induced osteoclastogenesis by promoting apoptosis and suppressing autophagy via the JNK1 signaling","volume":"328","author":"Lian","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e75610","DOI":"10.7554\/eLife.75610","article-title":"Nanoscale architecture and coordination of actin cores within the sealing zone of human osteoclasts","volume":"11","author":"Portes","year":"2022","journal-title":"Elife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1359\/jbmr.2000.15.1.103","article-title":"Transgenic mice overexpressing tartrate-resistant acid phosphatase exhibit an increased rate of bone turnover","volume":"15","author":"Angel","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.1242\/dev.122.10.3151","article-title":"Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis","volume":"122","author":"Hayman","year":"1996","journal-title":"Development"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/(SICI)1097-0029(19960201)33:2<171::AID-JEMT7>3.0.CO;2-W","article-title":"Cytoskeletal changes in osteoclasts during the resorption cycle","volume":"33","author":"Lakkakorpi","year":"1996","journal-title":"Microsc. Res. Tech."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Han, G., Zuo, J., and Holliday, L.S. (2019). Specialized Roles for Actin in Osteoclasts: Unanswered Questions and Therapeutic Opportunities. Biomolecules, 9.","DOI":"10.3390\/biom9010017"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1091\/mbc.e07-03-0227","article-title":"The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts","volume":"19","author":"Destaing","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.bone.2009.10.042","article-title":"Inhibition of osteoclast differentiation and bone resorption by rotenone, through down-regulation of RANKL-induced c-Fos and NFATc1 expression","volume":"46","author":"Kwak","year":"2010","journal-title":"Bone"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26475","DOI":"10.1074\/jbc.M313973200","article-title":"Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos","volume":"279","author":"Matsuo","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"233","DOI":"10.11005\/jbm.2014.21.4.233","article-title":"Regulation of NFATc1 in Osteoclast Differentiation","volume":"21","author":"Kim","year":"2014","journal-title":"J. Bone Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.7150\/ijbs.70620","article-title":"GPR125 positively regulates osteoclastogenesis potentially through AKT-NF-kappaB and MAPK signaling pathways","volume":"18","author":"Tang","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.1038\/s41467-019-13015-6","article-title":"Author Correction: Galpha13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3beta-NFATc1 signalling pathway","volume":"10","author":"Wu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"114176","DOI":"10.1016\/j.jep.2021.114176","article-title":"Glaucocalyxin A suppresses osteoclastogenesis induced by RANKL and osteoporosis induced by ovariectomy by inhibiting the NF-kappaB and Akt pathways","volume":"276","author":"Zhu","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Xu, H., Jia, Y., Li, J., Huang, X., Jiang, L., Xiang, T., Xie, Y., Yang, X., Liu, T., and Xiang, Z. (2022). Niloticin inhibits osteoclastogenesis by blocking RANKL-RANK interaction and suppressing the AKT, MAPK, and NF-kappaB signaling pathways. Biomed. Pharmacother., 149.","DOI":"10.1016\/j.biopha.2022.112902"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1002\/jbmr.396","article-title":"Molecular disease map of bone characterizing the postmenopausal osteoporosis phenotype","volume":"26","author":"Jemtland","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41413-023-00312-6","article-title":"Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity","volume":"12","author":"Hansen","year":"2024","journal-title":"Bone Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.bone.2019.07.022","article-title":"Transcriptional profiling of intramembranous and endochondral ossification after fracture in mice","volume":"127","author":"Coates","year":"2019","journal-title":"Bone"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"163","DOI":"10.4049\/jimmunol.1101254","article-title":"Akt induces osteoclast differentiation through regulating the GSK3beta\/NFATc1 signaling cascade","volume":"188","author":"Moon","year":"2012","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Pizzimenti, C., Fiorentino, V., Ruggeri, C., Franchina, M., Ercoli, A., Tuccari, G., and Ieni, A. (2024). Autophagy Involvement in Non-Neoplastic and Neoplastic Endometrial Pathology: The State of the Art with a Focus on Carcinoma. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212118"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Giaccari, C., Antonouli, S., Anifandis, G., Cecconi, S., and Di Nisio, V. (2024). An Update on Physiopathological Roles of Akt in the ReprodAKTive Mammalian Ovary. Life, 14.","DOI":"10.3390\/life14060722"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Pizzimenti, C., Fiorentino, V., Franchina, M., Martini, M., Giuffre, G., Lentini, M., Silvestris, N., Di Pietro, M., Fadda, G., and Tuccari, G. (2023). Autophagic-Related Proteins in Brain Gliomas: Role, Mechanisms, and Targeting Agents. Cancers, 15.","DOI":"10.3390\/cancers15092622"},{"key":"ref_56","first-page":"2319","article-title":"The Akt pathway in oncology therapy and beyond (Review)","volume":"53","author":"Nitulescu","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.vph.2015.05.008","article-title":"The critical role of Akt in cardiovascular function","volume":"74","author":"Abeyrathna","year":"2015","journal-title":"Vasc. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1016\/j.cellsig.2011.05.004","article-title":"Akt signalling in health and disease","volume":"23","author":"Hers","year":"2011","journal-title":"Cell. Signal."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"106423","DOI":"10.1016\/j.phrs.2022.106423","article-title":"Chi3L1 is a therapeutic target in bone metabolism and a potential clinical marker in patients with osteoporosis","volume":"184","author":"Park","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/bs.mie.2019.11.014","article-title":"Generation of mouse bone marrow-derived macrophages using tumor coculture assays to mimic the tumor microenvironment","volume":"632","author":"Guc","year":"2020","journal-title":"Methods Enzymol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1007\/s12272-017-0932-z","article-title":"RANKL-induced osteoclastogenesis is suppressed by 4-O-methylhonokiol in bone marrow-derived macrophages","volume":"40","author":"Park","year":"2017","journal-title":"Arch. Pharm. Res."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Yun, H.M., Kwon, H.S., Lee, J.Y., and Park, K.R. (2024). Vitexicarpin Induces Apoptosis and Inhibits Metastatic Properties via the AKT-PRAS40 Pathway in Human Osteosarcoma. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25073582"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Yun, H.M., Kim, S.H., Kwon, Y.J., and Park, K.R. (2024). Effect of Spicatoside a on Anti-Osteosarcoma MG63 Cells through Reactive Oxygen Species Generation and the Inhibition of the PI3K-AKT-mTOR Pathway. Antioxidants, 13.","DOI":"10.3390\/antiox13101162"}],"updated-by":[{"DOI":"10.3390\/ijms26157354","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T14:41:06Z","timestamp":1754232066000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,26]]},"references-count":63,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26073025"],"URL":"https:\/\/doi.org\/10.3390\/ijms26073025","relation":{"correction":[{"id-type":"doi","id":"10.3390\/ijms26157354","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,26]]}}}