{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T10:50:52Z","timestamp":1789296652988,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Project of Xi\u2032an Health Commission","award":["2023ms12"],"award-info":[{"award-number":["2023ms12"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Steroid-induced osteonecrosis of the femoral head (SONFH) is a common clinical disease caused by massive or prolonged use of steroids. Its pathogenesis is unclear, but its incidence is increasing annually. It is characterized by an insidious and rapid onset, and high disability rate, causing a great burden on patients\u2019 daily life. Therefore, clarifying its pathogenesis and providing early and effective treatment for steroid osteonecrosis is important. Methods: In vivo, we used methylprednisolone (MPS) to construct a SONFH rat model and employed Mirco-ct, Hematoxylin and eosin (H&amp;E) staining, and TdT-mediated dUTP nick end labeling (TUNEL) staining analysis to evaluate the therapeutic effects of proanthocyanidins (PACs). Network pharmacology analysis was conducted to mine targets associated with femoral head necrosis, and PACs analyzed possible molecular mechanisms. In vitro, PACs were added at different doses after treatment of cells with dexamethasone (DEX), and human osteoblast-like sarcoma(MG-63) cell apoptosis was determined by Annexin V-FITC-PI. The mechanisms by which PACs regulate bone metabolism via the Phosphoinositide 3-kinase(PI3K)\/protein kinase B(AKT)\/Recombinant Human B-Cell Leukemia\/Lymphoma 2 XL(Bcl-xL) axis were explored by Western blotting. Result: In vivo studies showed that PACs prevented SONFH in rat model. The PI3K\/AKT\/Bcl-xL signaling pathway was selected by network pharmacology approach; in vitro studies showed that proanthocyanidin-activated AKT and Bcl-xL inhibited osteoblast apoptosis. Conclusions: PACs can inhibit excessive osteoblast apoptosis in SONFH via the PI3K\/AKT\/Bcl-xL signaling axis and have potential therapeutic effects.<\/jats:p>","DOI":"10.3390\/nu15081936","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T02:30:03Z","timestamp":1681785003000},"page":"1936","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Proanthocyanidins Inhibit Osteoblast Apoptosis via the PI3K\/AKT\/Bcl-xL Pathway in the Treatment of Steroid-Induced Osteonecrosis of the Femoral Head in Rats"],"prefix":"10.3390","volume":"15","author":[{"given":"Hui","family":"Li","sequence":"first","affiliation":[{"name":"Department of Joint Surgery, Xi\u2019an Hong Hui Hospital, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710054, China"},{"name":"Department of Traditional Chinese and Western Medicine, First Clinical School of Shaanxi University of Traditional Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5956-9507","authenticated-orcid":false,"given":"Yufei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Xi\u2019an Hong Hui Hospital, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710054, China"},{"name":"Department of Traditional Chinese and Western Medicine, First Clinical School of Shaanxi University of Traditional Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangquan","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Xi\u2019an Hong Hui Hospital, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710054, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Xi\u2019an Hong Hui Hospital, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710054, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4000-464X","authenticated-orcid":false,"given":"Xingyu","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Xi\u2019an Hong Hui Hospital, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710054, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese and Western Medicine, First Clinical School of Shaanxi University of Traditional Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1182\/blood.2019003808","article-title":"How I treat warm autoimmune hemolytic anemia","volume":"137","author":"Barcellini","year":"2021","journal-title":"Blood"},{"key":"ref_2","first-page":"D3965","article-title":"Immunosuppressive agents for treating IgA nephropathy","volume":"3","author":"Natale","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/os.12857","article-title":"Epidemiological Study Based on China Osteonecrosis of the Femoral Head Database","volume":"13","author":"Tan","year":"2021","journal-title":"Orthop. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1093\/mr\/roab047","article-title":"Epidemiological study of osteonecrosis of the femoral head using the national registry of designated intractable diseases in Japan","volume":"32","author":"Sato","year":"2022","journal-title":"Mod. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1302\/0301-620X.103B3.BJJ-2020-0562.R2","article-title":"The lifetime risk of revision following total hip arthroplasty","volume":"103","author":"Nugent","year":"2021","journal-title":"Bone Joint J."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kwak, S.C., Cheon, Y.H., Lee, C.H., Jun, H.Y., Yoon, K.H., Lee, M.S., and Kim, J.Y. (2020). Grape Seed Proanthocyanidin Extract Prevents Bone Loss via Regulation of Osteoclast Differentiation, Apoptosis, and Proliferation. Nutrients, 12.","DOI":"10.3390\/nu12103164"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s11130-020-00807-1","article-title":"Cocoa Flavanols Protect Human Endothelial Cells from Oxidative Stress","volume":"75","author":"Martins","year":"2020","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1089\/jir.2019.0083","article-title":"Procyanidin B2 Suppresses Lipopolysaccharides-Induced Inflammation and Apoptosis in Human Type II Alveolar Epithelial Cells and Lung Fibroblasts","volume":"40","author":"Jiang","year":"2020","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11960","DOI":"10.1111\/jcmm.15818","article-title":"Proanthocyanidin B2 inhibits proliferation and induces apoptosis of osteosarcoma cells by suppressing the PI3K\/AKT pathway","volume":"24","author":"Wu","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/s00776-014-0654-8","article-title":"Beneficial effect of grape seed proanthocyanidin extract in rabbits with steroid-induced osteonecrosis via protecting against oxidative stress and apoptosis","volume":"20","author":"Song","year":"2015","journal-title":"J. Orthop. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1038\/nbt1007-1110","article-title":"Network pharmacology","volume":"25","author":"Hopkins","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e13319","DOI":"10.7717\/peerj.13319","article-title":"Glucocorticoids induce osteonecrosis of the femoral head in rats via PI3K\/AKT\/FOXO1 signaling pathway","volume":"10","author":"Sun","year":"2022","journal-title":"PeerJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.tips.2021.11.004","article-title":"Network pharmacology: Curing causal mechanisms instead of treating symptoms","volume":"43","author":"Nogales","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10175","DOI":"10.1111\/jcmm.16954","article-title":"Aucubin prevents steroid-induced osteoblast apoptosis by enhancing autophagy via AMPK activation","volume":"25","author":"Yue","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s13018-020-01688-5","article-title":"MiR-596 inhibits osteoblastic differentiation and cell proliferation by targeting Smad3 in steroid-induced osteonecrosis of femoral head","volume":"15","author":"Fu","year":"2020","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1111\/os.13127","article-title":"Oxidative Stress Induced Osteocyte Apoptosis in Steroid-Induced Femoral Head Necrosis","volume":"13","author":"Fan","year":"2021","journal-title":"Orthop. Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s11655-011-0940-7","article-title":"Effect of Huogu II Formula (II) with medicinal guide Radix Achyranthis Bidentatae on bone marrow stem cells directional homing to necrosis area after osteonecrosis of the femoral head in rabbit","volume":"18","author":"Kong","year":"2012","journal-title":"Chin. J. Integr. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/jemt.22798","article-title":"Tissue integrity, costs and time associated with different agents for histological bone preparation","volume":"80","author":"Abrantes","year":"2017","journal-title":"Microsc. Res. Tech."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: The universal protein knowledgebase in 2021","volume":"49","author":"Bateman","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"D360","DOI":"10.1093\/nar\/gkx1144","article-title":"mirDIP 4.1-integrative database of human microRNA target predictions","volume":"46","author":"Tokar","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"P3","DOI":"10.1186\/gb-2003-4-5-p3","article-title":"DAVID: Database for Annotation, Visualization, and Integrated Discovery","volume":"4","author":"Dennis","year":"2003","journal-title":"Genome Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/s41419-021-04313-3","article-title":"Activation of cannabinoid receptor 2 alleviates glucocorticoid-induced osteonecrosis of femoral head with osteogenesis and maintenance of blood supply","volume":"12","author":"Sun","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s13167-022-00302-4","article-title":"Identification of FERMT1 and SGCD as key marker in acute aortic dissection from the perspective of predictive, preventive, and personalized medicine","volume":"13","author":"Ainiwan","year":"2022","journal-title":"EPMA J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ma, L., Sun, Z., Zeng, Y., Luo, M., and Yang, J. (2018). Molecular Mechanism and Health Role of Functional Ingredients in Blueberry for Chronic Disease in Human Beings. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092785"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1002\/ptr.6320","article-title":"Effects of French maritime pine bark extract (Oligopin\u00ae) supplementation on bone remodeling markers in postmenopausal osteopenic women: A randomized clinical trial","volume":"33","author":"Panahande","year":"2019","journal-title":"Phytother. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12617","DOI":"10.1021\/acs.jafc.0c04898","article-title":"Cinnamtannin D1 Protects Pancreatic \u03b2-Cells from Glucolipotoxicity-Induced Apoptosis by Enhancement of Autophagy In Vitro and In Vivo","volume":"68","author":"Wang","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Li, J., Ge, Z., Fan, L., and Wang, K. (2017). Protective effects of molecular hydrogen on steroid-induced osteonecrosis in rabbits via reducing oxidative stress and apoptosis. BMC Musculoskelet. Disord., 18.","DOI":"10.1186\/s12891-017-1431-6"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1002\/tox.23327","article-title":"Overexpression of HIF-1\u03b1 enhances the protective effect of mitophagy on steroid-induced osteocytes apoptosis","volume":"36","author":"Xu","year":"2021","journal-title":"Environ. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9102012","DOI":"10.1155\/2020\/9102012","article-title":"Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts","volume":"2020","author":"Chen","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7830","DOI":"10.1039\/D0FO00837K","article-title":"Allicin inhibits osteoblast apoptosis and steroid-induced necrosis of femoral head progression by activating the PI3K\/AKT pathway","volume":"11","author":"Zhan","year":"2020","journal-title":"Food Funct."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112360","DOI":"10.1016\/j.biopha.2021.112360","article-title":"The endocytic pathway of Pt nanoclusters and their induced apoptosis of A549 and A549\/Cis cells through c-Myc\/p53 and Bcl-2\/caspase-3 signaling pathways","volume":"144","author":"Zhao","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yue, Z., Guan, X., Chao, R., Huang, C., Li, D., Yang, P., Liu, S., Hasegawa, T., Guo, J., and Li, M. (2019). Diallyl Disulfide Induces Apoptosis and Autophagy in Human Osteosarcoma MG-63 Cells through the PI3K\/Akt\/mTOR Pathway. Molecules, 24.","DOI":"10.3390\/molecules24142665"},{"key":"ref_35","first-page":"801","article-title":"MicroRNA-206 contributes to the progression of steroid-induced avascular necrosis of the femoral head by inducing osteoblast apoptosis by suppressing programmed cell death 4","volume":"17","author":"Zhang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41577-019-0178-8","article-title":"Osteoimmunology: Evolving concepts in bone-immune interactions in health and disease","volume":"19","author":"Tsukasaki","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3605","DOI":"10.2147\/IJN.S244453","article-title":"Magnetic Targeting of HU-MSCs in the Treatment of Glucocorticoid-Associated Osteonecrosis of the Femoral Head Through Akt\/Bcl2\/Bad\/Caspase-3 Pathway","volume":"15","author":"Duan","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1186\/s13018-021-02386-6","article-title":"Overexpression of CRABP2 inhibits dexamethasone-induced apoptosis in human osteoblast cells","volume":"16","author":"Zhang","year":"2021","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.biopha.2018.11.103","article-title":"Dexamethasone induces osteoblast apoptosis through ROS-PI3K\/AKT\/GSK3\u03b2 signaling pathway","volume":"110","author":"Deng","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13973","DOI":"10.1111\/jcmm.16006","article-title":"Administration of mircoRNA-135b-reinforced exosomes derived from MSCs ameliorates glucocorticoid-induced osteonecrosis of femoral head (ONFH) in rats","volume":"24","author":"Zhang","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/s41423-020-00630-3","article-title":"Necroptosis, pyroptosis and apoptosis: An intricate game of cell death","volume":"18","author":"Bertheloot","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/sj.leu.2402090","article-title":"Phosphorylation of Bcl2 and regulation of apoptosis","volume":"15","author":"Ruvolo","year":"2001","journal-title":"Leukemia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1158\/0008-5472.CAN-17-3024","article-title":"Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells","volume":"78","author":"Rahmani","year":"2018","journal-title":"Cancer Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/8\/1936\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:17:52Z","timestamp":1760123872000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/8\/1936"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,18]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["nu15081936"],"URL":"https:\/\/doi.org\/10.3390\/nu15081936","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,18]]}}}