{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T23:34:34Z","timestamp":1793230474793,"version":"4.5.0"},"reference-count":81,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brain Initiative Grant of the Ministry of Science and Technology, China","award":["STI2030-Major Projects 2022ZD0204700"],"award-info":[{"award-number":["STI2030-Major Projects 2022ZD0204700"]}]},{"name":"Brain Initiative Grant of the Ministry of Science and Technology, China","award":["32070965"],"award-info":[{"award-number":["32070965"]}]},{"name":"Brain Initiative Grant of the Ministry of Science and Technology, China","award":["32170969"],"award-info":[{"award-number":["32170969"]}]},{"name":"National Natural Science Foundation of China","award":["STI2030-Major Projects 2022ZD0204700"],"award-info":[{"award-number":["STI2030-Major Projects 2022ZD0204700"]}]},{"name":"National Natural Science Foundation of China","award":["32070965"],"award-info":[{"award-number":["32070965"]}]},{"name":"National Natural Science Foundation of China","award":["32170969"],"award-info":[{"award-number":["32170969"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a poor prognosis and limited therapeutic options. This study aimed to repurpose methylstat, a selective histone demethylase inhibitor, as a novel anti-glioma agent. We characterized its anti-proliferative efficacy, elucidated mechanisms of cell cycle regulation, and evaluated its blood\u2013brain barrier (BBB) permeability potential. Methods: Compounds with transcriptional profiles enriched for cell cycle arrest and tumor-suppressive pathways were identified via Connectivity Map (CMAP) analysis. Methylstat was selected based on its high connectivity score and favorable physicochemical properties. In vitro assays were performed to evaluate its effects on cell viability, proliferation, cell cycle progression, and expression of related molecular markers in U251 and HOG glioma cell lines. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed to evaluate the binding mode and stability of the Methylstat\u2013JMJD2A complex. An in vitro BBB model was established to assess the ability of Methylstat to cross the BBB. Results: Methylstat significantly inhibited glioma cell proliferation in a dose-dependent manner without inducing apoptosis. It caused G1-phase arrest in U251 cells and G2-phase arrest in HOG cells. Mechanistically, methylstat downregulated cyclins and cyclin-dependent kinases via the p53\/p21 pathway. Additionally, methylstat reduced the expression of JMJD2A and its downstream targets, including PDK1, AKT, and mTOR. Molecular docking studies and 200 ns MD simulations confirmed the stable binding of methylstat to the catalytic pocket of JMJD2A, effectively inhibiting its enzymatic activity. HPLC analysis confirmed that methylstat could penetrate the in vitro BBB model to varying extents. Conclusions: Methylstat is a promising small-molecule agent that effectively suppresses glioma cell growth by modulating key cell cycle regulators. Its ability to cross the BBB highlights its potential as a novel therapeutic strategy for GBM and other brain tumors.<\/jats:p>","DOI":"10.3390\/ph18091344","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T10:29:07Z","timestamp":1757327347000},"page":"1344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of Methylstat as a Potential Therapeutic Agent for Human Glioma Cells by Targeting Cell Cycle Arrest"],"prefix":"10.3390","volume":"18","author":[{"given":"Haoge","family":"Yao","sequence":"first","affiliation":[{"name":"Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyi","family":"Meng","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaping","family":"Tao","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Lu","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Specialty Agri-Product Quality and Hazard Controlling Technology of Zhejiang Province, College of Life Sciences, China Jiliang University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2045-4996","authenticated-orcid":false,"given":"Xiaofeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengsheng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aifen","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/noy131","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011\u20132015","volume":"20","author":"Ostrom","year":"2018","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1158\/2159-8290.CD-20-1474","article-title":"Diffuse Glioma Heterogeneity and Its Therapeutic Implications","volume":"11","author":"Nicholson","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","article-title":"Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sadowski, K., Jazdzewska, A., Kozlowski, J., Zacny, A., Lorenc, T., and Olejarz, W. (2024). Revolutionizing Glioblastoma Treatment: A Comprehensive Overview of Modern Therapeutic Approaches. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115774"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Roda, D., Veiga, P., Melo, J.B., Carreira, I.M., and Ribeiro, I.P. (2024). Principles in the Management of Glioblastoma. Genes, 15.","DOI":"10.3390\/genes15040501"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.wneu.2012.03.024","article-title":"Gamma Knife Surgery versus Reoperation for Recurrent Glioblastoma Multiforme","volume":"78","author":"Skeie","year":"2012","journal-title":"World Neurosurg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s13045-018-0683-4","article-title":"Proton beam therapy for cancer in the era of precision medicine","volume":"11","author":"Hu","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1001\/jama.2017.18718","article-title":"Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs. Maintenance Temozolomide Alone on Survival in Patients with Glioblastoma A Randomized Clinical Trial","volume":"318","author":"Stupp","year":"2017","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pan, P.C., and Magge, R.S. (2020). Mechanisms of EGFR Resistance in Glioblastoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228471"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.5114\/wo.2020.94726","article-title":"Receptor tyrosine kinase targeting in glioblastoma: Performance, limitations and future approaches","volume":"24","author":"Alexandru","year":"2020","journal-title":"Wspolczesna Onkol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Olejarz, W., Sadowski, K., and Radoszkiewicz, K. (2024). Extracellular Vesicles in Atherosclerosis: State of the Art. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010388"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Behrooz, A.B., Talaie, Z., Jusheghani, F., Los, M.J., Klonisch, T., and Ghavami, S. (2022). Wnt and PI3K\/Akt\/mTOR Survival Pathways as Therapeutic Targets in Glioblastoma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031353"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1038\/s41587-019-0192-1","article-title":"VCAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity","volume":"37","author":"Choi","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Li, Y.T., Sharma, A., Maciaczyk, J., and Schmidt-Wolf, I.G.H. (2022). Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031311"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.2147\/TCRM.S135865","article-title":"Dendritic cell vaccines for high-grade gliomas","volume":"14","author":"Eagles","year":"2018","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s11912-017-0586-5","article-title":"Immune Checkpoint Inhibitors in Gliomas","volume":"19","author":"Tan","year":"2017","journal-title":"Curr. Oncol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16432","DOI":"10.1021\/acsnano.2c12857","article-title":"Engineered Extracellular Vesicle-Delivered CRISPR\/Cas9 for Radiotherapy Sensitization of Glioblastoma","volume":"17","author":"Liu","year":"2023","journal-title":"ACS Nano"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/s41590-019-0433-y","article-title":"Mechanisms of immunotherapy resistance: Lessons from glioblastoma","volume":"20","author":"Jackson","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"138","DOI":"10.5306\/wjco.v14.i4.138","article-title":"Immunotherapy in glioblastoma treatment: Current state and future prospects","volume":"14","author":"Pinheiro","year":"2023","journal-title":"World J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fu, J.Y., Jiang, C.X., Wu, M.Y., Mei, R.Y., Yang, A.F., Tao, H.P., Chen, X.J., Zhang, J., Huang, L., and Zhao, X.F. (2021). Theabrownin Induces Cell Apoptosis and Cell Cycle Arrest of Oligodendroglioma and Astrocytoma in Different Pathways. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.664003"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ejca.2020.01.012","article-title":"A prospective study of coffee and tea consumption and the risk of glioma in the UK Biobank","volume":"129","author":"Creed","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1093\/advances\/nmaa117","article-title":"Tea Drinking and Risk of Cancer Incidence: A Meta-Analysis of Prospective Cohort Studies and Evidence Evaluation","volume":"12","author":"Zhao","year":"2021","journal-title":"Adv. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Li, W.L., Zhou, H.Z., Yao, S.S., Wang, N., Zhu, H., Mehmood, M.A., and Wu, T. (2023). Comprehensive characterization of theabrownin polymer structure in Tibetan tea. Food Biosci., 56.","DOI":"10.1016\/j.fbio.2023.103138"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1126\/science.1132939","article-title":"The Connectivity Map: Using gene-expression signatures to connect small molecules, genes, and disease","volume":"313","author":"Lamb","year":"2006","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4895","DOI":"10.1002\/jcp.26298","article-title":"Using the Connectivity Map to discover compounds influencing human osteoblast differentiation","volume":"233","author":"Brum","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1744-8069-6-56","article-title":"Evaluation of phenoxybenzamine in the CFA model of pain following gene expression studies and connectivity mapping","volume":"6","author":"Chang","year":"2010","journal-title":"Mol. Pain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1111\/febs.12672","article-title":"Discovery of the neuroprotective effects of alvespimycin by computational prioritization of potential anti-Parkinson agents","volume":"281","author":"Gao","year":"2014","journal-title":"FEBS J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1038\/s41587-021-00946-z","article-title":"Prediction of drug efficacy from transcriptional profiles with deep learning","volume":"39","author":"Zhu","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhao, Y.C., Chen, X.Q., Chen, J.J., and Qi, X. (2023). Decoding Connectivity Map-based drug repurposing for oncotherapy. Brief. Bioinform., 24.","DOI":"10.1093\/bib\/bbad142"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wang, H.Y., Liu, J.C., Yang, J., Wang, Z., Zhang, Z.H., Peng, J.X., Wang, Y., and Hong, L. (2022). A novel tumor mutational burden-based risk model predicts prognosis and correlates with immune infiltration in ovarian cancer. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.943389"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112517","DOI":"10.1016\/j.intimp.2024.112517","article-title":"Promotion of apoptosis in melanoma cells by taxifolin through the PI3K\/ AKT signaling pathway: Screening of natural products using WGCNA and CMAP platforms","volume":"138","author":"Wang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, R., Liu, Z., Zhao, Y., Cheng, X., Liu, B., Wang, Y., Wang, J., Lian, X., Zhu, Y., and Gao, Y. (2022). GNG12 as A Novel Molecular Marker for the Diagnosis and Treatment of Glioma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.726556"},{"key":"ref_33","first-page":"2194","article-title":"In silico analysis identified miRNA-based therapeutic agents against glioblastoma multiforme","volume":"41","author":"Xiong","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/s41401-021-00752-y","article-title":"Benzimidazoles induce concurrent apoptosis and pyroptosis of human glioblastoma cells via arresting cell cycle","volume":"43","author":"Ren","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.bbrc.2021.08.014","article-title":"B-Myb participated in ionizing radiation-induced apoptosis and cell cycle arrest in human glioma cells","volume":"573","author":"Shen","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/s41417-025-00874-z","article-title":"Methylstat sensitizes ovarian cancer cells to PARP-inhibition by targeting the histone demethylases JMJD1B\/C","volume":"32","author":"Schwarz","year":"2025","journal-title":"Cancer Gene Ther."},{"key":"ref_37","first-page":"2222","article-title":"The critical role of histone lysine demethylase KDM2B in cancer","volume":"10","author":"Yan","year":"2018","journal-title":"Am. J. Transl. Res."},{"key":"ref_38","first-page":"5","article-title":"Therapeutic Potentials of Inhibition of Jumonji C Domain\u2014Containing Demethylases in Acute Myeloid Leukemia","volume":"37","author":"Koca","year":"2020","journal-title":"Turk. J. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9451","DOI":"10.1021\/ja201597b","article-title":"A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases","volume":"133","author":"Luo","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.gpb.2021.08.001","article-title":"The Genome Sequence Archive Family: Toward Explosive Data Growth and Diverse Data Types","volume":"19","author":"Chen","year":"2021","journal-title":"Genome Proteom. Bioinform."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"CNCB-NGDC Members and Partners (2022). Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2022. Nucleic Acids Res., 50, D27\u2013D38.","DOI":"10.1093\/nar\/gkab951"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1007\/s00432-021-03577-8","article-title":"Blockage of glioma cell survival by truncated TEAD-binding domain of YAP","volume":"147","author":"Zhao","year":"2021","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1517\/14728222.2011.645805","article-title":"Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy","volume":"16","author":"Santarpia","year":"2012","journal-title":"Expert. Opin. Ther. Targets."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.arcmed.2020.01.012","article-title":"Synergistic Apoptotic Effects of Bortezomib and Methylstat on Multiple Myeloma Cells","volume":"51","author":"Kaci","year":"2020","journal-title":"Arch. Med. Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Cai, X., Duan, X., Tang, T.L., Cui, S., and Wu, T. (2023). JMJD2A participates in cytoskeletal remodeling to regulate castration-resistant prostate cancer docetaxel resistance. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10915-1"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Su, Y., Yu, Q.H., Wang, X.Y., Yu, L.P., Wang, Z.F., Cao, Y.C., and Li, J.D. (2017). JMJD2A promotes the Warburg effect and nasopharyngeal carcinoma progression by transactivating LDHA expression. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3473-4"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s12935-020-01177-z","article-title":"The histone demethylase JMJD2A promotes glioma cell growth via targeting Akt-mTOR signaling","volume":"20","author":"Li","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10818","DOI":"10.1073\/pnas.0704525104","article-title":"Structural basis of the recognition of a methylated histone tail by JMJD2A","volume":"104","author":"Chen","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"Software News and Update AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"Valiente","year":"2021","journal-title":"J. Chem. Theory. Comput."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA.py: An Efficient Program for End-State Free Energy Calculations","volume":"8","author":"Miller","year":"2012","journal-title":"J. Chem. Theory. Comput."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.bbrc.2022.06.083","article-title":"Simplified 3D co-culture-based blood-brain barrier model using transwell","volume":"620","author":"Kim","year":"2022","journal-title":"Biochem. Bioph. Res. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1002\/jps.23152","article-title":"Grafting of Cell-Penetrating Peptide to Receptor-Targeted Liposomes Improves their Transfection Efficiency and Transport across Blood-Brain Barrier Model","volume":"101","author":"Sharma","year":"2012","journal-title":"J. Pharm. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S1537-1891(02)00203-3","article-title":"The use of in vitro cell culture models for mechanistic studies and as permeability screens for the blood-brain barrier in the pharmaceutical industry--background and current status in the drug discovery process","volume":"38","author":"Lundquist","year":"2002","journal-title":"Vascul. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1080\/00498250701570285","article-title":"Challenges for blood-brain barrier (BBB) screening","volume":"37","author":"Jeffrey","year":"2007","journal-title":"Xenobiotica"},{"key":"ref_57","first-page":"395","article-title":"Current research status and progress of the theabrownine in dark tea","volume":"38","author":"Zhang","year":"2017","journal-title":"Sci. Technol. Food Ind."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Chen, X.Q., Hu, Y.X., Wang, B.J., Chen, Y., Yuan, Y., Zhou, W.L., Song, W., Wu, Z.Q., and Li, X.T. (2022). Characterization of Theabrownins Prepared From Tea Polyphenols by Enzymatic and Chemical Oxidation and Their Inhibitory Effect on Colon Cancer Cells. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.849728"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Xiao, Y., and Dong, J. (2021). The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective. Cancers, 13.","DOI":"10.3390\/cancers13246214"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1038\/sj.onc.1210414","article-title":"The ERK1\/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition","volume":"26","author":"Meloche","year":"2007","journal-title":"Oncogene"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1038\/jid.2008.19","article-title":"TNF-alpha impairs the S-G2\/M cell cycle checkpoint and cyclobutane pyrimidine dimer repair in premalignant skin cells: Role of the PI3K-Akt pathway","volume":"128","author":"Faurschou","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1016\/S1470-2045(22)00599-X","article-title":"Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: A first-in-patient, single-centre, single-arm, phase 1b trial","volume":"23","author":"Spinazzi","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1038\/nrd963","article-title":"Dual-specificity phosphatases as targets for antineoplastic agents","volume":"1","author":"Lyon","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1039\/B408184F","article-title":"Synthesis and biological evaluation of caulibugulones A\u2013E","volume":"2","author":"Wipf","year":"2004","journal-title":"Org. Biomol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1016\/j.bmcl.2005.12.080","article-title":"Synthesis of miltirone analogues as inhibitors of Cdc25 phosphatases","volume":"16","author":"Huang","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_66","first-page":"3067","article-title":"Pharmacology and antitumor activity of a quinolinedione Cdc25 phosphatase inhibitor DA3003-1 (NSC 663284)","volume":"27","author":"Guo","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"38230","DOI":"10.1039\/C4RA07154A","article-title":"A histone demethylase inhibitor, methylstat, inhibits angiogenesis in vitro and in vivo","volume":"4","author":"Cho","year":"2014","journal-title":"RSC Adv."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1073\/pnas.96.5.2147","article-title":"p53 regulates a G2 checkpoint through cyclin B1","volume":"96","author":"Innocente","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.canlet.2013.04.009","article-title":"Deregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G(1)\/S transition","volume":"336","author":"Kogure","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"755","DOI":"10.3892\/etm.2012.662","article-title":"Effects of siRNA-mediated knockdown of jumonji domain containing 2A on proliferation, migration and invasion of the human breast cancer cell line MCF-7","volume":"4","author":"Li","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1007\/s10120-019-01024-9","article-title":"JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8","volume":"23","author":"Nakagawa","year":"2020","journal-title":"Gastric Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1002\/mc.23753","article-title":"JMJD2A promotes the development of castration-resistant prostate cancer by activating androgen receptor enhancer and inhibiting the cGAS-STING pathway","volume":"63","author":"Cai","year":"2024","journal-title":"Mol. Carcinogen."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/s41388-018-0519-2","article-title":"CXCR7\/CXCR4 heterodimer-induced histone demethylation: A new mechanism of colorectal tumorigenesis","volume":"38","author":"Song","year":"2019","journal-title":"Oncogene"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.cell.2015.10.067","article-title":"Establishment and Dysfunction of the Blood-Brain Barrier","volume":"163","author":"Zhao","year":"2015","journal-title":"Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/nrg.2017.19","article-title":"Comparative transcriptomics in human and mouse","volume":"18","author":"Breschi","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Thomsen, L.B., Burkhart, A., and Moos, T. (2015). A Triple Culture Model of the Blood-Brain Barrier Using Porcine Brain Endothelial cells, Astrocytes and Pericytes. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134765"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12987-020-00202-7","article-title":"Modeling blood-brain barrier pathology in cerebrovascular disease in vitro: Current and future paradigms","volume":"17","author":"Andjelkovic","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1186\/s13073-014-0095-1","article-title":"Systematic evaluation of connectivity map for disease indications","volume":"6","author":"Cheng","year":"2014","journal-title":"Genome Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory. Comput."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/9\/1344\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:41:49Z","timestamp":1760035309000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/9\/1344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,8]]},"references-count":81,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ph18091344"],"URL":"https:\/\/doi.org\/10.3390\/ph18091344","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,8]]}}}