{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T21:06:30Z","timestamp":1789160790763,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Retinal ischemia is a key factor in the progression of vision-threatening ocular diseases, including central retinal artery\/vein occlusion, exudative age-related macular degeneration (eAMD), and proliferative diabetic retinopathy. This study investigates the effects of paeoniflorin along with its related neuroprotective molecular pathways in the treatment of retinal ischemia. Free radical or ischemic-like damage was induced by incubating retinal pigment epithelium (RPE) cells for 24 h with 1 mM hydrogen peroxide (H2O2) or by subjecting retinal neuronal cells to 8 h of oxygen\u2013glucose deprivation (OGD). Both treatments caused significant cell loss. Treatment with paeoniflorin significantly increased cell viability at 0.5 mM in both cell types. In a Wistar rat model of retinal ischemia and reperfusion (I\/R) elicited by sustained high intraocular pressure (HIOP), pre-treatment with 0.5 mM paeoniflorin mitigated the ischemia-induced decline in ERG b-wave amplitude, reduction in whole and inner retinal thickness, loss of fluorogold-labeled retinal ganglion cells, and formation of apoptotic cells. Meanwhile, paeoniflorin effectively downregulated pro-neovascular mediators \u03b2-catenin, hypoxia-inducible factor 1-alpha (HIF-1\u03b1), vascular endothelial growth factor (VEGF), and the pro-inflammatory\/angiogenic biomarker angiopoietin-2 (Ang-2), producing effects similar to the Wnt\/\u03b2-catenin inhibitor (dickkopf-related protein 1), anti-angiogenic pigment epithelium-derived factor (PEDF), and anti-VEGF Avastin (bevacizumab). These findings suggest that paeoniflorin may protect against retinal ischemia through its anti-inflammatory, anti-neovascular\/angiogenic, antioxidative, and neuroprotective properties.<\/jats:p>","DOI":"10.3390\/ijms262210924","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T10:56:27Z","timestamp":1762858587000},"page":"10924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Retinal Ischemia: Therapeutic Effects and Mechanisms of Paeoniflorin"],"prefix":"10.3390","volume":"26","author":[{"given":"Windsor Wen-Jin","family":"Chao","sequence":"first","affiliation":[{"name":"Department of Renal Medicine, New Cross Hospital, Wolverhampton WV10 0QP, UK"},{"name":"Department of Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard Wen-Haur","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Renal Medicine, Queen Elizabeth University Hospital, Birmingham B15 2TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pai-Huei","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shin Kong Hospital, Taipei 11101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6183-4987","authenticated-orcid":false,"given":"Yi-Tzu","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Department of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Emergency, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1545-9936","authenticated-orcid":false,"given":"Hsiao-Ming","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shin Kong Hospital, Taipei 11101, Taiwan"},{"name":"Institute of Pharmacology, Department of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Chinese Medicine, School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1080\/15548627.2020.1767371","article-title":"Autophagy and Post-Ischemic Conditioning in Retinal Ischemia","volume":"17","author":"Mathew","year":"2021","journal-title":"Autophagy"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chao, W.W., Chao, H.W., Lee, H.F., and Chao, H.M. (2024). The Effect of S-Allyl L-Cysteine on Retinal Ischemia: The Contributions of Mcp-1 and Pkm2 in the Underlying Medicinal Properties. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25021349"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100388","DOI":"10.1016\/j.xops.2023.100388","article-title":"A Datasheet for the Insight University Hospitals Birmingham Retinal Vein Occlusion Data Set","volume":"3","author":"Bilton","year":"2023","journal-title":"Ophthalmol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global Prevalence of Age-Related Macular Degeneration and Disease Burden Projection for 2020 and 2040: A Systematic Review and Meta-Analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"B\u00f6hm, E.W., Buonfiglio, F., Voigt, A.M., Bachmann, P., Safi, T., Pfeiffer, N., and Gericke, A. (2023). Oxidative Stress in the Eye and Its Role in the Pathophysiology of Ocular Diseases. Redox Biol., 68.","DOI":"10.1016\/j.redox.2023.102967"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"He, Q., Xiao, L., Shi, Y., Li, W., and Xin, X. (2023). Natural Products: Protective Effects against Ischemia-Induced Retinal Injury. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1149708"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Boia, R., Ruzafa, N., Aires, I.D., Pereiro, X., Ambr\u00f3sio, A.F., Vecino, E., and Santiago, A.R. (2020). Neuroprotective Strategies for Retinal Ganglion Cell Degeneration: Current Status and Challenges Ahead. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072262"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s12964-023-01427-3","article-title":"A Time Window for Rescuing Dying Retinal Ganglion Cells","volume":"22","author":"You","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.exer.2013.09.003","article-title":"Retinal Pigment Epithelium Development, Plasticity, and Tissue Homeostasis","volume":"123","author":"Fuhrmann","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.exer.2014.05.003","article-title":"A Detailed Three-Step Protocol for Live Imaging of Intracellular Traffic in Polarized Primary Porcine Rpe Monolayers","volume":"124","author":"Toops","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wang, B., Zhang, X., Chen, H., Koh, A., Zhao, C., and Chen, Y. (2022). A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.859951"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e000276","DOI":"10.1136\/bmjophth-2019-000276","article-title":"Patient-Reported Reasons for Delay in Diagnosis of Age-Related Macular Degeneration: A National Survey","volume":"4","author":"Parfitt","year":"2019","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.mayocpiqo.2024.05.003","article-title":"Recent Updates on the Diagnosis and Management of Age-Related Macular Degeneration","volume":"8","author":"Boopathiraj","year":"2024","journal-title":"Mayo. Clin. Proc. Innov. Qual. Outcomes"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3892\/ijmm.2022.5135","article-title":"Curcumin and Wnt\/\u0392-Catenin Signaling in Exudative Age-Related Macular Degeneration (Review)","volume":"49","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101026","DOI":"10.1016\/j.gendis.2023.04.042","article-title":"The Evolving Roles of Wnt Signaling in Stem Cell Proliferation and Differentiation, the Development of Human Diseases, and Therapeutic Opportunities","volume":"11","author":"Yu","year":"2024","journal-title":"Genes Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nguyen, H., Lee, S.J., and Li, Y. (2022). Selective Activation of the Wnt-Signaling Pathway as a Novel Therapy for the Treatment of Diabetic Retinopathy and Other Retinal Vascular Diseases. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112476"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.visres.2017.02.007","article-title":"Canonical Wnt Signaling in Diabetic Retinopathy","volume":"139","author":"Chen","year":"2017","journal-title":"Vis. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"C207","DOI":"10.1152\/ajpcell.00579.2008","article-title":"Arachidonic Acid Potentiates Hypoxia-Induced Vegf Expression in Mouse Embryonic Stem Cells: Involvement of Notch, Wnt, and Hif-1alpha","volume":"297","author":"Lee","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tang, L., Zhang, W., Liao, Y., Wang, W., Deng, X., Wang, C., and Shi, W. (2025). Autophagy: A Double-Edged Sword in Ischemia-Reperfusion Injury. Cell. Mol. Biol. Lett., 30.","DOI":"10.1186\/s11658-025-00713-x"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/IAE.0000000000003003","article-title":"The Angiopoietin\/Tie Pathway in Retinal Vascular Diseases: A Review","volume":"41","author":"Heier","year":"2021","journal-title":"Retina"},{"key":"ref_21","first-page":"e164","article-title":"Increased Intravitreal Angiopoietin-2 Levels in Patients with Retinal Vein Occlusion","volume":"92","author":"Tuuminen","year":"2013","journal-title":"Acta Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.15252\/emmm.201505889","article-title":"Targeting Key Angiogenic Pathways with a Bispecific Crossmab Optimized for Neovascular Eye Diseases","volume":"8","author":"Regula","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Canonica, J., Foxton, R., Garrido, M.G., Lin, C.-M., Uhles, S., Shanmugam, S., Antonetti, D.A., Abcouwer, S.F., and Westenskow, P.D. (2023). Delineating Effects of Angiopoietin-2 Inhibition on Vascular Permeability and Inflammation in Models of Retinal Neovascularization and Ischemia\/Reperfusion. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1192464"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Benest, A.V., Kruse, K., Savant, S., Thomas, M., Laib, A.M., Loos, E.K., Fiedler, U., and Augustin, H.G. (2013). Angiopoietin-2 Is Critical for Cytokine-Induced Vascular Leakage. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070459"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.ccr.2010.07.001","article-title":"Double Antiangiogenic Protein, Daap, Targeting Vegf-a and Angiopoietins in Tumor Angiogenesis, Metastasis, and Vascular Leakage","volume":"18","author":"Koh","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e001967","DOI":"10.1136\/bmjophth-2024-001967","article-title":"Switching to Faricimab from the Current Anti-Vegf Therapy: Evidence-Based Expert Recommendations","volume":"10","author":"Wong","year":"2025","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Xing, D., Ma, Y., Lu, M., Liu, W., and Zhou, H. (2023). Paeoniflorin Alleviates Hypoxia\/Reoxygenation Injury in Hk-2 Cells by Inhibiting Apoptosis and Repressing Oxidative Damage Via Keap1\/Nrf2\/Ho-1 Pathway. BMC Nephrol., 24.","DOI":"10.1186\/s12882-023-03366-0"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lu, Y., Yin, L., Yang, W., Wu, Z., and Niu, J. (2024). Antioxidant Effects of Paeoniflorin and Relevant Molecular Mechanisms as Related to a Variety of Diseases: A Review. Biomed. Pharmacother., 176.","DOI":"10.1016\/j.biopha.2024.116772"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"114571","DOI":"10.1016\/j.intimp.2025.114571","article-title":"Paeoniflorin Alleviated Stz-Induced Diabetic Retinopathy Via Regulation of the Pdi\/Adam17\/Mertk Pathway","volume":"155","author":"Qi","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_30","first-page":"482428","article-title":"Paeonia Lactiflora Extract Attenuating Cerebral Ischemia and Arterial Intimal Hyperplasia Is Mediated by Paeoniflorin Via Modulation of Vsmc Migration and Ras\/Mek\/Erk Signaling Pathway","volume":"2013","author":"Chen","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhang, H., Qi, Y., Yuan, Y., Cai, L., Xu, H., Zhang, L., Su, B., and Nie, H. (2017). Paeoniflorin Ameliorates Experimental Autoimmune Encephalomyelitis Via Inhibition of Dendritic Cell Function and Th17 Cell Differentiation. Sci. Rep., 7.","DOI":"10.1038\/srep41887"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"113332","DOI":"10.1016\/j.indcrop.2021.113332","article-title":"Preparation of Paeoniflorin from the Stems and Leaves of Paeonia Lactiflora Pall. \u2018Zhongjiang\u2019 through Green Efficient Microwave-Assisted Extraction and Subcritical Water Extraction","volume":"163","author":"Wu","year":"2021","journal-title":"Ind. Crop. Prod."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"He, D.-Y., and Dai, S.-M. (2011). Anti-Inflammatory and Immunomodulatory Effects of Paeonia Lactiflora Pall., a Traditional Chinese Herbal Medicine. Front. Pharmacol., 2.","DOI":"10.3389\/fphar.2011.00010"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1080\/13880209.2023.2220360","article-title":"Paeoniflorin Suppresses the Apoptosis and Inflammation of Human Coronary Artery Endothelial Cells Induced by Oxidized Low-Density Lipoprotein by Regulating the Wnt\/\u0392-Catenin Pathway","volume":"61","author":"Liu","year":"2023","journal-title":"Pharm. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107452","DOI":"10.1016\/j.pharmthera.2019.107452","article-title":"Anti-Inflammatory and Immunoregulatory Effects of Paeoniflorin and Total Glucosides of Paeony","volume":"207","author":"Zhang","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.2174\/1389201021666201009153808","article-title":"Paeoniflorin Affects Hepatocellular Carcinoma Progression by Inhibiting Wnt\/\u0392-Catenin Pathway through Downregulation of 5-Ht1d","volume":"22","author":"Zhou","year":"2021","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1002\/kjm2.12736","article-title":"Paeoniflorin Inhibits Colorectal Cancer Cell Stemness through the Mir-3194-5p\/Catenin Beta-Interacting Protein 1 Axis","volume":"39","author":"Su","year":"2023","journal-title":"Kaohsiung J. Med Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13020-016-0109-6","article-title":"Chi-Ju-Di-Huang-Wan Protects Rats against Retinal Ischemia by Downregulating Matrix Metalloproteinase-9 and Inhibiting P38 Mitogen-Activated Protein Kinase","volume":"11","author":"Cheng","year":"2016","journal-title":"Chin. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ren, X., and L\u00e9veillard, T. (2022). Modulating Antioxidant Systems as a Therapeutic Approach to Retinal Degeneration. Redox Biol., 57.","DOI":"10.1016\/j.redox.2022.102510"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1089\/jop.2011.0099","article-title":"The Effects and Underlying Mechanisms of S-Allyl L-Cysteine Treatment of the Retina after Ischemia\/Reperfusion","volume":"28","author":"Chen","year":"2012","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1189\/jlb.0302117","article-title":"Role of Mcp-1 and Mip-1alpha in Retinal Neovascularization During Postischemic Inflammation in a Mouse Model of Retinal Neovascularization","volume":"73","author":"Yoshida","year":"2003","journal-title":"J. Leukoc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S279","DOI":"10.1111\/aos.15872","article-title":"Catapol Might Protect against Retinal Ischaemia by Anti-Oxidation, Anti-Ischaemia, Wnt Pathway Inhibition and Vegf Downregulation","volume":"102","author":"Chao","year":"2024","journal-title":"Acta Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1007\/s00417-010-1486-7","article-title":"Pigment Epithelium-Derived Factor and Vascular Endothelial Growth Factor in Branch Retinal Vein Occlusion with Macular Edema","volume":"248","author":"Noma","year":"2010","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/jcp.10442","article-title":"Angiopoietin-2 Enhances Retinal Vessel Sensitivity to Vascular Endothelial Growth Factor","volume":"199","author":"Oshima","year":"2004","journal-title":"J. Cell. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/eye.2013.240","article-title":"Ritonavir Inhibits Hif-1\u03b1-Mediated Vegf Expression in Retinal Pigment Epithelial Cells in Vitro","volume":"28","author":"Vadlapatla","year":"2014","journal-title":"Eye"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Nguyen-Ba-Charvet, K.T., and Rebsam, A. (2020). Neurogenesis and Specification of Retinal Ganglion Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020451"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5920","DOI":"10.1167\/iovs.10-5264","article-title":"Effects of Ischemic Preconditioning and Bevacizumab on Apoptosis and Vascular Permeability Following Retinal Ischemia-Reperfusion Injury","volume":"51","author":"Abcouwer","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Wang, H., Peng, Z., Li, Y., Sahn, J.J., Hodges, T.R., Chou, T.H., Liu, Q., Zhou, X., Jiao, S., and Porciatti, V. (2022). \u03a3(2)R\/Tmem97 in Retinal Ganglion Cell Degeneration. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-24537-3"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1186\/s12967-024-05260-1","article-title":"Neuroprotective Effects of Apigenin on Retinal Ganglion Cells in Ischemia\/Reperfusion: Modulating Mitochondrial Dynamics in In Vivo and In Vitro Models","volume":"22","author":"Wu","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Chao, H.W.-H., Chen, Y.-K., Liu, J.-H., Pan, H.-T., Lin, H.-M., and Chao, H.-M. (2020). Emodin Protected against Retinal Ischemia Insulted Neurons through the Downregulation of Protein Overexpression of \u0392-Catenin and Vascular Endothelium Factor. BMC Complement. Med. Ther., 20.","DOI":"10.1186\/s12906-020-03136-7"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10924\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T05:15:22Z","timestamp":1763010922000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10924"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,11]]},"references-count":50,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262210924"],"URL":"https:\/\/doi.org\/10.3390\/ijms262210924","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,11]]}}}