{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:18:02Z","timestamp":1785403082015,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["22K09821"],"award-info":[{"award-number":["22K09821"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"award":["22K09821"],"award-info":[{"award-number":["22K09821"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Branch retinal vein occlusion (BRVO) represents a segmental retinal ischemic disorder characterized by localized oxidative\u2013inflammatory activation. While redox-driven cytokine responses have been described in central retinal vein occlusion, their role in BRVO-specific macular edema and treatment responsiveness remains unclear. This study investigated whether novel redox-related inflammatory mediators in the aqueous humor are associated with disease severity and structural response to anti-vascular endothelial growth factor (VEGF) therapy in BRVO. Methods: Aqueous humor samples were collected from 30 treatment-na\u00efve patients with BRVO and 19 control patients. Levels of VEGF and the novel redox-related inflammatory factors FMS-related tyrosine kinase 3 ligand (Flt-3L), fractalkine, CXCL-16, and endocan-1 were measured by suspension array, and the severity of macular edema was evaluated by measuring central macular thickness and neurosensory retinal thickness (TNeuro) by spectral-domain optical coherence tomography. Therapeutic response was assessed one month after intravitreal ranibizumab injection (IRI). Results: Aqueous levels of VEGF, Flt-3L, and endocan-1 were significantly higher in the BRVO group, and levels of Flt-3L, CXCL-16, and endocan-1\u2014markers associated with oxidative endothelial damage and leukocyte recruitment\u2014correlated significantly with each other and with aqueous flare values. Notably, baseline Flt-3L levels significantly correlated with the reduction in TNeuro, suggesting that this redox-sensitive signaling molecule is a potential biomarker for treatment sensitivity. Conclusions: These findings suggest that novel inflammatory factors, potentially driven by oxidative-nitrosative stress, play a pivotal role in the pathophysiology of BRVO. Baseline Flt-3L may serve as a predictive biomarker for structural responsiveness to anti-VEGF therapy in BRVO, suggesting that oxidative\u2013inflammatory signaling contributes not only to disease severity but also to therapeutic heterogeneity.<\/jats:p>","DOI":"10.3390\/antiox15050607","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:39:34Z","timestamp":1779295174000},"page":"607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Involvement of Oxidative Stress-Related Inflammatory Mediators in the Pathogenesis and Treatment Response of Macular Edema Secondary to Branch Retinal Vein Occlusion"],"prefix":"10.3390","volume":"15","author":[{"given":"Takuto","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji 193-0998, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6925-3063","authenticated-orcid":false,"given":"Hidetaka","family":"Noma","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Amimachi, Inashiki-gun 300-0395, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Mimura","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-0063, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji 193-0998, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Otawa","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Amimachi, Inashiki-gun 300-0395, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji 193-0998, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Shimura","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji 193-0998, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5185128","DOI":"10.1155\/2019\/5185128","article-title":"Cytokines and the Pathogenesis of Macular Edema in Branch Retinal Vein Occlusion","volume":"2019","author":"Noma","year":"2019","journal-title":"J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.ajo.2011.04.006","article-title":"Soluble vascular endothelial growth factor receptor-2 and inflammatory factors in macular edema with branch retinal vein occlusion","volume":"152","author":"Noma","year":"2011","journal-title":"Am. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1167\/iovs.14-13961","article-title":"Role of soluble vascular endothelial growth factor receptors-1 and -2, their ligands, and other factors in branch retinal vein occlusion with macular edema","volume":"55","author":"Noma","year":"2014","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s11481-012-9347-2","article-title":"Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina","volume":"8","author":"Kaur","year":"2013","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1007\/s10792-025-03687-z","article-title":"Exploring the role of oxidative stress in retinal vein occlusion: An updated and comprehensive review on the pathophysiology and treatment perspectives","volume":"45","author":"Zhang","year":"2025","journal-title":"Int. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1111\/jth.13482","article-title":"Erythrocyte oxidative stress is associated with cell deformability in patients with retinal vein occlusion","volume":"14","author":"Becatti","year":"2016","journal-title":"J. Thromb. Haemost."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"301","DOI":"10.3892\/ijmm.2015.2202","article-title":"3,3\u2032-Diindolylmethane inhibits VEGF expression through the HIF-1\u03b1 and NF-\u03baB pathways in human retinal pigment epithelial cells under chemical hypoxic conditions","volume":"36","author":"Park","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"120089","DOI":"10.1016\/j.lfs.2021.120089","article-title":"STING up-regulates VEGF expression in oxidative stress-induced senescence of retinal pigment epithelium via NF-\u03baB\/HIF-1\u03b1 pathway","volume":"293","author":"Chen","year":"2022","journal-title":"Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.ophtha.2011.12.005","article-title":"Ranibizumab for macular edema due to retinal vein occlusions: Long-term follow-up in the HORIZON trial","volume":"119","author":"Heier","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.ophtha.2014.08.031","article-title":"Intravitreal aflibercept for macular edema following branch retinal vein occlusion: The 24-week results of the VIBRANT study","volume":"122","author":"Campochiaro","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00417-009-1167-6","article-title":"Predictive factors for changes in macular edema in intravitreal bevacizumab therapy of retinal vein occlusion","volume":"248","author":"Ach","year":"2010","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1016\/j.ophtha.2010.03.060","article-title":"Antagonism of vascular endothelial growth factor for macular edema caused by retinal vein occlusions: Two-year outcomes","volume":"117","author":"Campochiaro","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1001\/2013.jamaophthalmol.228","article-title":"Association of inflammatory factors with macular edema in branch retinal vein occlusion","volume":"131","author":"Noma","year":"2013","journal-title":"JAMA Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"(1986). A randomized clinical trial. Branch Vein Occlusion Study Group. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. Arch. Ophthalmol., 104, 34\u201341.","DOI":"10.1001\/archopht.1986.01050130044017"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1097\/IAE.0b013e31821801de","article-title":"Vitreous inflammatory factors and serous macular detachment in branch retinal vein occlusion","volume":"32","author":"Noma","year":"2012","journal-title":"Retina"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yasuda, K., Noma, H., Mimura, T., Nonaka, R., Sasaki, S., Ofusa, A., and Shimura, M. (2023). Role of Novel Inflammatory Factors in Central Retinal Vein Occlusion with Macular Edema. Medicina, 60.","DOI":"10.3390\/medicina60010004"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Asakage, M., Noma, H., Yasuda, K., Goto, H., and Shimura, M. (2025). Dynamics of Inflammatory Factors in Aqueous Humor During Brolucizumab Treatment for Age-Related Macular Degenerations: A Case Series. Medicina, 61.","DOI":"10.3390\/medicina61030372"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1186025","DOI":"10.3389\/fnins.2023.1186025","article-title":"Increased intraocular inflammation in retinal vein occlusion is independent of circulating immune mediators and is involved in retinal oedema","volume":"17","author":"Zhou","year":"2023","journal-title":"Front. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/j.ophtha.2012.11.011","article-title":"Predictive value in retinal vein occlusions of early versus late or incomplete ranibizumab response defined by optical coherence tomography","volume":"120","author":"Bhisitkul","year":"2013","journal-title":"Ophthalmology"},{"key":"ref_20","first-page":"824","article-title":"Real-World Outcomes of Ranibizumab Treatment in French Patients with Visual Impairment due to Macular Edema Secondary to Retinal Vein Occlusion: 24-Month Results from the BOREAL-RVO Study","volume":"66","author":"Girmens","year":"2023","journal-title":"Ophthalmic Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1016\/j.ophtha.2014.03.021","article-title":"Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema","volume":"121","author":"Campochiaro","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"659735","DOI":"10.3389\/fphar.2021.659735","article-title":"FMS-Related Tyrosine Kinase 3 Ligand Promotes Radioresistance in Esophageal Squamous Cell Carcinoma","volume":"12","author":"Zhu","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1080\/10428194.2020.1834091","article-title":"FLT3 ligand in acute myeloid leukemia: A simple test with deep implications","volume":"62","author":"Peterlin","year":"2021","journal-title":"Leuk. Lymphoma."},{"key":"ref_24","first-page":"1","article-title":"Origin and development of classical dendritic cells","volume":"349","author":"Guermonprez","year":"2019","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.autrev.2013.09.010","article-title":"Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammation","volume":"13","author":"Ramos","year":"2014","journal-title":"Autoimmun. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1530\/EJE-22-0247","article-title":"Novel inflammatory biomarkers in thyroid eye disease","volume":"187","author":"Ueland","year":"2022","journal-title":"Eur. J. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kelkka, T., Pizzolla, A., Laurila, J.P., Friman, T., Gustafsson, R., K\u00e4llberg, E., Olsson, O., Leanderson, T., Rubin, K., and Salmi, M. (2013). Mice lacking NCF1 exhibit reduced growth of implanted melanoma and carcinoma tumors. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084148"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"122444","DOI":"10.1016\/j.biomaterials.2023.122444","article-title":"A programmable releasing versatile hydrogel platform boosts systemic immune responses via sculpting tumor immunogenicity and reversing tolerogenic dendritic cells","volume":"305","author":"Fu","year":"2024","journal-title":"Biomaterials"},{"key":"ref_29","first-page":"25","article-title":"Endocan or endothelial cell specific molecule-1 (ESM-1): A potential novel endothelial cell marker and a new target for cancer therapy","volume":"1","author":"Sarrazin","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5102","DOI":"10.1182\/blood-2009-07-230284","article-title":"Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching","volume":"115","author":"Strasser","year":"2010","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1158\/0008-5472.CAN-12-1855","article-title":"Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis","volume":"73","author":"Roudnicky","year":"2013","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1177\/147323001003800213","article-title":"Over-expression of the Endocan gene in endothelial cells from hepatocellular carcinoma is associated with angiogenesis and tumour invasion","volume":"38","author":"Chen","year":"2010","journal-title":"J. Int. Med. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"20458","DOI":"10.1074\/jbc.271.34.20458","article-title":"ESM-1 is a novel human endothelial cell-specific molecule expressed in lung and regulated by cytokines","volume":"271","author":"Lassalle","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.3892\/or.2012.2012","article-title":"Expression of endothelial cell-specific molecule-1 regulated by hypoxia inducible factor-1\u03b1 in human colon carcinoma: Impact of ESM-1 on prognosis and its correlation with clinicopathological features","volume":"28","author":"Kim","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"857380","DOI":"10.1155\/2013\/857380","article-title":"Expression of VEGF-A, Otx homeobox and p53 family genes in proliferative vitreoretinopathy","volume":"2013","author":"Azzolini","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115108","DOI":"10.1016\/j.bcp.2022.115108","article-title":"Cardiovascular risk factors and molecular routes underlying endothelial dysfunction: Novel opportunities for primary prevention","volume":"202","author":"Benincasa","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1002\/art.37981","article-title":"Evidence that CXCL16 is a potent mediator of angiogenesis and is involved in endothelial progenitor cell chemotaxis: Studies in mice with K\/BxN serum-induced arthritis","volume":"65","author":"Isozaki","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"R18","DOI":"10.1186\/ar3242","article-title":"Dysregulated expression of MIG\/CXCL9, IP-10\/CXCL10 and CXCL16 and their receptors in systemic sclerosis","volume":"13","author":"Rabquer","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.pan.2015.01.004","article-title":"The chemokine ligand CXCL16 is an indicator of bacterial infection in necrotizing pancreatitis","volume":"15","author":"Wittel","year":"2015","journal-title":"Pancreatology"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Romanowicz, A., \u0141ukaszewicz-Zaj\u0105c, M., and Mroczko, B. (2025). Potential of Selected C-X-C Motif Chemokines as Biomarkers in Colorectal Cancer Diagnosis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178715"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.4049\/jimmunol.172.6.3678","article-title":"A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine ligand 16","volume":"172","author":"Gough","year":"2004","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1100254","DOI":"10.3389\/fnmol.2023.1100254","article-title":"Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy","volume":"16","author":"Fu","year":"2023","journal-title":"Front. Mol. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s10456-024-09911-1","article-title":"Microglia in retinal angiogenesis and diabetic retinopathy","volume":"27","author":"Hu","year":"2024","journal-title":"Angiogenesis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"116550","DOI":"10.1016\/j.bcp.2024.116550","article-title":"Microglia in retinal diseases: From pathogenesis towards therapeutic strategies","volume":"230","author":"Xiao","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1007\/s11033-022-08113-6","article-title":"Neuroinflammation and neovascularization in diabetic eye diseases (DEDs): Identification of potential pharmacotherapeutic targets","volume":"50","author":"Panda","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s00018-025-06024-w","article-title":"FoxO1, together with Notch1, promotes microglial activation to induce pathological changes in the retinal vasculature under hypoxia","volume":"83","author":"Wu","year":"2025","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12974-025-03650-w","article-title":"Development of a humanized anti-fibrin monoclonal antibody for the treatment of neuroinflammatory and retinal diseases","volume":"23","author":"Kantor","year":"2025","journal-title":"J. Neuroinflamm."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/5\/607\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:51:49Z","timestamp":1779339109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/5\/607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,11]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["antiox15050607"],"URL":"https:\/\/doi.org\/10.3390\/antiox15050607","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,11]]}}}