Zhu Juming, Ding Dongmei, Sun Tao, Zhang Yuting, Miao Huizi, Gu Yunjie, Dai Ming, Zhu Manhui
Department of Ophthalmology, The First People's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, Jiangsu, China.
Department of Ophthalmology, Huizhou Hospital of Traditional Chinese Medicine, Huizhou, Guangzhou, China.
Invest Ophthalmol Vis Sci. 2025 Feb 3;66(2):56. doi: 10.1167/iovs.66.2.56.
To investigate the role and mechanism of oridonin (ORI), a bioactive diterpenoid extracted from the Chinese herbal medicine Rabdosia rubescens, on the integrity of outer blood-retinal barrier (oBRB) during choroidal neovascularization (CNV).
ARPE-19 cells were exposed to hypoxia and treated with ORI. The expression of ZO-1 and occludin in the axis of TGFβR/SUV39H1/KLF11 was detected by WB, chromatin immunoprecipitation, luciferin report activity assay, and immunofluorescence assay (IF), and the effect of ORI on the barrier properties of ARPE-19 cells was studied. A laser-induced mouse CNV model was constructed, and ORI was administrated by oral gavage. IF on mouse choroid flat mounts was done to confirm the effect of ORI on BRB integrity. Indocyanine green angiography and IF on mouse retina-RPE-choroid flat mounts were performed to determine the effect of ORI on CNV formation and retinal function. Hematoxylin and eosin staining and TUNEL staining were carried out to appraise ocular and systemic cytotoxicity caused by ORI.
ORI protected ARPE-19 cells from hypoxia-induced destruction of barrier properties and promoted the expression of ZO-1 and occludin by the TGFβR/SUV39H1/KLF11 axis, maintaining barrier properties of ARPE-19 cells with hypoxia. ORI improved BRB integrity during laser-induced CNV in mice and mitigated laser-induced CNV formation in mice without any ocular or systemic cytotoxicity (n = 4-5 in each group).
ORI ameliorates BRB integrity and subsequent formation of CNV via regulating the TGFβR/SUV39H1/KLF11 pathway in RPE cells.
研究从中药冬凌草中提取的生物活性二萜类化合物冬凌草甲素（ORI）在脉络膜新生血管形成（CNV）过程中对外血视网膜屏障（oBRB）完整性的作用及机制。
将ARPE - 19细胞置于缺氧环境并用ORI处理。通过蛋白质免疫印迹法（WB）、染色质免疫沉淀、荧光素酶报告基因活性测定和免疫荧光测定（IF）检测紧密连接蛋白1（ZO - 1）和闭合蛋白在转化生长因子β受体（TGFβR）/组蛋白赖氨酸N - 甲基转移酶39H1（SUV39H1）/ Kruppel样因子11（KLF11）轴中的表达，并研究ORI对ARPE - 19细胞屏障特性的影响。构建激光诱导的小鼠CNV模型，通过灌胃给予ORI。对小鼠脉络膜扁平标本进行IF以确认ORI对血视网膜屏障完整性的影响。进行吲哚菁绿血管造影和对小鼠视网膜 - 色素上皮 - 脉络膜扁平标本进行IF以确定ORI对CNV形成和视网膜功能的影响。进行苏木精 - 伊红染色和TUNEL染色以评估ORI引起的眼部和全身细胞毒性。
ORI保护ARPE - 19细胞免受缺氧诱导的屏障特性破坏，并通过TGFβR/SUV39H1/KLF11轴促进ZO - 1和闭合蛋白的表达，维持缺氧状态下ARPE - 19细胞的屏障特性。ORI改善了激光诱导的小鼠CNV过程中的血视网膜屏障完整性，并减轻了激光诱导的小鼠CNV形成，且无任何眼部或全身细胞毒性（每组n = 4 - 5）。
ORI通过调节视网膜色素上皮（RPE）细胞中的TGFβR/SUV39H1/KLF11途径改善血视网膜屏障完整性及随后的CNV形成。
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