Department of Ophthalmology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
Natural Product Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheonju, 28116, South Korea; Natural Product Central Bank, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheonju, 28116, South Korea.
Ocul Surf. 2023 Jul;29:469-479. doi: 10.1016/j.jtos.2023.06.016. Epub 2023 Jun 28.
Pseudognaphalium affine (P. affine), a medicinal plant, has long been used to treat various diseases due to its astringent and vulnerary effects. These therapeutic benefits are largely attributed to high contents of phytochemicals, such as flavonoids and polyphenols, that have anti-inflammatory and tissue-protective activities. Herein, we investigated the potential of dicaffeoylquinic acids (diCQAs), polyphenols from P. affine, as a novel treatment for dry eye disease (DED).
We isolated 1,5-, 3,4-, 3,5- and 4,5-diCQAs from the P. affine methanol extract, and tested the effects of diCQA isomers in cultures of human corneal epithelial cells (CECs) under desiccating hyperosmolar stress and in two mouse models for DED: desiccating environmental stress-induced DED and the NOD.B10-H2 mouse model of ocular Sjögren's syndrome.
Initial screening showed that, among the diCQAs, 1,5-diCQA significantly inhibited apoptosis and enhanced viability in cultures of CECs under hyperosmolar stress. Moreover, 1,5-diCQA protected CECs by promoting proliferation and downregulating inflammatory activation. Subsequent studies with two mouse models of DED revealed that topical 1,5-diCQA administration dose-dependently decreased corneal epithelial defects and increased tear production while repressing inflammatory cytokines and T cell infiltration on the ocular surface and in the lacrimal gland. 1,5-diCQA was more effective in alleviating DED, as compared with two commercially-available dry eye treatments, 0.05% cyclosporine and 0.1% sodium hyaluronate eye drops.
Together, our results demonstrate that 1,5-diCQA isolated from P. affine ameliorates DED through protection of corneal epithelial cells and suppression of inflammation, thus suggesting a novel DED therapeutic strategy based on natural compounds.
假泽兰（P. affine）是一种药用植物，由于其收敛和愈合作用，长期以来一直被用于治疗各种疾病。这些治疗益处主要归因于高含量的植物化学物质，如类黄酮和多酚，具有抗炎和组织保护活性。在此，我们研究了假泽兰中的二咖啡酰奎宁酸（diCQAs），作为治疗干眼症（DED）的一种新型治疗方法的潜力。
我们从假泽兰甲醇提取物中分离出 1,5-、3,4-、3,5-和 4,5-二咖啡酰奎宁酸，并在干燥高渗应激下培养人角膜上皮细胞（CECs）以及两种 DED 小鼠模型中测试了二 CQA 异构体的作用：干燥环境应激诱导的 DED 和 NOD.B10-H2 小鼠眼干燥综合征模型。
初步筛选表明，在二 CQA 中，1,5-二 CQA 可显著抑制高渗应激下 CECs 培养物中的细胞凋亡并提高细胞活力。此外，1,5-二 CQA 通过促进增殖和下调炎症激活来保护 CECs。随后用两种 DED 小鼠模型进行的研究表明，局部给予 1,5-二 CQA 剂量依赖性地减少角膜上皮缺损并增加泪液产生，同时抑制眼表面和泪腺中的炎症细胞因子和 T 细胞浸润。与两种市售的干眼症治疗药物，0.05%环孢素和 0.1%透明质酸钠滴眼液相比，1,5-二 CQA 对 DED 的缓解作用更有效。
总的来说，我们的结果表明，从假泽兰中分离出的 1,5-二 CQA 通过保护角膜上皮细胞和抑制炎症来改善 DED，从而提出了一种基于天然化合物的新型 DED 治疗策略。
