Fungal keratitis is a severely vision-threatening corneal infection, where the prognosis depends on both fungal virulence and host immune defense. Inappropriate host responses can induce substantial inflammatory damage to the cornea. Therefore, in the treatment of fungal keratitis, it is important to concurrently regulate the immune response while efforts are made to eliminate the pathogen. Ebselen is a widely studied organo-selenium compound and has been demonstrated to have antifungal, antibacterial, anti-inflammatory, and oxidative stress-regulatory properties. The effectiveness of ebselen for the treatment of fungal keratitis remains unknown. In this study, ebselen was demonstrated to produce a marked inhibitory effect on (), including spore germination inhibition, mycelial growth reduction, and fungal biofilm disruption. The antifungal activity of ebselen was related to the cell membrane damage caused by thioredoxin (Trx) system inhibition-mediated oxidative stress. On the contrary, ebselen enhanced the antioxidation of Trx system in mammalian cells. Further, ebselen was proven to suppress the expressions of inflammatory mediators (IL-1β, IL-6, TNF-α, COX-2, iNOS, and CCL2) and reduce the production of oxidative stress-associated indicators (ROS, NO, and MDA) in fungi-stimulated RAW264.7 cells. In addition, ebselen regulated PI3K/Akt/Nrf2 and p38 MAPK signaling pathways, which contributed to the improvement of inflammation and oxidative stress. Finally, we verified the therapeutic effect of ebselen on mouse fungal keratitis. Ebselen improved the prognosis and reduced the fungal burden in mouse corneas. Expressions of inflammatory mediators, as well as the infiltration of macrophages and neutrophils in the cornea were also obviously decreased by ebselen. In summary, ebselen exerted therapeutic effects by reducing fungal load and protecting host tissues in fungal keratitis, making it a promising treatment for fungal infections.

中文翻译：

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依布硒啉通过抗炎、抗氧化应激和抗真菌作用改善真菌性角膜炎


真菌性角膜炎是一种严重威胁视力的角膜感染，其预后取决于真菌毒力和宿主免疫防御。不适当的宿主反应可能会对角膜造成严重的炎症损伤。因此，在真菌性角膜炎的治疗中，在努力消灭病原体的同时，调节免疫反应非常重要。 Ebselen 是一种广泛研究的有机硒化合物，已被证明具有抗真菌、抗菌、抗炎和氧化应激调节特性。依布硒啉治疗真菌性角膜炎的有效性仍不清楚。在这项研究中，依布硒啉被证明对 () 产生显着的抑制作用，包括抑制孢子萌发、减少菌丝生长和破坏真菌生物膜。依布硒啉的抗真菌活性与硫氧还蛋白（Trx）系统抑制介导的氧化应激引起的细胞膜损伤有关。相反，依布硒啉增强哺乳动物细胞中Trx系统的抗氧化作用。此外，依布硒啉被证明可以抑制炎症介质（IL-1β、IL-6、TNF-α、COX-2、iNOS 和 CCL2）的表达，并减少氧化应激相关指标（ROS、NO 和MDA）在真菌刺激的 RAW264.7 细胞中。此外，依布硒啉还调节PI3K/Akt/Nrf2和p38 MAPK信号通路，有助于改善炎症和氧化应激。最后我们验证了依布硒啉对小鼠真菌性角膜炎的治疗效果。 Ebselen 改善了小鼠角膜的预后并减少了真菌负担。依布硒啉也明显减少角膜炎症介质的表达以及巨噬细胞和中性粒细胞的浸润。 综上所述，依布硒啉通过降低真菌负荷和保护真菌性角膜炎宿主组织发挥治疗作用，使其成为治疗真菌感染的一种有前途的治疗方法。