真菌性角膜炎是一种严重威胁视力的角膜感染,其中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诱导对角膜的实质性炎性损伤。因此,在真菌性角膜炎的治疗中,重要的是在努力消除病原体的同时同时调节免疫反应。Ebselen是一种广泛研究的有机硒化合物,已被证明具有抗真菌作用,抗菌,抗炎,和氧化应激调节特性。ebselen治疗真菌性角膜炎的有效性仍然未知。在这项研究中,依布硒被证明对烟曲霉产生明显的抑制作用(A.烟曲霉),包括孢子萌发抑制,菌丝体生长减少,和真菌生物膜破坏。依布硒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,依布硒可增强哺乳动物细胞中Trx系统的抗氧化作用。Further,依布硒被证明可以抑制炎症介质的表达(IL-1β,IL-6,TNF-α,COX-2,iNOS,和CCL2),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,依布硒醚调节PI3K/Akt/Nrf2和p38MAPK信号通路,这有助于改善炎症和氧化应激。最后,我们验证了依布硒对小鼠真菌性角膜炎的治疗作用。Ebselen改善了预后并减少了小鼠角膜中的真菌负担。炎症介质的表达,依布硒可明显减少角膜中巨噬细胞和中性粒细胞的浸润。总之,在真菌性角膜炎中,依布硒通过减少真菌负荷和保护宿主组织发挥治疗作用,使其成为真菌感染的有希望的治疗方法。
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 Aspergillus fumigatus (A. fumigatus), 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.