Proteomics-Based Retinal Target Engagement Analysis and Retina-Targeted Delivery of 17β-Estradiol by the DHED Prodrug for Ocular Neurotherapy in Males.
Proteomics-Based Retinal Target Engagement Analysis and Retina-Targeted Delivery of 17β-Estradiol by the DHED Prodrug for Ocular Neurotherapy in Males.
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基于蛋白质组学的视网膜目标参与分析和视网膜靶向17β-雌二醇的赋予男性眼神经疗法的递送。
DOI：
10.3390/pharmaceutics13091392
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发表时间：
2021-09-02
期刊：
影响因子：
5.4
通讯作者：
Prokai L
中科院分区：
文献类型：
--
作者：
Prokai-Tatrai K;Zaman K;Nguyen V;De La Cruz DL;Prokai L
我们研究了17β-雌二醇（E2）滴眼液对雄性大鼠视网膜蛋白质组谱调制的影响。通过发现驱动的蛋白质组学，我们已经确定了受我们治疗调节的蛋白质。这些蛋白质被组装到几个基于生物信息学的网络中，涉及E2在眼神经保护的广泛背景下对雄性大鼠视网膜的有益作用，包括维持视网膜稳态，促进受损蛋白质的有效处置和线粒体呼吸链生物合成。我们还首次表明，激素对男性视网膜的有益作用可以通过生物前体前药DHED治疗限制在该靶位点。DHED滴眼液不仅在雄性大鼠视网膜内产生大量E_2，而且在家兔视网膜内也产生大量E_2。然而，DHED治疗没有增加循环E2水平，从而确保男性的治疗安全性。针对E2靶向接合的选定生物标志物的靶向蛋白质组学进一步证实了前药在男性视网膜中代谢为E2，并表明DHED治疗对视网膜的影响与直接E2治疗的影响相同。总之，我们的研究显示了局部DHED治疗对男性视网膜的有效和安全保护的潜力，而没有与当前雌激素治疗相关的不必要的激素副作用。
We examined the impact of 17β-estradiol (E2) eye drops on the modulation of the proteome profile in the male rat retina. With discovery-driven proteomics, we have identified proteins that were regulated by our treatment. These proteins were assembled to several bioinformatics-based networks implicating E2’s beneficial effects on the male rat retina in a broad context of ocular neuroprotection including the maintenance of retinal homeostasis, facilitation of efficient disposal of damaged proteins, and mitochondrial respiratory chain biogenesis. We have also shown for the first time that the hormone’s beneficial effects on the male retina can be constrained to this target site by treatment with the bioprecursor prodrug, DHED. A large concentration of E2 was produced after DHED eye drops not only in male rat retinae but also in those of rabbits. However, DHED treatment did not increase circulating E2 levels, thereby ensuring therapeutic safety in males. Targeted proteomics focusing on selected biomarkers of E2’s target engagement further confirmed the prodrug’s metabolism to E2 in the male retina and indicated that the retinal impact of DHED treatment was identical to that of the direct E2 treatment. Altogether, our study shows the potential of topical DHED therapy for an efficacious and safe protection of the male retina without the unwanted hormonal side-effects associated with current estrogen therapies.
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