Abstract
The pathogenesis of diabetic retinopathy (DR) is complicated, and there is no effective drug. Oxidative stress-induced human retinal microvascular endothelial cells (HRMECs) injury is one of the pathogenic factors for DR. Molecular switches are considered high-risk targets in disease progression. Identification of molecular switch is crucial to interpret the pathogenesis of disease and screen effective ingredients. In this study, a systematic process was executed to discover therapeutic candidates for DR based on HRMECs injury. First of all, the molecular mechanism of HRMECs oxidative stress injury was revealed by transcriptomics and network pharmacology. We found that oxidative stress was one of the pivotal pathogenic factors, which interfered with vascular system development, inflammation, cell adhesion, and cytoskeleton damaged HRMECs through crosstalk. Then, network topology analysis was used to recognize molecular switches. The results indicated that the Keap1-Nrf2-ARE signaling pathway was the molecular switch in HRMECs oxidative stress injury. On this basis, the HEK293-ARE overexpression cell line was applied to obtain 18 active traditional Chinese medicine (TCM) ingredients. Furthermore, andrographolide, one of the 18 candidates, was applied in the HRMECs oxidative stress model to evaluate the accuracy of the systematic process. The efficacy evaluation results showed that andrographolide could regulate oxidative stress, vascular system development, inflammation, adhesion, and skeleton tissue to inhibit HRMECs injury cooperatively. And its mechanism was related to the Nrf2 signaling pathway. Overall, our data suggest that the Nrf2 signaling pathway is the molecular switch in the HRMECs oxidative stress injury. 18 potential Nrf2 agonists are likely to be promising DR candidates.
Highlights
Diabetic retinopathy (DR) is a common microvascular complication of diabetes
The results indicated that NFE2L2 and HMOX1 were the key genes, and the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway was the molecular switch in human retinal microvascular endothelial cells (HRMECs) oxidative stress (Figure 1(f))
We discovered 18 DR candidates through a systematic process
Summary
Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Epidemiological studies have shown that the global prevalence of DR was 27% from 2015 to 2019 [1]. In 2019, the American Academy of Ophthalmology issued the Diabetic Retinopathy Preferred Practice Pattern, describing the clinical treatment of DR [3]. The therapy methods currently available for DR include retinal laser photocoagulation, surgery, and drug therapy [4]. Vitrectomy is likely to cause complications such as iatrogenic retinal rupture and cataracts [6]. For administration of anti-VEGF drugs, serious side effects including endophthalmitis, retinal detachment, and uveitis have been observed [7]. This study is aimed at exploring DR therapeutic candidates based on a systematic process
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
