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Discovery of Therapeutic Candidates for Diabetic Retinopathy Based on Molecular Switch Analysis: Application of a
Yue Ren1, Yanan Liu1, Kaiyang Liu1
1Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China 102488.
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.
Insights
Diabetic retinopathy (DR) involves oxidative stress damaging retinal cells. Researchers identified the Keap1-Nrf2-ARE pathway as a key molecular switch, revealing 18 potential Traditional Chinese Medicine treatments for DR.
Area of Science:
- Ophthalmology and Molecular Biology
- Focuses on the molecular mechanisms underlying diabetic retinopathy (DR) and potential therapeutic interventions.
Background:
- Diabetic retinopathy (DR) pathogenesis is complex, with oxidative stress-induced human retinal microvascular endothelial cells (HRMECs) injury being a significant factor.
- Identifying molecular switches is crucial for understanding disease progression and screening effective therapeutic agents.
Purpose of the Study:
- To systematically discover therapeutic candidates for DR by investigating the molecular mechanism of HRMECs oxidative stress injury.
- To identify the key molecular switch involved in HRMECs oxidative stress injury.
Main Methods:
- Transcriptomics and network pharmacology were employed to elucidate the molecular mechanisms of HRMECs oxidative stress injury.
- Network topology analysis identified the Keap1-Nrf2-ARE signaling pathway as the molecular switch.
- An HEK293-ARE overexpression cell line was used to screen 18 active Traditional Chinese Medicine (TCM) ingredients.
- Andrographolide was tested in an HRMECs oxidative stress model for efficacy and mechanism validation.
Main Results:
- Oxidative stress was confirmed as a pivotal pathogenic factor in DR, affecting vascular development, inflammation, and cell adhesion.
- The Keap1-Nrf2-ARE signaling pathway was identified as the molecular switch regulating HRMECs oxidative stress injury.
- Andrographolide demonstrated efficacy in mitigating HRMECs injury by regulating multiple pathways, including oxidative stress and inflammation, via the Nrf2 signaling pathway.
- Eighteen potential Nrf2 agonists were identified as promising candidates for DR treatment.
Conclusions:
- The Nrf2 signaling pathway acts as a critical molecular switch in HRMECs oxidative stress injury relevant to diabetic retinopathy.
- The identified 18 TCM ingredients, particularly andrographolide, show promise as novel therapeutic candidates for diabetic retinopathy.
