Genipin ameliorates diabetic retinopathy via the HIF-1α and AGEs-RAGE pathways

作者全名：Sun, Kexin; Chen, Yanyi; Zheng, Shijie; Wan, Wenjuan; Hu, Ke

作者地址：[Sun, Kexin; Chen, Yanyi; Zheng, Shijie; Wan, Wenjuan; Hu, Ke] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst, Dept Ophthalmol,Chongqing Eye Inst,Chongqing Key L, 1 Youyi Rd, Chongqing, Peoples R China; [Sun, Kexin; Chen, Yanyi] Chongqing Med Univ, Chongqing, Peoples R China

通信作者：Wan, WJ; Hu, K (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst, Dept Ophthalmol,Chongqing Eye Inst,Chongqing Key L, 1 Youyi Rd, Chongqing, Peoples R China.

来源：PHYTOMEDICINE

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001230800000001

JCR分区：Q1

影响因子：6.7

年份：2024

卷号：129

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Network pharmacology; Genipin; Bioinformatics analysis; Diabetic retinopathy

摘要：Background: Traditional Chinese medicine (TCM) is useful in disease treatment and prevention. Genipin is an active TCM compound used to treat diabetic retinopathy (DR). In this study, a network pharmacology (NP) -based approach was employed to investigate the therapeutic mechanisms underlying genipin administration in DR. Methods: The potential targets of DR were identified using the gene expression omnibus (GEO) database. TCM database screening and NP were used to predict the potential active targets and pathways of genipin in DR. Cell viability was tested in vitro to determine the effects of different doses of glucose and genipin on Human Retinal Microvascular Endothelial Cells (hRMECs). CCK-8, CCK-F, colony formation, CellTiter-Lum, Annexin V-FITC, wound healing, Transwell, tube -forming, reactive oxygen species (ROS), and other assay kits were used to detect the effects of genipin on hRMECs during high levels of glucose. In vivo, a streptozotocin (STZ)-mouse intraocular genipin injection (IOI.) model was used to explore the effects of genipin on diabetes -induced retinal dysfunction. Western blotting was performed to identify the cytokines involved in proliferation, apoptosis, angiogenesis, ROS, and inflammation. The protein expression of the AKT/ PI3K/ HIF-1 alpha and AGEs/ RAGE pathways was also examined. Results: Approximately 14 types of TCM, and nearly 300 active ingredients, including genipin, were identified. The NP approach successfully identified the HIF-1 alpha and AGEs-RAGE pathways, with the EGR1 and UCP2 genes, as key targets of genipin in DR. In the in vitro and in vivo models, we discovered that high glucose increased cell proliferation, apoptosis, angiogenesis, ROS, and inflammation. However, genipin application regulated cell proliferation and apoptosis, inhibited angiogenesis, and reduced ROS and inflammation in the HRMECs exposed to high glucose. Furthermore, the retinal thickness in the genipin-treated group was lower than that in the untreated group. AKT/ PI3K/ HIF-1 alpha and AGEs/ RAGE signaling was increased by high glucose levels; however, genipin treatment decreased AKT/ PI3K and AGEs/ RAGE pathway expressions. Genipin also increased HIF-1 alpha phosphorylation, oxidative phosphorylation of ATP synthesis, lipid peroxidation, and the upregulation of oxidoreductase. Genipin was found to protect HG -induced hRMECs and the retina of STZ-mice, based on; 1 the inhibition of UCP2 and Glut1 decreased intracellular glucose, and glycosylation; 2 the increased presence of HIF1 alpha, which increased oxidative phosphorylation and decreased substrate phosphorylation; 3 the increase in oxidative phosphorylation from ATP synthesis increased lipid peroxidation and oxidoreductase activity, and; 4 the parallel effect of phosphorylation and glycosylation on vascular endothelial growth factor (VEGF), MMP9, and Scg3.

基金机构：National Natural Science Foundation of China [81870650, 81900885, 81970832]; Science and technology program Chongqing, China [CSTC2021jscx-gksb-N0017, cstc2022ycjh-bgzxm0121, cstc202ljcyj-msxm3178, CSTB2022NSCQ-MSX1561, cstc2021jcyj-msxmX0967]; First Clinical College of Chongqing Medical University [472020320220007]

基金资助正文：This research was supported in part by grants from the National Natural Science Foundation of China (81870650; 81900885; 81970832) , Science and technology program Chongqing, China (CSTC2021jscx-gksb-N0017; cstc2022ycjh-bgzxm0121; cstc202ljcyj-msxm3178; CSTB2022NSCQ-MSX1561 and cstc2021jcyj-msxmX0967; Chongqing, China) , and the First Clinical College of Chongqing Medical University (Grant no.472020320220007) .