The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism

Abstract Background: LingqiHuangban Granule(LQHBG) is a famous traditional Chinese medicine formula used to manage retinal diseases, as an effective holistic treatment through warming Yang to exert tonifying effects on kidney and invigorating spleen to remove dampness to nourish essence of effect. The study examined protection of LQHBG on oxidative stress-induced injury in human retinal endothelial cells(HRECs) in vitro, determined the potential molecular targets of LQHBG using network pharmacology.Methods: The potential targets of active ingredients in LQHBG were predicted using pharmmapper. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were carried out using Molecule Annotation System. The protein-protein interaction networks were constructed using Cytoscape. LQHBG was administered to rabbits to prepare medicated serum. The apoptosis of HRECs was evaluated by TUNEL and Flow Cytometry(FCM). MDA, SOD, LDH, GSH-Px, and T-AOC were detected. The mRNA expressions of Nrf2, NF-κB and HO-1 were detected, protein expression levels of Nrf2, Bcl-2, NF-κB, HO-1 and caspase-3 were analyzed.Results: TUNEL demonstrated the numbers of apoptotic cells in low-and high-dose LQHBG groups was obviously less than model group(P<0.05). FCM analysis revealed apoptotic rates of HRECs in low-and high-dose LQHBG groups were obviously reduced in a dose-dependent manner(P<0.05). The potential mechanism of LQHBG was the NF-κB pathway identified using PharmMapper. LQHBG significantly decreased MDA, LDH levels and enhanced SOD, GSH-Px and T-AOC generation. LQHBG inhibited upregulation of NF-κB, caspase-3 and enhanced Bcl-2, Nrf2, and HO-1 expression.Conclusion: LQHBG protected HRECs against oxidative-stress via suppression of apoptosis and elevation of antioxidant ability, which may involve activation of Nrf2/ARE/HO-1 pathway and inhibition of NF-κB pathway.

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High Glucose Down-regulates Intercellular Communication in Retinal Endothelial Cells by Enhancing Degradation of Connexin 43 by a Proteasome-dependent Mechanism

Journal of Biological Chemistry ◽

10.1074/jbc.m400446200 ◽

2004 ◽

Vol 279 (26) ◽

pp. 27219-27224 ◽

Cited By ~ 53

Author(s):

Rosa Fernandes ◽

Henrique Girão ◽

Paulo Pereira

Keyword(s):

Endothelial Cells ◽

Intercellular Communication ◽

High Glucose ◽

Connexin 43 ◽

Retinal Endothelial Cells ◽

Dependent Mechanism

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MiR-126 targets IL-17A to enhance proliferation and inhibit apoptosis in high-glucose-induced human retinal endothelial cells

Biochemistry and Cell Biology ◽

10.1139/bcb-2019-0174 ◽

2020 ◽

Vol 98 (2) ◽

pp. 277-283 ◽

Cited By ~ 1

Author(s):

Xiujuan Chen ◽

Xuequn Yu ◽

Xinxiang Li ◽

Li Li ◽

Fang Li ◽

...

Keyword(s):

Endothelial Cells ◽

High Glucose ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Vision Loss ◽

Retinal Endothelial Cells ◽

Interleukin 17A ◽

Novel Target ◽

Induced Apoptosis

Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM), which results in vision loss. This study explored the role of miR-126 in high-glucose-induced human retinal endothelial cells (HRECs) and its underlying molecular mechanisms. The results showed that the expression levels of miR-126 and interleukin-17A (IL-17A) in high-glucose-induced HRECs were downregulated and upregulated, respectively. Functionally, overexpression of miR-126 promoted proliferation and suppressed apoptosis in high-glucose-induced HRECs, while IL-17A reversed the effects induced by miR-126. However, overexpression of IL-17A inhibited the proliferation and induced apoptosis, while knockdown of IL-17A accelerated the proliferation and repressed apoptosis. In addition, miR-126 repressed the expression of IL-17A, Bax, and caspase-3, while promoting the expression of survivin and phosphorylation of PI3K and AKT; restoration of IL-17A rescued these effects. Furthermore, IL-17A was identified as a target of miR-126. This indicates that miR-126 enhances proliferation and inhibits apoptosis in high-glucose-induced HRECs by activating the PI3K–AKT pathway, increasing survivin levels, and decreasing Bax and caspase-3 expression by targeting IL-17A, suggesting that miR-126 could be a novel target for preventing DR.

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FAK and p38-MAP Kinase-Dependent Activation of Apoptosis and Caspase-3 in Retinal Endothelial Cells by α1(IV)NC1

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.09-3473 ◽

2009 ◽

Vol 50 (10) ◽

pp. 4567 ◽

Cited By ~ 15

Author(s):

Chandra S. Boosani ◽

Narasimharao Nalabothula ◽

Veerendra Munugalavadla ◽

Dominic Cosgrove ◽

Venkateshwar G. Keshamoun ◽

...

Keyword(s):

Endothelial Cells ◽

Map Kinase ◽

Caspase 3 ◽

P38 Map Kinase ◽

Retinal Endothelial Cells

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High Glucose-Induced Apoptosis Is Linked to Mitochondrial Connexin 43 Level in RRECs: Implications for Diabetic Retinopathy

Cells ◽

10.3390/cells10113102 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3102

Author(s):

Aravind Sankaramoorthy ◽

Sayon Roy

Keyword(s):

Endothelial Cells ◽

Diabetic Retinopathy ◽

High Glucose ◽

Connexin 43 ◽

Caspase 3 ◽

Vision Loss ◽

Mitochondrial Morphology ◽

Mitochondrial Fragmentation ◽

Retinal Endothelial Cells ◽

Induced Apoptosis

Diabetic retinopathy (DR) is one of the most common causes of vision loss and blindness among the working-age population. High glucose (HG)-induced decrease in mitochondrial connexin 43 (mtCx43) level is known to promote mitochondrial fragmentation, cytochrome c release, and apoptosis in retinal endothelial cells associated with DR. In this study, we investigated whether counteracting HG-induced decrease in mtCx43 level would preserve mitochondrial integrity and prevent apoptosis. Rat retinal endothelial cells (RRECs) were grown in normal (N; 5 mM glucose) or HG (30 mM glucose) medium for 7 days. In parallel, cells grown in HG were transfected with Cx43 plasmid, or empty vector (EV), as control. Western blot (WB) analysis showed a significant decrease in mtCx43 level concomitant with increased cleaved caspase-3, Bax, cleaved PARP, and mitochondrial fragmentation in cells grown in HG condition compared to those grown in N medium. When cells grown in HG were transfected with Cx43 plasmid, mtCx43 level was significantly increased and resulted in reduced cleaved caspase-3, Bax, cleaved PARP and preservation of mitochondrial morphology with a significant decrease in the number of TUNEL-positive cells compared to those grown in HG alone. Findings from the study indicate a novel role for mtCx43 in regulating apoptosis and that maintenance of mtCx43 level could be useful in preventing HG-induced apoptosis by reducing mitochondrial fragmentation associated with retinal vascular cell loss in DR.

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