Melatonin attenuates oxidative stress and inflammation of Müller cells in diabetic retinopathy via activating the Sirt1 pathway

: Accumulating evidence has indicated that inflammation, oxidative stress, apoptosis, and autophagy in retinal Müller cells are involved in diabetic retinopathy (DR). Notoginsenoside R1 (NGR1), a novel saponin extracted from Panax notoginseng, posesses pharmacological properties, including treating diabetic encephalopathy and improving microcirculatory disorders. Nevertheless, its beneficial effects on DR and the potential mechanism remain to be elucidated. In this study, we found retinal vascular degeneration, reduced retinal thickness, and impaired retinal function in db/db mice were all dramatically attenuated by oral treatment with NGR1 (30 mg/kg) for 12 weeks. NGR1 pretreatment also significantly inhibited apoptosis, markedly suppressed the VEGF expression, markedly increased PEDF expression and markedly inhibited oxidative stress and inflammation in rat retinal Müller cells (rMC-1) subjected to high glucose (HG) and in the retinas of db/db mice. Furthermore, NGR1 pre-treatment upregulated the level of PINK1 and Parkin, increased the LC3-II/LC3-I ratio, and downregulated the level of p62/SQSTM1 in rMC-1 cells induced by HG and in the retinas of db/db mice. Moreover, NGR1 administration enhanced the co-localization of GFP-LC3 puncta and MitoTracker in rMC-1 cells. Importantly, knockdown of PINK1 abolished the protective effects of NGR1. In conclusion, these phenomena suggested that NGR1 prevented DR via PINK1-dependent enhancement of mitophagy.

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Geniposide Attenuates Hyperglycemia-Induced Oxidative Stress and Inflammation by Activating the Nrf2 Signaling Pathway in Experimental Diabetic Retinopathy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9247947 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Yuanyuan Tu ◽

Lele Li ◽

Linling Zhu ◽

Yang Guo ◽

Shu Du ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Retinopathy ◽

Signaling Pathway ◽

Cell Activation ◽

Müller Cells ◽

In Vivo Model ◽

Muller Cells ◽

Nrf2 Signaling Pathway

Geniposide (GEN) is a natural antioxidant and anti-inflammatory product and plays an important role in the treatment of diabetes and diabetic complications. To explore the biological functions and mechanism of GEN in diabetic retinopathy (DR), we constructed the in vitro and in vivo model of DR by using primary cultured mouse retinal Müller cells and C57BL/6 mice, respectively. We found that GEN inhibited ROS accumulation, NF-κB activation, Müller cell activation, and inflammatory cytokine secretion both in vitro and in vivo, which is probably mediated through the Nrf2 pathway. Exendin (9-39) (EX-9), an antagonist of glucagon-like peptide-1 receptor (GLP-1R), abolished the protective effect of GEN on high glucose- (HG-) induced Müller cells. Additionally, GEN decreased hyperglycemia-induced damage to Müller cells and blood-retinal barrier in the retinas of mice with DR. We demonstrated that GEN was capable of protecting Müller cells and mice from HG-induced oxidative stress and inflammation, which is mostly dependent on the Nrf2 signaling pathway through GLP-1R. GEN may be an effective approach for the treatment of DR.

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Oxidative Stress-Induced Dysfunction of Müller Cells During Starvation

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.16-19275 ◽

2016 ◽

Vol 57 (6) ◽

pp. 2721 ◽

Cited By ~ 17

Author(s):

Anne Katrine Toft-Kehler ◽

Iswariaraja Scridevi Gurubaran ◽

Claus Desler ◽

Lene J. Rasmussen ◽

Dorte Marie Skytt ◽

...

Keyword(s):

Oxidative Stress ◽

Müller Cells ◽

Muller Cells

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Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina

Nutrients ◽

10.3390/nu13093216 ◽

2021 ◽

Vol 13 (9) ◽

pp. 3216

Author(s):

Maryvonne Ardourel ◽

Chloé Felgerolle ◽

Arnaud Pâris ◽

Niyazi Acar ◽

Khaoula Ramchani Ben Othman ◽

...

Keyword(s):

Oxidative Stress ◽

Müller Cells ◽

Nutritional Supplement ◽

Glutamine Metabolism ◽

Muller Cells ◽

Omega 3 ◽

Glutamine Synthesis ◽

The Impact

To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.

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DL-3-n-butylphthalide Protected Retinal Müller Cells Dysfunction from Oxidative Stress

Current Eye Research ◽

10.1080/02713683.2019.1624777 ◽

2019 ◽

Vol 44 (10) ◽

pp. 1112-1120 ◽

Cited By ~ 4

Author(s):

Xiaoli Xing ◽

Liangyu Huang ◽

Yingjuan Lv ◽

Xun Liu ◽

Ruihong Su ◽

...

Keyword(s):

Oxidative Stress ◽

Müller Cells ◽

Muller Cells

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Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1423765112 ◽

2015 ◽

Vol 112 (23) ◽

pp. E3030-E3039 ◽

Cited By ~ 47

Author(s):

Savalan Babapoor-Farrokhran ◽

Kathleen Jee ◽

Brooks Puchner ◽

Syed Junaid Hassan ◽

Xiaoban Xin ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Proliferative Diabetic Retinopathy ◽

Müller Cells ◽

Aqueous Fluid ◽

Angiogenic Factor ◽

Eye Disease ◽

Diabetic Patients ◽

Muller Cells ◽

Angiogenic Potential ◽

Diabetic Eye Disease

Diabetic eye disease is the most common cause of severe vision loss in the working-age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In PDR, retinal ischemia leads to the up-regulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some, but not all, diabetic patients, implicating additional factor(s) in PDR pathogenesis. Here we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identify angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from PDR patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease.

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Back Cover: Back Cover: Hydrogen peroxide modulates energy metabolism and oxidative stress in cultures of permanent human Müller cells MIO-M1 (J. Biophotonics 9/2017)

Journal of Biophotonics ◽

10.1002/jbio.201770093 ◽

2017 ◽

Vol 10 (9) ◽

pp. 1228-1228

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Energy Metabolism ◽

Müller Cells ◽

Muller Cells ◽

Back Cover ◽

And Oxidative Stress

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Knockdown of KCNQ1OT1 Alleviates the Activation of NLRP3 Inflammasome Through miR-17-5p/TXNIP Axis in Retinal Müller Cells

10.21203/rs.3.rs-870214/v1 ◽

2021 ◽

Author(s):

Yu Liu ◽

Guoping Cao ◽

Lili Dong ◽

Lele Li ◽

Yuping Dou ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Müller Cells ◽

Clinical Samples ◽

Inflammasome Activation ◽

Muller Cells ◽

Potential Mechanism ◽

Nlrp3 Inflammasome Activation ◽

Therapeutic Value

Abstract Diabetic retinopathy (DR) is one of the most severe and common complications caused by diabetic mellites. Inhibiting NLRP3 inflammasome activation displays a crucial therapeutic value in DR. Studies have shown that KCNQ1OT1 plays a critical role in regulating NLRP3 inflammasome activation and participates in the pathogenesis of diabetic complications. The present study aims to explore the role, and the potential mechanism of KCNQ1OT1 in regulating the activation of NLRP3 inflammasome in DR. The expression of KCNQ1OT1 and the activation of NLRP3 inflammasome were increased in experimental DR models. KCNQ1OT1 knockdown alleviated NLRP3 inflammasome-associated molecules expression. In addition, KCNQ1OT1 was found to be localized mainly in the cytoplasm of Müller cells and facilitated TXNIP expression by acting as a miR-17-5p sponge. KCNQ1OT1 promoted the activation of NLRP3 inflammasome through miR-17-5p/TXNIP axis. Moreover, the clinical samples of patients with DR showed that the expression of KCNQ1OT1 and the activation of NLRP3 inflammasome were all increased, further supporting the hypothesis that the KCNQ1OT1 dysregulation may be the molecular mechanism of the pathogenesis of DR. Therefore, KCNQ1OT1 may serve as a new therapeutic target for DR.

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Mediation of FoxO1 in Activated Neuroglia Deficient for Nucleoside Diphosphate Kinase B during Vascular Degeneration

Neuroglia ◽

10.3390/neuroglia1010019 ◽

2018 ◽

Vol 1 (1) ◽

pp. 280-291 ◽

Cited By ~ 1

Author(s):

Yi Qiu ◽

Hongpeng Huang ◽

Anupriya Chatterjee ◽

Loïc Teuma ◽

Fabienne Baumann ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Cell Activation ◽

Neurovascular Unit ◽

Nucleoside Diphosphate Kinase ◽

Müller Cells ◽

Müller Cell ◽

Muller Cells ◽

Nucleoside Diphosphate Kinase B ◽

Muller Cell ◽

Underlying Mechanisms

The pathogenesis of diabetic retinopathy is closely associated with the breakdown of the neurovascular unit including the glial cells. Deficiency of nucleoside diphosphate kinase B (NDPK-B) results in retinal vasoregression mimicking diabetic retinopathy. Increased retinal expression of Angiopoietin-2 (Ang-2) initiates vasoregression. In this study, Müller cell activation, glial Ang-2 expression, and the underlying mechanisms were investigated in streptozotocin-induced diabetic NDPK-B deficient (KO) retinas and Müller cells isolated from the NDPK-B KO retinas. Müller cells were activated and Ang-2 expression was predominantly increased in Müller cells in normoglycemic NDPK-B KO retinas, similar to diabetic wild type (WT) retinas. Diabetes induction in the NDPK-B KO mice did not further increase its activation. Additionally, cultured NDPK-B KO Müller cells were more activated and showed higher Ang-2 expression than WT cells. Müller cell activation and Ang-2 elevation were observed upon high glucose treatment in WT, but not in NDPK-B KO cells. Moreover, increased levels of the transcription factor forkhead box protein O1 (FoxO1) were detected in non-diabetic NDPK-B KO Müller cells. The siRNA-mediated knockdown of FoxO1 in NDPK-B deficient cells interfered with Ang-2 upregulation. These data suggest that FoxO1 mediates Ang-2 upregulation induced by NDPK-B deficiency in the Müller cells and thus contributes to the onset of retinal vascular degeneration.

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