The NLRP3 Inflammasome May Contribute to Pathologic Neovascularization in the Advanced Stages of Diabetic Retinopathy

Diabetic retinopathy (DR) is the main cause of working-age adult-onset blindness. The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR. Therefore, new pharmacological treatments for these early stages of the disease are required. In order to develop therapeutic strategies for early stages of DR new diagnostic tools are urgently needed. In this regard, circulating biomarkers could be useful to detect early disease, to identify those diabetic patients most prone to progressive worsening who ought to be followed up more often and who could obtain the most benefit from these therapies, and to monitor the effectiveness of new drugs for DR before more advanced DR stages have been reached. Research of biomarkers for DR has been mainly based on the pathogenic mechanism involved in the development of DR (i.e., AGEs, oxidative stress, endothelial dysfunction, inflammation, and proangiogenic factors). This review focuses on circulating biomarkers at both early and advanced stages that could be relevant for the prediction or detection of DR.

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Enhanced Expression of NLRP3 Inflammasome-Related Inflammation in Diabetic Retinopathy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.17-22816 ◽

2018 ◽

Vol 59 (2) ◽

pp. 978 ◽

Cited By ~ 20

Author(s):

Hui Chen ◽

Xiongze Zhang ◽

Nanying Liao ◽

Lan Mi ◽

Yuting Peng ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Nlrp3 Inflammasome ◽

Enhanced Expression

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Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy

Antioxidants ◽

10.3390/antiox9080705 ◽

2020 ◽

Vol 9 (8) ◽

pp. 705 ◽

Cited By ~ 1

Author(s):

Beatriz Martins ◽

Madania Amorim ◽

Flávio Reis ◽

António Francisco Ambrósio ◽

Rosa Fernandes

Keyword(s):

Diabetic Retinopathy ◽

Extracellular Vesicles ◽

Vision Loss ◽

Current Knowledge ◽

Critical Role ◽

Cell Communication ◽

Cell Junctions ◽

Low Grade ◽

Long Distance ◽

Advanced Stages

Diabetic retinopathy (DR) is a complex, progressive, and heterogenous retinal degenerative disease associated with diabetes duration. It is characterized by glial, neural, and microvascular dysfunction, being the blood-retinal barrier (BRB) breakdown a hallmark of the early stages. In advanced stages, there is formation of new blood vessels, which are fragile and prone to leaking. This disease, if left untreated, may result in severe vision loss and eventually legal blindness. Although there are some available treatment options for DR, most of them are targeted to the advanced stages of the disease, have some adverse effects, and many patients do not adequately respond to the treatment, which demands further research. Oxidative stress and low-grade inflammation are closely associated processes that play a critical role in the development of DR. Retinal cells communicate with each other or with another one, using cell junctions, adhesion contacts, and secreted soluble factors that can act in neighboring or long-distance cells. Another mechanism of cell communication is via secreted extracellular vesicles (EVs), through exchange of material. Here, we review the current knowledge on deregulation of cell-to-cell communication through EVs, discussing the changes in miRNA expression profiling in body fluids and their role in the development of DR. Thereafter, current and promising therapeutic agents for preventing the progression of DR will be discussed.

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Protective effects of sulforaphane on diabetic retinopathy: activation of the Nrf2 pathway and inhibition of NLRP3 inflammasome formation

Experimental Animals ◽

10.1538/expanim.18-0146 ◽

2019 ◽

Vol 68 (2) ◽

pp. 221-231 ◽

Cited By ~ 20

Author(s):

Sheng Li ◽

Hongwei Yang ◽

Xiaolong Chen

Keyword(s):

Diabetic Retinopathy ◽

Nlrp3 Inflammasome ◽

Protective Effects ◽

Nrf2 Pathway

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Pterostilbene Prevents Early Diabetic Retinopathy Alterations in a Rabbit Experimental Model

Nutrients ◽

10.3390/nu12010082 ◽

2019 ◽

Vol 12 (1) ◽

pp. 82

Author(s):

Iván Millán ◽

María del Carmen Desco ◽

Isabel Torres-Cuevas ◽

Salvador Pérez ◽

Inés Pulido ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Redox Regulation ◽

Rabbit Model ◽

Redox Status ◽

Diabetic Complication ◽

Protective Agent ◽

Nrf2 Pathway ◽

Oxidant Damage ◽

Advanced Stages

Oxidative stress generated by diabetes plays a key role in the development of diabetic retinopathy (DR), a common diabetic complication. DR remains asymptomatic until it reaches advanced stages, which complicate its treatment. Although it is known that good metabolic control is essential for preventing DR, knowledge of the disease is incomplete and an effective treatment with no side effects is lacking. Pterostilbene (Pter), a natural stilbene with good antioxidant activity, has proved to beneficially affect different pathologies, including diabetes. Therefore, our study aimed to analyse the protective and/or therapeutic capacity of Pter against oxidant damage by characterising early retinal alterations induced by hyperglycaemia, and its possible mechanism of action in a rabbit model of type 1 diabetes mellitus. Pter reduced lipid and protein oxidative damage, and recovered redox status and the main activities of antioxidant enzymes. Moreover, the redox regulation by Pter was associated with activation of the PI3K/AKT/GSK3β/NRF2 pathway. Our results show that Pter is a powerful protective agent that may delay early DR development.

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Nutraceuticals for the Treatment of Diabetic Retinopathy

Nutrients ◽

10.3390/nu11040771 ◽

2019 ◽

Vol 11 (4) ◽

pp. 771 ◽

Cited By ~ 20

Author(s):

Maria Grazia Rossino ◽

Giovanni Casini

Keyword(s):

Diabetic Retinopathy ◽

Molecular Mechanisms ◽

Treatment Options ◽

Vitreoretinal Surgery ◽

In Vivo Studies ◽

Early Diabetes ◽

Advanced Stages ◽

Endothelial Growth Factor

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus and is characterized by degeneration of retinal neurons and neoangiogenesis, causing a severe threat to vision. Nowadays, the principal treatment options for DR are laser photocoagulation, vitreoretinal surgery, or intravitreal injection of drugs targeting vascular endothelial growth factor. However, these treatments only act at advanced stages of DR, have short term efficacy, and cause side effects. Treatment with nutraceuticals (foods providing medical or health benefits) at early stages of DR may represent a reasonable alternative to act upstream of the disease, preventing its progression. In particular, in vitro and in vivo studies have revealed that a variety of nutraceuticals have significant antioxidant and anti-inflammatory properties that may inhibit the early diabetes-driven molecular mechanisms that induce DR, reducing both the neural and vascular damage typical of DR. Although most studies are limited to animal models and there is the problem of low bioavailability for many nutraceuticals, the use of these compounds may represent a natural alternative method to standard DR treatments.

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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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Elevated NLRP3 Inflammasome Levels Correlate With Vitamin D in the Vitreous of Proliferative Diabetic Retinopathy

Frontiers in Medicine ◽

10.3389/fmed.2021.736316 ◽

2021 ◽

Vol 8 ◽

Author(s):

Li Lu ◽

Gaocheng Zou ◽

Li Chen ◽

Qianyi Lu ◽

Mian Wu ◽

...

Keyword(s):

Vitamin D ◽

Diabetic Retinopathy ◽

Proliferative Diabetic Retinopathy ◽

Nlrp3 Inflammasome ◽

Serum Vitamin ◽

Vitamin D Supplementation ◽

Enzyme Linked Immunosorbent Assay ◽

Diabetic Patients ◽

Serum Samples ◽

Serum Vitamin D

Purpose: This study aims to determine vitamin D concentrations in the vitreous and serum, as well as the expression levels of NLRP3 inflammasome pathway in the vitreous of patients with proliferative diabetic retinopathy (PDR). In addition, we investigated the possible correlation between NLRP3 inflammasome levels and vitamin D concentrations.Methods: We obtained vitreous samples before vitrectomy from 55 PDR patients, 25 non-diabetic patients with idiopathic macular hole (IMH), and 10 non-proliferative diabetic retinopathy (NPDR) patients. We also collected serum samples from the same patients. Enzyme-linked immunosorbent assay (ELISA) was used to examine NLRP3 inflammasome pathway proteins, including NLRP3, caspase-1, IL-1β, and VEGF. In addition, vitamin D concentrations were analyzed in Roche Cobas 6000's module e601 platform using electrochemiluminescence immune assay.Results: The levels of NLRP3 inflammasome pathway and VEGF increased dramatically in PDR vitreous. However, vitamin D concentrations in vitreous and serum followed the opposite trend. Meanwhile, vitreous and serum vitamin D concentrations were significantly negatively correlated with vitreous NLRP3 expression in PDR patients. Moreover, serum and vitreous vitamin D concentrations were positively correlated and demonstrated discriminatory ability in DR. The subgroup analysis of PDR group revealed that eyes with tractional retinal detachment (TRD) had higher NLRP3 inflammasome pathway and VEGF levels but lower vitamin D concentrations. Conversely, eyes that received preoperative pan-retinal photocoagulation (PRP) exhibited lower levels of NLRP3 inflammasome pathway, but vitamin D concentrations were irrelevant to laser treatment.Conclusions: Our results demonstrate a strong correlation between increased NLRP3 inflammasome pathway and decreased vitamin D concentrations in the vitreous of PDR patients, which may be linked to PDR pathogenesis. In addition, vitamin D supplementation may play a key role in preventing, treating, and improving PDR prognosis due to its inhibitory impact on NLRP3 inflammasome pathway and VEGF.

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Vitamin D3 Protects against Diabetic Retinopathy by Inhibiting High-Glucose-Induced Activation of the ROS/TXNIP/NLRP3 Inflammasome Pathway

Journal of Diabetes Research ◽

10.1155/2018/8193523 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 24

Author(s):

Li Lu ◽

Qianyi Lu ◽

Wei Chen ◽

Jingwen Li ◽

Chunxia Li ◽

...

Keyword(s):

Vitamin D ◽

Diabetic Retinopathy ◽

Vascular Permeability ◽

Nlrp3 Inflammasome ◽

High Glucose ◽

Cell Apoptosis ◽

Vascular Endothelial Cell ◽

Vascular Damage ◽

Vascular Endothelial ◽

Retinal Vascular Permeability

Purpose. This study aimed to evaluate the mechanisms underlying the effects of 1,25-dihydroxyvitamin D (vitamin D3) on diabetes-induced retinal vascular damage and retinal vascular endothelial cell apoptosis. Methods. Diabetic and control rats were randomly assigned to receive vitamin D3 or vehicle for 6 months. Additionally, human retinal microvascular endothelial cells (HRMECs) were incubated in normal or high-glucose medium with or without vitamin D3. Morphological changes in retinal tissues and retinal vascular permeability were examined, and cellular apoptosis was detected by fluorescence staining. Intracellular reactive oxygen species (ROS) levels were determined using fluorescent probes. Proteins were examined by Western blotting. Results. Vitamin D3 significantly downregulated intracellular ROS and inhibited TRX-interacting protein (TXNIP)/NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway activation. Additionally, vitamin D3 reduced vascular endothelial growth factor (VEGF) expression and the Bax/Bcl-2 ratio. These changes were associated with retinal recovery and with decreases in retinal vascular permeability and retinal capillary cell apoptosis. Conclusions. Vitamin D3 decreases diabetes-induced ROS and exerts protective effects against retinal vascular damage and cell apoptosis in association with inhibition of the ROS/TXNIP/NLRP3 inflammasome pathway. Understanding the mechanisms of action of vitamin D3 has important implications for preventing and treating inflammatory-related illnesses such as diabetic retinopathy.

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Combination Approaches Targeting Neurodegeneration, Oxidative stress and Inflammation in the Treatment of Diabetic Retinopathy

Current Drug Targets ◽

10.2174/1389450122666210319113136 ◽

2021 ◽

Vol 22 ◽

Author(s):

Siddhi Dilip Chalke ◽

Pravin Popatrao Kale

Keyword(s):

Oxidative Stress ◽

Diabetic Retinopathy ◽

Vision Loss ◽

Treatment Options ◽

Treatment Strategies ◽

Early Stages ◽

Advanced Stages ◽

Severe Vision Loss ◽

Angiopoietin 2 ◽

Endothelial Growth Factor

: Diabetic Retinopathy (DR) is one of the most severe ocular problems of diabetes. It is a microvascular complication that impairs the vision of diabetic individuals and can cause acquired blindness. Currently available treatment options like laser therapy, vitrectomy, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and glucocorticoids help to reduce vision loss at advanced stages. In spite of the available therapies, patients with severe vision loss face difficulty in achieving normal vision. There is a need for development of newer treatment strategies to address the condition from the early stages. Multiple factors owing to complex pathophysiological events are responsible for this long-term complication. Neurodegeneration, inflammation, and oxidative stress are the three important factors associated with the development of DR. Oxidative stress is a major contributor to the onset and progression of DR. Pathological events like retinal neurodegeneration and inflammation damage the retina right in the early stages of DR. Different combinations of treatments targeting these pathological events are discussed in the present review. The first combination discussed is citicoline and resveratrol. The second combination is duloxetine and N-acetyl cysteine (NAC). These combinations may help in the early stages of DR. CD5-2 and angiopoietin-2 inhibitors is the third combination. This combination may help to manage diabetic macular edema. The main purpose of this article is to discuss the link between these pathologies and the three combination approaches with the objective of consideration of newer therapeutic approaches in research related to DR treatment.

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