Mounting evidence suggests that immunological mechanisms play a fundamental role in the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Upregulation of cytokines and other proinflammatory mediators leading to persistent low-grade inflammation is believed to actively contribute to the DR-associated damage to the retinal vasculature, inducing breakdown of the blood-retinal barrier, subsequent macular edema formation, and promotion of retinal neovascularization. This review summarizes the current knowledge of the biological processes providing an inflammatory basis for DR and DME. In addition, emerging therapeutic approaches targeting inflammation are discussed, including blockade of angiopoietin 2 and other molecular targets such as interleukin (IL)-6, IL-1β, plasma kallikrein, and integrins.

The role of inflammation in diabetic eye disease

Diabetic retinopathy (DR) is a diabetic complication which affects retinal function and results in severe loss of vision and relevant retinal diseases. Retinal vascular dysfunction caused by multifactors, such as advanced glycosylation end products and receptors, pro-inflammatory cytokines and chemokines, proliferator-activated receptor-γ disruption, growth factors, oxidative stress, and microRNA. These factors promote retinal endothelial dysfunction, which results in the development of DR. In this review, we summarize the contributors in the pathophysiology of DR for a better understanding of the molecular and cellular mechanism in the development of DR with a special emphasis on retinal endothelial dysfunction.

/pdf/endothelial-dysfunction-in-diabetic-retinopathy-4txyaslnb8.pdf

Endothelial Dysfunction in Diabetic Retinopathy.

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are microvascular complications of diabetes. Microvascular endothelial cells are thought to be the major targets of hyperglycemic injury. In diabetic microvasculature, the intracellular hyperglycemia causes damages to the vascular endothelium, via multiple pathophysiological process consist of inflammation, endothelial cell crosstalk with podocytes/pericytes and exosomes. In addition, DN and DR diseases development are involved in several critical regulators including the cell adhesion molecules (CAMs), the vascular endothelial growth factor (VEGF) family and the Notch signal. The present review attempts to gain a deeper understanding of the pathogenesis complexities underlying the endothelial dysfunction in diabetes diabetic and retinopathy, contributing to the development of new mechanistic therapeutic strategies against diabetes-induced microvascular endothelial dysfunction.

/pdf/mechanistic-pathogenesis-of-endothelial-dysfunction-in-8u9oujwu.pdf

Mechanistic Pathogenesis of Endothelial Dysfunction in Diabetic Nephropathy and Retinopathy

Various studies, especially in recent years, have shown that quercetin has beneficial therapeutic effects in various human diseases, including diabetes. Quercetin has significant anti-diabetic effects and may be helpful in lowering blood sugar and increasing insulin sensitivity. Quercetin appears to affect many factors and signaling pathways involved in insulin resistance and the pathogenesis of type 2 of diabetes. TNFα, NFKB, AMPK, AKT, and NRF2 are among the factors that are affected by quercetin. In addition, quercetin can be effective in preventing and ameliorating the diabetic complications, including diabetic nephropathy, cardiovascular complications, neuropathy, delayed wound healing, and retinopathy, and affects the key mechanisms involved in the pathogenesis of these complications. These positive effects of quercetin may be related to its anti-inflammatory and anti-oxidant properties. In this article, after a brief review of the pathogenesis of insulin resistance and type 2 diabetes, we will review the latest findings on the anti-diabetic effects of quercetin with a molecular perspective. Then we will review the effects of quercetin on the key mechanisms of pathogenesis of diabetes complications including nephropathy, cardiovascular complications, neuropathy, delayed wound healing, and retinopathy. Finally, clinical trials investigating the effect of quercetin on diabetes and diabetes complications will be reviewed.

Quercetin: an effective polyphenol in alleviating diabetes and diabetic complications.

Diabetic retinopathy is one of the most common complications of diabetes mellitus and the leading cause of low vision and blindness worldwide. Mounting evidence demonstrates that inflammation is a key mechanism driving diabetes-associated retinal disturbance, yet the pathophysiological process and molecular mechanisms of inflammation underlying diabetic retinopathy are not fully understood. Cytokines, chemokines, and adhesion molecules interact with each other to form a complex molecular network that propagates the inflammatory and pathological cascade of diabetic retinopathy. Therefore, it is important to understand and elucidate inflammation-related mechanisms behind diabetic retinopathy progression. Here, we review the current understanding of the pathology and pathogenesis of inflammation in diabetic retinopathy. In addition, we also summarize the relevant clinical trials to further suggest inflammation-targeted therapeutics for prevention and management of diabetic retinopathy.

/pdf/the-role-of-inflammation-in-immune-system-of-diabetic-2c66u1lt.pdf

The role of inflammation in immune system of diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications

Background: Interleukin-6 (IL-6) is produced by a variety of cells involved in inflammation and acts as local intensification signals in pathological processes associated with chronic eye inflammat...

Interleukin-6 and Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

Elevated levels of proinflammatory markers are evident in patients with diabetic retinopathy (DR) and are associated with disease progression and prognosis. Intercellular adhesion molecule-1 (ICAM-1) is involved in inflammation and acts as a local intensifying signal in the pathological processes associated with chronic eye inflammation. The aim of this systematic review and meta-analysis was to investigate the relationship between ICAM-1 level and DR. Online electronic databases were searched to retrieve all relevant articles published before December 2017. The standard mean difference (SMD) and their 95% CI were included and then pooled with a random effects model. Subgroup analysis and metaregression analysis were applied to explore the sources of heterogeneity, and publication bias was calculated to assess the quality of pooled studies. A total of 11 articles, containing 428 patients with DR and 789 healthy controls, were included in this meta-analysis. The results indicated a significant increase in ICAM-1 level in the DR group compared with the control group (SMD: 1.20, 95%CI 0.83 to 1.57, p<0.001). Subgroup analyses and metaregression analysis indicated that publication year, region, study method, diabetes mellitus type, Newcastle-Ottawa Scale and sample size were not the potential sources of heterogeneity. The results of this current meta-analysis indicated that the increased level of ICAM-1 generally exists in the patients with DR and it may associated with the severity of DR. However, large-scale and high-quality studies are required to confirm this finding in the future.

https://pmj.bmj.com/content/postgradmedj/95/1121/162.full.pdf

Association between ICAM-1 level and diabetic retinopathy: a review and meta-analysis

Objective NIMA-related kinase 2 (NEK2) has been reported to be overexpressed in various types of cancer and correlated with poor prognosis. The role(s) of NEK2 in cancer, however, is still uncertain. The aim of this study was to evaluate the prognostic value of NEK2 in human tumors. Methods A comprehensive literature search was performed for PubMed, Embase, Web of Science, and CNKI databases, and eligible studies were included based on the inclusion and exclusion criteria. A meta-analysis of the included studies was then carried out. Results Fifteen studies with 3,280 cancer patients were included in the present meta-analysis. All publications were of moderate to high quality, and had no significant heterogeneity (I2=46%, P=0.03) or publication bias was discovered. The results showed that a high NEK2 level was associated with shorter overall survival (OS) in patients with various types of cancers (pooled HR=1.72, 95% CI 1.49-2.00, P<0.00001). However, the disease-free survival (DFS) had no significant association with NEK2 level (HR=1.13, 95% CI: 0.29-4.38, P=0.85). In the subgroup analyses, high NEK2 level was correlated with an increased risk of poor OS in patients with hepatocellular carcinoma (HR=1.62, 95% CI: 1.25-2.10, P=0.02) and lung cancer (HR=2.18, 95% CI: 1.40-3.38, P=0.0005). However, other factors, including sample size, follow-up period, HR estimation method, and country, also affect the association between NEK2 expression and OS. Analysis of clinicopathological parameters further showed that increased NEK2 level was correlated with younger age, male gender, better tumor differentiation, and lower number of tumor nodules. Conclusion The results of this study indicated that increased expression of NEK2 was associated with unfavorable survival of cancer patients and that NEK2 could be used as a prognostic predictor for cancers.

/pdf/nima-related-kinase-2-overexpression-is-associated-with-poor-5blrd73jvo.pdf

NIMA-related kinase 2 overexpression is associated with poor survival in cancer patients: a systematic review and meta-analysis.

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Interleukin-6 and Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

Association between ICAM-1 level and diabetic retinopathy: a review and meta-analysis

NIMA-related kinase 2 overexpression is associated with poor survival in cancer patients: a systematic review and meta-analysis.