Anomalous Angiogenesis in Retina

Vega, Rocío; Carretero, Manuel; Bonilla, L. L.

doi:10.3390/biomedicines9020224

Cited by 8 publications

(6 citation statements)

References 66 publications

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“…At the beginning of the wet AMD, choriocapillaris degenerates with the formation of new leaky blood vessels that penetrate through the Bruch's membrane (Figure 2; Kaarniranta et al, 2013; McLeod et al, 2009; Muftuoglu et al, 2018; Qin & Rodrigues, 2008; Vega et al, 2021; Zajac‐Pytru et al, 2015). Changes in the choriocapillaris lead to neovascularization with haemorrhages, oedema and exudate formation and are followed by the degeneration and loss of RPE cells (Kaarniranta et al, 2013; McLeod et al, 2009; Muftuoglu et al, 2018; Qin & Rodrigues, 2008; Vega et al, 2021; Zajac‐Pytru et al, 2015). In the late stages of both disease forms of AMD, the RPE and choriocapillaris have become degenerated but the RPE degeneration is worse in dry AMD and choriocapillaris damage in the wet form (Biesemeier et al, 2014).…”

Section: Review Of the Literaturementioning

confidence: 99%

Regulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells

Harju

2022

Acta Ophthalmologica

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Age‐related macular degeneration (AMD) is an eye disease, which causes impaired vision that can lead to blindness. The incidence of AMD increases with age. Retinal pigment epithelial (RPE) cells maintain retinal homeostasis and support the functionality of photoreceptors. In the pathogenesis of AMD, the degeneration of the RPE cells precedes photoreceptor cell death. RPE cells are susceptible to oxidative stress, and chronic inflammation involving nucleotide‐binding domain, leucine‐rich repeat and pyrin domain 3 (NLRP3) inflammasome activation and impaired autophagy are challenges faced by aged RPE cells in AMD. There are two types of AMD, dry (85–90%) and wet (10–15%) disease forms. Choroidal neovascularization is typical for wet AMD, and anti‐vascular endothelial growth factor (anti‐VEGF) injections are used to prevent the progression of the disease but there is no curative treatment. There is no cure for the dry disease form, but antioxidants have been proposed as a potential treatment option.Ageing is the most important risk factor of AMD, and tobacco smoke is the most important environmental risk factor that can be controlled. Hydroquinone is a cytotoxic, immunotoxic, carcinogenic and pro‐oxidative component of tobacco smoke. The aim of this PhD thesis was to study hydroquinone‐induced oxidative stress and NLRP3 inflammasome activation in human RPE cells (ARPE‐19 cells). An age‐related eye disease study (AREDS) formulation (incl. omega‐3 fatty acids, vitamin C and E, copper, zinc, lutein and zeaxanthin), which is clinically investigated p.o. dosing combination of dietary supplements for AMD patients, has been evaluated as a possible treatment and restraining option for AMD. Resvega (4.1.1, Table 2) is a similar kind of product to AREDS with added resveratrol, and many of the components incorporated within Resvega can be considered as belonging to the normal antioxidative defence system of the retina. Another aim was to evaluate the effects of Resvega on hydroquinone‐induced oxidative stress or NLRP3 inflammasome activation induced by impaired protein clearance.The results of this study reveal that hydroquinone elevated the activity of NADPH oxidase which subsequently mediated the production of reactive oxygen species (ROS) and predisposed RPE cells to degeneration by reducing levels of vascular endothelial growth factor (VEGF) and pigment epithelium‐derived factor (PEDF). Hydroquinone induced an NLRP3‐independent IL‐18 release and NLRP3 accumulation inside the IL‐1α‐primed cells. Resvega treatment reduced the extent of hydroquinone‐induced ROS production and NLRP3 inflammasome activation evoked by impaired protein clearance. Thus, Resvega alleviated hydroquinone‐ and impaired protein clearance‐induced stress in human RPE cells, but more studies are needed, for example, to reveal the most optimal route of administration for targeting the cells in the retina, since both oxidative stress and NLRP3 inflammasome activation are important contributors to the development of AMD and represent significant treatment targets.

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Section: Review Of the Literaturementioning

confidence: 99%

Regulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells

Harju

2022

Acta Ophthalmologica

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“…Most of the building blocks for running an ISCT in the retina are already in place. When it comes to nAMD, there are already mechanistic models in place for the disease and intervention [136,283]. However, two main gaps still exist that are required to run successful ISCTs in retinal disease:…”

Section: Discussionmentioning

confidence: 99%

Advancing treatment of retinal disease through in silico trials

2023

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Treating retinal diseases to prevent sight loss is an increasingly important challenge. Thanks to the configuration of the eye, the retina can be examined relatively easily in situ. Owing to recent technological development in scanning devices, much progress has been made in understanding the structure of the retina and characterising retinal biomarkers. However, treatment options remain limited and are often of low efficiency and efficacy.In recent years, the concept of in silico clinical trials has been adopted by many pharmaceutical companies to optimise and accelerate the development of therapeutics. In silico clinical trials rely on the use of mathematical models based on the physical and biochemical mechanisms underpinning a biological system. With appropriate simplifications and assumptions, one can generate computer simulations of various treatment regimens, new therapeutic molecules, delivery strategies and so forth, rapidly and at a fraction of the cost required for the equivalent experiments. Such simulations have the potential not only to hasten the development of therapies and strategies but also tooptimise the use of existing therapeutics.In this paper, we review the state-of-the-art in in silico models of the retina for mathematicians, biomedical scientists and clinicians, highlighting the challenges to developing in silico clinical trials. Throughout this paper, we highlight key findings from in silico models about the physiology of the retina in health and disease. We describe the main building blocks of in silico clinical trials and identify challenges to developing in silico clinical trials of retinal diseases.

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“…Abnormal growth factor secretion of RPE was one of the most common pathological progresses and it would lead to neovascularization in choroidal (wet AMD) and retina (proliferative DR). 35 , 36 RPE was the outer BRB and impaired RPE tight junction would cause retinal edema, such as macular edema secondary to DR. 37 Both neovascularization and retinal edema were two important causes of blindness for patients with retinal disorders. In this current study, it was found that GSPE treatment could moderate the abnormal SASP levels as well as impaired BRB by alleviating RPE cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

Grape Seed Proanthocyanidin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway

Wan

Zhu

et al. 2021

JIR

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Background: Retinal pigment epithelium (RPE) cellular senescence is an important process in degenerative retinal disorders. Grape seed proanthocyanidin extract (GSPE) alleviates senescence-related degenerative disorders; however, the potential effects of GSPE intake on RPE cellular senescence through regulating NAMPT/SIRT1/NLRP3 pathway remain unclear. Methods: The effects of GSPE on NAMPT expression and NAD+ contents were detected with Western blot and assay kit in both in-vivo and in-vitro AMD models. Senescencerelated biomarkers, including p16, p21 expressions and β-gal staining, were conducted in different groups. The protective effects of GSPE treatment on the mitochondrial homeostasis and barrier function of RPE cells were detected using mtDNA lesions analyses, JC-1 staining, ZO1 staining and trans-epithelial cell resistance (TEER) detection. The expression of senescence-associated secretory phenotype (SASP) in different groups would be conducted with qPCR. To demonstrate the potential effects of NAMPT/SIRT1/NLRP3 pathway after GSPE treatment, the protein levels of relevant key regulators after applications of NAMPT inhibitor, Fk866, and SIRT1 inhibitor, EX-527. Results: GSPE significantly improves the NAMPT expression and NAD+ content in aging mice, and thus alleviates the RPE cellular senescence. In advanced in-vitro studies, GSPE significantly up-regulated NAMPT content and thus relieved H 2 O 2 induced NAD+ depression through analyzing the NAD+ contents in different groups. In advanced analyses, it was reported that GSPE could alleviate mitochondrial permeability, mtDNA damage, ZO1 expression and SASP levels in aging RPE cells. Thus, GSPE treatment significantly decreased senescencerelated protein p16 and p21, as well as SASP levels in in-vitro aging model, and it was demonstrated that GSPE could illustrate a significant anti-aging effect. The Western blot data in GSPE treatment of aging RPE cells demonstrated that GSPE could significantly improve NAMPT and SIRT1 levels, and thus depressed NLRP3 expression. Conclusion:This study indicated that GSPE alleviated RPE cellular senescence through NAMPT/SIRT1/NLRP3 pathway. This study highlighted the potential effects of GSPE on degenerative retinopathy through the crosstalk of NAD+ metabolism, SIRT1 function and NLRP3 activation.

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Anomalous Angiogenesis in Retina

Cited by 8 publications

References 66 publications

Regulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells

Regulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells

Advancing treatment of retinal disease through in silico trials

Grape Seed Proanthocyanidin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway

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