Balancing AhR-Dependent Pro-Oxidant and Nrf2-Responsive Anti-Oxidant Pathways in Age-Related Retinopathy: Is SERPINE1 Expression a Therapeutic Target in Disease Onset and Progression?

Higgins, Paul J.

doi:10.4172/1747-0862.1000101

Cited by 6 publications

(5 citation statements)

References 15 publications

(18 reference statements)

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“…Finally, IL1A has been proposed as an essential mediator of HF pathogenesis [72,73] through inflammation modulations, and serum levels of this protein have been found increased in MD patients [74]. In addition, as described in previous sections, classifiers FGB, SERPINE1, and SERPING1 have been linked to MD [52][53][54] and are also known to play a role in HF development [75][76][77][78]. According to these findings, the 10 potential biomarkers proposed by TPMS and identified with GUILDify might be prioritized when studying good responder HF patients at risk of MD development.…”

Section: Analysis Of Proposed Biomarkers With Guildifymentioning

confidence: 76%

“…In fact, since neovascular MD development is characterized by subretinal extravasations of novel vessels derived from the choroid (CNV) and the subsequent hemorrhage into the photoreceptor cell layer in the macula region [51], it might be reasonable to think that the modulation of fibrinolysis and blood coagulation pathways could play a role. The reported implication of some fibrinolysis related classifiers, such as FGB, SERPINE1 (PAI-1), and SERPING1, in neovascular MD development seems to support this hypothesis [52][53][54]. Besides, valsartan might be implicated in this mechanism, since it has been reported to modulate PAI-1 levels and promote fibrinolysis in different animal and human models [55,56].…”

Section: Identification Of Potential Biomarkers Differentiating MD Rementioning

confidence: 84%

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In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

et al. 2020

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Unveiling the mechanism of action of a drug is key to understand the benefits and adverse reactions of a medication in an organism. However, in complex diseases such as heart diseases there is not a unique mechanism of action but a wide range of different responses depending on the patient. Exploring this collection of mechanisms is one of the clues for a future personalized medicine. The Therapeutic Performance Mapping System (TPMS) is a Systems Biology approach that generates multiple models of the mechanism of action of a drug. Each molecular mechanism generated could be associated to particular individuals, here defined as prototype-patients, hence the generation of models using TPMS technology may be used for detecting adverse effects to specific patients. TPMS operates by (1) modelling the responses in humans with an accurate description of a protein network and (2) applying a Multilayer Perceptron-like and sampling strategy to find all plausible solutions. In the present study, TPMS is applied to explore the diversity of mechanisms of action of the drug combination sacubitril/valsartan. We use TPMS to generate a wide range of models explaining the relationship between sacubitril/valsartan and heart failure (the indication), as well as evaluating their association with macular degeneration (a potential adverse effect). Among the models generated, we identify a set of mechanisms of action associated to a better response in terms of heart failure treatment, which could also be associated to macular degeneration development. Finally, a set of 30 potential biomarkers are proposed to identify mechanisms (or prototype-patients) more prone of suffering macular degeneration when presenting good heart failure response. All prototype-patients models generated are completely theoretical and therefore they do not necessarily involve clinical effects in real patients. Data and accession to software are available at http://sbi.upf.edu/data/tpms/.

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Section: Analysis Of Proposed Biomarkers With Guildifymentioning

confidence: 76%

Section: Identification Of Potential Biomarkers Differentiating MD Rementioning

confidence: 84%

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

et al. 2020

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“…It has been reported that in lung mucus hepatocyte and breast derived can cell lines that activation of AhR increases ROS levels and oxidative stress 47 48 , possibly by the up regulation of NADPH oxidase. In retinal cells it has been shown AhR deficient mice have high levels of inflammation and maybe subjected to prolonged ROS stress 49 50 . This study suggests that in the eye activation of AhR by 2AI confers a protective role for AhR, probably by activating the AhR-NRF2 anti-oxidant battery of genes.…”

Section: Discussionmentioning

confidence: 99%

A novel AhR ligand, 2AI, protects the retina from environmental stress

Gutierrez

Davis

Rosko

et al. 2016

Sci Rep

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Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2′-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice.

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“…6 D list statistically significant genes involved in these pathways. Notable genes include CD36, serpine1 and calcitonin receptor-like receptor gene (Calcrl) [ [48] , [49] , [50] , [51] ], which may play a role in the homeostatic and immune dysregulation identified in some retinopathies.…”

Section: Resultsmentioning

confidence: 99%

Riboflavin deficiency leads to irreversible cellular changes in the RPE and disrupts retinal function through alterations in cellular metabolic homeostasis

et al. 2022

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Balancing AhR-Dependent Pro-Oxidant and Nrf2-Responsive Anti-Oxidant Pathways in Age-Related Retinopathy: Is SERPINE1 Expression a Therapeutic Target in Disease Onset and Progression?

Cited by 6 publications

References 15 publications

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

A novel AhR ligand, 2AI, protects the retina from environmental stress

Riboflavin deficiency leads to irreversible cellular changes in the RPE and disrupts retinal function through alterations in cellular metabolic homeostasis

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