Cell Death in AMD: The Rationale for Targeting Fas

Zacks, David N.; Kocab, Andrew J.; Choi, Joanne; Gregory-Ksander, Meredith; Cano, Marisol; Handa, James T.

doi:10.3390/jcm11030592

Cited by 15 publications

(7 citation statements)

References 58 publications

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“…Our results strongly suggest that 6R-FBP effectively blocks the Fas/FasL interaction, leading to the inhibition of apoptosis and inflammation, thereby positioning 6R-FBP as a promising inhibitor of AMD progression. These findings align with previous research demonstrating that Fas knockout mice are resistant to AMD progression, highlighting the potential benefits of blocking Fas activity in the retina for AMD treatment [ 31 ]. While pharmacologic inhibition of the Fas/FasL interaction has been achieved through intraocular injection of macromolecules, such as anti-Fas antibodies, soluble FasL, and Fas receptor antagonists, their application is limited by severe side effects [ 65 ].…”

Section: Discussionsupporting

confidence: 91%

“…Additionally, ROS-induced p53 upregulates Fas expression, sensitizing retinal cells to apoptosis [ 25 , 26 , 27 , 28 , 29 ]. As the inflammatory response progresses, FasL-expressing macrophages infiltrate the retinal layers, interacting with Fas-expressing RPE cells, thereby triggering Fas-mediated apoptosis [ 30 , 31 ]. Upon activation of Fas signaling, apoptosis is initiated through both the intrinsic and extrinsic pathways [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration

Yi,

Pyun,

Kim

et al. 2024

Cells

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Age-related macular degeneration (AMD), characterized by macular retinal degeneration, poses a significant health concern due to the lack of effective treatments for prevalent dry AMD. The progression of AMD is closely linked to reactive oxygen species and Fas signaling, emphasizing the need for targeted interventions. In this study, we utilized a NaIO3-induced retinal degeneration mouse model to assess the efficacy of Fas-blocking peptide (FBP). Intravitreal administration of FBP successfully suppressed Fas-mediated inflammation and apoptosis, effectively arresting AMD progression in mice. We developed a 6R-conjugated FBP (6R-FBP) for eye drop administration. 6R-FBP, administered as an eye drop, reached the retinal region, attenuating degeneration by modulating the expression of inflammatory cytokines and blocking Fas-mediated apoptosis in rodent and rabbit NaIO3-induced retinal degeneration models to address practical concerns. Intravitreal FBP and 6R-FBP eye drops effectively reduced retinal degeneration and improved retinal thickness in rodent and rabbit models. This study highlights the therapeutic potential of FBP, particularly 6R-FBP as an eye drop, in inhibiting Fas-mediated cell signaling and protecting against retinal cell death and inflammation in dry AMD. Future investigations should explore the translational prospects of this approach in primates with eye structures comparable to those of humans.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration

Yi,

Pyun,

Kim

et al. 2024

Cells

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“…Reducing RPE damage before the transition of early AMD to late AMD could be key to prevent dry AMD, because photoreceptor degeneration in dry AMD is caused by dysfunctional RPE cells that get atrophic [7,9,10]. Apoptosis, necroptosis, and ferroptosis are considered to be involved in RPE atrophy and AMD pathophysiology [11][12][13]. Apoptosis is the classic mode of regulated cell death involving several modulators and pathways in which caspases play a crucial role.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction

Henning

Blind²,

Larafa³

et al. 2022

Cell Death Dis

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Oxidative stress and hypoxia in the retinal pigment epithelium (RPE) have long been considered major risk factors in the pathophysiology of age-related macular degeneration (AMD), but systematic investigation of the interplay between these two risk factors was lacking. For this purpose, we treated a human RPE cell line (ARPE-19) with sodium iodate (SI), an oxidative stress agent, together with dimethyloxalylglycine (DMOG) which leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. We found that HIF stabilization aggravated oxidative stress-induced cell death by SI and iron-dependent ferroptosis was identified as the main cell death mechanism. Ferroptotic cell death depends on the Fenton reaction where H2O2 and iron react to generate hydroxyl radicals which trigger lipid peroxidation. Our findings clearly provide evidence for superoxide dismutase (SOD) driven H2O2 production fostering the Fenton reaction as indicated by triggered SOD activity upon DMOG + SI treatment as well as by reduced cell death levels upon SOD2 knockdown. In addition, iron transporters involved in non-transferrin-bound Fe2+ import as well as intracellular iron levels were also upregulated. Consequently, chelation of Fe2+ by 2’2-Bipyridyl completely rescued cells. Taken together, we show for the first time that HIF stabilization under oxidative stress conditions aggravates ferroptotic cell death in RPE cells. Thus, our study provides a novel link between hypoxia, oxidative stress and iron metabolism in AMD pathophysiology. Since iron accumulation and altered iron metabolism are characteristic features of AMD retinas and RPE cells, our cell culture model is suitable for high-throughput screening of new treatment approaches against AMD.

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“…Вікова макулярна дегенерація (ВМД), що уражає переважно населення середнього і старечого віку та призводить до незворотної сліпоти й втрати працездатности, є пріоритетною проблемою громадського здоров'я. З огляду на старіння європейської популяції ця проблема набуває щораз більшого значенняризик ураження центральної частини сітківки зростає з віком, а отже, збільшується кількість хворих на ВМД [44]. До чинників, які є основою клітинного старіння і розглядаються як біологічні тригери ВМД, належать: порушення регуляції проліферації судин, дерегуляції позаклітинного матриксу, ланцюгова реакція прозапальних медіаторів, ушкодження мітохонд рій з витоком мітохондріального вмісту, а також нагромадження активних форм кисню високореактивними клітинами сітківки [31].…”

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The Role Of HTRA Serine Peptidase 1, Vascular Endothelial Growth Factor А, Tumor Necrosis Factor Gene Polymorphisms in the Treatment Of Wet Age-Related Macular Degeneration

Malachkova¹,

Al-Jarrah²

2023

Lʹviv. klin. visn.

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Introduction. Age-related macular degeneration (AMD) of the retina is still considered the leading cause of vision loss in the elderly. The multifactoriality of the disease impairs the clinical effectiveness of modern AMD treatment methods. however, the study of single-nucleotide polymorphisms, in particular, of the HtrA serine peptidase 1 (HTRA1), vascular endothelial growth factor A (VEGF A) and tumor necrosis factor (TNF) genesis a promising link on the way to improve and develope more effective treatment strategies of the disease. The Aim of the Study. To investigate role of HTRA 1, VEGF A and TNF gene polymorphisms in the treatment of wet age-related macular degeneration. Materials and Methods. 162 people with diagnosed wet AMD took part in the investigation. They received anti-VEGF A therapy in the form of injections of aflibercept monthly for half a year. Structural changes of the eyes were studied using optical coherence tomography (OCT); polymerase chain reaction (PCR) studies were performed using a Bio-Rad CFX 96 apparatus (BioRad, USA) using a reagent package (Lytech, Russia). Statistical analysis of the obtained results was performed using a set of software packages Statistica 10 (StatSoft, Inc., USA) and SPSS 23.0. Results. It was revealed best prognostic significance in patients with the TC rs2010963 genotype of the VEGFA gene was registered during the analysis of OCT 2 (RR=2.7; 95% CI 1.556 – 4.8), OCT 4 (RR=2.9 ; 95% CI 1.7 – 5.03) and OCT 8 (RR=2.6; 95% CI 1.6 – 4.12) sections, while in patients with the CC genotype these indicators in the OCT 2 section were: RR= 6.1; 95% CI 3.66 – 10.27; in OCT zone 4 RR=4.9; 95% CI 2.9 – 8.29, and in the OCT section 8: RR=4.23; 95% CI 2.7 – 6.556, which indicates a more pronounced influence of the CC genotype. When analyzing rs1800629 of the TNF gene, the best prognostic significance of the GA genotype was established in the OCT 4 (RR=1.77; 95% CI 1.218 – 2.56) and OCT 8 (RR=1.9; 95% CI 1.17 – 3.175) areas (p-value less than 0.05), with the AA genotype in OCT 4 (RR=3.77; 95% CI 2.17 – 6.58), OCT 8 (RR=3.1; 95% CI 1 .7 – 5.59) zones and when evaluating changes in visual acuity of patients with wet AMD (RR=4.2; 95% CI 2 – 8.98). No statistically significant results were found in the evaluation of the HTRA1 gene rs11200638 (p-value more than 0.05). Conclusions. The data obtained in our study indicate a direct influence of the vascular endothelial growth factor A (rs2010963) and tumor necrosis factor (rs1800629) polymorphisms on the emergence of resistance to aflibercept. However, the study of this influence in the presence of the HtrA serine peptidase 1 gene rs11200638 requires further research.

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Cell Death in AMD: The Rationale for Targeting Fas

Cited by 15 publications

References 58 publications

Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration

Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration

Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction

The Role Of HTRA Serine Peptidase 1, Vascular Endothelial Growth Factor А, Tumor Necrosis Factor Gene Polymorphisms in the Treatment Of Wet Age-Related Macular Degeneration

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