Collectively, the present work establishes miR-144 as a potential target for preventing and treating degenerative retinal diseases in which oxidative stress is paramount and RPE is prominently affected (e.g., age-related macular degeneration and diabetic retinopathy).
Sixty-eight patients presenting pigment epithelial detachments resistant to ranibizumab (issued from ARI2 study, register number NCT02157077 on clinicaltrials.gov) were compared with two series of patients derived from previously published clinical studies, presenting neovascular AMD (NAT2 study n = 300 and PHRC study n = 1,127), and with healthy controls (n = 441).
Specifically, loss of the Nr1h3 isoform results in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 is associated with ocular lipoidal degeneration.
In particular, the interleukin 1 (IL-1) family consisting of both pro- and anti-inflammatory cytokines has been shown to be pivotal in the mediation of innate immunity and contribute directly to a number of retinal degenerations, including Age-Related Macular Degeneration (AMD), diabetic retinopathy, retinitis pigmentosa, glaucoma, and retinopathy of prematurity (ROP).
Our data indicate that A2E-induced upregulation of HMGB1、Caveolin-1 and HMGB1 release may relate to RPE cell senescence and play a role in the pathogenesis of AMD.
This cross-sectional questionnaire study used the validated HLS-EU-Q16 questionnaire to determine the health literacy of 225 patients with age-related macular degeneration (AMD), diabetic macular edema (DME) or retinal vein occlusion (RVO), receiving intravitreal treatment at the retinal clinic, Zealand University Hospital, Denmark.
Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis.
Here, we investigated monocyte CD200 expression - the circulating middleman negotiating retinal microglial activity - in a poorly understood subtype of age-related macular degeneration.
In the validation studies, miR-129-3p and miR-132-3p had no significant expression in AMD group compared to the controls. miR-486-5p and miR-626 had higher expression in AMD patients compared to the control group, while miR-885-5p showed significantly lower expression.
Therefore, the mitochondrial DNA damage reaction (mtDDR) is important in AMD prevention and in slowing down its progression as is ROS-targeting AMD therapy.
Together, these data suggest XIAP-mediated inhibition of inflammasome activity in RPE may provide insights into the biological consequences of inflammasome activation in RPE and reveals the caspase-1/XIAP/IL-1β/IL-18 axis as a target for broader applications in AMD biology and treatment design.
Nrf-2 (p < 0.05), HO-1 and GCLC expressions were lowered in the retina of AMD, whereas GCLM and GSTpi expressions were decreased (p < 0.05) with an increase in HO-1 in choroid-RPE of AMD.
Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis.
After correcting for multiple testing (n = 37,428), we identified four variants significantly associated with AMD: rs200437673 (LCN9, p = 1.50 × 10<sup>-11</sup>), rs151214675 (RTEL1, p = 3.18 × 10<sup>-8</sup>), rs140250387 (DLGAP1, p = 4.49 × 10<sup>-7</sup>), and rs115333865 (CGRRF1, p = 1.05 × 10<sup>-6</sup>).
In the validation studies, miR-129-3p and miR-132-3p had no significant expression in AMD group compared to the controls. miR-486-5p and miR-626 had higher expression in AMD patients compared to the control group, while miR-885-5p showed significantly lower expression.
We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways.
After correcting for multiple testing (n = 37,428), we identified four variants significantly associated with AMD: rs200437673 (LCN9, p = 1.50 × 10<sup>-11</sup>), rs151214675 (RTEL1, p = 3.18 × 10<sup>-8</sup>), rs140250387 (DLGAP1, p = 4.49 × 10<sup>-7</sup>), and rs115333865 (CGRRF1, p = 1.05 × 10<sup>-6</sup>).
The novel differentially methylated genes SKI and GTF2H4 have not been previously associated with AMD, and regulate disease pathways implicated in AMD, including TGF beta signaling (SKI) and transcription-dependent DNA repair mechanisms (GTF2H4).