Neuroinflammation in Primary Open-Angle Glaucoma

Vernazza, Stefania; Tirendi, Sara; Bassi, Anna Maria; Traverso, Carlo Enrico; Saccà, Sergio Claudio

doi:10.3390/jcm9103172

Cited by 62 publications

(42 citation statements)

References 354 publications

(424 reference statements)

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“…Oxidative stress and inflammation are closely related pathophysiological processes, one of which can be easily induced by another. Thus, both processes are simultaneously found in many chronical pathological conditions, such as glaucoma [ 104 ]. The immune activity is a necessary intrinsic response to promote tissue cleaning, healing, and regeneration process after injury [ 105 ].…”

Section: Discussionmentioning

confidence: 99%

Retinal Genomic Fabric Remodeling after Optic Nerve Injury

Victorino

Marra

Iacobaş

et al. 2021

Genes

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Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the genomic fabric paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers three independent characteristics for the expression of each gene: level, variability, and correlation with each other gene. Thus, the 17,657 quantified genes in our study generated a total of 155,911,310 values to analyze. This represents 8830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with 1,1′-dioctadecyl-3,3,3,3′-tetramethylindocarbocyanine perchlorate (DiI). We observed a higher relative expression variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted protein–protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among upregulated genes. Enrichment analysis showed that complement cascade and Notch signaling pathway, as well as oxidative stress and kit receptor pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pairwise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in complement cascade and Notch signaling pathway. This deep bioinformatic study provided novel insights beyond the regulation of individual gene expression and disclosed changes in the control of expression of complement cascade and Notch signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC.

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Section: Discussionmentioning

confidence: 99%

Retinal Genomic Fabric Remodeling after Optic Nerve Injury

Victorino

Marra

Iacobaş

et al. 2021

Genes

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“…Oxidative stress and inflammation are closely related pathophysiological processes, one of which can be easily induced by another. Thus, both processes are simultaneously found in many chronical pathological conditions, such as glaucoma [112]. The immune activity is a necessary intrinsic response to promote tissue cleaning, healing, and regeneration process after injury [113].…”

Section: Discussionmentioning

confidence: 99%

Retinal Genomic Fabrics Remodeling after Optic Nerve Injury

Victorino¹,

Marra²,

Iacobaş³

et al. 2021

Preprint

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Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the Genomic Fabric Paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers for the expression of each gene 3 independent characteristics: level, variability and correlation with each other gene. Thus, the 17,657 quantified genes our study generated a total of 155,911,310 values to analyze. This represents 8,830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with DiI. We observed a higher Relative Expression Variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted Protein-Protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among up-regulated genes. Enrichment analysis showed that Complement Cascade and Notch Signaling Pathway, as well as Oxidative Stress and Kit Receptor Pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pair-wise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in Complement Cascade and Notch Signaling Pathway. This deep bioinformatic study provides novel insights beyond the regulation of individual gene expression and discloses changes in the control of expression of Complement Cascade and Notch Signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC.

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“…The accumulation of ROS and the immune-stimulatory signaling enhanced by oxidative stress seem to result from the combination of TM tissue malfunction in the conventional outflow pathway and the neuroinflammation process [ 38 ]. Elevation of oxidative stress-related markers, low antioxidant resistance, dysfunction/activation of glial cells, activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, and the up-regulation of pro-inflammatory cytokines are all related to the development of POAG [ 25 ]. Promoting the matrix metalloproteinases’ (MMPs) expressions responsible for ECM degradation by activated NF-κB in the initial stage of glaucoma [ 39 ] is meaningful in lowering IOP.…”

Section: Oxidative Stress Effects On Poag Related Tissues and Mechmentioning

confidence: 99%

“…Mitochondrial matrix enzymes, the α-keto acid dehydrogenase complexes [ 42 ], the mitochondrial electron transport chain, and the loss of mitochondrial ability in buffering Ca 2+ [ 43 ] are all factors that stimulate ROS production in the mitochondria, resulting in cell death via apoptosis or necrosis [ 44 ]. In POAG, the accumulation of excessive ROS can induce TM damage, which results in conventional outflow pathway defects [ 25 ] and exacerbates the injury to the optic nerve head and RGC [ 38 ]. As high metabolism occurs in RGC, proper mitochondrial function is essential for these neurons that die in glaucoma [ 45 , 46 ].…”

Section: Oxidative Stress and Mitochondrial Dysfunction In Poag Pamentioning

confidence: 99%

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Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma

Tabak

Schreiber‐Avissar

Beit‐Yannai

2021

IJMS

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Reactive oxygen species (ROS) plays a key role in the pathogenesis of primary open-angle glaucoma (POAG), a chronic neurodegenerative disease that damages the trabecular meshwork (TM) cells, inducing apoptosis of the retinal ganglion cells (RGC), deteriorating the optic nerve head, and leading to blindness. Aqueous humor (AH) outflow resistance and intraocular pressure (IOP) elevation contribute to disease progression. Nevertheless, despite the existence of pharmacological and surgical treatments, there is room for the development of additional treatment approaches. The following review is aimed at investigating the role of different microRNAs (miRNAs) in the expression of genes and proteins involved in the regulation of inflammatory and degenerative processes, focusing on the delicate balance of synthesis and deposition of extracellular matrix (ECM) regulated by chronic oxidative stress in POAG related tissues. The neutralizing activity of a couple of miRNAs was described, suggesting effective downregulation of pro-inflammatory and pro-fibrotic signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), transforming growth factor-beta 2 (TGF-β2), Wnt/β-Catenin, and PI3K/AKT. In addition, with regards to the elevated IOP in many POAG patients due to increased outflow resistance, Collagen type I degradation was stimulated by some miRNAs and prevented ECM deposition in TM cells. Mitochondrial dysfunction as a consequence of oxidative stress was suppressed following exposure to different miRNAs. In contrast, increased oxidative damage by inhibiting the mTOR signaling pathway was described as part of the action of selected miRNAs. Summarizing, specific miRNAs may be promising therapeutic targets for lowering or preventing oxidative stress injury in POAG patients.

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Neuroinflammation in Primary Open-Angle Glaucoma

Cited by 62 publications

References 354 publications

Retinal Genomic Fabric Remodeling after Optic Nerve Injury

Retinal Genomic Fabric Remodeling after Optic Nerve Injury

Retinal Genomic Fabrics Remodeling after Optic Nerve Injury

Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma

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