Complement C3 deficiency alleviates alkylation-induced retinal degeneration in mice

Du, Lu; Peng, Guang-Hua

doi:10.1186/s40662-022-00292-4

Cited by 3 publications

(3 citation statements)

References 31 publications

(39 reference statements)

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“…Among the common DEGs, several genes might play a role in the response to DNA damage. Du et al [41] found that the activation of complement C3 contributed to retinal DNA damage and C3 deficiency alleviated alkylation-induced retinal degeneration in mice. Raso et al [42] reported that Isg15 upregulation promoted DNA replication fork progression, leading to extensive DNA damage and chromosomal aberrations in a human osteosarcoma cell line.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Zeng¹,

Zhao²,

Zhao³

et al. 2023

J. Integr. Neurosci.

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Background: Traumatic brain injury (TBI) is a common brain injury with a high morbidity and mortality. The complex injury cascade triggered by TBI can result in permanent neurological dysfunction such as cognitive impairment. In order to provide new insights for elucidating the underlying molecular mechanisms of TBI, this study systematically analyzed the transcriptome data of the rat hippocampus in the subacute phase of TBI. Methods: Two datasets (GSE111452 and GSE173975) were downloaded from the Gene Expression Omnibus (GEO) database. Systematic bioinformatics analyses were performed, including differentially expressed genes (DEGs) analysis, gene set enrichment analysis (GSEA), Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network construction, and hub gene identification. In addition, hematoxylin and eosin (HE), Nissl, and immunohistochemical staining were performed to assess the injured hippocampus in a TBI rat model. The hub genes identified by bioinformatics analyses were verified at the mRNA expression level. Results: A total of 56 DEGs were shared in the two datasets. GSEA results suggested significant enrichment in the MAPK and PI3K/Akt pathways, focal adhesion, and cellular senescence. GO and KEGG analyses showed that the common DEGs were predominantly related to immune and inflammatory processes, including antigen processing and presentation, leukocyte-mediated immunity, adaptive immune response, lymphocyte-mediated immunity, phagosome, lysosome, and complement and coagulation cascades. A PPI network of the common DEGs was constructed, and 15 hub genes were identified. In the shared DEGs, we identified two transcription co-factors and 15 immune-related genes. The results of GO analysis indicated that these immune-related DEGs were mainly enriched in biological processes associated with the activation of multiple cells such as microglia, astrocytes, and macrophages. HE and Nissl staining results demonstrated overt hippocampal neuronal damage. Immunohistochemical staining revealed a marked increase in the number of Iba1-positive cells in the injured hippocampus. The mRNA expression levels of the hub genes were consistent with the transcriptome data. Conclusions: This study highlighted the potential pathological processes in TBI-related hippocampal impairment. The crucial genes identified in this study may serve as novel biomarkers and therapeutic targets, accelerating the pace of developing effective treatments for TBI-related hippocampal impairment.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Zeng¹,

Zhao²,

Zhao³

et al. 2023

J. Integr. Neurosci.

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“…While their work corroborated that uncontrolled activation of C3, investigated through mice deficient in complement factor H (CFH), was associated with negative effects on retinal aging, including amyloid β deposition and inflammation, complete absence of C3 also had deleterious effects on retinal aging. Later studies involving complete C3 ablation have described a positive impacts of deletion, including decreased retinal degeneration [ 112 , 113 ]. Furthermore, exogenous delivery of C3 to murine RPE produces functional and anatomic changes resembling AMD [ 114 ].…”

Section: Targeting Complement Pathways In Retinal Diseasementioning

confidence: 99%

The Complement System as a Therapeutic Target in Retinal Disease

Ong,

Zarnegar,

Selvam

et al. 2024

Medicina

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The complement cascade is a vital system in the human body’s defense against pathogens. During the natural aging process, it has been observed that this system is imperative for ensuring the integrity and homeostasis of the retina. While this system is critical for proper host defense and retinal integrity, it has also been found that dysregulation of this system may lead to certain retinal pathologies, including geographic atrophy and diabetic retinopathy. Targeting components of the complement system for retinal diseases has been an area of interest, and in vivo, ex vivo, and clinical trials have been conducted in this area. Following clinical trials, medications targeting the complement system for retinal disease have also become available. In this manuscript, we discuss the pathophysiology of complement dysfunction in the retina and specific pathologies. We then describe the results of cellular, animal, and clinical studies targeting the complement system for retinal diseases. We then provide an overview of complement inhibitors that have been approved by the Food and Drug Administration (FDA) for geographic atrophy. The complement system in retinal diseases continues to serve as an emerging therapeutic target, and further research in this field will provide additional insights into the mechanisms and considerations for treatment of retinal pathologies.

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“…Modulation of complement cascade activity in general, and specifically downregulation of C3, has been linked to increased photoreceptor survival and improved visual function in a C3 knockout mouse model. 27 Immunohistochemistry of both primate and human retinas has shown C3 deposition in the choriocapillaris and, perhaps more surprisingly given the blood-retina barrier, also in the outer photoreceptor segments. [28][29][30][31] The protective effect of C3 inhibition could therefore be indirect at the choriocapillaris level, or direct at the level of the photoreceptors.…”

Section: Proposed Mechanism Of Pegcetacoplan and Ga Pathophysiologymentioning

confidence: 99%

Deep-learning automated quantification of longitudinal OCT scans demonstrates reduced RPE loss rate, preservation of intact macular area and predictive value of isolated photoreceptor degeneration in geographic atrophy patients receiving C3 inhibition treatment

Glinton

Lipkova

et al. 2023

Br J Ophthalmol

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ObjectiveTo evaluate the role of automated optical coherence tomography (OCT) segmentation, using a validated deep-learning model, for assessing the effect of C3 inhibition on the area of geographic atrophy (GA); the constituent features of GA on OCT (photoreceptor degeneration (PRD), retinal pigment epithelium (RPE) loss and hypertransmission); and the area of unaffected healthy macula.To identify OCT predictive biomarkers for GA growth.MethodsPost hoc analysis of the FILLY trial using a deep-learning model for spectral domain OCT (SD-OCT) autosegmentation. 246 patients were randomised 1:1:1 into pegcetacoplan monthly (PM), pegcetacoplan every other month (PEOM) and sham treatment (pooled) for 12 months of treatment and 6 months of therapy-free monitoring. Only participants with Heidelberg SD-OCT were included (n=197, single eye per participant).The primary efficacy endpoint was the square root transformed change in area of GA as complete RPE and outer retinal atrophy (cRORA) in each treatment arm at 12 months, with secondary endpoints including RPE loss, hypertransmission, PRD and intact macular area.ResultsEyes treated PM showed significantly slower mean change of cRORA progression at 12 and 18 months (0.151 and 0.277 mm, p=0.0039; 0.251 and 0.396 mm, p=0.039, respectively) and RPE loss (0.147 and 0.287 mm, p=0.0008; 0.242 and 0.410 mm, p=0.00809). PEOM showed significantly slower mean change of RPE loss compared with sham at 12 months (p=0.0313). Intact macular areas were preserved in PM compared with sham at 12 and 18 months (p=0.0095 and p=0.044). PRD in isolation and intact macula areas was predictive of reduced cRORA growth at 12 months (coefficient 0.0195, p=0.01 and 0.00752, p=0.02, respectively)ConclusionThe OCT evidence suggests that pegcetacoplan slows progression of cRORA overall and RPE loss specifically while protecting the remaining photoreceptors and slowing the progression of healthy retina to iRORA.

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Complement C3 deficiency alleviates alkylation-induced retinal degeneration in mice

Cited by 3 publications

References 31 publications

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

The Complement System as a Therapeutic Target in Retinal Disease

Deep-learning automated quantification of longitudinal OCT scans demonstrates reduced RPE loss rate, preservation of intact macular area and predictive value of isolated photoreceptor degeneration in geographic atrophy patients receiving C3 inhibition treatment

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