Comprehensive analysis of key genes and pathways for biological and clinical implications in thyroid-associated ophthalmopathy

Abstract

Background Thyroid-associated ophthalmopathy (TAO) is a common and organ-specific autoimmune disease. Early diagnosis and novel treatments are essential to improve the prognosis of TAO patients. Therefore, the current work was performed to identify the key genes and pathways for the biological and clinical implications of TAO through comprehensive bioinformatics analysis and a series of clinical validations. Methods GSE105149 and GSE185952 were obtained from the Gene Expression Omnibus (GEO) database for analysis. The data were normalized to identify the common differentially expressed genes (DEGs) between the two datasets, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to assess key pathways in TAO. Protein–protein interaction (PPI) networks and hub genes among the common DEGs were identified. Furthermore, we collected the general information and blood samples from 50 TAO patients and 20 healthy controls (HCs), and the expression levels of the proteins encoded by hub genes in serum were detected by enzyme-linked immunosorbent assay (ELISA). Then we further assessed the relationship between the ELISA data and the TAO development. Results Several common pathways, including neuroactive ligand-receptor interaction, the IL-17 signaling pathway, and the TNF signaling pathway, were identified in both datasets. In parallel, 52 common DEGs were identified. The KEGG analysis showed that these common DEGs are mainly enriched in long-term depression, the VEGF signaling pathway, the IL-17 signaling pathway, the TNF signaling pathway, and cytokine-cytokine receptor interactions. The key hub genes PRKCG, OSM, DPP4, LRRTM1, CXCL6, and CSF3R were screened out through the PPI network. As confirmation, the ELISA results indicated that protein expression levels of PRKCG, OSM, CSF3R, and DPP4 were significantly upregulated in TAO patients compared with HCs. In addition, PRKCG and DPP4 were verified to show value in diagnosing TAO, and CSF3R was found to be a valuable diagnostic marker in distinguishing active TAO from inactive TAO. Conclusions Inflammation- and neuromodulation-related pathways might be closely associated with TAO. Based on the clinical verification, OSM, CSF3R, CXCL6, DPP4, and PRKCG may serve as inflammation- or neuromodulation-related biomarkers for TAO, providing novel insights for the diagnosis and treatment of TAO.

Silver Nanoparticles Cause Neural and Vascular Disruption by Affecting Key Neuroactive Ligand-Receptor Interaction and VEGF Signaling Pathways

“… 56 , 57 We also found that the mRNA levels of kdr, prkcg, rac1b , and zgc:171775 were affected in zebrafish embryos after AgNP treatment. Previous studies demonstrated that the protein expression level of PRKCGA was up-regulated in patients with thyroid-associated ophthalmopathy, 58 and abnormal PKC regulation was associated with major depression. 59 Tan et al also found that Rac1 was essential for embryonic development because its endothelia-specific deletion led to an early embryonic lethal vascular phenotype.…”

A comprehensive epigenetic network can influence the occurrence of thyroid-associated ophthalmopathy by affecting immune and inflammatory response

“…This results in the migration of these cells to the affected area, causing tissue damage and exacerbating the inflammatory response. IL-17A and IL-17F are key members of this pathway, binding to IL-17 receptor A and C and activating transcription factors such as NF-kB, C/EBP, AP-1, STAT3, as well as downstream signaling pathways like PI3K/AKT, ERK1/2, and p38 MAPK 36 . These signaling pathways have the potential to impact various processes, including cell growth, survival, proliferation, and inflammatory response.…”

“…Inhibiting the secretion/expression of IL-17 has been proposed as a potential therapeutic strategy for autoimmune ocular inflammatory diseases, as demonstrated by the successful use of IL-23 and IL-17 antagonists. 36 . A study on a bovine ocular model found that IL-17 could mediate the inflammatory response induced by TSHR autoantibodies, leading to the occurrence of TAO 37 .…”

Identification of a diagnostic model and molecular subtypes of major depressive disorder based on endoplasmic reticulum stress-related genes

“…In addition, hub genes associated with SubB subtypes were screened by using WGCNA, such as NCF4, NCF2, CSF3R and FPR2. It has been showed that CSF3R is a cytokine that controls neutrophil expansion and differentiation, and can serve as a biomarker for neuromodulation; FPR2 knockdown may maintain hippocampal homeostasis by preventing depression-related neuronal damage ( 56 , 57 ). The proteins encoded by NCF4 are cytoplasmic regulatory components of superoxide-producing phagocytic NADPH oxidase, which is a multicomponent enzyme system important for host defence ( 58 ).…”