Exploring the Role of SRC in Extraocular Muscle Fibrosis of the Graves’ Ophthalmopathy

Hao, Mingyu; Sun, Jingxue; Zhang, Yaguang; Zhang, Dexin; Han, Jun; Zhang, Jirong; Qiao, Hong

doi:10.3389/fbioe.2020.00392

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…At first, we cultured primary OFs from GO mice and identified them and then screened the optimal DEX, exosome intervention concentration, and time of OFs. The GO mice used in this project were derived from our recently reported study ( 17 ). It could be seen that the eyes of the mice in the model group are obviously prominent, bulbar conjunctival edema, tears, and increased periocular secretions ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

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Plasma Exosomes Transfer miR-885-3p Targeting the AKT/NFκB Signaling Pathway to Improve the Sensitivity of Intravenous Glucocorticoid Therapy Against Graves Ophthalmopathy

et al. 2022

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Graves ophthalmopathy (GO), a manifestation of Graves’ disease, is an organ-specific autoimmune disease. Intravenous glucocorticoid therapy (ivGCs) is the first-line treatment for moderate-to-severe and active GO. However, ivGCs is only effective in 70%–80% of GO patients. Insensitive patients who choose 12-week ivGCs not only were delayed in treatment but also took the risk of adverse reactions of glucocorticoids. At present, there is still a lack of effective indicators to predict the therapeutic effect of ivGCs. Therefore, the purpose of this study is to find biomarkers that can determine the sensitivity of ivGCs before the formulation of treatment, and to clarify the mechanism of its regulation of ivGCs sensitivity. This study first characterized the miRNA profiles of plasma exosomes by miRNA sequencing to identify miRNAs differentially expressed between GO patients with significant improvement (SI) and non-significant improvement (NSI) after ivGCs treatment. Subsequently, we analyzed the function of the predicted target genes of differential miRNAs. According to the function of the target genes, we screened 10 differentially expressed miRNAs. An expanded cohort verification showed that compared with NSI patients, mir-885-3p was upregulated and mir-4474-3p and mir-615-3p were downregulated in the exosomes of SI patients. Based on statistical difference and miRNA function, mir-885-3p was selected for follow-up study. The in vitro functional analysis of exosomes mir-885-3p showed that exosomes from SI patients (SI-exo) could transfer mir-885-3p to orbital fibroblasts (OFs), upregulate the GRE luciferase reporter gene plasmid activity and the level of glucocorticoid receptor (GR), downregulate the level of inflammatory factors, and improve the glucocorticoid sensitivity of OFs. Moreover, these effects can be inhibited by the corresponding miR inhibitor. In addition, we found that high levels of mir-885-3p could inhibit the AKT/NFκB signaling pathway, upregulate the GRE plasmid activity and GR level, and downregulate the level of inflammatory factors of OFs. Moreover, the improvement of glucocorticoid sensitivity by mir-885-3p transmitted by SI-exo can also be inhibited by the AKT/NFκB agonist. Finally, through the in vivo experiment of the GO mouse model, we further determined the relationship between exosomes’ mir-885-3p sequence, AKT/NFκB signaling pathway, and glucocorticoid sensitivity. As a conclusion, plasma exosomes deliver mir-885-3p and inhibit the AKT/NFκB signaling pathway to improve the glucocorticoid sensitivity of OFs. Exosome mir-885-3p can be used as a biomarker to determine the sensitivity of ivGCs in GO patients.

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Section: Resultsmentioning

confidence: 99%

“…The GO animal model was established by Balb/c female mice aged 8–10 weeks. The establishment method of the model group was the same as our previous study ( 17 ), and the control group was given the same amount of PDF. After modeling, 3 mice in the model group and control group were randomly sacrificed.…”

Section: Methodsmentioning

confidence: 99%

Plasma Exosomes Transfer miR-885-3p Targeting the AKT/NFκB Signaling Pathway to Improve the Sensitivity of Intravenous Glucocorticoid Therapy Against Graves Ophthalmopathy

et al. 2022

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“…SRC belongs to the non-receptor protein-tyrosine kinases family, playing key roles in cell growth, division, migration, and survival signaling pathways [ 41 ]. Multiple studies indicated that SRC regulated the PI3K-AKT pathway in inflammation-related diseases such as multiple sclerosis (MS), Grave’s Disease (GD), and in the neutrophil extracellular traps (NET) formation [ 42 , 43 , 44 ]. In our experiments, we found that the phosphorylation level of SRC was significantly upregulated in hepatic tissue in two AIH models and was drastically decreased in the costunolide group.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effect of Costunolide in Autoimmune Hepatitis: Network Pharmacology and Experimental Validation

et al. 2023

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Novel treatments for autoimmune hepatitis (AIH) are highly demanded due to the limitations of existing therapeutic agents. Costunolide is a promising candidate due to its anti-inflammatory and hepatoprotective function, but its effect in AIH remains obscure. In this study, we integrated network pharmacology and experimental validation to reveal the effect and mechanism of costunolide in AIH. A total of 73 common targets of costunolide and AIH were obtained from databases. Pathway enrichment analysis indicated that PI3K-AKT pathway was the core pathway of costunolide in AIH. Protein–protein interaction network analysis and molecular docking revealed that SRC and IGF1R might play critical roles. In two murine AIH models, costunolide significantly attenuated liver injury, inflammation, and fibrosis reflected by the liver gross appearance, serum transaminases, necrosis area, spleen index, immune cell infiltration, and collagen deposition. Western blot and immunohistochemistry confirmed that phosphorylated AKT, SRC, and IGF1R were upregulated in AIH models, and costunolide administration could inhibit the phosphorylation of these proteins. In summary, costunolide significantly ameliorates murine AIH. The therapeutic effect might work by suppressing the activation of PI3K-AKT pathway and inhibiting the phosphorylation of SRC and IGF1R. Our research reveals the potent therapeutic effect of costunolide in AIH and the potential role of SRC and IGF1R in AIH for the first time, which may further contribute to the novel drug development for AIH and other autoimmune diseases.

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“…While peroxisome proliferator-activated receptor-c (PPAR-c) signal transduction has been identified as the primary inducer of adipogenesis [31,32], studies have revealed interactions between TGF-β signaling and PPAR-c signaling [33]. Studies have shown that the Smad signal plays an important role in periorbital fibrosis in TAO [34][35][36], and Smad7 is predicted to be one of the target genes of miR-96-5p (StarBase, URL: http://starbase.sysu.edu.cn/agoClipRNA. php?source�mRNA).…”

Section: Introductionmentioning

confidence: 99%

miR-96-5p Induces Orbital Fibroblasts Differentiation by Targeting Smad7 and Promotes the Development of Thyroid-Associated Ophthalmopathy

Kang

Zou

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Recent evidence shows that adipogenic differentiation of orbital fibroblasts (OFs) promotes the development of thyroid-associated ophthalmopathy (TAO), an organ-specific immune disease. Furthermore, miR-96-5p has been linked to adipogenic differentiation of C2C12 myoblasts and is significantly correlated with the severity of TAO. The purpose of this study is to look into the role of miR-96-5p in the adipogenesis of OFs with TAO. Methods. The orbital tissues from TAO patients and non-TAO participants were collected, and primary OFs were isolated and cultured for further analysis. miR-96-5p expression was examined using qRT-PCR. The adipogenic differentiation of OFs was then studied. Results. Orbital fibroblasts isolated from adipose tissues of TAO patients (t-OFs) demonstrated greater adipogenic differentiation ability than OFs isolated from adipose tissues of non-TAO participants. miR-96-5p was found to be overexpressed in the orbital tissues of TAO patients and t-OFs. Further research revealed that miR-96-5p, by targeting Smad7, could exacerbate PPAR-γ/C/EBPα signaling-induced adipogenic differentiation of t-OFs. However, inhibiting miR-96-5p could block t-OFs adipogenic differentiation-mediated adipogenesis via Smad7/PPAR-γ/C/EBPα. Conclusions. miR-96-5p plays a critical regulatory role in the development of TAO by targeting Smad7 and promoting adipogenic differentiation of OFs.

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Exploring the Role of SRC in Extraocular Muscle Fibrosis of the Graves’ Ophthalmopathy

Cited by 5 publications

References 39 publications

Plasma Exosomes Transfer miR-885-3p Targeting the AKT/NFκB Signaling Pathway to Improve the Sensitivity of Intravenous Glucocorticoid Therapy Against Graves Ophthalmopathy

Plasma Exosomes Transfer miR-885-3p Targeting the AKT/NFκB Signaling Pathway to Improve the Sensitivity of Intravenous Glucocorticoid Therapy Against Graves Ophthalmopathy

Therapeutic Effect of Costunolide in Autoimmune Hepatitis: Network Pharmacology and Experimental Validation

miR-96-5p Induces Orbital Fibroblasts Differentiation by Targeting Smad7 and Promotes the Development of Thyroid-Associated Ophthalmopathy

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