scholarly journals Tear-Derived Exosome Proteins Are Increased in Patients with Thyroid Eye Disease

2021 ◽  
Vol 22 (3) ◽  
pp. 1115
Author(s):  
Jeong-Sun Han ◽  
Sung Eun Kim ◽  
Jun-Qing Jin ◽  
Na Ri Park ◽  
Ji-Young Lee ◽  
...  
Keyword(s):  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Intercellular Signaling ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reactive Protein ◽  
Control Subjects ◽  
Specific Proteins ◽  
Vascular Adhesion ◽  
And Control ◽  
Orbital Fibroblasts

Exosomes contain proteins, lipids, RNA, and DNA that mediate intercellular signaling. Exosomes can contribute to the pathological processes of various diseases, although their roles in ocular diseases are unclear. We aimed to isolate exosomes from tear fluids (TF) of patients with Thyroid eye disease (TED) and analyze the exosomal proteins. TFs were collected from eight patients with TED and eight control subjects. The number of TF exosomes were measured using nanoparticle-tracking analysis. The expression of specific proteins in the purified exosome pellets were analyzed using a Proteome Profiler Array Kit. Cultured normal orbital fibroblasts were incubated with TF exosomes from patients with TED and control subjects, and changes in inflammatory cytokine levels were compared. TF exosomes from TED patients showed more exosomes than the control subjects. The expression levels of exosomal proteins vitamin D-binding (VDB) protein, C-reactive protein (CRP), chitinase 3-like 1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), and vascular adhesion molecule-1 (VCAM-1) were significantly increased in patients with TED, compared to those of controls. Orbital fibroblasts exposed to TF exosomes from patients with TED showed significantly higher levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) production than those treated with control TF exosomes. Specific proteins showed higher expression in exosomes from TED patients, implying that they may play keys roles in TED pathogenesis.

Inhibition of TSH/IGF-1 receptor crosstalk by Teprotumumab as a treatment modality of Thyroid Eye Disease

2021 ◽  
Author(s):  
Christine C Krieger ◽  
Xiangliang Sui ◽  
George J Kahaly ◽  
Susanne Neumann ◽  
Marvin C Gershengorn
Keyword(s):  
Dose Response ◽  
Treatment Modality ◽  
Thyroid Eye Disease ◽  
Tsh Receptor ◽  
Eye Disease ◽  
Receptor Crosstalk ◽  
Orbital Fibroblast ◽  
Orbital Fibroblasts ◽  
Biphasic Dose Response

Abstract Context We previously presented evidence that TSH receptor (TSHR)-stimulating autoantibodies (TSAbs) bind to and activate TSHRs but do not bind to IGF1 receptors (IGF1Rs). Nevertheless, we showed that IGF1Rs were involved in thyroid eye disease (TED) pathogenesis because TSAbs activated crosstalk between TSHR and IGF1R. Teprotumumab, originally generated to inhibit IGF1 binding to IGF1R, was recently approved for the treatment of TED (Tepezza®). Objective To investigate the role of TSHR/IGF1R crosstalk in teprotumumab treatment of TED. Design We used orbital fibroblasts from patients with TED (TEDOFs) and measured stimulated hyaluronan (HA) secretion as a measure of orbital fibroblast activation by TED immunoglobulins (TED-Igs) and monoclonal TSAb M22. We previously showed that M22, which does not bind to IGF1R, stimulated HA in a biphasic dose-response with the higher-potency phase dependent on TSHR/IGF1R crosstalk and the lower-potency phase independent of IGF1R. Stimulation by TED-Igs and M22 was measured in the absence or presence of Teprotumumab Biosimilar (Tepro) or K1-70, an antibody that inhibits TSHR. Results We show: 1) Tepro dose-dependently inhibits stimulation by TED-Igs; 2) Tepro does not bind to TSHRs; 3) Tepro inhibits IGF1R-dependent M22-induced HA production, which is mediated by TSHR/IGF1R crosstalk, but not IGF1R-independent M22 stimulation; and 4) β-arrestin 1 knockdown, which blocks TSHR/IGF1R crosstalk, prevents Tepro inhibition of HA production by M22 and by a pool of TED-Igs. Conclusion We conclude that Tepro inhibits HA production by TEDOFs by inhibiting TSHR/IGF1R crosstalk and suggest that inhibition of TSHR/IGF1R crosstalk is the mechanism of its action in treating TED.

LncRNA LPAL2/miR-1287-5p/EGFR axis modulates TED derived orbital fibroblast activation through cell adhesion factors

2021 ◽  
Author(s):  
Nuo Wang ◽  
Shi-ying Hou ◽  
Xin Qi ◽  
Mi Deng ◽  
Jia-min Cao ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Akt Signaling ◽  
Thyroid Eye Disease ◽  
Differentially Expressed ◽  
Eye Disease ◽  
Fibroblast Activation ◽  
Orbital Fibroblast ◽  
Orbital Fibroblasts ◽  
Adhesion Factor ◽  
Tgf Β1

Abstract Background and aims The activation of orbital fibroblasts, the prime targets in thyroid eye disease, is central to its underlying pathogenesis. We aimed to investigate the mechanism of thyroid eye disease orbital fibroblast activation from the perspective of non-coding RNA regulation. Methods Immunofluorescence (IF) staining was applied to evaluate the fibrotic changes in target cells. Cell proliferation were evaluated by EDU and colony formation assays. Collagen I concentration was determined by ELISA assay. Human microarray analysis was performed on three thyroid eye disease and 3 healthy control orbital tissue samples. Results Bioinformatics analysis showed that cell adhesion signaling factors were differentially expressed in thyroid eye disease tissues, including I-CAM-1, I-CAM-4, V-CAM, and CD44, which were all upregulated in diseased orbital tissues. LncRNA LPAL2 level was also upregulated in orbital tissues and positively correlated with I-CAM-1 and I-CAM-4 expression. Stimulation of the thyroid eye disease orbital fibroblasts by TGF-β1 significantly increased the expression of I-CAM-1, I-CAM-4, and LPAL2. Knockdown of LPAL2 in orbital fibroblasts inhibited TGF-β1-induced increases in cell adhesion factor levels and orbital fibroblast activation. Microarray profiling was performed on thyroid eye disease and normal orbital tissues to identify differentially expressed miRNAs and miR-1287-5p was remarkably reduced within diseased orbital samples. miR-1287-5p was directly bound to EGFR 3’UTR and LPAL2 and LPAL2 modulated EGFR/AKT signaling through targeting miR-1287-5p. Conclusions The LPAL2/miR-1287-5p axis modulated TGF-β1-induced increases in cell adhesion factor levels and thyroid eye disease orbital fibroblast activation through EGFR/AKT signaling.

scholarly journals High Proteoglycan Decorin Levels Are Associated With Acute Coronary Syndrome and Provoke an Imbalanced Inflammatory Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Lingfang Zhuang ◽  
Yulong Ge ◽  
Xiao Zong ◽  
Qian Yang ◽  
Ruiyan Zhang ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Inflammatory Response ◽  
White Blood Cells ◽  
High Sensitivity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Reactive Protein ◽  
Coronary Syndrome ◽  
Control Subjects ◽  
Novel Biomarkers ◽  
And Control

Background and Aims: Acute coronary syndrome (ACS) has become one of the most common causes of disability. It is thus important to identify ACS early in the disease course of patients using novel biomarkers for prompt management. Decorin (DCN) was well-acknowledged for its effect on collagen fibrillogenesis and maintaining tissue integrity. Additionally, DCN could release as secreted proteoglycan under pathological conditions. Hence, we aimed to determine the relationship between serum DCN concentration and ACS.Methods: A total of 388 patients who underwent coronary angiography (CAG) in the cardiovascular center of Ruijin Hospital between June 2016 and December 2017 were enrolled in this study. Blood samples were drawn during CAG surgery to determine the serum DCN level of patients with ACS (n = 210) and control subjects (n = 178) using enzyme-linked immunosorbent assay.Results: We found that the serum DCN levels of ACS patients were elevated compared with those of the control subjects (13.59 ± 0.50 vs. 13.17 ± 0.38, respectively, p < 0.001). Furthermore, the serum DCN level, after being adjusted with other cardiovascular factors, was independently associated with ACS. Moreover, an increased serum DCN level was positively correlated with the number of white blood cells and the level of high-sensitivity C-reactive protein (R = 0.3 and 0.11, respectively). Mechanistically, DCN might have elicited an imbalanced inflammatory response during cardiac ischemia by suppressing the expression of anti-inflammatory genes.Conclusion: Serum DCN is a novel biomarker of ACS and contributes to the increased inflammatory response in ischemic heart disease.

scholarly journals High-sensitivity C-reactive protein is associated with 24-hour ambulatory blood pressure variability in type 2 diabetes and control subjects

2016 ◽  
Vol 24 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Dana Mihaela Ciobanu ◽  
Cornelia Gabriela Bala ◽  
Ioan Andrei Veresiu ◽  
Petru Adrian Mircea ◽  
Gabriela Roman
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
High Sensitivity ◽  
C Reactive Protein ◽  
Cross Sectional ◽  
Reactive Protein ◽  
Control Subjects ◽  
Ambulatory Bp Monitoring ◽  
And Control

Abstract Background and Aim: Type 2 diabetes (T2DM) has been associated with hypertension (HTN) and elevated high-sensitivity C-reactive protein (hsCRP), but the possible implication of blood pressure (BP) variability in increasing hsCRP in T2DM are incompletely understood. We aimed to assess the association between hsCRP and BP variability during 24-hour ambulatory BP monitoring in T2DM and healthy control subjects. Material and Method: The cross-sectional study included data from T2DM patients with normal BP (n=9), controlled HTN (n=46), uncontrolled HTN (n=20), and healthy controls (n=11). HsCRP was assessed using ELISA technique. All subjects underwent 24-hour ambulatory BP monitoring; BP variability was calculated using standard deviation. Results: We found that hsCRP was associated with daytime and 24-hours systolic and diastolic BP variability. Higher hsCRP were observed in T2DM patients with uncontrolled HTN and high BP variability compared to the other three groups. In multiple regression analysis, hsCRP was predicted by daytime and 24-hour diastolic BP variability. Conclusions: Our findings suggest that high hsCRP was associated with increased ambulatory BP variability in T2DM and control subjects. The contribution of both hsCRP and BP variability to cardiovascular risk stratification in T2DM needs to be evaluated in prospective studies.

scholarly journals Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease

2020 ◽  
Vol 9 (Suppl. 1) ◽  
pp. 59-65
Author(s):  
Susanne Neumann ◽  
Christine C. Krieger ◽  
Marvin C. Gershengorn
Keyword(s):  
Thyroid Stimulating Hormone ◽  
Thyroid Eye Disease ◽  
Therapeutic Interventions ◽  
Eye Disease ◽  
Thyroid Cells ◽  
Hormone Synthesis ◽  
Dependent Component ◽  
Graves Orbitopathy ◽  
Blocking Antibodies ◽  
Orbital Fibroblasts

Graves’ disease (GD) is an autoimmune disease caused in part by thyroid-stimulating antibodies (TSAbs) that activate the thyroid-stimulating hormone receptor (TSHR). In Graves’ hyperthyroidism (GH), TSAbs cause persistent stimulation of thyroid cells leading to continuous thyroid hormone synthesis and secretion. Thyroid eye disease (TED), also called Graves’ orbitopathy, is an orbital manifestation of GD. We review the important roles of the TSHR and the insulin-like growth factor 1 receptor (IGF-1R) in the pathogenesis of TED and discuss a model of TSHR/IGF-1R crosstalk that considers two pathways initiated by TSAb activation of TSHR in the eye, an IGF-1R-independent and an IGF-1R-dependent signaling pathway leading to hyaluronan (HA) secretion in orbital fibroblasts. We discuss current and future therapeutic approaches targeting the IGF-1R and TSHR. Teprotumumab, a human monoclonal anti-IGF-1R-blocking antibody, has been approved as an effective treatment in patients with TED. However, as the TSHR seems to be the primary target for TSAbs in patients with GD, future therapeutic interventions directly targeting the TSHR, e.g. blocking antibodies and small molecule antagonists, are being developed and have the advantage to inhibit the IGF-1R-independent as well as the IGF-1R-dependent component of TSAb-induced HA secretion. Antigen-specific immunotherapies using TSHR peptides to reduce serum TSHR antibodies are being developed also. These TSHR-targeted strategies also have the potential to treat both GH and TED with the same drug. We propose that combination therapy targeting TSHR and IGF-1R may be an effective and better tolerated treatment strategy for TED.

scholarly journals An investigation of non-invasive tear break up time and tear meniscus height of keratoconic versus non-keratoconic individuals

2016 ◽  
Vol 75 (1) ◽  
Author(s):  
Deanne L. Nicholas ◽  
Wayne D.H. Gillan
Keyword(s):  
Dry Eye ◽  
Tear Film ◽  
Dry Eye Disease ◽  
Eye Disease ◽  
Non Invasive ◽  
Control Subjects ◽  
Tear Meniscus ◽  
Break Up ◽  
Tear Meniscus Height ◽  
And Control

Keratoconus is a debilitating condition where the cornea develops a conical shape rather than the characteristic round shape due to various physiological and structural changes taking place within the layers of the cornea. As a result of the pathogenesis of keratoconus, there are numerous changes that may occur within the tears of these patients. Research has shown changes in the tear metabolome, the presence of degradation products as well as loss of goblet cells into the tears. Could the changes occurring within the tear structure of these patients affect the results of various tear quantity and quality tests? Non-invasive tear break up time (NTBUT) is a diagnostic test used to determine the quality of the tear film and has been used extensively when diagnosing dry eye disease. This test is utilised in order to determine the time taken for the tear film to begin breaking apart, signalling thinning of the tears. Shorter break up times are therefore indicative of instability or changes occurring within the tear film which could be diagnostic of dry eye disease. Tear meniscus height (TMH) measurements have also been utilised in clinical practice, where these measurements provide an indication of the volume of tears contained within the upper and lower menisci. Lower tear volumes have been shown to be present in cases of dry eye disease where either tear production or tear drainage may be affected. Changes in the quality and quantity of the tear film in subjects with dry eye disease have been thoroughly investigated; however, the same cannot be said for subjects with keratoconus. Could the same findings be possible in subjects with keratoconus? Is it possible that the changes occurring within the tears of keratoconic subjects could lead to abnormal NTBUT and TMH measurements when compared to those of control subjects? Could the results of the NTBUT and TMH tests be related to one another? This study compares the NTBUT and TMH measurements of both keratoconic and control subjects by making use of a single type of instrumentation, namely the Oculus Keratograph 4 (OK4). The results of this study reveal that the values obtained for each of the two subject groups are not shown to be statistically significantly different and that there is no significant correlation between the NTBUT and TMH measurements when comparing keratoconic and control subjects.

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