scholarly journals miR-199a Downregulation as a Driver of the NOX4/HIF-1α/VEGF-A Pathway in Thyroid and Orbital Adipose Tissues from Graves′ Patients

2021 ◽  
Vol 23 (1) ◽  
pp. 153
Author(s):  
Julie Craps ◽  
Virginie Joris ◽  
Lelio Baldeschi ◽  
Chantal Daumerie ◽  
Alessandra Camboni ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Metabolic Pathways ◽  
Graves Disease ◽  
Quantitative Real Time Pcr ◽  
Adipose Tissues ◽  
Nadph Oxidase 4 ◽  
Graves Orbitopathy ◽  
High Oxidative Stress

Graves’ disease (GD) is an autoimmune thyroiditis often associated with Graves’ orbitopathy (GO). GD thyroid and GO orbital fat share high oxidative stress (OS) and hypervascularization. We investigated the metabolic pathways leading to OS and angiogenesis, aiming to further decipher the link between local and systemic GD manifestations. Plasma and thyroid samples were obtained from patients operated on for multinodular goiters (controls) or GD. Orbital fats were from GO or control patients. The NADPH-oxidase-4 (NOX4)/HIF-1α/VEGF-A signaling pathway was investigated by Western blotting and immunostaining. miR-199a family expression was evaluated following quantitative real-time PCR and/or in situ hybridization. In GD thyroids and GO orbital fats, NOX4 was upregulated and correlated with HIF-1α stabilization and VEGF-A overexpression. The biotin assay identified NOX4, HIF-1α and VEGF-A as direct targets of miR-199a-5p in cultured thyrocytes. Interestingly, GD thyroids, GD plasmas and GO orbital fats showed a downregulation of miR-199a-3p/-5p. Our results also highlighted an activation of STAT-3 signaling in GD thyroids and GO orbital fats, a transcription factor known to negatively regulate miR-199a expression. We identified NOX4/HIF-1α/VEGF-A as critical actors in GD and GO. STAT-3-dependent regulation of miR-199a is proposed as a common driver leading to these events in GD thyroids and GO orbital fats.

PERK mediates oxidative stress and adipogenesis in Graves’ orbitopathy pathogenesis

2021 ◽  
Author(s):  
JaeSang Ko ◽  
Ji-Young Kim ◽  
Min Kyung Chae ◽  
Eun Jig Lee ◽  
Jin Sook Yoon
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Adipogenic Differentiation ◽  
Ros Generation ◽  
Mrna Levels ◽  
Graves Orbitopathy ◽  
Orbital Fibroblasts

We examined endoplasmic reticulum (ER) stress-related gene expression in orbital tissues from patients with Graves’ orbitopathy (GO) and the effects of silencing protein kinase RNA-like endoplasmic reticulum kinase (PERK) in primary orbital fibroblast cultures to demonstrate the therapeutic potential of PERK-modulating agents in GO management. The expression of ER stress related genes in orbital tissue harvested from individuals with or without GO was studied using real-time polymerase chain reaction. The role of PERK in GO pathogenesis was examined through small-interfering RNA (siRNA)-mediated silencing in cultured primary orbital fibroblasts. Intracellular reactive oxygen species (ROS) levels induced in response to cigarette smoke extract (CSE) or hydrogen peroxide were measured using 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. Cells were stained with Oil Red O, and adipogenesis-related transcription factor expression was evaluated through western blotting after adipogenic differentiation. PERK, activating transcription factor 4 (ATF4), and CCAAT-enhancer-binding protein (C/EBP)-homologous protein(CHOP)mRNA levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. PERK silencing inhibited CSE- or hydrogen peroxide-induced ROS generation. After adipogenic differentiation, GO orbital fibroblasts revealed decreased lipid droplets and downregulation of C/EBPα, C/EBPβ, and peroxisome proliferator-activator gamma (PPARγ) in PERK siRNA-transfected cells. The orbital tissues of patients with GO were exposed to chronic ER stress and subsequently exhibited enhanced unfolded protein response (especially through the PERK pathway). PERK silencing reduced oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. Our results imply that PERK-modulating agents can potentially be used to manage GO.

scholarly journals The Role of Oxidative Stress on the Pathogenesis of Graves' Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Miloš Žarković
Keyword(s):  
Oxidative Stress ◽  
The Other ◽  
Graves Disease ◽  
Graves Ophthalmopathy ◽  
Selenium Treatment ◽  
Graves Orbitopathy ◽  
Eye Involvement ◽  
Orbital Fibroblasts

Graves' disease is a most common cause of hyperthyroidism. It is an autoimmune disease, and autoimmune process induces an inflammatory reaction, and reactive oxygen species (ROSs) are among its products. When balance between oxidants and antioxidants is disturbed, in favour of the oxidants it is termed “oxidative stress” (OS). Increased OS characterizes Graves' disease. It seems that the level of OS is increased in subjects with Graves' ophthalmopathy compared to the other subjects with Graves' disease. Among the other factors, OS is involved in proliferation of orbital fibroblasts. Polymorphism of the 8-oxoG DNA N-glycosylase 1 (hOGG1) involved in repair of the oxidative damaged DNA increases in the risk for developing Grave's disease. Treatment with glucocorticoids reduces levels of OS markers. A recent large clinical trial evaluated effect of selenium on mild Graves' ophthalmopathy. Selenium treatment was associated with an improved quality of life and less eye involvement and slowed the progression of Graves' orbitopathy, compared to placebo.

Selenium usage and oxidative stress in Graves’ disease and Graves’ orbitopathy

Pathology ◽  
2020 ◽  
pp. 335-344
Author(s):  
Michele Marinò ◽  
Giulia Lanzolla ◽  
Giovanna Rotondo Dottore ◽  
Claudio Marcocci
Keyword(s):  
Oxidative Stress ◽  
Graves Disease ◽  
Graves Orbitopathy ◽  
And Oxidative Stress

Mechanistic Pathways of Selenium in the Treatment of Graves’ Disease and Graves’ Orbitopathy

2018 ◽  
Vol 50 (12) ◽  
pp. 887-893 ◽  
Author(s):  
Michele Marinò ◽  
Giovanna Dottore ◽  
Marenza Leo ◽  
Claudio Marcocci
Keyword(s):  
Oxidative Stress ◽  
Clinical Practice ◽  
Graves Disease ◽  
Graves Orbitopathy ◽  
Antioxidant Agent ◽  
The Subject

AbstractBased on the role of oxidative stress in the pathogenesis of Graves’ hyperthyroidism and Graves’ orbitopathy, the use of the antioxidant agent selenium has been proposed and several studies on the subject have been conducted, both in vitro and in vivo. Whereas a true benefit related to the use of selenium in patients with Graves’ hyperthyroidism has been questioned, its use in patients with mild Graves’ orbitopathy is generally believed to be beneficial because of which selenium has entered in the clinical practice for this eye condition.

Novel treatment opportunities in Graves’ orbitopathy

2014 ◽  
Vol 155 (33) ◽  
pp. 1295-1300
Author(s):  
Annamária Erdei ◽  
Annamária Gazdag ◽  
Miklós Bodor ◽  
Eszter Berta ◽  
Mónika Katkó ◽  
...  
Keyword(s):  
Clinical Experience ◽  
Clinical Course ◽  
Treatment Protocol ◽  
Treatment Modalities ◽  
Graves Disease ◽  
Novel Treatment ◽  
Graves Orbitopathy ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Novel Therapeutic

Graves’ orbitopathy is the most common extrathyroidal manifestation of Graves’ disease. Up to now, curative treatment modalities for the most severe sight-threatening cases have not been developed. Here the authors summarize the treatment protocol of Graves’ orbitopathy and review novel therapeutic options. They review the literature on this topic and present their own clinical experience. The authors point out that anti-CD20 antibody could positively influence the clinical course of Graves’ orbitopathy. Selenium is efficient in mild cases. Further prospective investigations are warranted. Orv. Hetil., 2014, 155(33), 1295–1300.

The Effect of Immunosuppression on Selected Antioxidant Parameters in Patients with Graves’ Disease with Active Thyroid-Associated Orbitopathy

2020 ◽  
Author(s):  
Magdalena Londzin-Olesik ◽  
Beata Kos-Kudla ◽  
Jacek Karpe ◽  
Aleksandra Nowak ◽  
Mariusz Nowak
Keyword(s):  
Oxidative Stress ◽  
Clinical Symptoms ◽  
Immunosuppressive Treatment ◽  
Serum Vitamin ◽  
Serum Levels ◽  
Paraoxonase 1 ◽  
Control Group ◽  
Graves Disease ◽  
Methylprednisolone Treatment ◽  
Antioxidant Parameters

Abstract Background and Study Aims Thyroid-associated orbitopathy, the most common extrathyroidal manifestation of Graves’ disease, is an autoimmune inflammation of orbital soft tissue. We report the study assessing the effect of immunosuppressive treatment with methylprednisolone on selected antioxidant parameters in patients with Graves’ disease with active thyroid-associated orbitopathy. Patients and Methods Activity and serum levels of selected antioxidant parameters as well as lipid peroxidation products were determined in a group of 56 patients with active thyroid-associated orbitopathy at three time-points: at baseline, after the discontinuation of intravenous methylprednisolone treatment and at 3 months after the discontinuation of additional oral methylprednisolone treatment. A control group consisted of 20 healthy age- and sex-matched volunteers. Results We found an increased activity of superoxide dismutase and glutathione peroxidase and increased serum levels of uric acid, malondialdehyde and conjugated dienes, as well as a reduced activity of paraoxonase-1 and reduced serum vitamin C level in the study group at baseline. Systemic intravenous and oral methylprednisolone therapy led to normalization of activity and concentration of the most studied parameters. Conclusion Results of our study confirmed that oxidative stress is one of the factors involved in the pathogenesis of thyroid-associated orbitopathy and the methyloprednisolone treatment is effective in reducing both clinical symptoms and oxidative stress in patients with this disease.

Clinical relevance of T lymphocyte subsets in pediatric Graves’ disease

2020 ◽  
Vol 33 (11) ◽  
pp. 1425-1430
Author(s):  
Ting Chen ◽  
Linqi Chen ◽  
Haojie Song ◽  
Xiuli Chen ◽  
Rongrong Xie ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Clinical Characteristics ◽  
Hepatic Dysfunction ◽  
Lymphocyte Subsets ◽  
Cytotoxic T Cell ◽  
Graves Disease ◽  
T Lymphocyte Subsets ◽  
Graves Orbitopathy ◽  
Normal Alanine Aminotransferase

AbstractObjectivesGraves’ disease (GD) is an autoimmune disease involving intimate response of both T cells and B cells. Immunophenotyping of peripheral blood lymphocyte subsets in GD children with different clinical characteristics can provide further information of the pathogenesis of GD.MethodsWe studied the lymphocyte subsets in peripheral blood of 141 children with GD. We repeatedly divided the patients into two groups in accordance with different clinical characteristics (abnormal or normal alanine aminotransferase (ALT) levels, the presence or absence of Graves’ orbitopathy (GO), and the presence or absence of hematuria. Then we compared the lymphocyte subsets measurements between two paired groups.ResultsWe found that serum ALT levels correlated positively with CD3+CD8+ T cell percentages in children with GD. Moreover, we detected higher percentages of CD3−CD19+ cells and higher ratio of CD4/CD8 in patients with GO. However, no correlation was found between GO status and lymphocyte subsets after excluding confounding effect of TRAb. No difference of lymphocyte subset percentages was found between groups with or without hematuria.ConclusionsSerum ALT levels correlate positively with cytotoxic T cell percentages in the peripheral blood of children with GD. The cytotoxic T cell may play a role in the pathogenesis of hepatic dysfunction in children with GD.

scholarly journals SHR/NCrl rats as a model of ADHD can be discriminated from controls based on their brain, blood, or urine metabolomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Camille Dupuy ◽  
Pierre Castelnau ◽  
Sylvie Mavel ◽  
Antoine Lefevre ◽  
Lydie Nadal-Desbarats ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Attention Deficit Hyperactivity Disorder ◽  
Animal Model ◽  
Metabolic Pathways ◽  
Neurodevelopmental Disorder ◽  
Hyperactivity Disorder ◽  
Pathophysiological Condition ◽  
The Brain ◽  
And Oxidative Stress ◽  
Peripheral Samples

AbstractAttention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorder characterized by inattention, impulsivity, and hyperactivity. The neurobiological mechanisms underlying ADHD are still poorly understood, and its diagnosis remains difficult due to its heterogeneity. Metabolomics is a recent strategy for the holistic exploration of metabolism and is well suited for investigating the pathophysiology of diseases and finding molecular biomarkers. A few clinical metabolomic studies have been performed on peripheral samples from ADHD patients but are limited by their access to the brain. Here, we investigated the brain, blood, and urine metabolomes of SHR/NCrl vs WKY/NHsd rats to better understand the neurobiology and to find potential peripheral biomarkers underlying the ADHD-like phenotype of this animal model. We showed that SHR/NCrl rats can be differentiated from controls based on their brain, blood, and urine metabolomes. In the brain, SHR/NCrl rats displayed modifications in metabolic pathways related to energy metabolism and oxidative stress further supporting their importance in the pathophysiology of ADHD bringing news arguments in favor of the Neuroenergetic theory of ADHD. Besides, the peripheral metabolome of SHR/NCrl rats also shared more than half of these differences further supporting the importance of looking at multiple matrices to characterize a pathophysiological condition of an individual. This also stresses out the importance of investigating the peripheral energy and oxidative stress metabolic pathways in the search of biomarkers of ADHD.

scholarly journals Metabolome and proteome analyses reveal transcriptional misregulation in glycolysis of engineered E. coli

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chun-Ying Wang ◽  
Martin Lempp ◽  
Niklas Farke ◽  
Stefano Donati ◽  
Timo Glatter ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Site ◽  
Metabolic Pathways ◽  
Glycerol Production ◽  
Inducible Promoters ◽  
E Coli ◽  
Inhibition Of Glycolysis ◽  
Underlying Mechanisms ◽  
Rate Limiting ◽  
Engineered Bacteria

AbstractSynthetic metabolic pathways are a burden for engineered bacteria, but the underlying mechanisms often remain elusive. Here we show that the misregulated activity of the transcription factor Cra is responsible for the growth burden of glycerol overproducing E. coli. Glycerol production decreases the concentration of fructose-1,6-bisphoshate (FBP), which then activates Cra resulting in the downregulation of glycolytic enzymes and upregulation of gluconeogenesis enzymes. Because cells grow on glucose, the improper activation of gluconeogenesis and the concomitant inhibition of glycolysis likely impairs growth at higher induction of the glycerol pathway. We solve this misregulation by engineering a Cra-binding site in the promoter controlling the expression of the rate limiting enzyme of the glycerol pathway to maintain FBP levels sufficiently high. We show the broad applicability of this approach by engineering Cra-dependent regulation into a set of constitutive and inducible promoters, and use one of them to overproduce carotenoids in E. coli.

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