scholarly journals A New Small-Molecule Antagonist Inhibits Graves' Disease Antibody Activation of the TSH Receptor

2011 ◽  
Vol 96 (2) ◽  
pp. 548-554 ◽  
Author(s):  
Susanne Neumann ◽  
Elena Eliseeva ◽  
Joshua G. McCoy ◽  
Giorgio Napolitano ◽  
Cesidio Giuliani ◽  
...  
Keyword(s):  
Small Molecule ◽  
Primary Cultures ◽  
Receptor Activation ◽  
Inverse Agonist ◽  
Tsh Receptor ◽  
Thyroid Peroxidase ◽  
Graves Disease ◽  
Mrna Levels ◽  
Camp Production ◽  
Small Molecule Antagonist

abstract Context: Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate the TSH receptor (TSHR). We previously reported the first small-molecule antagonist of human TSHR and showed that it inhibited receptor signaling stimulated by sera from four patients with GD. Objective: Our objective was to develop a better TSHR antagonist and use it to determine whether inhibition of TSAb activation of TSHR is a general phenomenon. Design: We aimed to chemically modify a previously reported small-molecule TSHR ligand to develop a better antagonist and determine whether it inhibits TSHR signaling by 30 GD sera. TSHR signaling was measured in two in vitro systems: model HEK-EM293 cells stably overexpressing human TSHRs and primary cultures of human thyrocytes. TSHR signaling was measured as cAMP production and by effects on thyroid peroxidase mRNA. Results: We tested analogs of a previously reported small-molecule TSHR inverse agonist and selected the best NCGC00229600 for further study. In the model system, NCGC00229600 inhibited basal and TSH-stimulated cAMP production. NCGC00229600 inhibition of TSH signaling was competitive even though it did not compete for TSH binding; that is, NCGC00229600 is an allosteric inverse agonist. NCGC00229600 inhibited cAMP production by 39 ± 2.6% by all 30 GD sera tested. In primary cultures of human thyrocytes, NCGC00229600 inhibited TSHR-mediated basal and GD sera up-regulation of thyroperoxidase mRNA levels by 65 ± 2.0%. Conclusion: NCGC00229600, a small-molecule allosteric inverse agonist of TSHR, is a general antagonist of TSH receptor activation by TSAbs in GD patient sera.

scholarly journals A Pilot Study on the Beneficial Effects of the Additional Selenium Supplementation to Methimazole for Treating Patients with Graves? disease

2019 ◽  
Author(s):  
BIN XU ◽  
DI WU ◽  
HONG YING ◽  
YING ZHANG
Keyword(s):  
Protein Expression ◽  
Combination Group ◽  
Thyroid Peroxidase ◽  
Graves Disease ◽  
Mrna Levels ◽  
Thyroid Cells ◽  
Beneficial Effects ◽  
Thyroid Peroxidase Antibody ◽  
Thyroglobulin Antibody

Backgroud/aim: The aim of this study was to assess the effect of a combination use of methimazole (MMI) and selenium (Se) in the treatment of Graves’ disease (GD). Materials and methods: A total of 103 newly-diagnosed hyperthyroidism patients were randomized to MMI and MMI+Se combination group. After treatment for six months, the levels of triiodothyronine (FT3), free thyroxine (FT4), thyrotrophin receptor antibody (TRAb), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) were observed. Besides, an in vitro culture model of thyroid cells was established and the protein expression and mRNA levels of TRAb, TPOAb and TGAb were determined by western blot and RT-PCR. Results: A significant decrease in the levels of FT3, FT4, TRAb, TPOAb and TGAb were observed in both groups along with a marked increase in TSH levels. Furthermore, the in vitro experiments showed that the protein expression and mRNA levels of TRAb, TPOAb and TGAb decreased significantly. Also, compared to the MMI group, there was a greater improvement of these indices in the MMI+Se group. Conclusion: We suggest that the combined use of MMI and Se could improve the thyroid activity in patients which may provide effective therapy for the treatment of GD in clinical settings. Key words: Graves’ disease; methimazole; selenium; TRAb; TPOAb; TGAb

Quantitative thyroid scintigraphy for the differentiation of Graves’ disease and hyperthyroid autoimmune thyroiditis

2004 ◽  
Vol 43 (04) ◽  
pp. 124-128 ◽  
Author(s):  
C. O. Sahlmann ◽  
U. Siefker ◽  
K. Lehmann ◽  
E. Harms ◽  
M. Conrad ◽  
...  
Keyword(s):  
Autoimmune Thyroiditis ◽  
Subclinical Hypothyroidism ◽  
Spontaneous Remission ◽  
Tsh Receptor ◽  
Thyroid Peroxidase ◽  
Graves Disease ◽  
Thyroid Scintigraphy ◽  
Thyroid Uptake ◽  
Reliable Differentiation ◽  
Overt Hyperthyroidism

Summary Aim: The TCTUs (global 99mTc-pertechnetate thyroid uptake under suppression) can be used as an estimate of the iodine clearance of non-TSH regulated tissue. High TCTUs levels are characteristic for Graves’ disease (GD). Decreased uptake has been described in autoimmune thyroiditis (AIT). However, systematically investigated data in a larger series of AIT-patients with subclinical or overt hyperthyroidism are not published so far. The purpose of this study is the evaluation of the TCTUs in the differentiation between AIT and GD in patients with hyperthyroidism. Methods: We determined the TCTUs in 59 patients with untreated hyperthyroid GD and in 51 patients with AIT who had subclinical or manifest hyperthyroidism without medication. Patients with GD were characterized by the presence of hyperthyroidism, decreased echogenicity of the thyroid, elevation of TSH-receptor autoantibodies (TRAb). AIT was defined by a decreased echogenicity of the thyroid, absence of elevated TSH-receptor autoantibodies (TRAb), autoantibodies against the thyroid peroxidase (anti-TPO) and spontaneous remission or development of subclinical hypothyroidism within 3 months. Results: Thyroid volumes of patients with AIT were significantly lower than those of patients with GD (p <0.05). TRAb levels were significantly higher in GD-patients (median: 19.5 U/ml; range: 15.3-35 U/ml) than in AIT-patients (median: 1.3 U/ml; range: 0-4.1 U/ml). 73% (38/59) of patients with GD had elevated anti-TPO levels. In these patients anti-TPO levels (median: 768 U/l; range: 83-6397 U/l) were not significantly different from anti-TPO levels of patients with AIT (median: 834 U/l; range: 107-8675 U/l; p = 0.17). TCTUs values of patients with AIT were significantly lower (p <0.05; median: 0.9%; range: 0.1-3.2%) than those of patients with GD (median: 5.7%; range: 1.9-28.3%). Conclusion: In our patients quantitative thyroid scintigraphy with 99mTcO4 - offered rapid and reliable differentiation between hyperthyroid GD and AIT.

scholarly journals A Case of Marine-Lenhart Syndrome with a Negative TSH Receptor Antibody Titer Successfully Treated with a Fixed, Low Dose of I131

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Masahiro Takei ◽  
Hiroaki Ishii ◽  
Yoshihiko Sato ◽  
Mitsuhisa Komatsu
Keyword(s):  
Thyroid Gland ◽  
Antibody Titer ◽  
Color Doppler ◽  
Laboratory Data ◽  
Tsh Receptor ◽  
Thyroid Peroxidase ◽  
Graves Disease ◽  
Receptor Antibody ◽  
Tsh Receptor Antibody ◽  
The Right

We herein describe a case of Marine-Lenhart syndrome with a negative TSH receptor antibody titer. A 75-year-old female presented to our hospital with malaise, palpitations, and mild fine tremors. She did not have any signs suggestive of Graves’ ophthalmopathy, including conjunctival injection, periorbital edema, or proptosis. Her laboratory data were negative for thyroid autoantibodies, including anti-thyroid peroxidase antibodies, anti-thyroglobulin antibodies, and anti-TSH receptor antibodies (TRAb). Ultrasonography of the thyroid gland revealed a tumor in the right lobe. The remaining thyroid gland had an inhomogeneous and rough texture with a high color Doppler flow. I123scintigraphy disclosed a hot nodule in the right thyroid gland corresponding to the tumor detected on ultrasonography, suggesting Plummer disease. Furthermore, there was an increased uptake of radionuclide in the rest of the thyroid gland, despite the suppressed level of TSH and negative titer of TRAb, suggesting underlying Graves’ disease. The present findings suggested a diagnosis of Marine-Lenhart syndrome with a negative TRAb titer. Treatment with 10 mCi of radioiodine was highly effective in treating hyperthyroidism in this case. A negative TSH receptor antibody titer does not necessarily rule out the existence of Graves’ disease in patients with Plummer disease.

scholarly journals The Core Stem Genes SOX2, POU5F1/OCT4, and NANOG Are Expressed in Human Parathyroid Tumors and Modulated by MEN1, YAP1, and β-Catenin Pathways Activation

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 637
Author(s):  
Chiara Verdelli ◽  
Annamaria Morotti ◽  
Giulia Stefania Tavanti ◽  
Rosamaria Silipigni ◽  
Silvana Guerneri ◽  
...  
Keyword(s):  
Primary Cultures ◽  
Suppressor Gene ◽  
Receptor Activation ◽  
Parathyroid Glands ◽  
Mrna Levels ◽  
Opposite Pattern ◽  
Sox2 Expression ◽  
Oct4 Expression ◽  
The Core ◽  
Parathyroid Tumors

Tumors of the parathyroid glands are the second most common endocrine neoplasia. Epigenetic studies revealed an embryonic signature involved in parathyroid tumorigenesis. Here, we investigated the expression of the stem core genes SOX2, POU5F1/OCT4, and NANOG. Rare cells within normal parathyroid glands expressed POU5F1/OCT4 and NANOG, while SOX2 was undetectable. Nuclear SOX2 expression was detectable in 18% of parathyroid adenomas (PAds, n = 34) involving 5–30% of cells, while OCT4 and NANOG were expressed at the nuclear level in a more consistent subset of PAds involving 15–40% of cells. Most parathyroid carcinomas expressed the core stem genes. SOX2-expressing cells co-expressed parathormone (PTH). In PAds-derived primary cultures, silencing of the tumor suppressor gene MEN1 induced the expression of SOX2, likely through a MEN1/HAR1B/SOX2 axis, while calcium-sensing receptor activation increased SOX2 mRNA levels through YAP1 activation. In addition, inducing nuclear β-catenin accumulation in PAds-derived primary cultures by short-term incubation with lithium chloride (LiCl), SOX2 and POU5F1/OCT4 expression levels increased, while NANOG transcripts were reduced, and LiCl long-term incubation induced an opposite pattern of gene expression. In conclusion, detection of the core stem genes in parathyroid tumors supports their embryogenic signature, which is modulated by crucial genes involved in parathyroid tumorigenesis.

scholarly journals A Small Molecule Inverse Agonist for the Human Thyroid-Stimulating Hormone Receptor

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3454-3459 ◽  
Author(s):  
Susanne Neumann ◽  
Wenwei Huang ◽  
Elena Eliseeva ◽  
Steve Titus ◽  
Craig J. Thomas ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Potential ◽  
Primary Cultures ◽  
Inverse Agonist ◽  
Thyroid Stimulating Hormone ◽  
Human Thyroid ◽  
Sodium Iodide Symporter ◽  
Wild Type ◽  
Inverse Agonists ◽  
293 Cells

Small molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe the first small-molecule ligand [1;2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one] that exhibits inverse agonist properties at TSHR. 1 inhibits basal and TSH-stimulated signaling, measured as cAMP production, by TSHRs in HEK-EM 293 cells stably expressing wild-type TSHRs; the antagonism of TSH-mediated signaling is competitive. 1 also inhibits basal signaling by wild-type TSHRs, and four constitutively active mutants of TSHR expressed transiently in HEK-EM 293 cells. 1 was active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited basal levels of mRNA transcripts for thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR. These data serve as proof of principle that small, drug-like molecules can inhibit basal signaling by TSHR. We suggest that this small molecule is a lead compound for the development of higher-potency inverse agonists that can be used as probes of TSHR biology with therapeutic potential.

scholarly journals Experimental Reproduction of Dynamic Fluctuation of TSH Receptor–Binding Antibodies Between Stimulation and Inhibition

2019 ◽  
Vol 3 (12) ◽  
pp. 2361-2373
Author(s):  
Tetsuya Tagami ◽  
Kaho Hiroshima-Hamanaka ◽  
Hironobu Umakoshi ◽  
Mika Tsuiki-Naruse ◽  
Toru Kusakabe ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Tsh Receptor ◽  
Graves Disease ◽  
Camp Production ◽  
Isolated Cells ◽  
Human Mabs ◽  
Experimental Reproduction ◽  
Dynamic Fluctuation ◽  
Stimulation Of

Abstract Context Hyperthyroidism in Graves disease (GD) is caused by autoantibody stimulation of the TSH receptor (TSHR). TSHR autoantibody (TSHR-Ab) activity is measured routinely by inhibition of labeled ligand (TSH or M22) binding to the TSHR [TSH-binding inhibitory immunoglobulins (TBIIs)] or by stimulation of cAMP production in isolated cells [TSH receptor–stimulating antibodies (TSAbs)]. Usually, measurements of TSHR-Abs by TBIIs agree reasonably well with TSAb values at least in the setting of hyperthyroidism, and both measurements tend to change in parallel during treatment with some exceptions. In this study, we describe three unusual cases, which illustrate nearly pure stimulating, blocking, or neutral properties of TSHR-Abs. Objective Whether patient serum TSHR-Abs can be reproduced by mixtures of human monoclonal autoantibodies to the TSHR was studied because the sera in most patients show moderate properties having both of TBII and TSAb activities. Design We compared the TBII and TSAb activities of serum from four unusual patients in detail with mixtures of human monoclonal TSHR-Abs (mAbs) M22 (stimulating), K1-18 (stimulating), and K1-70 (blocking). Results Characteristic of a patient’s serum was similar to M22 or K1-18, another was similar to K1-70, whereas another was similar to a mixture of K1-70 and M22 (or K1-18). Additionally, some patients seemed to have neutral TSHR-Abs in their sera. Conclusions Our studies suggest that the characteristics of TSHR-Abs in the patient serum can be mimicked by mixtures of human mAbs to the TSHR, stimulating, blocking, and neutral if any.

scholarly journals A Small Molecule Inverse Agonist for the Human Thyroid-Stimulating Hormone Receptor

2010 ◽  
Vol 31 (3) ◽  
pp. 403-403
Author(s):  
Susanne Neumann ◽  
Wenwei Huang ◽  
Elena Eliseeva ◽  
Steve Titus ◽  
Craig J. Thomas ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Potential ◽  
Primary Cultures ◽  
Inverse Agonist ◽  
Thyroid Stimulating Hormone ◽  
Human Thyroid ◽  
Sodium Iodide Symporter ◽  
Wild Type ◽  
Inverse Agonists ◽  
293 Cells

ABSTRACT Small molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe the first small-molecule ligand [1, 2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one] that exhibits inverse agonist properties at TSHR. 1 inhibits basal and TSH-stimulated signaling, measured as cAMP production, by TSHRs in HEK-EM 293 cells stably expressing wild-type TSHRs; the antagonism of TSH-mediated signaling is competitive. 1 also inhibits basal signaling by wild-type TSHRs, and four constitutively active mutants of TSHR expressed transiently in HEK-EM 293 cells. 1 was active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited basal levels of mRNA transcripts for thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR. These data serve as proof of principle that small, drug-like molecules can inhibit basal signaling by TSHR. We suggest that this small molecule is a lead compound for the development of higher-potency inverse agonists that can be used as probes of TSHR biology with therapeutic potential.

scholarly journals Serum thyroglobulin is associated with orbitopathy in Graves’ disease

2021 ◽  
Author(s):  
S. Khamisi ◽  
M. Lundqvist ◽  
P. Emadi ◽  
K. Almby ◽  
Ö. Ljunggren ◽  
...  
Keyword(s):  
Clinical Signs ◽  
Signs And Symptoms ◽  
Drug Regimen ◽  
Tsh Receptor ◽  
Thyroid Peroxidase ◽  
Graves Disease ◽  
Serum Thyroglobulin ◽  
Increased Risk ◽  
Eye Symptoms ◽  
Clinical Signs And Symptoms

Abstract Purpose Serum thyroglobulin levels are often elevated in Graves’ disease (GD) and in most cases decrease during treatment. Its relation to Graves’ orbitopathy (GO) has not been clarified. Previously, a risk of GO has been linked to smoking, TSH receptor stimulation, high TSH-receptor antibodies (TRAb), low thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb). Methods We examined Tg levels in 30 consecutive patients with GD were given drug therapy (methimazole + thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. 17 patients had GO, 11 of whom had it at diagnosis while 6 developed GO during treatment. During the study, 5 subjects were referred to radioiodine treatment, 3 to surgery. The remaining 22 subjects (GO n = 12, non-GO n = 10) completed the drug regimen. Results At diagnosis, Tg levels in GO patients (n = 11) were higher (84, 30–555 µg/L, median, range) than in non-GO patients (n = 19) (38, 3.5–287 µg/L), p = 0.042. Adding the 6 subjects who developed eye symptoms during treatment to the GO group (n = 17), yielded p = 0.001 vs. non-GO (n = 13). TRAb tended to be higher, while TPOAb and TgAb tended to be lower in the GO group. For the 22 patients who completed the drug regimen, Tg levels were higher in GO (n = 12) vs. non-GO (n = 10), p = 0.004, whereas TRAb levels did not differ. Conclusion The data may suggest that evaluation of thyroglobulin levels in GD could contribute to identify patients at increased risk of developing GO. Possibly, thyroidal release of Tg in GD reflects a disturbance that also impacts retroorbital tissues.

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