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26 pages, 1855 KiB

Open AccessArticle

Effect of a Low-Molecular-Weight Allosteric Agonist of the Thyroid-Stimulating Hormone Receptor on Basal and Thyroliberin-Stimulated Activity of Thyroid System in Diabetic Rats

by Kira V. Derkach, Alena S. Pechalnova, Viktor N. Sorokoumov, Inna I. Zorina, Irina Y. Morina, Elizaveta E. Chernenko, Egor A. Didenko, Irina V. Romanova and Alexander O. Shpakov

Int. J. Mol. Sci. 2025, 26(2), 703; https://doi.org/10.3390/ijms26020703 - 15 Jan 2025

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Abstract

The approaches to correct thyroid deficiency include replacement therapy with thyroid hormones (THs), but such therapy causes a number of side effects. A possible alternative is thyroid-stimulating hormone (TSH) receptor activators, including allosteric agonists. The aim of this work was to study the [...] Read more.

The approaches to correct thyroid deficiency include replacement therapy with thyroid hormones (THs), but such therapy causes a number of side effects. A possible alternative is thyroid-stimulating hormone (TSH) receptor activators, including allosteric agonists. The aim of this work was to study the effect of ethyl-2-(4-(4-(5-amino-6-(tert-butylcarbamoyl)-2-(methylthio)thieno[2,3-d]pyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) acetate (TPY3m), a TSH receptor allosteric agonist developed by us, on basal and thyroliberin (TRH)-stimulated TH levels and the hypothalamic-pituitary-thyroid (HPT) axis in male rats with high-fat diet/low-dose streptozotocin-induced type 2 diabetes mellitus (T2DM). Single and three-day administration of TPY3m (i.p., 20 mg/kg) was studied, and the effect of TPY3m on the HPT axis was compared with that of levothyroxine. TPY3m increased TH levels when administered to both healthy and diabetic rats, normalizing thyroxine and triiodothyronine levels in T2DM and, unlike levothyroxine, without negatively affecting TSH levels or the expression of hypothalamic and pituitary genes responsible for TSH production. TPY3m pretreatment preserved the stimulatory effects of TRH on TH levels and thyroid gene expression. This indicates the absence of competition between TPY3m and endogenous TSH for TSH receptor activation and is supported by our in vitro results on TPY3m- and TSH-stimulated adenylate cyclase activity in rat thyroid membranes. Morphological analysis of thyroid glands in diabetic rats after three-day TPY3m administration shows an increase in its functional activity without destructive changes. To summarize, TPY3m, with the activity of a partial allosteric agonist of the TSH receptor, was created as a prototype of drugs to correct thyroid insufficiency in T2DM. Full article

(This article belongs to the Special Issue Thyroid Hormone and Molecular Endocrinology)

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16 pages, 5214 KiB

Open AccessArticle

Bichromatic Splicing Detector Allows Quantification of THRA1 and THRA2 Splicing Isoforms in Single Cells by Fluorescent Live-Cell Imaging

by Eugenio Graceffo, Elisa Pedersen, Marta Rosário, Heiko Krude and Markus Schuelke

Int. J. Mol. Sci. 2024, 25(24), 13512; https://doi.org/10.3390/ijms252413512 - 17 Dec 2024

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Abstract

Thyroid hormone receptor alpha (THRα) is a nuclear hormone receptor that binds triiodothyronine (T3) and acts as an important transcription factor in development, metabolism, and reproduction. The coding gene, THRA, has two major splicing isoforms in mammals, THRA1 and THRA2 [...] Read more.

Thyroid hormone receptor alpha (THRα) is a nuclear hormone receptor that binds triiodothyronine (T3) and acts as an important transcription factor in development, metabolism, and reproduction. The coding gene, THRA, has two major splicing isoforms in mammals, THRA1 and THRA2, which encode THRα1 and THRα1, respectively. The better characterized isoform, THRα1, is a transcriptional stimulator of genes involved in cell metabolism and growth. The less well-characterized isoform, THRα2, lacks the ligand-binding domain (LBD) and may act as an inhibitor of THRα1 activity. Thus, the ratio of THRα1 to THRα2 isoforms is critical for transcriptional regulation in various tissues and during development and may be abnormal in a number of thyroid hormone resistance syndromes. However, the complete characterization of the THRα isoform expression pattern in healthy human tissues, and especially the study of changes in the ratio of THRα1 to THRα2 in cultured patient cells, has been hampered by the lack of suitable tools to detect the isoform-specific expression patterns. Therefore, we developed a plasmid pCMV-THRA-RFP-EGFP splicing detector that allows the visualization and quantification of the differential expression of THRA1 and THRA2 splicing isoforms in living single cells during time-lapse and perturbation experiments. This tool enables experiments to further characterize the role of THRα2 and to perform high-throughput drug screening. Molecules that modify THRA splicing may be developed into drugs for the treatment of thyroid hormone resistance syndromes. Full article

(This article belongs to the Special Issue Thyroid Hormone and Molecular Endocrinology)

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13 pages, 3981 KiB

Open AccessArticle

Thyroid Hormone Upregulates Cav1.2 Channels in Cardiac Cells via the Downregulation of the Channels’ β4 Subunit

by Elba D. Carrillo, Juan A. Alvarado, Ascención Hernández, Ivonne Lezama, María C. García and Jorge A. Sánchez

Int. J. Mol. Sci. 2024, 25(19), 10798; https://doi.org/10.3390/ijms251910798 - 8 Oct 2024

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Abstract

Thyroid hormone binds to specific nuclear receptors, regulating the expression of target genes, with major effects on cardiac function. Triiodothyronine (T3) increases the expression of key proteins related to calcium homeostasis, such as the sarcoplasmic reticulum calcium ATPase pump, but the detailed mechanism [...] Read more.

Thyroid hormone binds to specific nuclear receptors, regulating the expression of target genes, with major effects on cardiac function. Triiodothyronine (T3) increases the expression of key proteins related to calcium homeostasis, such as the sarcoplasmic reticulum calcium ATPase pump, but the detailed mechanism of gene regulation by T3 in cardiac voltage-gated calcium (Cav1.2) channels remains incompletely explored. Furthermore, the effects of T3 on Cav1.2 auxiliary subunits have not been investigated. We conducted quantitative reverse transcriptase polymerase chain reaction, Western blot, and immunofluorescence experiments in H9c2 cells derived from rat ventricular tissue, examining the effects of T3 on the expression of α1c, the principal subunit of Cav1.2 channels, and Cavβ4, an auxiliary Cav1.2 subunit that regulates gene expression. The translocation of phosphorylated cyclic adenosine monophosphate response element-binding protein (pCREB) by T3 was also examined. We found that T3 has opposite effects on these channel proteins, upregulating α1c and downregulating Cavβ4, and that it increases the nuclear translocation of pCREB while decreasing the translocation of Cavβ4. Finally, we found that overexpression of Cavβ4 represses the mRNA expression of α1c, suggesting that T3 upregulates the expression of the α1c subunit in response to a decrease in Cavβ4 subunit expression. Full article

(This article belongs to the Special Issue Thyroid Hormone and Molecular Endocrinology)

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14 pages, 2621 KiB

Open AccessArticle

Genetic and Functional Studies of Patients with Thyroid Dyshormonogenesis and Defects in the TSH Receptor (TSHR)

by Diego Yeste, Noelia Baz-Redón, María Antolín, Elena Garcia-Arumí, Eduard Mogas, Ariadna Campos-Martorell, Núria González-Llorens, Cristina Aguilar-Riera, Laura Soler-Colomer, María Clemente, Mónica Fernández-Cancio and Núria Camats-Tarruella

Int. J. Mol. Sci. 2024, 25(18), 10032; https://doi.org/10.3390/ijms251810032 - 18 Sep 2024

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Abstract

Genetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in [...] Read more.

Genetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in vitro. We aimed to genetically characterize patients with thyroid dyshormonogenesis with TSHR defects and to study in vitro the effect of the genetic variants to establish the genotype–phenotype relationship. Pediatric patients with thyroid dyshormonogenesis (160 patients, Catalan CH neonatal screening program, confirmation TSH range: 18.4–100 mIU/L), were analyzed by a high-throughput gene panel. In vitro studies measuring the TSH-dependent cAMP–response–element activation were performed. Five patients with mild or severe thyroid dyshormonogenesis presented six TSHR variants, two unpublished. Each variant showed a different in vitro functional profile that was totally or partially deleterious. Depending on the genotype, some of the variants showed partial deficiency in both genotypes, whereas others presented a different effect. In conclusion, the percentage of patients with thyroid dyshormonogenesis and candidate variants in TSHR is 3.13%. Our in vitro studies contributed to the confirmation of the pathogenicity of the variants and highlighted the importance of studying the effect of the patient’s genotype for a correct diagnostic confirmation. Full article

(This article belongs to the Special Issue Thyroid Hormone and Molecular Endocrinology)

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15 pages, 3297 KiB

Open AccessArticle

Normal Values for the fT3/fT4 Ratio: Centile Charts (0–29 Years) and Their Application for the Differential Diagnosis of Children with Developmental Delay

by Nina-Maria Wilpert, Roma Thamm, Michael Thamm, Jürgen Kratzsch, Dominik Seelow, Mandy Vogel, Heiko Krude and Markus Schuelke

Int. J. Mol. Sci. 2024, 25(16), 8585; https://doi.org/10.3390/ijms25168585 - 6 Aug 2024

Cited by 1 | Viewed by 2175

Abstract

Primary congenital hypothyroidism is easily diagnosed on the basis of elevated plasma levels of thyroid-stimulating hormone (TSH). In contrast, in the rare disorders of thyroid hormone resistance, TSH and, in mild cases, also thyroid hormone levels are within the normal range. Thyroid hormone [...] Read more.

Primary congenital hypothyroidism is easily diagnosed on the basis of elevated plasma levels of thyroid-stimulating hormone (TSH). In contrast, in the rare disorders of thyroid hormone resistance, TSH and, in mild cases, also thyroid hormone levels are within the normal range. Thyroid hormone resistance is caused by defects in hormone metabolism, transport, or receptor activation and can have the same serious consequences for child development as congenital hypothyroidism. A total of n = 23,522 data points from a large cohort of children and young adults were used to generate normal values and sex-specific percentiles for the ratio of free triiodothyronine (T3) to free thyroxine (T4), the fT3/fT4 ratio. The aim was to determine whether individuals with developmental delay and genetically confirmed thyroid hormone resistance, carrying defects in Monocarboxylate Transporter 8 (MCT8), Thyroid Hormone Receptor alpha (THRα), and Selenocysteine Insertion Sequence-Binding Protein 2 (SECISBP2), had abnormal fT3/fT4 ratios. Indeed, we were able to demonstrate a clear separation of patient values for the fT3/fT4 ratio from normal and pathological controls (e.g., children with severe cerebral palsy). We therefore recommend using the fT3/fT4 ratio as a readily available screening parameter in children with developmental delay for the identification of thyroid hormone resistance syndromes. The fT3/fT4 ratio can be easily plotted on centile charts using our free online tool, which accepts various SI and non-SI units for fT3, fT4, and TSH. Full article

(This article belongs to the Special Issue Thyroid Hormone and Molecular Endocrinology)

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14 pages, 660 KiB

Open AccessCommunication

Patients with Thyroid Dyshormonogenesis and DUOX2 Variants: Molecular and Clinical Description and Genotype–Phenotype Correlation

by Noelia Baz-Redón, María Antolín, María Clemente, Ariadna Campos, Eduard Mogas, Mónica Fernández-Cancio, Elisenda Zafon, Elena García-Arumí, Laura Soler, Núria González-Llorens, Cristina Aguilar-Riera, Núria Camats-Tarruella and Diego Yeste

Int. J. Mol. Sci. 2024, 25(15), 8473; https://doi.org/10.3390/ijms25158473 - 3 Aug 2024

Cited by 3 | Viewed by 1862

Abstract

Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to [...] Read more.

Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype–phenotype correlation in patients with THD and candidate variants in DUOX2. A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype–phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants. Full article

(This article belongs to the Special Issue Thyroid Hormone and Molecular Endocrinology)

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11 pages, 1741 KiB

Open AccessArticle

Ultrasound Parameters Can Accurately Predict the Risk of Malignancy in Patients with “Indeterminate TIR3b” Cytology Nodules: A Prospective Study

by Valentina Guarnotta, Roberta La Monica, Vincenza Rita Ingrao, Claudia Di Stefano, Riccardo Salzillo, Giuseppe Pizzolanti, Antonino Giulio Giannone, Piero Luigi Almasio, Pierina Richiusa and Carla Giordano

Int. J. Mol. Sci. 2023, 24(9), 8296; https://doi.org/10.3390/ijms24098296 - 5 May 2023

Cited by 3 | Viewed by 1824

Abstract

The increase in the incidence of thyroid nodules with cytological findings of TIR3b requires the identification of predictive factors of malignancy. We prospectively evaluated 2160 patients from January 2018 to June 2022 and enrolled 103 patients with indeterminate cytology TIR3b nodules who underwent [...] Read more.

The increase in the incidence of thyroid nodules with cytological findings of TIR3b requires the identification of predictive factors of malignancy. We prospectively evaluated 2160 patients from January 2018 to June 2022 and enrolled 103 patients with indeterminate cytology TIR3b nodules who underwent total (73 patients) and hemi-thyroidectomy (30 patients). Among them, 61 had a histological diagnosis of malignancy (30 classic papillary thyroid carcinoma, 19 had follicular papillary thyroid carcinoma variant, 3 had Hurtle cell carcinoma and 9 had follicular thyroid carcinoma), while 42 had a benign histology. Clinical, ultrasonographic and cytological characteristics were recorded. In addition, BRAF mutation was analysed. Patients with a histological diagnosis of malignancy had a higher frequency of nodule diameter ≤11 mm (p = 0.002), hypoechogenicity (p < 0.001), irregular borders (p < 0.001), peri- and intralesional vascular flows (p = 0.004) and microcalcifications (p = 0.001) compared to patients with benign histology. In contrast, patients with benign histology had more frequent nodules with a halo sign (p = 0.012) compared to patients with histological diagnosis of malignancy. No significant differences were found in BRAF mutation between the two groups. Our study suggests that the combination of ultrasonographic and cytological data could be more accurate and reliable than cytology alone in identifying those patients with TIR3b cytology and a histology of malignancy to be referred for thyroidectomy, thus reducing the number of patients undergoing thyroidectomy for benign thyroid disease. Full article

(This article belongs to the Special Issue Thyroid Hormone and Molecular Endocrinology)

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Review

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33 pages, 1490 KiB

Open AccessReview

A Comprehensive Review of Thyroid Eye Disease Pathogenesis: From Immune Dysregulations to Novel Diagnostic and Therapeutic Approaches

by Merve Kulbay, Stuti M. Tanya, Nicolas Tuli, Jade Dahoud, Andrea Dahoud, Fares Alsaleh, Bryan Arthurs and Christian El-Hadad

Int. J. Mol. Sci. 2024, 25(21), 11628; https://doi.org/10.3390/ijms252111628 - 29 Oct 2024

Cited by 2 | Viewed by 3861

Abstract

Thyroid eye disease is a complex inflammatory disorder of the orbit that has gained tremendous interest over the past years, and numerous scientific efforts have been deployed to elucidate its pathophysiology for novel drug development. Our manuscript will delve into the molecular dysregulations [...] Read more.

Thyroid eye disease is a complex inflammatory disorder of the orbit that has gained tremendous interest over the past years, and numerous scientific efforts have been deployed to elucidate its pathophysiology for novel drug development. Our manuscript will delve into the molecular dysregulations involved in the pathogenesis of thyroid eye disease that led to its clinical manifestations. Abnormalities within the apoptotic pathway, inflammatory cascade, and autoimmune regulatory systems will be covered. We will further discuss the challenges involved in its diagnosis and management and provide a summary of the current diagnostic tools (i.e., molecular biomarkers, diagnostic scores) from the perspective of clinicians. Finally, our comprehensive literature review will provide a thorough summary of most recent preclinical and clinical studies around the topic of thyroid eye disease, with an emphasis on the manuscripts published within the last five years. We believe our manuscript will bring novelty within the field by bridging the fundamental sciences with the clinical aspect of this disease. This review will be a great tool for clinicians in better understanding the pathogenesis of thyroid eye disease while providing an outlook on future perspectives (i.e., liquid biopsies, artificial intelligence). Full article

(This article belongs to the Special Issue Thyroid Hormone and Molecular Endocrinology)

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