Deiodinase Gene Research Articles

The Thr92Ala polymorphism in the type 2 deiodinase gene is linked to depression in patients with COVID-19 after hospital discharge.

The Thr92Ala-DIO2 polymorphism has been associated with clinical outcomes in hospitalized patients with COVID-19 and neuropsychiatric diseases. This study examines the impact of the Thr92Ala-DIO2 polymorphism on neuropsychological symptoms, particularly depressive symptoms, in patients who have had moderate to severe SARS-CoV-2 infection and were later discharged. Our prospective cohort study, conducted from June to August 2020, collected data from 273 patients hospitalized with COVID-19. This included thyroid function tests, inflammatory markers, hematologic indices, and genotyping of the Thr92Ala-DIO2 polymorphism. Post-discharge, we followed up with 68 patients over 30 to 45 days, dividing them into depressive (29 patients) and non-depressive (39 patients) groups based on their Beck Depression Inventory scores. We categorized 68 patients into three groups based on their genotypes: Thr/Thr (22 patients), Thr/Ala (41 patients), and Ala/Ala (5 patients). Depressive symptoms were less frequent in the Thr/Ala group (29.3%) compared to the Thr/Thr (59.1%) and Ala/Ala (60%) groups (p = 0.048). The Thr/Ala heterozygous genotype correlated with a lower risk of post-COVID-19 depression, as shown by univariate and multivariate logistic regression analyses. These analyses, adjusted for various factors, indicated a 70% to 81% reduction in risk. Our findings appear to be the first to show that heterozygosity for Thr92Ala-DIO2 in patients with COVID-19 may protect against post-COVID-19 depression symptoms up to 2 months after the illness.

Association between TSH suppression therapy and type 2 deiodinase gene polymorphism in differentiated thyroid carcinoma.

Oral levothyroxine (L-T4) suppression of thyroid-stimulating hormone (TSH) levels is the most commonly used clinical approach to manage and treat patients after thyroid cancer surgery. This study aimed to investigate the association between TSH suppression therapy and type 2 deiodinase gene (DIO2) polymorphism in differentiated thyroid carcinoma (DTC). A total of 240 patients with DTC who received total thyroidectomy (TT; 120) and hemithyroidectomy (HT; 120) were enrolled in this study. The serum TSH, free triiodothyronine (FT3), and free thyroxine (FT4) levels were detected using an automatic serum immune analyser and electrochemiluminescence immunoassay. Based on the results of DIO2 gene detection, 3 genotypes of Thr92Ala were detected. The serum TSH levels were inhibited after oral L-T4 treatment, but the proportion of patients who reached the TSH suppression standard in the hemithyroidectomy group was higher than in the total thyroidectomy group. After TSH suppression treatment, serum FT4 levels were increased in both total thyroidectomy and hemithyroidectomy. The difference in serum TSH, FT3, and FT4 levels was associated with different genotypes, and patients with high cytosine cytosine (CC) genotypes may have difficulty meeting the TSH suppression criteria. Patients who underwent total thyroidectomy exhibited higher postoperative serum FT4 levels than patients in the hemithyroidectomy group after TSH suppression therapy. The Thr92Ala polymorphism of type 2 deiodinase (D2) was associated with TSH suppression therapy.

The Association of Iodothyronine Deiodinase Gene Polymorphisms and Hashimoto's Thyroiditis: Does Free T3 Play a Role?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Cloning and expression of two isoforms of deiodinase gene DIO3 in spotted sea bass (Lateolabrax maculatus)

Type 3 iodothyronine deiodinase (DIO3) is a key enzyme for thyroid hormones, which plays a role in the growth and development of animals. In this study, we identified and cloned two isoforms of DIO3 (LmDIO3a and LmDIO3b) from spotted sea bass (Lateolabrax maculatus). The nucleotide sequences of both LmDIO3a and LmDIO3b had a SECIS (SElenoCysteine Insertion Sequence) element and a T4 domain, and the deduced amino acid sequence similarity was 64.42 %. The mRNAs of both LmDIO3 isoforms were widely distributed in the brain, with high expression levels in the hypothalamus, pituitary, telencephalon and saccus vasculosus (SV). In the non-brain tissues, the expression of LmDIO3a was higher in the retina, heart and spleen, while LmDIO3b was highly expressed in the head kidney and skin. The expression levels of LmDIO3a and LmDIO3b in the hypothalamus and SV were lower in the early stage of gonadal development. However, the expression levels of both in the hypothalamus increased significantly in the stage IV of gonadal development, but in the SV were up-regulated significantly in the stage V. The photoperiod experiment showed that the expressions of them were promoted by short photoperiod (8L:16D) and inhibited by long photoperiod (16L:8D) in the hypothalamus. In the SV, their expression trends were consistent (They firstly decreased, and then increased). In the pituitary, the expression of LmDIO3a presented a trend of up and down, while the expression of LmDIO3b showed an opposite trend. In the gonad, long photoperiod promoted the expression of LmDIO3a, but inhibited the expression of LmDIO3b (P < 0.05). There was no significant change in the expression of LmDIO3a in the retina, but the expression of LmDIO3b was significantly inhibited by short photoperiod and promoted by long photoperiod (P < 0.05). That different tissues have different responses to photoperiod, indicating photoperiod induction may have tissue specificity. Altogether, this study provides a reference for further research on the photoperiod regulation mechanism of DIO3 gene in fish.

Polymorphisms of Placental Iodothyronine Deiodinase Genes in a Rural Area of Northern China with High Prevalence of Neural Tube Defects

Introduction: We have reported that high total homocysteine and the coexistence of inadequate thyroid hormones in maternal serum increase the risk of fetal neural tube defects (NTDs). Placental iodothyronine deiodinases (DIOs: DIO1, DIO2, and DIO3) play a role in regulating the conversions between different forms of maternal thyroid hormones. This study hypothesized that single nucleotide polymorphisms (SNPs) in placental DIOs genes could be related to NTDs. Methods: We performed a case-control study from 2007 to 2009 that included pregnant women from Lüliang, Shanxi Province, China. Nine distinct SNPs in DIOs genes were analyzed, and placental samples were obtained from 83 pregnant women with NTD fetuses and 90 pregnant women with normal fetuses. The nine SNPs were analyzed using the Cochran-Armitage test and the Fisher’s exact test. Results: There were no statistically significant differences between case and control in the nine SNPs of DIOs (p > 0.05). Conclusions: The results of this study suggested that SNPs of DIO genes in the placenta among pregnant women have no statistically significant difference between the two groups, suggesting that other factors might be involved in metabolism of maternal thyroid hormone provided to fetuses, such as epigenetic modification of methylation and homocysteinylation and genomic imprinting in the placenta. Further functional studies on placenta samples are necessary.

Factors of local conversion of iodothyronines correlate with indicators of hormonal, biochemical, and hematological profiles in patients with spinal canal and dural sac stenosis of the lumbar spine

In order to find out the mechanisms of pathogenesis of degenerative-dystrophic diseases of the spine, it is of particular interest to search for body parameters which are directly or indirectly interrelated with the key factors of peripheral conversion of nidus iodothyronines and constitute a system of network interactions, affecting metabolic indicators at the local and systemic level.The aim. To search for correlations of local key factors of peripheral conversion of Ligamentum flavum iodothyronines with indicators of biochemical, hematological and hormonal blood profiles of patients with stenosing processes of the spinal canal and dural sac in the lumbar spine.Materials and methods. 33 patients (15 males, 18 females) with stenosing processes of the spinal canal and dural sac in the lumbar spine were examined (mean age – 45.73 ± 1.95 years). The expression of deiodinase genes and other candidate genes was determined in Ligamentum flavum biopsies collected during surgical treatment. Biochemical, hematological and hormonal parameters were determined in peripheral blood. The resulting data array was processed in order to find correlations between the parameters of systemic and local metabolism.Results. The relationships of deiodinases with the expression of GDF5, MMP1, MMP3 and TIMP1 in Ligamentum flavum (p &lt; 0.05) were found. Of the hormonal profile of the blood serum, the most significant indicators were thyreotropin, free triiodothyronine and thyroperoxidase antibodies. In the biochemical profile, levels of direct bilirubin, total cholesterol, HDL and LDL cholesterol and triglycerides changed along with the expression of deiodinases. Correlative relationships with the expression of deiodinases were found for the following hematological analytes of whole peripheral blood: hemoglobin, mean corpuscular hemoglobin concentration, numbers of granulocytes, lymphocytes, eosinophils, monocytes, band neutrophils, red cell distribution width and platelet crit. The data obtained indicate the involvement of peripheral conversion factors in the pathogenetic process and provide information to form a new view on the pathogenesis of degenerative-dystrophic processes in the Ligamentum flavum of patients with stenosing processes of the spinal canal and the dural sac in the lumbar spine.

Alterations of DNA methylation and expression of genes related to thyroid hormone metabolism in colon epithelium of obese patients

BackgroundColorectal cancer is common among obese individuals. The purpose of the current study was to determine changes in DNA methylation status and mRNA expression of thyroid hormone receptor beta (THRB), as a tumor suppressor, and thyroid hormone inactivating enzyme, type 3 deiodinase (DIO3) genes, in human epithelial colon tissues of healthy obese individuals.MethodsColon biopsies were analyzed by methylation sensitive-high resolution melting (MS-HRM) to investigate promoter methylation of DIO3 and THRB, and by quantitative real-time polymerase chain reaction to assay expression of DIO3 and THRB mRNA on eighteen obese and twenty-one normal-weight healthy men.ResultsThere was no significant difference in mean methylation levels at the THRB promoter region between the two groups. Nevertheless, obesity decreased THRB expression levels, significantly (P < 0.05; fold change: 0.19). Furthermore, obesity attenuated DNA methylation (P < 0.001) and enhanced mRNA expression of DIO3 (P < 0.05; fold change: 3).ConclusionsOur findings suggest that obesity may alter expression of THRB and DIO3 genes through epigenetic mechanism. Alterations of THRB and DIO3 expressions may predispose colon epithelium of obese patients to neoplastic transformation.

Association between phenols and thyroid hormones: The role of iodothyronine deiodinase genes

Previous literature on prenatal phenol exposure and thyroid hormone (TH) alteration is conflicting, and the possible mechanisms of action involved remain unclear. We aimed to examine the association between prenatal phenol exposure and levels of maternal and neonatal THs, as well as the possible role of iodothyronine deiodinase (DIO) gene polymorphisms in this relation.We studied 387 Spanish mother–neonate pairs with measurements of maternal phenols, total triiodothyronine (TT3) and free thyroxine (FT4), maternal and neonatal thyroid-stimulating hormone (TSH), and maternal genotypes for single nucleotide polymorphisms in the DIO1(rs2235544) and DIO2(rs12885300) genes. We implemented multivariate linear and weighted quantile sum (WQS) regressions to examine the association between phenols and THs (including sex-stratified models for neonatal TSH) and investigated effect modification of genotypes in the maternal phenol-TH associations.In single exposure models, we found negative associations between maternal triclosan (TCS) and neonatal TSH (% change [95%CI]: −2.95 [-5.70, -0.11], per twofold phenol increase) – stronger for girls – and less clearly for maternal ethylparaben (EPB) and TSH (−2.27 [-4.55, 0.07]). In phenol mixture models, we found no association with THs. In the genetic interaction models, we found some evidence of effect modification of DIO gene polymorphisms with stronger negative associations between methylparaben (MPB), propylparaben (PPB), butylparaben (BPB) and TT3 as well as bisphenol A (BPA) and FT4 for DIO1(rs2235544)-CC. Stronger inverse associations for genotypes DIO2(rs12885300)-CC and DIO2(rs12885300)-CT and positive ones for DIO2(rs12885300)-TT were also reported for BPA and FT4.In conclusion, we found some evidence of an association between phenols and TSH during pregnancy and at birth in single exposure models, the latter being stronger for girls. Since no association was observed between maternal levels of phenols and TT3 or FT4, the possible role of the genetic background in these associations warrants further investigation.

Knockdown of Two Iodothyronine Deiodinase Genes Inhibits Epinephrine-Induced Larval Metamorphosis of the Hard-Shelled Mussel Mytilus coruscus

The metamorphosis process is a critical life-changing event for marine invertebrate planktonic larvae to transform into benthic adults, which is crucial for the shellfish bed’s ecosystem stability and seed production in aquaculture. The mechanism of neuroendocrine regulation in the larval metamorphosis of bivalves remains ambiguous. In the present study, the expression of two deiodinase genes, McDx and McDy, was analyzed by whole-mount in situ hybridization at four larval stages in the hard-shelled mussel Mytilus coruscus. The McDx and McDy localized in visceral tissues, nervous system, mantle, and velum, indicating that two deiodinase genes are essential for larval development in M. coruscus. Knockdown of the McDx and McDy in the pediveliger larvae of M. coruscus using electroporation of siRNA significantly (p &amp;lt; 0.001) reduced McDx and McDy expression. McDx and McDy knockdown reduced larval metamorphosis in 45% and 49% of the pediveliger larvae induced by epinephrine (EPI). It is hypothesised that the knockdown effects of McDx and McDy repress metamorphic induction rather than larval viability, which does not elicit a lethal effect. The present study corroborates a synergistic action of the adrenergic and thyroid hormones signalling pathway in M. coruscus, and suggests the role of McDx and McDy in larval development and metamorphic transition.

Type 2 deiodinase p.Thr92Ala polymorphism does not affect the severity of obesity and weight loss after bariatric surgery

A single nucleotide polymorphism in the Type 2 deiodinase (DIO2) gene (p.Thr92Ala) was found to be associated with hypertension, type 2 diabetes mellitus (T2DM), insulin resistance, and body mass index (BMI). We retrospectively evaluated 182 patients to assess whether the DIO2 p.Thr92Ala was associated with severe obesity and response to bariatric surgery. Genomic DNA was extracted from peripheral blood leukocytes before surgery. Glycemic control parameters, cardiometabolic risk biomarkers (waist circumference, lipid assessment and blood pressure) and hormonal parameters were assessed at baseline and after surgery. Based on genotype evaluation, 78/182 (42.9%) patients were homozygous wild-type (Thr/Thr), 83/182 (45.6%) heterozygous (Thr/Ala), and 21/182 (11.5%) rare homozygous (Ala/Ala). Age at the time of the first evaluation in our Unit was significantly lower in patients with DIO2 p.Thr92Ala. No significant association was observed between DIO2 p.Thr92Ala and BMI, excess weight, waist circumference, Homa Index. The prevalence of comorbidities was not associated with allele distribution except for hypertension that was more frequent in wild-type patients (p = 0.03). After bariatric surgery, excess weight loss (EWL) % and remission from comorbidities occurred without differences according to genotypes. DIO2 p.Thr92Ala does not affect the severity of obesity and its complications, but it seems to determine an earlier onset of morbid obesity. The presence of polymorphism seems not to impact on the response to bariatric surgery, both in terms of weight loss and remission of comorbidities.

The Association between Phenols and Thyroid Hormones: The Role of Iodothyronine Deiodinase Genes

The Association between Phenols and Thyroid Hormones: The Role of Iodothyronine Deiodinase Genes

PSVI-17 Dissimilarities in thyroid profiles and pregnancy rates in dairy cows with different polymorphic variants of the DIO1 gene

Abstract Thyroid hormones are implicated in regulation of the reproductive function in cattle. In turn, thyroid metabolism is determined by the activity of different types deiodinases. Our research was aimed to compare post-insemination thyroid profiles and pregnancy rates in dairy cows with different SNP genotypes in the deiodinase gene of the first type (DIO1). Thirty lactating Russian Black Pied cows were synchronized using the Ovsynch protocol and artificially inseminated (AI). Blood samples from the cows were collected on Days 0, 7, 14, 21, and 33 after AI. Hormonal levels in the serum were measured by ELISA. Pregnancy was confirmed by progesterone concentrations and ultrasonography. Genetic variants for the DIO1 gene were tested by RT-PCR and polymorphism at position 13149 (NC_037330) was found. The occurrence frequency of cows with genotypes CC, CG, and GG was 43.3, 33.3, and 23.3 %, respectively. A proportion of pregnant cows in the CC group was higher than in the CG group (84.6 vs. 40.0%, P &amp;lt; 0.05) and tended to be higher than in the GG group (42.9%). The concentration of triiodothyronine (T3) in the blood of CC animals did not change during the studied period, whereas that in CG animals decreased between Days 0 and 14 (from 1.60±0.21 to 1.10±0.22 nmol/L, P &amp;lt; 0.05). Concurrently, the T3 concentration on Day 0 was 1.4 times lower (P &amp;lt; 0.05) in the CC group than in the CG group. Furthermore, the level of reverse T3 on Day 7 in the GG group was 1.3 times higher (P &amp;lt; 0.05) than in the CC or CG groups. Thus, cows with DIO1 gene CC genotype have a higher reproductive ability than cows with CG or GG genotypes, which may be due to peculiarities of thyroid profiles during the first two weeks of pregnancy. The study was supported by Russian Ministry of Science and Higher Education (0445-2021-0004).

Larval metamorphosis is inhibited by methimazole and propylthiouracil that reveals possible hormonal action in the mussel Mytilus coruscus

Larval metamorphosis in bivalves is a key event for the larva-to-juvenile transformation. Previously we have identified a thyroid hormone receptor (TR) gene that is crucial for larvae to acquire “competence” for the metamorphic transition in the mussel Mytilus courscus (Mc). The mechanisms of thyroid signaling in bivalves are still largely unknown. In the present study, we molecularly characterized the full-length of two iodothyronine deiodinase genes (McDx and McDy). Phylogenetic analysis revealed that deiodinases of molluscs (McDy, CgDx and CgDy) and vertebrates (D2 and D3) shared a node representing an immediate common ancestor, which resembled vertebrates D1 and might suggest that McDy acquired specialized function from vertebrates D1. Anti-thyroid compounds, methimazole (MMI) and propylthiouracil (PTU), were used to investigate their effects on larval metamorphosis and juvenile development in M. coruscus. Both MMI and PTU significantly reduced larval metamorphosis in response to the metamorphosis inducer epinephrine. MMI led to shell growth retardation in a concentration-dependent manner in juveniles of M. coruscus after 4 weeks of exposure, whereas PTU had no effect on juvenile growth. It is hypothesized that exposure to MMI and PTU reduced the ability of pediveliger larvae for the metamorphic transition to respond to the inducer. The effect of MMI and PTU on larval metamorphosis and development is most likely through a hormonal signal in the mussel M. coruscus, with the implications for exploring the origins and evolution of metamorphosis.

ABCD of Thyroid Hormone Action: After and Before Cloning of Deiodinase Genes.

ABCD of Thyroid Hormone Action: After and Before Cloning of Deiodinase Genes.

Improvement of Treatment Resistant Depression in a Patient With Primary Hypothyroidism and Thr92Ala5’ Type 2 Deiodinase Gene Polymorphism With Multiple Daily Doses of Triiodothyronine

Introduction: The augmentation pharmacologic therapy used in patients with treatment-resistant depression (TRD) includes drugs such as lithium, buspirone, triiodothyronine (LT3) and other drugs. We report a patient with TRD and primary hypothyroidism who responded to a combination of LT3, given in divided doses, and levothyroxine (LT4), rather than LT4 alone, even though the serum TSH levels were in the normal range with these treatments. Interestingly, the patient had a Thr92Ala5’ type 2 deiodinase polymorphism. Case Report: A 54-year old male presented to our emergency room with suicidal ideation 8 years ago. The patient had severe depression and developed uncontrollable urges to surf the internet, generally prohibited sites, approximately 3 months prior to his visit to the emergency room. He had noted a 12-lbs weight gain, cold intolerance, dry skin, and excessive sleepiness for 3 months. Patient was admitted to the psychiatry ward and laboratory testing showed a serum TSH 180 µIU/mL, FT4 0.48 ng/dL, total T3 46 ng/mL, and TPO antibody 278 IU/mL. A thyroid ultrasound was consistent with Hashimoto’s thyroiditis. A diagnosis of major depressive disorder and primary hypothyroidism was made. He was started on citalopram (20 mg/day) and levothyroxine (175 mcg/day). The Beck Depression Scores (BDS) during the initial weeks was 37.5 ± 5.1 (Mean ± SD) (normal 0-9) with corresponding TSH 164 ± 133 µIU/mL, FT4 0.70 ± 0.25 ng/dL, and total T3 61 ± 7.9 ng/mL. Two weeks later the dose of citalopram was increased to 40 mg/day and then buspirone 10 mg/day was added. At the end of 11 months the BDS was 27.81 ± 2.1 with a corresponding TSH 1.5 ± 0.1 µIU/mL. After 4 months, 7.5 mg of aripiprazole was added. After 11 months of treatment, he was treated with a combination of LT4 + LT3 (5 mcg once daily) and TSH became 0.76 ± 0.1 µIU/mL with a corresponding BDS of 18.0 ± 1.9. Twelve months later, the patient was switched back to LT4 alone and during LT4 treatment the BDS score was 24.2 ± 22.2 with a TSH of 1.44 ± 0.11. Nine months later patient was changed to LT4 + LT3 (5 mcg three times daily) and his BDS score was 10.3 ± 1.2 with a TSH of 0.72 ± 0.09 µIU/mL. When he was on LT4 + LT3 TID he was able to discontinue all the antidepressant drugs and he had no urge to surf on internet. His depression was controlled by over-the-counter antidepressant drugs (S-adenosylmethionine and rhodiola). A genetic test confirmed Thr92Ala5’ type 2 deiodinase polymorphism. Discussion and Conclusion: In our patient, there was a good correlation between the BDS improvement and the serum T3 levels (r: -0.7 p-value: 0.01). Thus, in patient with Thr92Ala5’ type 2 deiodinase polymorphism TID T3 dosing may significantly improve depression. Additional studies are needed.

The Deiodinases: Their Identification and Cloning of Their Genes.

In this minireview, we provide a historical outline of the events that led to the identification and characterization of the deiodinases, the recognition that deiodination plays a major role in thyroid hormone action, and the cloning of the 3 deiodinase genes. The story starts in 1820, when it was first determined that elemental iodine was important for normal thyroid function. Almost 100 years later, it was found that the primary active principle of the gland, T4, contains iodine. Once radioactive iodine became available in the 1940s, it was demonstrated that the metabolism of T4 included deiodination, but at the time it was assumed to be merely a degradative process. However, this view was questioned after the discovery of T3 in 1952. We discuss in some detail the events of the next 20 years, which included some failures followed by the successful demonstration that deiodination is indeed essential to normal thyroid hormone action. Finally, we describe how the 3 deiodinases were identified and characterized and their genes cloned.

Assessment of children in the autistic spectrum disorder that carry the Thr92Ala-DIO2 polymorphism.

A polymorphism in the type 2 deiodinase (Thr92Ala-DIO2) gene has been associated with behavioral and cognitive dysfunction as well as neurodegeneration and oxidative stress in the central nervous system. To test whether the minor allele (Ala92) frequency (MAF) is increased in children in the autism spectrum disorder (ASD), and whether carriers of the minor allele exhibit more severe symptoms and/or worse adaptive behavior. ASD children were evaluated at baseline and yearly throughout the study by psychologists using the following tools: autism behavior checklist, Vineland Adaptative Behaviour Scales II, non-verbal intelligence test SON-R 21/2-7, SON-R 6-40, Weschler scale for intelligence, and autism treatment evaluation checklist. Academic outpatient mental health facility in Sao Paulo, Brazil. ASD boys and girls younger than 18years of age. 132 consecutive ASD children, mostly boys (~ 80%); ~ 50% was classified as verbal. Exclusion criteria were coexistence of sensory and/or physical impairment, or any associated genetic syndromes. Median follow-up was for an uninterrupted period of 937days (139-1375days), which did not vary significantly among the genotypes. The MAF was 47% in ASD patients vs. 51% in a local reference population with similar ethnic background; the clinical severity and progression were not affected by the minor allele. Carriers of the minor allele exhibited higher adaptive behavior in the domains "daily living skills" and "communication", which correlated positively with the dose of the minor allele. The MAF is not different in ASD children, but carriers of the Thr92Ala-DIO2 polymorphism exhibited higher adaptive behavior.

Ethionamide Alters Thyroid Receptor Gene Expression in Rats' Muscle

BACKGROUND: Ethionamide usage as one of the drug regimens still becomes a challenge due to high numbers of patients developing hypothyroid. Ethionamide had been associated with the inhibition of thyroid hormone (TH) synthesis and interestingly, ethionamide (C8H10N2S)-induced hypothyroidism is supported by its similar structure with thioamides, propythiouracil (C7H8N2S). However, hypothyroidism is not solely caused by its production, it could be caused by signaling alteration. Therefore, knowing that important TH action is determined via genomic pathway, alteration of this receptor could bring serious clinical problem. Unfortunately, there is limited study about the regulation of ethionamide and its connection on TH genomic signaling especially thyroid hormone receptor (TR) gene expression in soleus, gastrocnemius and cardiac muscle.METHODS: Thirty-eight rats were divided into control, ethionamide and propylthiouracyl groups. After 12-week treatment, rat were sacrificed, then gastrocnemius, soleus and cardiac muscles were dissected out, snap freezed using liquid nitrogen, and stored in -80oC until use. RNA was extracted and run for reverse transcription polymerase chain reaction (RT-PCR).RESULTS: In soleus muscle, ethionamide stimulated TR mRNA expressions and deiodinase compared to control group. In contrast, TRα1 gene expression was not affected by ethionamide administration. In gastrocnemius muscle, only TRβ1 gene and Dio2 gene expressions that were significantly increased compared to control group. In cardiac muscle, ethionamide significantly stimulated all the thyroid hormone receptor isoform and iodothyronine deiodinase gene expression compared to the control group.CONCLUSION: Long ethionamide treatment upregulates TR gene expressions and deiodinase in soleus and cardiac muscle, there is different expression pattern of soleus, gastrocnemius and cardiac muscle after ethionamide stimulation.KEYWORDS: ethionamide, hypothyroid, TRα1, TRα2, TRβ1, TRβ2

Targeting the right population for T3 + T4 combined therapy: where are we now and where to next?

The universal applicability of levothyroxine (LT4) monotherapy for the treatment of hypothyroidism has been questioned in recent years. Indeed, it is now clear that about 10-15% of LT4-treated hypothyroid patients are dissatisfied with their treatment. It is plausible that this subset of hypothyroid patients may need T3 + T4 combined therapy to restore peripheral euthyroidism. To address this issue, many clinical trials have investigated the effect of T3 + T4 combinations versus standard LT4-based therapy. However, to date, results have been inconclusive, mainly due to the lack of markers that identify candidates for combination therapy. A breakthrough in this field came with the recent finding that several single-nucleotide polymorphisms in the deiodinase genes are associated with the persistence of hypothyroid symptoms in biochemically euthyroid LT4-treated patients, and are thus markers of candidates for combination therapy. In addition, whole-genome association studies are expanding our knowledge of other genes of the thyroid hormone (TH) pathway that affect serum TH levels. To target the right population for the T3 + T4 combined therapy, the next step is to translate these new findings into prospective trials. Hopefully, this will pave the way to personalized therapy for each hypothyroid patient.

Deregulated expression of the imprinted DLK1-DIO3 region in glioblastoma stemlike cells: tumor suppressor role of lncRNA MEG3.

BackgroundGlioblastoma (GBM) stemlike cells (GSCs) are thought to be responsible for the maintenance and aggressiveness of GBM, the most common primary brain tumor in adults. This study aims at elucidating the involvement of deregulations within the imprinted delta-like homolog 1 gene‒type III iodothyronine deiodinase gene (DLK-DIO3) region on chromosome 14q32 in GBM pathogenesis.MethodsReal-time PCR analyses were performed on GSCs and GBM tissues. Methylation analyses, gene expression, and reverse-phase protein array profiles were used to investigate the tumor suppressor function of the maternally expressed 3 gene (MEG3).ResultsLoss of expression of genes and noncoding RNAs within the DLK1-DIO3 region was observed in GSCs and GBM tissues compared with normal brain. This downregulation is mainly mediated by epigenetic silencing. Kaplan–Meier analysis indicated that low expression of MEG3 and MEG8 long noncoding (lnc)RNAs significantly correlated with short survival in GBM patients. MEG3 restoration impairs tumorigenic abilities of GSCs in vitro by inhibiting cell growth, migration, and colony formation and decreases in vivo tumor growth, reducing infiltrative growth. These effects were associated with modulation of genes involved in cell adhesion and epithelial-to-mesenchymal transition (EMT).ConclusionIn GBM, MEG3 acts as a tumor suppressor mainly regulating cell adhesion, EMT, and cell proliferation, thus providing a potential candidate for novel GBM therapies.