Thyroid Hormone Analogues Research Articles

Cell-Specific Transport and Thyroid Hormone Receptor Isoform Selectivity Account for Hepatocyte-Targeted Thyromimetic Action of MGL-3196.

Thyroid hormones (THs) and TH receptor-beta (TRβ) reduce hepatic triglycerides, indicating a therapeutic potential for TH analogs in liver steatosis. To avoid adverse extrahepatic, especially TRα-mediated effects such as tachycardia and bone loss, TH analogs with combined TRβ and hepatocyte specificity are desired. MGL-3196 is a new TH analog that supposedly meets these criteria. Here, we characterize the thyromimetic potential of MGL-3196 in cell-based assays and address its cellular uptake requirements. We studied the contribution of liver-specific organic anion transporters (OATP)1B1 and 1B3 to MGL-3196 action. The TR isoform-specific efficacy of MGL-3196 compared with 3,5,3'-triiodothyronine (T3) was determined with luciferase assays and gene expression analysis in OATP1B1 and OATP1B3 and TRα- or TRβ-expressing cells and in primary murine hepatocytes (PMHs) from wild-type and TRβ knockout mice. We measured the oxygen consumption rate to compare the effects of MGL-3196 and T3 on mitochondrial respiration. We identified OATP1B1 as the primary transporter for MGL-3196. MGL-3196 had a high efficacy (90% that of T3) in activating TRβ, while the activation of TRα was only 25%. The treatment of PMHs with T3 and MGL-3196 at EC50 resulted in a similar induction of Dio1 and repression of Serpina7. In HEK293 cells stably expressing OATP1B1, MGL-3196 had comparable effects on mitochondrial respiration as T3. These data indicate that MGL-3196's hepatic thyromimetic action, the basis for its therapeutic use, results from a combination of hepatocyte-specific transport by OATP1B1 and the selective activation of TRβ over TRα.

Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency.

A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. MCT8 transports thyroid hormones across cell membranes. While thyroid hormone analogues improve peripheral changes of MCT8 deficiency, no treatment of the neurological symptoms is available so far. Therefore, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased tri-iodothyronine (T3) levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.

Thyroid hormone resistance: Mechanisms and therapeutic development

As an essential primary hormone, thyroid hormone (TH) is indispensable for human growth, development and metabolism. Impairment of TH function in several aspects, including TH synthesis, activation, transportation and receptor-dependent transactivation, can eventually lead to thyroid hormone resistance syndrome (RTH). RTH is a rare syndrome that manifests as a reduced target cell response to TH signaling. The majority of RTH cases are related to thyroid hormone receptor β (TRβ) mutations, and only a few RTH cases are associated with thyroid hormone receptor α (TRα) mutations or other causes. Patients with RTH suffer from goiter, mental retardation, short stature and bradycardia or tachycardia. To date, approximately 170 mutated TRβ variants and more than 20 mutated TRα variants at the amino acid level have been reported in RTH patients. In addition to these mutated proteins, some TR isoforms can also reduce TH function by competing with primary TRs for TRE and RXR binding. Fortunately, different treatments for RTH have been explored with structure-activity relationship (SAR) studies and drug design, and among these treatments. With thyromimetic potency but biochemical properties that differ from those of primary TH (T3 and T4), these TH analogs can bypass specific defective transporters or reactive mutant TRs. However, these compounds must be carefully applied to avoid over activating TRα, which is associated with more severe heart impairment. The structural mechanisms of mutation-induced RTH in the TR ligand-binding domain are summarized in this review. Furthermore, strategies to overcome this resistance for therapeutic development are also discussed.

A novel variant in SLC16A2 associated with typical Allan-Herndon-Dudley syndrome: a case report

BackgroundAllan-Herndon-Dudley syndrome (AHDS) is an X-linked recessive neurodegenerative disorder caused by mutations in the SLC16A2 gene that encodes thyroid hormone transporter. AHDS has been rarely reported in China.Case presentationThis study reported a novel splicing mutation in the SLC16A2 gene in an 18-month-old male patient with AHDS. The patient was born to non-consanguineous, healthy parents of Chinese origin. He passed new-born screening for hypothyroidism, but failed to reach developmental milestones. He presented with hypotonia, severe mental retardation, dysarthria and ataxia. Genetic analysis identified a novel splicing mutation, NM_006517.4: c.431-2 A > G, in the SLC16A2 gene inherited from his mother. The patient received Triac treatment, (triiodothyroacetic acid), a thyroid hormone analogue for 3 months. Triac treatment effectively reduced serum TSH concentrations and normalized serum T3 concentrations in the patient.ConclusionsThis study reported the first case of AHDS treated by Triac in China. And the study expanded the mutational spectrum of the SLC16A2 gene in AHDS patients.

In Vivo Clearance of Apoptotic Debris From Tumor Xenografts Exposed to Chemically Modified Tetrac: Is There a Role for Thyroid Hormone Analogues in Efferocytosis?

Apoptosis is induced in cancer cells and tumor xenografts by the thyroid hormone analogue tetraiodothyroacetic acid (tetrac) or chemically modified forms of tetrac. The effect is initiated at a hormone receptor on the extracellular domain of plasma membrane integrin αvβ3. The tumor response to tetrac includes 80% reduction in size of glioblastoma xenograft in two weeks of treatment, with absence of residual apoptotic cancer cell debris; this is consistent with efferocytosis. The molecular basis for efferocytosis linked to tetrac is incompletely understood, but several factors are proposed to play roles. Tetrac-based anticancer agents are pro-apoptotic by multiple intrinsic and extrinsic pathways and differential effects on specific gene expression, e.g., downregulation of the X-linked inhibitor of apoptosis (XIAP) gene and upregulation of pro-apoptotic chemokine gene, CXCL10. Tetrac also enhances transcription of chemokine CXCR4, which is relevant to macrophage function. Tetrac may locally control the conformation of phagocyte plasma membrane integrin αvβ3; this is a cell surface recognition system for apoptotic debris that contains phagocytosis signals. How tetrac may facilitate the catabolism of the engulfed apoptotic cell debris requires additional investigation.

S1156 Hypothyroidism-Related Development of Non-Alcoholic Fatty Liver Disease - Is Levothyroxine the Answer?

Introduction: Non-alcoholic fatty liver disease (NAFLD) refers to fatty infiltration of the liver, with or without inflammation and fibrosis. NAFLD is the most common cause of liver disease in Western countries. Numerous studies have demonstrated a positive association between hypothyroidism and the development of non-alcoholic fatty liver disease. It has been proposed that treatment with thyroid hormone could reduce the risk of developing liver disease. Our aim is to determine if hypothyroidism patients treated with levothyroxine, a thyroid hormone analogue, are at lower risk of developing NAFLD and cirrhosis. Methods: We performed a retrospective analysis in the IBM Explorys database (1999-2021), a pooled, de-identified clinical database of over 75 million unique patients across the United States. Patient populations were identified using SNOMED and ICD codes. Inclusion criteria were patients with hypothyroidism and patients taking levothyroxine. Adverse events included a diagnosis of NAFLD, non-alcoholic steatohepatitis (NASH), or cirrhosis. Odds ratios (OR) with a 95% confidence interval (CI) were calculated for NAFLD/NASH and cirrhosis in hypothyroidism and patients on levothyroxine. Results: 3,720,320 patients with hypothyroidism were included in this study. Patients with hypothyroidism were at increased risk of developing NAFLD/NASH (OR 7.8058, 95% CI 7.6617 to 7.9527, P-value < 0.0001) or cirrhosis (OR 5.7648, 95% CI 5.7176 – 5.8124, P-value < 0.0001). Patients taking levothyroxine were not at lower risk of developing NASH/NAFLD (OR 6.7248, 95% CI 6.5265 to 6.9291, P-value < 0.0001) or cirrhosis (OR 4.3715, 95% CI 4.3069 to 4.4371, P-value < 0.0001). Conclusion: Our study confirmed a positive clinical association between hypothyroidism and the development of liver disease such as NAFLD/NASH and cirrhosis. Treatment of hypothyroidism with levothyroxine did not positively impact the progression of liver disease to NAFLD/NASH or cirrhosis. Further research is needed to understand how to modulate thyroid hormone to decrease the progression of liver disease in hypothyroid patients.

A UNIQUE CASE OF HEART FAILURE: COXSACKIE DILATED CARDIOMYOPATHY

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Dilated cardiomyopathy is characterized by structural defects leading to impaired ventricular function. The etiology is often elusive. Viruses are some of the most common causes world-wide (1). Here we present a male with non-ischemic cardiomyopathy and heart failure due to Coxsackie B myocarditis. CASE PRESENTATION: A 36 year old male with history of heart failure with reduced ejection fraction (35%), non-ischemic cardiomyopathy, and ventricular tachycardia presented for syncope. He was found to be in cardiogenic shock. Work-up revealed an elevated troponin and NT-proBNP, 0.064 and 5570, acute kidney injury, creatinine 3.28, and congestive hepatopathy. Prior cardiac work-up consisted of a left and right heart catheterization which showed no atherosclerotic disease and elevated filling pressures (Pulmonary Capillary Wedge Pressure 16 and Pulmonary Artery Mean Pressure 33). Cardiac MRI showed global dilation of the cardiac chambers, global hypokinesis, and late gadolinium enhancement of the base and septum. This was suggestive of dilated cardiomyopathy and prior myocarditis. Echocardiogram revealed a severe decline in ejection fraction, < 15%, and EKG showed a widened QRS complex with left bundle branch block. Serologic tests were positive for Coxsackie B antibodies. Inotropic support was initiated. Bridge therapy and heart transplant were indicated. However, due to his uninsured status and COVID-19 restrictions, he was unable to be transferred to a heart transplant center. Cardiac Resynchronization Therapy was pursued instead. He was clinically stabilized, initiated on GDMT, and was discharged with close follow-up. Even though serologic antibodies lack specificity, given the history, cardiac MRI findings, and diagnosis of NICM, his clinical picture was presumed to be due to Coxsackie B. DISCUSSION: Myocarditis is an inflammatory condition of the myocardium. Viral is the most common cause in Western nations but Rheumatic and Chagas remain prevalent in the developing world. Diagnosis is confirmed with endomyocardial biopsy. This makes it difficult to ascertain the true incidence but there are approximately 1.5 million cases every year. COVID-19 has been frequently associated with myocardial injury and clinical myocarditis. In most cases, tissue diagnosis is lacking. Viral myocarditis can lead to dilated cardiomyopathy through a variety of mechanisms. It is hypothesized to be the result of direct toxicity via receptor mediated entry or an autoimmune response against viral fragments that are not cleared (2). CONCLUSIONS: Unfortunately, this case highlights the disparities of our healthcare system and how that can directly impact patient care. Viral myocarditis remains a difficult clinical scenario. Treatment is largely supportive but the sequelae of disease can be severe. Antivirals and interferon therapy are promising but further research is needed to explore more pharmacologic options (3). REFERENCE #1: Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342:1077. REFERENCE #2: Kang M, An J. Viral Myocarditis. [Updated 2021 May 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459259/ REFERENCE #3: Coletta AP, Clark AL, Cleland JG. Clinical trials update from the Heart Failure Society of America and the American Heart Association meetings in 2008: SADHART-CHF, COMPARE, MOMENTUM, thyroid hormone analogue study, HF-ACTION, I-PRESERVE, beta-interferon study, BACH, and ATHENA. Eur J Heart Fail 2009; 11:214. DISCLOSURES: No relevant relationships by Adhish Singh, source=Web Response No relevant relationships by Michael Vu, source=Web Response

Monocarboxylate Transporter 8 Deficiency: From Pathophysiological Understanding to Therapy Development.

Genetic defects in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in MCT8 deficiency. This disorder is characterized by a combination of severe intellectual and motor disability, caused by decreased cerebral thyroid hormone signalling, and a chronic thyrotoxic state in peripheral tissues, caused by exposure to elevated serum T3 concentrations. In particular, MCT8 plays a crucial role in the transport of thyroid hormone across the blood-brain-barrier. The life expectancy of patients with MCT8 deficiency is strongly impaired. Absence of head control and being underweight at a young age, which are considered proxies of the severity of the neurocognitive and peripheral phenotype, respectively, are associated with higher mortality rate. The thyroid hormone analogue triiodothyroacetic acid is able to effectively and safely ameliorate the peripheral thyrotoxicosis; its effect on the neurocognitive phenotype is currently under investigation. Other possible therapies are at a pre-clinical stage. This review provides an overview of the current understanding of the physiological role of MCT8 and the pathophysiology, key clinical characteristics and developing treatment options for MCT8 deficiency.

Actions of Thyroid Hormones on Thyroid Cancers.

L-Thyroxine (T4) is the principal ligand of the thyroid hormone analogue receptor on the extracellular domain of integrin αvβ3. The integrin is overexpressed and activated in cancer cells, rapidly dividing endothelial cells, and platelets. The biologic result is that T4 at physiological concentration and without conversion to 3,3’,5-triiodo-L-thyronine (T3) may stimulate cancer cell proliferation and cancer-relevant angiogenesis and platelet coagulation. Pro-thrombotic activity of T4 on platelets is postulated to support cancer-linked blood clotting and to contribute to tumor cell metastasis. We examine some of these findings as they may relate to cancers of the thyroid. Differentiated thyroid cancer cells respond to physiological levels of T4 with increased proliferation. Thus, the possibility exists that in patients with differentiated thyroid carcinomas in whom T4 administration and consequent endogenous thyrotropin suppression have failed to arrest the disease, T4 treatment may be stimulating tumor cell proliferation. In vitro studies have shown that tetraiodothyroacetic acid (tetrac), a derivative of T4, acts via the integrin to block T4 support of thyroid cancer and other solid tumor cells. Actions of T4 and tetrac or chemically modified tetrac modulate gene expression in thyroid cancer cells. T4 induces radioresistance via induction of a conformational change in the integrin in various cancer cells, although not yet established in thyroid cancer cells. The thyroid hormone receptor on integrin αvβ3 mediates a number of actions of T4 on differentiated thyroid cancer cells that support the biology of the cancer. Additional studies are required to determine whether T4 acts on thyroid cancer cells.

The Role of Thyroid Hormone in Neuronal Protection.

Thyroid hormone is essential for brain development and brain function in the adult. During development, thyroid hormone acts in a spatial and temporal-specific manner to regulate the expression of genes essential for normal neural cell differentiation, migration, and myelination. In the adult brain, thyroid hormone is important for maintaining normal brain function. Thyroid hormone excess, hyperthyroidism, and thyroid hormone deficiency, hypothyroidism, are associated with disordered brain function, including depression, memory loss, impaired cognitive function, irritability, and anxiety. Adequate thyroid hormone levels are required for normal brain function. Thyroid hormone acts through a cascade of signaling components: activation and inactivation by deiodinase enzymes, thyroid hormone membrane transporters, and nuclear thyroid hormone receptors. Additionally, the hypothalamic-pituitary-thyroid axis, with negative feedback of thyroid hormone on thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) secretion, regulates serum thyroid hormone levels in a narrow range. Animal and human studies have shown both systemic and local reduction in thyroid hormone availability in neurologic disease and after brain trauma. Treatment with thyroid hormone and selective thyroid hormone analogs has resulted in a reduction in injury and improved recovery. This article will describe the thyroid hormone signal transduction pathway in the brain and the role of thyroid hormone in the aging brain, neurologic diseases, and the protective role when administered after traumatic brain injury. © 2021 American Physiological Society. Compr Physiol 11:1-21, 2021.

Effectiveness of Foliar Biofortification of Carrot With Iodine and Selenium in a Field Condition.

Iodine (I) and selenium (Se) are essential to human and animal development. There is a worldwide deficit of I and Se in the diet of humans, as well as in animals. It is advisable to enrich plants with these elements to ensure adequate uptake in animals and humans. The aim of this study was to determine the efficacy of the application of I and Se in the cultivation of carrot crops, to better understand the metabolic pathways and processes of I applied through foliar spray. Carrots were fertilized with 4-fold foliar applications of I and Se, which were applied as the liquid fertilizers “I + Se”, “Solo iodine” and “Solo selenium”, all containing an organic stabilizer, in two field trials. Foliar nutrient applications of I and Se were translocated by the plant for storage in the roots. The level of enriched I and Se in the roots was considered safe for the consumer. The Recommended Daily Allowance values for I and Se in the roots of 100 g of fresh carrots are 4.16% and 4.37%, respectively. Furthermore, I and Se accumulated in the roots to a level that was physiologically tolerated by carrot. Biofortification through foliar feeding did not impact negatively on the yield or quality of the carrot crop. Iodides applied via foliar application were the dominant form of I in the plant tissues and were included in the metabolic process of the synthesis of iodosalicylates, iodobenzoates, iodotyrosine (I-Tyr), and plant-derived thyroid hormone analogs. No synergistic or antagonistic interaction between I and Se, with respect to the effectiveness of biofortification in roots, was observed in any treatments. The molar ratio of I:Se in the roots after foliar application of both elements was approximately 1.6:1 and was similar to the control (1.35:1).

Chemically-Modified Tetraiodothyroacetic Acid (Tetrac) Induces Cancer Cell Apoptosis and Facilitates Clearance of Apoptotic Debris (Efferocytosis)

Tetraiodothyroaetic acid (tetrac) is a derivative of L-thyroxine with anticancer properties. By multiple molecular mechanisms, tetrac and chemically-modified tetrac induce apoptosis in a variety of human cancer cells in vitro and in xenografts. The anticancer activities of tetrac are initiated at the thyroid hormone analogue receptor on the extracellular domain of plasma membrane integrin αvβ3 (PJ Davis et al., Physiol Rev 101:319-352, 2021). Induction of apoptosis in glioblastoma xenograft with chemically modified tetrac (P-bi-TAT) has yielded 90% in volume of grafts that continues after discontinuation of tetrac. In the present study, we show that human glioblastoma xenograft shrinkage in response to P-bi-TAT is associated with local appearance of phagocytic monocytes and clearance of apoptotic debris (efferocytosis). Primary culture xenograft of glioblastoma cells (GBM 052814, kindly provided by the University of Pittsburgh Medical Center, Department of Neurosurgery) and U87-luc (ATCC, Manassas, VA) xenografts were generated in 5-member groups of nude mice for each tumor cell type and for controls. Five days post-implantation, injection of animals was begun with PBS (control) or P-bi-TAT (10 mg/kg body weight). Injection was continued X21 days and animals were then maintained off-treatment for an additional 21 days. Tumors were harvested, formalin-fixed and slide-mounted, then analyzed by TUNEL assay for apoptosis and by anti-CD68 staining for monocytic macrophage content. Histologic analysis (H&E staining) was also carried out. TUNEL analysis and histopathology of both xenograft models revealed more than 90% apoptotic change with 21-days of P-bi-TAT treatment (P <0.001) and persistence of 40% apoptotic change 3 weeks post-discontinuation of drug (P<0.001 vs. end of treatment change). By H&E histology and CD68 analysis, monocytes accounted for more than 90% of the viable cells after 3 weeks’ drug treatment. Sixty percent of the end-of-treatment monocyte population persisted 3 weeks after discontinuation of P-bi-TAT (P <0.001). Histology revealed negligible cell debris after 3 weeks of drug treatment and at 3 weeks post-discontinuation of P-bi-TAT. Thus, the anticancer/pro-apoptotic action of tetrac-containing P-bi-TAT is associated with efferocytosis that contributes to the frank tumor shrinkage that results from P-bi-TAT treatment of human glioblastoma xenografts. This is the first documentation of efferocytosis regulated from the thyroid hormone analogue receptor on tumor cell integrin αvβ3.

New Aspects of Uptake and Metabolism of Non-organic and Organic Iodine Compounds-The Role of Vanadium and Plant-Derived Thyroid Hormone Analogs in Lettuce.

The process of uptake and translocation of non-organic iodine (I) ions, I– and IO3–, has been relatively well-described in literature. The situation is different for low-molecular-weight organic aromatic I compounds, as data on their uptake or metabolic pathway is only fragmentary. The aim of this study was to determine the process of uptake, transport, and metabolism of I applied to lettuce plants by fertigation as KIO3, KIO3 + salicylic acid (KIO3+SA), and iodosalicylates, 5-iodosalicylic acid (5-ISA) and 3,5-diiodosalicylic acid (3,5-diISA), depending on whether additional fertilization with vanadium (V) was used. Each I compound was applied at a dose of 10 μM, SA at a dose of 10 μM, and V at a dose of 0.1 μM. Three independent 2-year-long experiments were carried out with lettuce; two with pot systems using a peat substrate and mineral soil and one with hydroponic lettuce. The effectiveness of I uptake and translocation from the roots to leaves was as follows: 5-ISA > 3,5-diISA > KIO3. Iodosalicylates, 5-ISA and 3,5-diISA, were naturally synthesized in plants, similarly to other organic iodine metabolites, i.e., iodotyrosine, as well as plant-derived thyroid hormone analogs (PDTHA), triiodothyronine (T3) and thyroxine (T4). T3 and T4 were synthesized in roots with the participation of endogenous and exogenous 5-ISA and 3,5-diISA and then transported to leaves. The level of plant enrichment in I was safe for consumers. Several genes were shown to perform physiological functions, i.e., per64-like, samdmt, msams5, and cipk6.

The molecular mechanism of a novel derivative of BTO-956 induced apoptosis in human myelomonocytic lymphoma cells.

Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system. Although the effectiveness of arsenic compounds has been recognized and applied clinically, some patients are still found resistant to this chemotherapy. In this study, we investigated that a synthetic thyroid hormone analog (TA), 2-iodo-4-nitro-1-(o-tolyloxy) benzene, had a strong apoptosis effect on U937 cells. U937 cells were treated with TA, and examinted the generation of reactive oxygen species (ROS), dysfunction of mitochondria, expression of pro-apoptosis and anti-apoptosis, and cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP). Further, it is also evaluated that insight molecular mechanism and signaling pathways involved in the study. It is found that TA significantly induced apoptosis in U937 cells through production of ROS, dysfunction of mitochondria, and activation of caspase cascade. It was also observed that MAPK signaling pathway including ERK, JNK, and P38 signals are involved in the induction of apoptosis. Moreover, marked activation of autophagy and ER stress markers such as LC3, P62, Beclin1 and GRP78, CHOP were observed, respectively. Pretreatment with ER stress inhibitor tauroursodeoxycholic acid (TUDCA) and autophagy inhibitor 3-Methyladenine (3-MA) have successfully attenuated and aggravated TA-induced apoptosis, respectively. We further confirmed the active involvement of ER stress and autophagy signals. In conclusion, TA induced apoptosis through ER stress and activation of autophagy, and the latter is not conducive to TA-induced cell death. Our results may provide a new insight into the strategic development of novel therapy for the treatment of AML.

Thyroid Hormone Analogues: An Update.

The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and β subtypes of nuclear TH receptors (TRα and TRβ) showed that TRα and TRβ are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRβ selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRβ agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRβ agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3′-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRβ mutations, and interesting results have recently been reported in patients with the Allan–Herndon–Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by β-amyloid or by convulsive agents, but no clinical data are available so far.

Thyroid Hormone Signaling and the Liver.

Thyroid hormone (TH) plays a critical role in maintaining metabolic homeostasis throughout life. It is well known that the liver and thyroid are intimately linked, with TH playing important roles in de novo lipogenesis, beta-oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Indeed, patients with hypothyroidism have abnormal lipid panels with higher levels of low-density lipoprotein levels, triglycerides (triacylglycerol; TAG), and apolipoprotein B levels. Even in euthyroid patients, lower serum-free thyroxine levels are associated with higher total cholesterol levels, LDL, and TAG levels. In addition to abnormal serum lipids, the risk of nonalcoholic fatty liver disease (NAFLD) increases with lower free thyroxine levels. As free thyroxine rises, the risk of NAFLD is reduced. This has led to numerous animal studies and clinical trials investigating TH analogs and TH receptor agonists as potential therapies for NAFLD and hyperlipidemia. Thus, TH plays an important role in maintaining hepatic homeostasis, and this continues to be an important area of study. A review of TH action and TH actions on the liver will be presented here.

Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders.

Thyroid hormones (THs) elicit significant effects on numerous physiological processes, such as growth, development, and metabolism. A lack of thyroid hormones is not compatible with normal health. Most THs effects are mediated by two different thyroid hormone receptor (TR) isoforms, namely TRα and TRβ, with the TRβ isoform known to be responsible for the main beneficial effects of TH on liver. In brain, despite the crucial role of TRα isoform in neuronal development, TRβ has been proposed to play a role in the remyelination processes. Consequently, over the past two decades, much effort has been applied in developing thyroid hormone analogs capable of uncoupling beneficial actions on liver (triglyceride and cholesterol lowering) and central nervous system (CNS) (oligodendrocyte proliferation) from deleterious effects on the heart, muscle and bone. Sobetirome (GC-1) and subsequently Eprotirome (KB2115) were the first examples of TRβ selective thyromimetics, with Sobetirome differing from the structure of thyronines because of the absence of halogens, biaryl ether oxygen, and amino-acidic side chain. Even though both thyromimetics showed encouraging actions against hypercholesterolemia, non-alcoholic steatohepatitis (NASH) and in the stimulation of hepatocytes proliferation, they were stopped after Phase 1 and Phase 2–3 clinical trials, respectively. In recent years, advances in molecular and structural biology have facilitated the design of new selective thyroid hormone mimetics that exhibit TR isoform-selective binding, and/or liver- and tissue-selective uptake, with Resmetirom (MGL-3196) and Hep-Direct prodrug VK2809 (MB07811) probably representing two of the most promising lipid lowering agents, currently under phase 2–3 clinical trials. More recently the application of a comprehensive panel of ADME-Toxicity assays enabled the selection of novel thyromimetic IS25 and its prodrug TG68, as very powerful lipid lowering agents both in vitro and in vivo. In addition to dyslipidemia and other liver pathologies, THs analogs could also be of value for the treatment of neurodegenerative diseases, such as multiple sclerosis (MS). Sob-AM2, a CNS- selective prodrug of Sobetirome has been shown to promote significant myelin repair in the brain and spinal cord of mouse demyelinating models and it is rapidly moving into clinical trials in humans. Taken together all these findings support the great potential of selective thyromimetics in targeting a large variety of human pathologies characterized by altered metabolism and/or cellular differentiation.

Actions of L-thyroxine (T4) and Tetraiodothyroacetic Acid (Tetrac) on Gene Expression in Thyroid Cancer Cells.

The clinical behavior of thyroid cancers is seen to reflect inherent transcriptional activities of mutated genes and trophic effects on tumors of circulating pituitary thyrotropin (TSH). The thyroid hormone, L-thyroxine (T4), has been shown to stimulate proliferation of a large number of different forms of cancer. This activity of T4 is mediated by a cell surface receptor on the extracellular domain of integrin αvβ3. In this brief review, we describe what is known about T4 as a circulating trophic factor for differentiated (papillary and follicular) thyroid cancers. Given T4′s cancer-stimulating activity in differentiated thyroid cancers, it was not surprising to find that genomic actions of T4 were anti-apoptotic. Transduction of the T4-generated signal at the integrin primarily involved mitogen-activated protein kinase (MAPK). In thyroid C cell-origin medullary carcinoma of the thyroid (MTC), effects of thyroid hormone analogues, such as tetraiodothyroacetic acid (tetrac), include pro-angiogenic and apoptosis-linked genes. Tetrac is an inhibitor of the actions of T4 at αvβ3, and it is assumed, but not yet proved, that the anti-angiogenic and pro-apoptotic actions of tetrac in MTC cells are matched by T4 effects that are pro-angiogenic and anti-apoptotic. We also note that papillary thyroid carcinoma cells may express the leptin receptor, and circulating leptin from adipocytes may stimulate tumor cell proliferation. Transcription was stimulated by leptin in anaplastic, papillary, and follicular carcinomas of genes involved in invasion, such as matrix metalloproteinases (MMPs). In summary, thyroid hormone analogues may act at their receptor on integrin αvβ3 in a variety of types of thyroid cancer to modulate transcription of genes relevant to tumor invasiveness, apoptosis, and angiogenesis. These effects are independent of TSH.

Nongenomic Actions of Thyroid Hormone: The Integrin Component.

The extracellular domain of plasma membrane integrin αvβ3 contains a cell surface receptor for thyroid hormone analogues. The receptor is largely expressed and activated in tumor cells and rapidly dividing endothelial cells. The principal ligand for this receptor is l-thyroxine (T4), usually regarded only as a prohormone for 3,5,3'-triiodo-l-thyronine (T3), the hormone analogue that expresses thyroid hormone in the cell nucleus via nuclear receptors that are unrelated structurally to integrin αvβ3. At the integrin receptor for thyroid hormone, T4 regulates cancer and endothelial cell division, tumor cell defense pathways (such as anti-apoptosis), and angiogenesis and supports metastasis, radioresistance, and chemoresistance. The molecular mechanisms involve signal transduction via mitogen-activated protein kinase and phosphatidylinositol 3-kinase, differential expression of multiple genes related to the listed cell processes, and regulation of activities of other cell surface proteins, such as vascular growth factor receptors. Tetraiodothyroacetic acid (tetrac) is derived from T4 and competes with binding of T4 to the integrin. In the absence of T4, tetrac and chemically modified tetrac also have anticancer effects that culminate in altered gene transcription. Tumor xenografts are arrested by unmodified and chemically modified tetrac. The receptor requires further characterization in terms of contributions to nonmalignant cells, such as platelets and phagocytes. The integrin αvβ3 receptor for thyroid hormone offers a large panel of cellular actions that are relevant to cancer biology and that may be regulated by tetrac derivatives.

Exploring non-covalent interactions for metformin-thyroid hormones stabilization: Structure, Hirshfeld atomic charges and solvent effect

Metformin has long been known as an inexpensive and active molecule for the type 2 diabetic treatments, yet its role as a thyroid nodule reagent is an active area of research. Here, the molecular interaction between metformin (MET) and different thyroid hormones (TSH) analogues such as T3, rT3, and T4 were investigated using DFT calculations (wB97XD/def2tzvpp). The non-covalent interactions stabilizes the TnMET adducts were investigated by exploring the molecular electrostatic potential. Hydrogen bonding (HB) and Van der Waals (vdW) forces were responsible for the binding in TnMET adducts. The nature of the stabilizing forces was confirmed by the reduced density gradient (RDG) analysis and non-covalent interactions isosurface plots (NCI). Stabilization of the Tn and TnMET were investigated both in the gas phase and H2O. TnMET adducts stability increases was in the order T4MET > T3MET > rT3MET in the gas phase, while in aqueous phase rT3MET was the most stable adduct. The stability of rT3MET in H2O was in accordance with the increased both dipole moment and charge transfer from MET to rTn in H2O. The selectivity of MET binding with Tn in the gas phase and H2O helps the future understanding of nodule treatment clinical results.