Thyroid Hormone Action Research Articles

TRα1mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility.

Thyroid hormone receptors (TRs) mediate the genomic actions of thyroid hormone. Mutations of THRA gene cause a human disease known as resistance to thyroid hormone (RTHα). We created a mouse model expressing a dominant negative mutated TRα1 (Thra1PV/+ mice) that exhibits growth retardation, bone abnormalities, constipation, and anemia, as found in RTHα patients. In addition, female Thra1PV/+ mice exhibit decreased fertility. In the present study, we aimed to characterize the molecular events leading to infertility. Histologically, there was progressive uterine atrophy in Thra1PV/+ mutant mice, characterized by squamous metaplasia of the endometrial mucosa and endometrial fibrosis. RNA-seq analysis of laser-captured micro-dissected endometrium and spatial transcriptomics revealed a key role for Krüppel-like factor (Klf9), a directly-regulated TR target gene, in normal endometrial differentiation. Klf9 was suppressed in the endometrium of mice harboring mutated TRα1 and pathway analysis revealed that deficient Klf9 signaling was associated with squamous differentiation, consistent with the endometrial metaplasia observed histologically. Further, we showed that this metaplastic endometrial mucosa was the source of ectopic IL-33, which was associated with increased T-cell infiltrates, destruction of glands, and endometrial fibrosis. Our studies provide new insights to understand uterine epithelial morphogenesis and how thyroid dysfunction could lead to female infertility.

Endocrine Disruptors Chemicals: Impacts of Bisphenol A, Tributyltin and Lead on Thyroid Function.

The large-scale industrial production characteristic of the last century led to an increase in man-made compounds and mobilization of natural compounds, many of which can accumulate in the environment and organisms due to their bioaccumulation and biomagnification properties. The endocrine system is especially vulnerable to these compounds that are known as endocrine disruptor chemicals (EDCs). Thyroid hormones (THs) are essential for normal development and growth, besides being the main regulators of basal metabolic rate. Thus, compounds able to affect THs synthesis, transport, and action could produce important deleterious effects, impacting the development of metabolic and endocrine diseases. Herein, we will review the main effects of EDCs on the thyroid axis, with special emphasis on the widely used substances bisphenol A (BPA), employed in the synthesis of polycarbonate plastics and epoxy resins; tributyltin (TBT), an organotin chemical substance widely used in several agro-industrial applications; and lead (Pb), a ubiquitous environmental and occupational polluting heavy metal. Exposure to these EDCs occurs mainly from the ingestion of contaminated food and beverages. Furthermore, there are few epidemiological studies evaluating human risk, and experimental studies employ different exposure models, making it difficult to integrate results. However, even low doses of these EDCs warn of thyrotoxicity. Since THs homeostasis is essential for health and humans are increasingly being exposed to EDCs, it is important to clarify which substances might act as thyroid hormone system disrupting chemicals and how they act in order to try to overcome their deleterious effects and limit the exposure to these compounds.

Thyroid Hormone Activation Regulates the Crosstalk between Breast Cancer and Mesenchymal Stem Cells.

Thyroid Hormones (THs) critically impact human cancer. Although endowed with both tumor-promoting and inhibiting effects in different cancer types, excess of THs has been linked to enhanced tumor growth and progression. Breast cancer depends on the interaction between bulk tumor cells and the surrounding microenvironment in which mesenchymal stem cells (MSCs) exert powerful pro-tumorigenic activities. Primary human MSCs from healthy female donors were co-cultured with DIO2 knock out (D2KO) and wild type (WT) MCF7 breast cancer cells to assess cell growth, migration, invasion and the expression of known epithelial-mesenchymal transition (EMT)- and inflammation-related markers. Furthermore, a surgery-free intraductal delivery model, i.e., the Mouse-INtraDuctal (MIND) injection method, was used as a tool for in vivo characterization of breast tumor formation and progression. In this study, we uncovered a novel role of THs in regulating the tumor-stroma crosstalk. MCF7 cells enhanced the intracellular activation of THs through the TH-activating enzyme, D2, fostering their EMT properties and the dialogue with MSCs. D2 inactivation reduced the invasiveness of MCF7 cells and their responsiveness to the pro-tumorigenic induction via MSCs, both in vivo and in vitro. Thus, we argue that intracellular activation of THs via D2 is a critical requirement for invasive and metastatic conversion of breast cancer cells, advising the blocking of D2 as a potential therapeutic tool for cancer therapy.

The thyroid hormone activating enzyme, DIO2, is a potential pan-cancer biomarker and immunotherapy target.

Type 2 deiodinase (D2), encoded by DIO2 gene, catalyzes the activation of the prohormone thyroxine (T4) into the bioactive hormone triiodothyronine (T3) in peripheral tissues, thereby regulating the intracellular Thyroid Hormone (TH) availability. Recently, several studies have demonstrated that a drastic increase in the peripheral activation of TH, via D2, fosters tumor progression, metastasis, and immunity. To further prove the clinical relevance of D2 in human cancer, based on public Database of The Cancer Genome Atlas (TCGA), we conducted a pan-cancer analysis of DIO2 expression in various cancer types and investigated the association of DIO2 expression with the tumor microenvironment (TME) components and immune cell infiltration, along with the DIO2 genetic alteration types. Although with different expression levels between the various cancer types, the pan-cancer analysis showed that DIO2 was highly expressed in most tumors and related to the progression of some tumor types. Furthermore, DIO2 expression was also significantly correlated with TME components, immune cell infiltration, and immunoinhibitory and immunostimulatory gene subsets. The relevance of this study is that it adds a clinical relevance to the recent demonstrations that D2 accelerates tumor invasion in animal models and poses DIO2 gene as a potential prognostic marker in various human cancers.

Digenic Inheritance Mode in Congenital Hypothyroidism due to Thyroid Dysgenesis: HYPOTYGEN translational cohort study.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and is chiefly caused by thyroid dysgenesis (CHTD). The inheritance mode of the disease remains complex. Gain insight into the inheritance mode of CHTD. Prospective multicenter nationwide translational study in France. We prospectively included 514 patients with CH diagnosed through systematic newborn screening (HYPOTYGEN cohort). We focused on CHTD cases and studied their clinical and molecular phenotypes. Targeted next-generation sequencing using a 78-gene panel, including genes involved in thyroid development, function, transport, metabolism and action of thyroid hormones. Statistical analysis, familial segregation and in vitro functional studies focusing on cell migration have been performed. We analyzed the clinical phenotypes of 458 patients with CH. Cardiac and renal malformations were present in 7.7%(14/182) and 3.9%(7/178) of patients, respectively. Genetic analysis was performed on 292 patients of the cohort, based on criteria for ethnicity and availability of DNA samples for index cases and their parents. A disease-causing mutation in one of the 10 known genes for CHTD was identified in 20/292 (6.8%) patients. We found a digenic mode of inheritance in 16 (5.5%) patients, each carrying a variant in a thyroid development gene and a variant in the H2O2 generation complex gene DUOX2/DUOXA2. Familial segregation analysis and in vitro functional studies supported this model. This work expands our understanding of the molecular causes of CHTD by demonstrating that digenic inheritance can be implicated, with deleterious variants in thyroid development and DUOX2/DUOXA2 genes. The complexity of this model implies a revision of the genetic landscape of CHTD and specific clinical care of patients during long-term follow-up. NCT01916018.

Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are pivotal in regulating various physiological processes including growth, development, and metabolism. The biological actions of thyroid hormones are primarily initiated by binding to nuclear thyroid hormone receptors (TRs). These receptors, belonging to the superfamily of nuclear receptors, act as ligand-dependent transcription factors. Transcriptional regulation by TRs is mediated by the recruitment of coregulators, governing activation and repression of target genes, thereby modulating cellular responses to thyroid hormones. Beyond this canonical genomic pathway, TH can regulate the expression of genes not directly bound by TRs through cross-talk mechanisms with other transcription factors and signaling pathways. Thyroid hormones can also elicit rapid non-genomic effects, potentially mediated by extranuclear TR proteins or by interactions with membrane receptors such as integrin αvβ3. This non-genomic mode of action adds another layer of complexity to the diverse array of physiological responses orchestrated by thyroid hormones, expanding our understanding of their multifaceted actions.

Thyroid hormone and the Liver.

It is known that thyroid hormone can regulate hepatic metabolic pathways including cholesterol, de novo lipogenesis, fatty acid oxidation, lipophagy, and carbohydrate metabolism. Thyroid hormone action is mediated by the thyroid hormone receptor (THR) isoforms and their coregulators, and THRβ is the main isoform expressed in the liver. Dysregulation of thyroid hormone levels, as seen in hypothyroidism, has been associated with dyslipidemia and metabolic dysfunction-associated fatty liver disease. Given the beneficial effects of thyroid hormone in liver metabolism and the advances illuminating the use of thyroid hormone analogs such as resmetirom as therapeutic agents in the treatment of metabolic dysfunction-associated fatty liver disease, this review aims to further explore the relationship between TH, the liver, and metabolic dysfunction-associated fatty liver disease. Herein, we summarize the current clinical therapies and highlight future areas of research.

Type 3 deiodinase activation mediated by the Shh/Gli1 axis promotes sepsis-induced metabolic dysregulation in skeletal muscles.

Non-thyroidal illness syndrome is commonly observed in critically ill patients, characterized by the inactivation of systemic thyroid hormones (TH), which aggravates metabolic dysfunction. Recent evidence indicates that enhanced TH inactivation is mediated by the reactivation of type 3 deiodinase (Dio3) at the tissue level, culminating in a perturbed local metabolic equilibrium. This study assessed whether targeted inhibition of Dio3 can maintain tissue metabolic homeostasis under septic conditions and explored the mechanism behind Dio3 reactivation. A retrospective clinical study was conducted to investigate the attributes of rT3. The expression of Dio3 was detected by immunoblotting, immunofluorescence, and immunohistochemical staining in tissues extracted from CLP-induced septic rats and human biopsy samples. In addition, the effect of Dio3 inhibition on skeletal muscle metabolism was observed in rats with targeted Dio3 knockdown using an adeno-associated virus. The effectiveness of Sonic hedgehog (Shh) signaling inhibition on systemic TH levels was observed in CLP-induced septic rats receiving cyclopamine. The mechanisms underlying such inhibition were explored using immunoblotting, RNA-seq, and chromatin immunoprecipitation-qPCR assays. The main product of Dio3, rT3, is strongly associated with organ function. Early sepsis leads to significant upregulation of Dio3 in the skeletal muscles and lung tissues of septic rats. The targeted inhibition of Dio3 in skeletal muscle restores TH responsiveness, prevents fast-to-slow fiber conversion, preserves glucose transporter type 4 functionality, and maintains metabolic balance between protein synthesis and proteolysis, which leads to preserved muscle mass. The reactivation of Dio3 is transcriptionally regulated by the Shh pathway induced by the signal transducer and activator of transcription 3. The suppression of Dio3 restores tissue TH actions, attenuates proteolysis, and ameliorates anabolic resistance in the skeletal muscles of septic rats, thereby improving local metabolic homeostasis. Our results provide insights into the mechanisms of Dio3 reactivation and its critical role in local metabolic alterations induced by sepsis, while also suggesting novel targets aimed at ameliorating tissue-specific metabolic disorders.

Thyroid Hormones and Co-workers: An Overview.

The hypothalamus secretes the thyroid-releasing hormone(TRH) that induces the pituitary gland to release the thyroid-stimulating hormone(TSH) which stimulates thyroid follicular cells to release the thyroid hormones(THs), thyroxine (T4), and triiodothyronine (T3). The process of synthesizing T3 and T4 hormones involves various enzymatic steps, starting with the iodination of L-tyrosine residues present in the protein thyroglobulin. Thyroid hormones are released into the bloodstream, where they bind to thyroid hormone distributor proteins (THDPs) which transport them in the circulation. The conversion of T4 to T3 (the more biologically active hormone) in target tissues is facilitated by selenoprotein enzymes known as deiodinases. THscan bind to different molecules located on the plasma membrane, such as integrin αvβ3, through which they exercise regulatory non-genomic control. Nevertheless,most of thyroid hormone's actions are mediated intracellularly by binding to thyroid hormone receptors(TRs). Thyroid hormone receptors act as ligand-dependent transcription factors, Thyroid hormone receptors activate thyroid hormone response elements on gene promoters through canonical signaling. Thyroid hormones mediate several critical physiological processes including organ development, cell differentiation, metabolism, and cell growth and maintenance.

Absence of cholesterol gallstone formation in male C57BL/6 mice by abrogation of hepatic thyroid hormone action

Absence of cholesterol gallstone formation in male C57BL/6 mice by abrogation of hepatic thyroid hormone action

Triiodothyronine activates THRβ to promote PGC1α expression alleviating PQ-induced pulmonary fibrosis.

Thyroid hormone (TH) and it most active form triiodothyronine (T3) are crucial in promoting mitochondrial biogenesis and maintaining cellular homeostasis during the stress response, but their role in paraquat (PQ)-induced pulmonary fibrosis isunclear. The aim of this study was to examine whether there was a deficiency of TH in mouse lung tissue after PQ administration, and to explore the effect of T3, and potential mechanisms of action, in alleviation of PQ-induced pulmonary fibrosis. We found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in the lungs of patients with pulmonary fibrosis than in controls. The expression of DIO2 in lung tissue of PQ injured mice was significantly increased compared to controls (P < 0.001), while the serum T3 level was significantly reduced, compared to the control group (P < 0.001). T3 nebulization significantly improved PQ-induced pulmonary fibrosis in mice, possibly by activating thyroid hormone receptor beta (THRβ). T3 and sobetirome, a specific THRβ agonist significantly upregulated peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC1α) expression, and NH-3 (an antagonist of the thyroid hormone receptor), a THRβ-specific antagonist, significantly inhibited (P < 0.0001) the beneficial effects of T3 on the PQ-induced mitochondrial apoptotic pathway in an epithelial cell line, in vitro. T3 via the THRβ / PGC1α pathway protected against PQ induced pulmonary fibrosis, furnishing a scientific basis for further research on T3 and this pathway could offer a potential novel therapeutic strategy for treating PQ poisoning in humans.

Специфика влияния уровней тиреоидных гормонов на адаптационные возможности организма (обзор)

Thyroid hormones take an active part in the regulation of many body reactions, including adaptive responses. The purpose of this review was to analyse the role of thyroid hormones in the adaptive response of the body to stress factors. Materials and methods. The data presented in articles published in Russian and foreign scientific periodicals from 2019 to 2023 were studied. The following databases were searched: PubMed, Google Scholar, SpringerLink and eLIBRARY.RU. According to the results of this theoretical study, thyroid hormones are involved in almost all physiological processes, exerting a metabolic effect on a number of tissues and systems as well as influencing pro- and antioxidant mechanisms. In response to stress, the body consistently develops a number of adaptive reactions associated with the activity of thyroid hormones. Stressors of various nature affect the level of thyroid hormones in the body. A connection between the symptoms of thyroid dysfunction and a decrease in the body’s stress resistance has been noted, while the development of both hypo- and hyperthyroidism negatively affects the functioning of a number of organs and systems. The paper describes an interdependence between hypo-/hyperthyroidism and the body’s adaptive capabilities. The influence of thyroid hormones on the adaptive mechanisms realized at the metabolic level has been proven. There is data confirming the central role of thyroid hormones in the formation of exploratory behaviour and adaptive response. A more extensive investigation is required into the correlation between changes in the level of thyroid hormones and adaptive immune responses, as well as into the effect of thyroid hormones on the function of individual immune cells. Among the ongoing research, the article highlights studies aimed to determine patterns of changes in the level of thyroid hormones during adaptation to extreme stress, including climatic and geographical factors, as well as to find approaches to non-hormonal regulation of their concentrations in the body.

Fish collagen peptides supplementation ameliorates skeletal muscle injury in high-fat diet mice associated with thyroid function recovery

This study aims to explore the effects of fish collagen peptides (FCP) supplementation on skeletal muscle injury in high-fat (HF) diet mice and their possible mechanisms. Experimental mice were fed a normal diet (4 % fat), HF diet (20 % fat), or FCP diet (20 % fat and 1 % FCPs) for 22 consecutive weeks. Results show that FCP supplementation improves skeletal muscle motor function and histomorphology, and lipid levels; promotes protein synthesis, and inhibits protein degradation in skeletal muscle. Moreover, FCP supplementation also improves mitochondrial biogenesis, promotes energy metabolism and ATP production. Furthermore, FCP supplementation increases antioxidant defenses in the thyroid and skeletal muscle, improves thyroid morphological structure, promotes the synthesis and secretion of thyroid hormones, and enhances the actions of thyroid hormones on its receptor organ skeletal muscle. Cumulatively, these findings indicate that FCP supplementation can alleviate skeletal muscle injury induced by an HF diet associated with thyroid function recovery.

Pyrethroid exposure biomarker 3-phenoxybenzoic acid (3-PBA) binds to transthyretin and is positively associated with free T3 in pregnant women

Pyrethroids constitute a large group of insecticides widely used in agriculture, indoor environments, and in vector control. Structurally, pyrethroids resemble thyroid hormones, and have been suggested to be thyroid hormone disruptors based on experimental studies. During pregnancy, even minor disturbances in maternal levels can affect fetal brain development. Therefore, we aimed to investigate whether three commonly used pyrethroids and their common metabolite, 3-PBA, were able to trigger thyroid disrupting effects on thyroid hormone production and transport, activation or deactivation of thyroid hormones, recycling of iodine, or on iodide uptake into the thyroid. Furthermore, we investigated associations between urinary 3-PBA concentrations (as biomarker of pyrethroid exposure) and serum concentrations of thyroid hormones in early pregnancy in the large prospective Odense Child Cohort (OCC).We found that the generic metabolite, 3-PBA, was capable of binding to transthyretin (TTR) at low concentrations, comparable to those reported in human cord blood. Among pregnant women in OCC, we found urinary 3-PBA concentrations to be positively associated with free triiodothyronine (fT3) serum levels. Displacement of thyroid hormones from TTR by pyrethroid exposure in early pregnancy may disturb the transplacental transport of thyroid hormones to the fetus during a very vulnerable window of development, including neural maturation. We did not find any evidence for thyroid disrupting effects in vitro for the three pyrethroids: Deltamethrin, α-cypermethrin, and etofenprox.

The effect of diet-induced weight-loss on subcutaneous adipose tissue expression of genes associated with thyroid hormone action

Background & AimsWe have recently demonstrated that subcutaneous adipose tissue (SAT) expression of genes associated with thyroid hormone (TH) action is altered in obesity and insulin resistance. The aim of the present study was to examine the effect of diet-induced weight-loss on SAT expression of genes associated with TH action. MethodsThe study group comprised 38 individuals with overweight/obesity, which completed 12-week dietary intervention program. Hyperinsulinemic-euglycemic clamp and SAT biopsy were performed before and after the program. Fifteen normal-weight individuals were examined at baseline only. ResultsOverweight/obese individuals had lower free thyroxine (fT4) and higher free triiodothyronine (fT3)/fT4 ratio, lower SAT TH receptor isoforms (TRα and TRβ, encoded by THRA and THRB, respectively) and peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) mRNA expression and higher SAT type II and type III iodothyronine deiodinase (encoded by DIO2 and DIO3, respectively) and nuclear receptor corepressor (NCOR1) mRNA expression in comparison with normal-weight individuals. Diet-induced weight loss resulted in a decrease in fT3 and fT3/fT4 ratio and an increase in SAT THRA, THRB and PPARGC1A. SAT NCOR1 and forkhead box protein O1 (FOXO1) decreased only in individuals, who lost at least 10 kg (n=20). Higher increase in insulin sensitivity after weight loss was associated with a lower decrease in fT3/fT4 ratio. ConclusionsDiet-induced weight loss partly reverses alterations in SAT expression of genes associated with TH action. Responses of circulating TH and SAT expression of genes associated with TH action to diet-induced weight loss are related to body weight and insulin sensitivity.

Inclusive Exploration of Harmonizing and Alternative Treatments for Hypothyroidism

: A clinical syndrome known as hypothyroidism occurs due to a shortage of thyroid hormone as a result of decreased production, abnormal distribution, or no action of thyroid hormones. The most typical clinical symptoms included are dry skin, hair loss, weight gain, painful-prolonged periods, infertility, balance problems, slow speech, bradycardia, hypothermia, fatigue, anxiety &amp; depression, joint pain, and indigestion. Basically, age, gender, the severity of the ailment, and a few other factors affect the various signs and symptoms of hypothyroidism. The limitations of allopathic modalities necessitate the investigation of alternative treatment options. Future healthcare initiatives for the poor world will increasingly depend on CAM approaches to these concerns because lifestyle, diet, obesity, lack of exercise, and stress are significant contributing factors to the development of hypothyroidism. This review's objective is to provide information on herbs as well as complementary and alternative medications which are grouped into five major domains: Biologically Based therapies, Manipulative body-based therapies, Mind body-based therapies, and the whole Medical system. These have traditionally been used to treat thyroid dysfunction. The distribution of diseases in emerging nations is altering as a result of globalization. Hence the existing and potential roles of CAM techniques in the general practice of medicine are illustrated in these approaches. Scientists are being compelled to consider traditional herbal medical treatments and CAM therapy in order to combat adverse medication occurrences, high treatment costs, and compliance problems thus described in this review paper.

In Silico, In Vitro, and In Vivo Studies Indicate the Endocrine-Disrupting Effects of Cyproconazole Stereoisomers.

The widespread use of chiral triazole fungicide cyproconazole (CPZ) in agricultural fields has led to frequent detection of CPZ in the environment. The restriction of CPZ in the EU raised wide concerns regarding its potential endocrine-disrupting effects (EDEs). The present study was conducted to evaluate EDEs of CPZ stereoisomers in vitro, in silico, and in vivo. The reporter gene assay indicated that all CPZ stereoisomers were agonists to the human estrogenic receptor α. (2S,3S)-(+)- and (2R,3S)-(-)-CPZ exhibited stronger binding capacities to ERα compared with (2R,3R)-(-)- and (2S,3R)-(+)-CPZ. Our computational studies showed consistent results with reporter gene assay, elucidating the stereoselective binding mode of CPZ to estrogen receptor. In zebrafish embryos, the 96h-lethality of CPZ stereoisomers ordered (2R,3R)-(-)- > (2R,3S)-(-)- > (2S,3S)-(+)- > Rac- > (2S,3R)-(+)-CPZ. Stereoselective developmental toxicity of CPZ was observed while (2R,3S)-(-)-CPZ is the most toxic isomer. The estrogenic hormones were significantly decreased in (2S,3R)-(+)- and (2R,3S)-(-)-CPZ groups and enhanced in (2S,3S)-(+)- and (2R,3R)-(-)-CPZ, along with the gene expression in hypothalamic-pituitary-gonad axis altered. CPZ shows no thyroid hormone activity. These data clarified that CPZ is a new-found endocrine disruptor threatening human health and each stereoisomer of CPZ showed stereoselective EDEs by regulating the nuclear receptor-mediated gene expression.

Thyroid Hormone Neuroprotection Against Perfluorooctane Sulfonic Acid Cholinergic and Glutamatergic Disruption and Neurodegeneration Induction.

Background: Perfluorooctane sulfonic acid (PFOS), a widely used industrial chemical, was reported to induce memory and learning process dysfunction. Some studies tried to reveal the mechanisms that mediate these effects, but how they are produced is still unknown. Basal forebrain cholinergic neurons (BFCN) maintain cognitive function and their selective neurodegeneration induces cognitive decline, as observed in Alzheimer's disease. PFOS was reported to disrupt cholinergic and glutamatergic transmissions and thyroid hormone action, which regulate cognitive processes and maintain BFCN viability. Objective/Methods: To evaluate PFOS neurodegenerative effects on BFCN and the mechanisms that mediate them, SN56 cells (a neuroblastoma cholinergic cell line from the basal forebrain) were treated with PFOS (0.1 µM to 40 µM) with or without thyroxine (T3; 15 nM), MK-801 (20 µM) or acetylcholine (ACh; 10 µM). Results: In the present study, we found that PFOS treatment (1 or 14 days) decreased thyroid receptor α (TRα) activity by decreasing its protein levels and increased T3 metabolism through increased deiodinase 3 (D3) levels. Further, we observed that PFOS treatment disrupted cholinergic transmission by decreasing ACh content through decreased choline acetyltransferase (ChAT) activity and protein levels and through decreasing muscarinic receptor 1 (M1R) binding and protein levels. PFOS also disrupted glutamatergic transmission by decreasing glutamate content through increased glutaminase activity and protein levels and through decreasing N-methyl-D-aspartate receptor subunit 1 (NMDAR1); effects mediated through M1R disruption. All these effects were mediated through decreased T3 activity and T3 supplementation partially restored to the normal state. Conclusions: These findings may assist in understanding how PFOS induces neurodegeneration, and the mechanisms involved, especially in BFCN, to explain the process that could lead to cognitive dysfunction and provide new therapeutic tools to treat and prevent its neurotoxic effects.

Actions of thyroid hormones and thyromimetics on the liver.

Thyroid hormones (triiodothyronine and thyroxine) are pivotal for metabolic balance in the liver and entire body. Dysregulation of the hypothalamus-pituitary-thyroid axis can contribute to hepatic metabolic disturbances, affecting lipid metabolism, glucose regulation and protein synthesis. In addition, reductions in circulating and intrahepatic thyroid hormone concentrations increase the risk of metabolic dysfunction-associated steatotic liver disease by inducing lipotoxicity, inflammation and fibrosis. Amelioration of hepatic metabolic disease by thyroid hormones in preclinical and clinical studies has spurred the development of thyromimetics that target THRB (the predominant thyroid hormone receptor isoform in the liver) and/or the liver itself to provide more selective activation of hepatic thyroid hormone-regulated metabolic pathways while reducing thyrotoxic side effects in tissues that predominantly express THRA such as the heart and bone. Resmetirom, a liver and THRB-selective thyromimetic, recently became the first FDA-approved drug for metabolic dysfunction-associated steatohepatitis (MASH). Thus, a better understanding of the metabolic actions of thyroid hormones and thyromimetics in the liver is timely and clinically relevant. Here, we describe the roles of thyroid hormones in normal liver function and pathogenesis of MASH, as well as some potential clinical issues that might arise when treating patients with MASH with thyroid hormone supplementation or thyromimetics.

A-9-Years-Old Female with Diabetes Mellitus Type 1 with Hyperthyroidism

Diabetes Mellitus Type 1 (DMT1) and thyroid disease can occur together, which is defined as a variant of autoimmune polyglandular syndrome type 3. It is known that the action of insulin and thyroid hormones affect cellular metabolism, thyroid hormones contribute to carbohydrate metabolism and pancreatic function. Since the thyroid gland plays a central role in the regulation of metabolism, abnormal thyroid function can have a major impact on the control of diabetes and poor glycemic control can cause alterations in thyroid hormone. A female, 9 years old, with decreased consciousness. Previous medical history, polyuria, increased appetite, and drastic weight loss. She also complained of sweating even in a cold room and was often emotional. On physical examination, there was fever, shortness of breath, tachycardia, and a soft and diffused slightly enlarged thyroid gland, with no bruit on auscultation. Laboratory tests showed blood glucose levels at 739 mg/dL, HbA1c 9.2%, C-peptide 0.2 ng/mL, TSH levels 0.01 µIU/mL, FT4 levels 2.77 ng/dL, the presence of metabolic acidosis, proteinuria, glucosuria, and ketonuria. Thyroid dysfunction will have a negative effect on DM control while poor glucose control will harm the work of thyroid hormones. Improvement in glycemic control and routine insulin injection with the right dose will reduce the risk of diabetic vascular and metabolic complications onset and progression.