Redox Properties of 3-Iodothyronamine (T1AM) and 3-Iodothyroacetic Acid (TA1).

3-iodothyronamine (T1AM) and 3-iodothyroacetic acid (TA1) are thyroid-hormone-related compounds endowed with pharmacological activity through mechanisms that remain elusive. Some evidence suggests that they may have redox features. We assessed the chemical activity of T1AM and TA1 at pro-oxidant conditions. Further, in the cell model consisting of brown adipocytes (BAs) differentiated for 6 days in the absence (M cells) or in the presence of 20 nM T1AM (M + T1AM cells), characterized by pro-oxidant metabolism, or TA1 (M + TA1 cells), we investigated the expression/activity levels of pro- and anti-oxidant proteins, including UCP-1, sirtuin-1 (SIRT1), mitochondrial monoamine (MAO-A and MAO-B), semicarbazide-sensitive amine oxidase (SSAO), and reactive oxygen species (ROS)-dependent lipoperoxidation. T1AM and TA1 showed in-vitro antioxidant and superoxide scavenging properties, while only TA1 acted as a hydroxyl radical scavenger. M + T1AM cells showed higher lipoperoxidation levels and reduced SIRT1 expression and activity, similar MAO-A, but higher MAO-B activity in terms of M cells. Instead, the M + TA1 cells exhibited increased levels of SIRT1 protein and activity and significantly lower UCP-1, MAO-A, MAO-B, and SSAO in comparison with the M cells, and did not show signs of lipoperoxidation. Our results suggest that SIRT1 is the mediator of T1AM and TA1 pro-or anti-oxidant effects as a result of ROS intracellular levels, including the hydroxyl radical. Here, we provide evidence indicating that T1AM and TA1 administration impacts on the redox status of a biological system, a feature that indicates the novel mechanism of action of these two thyroid-hormone-related compounds.

Trace Amine-Associated Receptor 1 (TAAR1) Is a Positive Prognosticator for Epithelial Ovarian Cancer.

Trace amine-associated receptor 1 (TAAR1) is a Gαs- protein coupled receptor that plays an important role in the regulation of the immune system and neurotransmission in the CNS. In ovarian cancer cell lines, stimulation of TAAR1 via 3-iodothyronamine (T1AM) reduces cell viability and induces cell death and DNA damage. Aim of this study was to evaluate the prognostic value of TAAR1 on overall survival of ovarian carcinoma patients and the correlation of TAAR1 expression with clinical parameters. Ovarian cancer tissue of n = 156 patients who were diagnosed with epithelial ovarian cancer (serous, n = 110 (high-grade, n = 80; low-grade, n = 24; unknown, n = 6); clear cell, n = 12; endometrioid, n = 21; mucinous, n = 13), and who underwent surgery at the Department of Obstetrics and Gynecology, University Hospital of the Ludwig-Maximilians University Munich, Germany between 1990 and 2002, were analyzed. The tissue was stained immunohistochemically with anti-TAAR1 and evaluated with the semiquantitative immunoreactive score (IRS). TAAR1 expression was correlated with grading, FIGO and TNM-classification, and analyzed via the Spearman's rank correlation coefficient. Further statistical analysis was obtained using nonparametric Kruskal-Wallis rank-sum test and Mann-Whitney-U-test. This study shows that high TAAR1 expression is a positive prognosticator for overall survival in ovarian cancer patients and is significantly enhanced in low-grade serous carcinomas compared to high-grade serous carcinomas. The influence of TAAR1 as a positive prognosticator on overall survival indicates a potential prognostic relevance of signal transduction of thyroid hormone derivatives in epithelial ovarian cancer. Further studies are required to evaluate TAAR1 and its role in the development of ovarian cancer.

Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study.

Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood-brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.

Expression dynamics of genes in the hypothalamic-pituitary-thyroid (HPT) cascade and their responses to 3,3',5-triiodo-l-thyronine (T3) highlights potential vulnerability to thyroid-disrupting chemicals in zebrafish (Danio rerio) embryo-larvae.

Some chemicals in the environment disrupt thyroid hormone (TH) systems leading to alterations in organism development, but their effect mechanisms are poorly understood. In fish, this has been limited by a lack of fundamental knowledge on thyroid gene ontogeny and tissue expression in early life stages. Here we established detailed expression profiles for a suite of genes in the hypothalamic-pituitary-thyroid (HPT) axis of zebrafish (Danio rerio) between 24-120 h post fertilisation (hpf) and quantified their responses following exposure to 3,3',5-triiodo-L-thyronine (T3) using whole mount in situ hybridisation (WISH) and qRT-PCR (using whole-body extracts). All of the selected genes in the HPT axis demonstrated dynamic transcript expression profiles across the developmental stages examined. The expression of thyroid receptor alpha (thraa) was observed in the brain, gastrointestinal tract, craniofacial tissues and pectoral fins, while thyroid receptor beta (thrb) expression occurred in the brain, otic vesicles, liver and lower jaw. The TH deiodinases (dio1, dio2 and dio3b) were expressed in the liver, pronephric ducts and brain and the patterns differed depending on life stage. Both dio1 and dio2 were also expressed in the intestinal bulb (96-120 hpf), and dio2 expression occurred also in the pituitary (48-120 hpf). Exposure of zebrafish embryo-larvae to T3 (30 and 100 µg L-1) for periods of 48, 96 or 120 hpf resulted in the up-regulation of thraa, thrb, dio3b, thyroid follicle synthesis proteins (pax8) and corticotropin-releasing hormone (crhb) and down-regulation of dio1, dio2, glucuronidation enzymes (ugt1ab) and thyroid stimulating hormone (tshb) (assessed via qRT-PCR) and responses differed across life stage and tissues. T3 induced thraa expression in the pineal gland, pectoral fins, brain, somites, gastrointestinal tract, craniofacial tissues, liver and pronephric ducts. T3 enhanced thrb expression in the brain, jaw cartilage and intestine, while thrb expression was suppressed in the liver. T3 exposure suppressed the transcript levels of dio1 and dio2 in the liver, brain, gastrointestinal tract and craniofacial tissues, while dio2 signalling was also suppressed in the pituitary gland. Dio3b expression was induced by T3 exposure in the jaw cartilage, pectoral fins and brain. The involvement of THs in the development of numerous body tissues and the responsiveness of these tissues to T3 in zebrafish highlights their potential vulnerability to exposure to environmental thyroid-disrupting chemicals.

Endocrine, Metabolic and Pharmacological Effects of Thyronamines (TAM), Thyroacetic Acids (TA) and Thyroid Hormone Metabolites (THM) - Evidence from in vitro, Cellular, Experimental Animal and Human Studies.

Thyroid hormone metabolites (THM) with few or no iodine substituents such as 3,5-T2, the thyronamines 3-T1AM and T0AM, and their oxidation products, the thyroacetic acids (TA) formed by monoamine oxidases, have recently attracted major interest due to their metabolic actions which are in part distinct from those of the classical thyromimetic hormone T3, the major ligand of T3 receptors. This review compiles and discusses in vitro effects of 3,5-T2, TAM and TA reported for thyrocytes, pancreatic islets and hepatocytes as well as findings from in vivo studies in mouse models after single or repeated administration of pharmacological doses of these agents. Comparison of the 3,5-T2 effects on the transcriptome with not yet published proteome data in livers of obese mice on high fat diet indicate a distinct anti-steatotic effect of this THM. Furthermore, uptake, metabolism, and cellular actions via various receptors such as trace amine-associated receptors (TAAR), alpha-adrenergic, GPCR and T3 receptors are discussed. Studies on postulated pathways of biosynthesis of 3-T1AM, its effects on the HPT-axis and thyroid gland as well as insulin secretion are reviewed. 3-T1AM also acts on hepatocytes and interferes with TRPM8-dependent signaling in human cell lines related to the eye compartment. Human studies are presented which address potential biosynthesis routes of 3,5-T2 and 3-T1AM from THM precursors, especially T3. The current state of diagnostic analytics of these minor THM in human blood is portrayed comparing and critically discussing the still divergent findings based on classical immunoassay and recently developed liquid-chromatography/mass- spectrometry methods, which allow quantification of the thyronome spectrum from one single small volume serum sample. The clinical perspectives of use and potential abuse of these biologically active THM is addressed.

More Than Fever - Novel Concepts in the Regulation of Body Temperature by Thyroid Hormones.

Thyroid hormone is well known for its profound effects on body temperature. This minireview summarizes the recent discoveries on the underlying mechanisms, including the role of the hormone's central actions in the control of brown adipose tissue thermogenesis, its effect on browning of white adipose tissue, the possible involvement of thyroid hormone transporters, and the potential contribution of its downstream metabolites such as 3-iodothyronamine.

3-Iodothyronamine Induces Diverse Signaling Effects at Different Aminergic and Non-Aminergic G-Protein Coupled Receptors.

The thyroid hormone metabolite 3-iodothyronamine (3-T1AM) exerts diverse physiological reactions such as a decrease of body temperature, and negative inotropic and chronotropic effects. This observed pleomorphic effect in physiology can be barely explained by interaction with only one target protein such as the trace-amine receptor 1 (TAAR1), a class A G-protein coupled receptor (GPCR). Moreover, Taar1 knock-out mice still react to 3-T1AM through physiological responses with a rapid decrease in body temperature. These facts propelled our group and others to search for further targets for this molecule.The group of TAARs evolved early in evolution and, according to sequence similarities, they are closely related to adrenoceptors and other aminergic receptors. Therefore, several of these receptors were characterized by their potential to interplay with 3-T1AM. Indeed, 3-T1AM acts as a positive allosteric modulator on the beta2-adrenoceptor (ADRB2) and as a biased agonist on the serotonin receptor 1B (5HT1b) and the alpha2-adrenoceptor (ADRA2A). In addition, 3-T1AM was reported to be a weak antagonist at a non-aminergic muscarinic receptor (M3).These findings impressively reflect that such trace amines can unselectively and simultaneously function at different receptors expressed by one cell or at different tissues. In conclusion, the role of 3-T1AM is hypothesized to concert the fine-tuning of specific cell reactions by the accentuation of certain pathways dependent on distinct receptors. 3-T1AM acts as a regulator of signals by blocking, modulating, or inducing simultaneously distinct intracellular signaling cascades via different GPCRs.

Novel thyroid hormones.

The field of thyroid hormone signaling has grown more complex in recent years. In particular, it has been suggested that some thyroid hormone derivatives, tentatively named "novel thyroid hormones" or "active thyroid hormone metabolites", may act as independent chemical messengers. They include 3,5-diiodothyronine (T2), 3-iodothyronamine (T1AM), and several iodothyroacetic acids, i.e., 3,5,3',5'-thyroacetic acid (TA4), 3,5,3'-thyroacetic acid (TA3), and 3-thyroacetic acid (TA1). We summarize the present knowledge on these compounds, namely their biosynthetic pathways, endogenous levels, molecular targets, and the functional effects elicited in experimental preparations or intact animals after exogenous administration. Their physiological and pathophysiological role is discussed, and potential therapeutic applications are outlined. The requirements needed to qualify these substances as chemical messengers must still be validated, although promising evidence has been collected. At present, the best candidate to the role of independent chemical messenger appears to be T1AM, and its most interesting effects concern metabolism and brain function. The responses elicited in experimental animals have suggested potential therapeutic applications. TA3 has an established role in thyroid hormone resistance syndromes, and is under investigation in Allen-Herndon-Dudley syndrome. Other potential targets are represented by obesity and dyslipidemia (for T2 and T1AM); dementia and degenerative brain disease (for T1AM and TA1); cancer (for T1AM and TA4). Another intriguing and unexplored question is the potential relevance of these metabolites in the clinical picture of hypothyroidism and in the response to replacement therapy.

Differential expression patterns of specific long noncoding RNAs and competing endogenous RNA network in alopecia areata.

BACKGROUND: Long noncoding RNAs (lncRNAs) regulate gene expression by acting with microRNAs (miRNAs) and indirectly interact with messenger RNA (mRNAs). However, the roles of specific lncRNA and its related competing endogenous RNAs (ceRNA) network in alopecia areata (AA) are not fully understood. METHODS: The blood lncRNA profiles were obtained by microarray from 10 samples, including five alopecia areata samples and five normal samples. Based on bioinformatics generated from miRcode, starBase, and miRTarBase, we constructed an lncRNA-miRNA-mRNA network (ceRNA network) in alopecia areata. RESULTS: We found 154 differentially expressed lncRNAs and 46 differentially expressed genes (DEGs). The functional enrichment indicated that the DEGs mainly regulated the pathways of focal adhesion, Mucin type O-glycan biosynthesis, and so on. The differentially expressed lncRNA (DElncRNA) involved in the pathway of thyronamine and iodothyronamine metabolism and so on. Through integrated lncRNA-mRNA and miRNA-mRNA pairs, the ceRNA network was constructed, thereafter, six ceRNA subnetworks were identified and subnetwork 1 were found to be significantly associated with the occurrence of alopecia areata. CONCLUSION: Our results showed blood lncRNA expression patterns and a complex ceRNA network in alopecia areata. However, futher studies on blood and tissue verification of these lncRNAs and relative pathways are needed.

3-Iodothyronamine-A Thyroid Hormone Metabolite With Distinct Target Profiles and Mode of Action.

The rediscovery of the group of thyronamines (TAMs), especially the first detailed description of their most prominent congener 3-iodothyronamine (3T1AM) 14 years ago, boosted research on this thyroid hormone metabolite tremendously. TAMs exert actions partly opposite to and distinct from known functions of thyroid hormones. These fascinating metabolic, anapyrexic, cytoprotective, and brain effects quickly evoked the hope to use hormone-derived TAMs as a therapeutic option. The G protein-coupled receptor (GPCR) TAAR1, a member of the trace amine-associated receptor (TAAR) family, was identified as the first target and effector of TAM action. The initial enthusiasm on pharmacological actions of exogenous TAMs elicited many questions, such as sites of biosynthesis, analytics, modes of action, inactivation, and role of TAMs in (patho)physiology. Meanwhile, it became clear that TAMs not only interact with TAAR1 or other TAAR family members but also with several aminergic receptors and non-GPCR targets such as transient receptor potential channels, mitochondrial proteins, and the serum TAM-binding protein apolipoprotein B100, thus classifying 3T1AM as a multitarget ligand. The physiological mode of action of TAMs is still controversial because regulation of endogenous TAM production and the sites of its biosynthesis are not fully elucidated. Methods for 3T1AM analytics need further validation, as they revealed different blood and tissue concentrations depending on detection principles used such as monoclonal antibody-based immunoassay vs liquid chromatography- matrix-assisted laser desorption/ionization mass spectrometry or time-of-flight mass spectrometry. In this review, we comprehensively summarize and critically evaluate current basic, translational, and clinical knowledge on 3T1AM and its main metabolite 3-iodothyroacetic acid, focusing on endocrine-relevant aspects and open but highly challenging issues.

Thyroid hormone binding motifs and iodination pattern of thyroglobulin.

A phylogenetically conserved 5-residue thyroid hormone (TH)- binding motif was originally found in a few TH plasma carriers and, more recently, in all known plasma and cell-associated proteins interacting with TH as well as in proteins involved in iodide uptake. Minor variations of the motif were found, depending on the particular class of those proteins. Since thyroglobulin (Tg) is the protein matrix for TH synthesis starting from iodination of a selected number of tyrosines (to form first monoiodotyrosine (MIT) and diiodotyrosine (DIT) and then T3 and T4), we hypothesized that by searching the presence of perfect or imperfect versions of that motif in two Tg species (human and murine) in which the iodinated tyrosines and pattern of iodotyrosine/iodothyronine formation are known, we could have found relevant explanations. Explanations, which are not furnished by the simple possession of tyrosine-iodination motifs and sequence of the iodination motif, concern why only some (but not other) tyrosine residues in one species are iodinated and why they have a particular iodination pattern. In this bioinformatics study, we provide such explanations.

Thyroid Hormones and Derivatives: Endogenous Thyroid Hormones and Their Targets.

More than a century after the discovery of L-Thyroxine, the main thyroid hormone secreted solely by the thyroid gland, several metabolites of this iodinated, tyrosine-derived ancestral hormone have been identified. These are utilized as hormones during development, differentiation, metamorphosis, and regulation of most biochemical reactions in vertebrates and their precursor species. Among those metabolites are the thyromimetically active 3,3',5-Triiodo-L-thyronine (T3) and 3,5-Diiodo-L-thronine, reverse-T3 (3,3',5'-Triiodo-L-thyronine) with still unclear function, the recently re-discovered thyronamines (e.g., 3-Iodo-thyronamine), which exert in part T3-antagonistic functions, the thyroacetic acids (e.g., Tetrac and Triac), as well as various sulfated or glucuronidated metabolites of this panel of iodinated signaling compounds. In the blood most of these hydrophobic metabolites are tightly bound to the serum distributor proteins thyroxine binding globulin (TBG), transthyretin (TTR), albumin or apolipoprotein B100. Cellular import and export of these charged, highly hydrophobic amino acid derivatives requires a number of cell-membrane transporters or facilitators such as MCT8 or MCT10 and members of the OATP and LAT families of transporters. Depending on their structure, the thyroid hormone metabolites exert their cellular action by binding and thus modulating the function of various receptors systems (e.g., ανß3 integrin receptor and transient receptor potential channels (TRPM8) of the cell membrane), in part linked to intracellular downstream kinase signaling cascades, and several isoforms of membrane-associated, mitochondrial or nuclear thyroid hormone receptors (TR), which are members of the c-erbA family of ligand-modulated transcription factors. Intracellular deiodinase selenoenzymes, which obligatory are membrane integrated enzymes, ornithine decarboxylase and monoamine oxidases control local availability of biologically active thyroid hormone metabolites. Inactivation of thyroid hormone metabolites occurs mainly by deiodination, sulfation or glucuronidation, reactions which favor their renal or fecal elimination.

Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases.

INTRODUCTION: The trace amines, endogenous amines closely related to the biogenic amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a trace amine-sensitive G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of trace amine signaling. Areas covered: Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed. Focused application of TAAR1 mutants, synthetic TAAR1 ligands, and endogenous biomolecules such as 3-iodothyronamine (T1AM) has yielded a basic functional portrait for TAAR1, despite a complex biochemistry and pharmacology. The close functional relationship between TAAR1 and dopaminergic signaling is likely to underlie many of its CNS effects. However, TAAR1's influences on serotonin and glutamate neurotransmission will also be highlighted. Expert opinion: TAAR1 holds great promise as a therapeutic target for mental illness, addiction, and sleep disorders. A combination of preclinical and translationally driven studies has solidified TAAR1 as a key node in the regulation of dopaminergic signaling. Continued focus on the mechanisms underlying TAAR1's regulation of serotonin and glutamate signaling, as well as dopamine, will yield further disease-relevant insights.

The Deposition and Elimination of Glucosinolate Metabolites Derived from Rapeseed Meal in Eggs of Laying Hens.

This study was to investigate the deposition and elimination of glucosinolate metabolites including 5-vinyl-1,3-oxazolidine-2-thione (5-VOT) and thiocyanate ion (SCN-) derived from rapeseed meal (RSM) in hen eggs. During 12 weeks accumulation phase, the serum triiodothyronine, thyronine, blood urea nitrogen, kidney index, and thyroid index linearly increased with the RSM at week 12 (P < 0.05). The thyroid histopathology revealed a sign of hyperplastic goiter in hens fed with 17.64-29.40% RSM. The 5-VOT content of eggs (Y, ng/g) was correlated with 5-VOT intake (X2, µg/d·bird) and 5-VOT feeding time (X1, week): Y = 54.94X1 + 0.51X2 - 430.34 (P < 0.01, R2 = 0.80). The SCN- content of eggs (Y, mg/kg) was correlated with RSM intake (X2, µg/d·bird) and RSM feeding time (X1, week): Y = 0.095X1 + 0.302X2 - 0.4211 (P < 0.01, R2 = 0.70). After a 4-week withdrawal of RSM, the 5-VOT and SCN- did not show in eggs. Taken together, 5.88% RSM with dietary supplements of 23.55 mg/kg 5-VOT and 10.76 mg/kg SCN- had no effects on hens with regard to serum parameters, organ index, and thyroid histopathology, and more than 4 weeks withdrawal should be considered for human and hen health.

3-Iodothyroacetic acid (TA1), a by-product of thyroid hormone metabolism, reduces the hypnotic effect of ethanol without interacting at GABA-A receptors.

3-iodothyroacetic acid (TA1) is among the by-products of thyroid hormone metabolism suspected to mediate the non-genomic effects of the hormone (T3). We aim to investigate whether TA1 systemically administered to mice stimulated mice wakefulness, an effect already described for T3 and for another T3 metabolite (i.e. 3-iodothryonamine; T1AM), and whether TA1 interacted at GABA-A receptors (GABA-AR). Mice were pre-treated with either saline (vehicle) or TA1 (1.32, 4 and 11 µg/kg) and, after 10 min, they received ethanol (3.5 g/kg, i.p.). In another set of experiments, TA1 was administered 5 min after ethanol. The latency of sleep onset and the time of sleep duration were recorded. Voltage-clamp experiments to evaluate the effect of 1 µM TA1 on bicuculline-sensitive currents in acute rat hippocampal slice neurons and binding experiments evaluating the capacity of 1, 10, 100 µM TA1 to displace [3H]flumazenil from mice brain membranes were also performed. 4 µg/kg TA1 increases the latency of onset and at 1.32 and 4 µg/kg it reduces the duration of ethanol-induced sleep only if administered before ethanol. TA1 does not functionally interact at GABA-AR. Overall these results indicate a further similarity between the pharmacological profile of TA1 and that of T1AM.

Targeting species-specific trace amine-associated receptor 1 ligands: to date perspective of the rational drug design process.

G-protein-coupled receptors represent main targets of several clinically relevant drugs, playing nowadays a leading part for further drug discovery process. Trace amine-associated receptor's family (TAARs) assumed an intriguing role as druggable target in medicinal chemistry, being TAAR1 the most investigated. Indeed, related ligands proved to be intertwined in several circuits involved in pathological pathways or therapeutic routes. Herein, we highlight relevant efforts in the search of novel agonists, focusing on responsiveness featured by different chemotypes toward rodent and human TAAR1, in order to explore species-specificity preferences. We also discuss the main strategies guiding so far the design of new TAAR1 agonists, giving a perspective of the structure-based methodologies aimed at deriving new insights for more potent and selective derivatives.

Directional thyroid hormone distribution via the blood stream to target sites.

Thyroid hormones are bound to three major serum transport proteins, thyroxin-binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). TBG has the strongest affinity for thyroid hormones, TTR is also found in the cerebrospinal fluid and HSA is the most abundant protein in plasma. Combination defects of either a high affinity TTR or HSA variant do not compensate TBG deficiency, underscoring the dominant role of TBG among the thyroid hormone transport proteins. On the other hand, coexistence of raised affinity TTR and HSA variants causes an augmented hyperthyroxinemia. Variations in thyroid hormone transport proteins may alter thyroid function tests to mimic hypo- or hyperthyroidism. As affected individuals are clinically euthyroid and do not require treatment, identification of thyroid hormone transport protein defects is important to avoid unnecessary diagnostic and therapeutic interventions. Mammals share the multilayered system of thyroid hormone binding proteins with humans. Some of them, especially carnivores, do not express TBG. In dogs, this defect has been shown to be caused by a defective hepatocyte nuclear factor-1 binding site in the TBG promoter, preventing TBG synthesis in the liver. The major endogenous thyroid hormone metabolite 3-iodothyronamine (3-T1AM) exerts marked cryogenic, metabolic, cardiac and central nervous system actions. It is bound to apolipoproteinB-100 (ApoB100), possibly facilitating its cellular uptake via interaction with the low density lipoprotein-receptor. This review summarizes the handling of hydrophobic charged thyroid hormone signaling molecules and their metabolite 3-T1AM in aqueous body fluids and the advantages and limits of their serum distributor proteins.

"With a little help from my friends" - The role of microbiota in thyroid hormone metabolism and enterohepatic recycling.

The gut microbiota is composed of over 1200 species of anaerobes and aerobes bacteria along with bacteriophages, viruses and fungal species. Increasing evidence indicates that the intestinal microbiota, beside digestive equilibrium, is also crucial for immunologic, hormonal and metabolic homeostasis. The intestinal microbiota interacts with distant organs by signals which may be part of the bacteria themselves or their metabolites. Dysbiosis has been observed in inflammatory or autoimmune disorders such as multiple sclerosis or type 1 diabetes as well as in obesity and type 2 diabetes. Functional thyroid disorders were associated with bacterial overgrowth and a different microbial composition. Although thyroid metabolism was apparently disregarded, the interference of microbiota on peripheral iodothyronine homeostasis is an intriguing issue. In this review we focused on the interactions of intestinal microbiota with thyroid-related micronutrients and with the metabolic steps of endogenous and exogenous iodothyronines.

Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine.

Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk between endocrine and lipid metabolic pathways, we administered 3-iodothyronamine (T1AM), a natural analog of thyroid hormone, in a mouse model of PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue-specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR, CYP11A1, and CYP17A1. Biochemical measurements provide further evidence of significant reduction in liver cholesterol and triglycerides in post-T1AM treatment. Our results shed light onto tissue-specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies within the pathophysiology of PCOS This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex metabolic diseases.

Cardiac actions of thyroid hormone metabolites.

Thyroid hormones (THs) have a major role in regulating cardiac function. Their classical mechanism of action is genomic. Recent findings have broadened our knowledge about the (patho)physiology of cardiac regulation by THs, to include non-genomic actions of THs and their metabolites (THM). This review provides an overview of classical and non-classical cardiac effects controlled by: i) iodothyronines (thyroxine, T4; 3,5,3'-triiodothyronine,T3; 3, 5-diiodothyronine, T2); ii) thyronamines (thyronamine, T0AM; 3-iodothyronamine, T1AM); and iii) iodothyroacetic acids (3, 5, 3', 5'-tetraiodothyroacetic acid, tetrac; 3, 5, 3'-triiodothyroacetic acid, triac; 3-iodothyroacetic acid, TA1). Whereas iodothyronines enhance both diastolic and systolic function and heart rate, thyronamines were observed to have negative inotropic and chronotropic effects and might function as a brake with respect to THs, although their physiological role is unclear. Moreover, thyronamines showed a cardioprotective effect at physiological concentrations. The cardiac effects of iodothyroacetic acids seem to be limited and need to be elucidated.