Journal articles: 'T1AM'

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Rogowski, Michael, Lorenza Bellusci, Martina Sabatini, Simona Rapposelli, Shaikh M. Rahman, Grazia Chiellini, and Fariba M. Assadi-Porter. "Lipolytic Effects of 3-Iodothyronamine (T1AM) and a Novel Thyronamine-Like Analog SG-2 through the AMPK Pathway." International Journal of Molecular Sciences 20, no. 16 (August 20, 2019): 4054. http://dx.doi.org/10.3390/ijms20164054.

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3-Iodothyronamine (T1AM) and its synthetic analog SG-2 are rapidly emerging as promising drivers of cellular metabolic reprogramming. Our recent research indicates that in obese mice a sub-chronic low dose T1AM treatment increased lipolysis, associated with significant weight loss independent of food consumption. The specific cellular mechanism of T1AM’s lipolytic effect and its site of action remains unknown. First, to study the mechanism used by T1AM to gain entry into cells, we synthesized a fluoro-labeled version of T1AM (FL-T1AM) by conjugating it to rhodamine (TRITC) and analyzed its cellular uptake and localization in 3T3-L1 mouse adipocytes. Cell imaging using confocal microscopy revealed a rapid intercellular uptake of FL-T1AM into mitochondria without localization to the lipid droplet or nucleus of mature adipocytes. Treatment of 3T3-L1 adipocytes with T1AM and SG-2 resulted in decreased lipid accumulation, the latter showing a significantly higher potency than T1AM (10 µM vs. 20 µM, respectively). We further examined the effects of T1AM and SG-2 on liver HepG2 cells. A significant decrease in lipid accumulation was observed in HepG2 cells treated with T1AM or SG-2, due to increased lipolytic activity. This was confirmed by accumulation of glycerol in the culture media and through activation of the AMPK/ACC signaling pathways.

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Saba, Alessandro, Grazia Chiellini, Sabina Frascarelli, Maja Marchini, Sandra Ghelardoni, Andrea Raffaelli, Massimo Tonacchera, Paolo Vitti, Thomas S. Scanlan, and Riccardo Zucchi. "Tissue Distribution and Cardiac Metabolism of 3-Iodothyronamine." Endocrinology 151, no. 10 (August 25, 2010): 5063–73. http://dx.doi.org/10.1210/en.2010-0491.

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3-Iodothyronamine (T1AM) is a novel relative of thyroid hormone, able to interact with specific G protein-coupled receptors, known as trace amine-associated receptors. Significant functional effects are produced by exogenous T1AM, including a negative inotropic and chronotropic effect in cardiac preparations. This work was aimed at estimating endogenous T1AM concentration in different tissues and determining its cardiac metabolism. A novel HPLC tandem mass spectrometry assay was developed, allowing detection of T1AM, thyronamine, 3-iodothyroacetic acid, and thyroacetic acid. T1AM was detected in rat serum, at the concentration of 0.3 ± 0.03 pmol/ml, and in all tested organs (heart, liver, kidney, skeletal muscle, stomach, lung, and brain), at concentrations significantly higher than the serum concentration, ranging from 5.6 ± 1.5 pmol/g in lung to 92.9 ± 28.5 pmol/g in liver. T1AM was also identified for the first time in human blood. In H9c2 cardiomyocytes and isolated perfused rat hearts, significant Na+-dependent uptake of exogenous T1AM was observed, and at the steady state total cellular or tissue T1AM concentration exceeded extracellular concentration by more than 20-fold. In both preparations T1AM underwent oxidative deamination to 3-iodothyroacetic acid. T1AM deamination was inhibited by iproniazid but not pargyline or semicarbazide, suggesting the involvement of both monoamine oxidase and semicarbazide-sensitive amine oxidase. Thyronamine and thyroacetic acid were not detected in heart. Finally, evidence of T1AM production was observed in cardiomyocytes exposed to exogenous thyroid hormone, although the activity of this pathway was very low.

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Dinter, Juliane, Noushafarin Khajavi, Jessica Mühlhaus, Carolin Leonie Wienchol, Maxi Cöster, Thomas Hermsdorf, Claudia Stäubert, et al. "The Multitarget Ligand 3-Iodothyronamine Modulates β-Adrenergic Receptor 2 Signaling." European Thyroid Journal 4, Suppl. 1 (2015): 21–29. http://dx.doi.org/10.1159/000381801.

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Background: 3-Iodothyronamine (3-T1AM), a signaling molecule with structural similarities to thyroid hormones, induces numerous physiological responses including reversible body temperature decline. One target of 3-T1AM is the trace amine-associated receptor 1 (TAAR1), which is a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs). Interestingly, the effects of 3-T1AM remain detectable in TAAR1 knockout mice, suggesting further targets for 3-T1AM such as adrenergic receptors. Therefore, we evaluated whether β-adrenergic receptor 1 (ADRB1) and 2 (ADRB2) signaling is affected by 3-T1AM in HEK293 cells and in human conjunctival epithelial cells (IOBA-NHC), where these receptors are highly expressed endogenously. Methods: A label-free EPIC system for prescreening the 3-T1AM-induced effects on ADRB1 and ADRB2 in transfected HEK293 cells was used. In addition, ADRB1 and ADRB2 activation was analyzed using a cyclic AMP assay and a MAPK reporter gene assay. Finally, fluorescence Ca2+ imaging was utilized to delineate 3-T1AM-induced Ca2+ signaling. Results: 3-T1AM (10-5- 10-10M) enhanced isoprenaline-induced ADRB2-mediated Gs signaling but not that of ADRB1-mediated signaling. MAPK signaling remained unaffected for both receptors. In IOBA-NHC cells, norepinephrine-induced Ca2+ influxes were blocked by the nonselective ADRB blocker timolol (10 µM), indicating that ADRBs are most likely linked with Ca2+ channels. Notably, timolol was also found to block 3-T1AM (10-5M)-induced Ca2+ influx. Conclusions: The presented data support that 3-T1AM directly modulates β-adrenergic receptor signaling. The relationship between 3-T1AM and β-adrenergic signaling also reveals a potential therapeutic value for suppressing Ca2+ channel-mediated inflammation processes, occurring in eye diseases such as conjunctivitis.

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Ghelardoni, Sandra, Grazia Chiellini, Sabina Frascarelli, Alessandro Saba, and Riccardo Zucchi. "Uptake and metabolic effects of 3-iodothyronamine in hepatocytes." Journal of Endocrinology 221, no. 1 (April 2014): 101–10. http://dx.doi.org/10.1530/joe-13-0311.

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3-Iodothyronamine (T1AM) is an endogenous relative of thyroid hormone with profound metabolic effects. In different experimental models, T1AM increased blood glucose, and it is not clear whether this effect is entirely accounted by changes in insulin and/or glucagone secretion. Thus, in the present work, we investigated the uptake of T1AM by hepatocytes, which was compared with the uptake of thyroid hormones, and the effects of T1AM on hepatic glucose and ketone body production. Two different experimental models were used: HepG2 cells and perfused rat liver. Thyronines and thyronamines (T0AMs) were significantly taken up by hepatocytes. In HepG2 cells exposed to 1 μM T1AM, at the steady state, the cellular concentration of T1AM exceeded the medium concentration by six- to eightfold. Similar accumulation occurred with 3,5,3′-triiodothyronine and thyroxine. Liver experiments confirmed significant T1AM uptake. T1AM was partly catabolized and the major catabolites were 3-iodothyroacetic acid (TA1) (in HepG2 cells) and T0AM (in liver). In both preparations, infusion with 1 μM T1AM produced a significant increase in glucose production, if adequate gluconeogenetic substrates were provided. This effect was dampened at higher concentration (10 μM) or in the presence of the amine oxidase inhibitor iproniazid, while TA1 was ineffective, suggesting that T1AM may have a direct gluconeogenetic effect. Ketone body release was significantly increased in liver, while variable results were obtained in HepG2 cells incubated with gluconeogenetic substrates. These findings are consistent with the stimulation of fatty acid catabolism, and a shift of pyruvate toward gluconeogenesis. Notably, these effects are independent from hormonal changes and might have physiological and pathophysiological importance.

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Dinter, Juliane, Jessica Mühlhaus, Simon Friedrich Jacobi, Carolin Leonie Wienchol, Maxi Cöster, Jaroslawna Meister, Carolin Stephanie Hoefig, et al. "3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling." Journal of Molecular Endocrinology 54, no. 3 (June 2015): 205–16. http://dx.doi.org/10.1530/jme-15-0003.

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Mostin vivoeffects of 3-iodothyronamine (3-T1AM) have been thus far thought to be mediated by binding at the trace amine-associated receptor 1 (TAAR1). Inconsistently, the 3-T1AM-induced hypothermic effect still persists inTaar1knockout mice, which suggests additional receptor targets. In support of this general assumption, it has previously been reported that 3-T1AM also binds to the α-2A-adrenergic receptor (ADRA2A), which modulates insulin secretion. However, the mechanism of this effect remains unclear. We tested two different scenarios that may explain the effect: the sole action of 3-T1AM at ADRA2A and a combined action of 3-T1AM at ADRA2A and TAAR1, which is also expressed in pancreatic islets. We first investigated a potential general signaling modification using the label-free EPIC technology and then specified changes in signaling by cAMP inhibition and MAPKs (ERK1/2) determination. We found that 3-T1AM induced Gi/oactivation at ADRA2A and reduced the norepinephrine (NorEpi)-induced MAPK activation. Interestingly, in ADRA2A/TAAR1 hetero-oligomers, application of NorEpi resulted in uncoupling of the Gi/osignaling pathway, but it did not affect MAPK activation. However, 3-T1AM application in mice over a period of 6 days at a daily dose of 5 mg/kg had no significant effects on glucose homeostasis. In summary, we report an agonistic effect of 3-T1AM on the ADRA2A-mediated Gi/opathway but an antagonistic effect on MAPK induced by NorEpi. Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate Gi/osignaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.

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Haiyan, Zhou, Hu Bailong, Zhang Bei, Wang Yiming, and Liu Xingde. "Comparative Transcriptome Analysis Reveals the Potential Cardiovascular Protective Targets of the Thyroid Hormone Metabolite 3-Iodothyronamine (3-T1AM)." BioMed Research International 2020 (June 20, 2020): 1–10. http://dx.doi.org/10.1155/2020/1302453.

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Background. The thyroid hormone metabolite 3-iodothyronamine (3-T1AM) is rapidly emerging as a promising compound in decreasing the heart rate and lowering the cardiac output. The aim of our study was to fully understand the molecular mechanism of 3-T1AM on cardiomyocytes and its potential targets in cardiovascular diseases. Materials and Methods. In our study, we utilized RNA-Seq to characterize the gene expression in H9C2 cells after 3-T1AM treatment. Comparative transcriptome analysis, including gene ontology, signaling pathways, disease connectivity analysis, and protein-protein interaction networks (PPI), was presented to find the critical gene function, hub genes, and related pathways. Results. A total of 1494 differently expressed genes (DEGs) were identified (192 upregulated and 1302 downregulated genes) in H9C2 cells for 3-T1AM treatment. Of these, 90 genes were associated with cardiovascular diseases. The PPI analysis indicated that 5 hub genes might be the targets of 3-T1AM. Subsequently, eight DEGs characterized using RNA-Seq were confirmed by RT-qPCR assays. Conclusions. Our study provides a comprehensive analysis of 3-T1AM on H9C2 cells and delineates a new insight into the therapeutic intervention of 3-T1AM for the cardiovascular diseases.

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Cöster, Maxi, Heike Biebermann, Torsten Schöneberg, and Claudia Stäubert. "Evolutionary Conservation of 3-Iodothyronamine as an Agonist at the Trace Amine-Associated Receptor 1." European Thyroid Journal 4, Suppl. 1 (2015): 9–20. http://dx.doi.org/10.1159/000430839.

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Objectives: The trace amine-associated receptor 1 (Taar1) is a Gs protein-coupled receptor activated by trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T1AM). T1AM is an endogenous biogenic amine and thyroid hormone derivative that exerts several biological functions. However, the physiological relevance of T1AM acting via Taar1 is still under discussion. Therefore, we studied the structural and functional evolution of Taar1 in vertebrates to provide evidence for a conserved Taar1-mediated T1AM function. Study Design: We searched public sequence databases to retrieve Taar1 sequence information from vertebrates. We cloned and functionally characterized Taar1 from selected vertebrate species using cAMP assays to determine the evolutionary conservation of T1AM action at Taar1. Results: We found intact open reading frames of Taar1 in more than 100 vertebrate species, including mammals, sauropsids and amphibians. Evolutionary conservation analyses of Taar1 protein sequences revealed a high variation in amino acid residues proposed to be involved in agonist binding, especially in rodent Taar1 orthologs. Functional characterization showed that T1AM, β-PEA and p-tyramine (p-Tyr) act as agonists at all tested orthologs, but EC50 values of T1AM at rat Taar1 differed significantly when compared to all other tested vertebrate Taar1. Conclusions: The high structural conservation of Taar1 throughout vertebrate evolution highlights the physiological relevance of Taar1, but species-specific differences in T1AM potency at Taar1 orthologs suggest a specialization of rat Taar1 for T1AM recognition. In contrast, β-PEA and p-Tyr potencies were rather conserved throughout all tested Taar1 orthologs. We provide evidence that the observed differences in potency are related to differences in constraint during Taar1 evolution.

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Gencarelli, Manuela, Annunziatina Laurino, Elisa Landucci, Daniela Buonvicino, Costanza Mazzantini, Grazia Chiellini, and Laura Raimondi. "3-Iodothyronamine Affects Thermogenic Substrates’ Mobilization in Brown Adipocytes." Biology 9, no. 5 (May 4, 2020): 95. http://dx.doi.org/10.3390/biology9050095.

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We investigated the effect of 3-iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations. When compared to cells not exposed, M+T1AM cells showed increased p-PKA/PKA, p-AKT/AKT, p-CREB/CREB, p-P38/P38, and p-AMPK/AMPK, downregulation of DIO2 and β1AR, and upregulation of glycosylated β3AR, GLUT4, and adiponectin. At basal conditions, glycerol release was higher for M+T1AM cells than M cells, without any significant differences in basal glucose uptake. Notably, in M+T1AM cells, adrenergic agonists failed to activate PKA and lipolysis and to increase ATP level, but the glucose uptake in response to insulin exposure was more pronounced than in M cells. In conclusion, our results suggest that BAs conditioning with T1AM promote a catabolic condition promising to fight obesity and insulin resistance.

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Galli, Elena, Maja Marchini, Alessandro Saba, Sergio Berti, Massimo Tonacchera, Paolo Vitti, Thomas S. Scanlan, Giorgio Iervasi, and Riccardo Zucchi. "Detection of 3-Iodothyronamine in Human Patients: A Preliminary Study." Journal of Clinical Endocrinology & Metabolism 97, no. 1 (January 1, 2012): E69—E74. http://dx.doi.org/10.1210/jc.2011-1115.

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Context and Objective: The primary purpose of this study was to detect and quantify 3-iodothyronamine (T1AM), an endogenous biogenic amine related to thyroid hormone, in human blood. Design: T1AM, total T3, and total T4 were assayed in serum by a novel HPLC tandem mass spectrometry assay, which has already been validated in animal investigations, and the results were related to standard clinical and laboratory variables. Setting and Patients: The series included one healthy volunteer, 24 patients admitted to a cardiological ward, and 17 ambulatory patients suspected of thyroid disease, who underwent blood sampling at admission for routine diagnostic purposes. Seven patients were affected by type 2 diabetes, and six patients showed echocardiographic evidence of impaired left ventricular function. Interventions: No intervention or any patient selection was performed. Main Outcome Measures: serum T1AM, total and free T3 and T4, routine chemistry, routine hematology, and echocardiographic parameters were measured. Results: T1AM was detected in all samples, and its concentration averaged 0.219 ± 0.012 pmol/ml. The T1AM concentration was significantly correlated to total T4 (r = 0.654, P < 0.001), total T3 (r = 0.705, P < 0.001), glycated hemoglobin (r = 0.508, P = 0.013), brain natriuretic peptide (r = 0.543, P = 0.016), and γ-glutamyl transpeptidase (r = 0.675, P < 0.001). In diabetic vs. nondiabetic patients T1AM concentration was significantly increased (0.232 ± 0.014 vs. 0.203 ± 0.006 pmol/ml, P = 0.044), whereas no significant difference was observed in patients with cardiac dysfunction. Conclusions: T1AM is an endogenous messenger that can be assayed in human blood. Our results are consistent with the hypothesis that circulating T1AM is produced from thyroid hormones and encourage further investigations on the potential role of T1AM in insulin resistance and heart failure.

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Hackenmueller, Sarah A., Maja Marchini, Alessandro Saba, Riccardo Zucchi, and Thomas S. Scanlan. "Biosynthesis of 3-Iodothyronamine (T1AM) Is Dependent on the Sodium-Iodide Symporter and Thyroperoxidase but Does Not Involve Extrathyroidal Metabolism of T4." Endocrinology 153, no. 11 (November 1, 2012): 5659–67. http://dx.doi.org/10.1210/en.2012-1254.

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Abstract 3-Iodothyronamine (T1AM) is an endogenous thyroid hormone derivative with unknown biosynthetic origins. Structural similarities have led to the hypothesis that T1AM is an extrathyroidal metabolite of T4. This study uses an isotope-labeled T4 [heavy-T4 (H-T4)] that can be distinguished from endogenous T4 by mass spectrometry, which allows metabolites to be identified based on the presence of this unique isotope signature. Endogenous T1AM levels depend upon thyroid status and decrease upon induction of hypothyroidism. However, in hypothyroid mice replaced with H-T4, the isotope-labeled H-T3 metabolite is detected, but no isotope-labeled T1AM is detected. These data suggest that T1AM is not an extrathyroidal metabolite of T4, yet is produced by a process that requires the same biosynthetic factors necessary for T4 synthesis.

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Agretti, Patrizia, Giuseppina De Marco, Laura Russo, Alessandro Saba, Andrea Raffaelli, Maja Marchini, Grazia Chiellini, et al. "3-Iodothyronamine metabolism and functional effects in FRTL5 thyroid cells." Journal of Molecular Endocrinology 47, no. 1 (April 21, 2011): 23–32. http://dx.doi.org/10.1530/jme-10-0168.

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3-Iodothyronamine (T1AM), produced from thyroid hormones (TH) through decarboxylation and deiodination, is a potent agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor belonging to the family of TAARs.In vivoT1AM induces functional effects opposite to those produced on a longer time scale by TH and might represent a novel branch of TH signaling. In this study, we investigated the action of T1AM on thyroid and determined its uptake and catabolism using FRTL5 cells. The expression of TAAR1 was determined by PCR and western blot in FRTL5 cells, and cAMP, iodide uptake, and glucose uptake were measured after incubation with increasing concentrations of T1AM for different times. T1AM and its catabolites thyronamine (T0AM), 3-iodothyroacetic acid (TA1), and thyroacetic acid (TA0) were analyzed in FRTL5 cells by HPLC coupled to tandem mass spectrometry. The product of amplification ofTAAR1gene and TAAR1 protein was demonstrated in FRTL5 cells. No persistent and dose-dependent response to T1AM was observed after treatment with increasing doses of this substance for different times in terms of cAMP production and iodide uptake. A slight inhibition of glucose uptake was observed in the presence of 100 μM T1AM after 60 and 120 min (28 and 32% respectively), but the effect disappeared after 18 h. T1AM was taken up by FRTL5 cells and catabolized to T0AM, TA1, and TA0confirming the presence of deiodinase and amine oxidase activity in thyroid. In conclusion, T1AM determined a slight inhibition of glucose uptake in FRTL5 cells, but it was taken up and catabolized by these cells.

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Scanlan, Thomas S. "3-Iodothyronamine (T1AM): A New Player on the Thyroid Endocrine Team?" Endocrinology 150, no. 3 (December 30, 2008): 1108–11. http://dx.doi.org/10.1210/en.2008-1596.

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3-Iodothyronamine (T1AM) is an endogenous compound with chemical features that are similar to thyroid hormone. T1AM has a carbon skeleton identical to that of T4 and contains a single carbon-iodine bond. Theoretically, T1AM could be produced from T4 by enzymatic decarboxylation and deiodination. Recent studies show that T1AM and higher iodinated thyronamines are subject to similar metabolic processing as iodothyronines such as T4, suggesting a biological linkage between iodothyronines and iodothyronamines. In addition, single doses of T1AM administered to rodents induce a hypometabolic state that in certain ways resembles hibernation and is opposite to the effects of excess T4. This review will discuss the latest developments on this recently discovered thyroid hormone derivative. 3-Iodothyronamine is a biologically active, endogenous derivative of thyroid hormone that may represent a new arm of the thyroid endocrine system.

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Gencarelli, Manuela, Maura Lodovici, Lorenza Bellusci, Laura Raimondi, and Annunziatina Laurino. "Redox Properties of 3-Iodothyronamine (T1AM) and 3-Iodothyroacetic Acid (TA1)." International Journal of Molecular Sciences 23, no. 5 (February 28, 2022): 2718. http://dx.doi.org/10.3390/ijms23052718.

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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.

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Ackermans, M. T., L. P. Klieverik, P. Ringeling, E. Endert, A. Kalsbeek, and E. Fliers. "An online solid-phase extraction–liquid chromatography–tandem mass spectrometry method to study the presence of thyronamines in plasma and tissue and their putative conversion from 13C6-thyroxine." Journal of Endocrinology 206, no. 3 (July 5, 2010): 327–34. http://dx.doi.org/10.1677/joe-10-0060.

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Thyronamines are exciting new players at the crossroads of thyroidology and metabolism. Here, we report the development of a method to measure 3-iodothyronamine (T1AM) and thyronamine (T0AM) in plasma and tissue samples. The detection limit of the method was 0.25 nmol/l in plasma and 0.30 pmol/g in tissue both for T1AM and for T0AM. Using this method, we were able to demonstrate T1AM and T0AM in plasma and liver from rats treated with synthetic thyronamines. Although we demonstrated the in vivo conversion of 13C6-thyroxine (13C6-T4) to 13C6-3,5,3′-triiodothyronine, we did not detect 13C6-T1AM in plasma or brain samples of rats treated with 13C6-T4. Surprisingly, our method did not detect any endogenous T1AM or T0AM in plasma from vehicle-treated rats, nor in human plasma or thyroid tissue. Although we are cautious to draw general conclusions from these negative findings and in spite of the fact that insufficient sensitivity of the method related to extractability and stability of T0AM cannot be completely excluded at this point, our findings raise questions on the biosynthetic pathways and concentrations of endogenous T1AM and T0AM.

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Rutigliano, Grazia, Lavinia Bandini, Simona Sestito, and Grazia Chiellini. "3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?" International Journal of Molecular Sciences 21, no. 6 (March 15, 2020): 2005. http://dx.doi.org/10.3390/ijms21062005.

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In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties of T1AM, including its structural and functional relationship to thyroid hormone, its endogenous levels, molecular targets, as well as its genomic and non-genomic effects on metabolism elicited in experimental models after exogenous administration. The physiological and pathophysiological relevance of T1AM in the regulation of energy homeostasis and metabolism is also discussed, along with its potential therapeutic applications in metabolic disturbances. Finally, we examine a number of T1AM analogs that have been recently developed with the aim of designing novel pharmacological agents for the treatment of interlinked diseases, such as metabolic and neurodegenerative disorders, as well as additional synthetic tools that can be exploited to further explore T1AM-dependent mechanisms and the physiological roles of trace amine-associated receptor 1 (TAAR1)-mediated effects.

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di Leo, Nicoletta, Stefania Moscato, Marco Borso', Simona Sestito, Beatrice Polini, Lavinia Bandini, Agostina Grillone, et al. "Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study." Molecules 26, no. 6 (March 14, 2021): 1616. http://dx.doi.org/10.3390/molecules26061616.

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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.

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Bandini, Lavinia, Ginevra Sacripanti, Marco Borsò, Maria Tartaria, Maria Pia Fogliaro, Giulia Giannini, Vittoria Carnicelli, et al. "Exogenous 3-Iodothyronamine (T1AM) Can Affect Phosphorylation of Proteins Involved on Signal Transduction Pathways in In Vitro Models of Brain Cell Lines, but These Effects Are Not Strengthened by Its Catabolite, 3-Iodothyroacetic Acid (TA1)." Life 12, no. 9 (August 30, 2022): 1352. http://dx.doi.org/10.3390/life12091352.

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T1AM, a derivative of thyroid hormones, and its major catabolite, TA1, produce effects on memory acquisition in rodents. In the present study, we compared the effects of exogenous T1AM and TA1 on protein belonging to signal transduction pathways, assuming that TA1 may strengthen T1AM’s effects in brain tissue. A hybrid line of cancer cells of mouse neuroblastoma and rat glioma (NG 108-15), as well as a human glioblastoma cell line (U-87 MG) were used. We first characterized the in vitro model by analyzing gene expression of proteins involved in the glutamatergic cascade and cellular uptake of T1AM and TA1. Then, cell viability, glucose consumption, and protein expression were assessed. Both cell lines expressed receptors implicated in glutamatergic pathway, namely Nmdar1, Glur2, and EphB2, but only U-87 MG cells expressed TAAR1. At pharmacological concentrations, T1AM was taken up and catabolized to TA1 and resulted in more cytotoxicity compared to TA1. The major effect, highlighted in both cell lines, albeit on different proteins involved in the glutamatergic signaling, was an increase in phosphorylation, exerted by T1AM but not reproduced by TA1. These findings indicate that, in our in vitro models, T1AM can affect proteins involved in the glutamatergic and other signaling pathways, but these effects are not strengthened by TA1.

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Biebermann, Heike, and Gunnar Kleinau. "3-Iodothyronamine Induces Diverse Signaling Effects at Different Aminergic and Non-Aminergic G-Protein Coupled Receptors." Experimental and Clinical Endocrinology & Diabetes 128, no. 06/07 (November 7, 2019): 395–400. http://dx.doi.org/10.1055/a-1022-1554.

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AbstractThe 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.

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Hoefig, Carolin S., Tilo Wuensch, Eddy Rijntjes, Ina Lehmphul, Hannelore Daniel, Ulrich Schweizer, Jens Mittag, and Josef Köhrle. "Biosynthesis of 3-Iodothyronamine From T4 in Murine Intestinal Tissue." Endocrinology 156, no. 11 (September 8, 2015): 4356–64. http://dx.doi.org/10.1210/en.2014-1499.

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The endogenous metabolite 3-iodothyronamine (3-T1AM) induces strong hypothermia and bradycardia at pharmacological doses. Although its biosynthesis from thyroid hormone precursors appears likely, the sequence and sites of reactions are still controversial: studies in T4-substituted thyroid cancer patients lacking functional thyroid tissue suggested extrathyroidal 3-T1AM production, whereas studies using labeled T4 in mice indicated intrathyroidal formation. However, because the patients received T4 orally, whereas the mice were injected ip, we hypothesized that 3-T1AM synthesis requires the intestinal passage of T4. Using the everted gut sac model in combination with mass spectrometry, we demonstrate 3-T1AM production from T4 in mouse intestine via several deiodination and decarboxylation steps. Gene expression analysis confirmed the expression of all 3 deiodinases as well as ornithine decarboxylase (ODC) in intestine. Subsequent experiments employing purified human ODC revealed that this enzyme can in fact mediate decarboxylation of 3,5-T2 and T4 to the respective thyronamines (TAMs), demonstrating that the intestine expresses the entire molecular machinery required for 3-T1AM biosynthesis. Interestingly, TAM production was strongly affected by the antithyroid treatment methimazole and perchlorate independently of thyroid status, limiting the validity of the respective mouse models in this context. Taken together, our data demonstrate intestinal 3-T1AM biosynthesis from T4 involving decarboxylation through ODC with subsequent deiodination, and explain the apparent discrepancy between 3-T1AM serum levels in patients substituted orally and mice injected ip with T4. Identifying ODC as the first enzyme capable of decarboxylating thyroid hormone, our findings open the path to further investigations of TAM metabolism on molecular and cellular levels.

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Chiellini, Grazia, Paola Erba, Vittoria Carnicelli, Chiara Manfredi, Sabina Frascarelli, Sandra Ghelardoni, Giuliano Mariani, and Riccardo Zucchi. "Distribution of exogenous [125I]-3-iodothyronamine in mouse in vivo: relationship with trace amine-associated receptors." Journal of Endocrinology 213, no. 3 (March 22, 2012): 223–30. http://dx.doi.org/10.1530/joe-12-0055.

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3-Iodothyronamine (T1AM) is a novel chemical messenger, structurally related to thyroid hormone, able to interact with G protein-coupled receptors known as trace amine-associated receptors (TAARs). Little is known about the physiological role of T1AM. In this prospective, we synthesized [125I]-T1AM and explored its distribution in mouse after injecting in the tail vein at a physiological concentration (0.3 nM). The expression of the nine TAAR subtypes was evaluated by quantitative real-time PCR. [125I]-T1AM was taken up by each organ. A significant increase in tissue vs blood concentration occurred in gallbladder, stomach, intestine, liver, and kidney. Tissue radioactivity decreased exponentially over time, consistent with biliary and urinary excretion, and after 24 h, 75% of the residual radioactivity was detected in liver, muscle, and adipose tissue. TAARs were expressed only at trace amounts in most of the tissues, the exceptions being TAAR1 in stomach and testis and TAAR8 in intestine, spleen, and testis. Thus, while T1AM has a systemic distribution, TAARs are only expressed in certain tissues suggesting that other high-affinity molecular targets besides TAARs exist.

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Wei, Bo, Hanbing Zhao, Bailong Hu, Lujun Dai, Guoning Zhang, Lili Mo, Niwen Huang, et al. "T1AM Attenuates the Hypoxia/Reoxygenation-Induced Necroptosis of H9C2 Cardiomyocytes via RIPK1/RIPK3 Pathway." BioMed Research International 2022 (February 28, 2022): 1–8. http://dx.doi.org/10.1155/2022/4833791.

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Purpose. To investigate the detailed mechanism of 3-iodothyronamine (T1AM) in cell apoptosis and programmed necrosis of hypoxia/reoxygenation- (H/R-) induced H9C2 injury. Materials and Methods. Cardiomyocyte H9C2 cells were cultured in vitro for the establishment of cardiomyocyte H/R models. Cells were randomly divided into four groups: the control group, H/R group, T1AM pretreatment group, T1AM pretreatment and H/R (6 μm T1AM+H/R) group. The degree of myocardial injury was determined by the detection of the cardiomyocyte inhibition rate by CCK8 and the detection of lactic dehydrogenase (LDH) activity. Cell apoptosis was assessed through TUNEL assay and flow cytometry analysis. The protein level and mRNA level of RIPK1, RIPK3, and CAMKII were detected by western blotting and qRT-PCR. Results. Compared with the control group, the cell inhibition rate was dramatically elevated in the H/R group. LDH release of cardiomyocytes was significantly increased. Protein and mRNA expressions of RIPK1, RIPK3, and CAMKII were significantly enhanced. Compared with the H/R group, the cell inhibition rate, LDH release, cardiomyocyte necroptosis rate, and protein and mRNA levels of RIPK1, RIPK3, and CAMKII of the T1AM+H/R group were significantly decreased. Conclusion. Pretreatment with T1AM could alleviate cardiomyocytes’ H/R injury and inhibit necroptosis of cardiomyocytes, which might exert a protective function upon activation of the RIPK1/RIPK3 pathway.

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Diab, Nour, Sameer Desale, Mark Danielsen, Josef Köhrle, Nawar Shara, and Jacqueline Jonklaas. "Changes in Thyroid Metabolites after Liothyronine Administration: A Secondary Analysis of Two Clinical Trials That Incorporated Pharmacokinetic Data." Metabolites 12, no. 6 (May 24, 2022): 476. http://dx.doi.org/10.3390/metabo12060476.

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We examined relationships between thyroid hormone (TH) metabolites in humans by measuring 3,5-diiodothyronine (3,5-T2) and 3-iodothyronamine (3-T1AM) levels after liothyronine administration. In secondary analyses, we measured 3,5-T2 and 3-T1AM concentrations in stored samples from two clinical trials. In 12 healthy volunteers, THs and metabolites were documented for 96 h after a single dose of 50 mcg liothyronine. In 18 patients treated for hypothyroidism, levothyroxine therapy was replaced by daily dosing of 30–45 mcg liothyronine. Analytes were measured prior to the administration of liothyronine weekly for 6 weeks, and then hourly for 8 h after the last liothyronine dose of the study. In the weekly samples from the hypothyroid patients, 3,5-T2 was higher by 0.033 nmol/L with each mcg/dL increase in T4 and 0.24 nmol/L higher with each ng/dL increase in FT4 (p-values = 0.007, 0.0365). In hourly samples after the last study dose of liothyronine, patients with T3 values higher by one ng/dL had 3-T1AM values that were lower by 0.004 nmol/L (p-value = 0.0473); patients with 3,5-T2 higher by one nmol/L had 3-T1AM values higher by 2.45 nmol/L (p-value = 0.0044). The positive correlations between weekly trough levels of 3,5-T2 and T4/FT4 during liothyronine therapy may provide insight into 3,5-T2 production, possibly supporting some production of 3,5-T2 from endogenous T4, but not from exogenous liothyronine. In hourly sampling after liothyronine administration, the negative correlation between T3 levels and 3-T1AM, but positive correlation between 3,5-T2 levels and 3-T1AM could support the hypothesis that 3-T1AM production occurs via 3,5-T2 with negative regulation by T3.

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Klieverik, Lars P., Ewout Foppen, Mariëtte T. Ackermans, Mireille J. Serlie, Hans P. Sauerwein, Thomas S. Scanlan, David K. Grandy, Eric Fliers, and Andries Kalsbeek. "Central effects of thyronamines on glucose metabolism in rats." Journal of Endocrinology 201, no. 3 (March 6, 2009): 377–86. http://dx.doi.org/10.1677/joe-09-0043.

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Thyronamines are naturally occurring, chemical relatives of thyroid hormone. Systemic administration of synthetic 3-iodothyronamine (T1AM) and – to a lesser extent – thyronamine (T0AM), leads to acute bradycardia, hypothermia, decreased metabolic rate, and hyperglycemia. This profile led us to hypothesize that the central nervous system is among the principal targets of thyronamines. We investigated whether a low dose i.c.v. infusion of synthetic thyronamines recapitulates the changes in glucose metabolism that occur following i.p. thyronamine administration. Plasma glucose, glucoregulatory hormones, and endogenous glucose production (EGP) using stable isotope dilution were monitored in rats before and 120 min after an i.p. (50 mg/kg) or i.c.v. (0.5 mg/kg) bolus infusion of T1AM, T0AM, or vehicle. To identify the peripheral effects of centrally administered thyronamines, drug-naive rats were also infused intravenously with low dose (0.5 mg/kg) thyronamines. Systemic T1AM rapidly increased EGP and plasma glucose, increased plasma glucagon, and corticosterone, but failed to change plasma insulin. Compared with i.p.-administered T1AM, a 100-fold lower dose administered centrally induced a more pronounced acute EGP increase and hyperglucagonemia while plasma insulin tended to decrease. Both systemic and central infusions of T0AM caused smaller increases in EGP, plasma glucose, and glucagon compared with T1AM. Neither T1AM nor T0AM influenced any of these parameters upon low dose i.v. administration. We conclude that central administration of low-dose thyronamines suffices to induce the acute alterations in glucoregulatory hormones and glucose metabolism following systemic thyronamine infusion. Our data indicate that thyronamines can act centrally to modulate glucose metabolism.

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Homuth, Georg, Julika Lietzow, Nancy Schanze, Janine Golchert, and Josef Köhrle. "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." Experimental and Clinical Endocrinology & Diabetes 128, no. 06/07 (May 25, 2020): 401–13. http://dx.doi.org/10.1055/a-1139-9200.

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AbstractThyroid 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.

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Bellusci, Lorenza, Massimiliano Runfola, Vittoria Carnicelli, Simona Sestito, Federica Fulceri, Filippo Santucci, Paola Lenzi, et al. "Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6." Molecules 25, no. 5 (February 26, 2020): 1054. http://dx.doi.org/10.3390/molecules25051054.

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3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these novel drug candidates, here we investigated whether the modulation of SIRT6, known to play a key role in reprogramming energy metabolism, might also drive the activation of clearing pathways, such as autophagy and ubiquitine-proteasome (UP), as further mechanisms against neurodegeneration. We show that both T1AM and SG-2 increase autophagy in U87MG cells by inducing the expression of SIRT6, which suppresses Akt activity thus leading to mTOR inhibition. This effect was concomitant with down-regulation of autophagy-related genes, including Hif1α, p53 and mTOR. Remarkably, when mTOR was inhibited a concomitant activation of autophagy and UP took place in U87MG cells. Since both compounds activate autophagy, which is known to sustain long term potentiation (LTP) in the entorhinal cortex (EC) and counteracting AD pathology, further electrophysiological studies were carried out in a transgenic mouse model of AD. We found that SG-2 was able to rescue LTP with an efficacy comparable to T1AM, further underlying its potential as a novel pleiotropic agent for neurodegenerative disorders treatment.

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Scanlan, Thomas S. "Endogenous 3-Iodothyronamine (T1AM): More Than We Bargained For." Journal of Clinical Endocrinology & Metabolism 96, no. 6 (June 2011): 1674–76. http://dx.doi.org/10.1210/jc.2011-0688.

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Laurino, Annunziatina, Rosanna Matucci, Giulio Vistoli, and Laura Raimondi. "3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors." European Journal of Pharmacology 793 (December 2016): 35–42. http://dx.doi.org/10.1016/j.ejphar.2016.10.027.

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Stavrou, Stavroula, Michael Gratz, Eileen Tremmel, Christina Kuhn, Simone Hofmann, Helene Heidegger, Mina Peryanova, et al. "TAAR1 induces a disturbed GSK3β phosphorylation in recurrent miscarriages through the ODC." Endocrine Connections 7, no. 2 (February 2018): 372–84. http://dx.doi.org/10.1530/ec-17-0272.

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Objectives Thyroid hormones play an important role in the maintenance of pregnancy. Their derivates, endogenous amines, act via binding to the trace amine-associated receptor (TAAR1). The aim of our study was to analyse the regulation of TAAR1, serine/threonine kinase (pGSK3β) and ornithine decarboxylase (ODC) in placentas of healthy pregnancies, spontaneous (SM) and recurrent miscarriages (RM) and to investigate the influence of thyroid hormone derivates on TAAR1 expression in trophoblast model cells in vitro. Methods Patients with SM (n = 15) and RM (n = 15) were compared with patients with healthy pregnancies (n = 15) (pregnancy weeks 7–13 each). Immunohistochemistry was applied to analyse placental TAAR1, pGSK3β and ODC expression. Protein expression of the receptors after stimulation with T3, T1AM and RO5203548 in BeWo trophoblast model cells was determined via Western blot. Double-immunofluorescence was used to determine placental expression of TAAR1 and ODC. Results Levels of TAAR1, pGSK3β and ODC were higher in placentas of RM in comparison to healthy controls. Stimulation of BeWo cells with T3, T1AM and RO5203548 significantly increased TAAR1 expression. ODC expression in BeWo cells was upregulated through T3. Via double-immunofluorescence, TAAR1 and ODC-positive EVT could be detected. Conclusions Upregulation of placental TAAR1 may indicate an increased decarboxylation of thyroid hormones in miscarriages. Patients with RM may have a lack of T3 through an enhanced transformation of T3 into T1AM induced by the ODC. Future investigations could be carried out to analyse what role a prophylactic T3 substitution plays for patients.

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Miyakawa, Motonori, and Thomas S. Scanlan. "Synthesis of [125I]‐, [2H]‐, and [3H]‐Labeled 3‐Iodothyronamine (T1AM)." Synthetic Communications 36, no. 7 (March 1, 2006): 891–902. http://dx.doi.org/10.1080/00397910500466074.

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Ianculescu, Alexandra G., and Thomas S. Scanlan. "3-Iodothyronamine (T1AM): a new chapter of thyroid hormone endocrinology?" Molecular BioSystems 6, no. 8 (2010): 1338. http://dx.doi.org/10.1039/b926583j.

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Gratz, Michael J., Stavroula Stavrou, Christina Kuhn, Simone Hofmann, Kerstin Hermelink, Helene Heidegger, Stefan Hutter, et al. "Dopamine synthesis and dopamine receptor expression are disturbed in recurrent miscarriages." Endocrine Connections 7, no. 5 (May 2018): 727–38. http://dx.doi.org/10.1530/ec-18-0126.

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Objectives l-dopa decarboxylase (DDC) is responsible for the synthesis of dopamine. Dopamine, which binds to the D2-dopamine receptor (D2R), plays an important role in the maintenance of pregnancy. Aim of our study was the analysis of DDC and D2R expression in placentas of spontaneous miscarriages (SMs) and recurrent miscarriages (RMs) in comparison to healthy controls. Methods Patients with SM (n = 15) and RM (n = 15) were compared with patients from healthy pregnancies (n = 15) (pregnancy weeks 7–13 each). Placental tissue has been collected from SMs and RMs from the first trimester (Department of Gynaecology and Obstetrics, LMU Munich) and from abruptions (private practice, Munich). Placental cell lines, BeWo- and JEG-3 cells, were stimulated with the trace amines T0AM and T1AM in vitro. Results Levels of DDC and D2R in trophoblasts and the decidua were lower in RMs in comparison to healthy controls. Stimulation of BeWo cells with T1AM significantly reduced DDC mRNA and protein levels. Via double-immunofluorescence, a DDC-positive cell type beneath decidual stromal cells and foetal EVT in the decidua could be detected. Conclusions Downregulation of DDC and D2R in trophoblasts of RMs reflects a reduced signal cascade of catecholamines on the foetal side.

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Tozzi, Francesca, Grazia Rutigliano, Marco Borsò, Chiara Falcicchia, Riccardo Zucchi, and Nicola Origlia. "T1AM-TAAR1 signalling protects against OGD-induced synaptic dysfunction in the entorhinal cortex." Neurobiology of Disease 151 (April 2021): 105271. http://dx.doi.org/10.1016/j.nbd.2021.105271.

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la Cour, Jeppe Lerche, Heidi M. Christensen, Josef Köhrle, Ina Lehmphul, Caroline Kistorp, Birte Nygaard, and Jens Faber. "Association Between 3-Iodothyronamine (T1am) Concentrations and Left Ventricular Function in Chronic Heart Failure." Journal of Clinical Endocrinology & Metabolism 104, no. 4 (October 31, 2018): 1232–38. http://dx.doi.org/10.1210/jc.2018-01466.

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Chiellini, Grazia, Sandra Ghelardoni, Sabina Frascarelli, Simonetta Testoni, Thomas S. Scanlan, David K. Grandy, and Riccardo Zucchi. "3-Iodothyronamine (T1AM) induces variation in phosphorylation pattern of tyrosine residues in rat heart." Journal of Molecular and Cellular Cardiology 44, no. 4 (April 2008): 773–74. http://dx.doi.org/10.1016/j.yjmcc.2008.02.149.

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Gonçalves, Luís M., Manuela M. Moreira, Carla F. Azevedo, Inês M. Valente, João C. Sousa, Thomas S. Scanlan, Richard G. Compton, and José A. Rodrigues. "Proof of Concept of the Electrochemical Sensing of 3-Iodothyronamine (T1AM) and Thyronamine (T0AM)." ChemElectroChem 1, no. 10 (August 25, 2014): 1623–26. http://dx.doi.org/10.1002/celc.201402165.

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Li, Zhong-Min, Manuel Miller, Sogol Gachkar, Jens Mittag, Sonja C. Schriever, Paul T. Pfluger, Karl-Werner Schramm, and Meri De Angelis. "Determination of 3-iodothyronamine (3-T1AM) in mouse liver using liquid chromatography-tandem mass spectrometry." Journal of Chromatography B 1165 (February 2021): 122553. http://dx.doi.org/10.1016/j.jchromb.2021.122553.

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Langouche, Lies, Ina Lehmphul, Sarah Vander Perre, Josef Köhrle, and Greet Van den Berghe. "Circulating 3-T1AM and 3,5-T2 in Critically Ill Patients: A Cross-Sectional Observational Study." Thyroid 26, no. 12 (December 2016): 1674–80. http://dx.doi.org/10.1089/thy.2016.0214.

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Laurino, Annunziatina, Ersilia Lucenteforte, Gaetano De Siena, and Laura Raimondi. "The impact of scopolamine pretreatment on 3-iodothyronamine (T1AM) effects on memory and pain in mice." Hormones and Behavior 94 (August 2017): 93–96. http://dx.doi.org/10.1016/j.yhbeh.2017.07.003.

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Laurino, Annunziatina, Manuela Gencarelli, and Laura Raimondi. "The 3-iodothyronamine (T1AM) and the 3-iodothyroacetic acid (TA1) indicate a novel connection with the histamine system for neuroprotection." European Journal of Pharmacology 912 (December 2021): 174606. http://dx.doi.org/10.1016/j.ejphar.2021.174606.

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Manni, Maria Elena, Gaetano De Siena, Alessandro Saba, Maja Marchini, Elisa Landucci, Elisabetta Gerace, Marina Zazzeri, et al. "Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold." British Journal of Pharmacology 168, no. 2 (December 20, 2012): 354–62. http://dx.doi.org/10.1111/j.1476-5381.2012.02137.x.

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Assadi-Porter, Fariba, Hannah Reiland, Martina Sabatini, Leonardo Lorenzini, Vittoria Carnicelli, Micheal Rogowski, Ebru Selen Alpergin, et al. "Metabolic Reprogramming by 3-Iodothyronamine (T1AM): A New Perspective to Reverse Obesity through Co-Regulation of Sirtuin 4 and 6 Expression." International Journal of Molecular Sciences 19, no. 5 (May 22, 2018): 1535. http://dx.doi.org/10.3390/ijms19051535.

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Landucci, Elisa, Manuela Gencarelli, Costanza Mazzantini, Annunziatina Laurino, Domenico Edoardo Pellegrini-Giampietro, and Laura Raimondi. "N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity." Neurochemistry International 129 (October 2019): 104460. http://dx.doi.org/10.1016/j.neuint.2019.05.004.

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Han, Hong-Seok, Hyun-June Paik, Jai Min Ryu, Sungmin Park, Ha Woo Yi, Suyeon Bae, Sekyung Lee, et al. "Comparison of prognosis and specific features according to tumor size in small-sized breast cancer with extensive lymph node involvement." Journal of Clinical Oncology 33, no. 28_suppl (October 1, 2015): 81. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.81.

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81 Background: As known, larger tumor size and more extensive lymph node (LN) involvement have been considered an independent factor for poor prognosis of breast cancer. We evaluated if very small tumor size may be a factor of worse prognosis compared to larger tumor in small sized breast cancer with LN involvement. Methods: A retrospective analysis was made in a single center of all 1400 patients with small (below 2cm, T1) sized and LN involved (N1~N3) breast cancer without metastasis diagnosed between 2004 and 2014. Their ages ranged from 23 to 88 years (mean age 49.1 ± 9.9 years) and mean follow-up was 31 months. All patients were performed with surgery including axillary LN dissection without neo-adjuvant chemotherapy. We subdivided their tumor size to 4 group (T1m, T1a, T1b and T1c) grading by 7th AJCC cancer staging. The number of patients in each group is as follows: T1m = 17, T1a = 63, T1b = 214, T1c = 1106. The specific features related to mortality were analyzed according to the minor groups and they were compared with one another by Chi-square test and Kaplan-Meier analysis. Results: Total expired patients were 39 (2.8%) and the number (the rate in each group) of the minor groups is as follows: T1m = 1 (5.9%), T1a = 1 (1.6%), T1b = 7 (3.3%), T1c = 22 (2.0%). Overall survival of smaller sized tumor groups ( ≤ 1cm, T1m+T1a+T1b) are significantly decreased than the other larger sized group T1c in T1N1 staged patients (p = 0.004). There are significant differences in estrogen receptor, progesterone receptor, nuclear grade, recurrence among the 4 minor groups in whole patients group. In the analysis of nuclear grade, the results show higher grade in T1m than T1a, T1m than T1b, T1b than T1c. Especially, recurrence of T1m is significantly more frequent than T1a (17.6% vs 3.2%, P = 0.03) or T1b (17.6% vs 4.2%, p = 0.016). Conclusions: In conclusion, this study indicates smaller sized tumor with LN involvement can progress worse compared to larger tumor. This result supports very small size can be another predictive factor for prognosis in small sized breast cancer with LN involvement.

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Laurino, Annunziatina, Gaetano De Siena, Alessandro Saba, Grazia Chiellini, Elisa Landucci, Riccardo Zucchi, and Laura Raimondi. "In the brain of mice, 3-iodothyronamine (T1AM) is converted into 3-iodothyroacetic acid (TA1) and it is included within the signaling network connecting thyroid hormone metabolites with histamine." European Journal of Pharmacology 761 (August 2015): 130–34. http://dx.doi.org/10.1016/j.ejphar.2015.04.038.

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Vogelsang, Tilman L. R., Aurelia Vattai, Elisa Schmoeckel, Till Kaltofen, Anca Chelariu-Raicu, Mingjun Zheng, Sven Mahner, Doris Mayr, Udo Jeschke, and Fabian Trillsch. "Trace Amine-Associated Receptor 1 (TAAR1) Is a Positive Prognosticator for Epithelial Ovarian Cancer." International Journal of Molecular Sciences 22, no. 16 (August 6, 2021): 8479. http://dx.doi.org/10.3390/ijms22168479.

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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.

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Dietrich, Johannes W., Patrick Müller, Fabian Schiedat, Markus Schlömicher, Justus Strauch, Apostolos Chatzitomaris, Harald H. Klein, et al. "Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling." European Thyroid Journal 4, no. 2 (2015): 129–37. http://dx.doi.org/10.1159/000381543.

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Background: Although hyperthyroidism predisposes to atrial fibrillation, previous trials have suggested decreased triiodothyronine (T3) concentrations to be associated with postoperative atrial fibrillation (POAF). Therapy with thyroid hormones (TH), however, did not reduce the risk of POAF. This study reevaluates the relation between thyroid hormone status, atrial electromechanical function and POAF. Methods: Thirty-nine patients with sinus rhythm and no history of atrial fibrillation or thyroid disease undergoing cardiac surgery were prospectively enrolled. Serum concentrations of thyrotropin, free (F) and total (T) thyroxine (T4) and T3, reverse (r)T3, 3-iodothyronamine (3-T1AM) and 3,5-diiodothyronine (3,5-T2) were measured preoperatively, complemented by evaluation of echocardiographic and electrophysiological parameters of cardiac function. Holter-ECG and telemetry were used to screen for POAF for 10 days following cardiac surgery. Results: Seven of 17 patients who developed POAF demonstrated nonthyroidal illness syndrome (NTIS; defined as low T3 and/or low T4 syndrome), compared to 2 of 22 (p < 0.05) patients who maintained sinus rhythm. In patients with POAF, serum FT3 concentrations were significantly decreased, but still within their reference ranges. 3,5-T2 concentrations directly correlated with rT3 concentrations and inversely correlated with FT3 concentrations. Furthermore, 3,5-T2 concentrations were significantly elevated in patients with NTIS and in subjects who eventually developed POAF. In multivariable logistic regression FT3, 3,5-T2, total atrial conduction time, left atrial volume index and Fas ligand were independent predictors of POAF. Conclusion: This study confirms reduced FT3 concentrations in patients with POAF and is the first to report on elevated 3,5-T2 concentrations in cardiac NTIS. The pathogenesis of NTIS therefore seems to involve more differentiated allostatic mechanisms.

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Rathmann, Daniel, Eddy Rijntjes, Julika Lietzow, and Josef Köhrle. "Quantitative Analysis of Thyroid Hormone Metabolites in Cell Culture Samples Using LC-MS/MS." European Thyroid Journal 4, Suppl. 1 (2015): 51–58. http://dx.doi.org/10.1159/000430840.

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A liquid-liquid extraction and liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) method to determine iodothyronines and thyronamines (TAM) from cell culture media was developed. Thyroid hormones (TH) are metabolized by sequential deiodination to eventually yield thyronine (T₀), but can also be decarboxylated, resulting in TAM. The method presented here for extraction of DMEM/F12 cell culture media is a fundamental procedure for a precise determination of 9 TH and 6 TAM from a single LC run. Analytes and internal standards (IS) were extracted from DMEM/F12 (w/o phenol red) by liquid-liquid extraction using isopropanol-TBME (30:70 v/v). Measurement of TH and TAM was performed during a 10-min run time using 13C6-T4, 13C6-T3, 13C6-rT3, 13C6-3,3′T2 and 2H4-T1AM as IS. Calibration curves covered 11 calibrators measured as triplicates each for the analysis of the 9 TH and 6 TAM metabolites, and the 5 IS were linear and reproducible in the range of 0.12-120 nM (R2 0.991-0.999) for all calibrators. The lower limit of quantification was 0.078-0.234 nM. Method validation and robustness were demonstrated by the analysis of precision, accuracy, process efficiency, matrix effects and recoveries, as well as intra- and interassay stability. These parameters were investigated for high, middle and low concentrations of quality controls of all 9 TH and 6 TAM metabolites. This validated, sensitive and interaction-free LC-MS/MS method allows rapid analysis and accurate determination of TH and TAM from DMEM/F12 (w/o phenol red) conditioned media and seems to be easily transferable and applied to commonly used buffers and cell culture media.

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Fehrenbacher, Louis, Angela M. Capra, Charles P. Quesenberry, Regan Fulton, Parveen Shiraz, and Laurel A. Habel. "Distant Invasive Breast Cancer Recurrence Risk in Human Epidermal Growth Factor Receptor 2–Positive T1a and T1b Node-Negative Localized Breast Cancer Diagnosed From 2000 to 2006: A Cohort From an Integrated Health Care Delivery System." Journal of Clinical Oncology 32, no. 20 (July 10, 2014): 2151–58. http://dx.doi.org/10.1200/jco.2013.52.0858.

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Purpose To determine the invasive recurrence (IR) risk among patients with small, node-negative human epidermal growth factor receptor 2 (HER2) –positive breast cancer. Patients and Methods Among 16,975 consecutive patients with invasive breast cancer diagnosed from January 1, 2000, to December 31, 2006, in a large, integrated health care system, we identified a cohort of 234 patients with HER2-positive T1aN0M0 or T1bN0M0 (T1abN0M0) disease with a median follow-up of 5.8 years. Kaplan-Meier methods were used to estimate the percentage of patients who were free of invasive recurrence (recurrence-free interval [RFI]) at 5 years for both distant (DRFI) and local (LRFI) recurrences. Results Of 15 IRs, 47% were locoregional only. Among T1ab patients not treated with adjuvant trastuzumab or chemotherapy (n = 171), the 5-year invasive DRFI was 98.2% (95% CI, 94.5% to 99.4%); it was 99.0% (95% CI, 93.0% to 99.9%) for T1a patients, and 97.0% (95% CI, 88.6% to 99.2%) for T1b patients. Locoregional plus distant 5-year invasive RFI was 97.0% (95% CI, 90.9% to 99.0%) for T1a and 91.9% (95% CI, 81.5% to 96.6%) for T1b patients; it was 89.4% (95% CI, 70.6% to 96.5%) for T1b tumors reported at 1.0 cm. T1b tumors reported at 1.0 cm accounted for 24% of the T1ab cohort, 61% of the cohort total tumor volume, and 75% of distant recurrences. Invasive RFI for T1b 1.0 cm tumors was lower than that for T1a tumors: 84.5% versus 97.4% (P = .009). Conclusion The distant IR risk of T1a HER2-positive breast cancer appears quite low. The distant IR risk in T1b patients, particularly those with 1.0-cm tumors, is higher. Potential risk differences for T1a and T1b, including the 1.0-cm tumors, should be considered when making treatment decisions.

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Kanayama, Naoki, Mitsuyoshi Ueda, Haruyuki Atomi, and Atsuo Tanaka. "Genetic Evaluation of Physiological Functions of Thiolase Isozymes in the n-Alkane-Assimilating YeastCandida tropicalis." Journal of Bacteriology 180, no. 3 (February 1, 1998): 690–98. http://dx.doi.org/10.1128/jb.180.3.690-698.1998.

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ABSTRACT The n-alkane-assimilating diploid yeast Candida tropicalis possesses three thiolase isozymes encoded by two pairs of alleles: cytosolic and peroxisomal acetoacetyl-coenzyme A (CoA) thiolases, encoded by CT-T1A and CT-T1B, and peroxisomal 3-ketoacyl-CoA thiolase, encoded by CT-T3A andCT-T3B. The physiological functions of these thiolases have been examined by gene disruption. The homozygousct-t1aΔ/t1bΔ null mutation abolished the activity of acetoacetyl-CoA thiolase and resulted in mevalonate auxotrophy. The homozygous ct-t3aΔ/t3bΔ null mutation abolished the activity of 3-ketoacyl-CoA thiolase and resulted in growth deficiency on n-alkanes (C10 to C13). All thiolase activities in this yeast disappeared with thect-t1aΔ/t1bΔ and ct-t3aΔ/t3bΔ null mutations. To further clarify the function of peroxisomal acetoacetyl-CoA thiolases, the site-directed mutation leading acetoacetyl-CoA thiolase without a putative C-terminal peroxisomal targeting signal was introduced on the CT-T1A locus in thect-t1bΔ null mutant. The truncated acetoacetyl-CoA thiolase was solely present in cytoplasm, and the absence of acetoacetyl-CoA thiolase in peroxisomes had no effect on growth on all carbon sources employed. Growth on butyrate was not affected by a lack of peroxisomal acetoacetyl-CoA thiolase, while a retardation of growth by a lack of peroxisomal 3-ketoacyl-CoA thiolase was observed. A defect of both peroxisomal isozymes completely inhibited growth on butyrate. These results demonstrated that cytosolic acetoacetyl-CoA thiolase was indispensable for the mevalonate pathway and that both peroxisomal acetoacetyl-CoA thiolase and 3-ketoacyl-CoA thiolase could participate in peroxisomal β-oxidation. In addition to its essential contribution to the β-oxidation of longer-chain fatty acids, 3-ketoacyl-CoA thiolase contributed greatly even to the β-oxidation of a C4 substrate butyrate.

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Oyama, Tsuneo, and Akiko Takahashi. "PS02.025: CHARACTERISTICS OF SUPERFICIAL BASALOID SQUAMOUS CELL CARCINOMA TREATED BY ENDOSCOPIC RESECTION." Diseases of the Esophagus 31, Supplement_1 (September 1, 2018): 127. http://dx.doi.org/10.1093/dote/doy089.ps02.025.

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Abstract Background Basaloid squamous cell carcinoma (BSCC) is a rare esophageal carcinoma. And the characteristics especially in early stage is unknown. Methods The aim of this study is to clarify the characteristics of superficial BSCC. Thirteen patients (9 males and 4 females) with BSCC treated by endoscopic resection (12 ESD and 1 EMRC) from January 2000 to March 2017 were enrolled in this retrospective study. The median age was 67 (57–83). The median follow-up period was 24 (12–115) months. T1a-EP/LPM and T1a-MM/T1b-SM1 without lymph duct invasion (LDI) was followed up. T1a-MM/T1b-SM1 with LDI or T1b-SM2 were treated by additional treatment (AT). Results 1. En-bloc resection and R0 resection rate was 100% and 100%, respectively. 2. Macroscopic type; 0-IIa, 0-IIb and 0-IIc was 4, 1 and 8, respectively. 3. The median tumor diameter was 27 (2–62) mm. 4. Invasion depth; T1a-LPM, T1a-MM/T1b-SM1, and T1b-SM2 was 3, 5 and 5, respectively. 5. Histological characteristics; All BSCC were covered by SCC or non-neoplastic squamous epithelium. 6. Endoscopic characteristics; SMT like appearance was found in 46% (6/13). Yellowish nodules were observed in 23% (3/13). This finding was observed, when BSCC exist superficial epithelial layer covered by thin non-neoplastic epithelium. 7. Prognosis A: T1a-LPM (N = 3). Two patients are alive without recurrence, and 1 patient died of other disease. B: T1a-MM/SM1 (N = 5). Two of 3 patients without LDI were followed up and alive. Remaining one patient wanted to be treated by CRT, and alive. Two patients had LVI, however they were followed up without AT because of patient's hope. One is alive, and another died of other disease. C: T1b-SM2 (N = 5). Two and one patients were treated by surgery and chemotherapy, respectively, and alive without recurrence. Remaining two patients were followed up without AT. One of 2 patients are alive without recurrence. Another patient dead of other disease. Conclusion 1. All of BSCC were covered by SCC or non-neoplastic epithelium. 2. SMT like appearance and yellowish nodules under squamous cell epithelium were the characteristic endoscopic findings. 3. 40% of T1aMM/T1bSM1 had LDI. It's higher than that of SCC. Therefore, En-bloc resection is necessary for the detailed histological examination. Disclosure All authors have declared no conflicts of interest.

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Journal articles on the topic 'T1AM'

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