Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 15, Issue 1, 2015

Thyroid hormones affect growth, development and metabolism of vertebrates, and are considered the main regulators of their homeostasis. On the other hand, elevated circulating levels of thyroid hormones are associated with modifications in the whole organism (weight loss and increased metabolism and temperature) and in several body regions. Indeed, tachycardia, atrial arrhythmias, heart failure, muscle weakness and wasting, bone mass loss, and hepatobiliary complications are commonly found in hyperthyroid animals and humans. Most of the thyroid hormone actions result from influences on transcription of T3-responsive genes, which are mediated through nuclear receptors. However, there is significant evidence for involvement of tissue oxidative stress in some dysfunctions shown in hyperthyroid state. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction, through several mechanisms including increased expression of uncoupling proteins, proteolytic enzymes and transcriptional coactivator PGC-1, and stimulated opening of permeability transition pores. Actually, examination of the most recent data confirms that, in hyperthyroid state, mitochondria play a major role in tissue oxidative stress and rescue from excessive dysfunction. However, such data have also shown the substantial interplay between mitochondria and other sources of ROS and the role that, in pathological conditions, such sources play in generating oxidative stress and promoting survival mechanisms, such as autophagy and apoptosis. These observations suggest that cellular ROS producers could provide a significant contribution to processes that, in hyperthyroid state, oxidatively damage tissues and assure their survival.

Thyroid hormones (THs) are important regulators of cell physiology. They are essential for the normal development and growth of mammals, especially for the neural differentiation and the regulation of the metabolism and the immune system. THs also induce the proliferation of several cell types. In human and murine T cell lymphomas (TCL) this effect involves the participation of genomic and nongenomic mechanisms as it was described by the use of free THs and non-cell permeable THs coupled to agarose (TH-ag). The classic actions of thyroid hormones involve the alteration of gene transcription via specific nuclear receptors. The discovery of other effects, independent of this classic mechanism, characterizes a new and non-classic mechanism that involves different signaling pathways. Both, free THs and TH-ag, activate protein kinase C, extracellular signalregulated kinases and NF-kB and they increase the intracellular calcium levels. However, only the preincubation of T cells with free THs leads to an increased intracellular content of signaling enzymes. T lymphomas display high expression levels of both, the TH nuclear receptors (TRs) and the putative membrane receptor for THs, the integrin αvβ3, which has been demonstrated to be responsible for THs non-genomic actions. Here, we reviewed the mechanisms involved in THs modulation of the lymphocyte physiology, analyzing the interplay between genomic and nongenomic actions in T cells and its contribution in the development of lymphomas.

Thyroid hormones (THs) and their metabolites are potent regulators of energy and lipid metabolism in the liver. Besides the physiological role of THs in liver cell homeostasis, thyroid dysfunctions have been shown to play an essential part in the onset and progression of some liver diseases. Among these, non-alcoholic fatty liver disease (NAFLD), the current leading reason of development of chronic liver diseases worldwide, has emerged. In the present review, we analyse the main biological activities of THs and of some of their metabolites, along with their mechanisms of action, focusing on their role as master regulators of energy metabolism. We describe the relationship between thyroid dysfunctions and the development of NAFLD. Finally, we underline how the study of THs and their metabolites might be useful to develop new therapeutic approaches for NAFLD.

Anxiety and cognition are both linked to deficits in thyroid hormone concentrations in humans and in rodent models. Both processes have also been shown to be affected by the loss of the thyroid hormone receptors (TR) or by mutant transgenic TRs. Specifically, the unbalanced action of the unliganded TRα1 is thought to be important in the memory deficit and extreme anxiety seen in transgenic mice. The contribution of TRβ is less well defined and the molecular mechanisms that underlie these deficits are also unknown. We review the literature that demonstrates the importance of the thyroid hormone (TH) and the TR in these processes and focus on the mechanisms, in particular adult hippocampal neurogenesis in the dentate gyrus, that might be important in mediating both state anxiety and cognition by thyroid hormone.

Nongenomic effects of thyroid hormones typically start at the cell surface and do not primarily involve the classical nuclear receptors, but rather a plasma membrane receptor site identified about ten years ago on the integrin αvβ3. Transduction of the thyroid hormone signal from this integrin receptor involves activation of the MAPK pathway and may lead to events such as angiogenesis or tumor cell proliferation. This review focuses on the interaction of thyroid hormones with growth factors, in fact the integrin αvβ3 has been reported to a be a co-receptor for several growth factors such as EGF, IGF-1 and the FGF family, but also for small molecules like resveratrol. Binding of the ligand to integrin αvβ3 is inhibited by tetrac, a metabolite of L-thyroxine, and by its nanoparticulate formulation nanotetrac. Recent microarray studies on tumor cells have shown that tetrac has antiinflammatory effects that are mediated by integrin αvβ3, and tetrac can downregulate the expression of several interleukin genes. Crosstalk between thyroid hormones and vascular growth factors is important for cell migration, vascular calcification and the angiogenic process. Thyroid hormones also show pleiotropic effects on osteoblast function and differentiation, as well as in early pregnancy. The importance of thyroid hormone interaction with neurotrophins and interleukins has also been examined. With integrin αvβ3 firmly established as the plasma membrane receptor future studies will focus on the crosstalk between thyroid hormones and growth factors in order to verify the efficiency of new pharmacological tools, such as nanotetrac.

Several recent studies suggest that thyroid hormones role is not completely understood in insulin resistance as well as in the development of type 2 diabetes mellitus. Through the perturbation of gene expression linked to glucose metabolism both hyper- and hypothyroidism may cause impaired glucose utilization in skeletal muscle or overproduction of hepatic glucose, thus contributing to the induction of insulin resistance. The complex crosstalk between immune cells and skeletal muscle cells and adipose tissue, the ability of macrophages to release thyroid hormones, the ability of T3 to induce M2 macrophage polarization, the proinflammatory role of thyroid hormones and the antinflammatory effects of insulin all represent important events where thyroid hormone interference may lead to insulin resistance. The crosstalk between thyroid hormones and insulin in the modulation of oxidative status, and also to some extent in the antagonistic effects on several aspects of mitochondrial activities, could represent novel downstream targets for future therapeutic strategies in the treatment of insulin resistance and type 2 diabetes.

Genomic actions of thyroid hormone require the intranuclear binding by nuclear thyroid hormone receptors (TRs) of 3,5,3’-triiodo-L-thyronine (T3). Nongenomic actions of the hormone have been described that are initiated at the plasma membrane, in cytoplasm or in the mitochondrion. These are complex processes associated with maintenance of the cytoskeleton, control of cell respiration, cell proliferation—including tumor cell proliferation and angiogenesis—and nervous system function. We briefly review here the nature of the proteins which are now appreciated to initiate nongenomic actions of the hormone when they bind T3 or L-thyroxine (T4). These receptor proteins for nongenomic effects include truncated isoforms of TR