The Experts below are selected from a list of 45 Experts worldwide ranked by ideXlab platform
G. Salvatore - One of the best experts on this subject based on the ideXlab platform.
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Thyroid hormone biosynthesis in agnatha and protochordata
General and Comparative Endocrinology, 2004Co-Authors: G. SalvatoreAbstract:Abstract In the present review the problem of the evolutionary level at which the biosynthesis of thyroid hormones first appeared in the zoological scale is discussed. Thyroid hormones are certainly present in all Chordata, Urochordata, Cephalocordata, and Vertebrata. However, although concentration and organification of iodine are widespread processes occurring throughout the animal kingdom, the synthesis of thyroid hormones, i.e., iodothyronines, has not been clearly established below the Chordata. The biochemical mechanism leading to hormone synthesis follows the same general pattern from its first appearance in the Protochordata. The coupling of iodotyrosines to yield iodothyronines occurs within the polypeptide chains of specific proteins. In vertebrates, from the cyclostomes up to the mammals, the polymerization of similar, but perhaps not identical, subunits, leads to the formation of a family of thyroid proteins of increasing molecular size, i.e., 12 S, 19 S (thyroglobulin), and 27 S Iodoproteins.
Marvin C. Gershengorn - One of the best experts on this subject based on the ideXlab platform.
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History of the clinical endocrinology branch of the National Institute of Diabetes and Digestive and Kidney Diseases: impact on understanding and treatment of diseases of the thyroid gland.
Thyroid, 2012Co-Authors: Marvin C. GershengornAbstract:In 1955, the National Institute of Arthritis and Metabolic Diseases, the predecessor of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), established the Clinical Endocrinology Branch (CEB).1 A multidisciplinary group of scientists were brought together to collaborate in the study of the physiology and diseases of the thyroid gland. During the next 55 years, this area of research was expanded to include many aspects of the hypothalamic-pituitary-thyroid axis from the very basic molecular, cellular, and structural biology through translational research to patient-oriented clinical studies. Members of CEB, and the off-shoot Molecular, Cellular and Nutritional Endocrinology Branch, made important contributions to many of these areas of research (Table 1). In this commentary, I will describe a few of these many accomplishments and attempt to demonstrate the importance of multidisciplinary collaborations in these studies.2 Table 1. Areas of Study of the Hypothalamic–Pituitary–Thyroid Axis by Members of the Clinical Endocrinology Branch During the initial two decades, a number of studies that used radioactive iodine (RAI), which was at the time newly available, were performed by CEB scientists. Dr. Joseph Edward (Ed) Rall, the founding Chief of CEB, and Dr. Jacob (Jack) Robbins, who later became CEB Chief, performed a series of studies, which they had been begun with Dr. Rulon Rawson at Memorial-Sloan Kettering Cancer Center in New York, on the use of RAI in the diagnosis and treatment of thyroid diseases, in particular of thyroid cancer. Drs. Rall and Robbins established the safety and efficacy of RAI usage and in collaboration with computational biologists, in particular Dr. Mones Berman of another NIDDK laboratory, developed a kinetic model of iodine metabolism that was used to optimize the effective RAI dose administered, while reducing its suppressive effects on the bone marrow (1). Simultaneously, Drs. Rall and Robbins began their studies of serum thyroid hormone (TH) binding proteins that led to the breakthrough “free” TH hypothesis in which they elucidated the role of free (or unbound) TH, as opposed to total TH in blood, as the biologically relevant TH component (2). These studies were part of one of the most successful collaborations in the history of thyroid research. Another early recruit to CEB was Dr. Jan Wolff. While in the laboratory of Dr. I.L. Chaikoff at the University of California, Berkeley, Dr. Wolff discovered the inhibitory effect of high concentrations of iodide on iodine organification in the thyroid, a major regulator of thyroid gland function (“Wolff-Chaikoff effect”). Dr. Wolff, in some studies in collaboration with Drs. Rall and Robbins, made a number of seminal contributions to our understanding of the transport of iodide and other anions in the thyroid gland that predicted the discovery of the sodium-iodide symporter (3). A related finding by Drs. Wolff and Robbins was that lithium ion was an inhibitor of iodide uptake by the thyroid. This finding, as with so many basic discoveries by NIDDK investigators, was translated into clinical use of lithium in the treatment of hyperthyroidism and as an adjunct in the RAI treatment of thyroid cancer (4). The initial studies of TH binding proteins were extended by a collaboration within CEB between Dr. Robbins and Dr. Harold Edelhoch. In these experiments, the structure and binding properties of thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (transthyretin) were elucidated. For example, the single polypeptide chain functional unit of TBG, which binds a single molecule of TH, was shown to be different than the oligomeric transthyretin, which binds two molecules of TH in a negatively cooperative manner and binds retinol-binding protein. Another important area of collaboration amongst Drs. Rall, Robbins, and Edelhoch involved studies of thyroidal Iodoproteins, in particular thyroglobulin. For example, in a series of elegant studies, they delineated the structure of thyroglobulin and its role as a substrate for iodination as the precursor of THs (5). Studies of thyroglobulin and other Iodoproteins were joined by Dr. Hans Cahnmann who delineated the coupling mechanism within thyroglobulin that led to TH synthesis and also synthesized many TH analogs that were used to study TH metabolism (6). At the same time the structural studies of TBG were being performed, experiments to elucidate the site and regulation of the biosynthesis of TBG were ongoing. For example, Dr. Robbins' laboratory showed conclusively that TBG is synthesized in the liver and both the synthesis and secretion of TBG are enhanced by estrogen (7). Clinical research collaborations that included Drs. Rall, Robbins, and Wolff involved their participation in studies of RAI fallout after hydrogen bomb testing in the Pacific Ocean near the Marshall Islands and after the Chernobyl accident, and of reactor protection measures in the United States (8). Initially in collaboration with Dr. Rall, Dr. Vera M. Nikodem and then Dr. Sheue-yann Cheng performed studies of TH nuclear receptors. Their research, in which they used triiodothyronine (T3) derivatives to covalently label the receptor, provided early insights into the structure and function of the nuclear receptor by showing that it was a single polypeptide chain that binds either T3 or thyroxine (9). More recently, Dr. Douglas Forrest continued studies of the molecular biology of THs. His continuing research focuses on the roles of THs, TH deiodinases, and TH receptors in development of mammalian sensory systems. In particular, Dr. Forrest has described the critical role of local generation of T3 in the development and homeostasis of the mammalian retina (10). Dr. Bruce D. Weintraub performed research on several aspects of the biology of the pituitary–thyroid axis. He studied the regulation of thyrotropin (TSH) gene transcription and cloned the complementary DNA (cDNA) for the TSH beta-subunit. He produced biologically active, dimeric TSH in cells in tissue culture that led to a series of collaborations in which recombinant human TSH was developed for use in patients. Dr. Weintraub studied the structure–function relationships of TSH and created novel TSH mutants that exhibited increased activities (11). His translational and clinical research also included studies of pituitary (12) and TH resistance syndromes and TSH-secreting pituitary tumors in collaboration with many extramural investigators (13). Upon returning to the CEB, I continued my studies of the thyrotropin releasing hormone (TRH)/TRH receptor (TRH-R) and the TSH/TSH receptor (TSH-R) systems. Our studies focus on understanding how the TRH-R and the TSH-R function at the molecular level and on the development of small molecule ligands (SMLs) for these receptors. Our studies involve collaborations with computational chemists, organic chemists, molecular pharmacologists, and neuroscientists. For the TRH-R and the TSH-R, we characterized molecular details of their signaling and regulation in in vitro models, of their biology in intact animal models (14–16), and developed SMLs as probes of extra-pituitary functions of the TRH-R (17) and extra-thyroidal functions of the TSH-R (18). We think that SMLs for the TRH-R may be used in the future as treatment for several nervous system disorders, SML agonists for the TSH-R may be used in clinical practice to stimulate radioiodine uptake by residual thyroid cancer cells in the diagnosis and treatment of patients with thyroid cancer, and SML antagonists for the TSH-R to treat Graves' disease, especially ophthalmopathy. In summary, there have been wide-ranging studies of the hypothalamic–pituitary–thyroid axis conducted by CEB investigators,3 which have impacted our understanding and treatment of diseases of the thyroid gland. The success of these collaborations amongst multidisciplinary teams of scientists, which began in CEB more than 50 years ago, is still a model for biomedical research into the future.
John H. Youson - One of the best experts on this subject based on the ideXlab platform.
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kclo4 inhibits thyroidal activity in the larval lamprey endostyle in vitro
General and Comparative Endocrinology, 2002Co-Authors: Richard G Manzon, John H. YousonAbstract:Abstract An in vitro experimental system was devised to assess the direct effects of the goitrogen, potassium perchlorate (KClO 4 ), on radioiodide uptake and organification by the larval lamprey endostyle. Organification refers to the incorporation of iodide into lamprey thyroglobulin (Tg). Histological and biochemical evidence indicated that endostyles were viable at the termination of a 4 h in vitro incubation. A single Iodoprotein, designated as lamprey Tg, was identified in the endostylar homogenates by polyacrylamide gel electrophoresis and Western blotting. Lamprey Tg was immunoreactive with rabbit anti-human Tg serum and had an electrophoretic mobility similar to that of reduced porcine Tg. When KClO 4 was added to the incubation medium, both iodide uptake and organification by the endostyle were significantly reduced relative to controls as determined by gamma counting, and gel-autoradiography and densitometry, respectively. Western blotting showed that KClO 4 significantly lowered the total amount of lamprey Tg in the endostyle. Based on the results of this in vitro investigation, we conclude that KClO 4 acts directly on the larval lamprey endostyle to inhibit thyroidal activity. These data support a previous supposition from in vivo experimentation that KClO 4 acts directly on the endostyle to suppress the synthesis of thyroxine and triiodothyronine, resulting in a decrease in the serum levels of these two hormones.
William L. Green - One of the best experts on this subject based on the ideXlab platform.
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Separation of iodo compounds in serum by chromatography on Sephadex columns.
Journal of Chromatography A, 2001Co-Authors: William L. GreenAbstract:Abstract The migration of iodothyronines through Sephadex columns is greatly influenced by the pH and ionic strength of the eluents. By controlling these variables, a method has been developed for separating the iodo compounds of serum into four discrete fractions: Iodoprotein, iodide, triiodothyronine and thyroxine, during a single passage through a column of Sephadex G-25. The method is relatively rapid (less than 3 h per column run), and cam be employed with large samples of serum. Recovery of labeled iodothyronines added to serum is essentially complete. Chromatography of purified labeled compounds showed less than 0.2% deiodination; no conversion of thyroxine to triiodothyronine during the procedure could be demonstrated.
Richard G Manzon - One of the best experts on this subject based on the ideXlab platform.
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kclo4 inhibits thyroidal activity in the larval lamprey endostyle in vitro
General and Comparative Endocrinology, 2002Co-Authors: Richard G Manzon, John H. YousonAbstract:Abstract An in vitro experimental system was devised to assess the direct effects of the goitrogen, potassium perchlorate (KClO 4 ), on radioiodide uptake and organification by the larval lamprey endostyle. Organification refers to the incorporation of iodide into lamprey thyroglobulin (Tg). Histological and biochemical evidence indicated that endostyles were viable at the termination of a 4 h in vitro incubation. A single Iodoprotein, designated as lamprey Tg, was identified in the endostylar homogenates by polyacrylamide gel electrophoresis and Western blotting. Lamprey Tg was immunoreactive with rabbit anti-human Tg serum and had an electrophoretic mobility similar to that of reduced porcine Tg. When KClO 4 was added to the incubation medium, both iodide uptake and organification by the endostyle were significantly reduced relative to controls as determined by gamma counting, and gel-autoradiography and densitometry, respectively. Western blotting showed that KClO 4 significantly lowered the total amount of lamprey Tg in the endostyle. Based on the results of this in vitro investigation, we conclude that KClO 4 acts directly on the larval lamprey endostyle to inhibit thyroidal activity. These data support a previous supposition from in vivo experimentation that KClO 4 acts directly on the endostyle to suppress the synthesis of thyroxine and triiodothyronine, resulting in a decrease in the serum levels of these two hormones.
