Thyronine

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Paul J Davis - One of the best experts on this subject based on the ideXlab platform.

  • the induction of myeloma cell death and dna damage by tetrac a thyroid hormone derivative
    Endocrine-related Cancer, 2018
    Co-Authors: Keren Cohen, Uri Abadi, Paul J Davis, Aleck Hercbergs, Martin Ellis, Osnat Ashurfabian
    Abstract:

    : Multiple myeloma (MM) is a plasma cell malignancy in which involvement of the thyroid hormone-integrin αvβ3 pathway was shown, and pharmacologic inhibition of this pathway is a rational approach to disease management. A thyroid hormone derivative, tetraiodothyroacetic acid (tetrac), which inhibits l-thyroxine (T4) and 3,5,3'-triiodo-l-Thyronine (T3) binding to αvβ3 integrin, was studied in five MM cell lines and primary bone marrow (BM) MM cells. Tetrac inhibited MM cell proliferation (absolute cell number/viability) and induced caspase-dependent apoptosis (annexin-V/PI and cell cycle). Activation of caspase-9 and caspase-3 was further demonstrated. Moreover, DNA damage markers, ataxia-telangiectasia-mutated (ATM) kinase, poly ADP-ribose polymerase (PARP-1) and histone γH2AX were induced by tetrac. The various tetrac-initiated effects were attenuated by Arg-Gly-Asp (RGD) peptide, suggesting integrin involvement. Primary BM mononuclear cells were harvested from MM patients (n = 39) at various disease stages. Tetrac-induced apoptosis (12/17 samples) and sensitized the cytotoxic action of bortezomib (6/9 samples). Lastly, expression of plasma membrane integrin αvβ3 was shown not only in the malignant plasma clone, but also in other cell populations within the BM samples (n = 25). Tetrac is anti-proliferative and pro-apoptotic in MM and cells may offer a therapeutic approach for this disease.

  • Bioactivity of Thyroid Hormone Analogs at Cancer Cells
    Frontiers Media S.A., 2018
    Co-Authors: Paul J Davis, Heng Yuan Tang, Aleck Hercbergs, Hung Yun Lin, Kelly A. Keating, Shaker A Mousa
    Abstract:

    In the context of genomic thyroid hormone actions in normal (noncancer) cells that involve primary interactions with nuclear thyroid hormone receptors (TRs), L-thyroxine (T4), and 3,3′,5′-triiodo-L-Thyronine (reverse T3, rT3) have little bioactivity. In terms of TRs, T4 is a prohormone from which the active nuclear ligand, 3,5,3′-triido-L-Thyronine (T3), is generated by deiodination. Deaminated T4 and T3 metabolites have different genomic effects: tetraiodothyroacetic acid (tetrac) is a low grade thyromimetic derivative of T4, whereas triiodothyroacetic acid (triac), the acetic acid metabolite of T3, has substantial thyromimetic activity. In cancer cells, the cell surface receptor for thyroid hormone on integrin αvβ3 mediates non-genomic actions of thyroid hormone analogs. The integrin is expressed in large measure by cancer cells and dividing endothelial cells and has a substantially different panel of responses to thyroid hormone analogs. At αvβ3, T4 is a potent proliferative, anti-apoptotic and pro-angiogenic hormone and is the primary ligand. rT3 may also be proliferative at this site. In contrast, tetrac and triac are antagonists of T4 at αvβ3, but also have anticancer properties at this site that are independent of their effects on the binding of T4

  • they live in the land down under thyroid function and basal metabolic rate in the blind mole rat spalax
    Endocrine Research, 2014
    Co-Authors: Aaron Avivi, Keren Cohen, Paul J Davis, Aleck Hercbergs, Martin Ellis, Eviatar Nevo, Nick Sotnichenko, Mark Band, Osnat Ashurfabian
    Abstract:

    AbstractThe Israeli blind subterranean mole rat (Spalax ehrenbergi superspecies) lives in sealed underground burrows under extreme, hypoxic conditions. The four Israeli Spalax allospecies have adapted to different climates, the cool–humid (Spalax galili, 2 n = 52 chromosomes), semihumid (S. golani, 2 n = 54) north regions, warm–humid (S. carmeli, 2 n = 58) central region and the warm–dry S. judaei, 2 n = 60) southern regions. A dramatic interspecies decline in basal metabolic rate (BMR) from north to south, even after years of captivity, indicates a genetic basis for this BMR trait. We examined the possibility that the genetically-conditioned interspecies BMR difference was expressed via circulating thyroid hormone. An unexpected north to south increase in serum free thyroxine (FT4) and total 3, 5, 3′-triiodo-L-Thyronine (T3) (p < 0.02) correlated negatively with previously published BMR measurements. The increases in serum FT4 and T3 were symmetrical, so that the T3:FT4 ratio – interpretable as an index ...

  • thyroid hormones as modulators of immune activities at the cellular level
    Thyroid, 2011
    Co-Authors: Paolo De Vito, Sandra Incerpi, Jens Z Pedersen, Faith B Davis, P. Luly, Paul J Davis
    Abstract:

    Background: Increasing evidence suggests that thyroid hormones, L-thyroxine (T4) and 3,3′,5-triiodo-L-Thyronine (T3), are modulators of the immune response. In monocytes, macrophages, leukocytes, n...

  • membrane receptor for thyroid hormone physiologic and pharmacologic implications
    Annual Review of Pharmacology and Toxicology, 2011
    Co-Authors: Paul J Davis, Faith B Davis, Shaaban A Mousa, Mary K Luidens
    Abstract:

    Plasma membrane integrin αvβ3 is a cell surface receptor for thyroid hormone at which nongenomic actions are initiated. L-thyroxine (T4) and 3,3′,5-triiodo-L-Thyronine (T3) promote angiogenesis and tumor cell proliferation via the receptor. Tetraiodothyroacetic acid (tetrac), a deaminated T4 derivative, blocks the nongenomic proliferative and proangiogenic actions of T4 and T3. Acting at the integrin independently of T4 and T3, tetrac and a novel nanoparticulate formulation of tetrac that acts exclusively at the cell surface have oncologically desirable antiproliferative actions on multiple tumor cell survival pathway genes. These agents also block the angiogenic activity of vascular growth factors. Volume and vascular support of xenografts of human pancreatic, kidney, lung, and breast cancers are downregulated by tetrac formulations. The integrin αvβ3 receptor site for thyroid hormone selectively regulates signal transduction pathways and distinguishes between unmodified tetrac and the nanoparticulate fo...

Faith B Davis - One of the best experts on this subject based on the ideXlab platform.

  • thyroid hormones as modulators of immune activities at the cellular level
    Thyroid, 2011
    Co-Authors: Paolo De Vito, Sandra Incerpi, Jens Z Pedersen, Faith B Davis, P. Luly, Paul J Davis
    Abstract:

    Background: Increasing evidence suggests that thyroid hormones, L-thyroxine (T4) and 3,3′,5-triiodo-L-Thyronine (T3), are modulators of the immune response. In monocytes, macrophages, leukocytes, n...

  • membrane receptor for thyroid hormone physiologic and pharmacologic implications
    Annual Review of Pharmacology and Toxicology, 2011
    Co-Authors: Paul J Davis, Faith B Davis, Shaaban A Mousa, Mary K Luidens
    Abstract:

    Plasma membrane integrin αvβ3 is a cell surface receptor for thyroid hormone at which nongenomic actions are initiated. L-thyroxine (T4) and 3,3′,5-triiodo-L-Thyronine (T3) promote angiogenesis and tumor cell proliferation via the receptor. Tetraiodothyroacetic acid (tetrac), a deaminated T4 derivative, blocks the nongenomic proliferative and proangiogenic actions of T4 and T3. Acting at the integrin independently of T4 and T3, tetrac and a novel nanoparticulate formulation of tetrac that acts exclusively at the cell surface have oncologically desirable antiproliferative actions on multiple tumor cell survival pathway genes. These agents also block the angiogenic activity of vascular growth factors. Volume and vascular support of xenografts of human pancreatic, kidney, lung, and breast cancers are downregulated by tetrac formulations. The integrin αvβ3 receptor site for thyroid hormone selectively regulates signal transduction pathways and distinguishes between unmodified tetrac and the nanoparticulate fo...

  • human platelet aggregation and degranulation is induced in vitro by l thyroxine but not by 3 5 3 triiodo l Thyronine or diiodothyropropionic acid ditpa
    Clinical and Applied Thrombosis-Hemostasis, 2010
    Co-Authors: Shaymaa S Mousa, Faith B Davis, Paul J Davis, Shaker A Mousa
    Abstract:

    The endogenous thyroid hormones L-thyroxine (T4) and 3,5,3′-triiodo-L-Thyronine (T3) induce angiogenesis via an endothelial cell iodoThyronine receptor on integrin αVβ3. This receptor also exists on platelets. Diiodothyropropionic acid (DITPA) and GC-1, a noniodinated thyroid hormone analog, also induce angiogenesis. Here we examined the effects of iodoThyronines (L-T4 vs L-T3) and analogs DITPA and GC-1 on human platelet function. Subthreshold aggregation of platelets obtained from healthy human donors was induced with collagen. Platelet activation (proaggregation) and adenosine triphosphate (ATP) secretion (degranulation) induced by L-T 4, L-T4-agarose, L-T3, DITPA, or GC-1 were determined simultaneously. Platelet aggregation and ATP secretion induced by a subthreshold level of collagen were enhanced 3-fold by either L-T4 or L-T 4-agarose (0.01 μmol/L) as compared to control, whereas, L-T 3, DITPA, or GC-1 had no effect under the same conditions. The platelet proaggregatory and degranulation effects of ...

  • l thyroxine vs 3 5 3 triiodo l Thyronine and cell proliferation activation of mitogen activated protein kinase and phosphatidylinositol 3 kinase
    American Journal of Physiology-cell Physiology, 2009
    Co-Authors: Heng Yuan Tang, Mary K Luidens, Sandra Incerpi, Faith B Davis, George L Drusano, Shaker A Mousa, Paul J Davis
    Abstract:

    3,5,3′-Triiodo-l-Thyronine (T3), but not l-thyroxine (T4), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an αvβ3 integrin receptor on human glioblasto...

  • l thyroxine vs 3 5 3 triiodo l Thyronine and cell proliferation activation of mitogen activated protein kinase and phosphatidylinositol 3 kinase
    American Journal of Physiology-cell Physiology, 2009
    Co-Authors: Hung Yun Lin, Mary K Luidens, Sandra Incerpi, Faith B Davis, Heng Yuan Tang, George L Drusano, Shaker A Mousa, Mingzeng Sun, Cassie Lin, Paul J Davis
    Abstract:

    3,5,3'-Triiodo-l-Thyronine (T(3)), but not l-thyroxine (T(4)), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an alpha(v)beta(3) integrin receptor on human glioblastoma U-87 MG cells. Although both T(3) and T(4) stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T(3)-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T(3) and T(4). Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T(3)-treated U-87 MG cells. T(3) and T(4) both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T(3) on U-87 MG cells. PI3-kinase-dependent actions of T(3) in these cells included shuttling of nuclear thyroid hormone receptor-alpha (TRalpha) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1alpha mRNA; LY-294002 inhibited these actions. Results of studies involving alpha(v)beta(3) receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T(3) from the integrin by unlabeled T(3) and by unlabeled T(4), are consistent with the presence of two iodoThyronine receptor domains on the integrin. A model proposes that one site binds T(3) exclusively, activates PI3-kinase via Src kinase, and stimulates TRalpha trafficking and HIF-1alpha gene expression. Tetrac and RGD peptide both inhibit T(3) action at this site. The second site binds T(4) and T(3), and, via this receptor, the iodoThyronines stimulate ERK1/2-dependent tumor cell proliferation. T(3) action here is inhibited by tetrac alone, but the effect of T(4) is blocked by both tetrac and the RGD peptide.

Heqing Shen - One of the best experts on this subject based on the ideXlab platform.

  • determination of thyroid hormones in placenta using isotope dilution liquid chromatography quadrupole time of flight mass spectrometry
    Journal of Chromatography A, 2018
    Co-Authors: Zhongmin Li, Florian Giesert, Daniela Vogtweisenhorn, Ulla Feldtrasmussen, Niels E Skakkebaek, Hannu Kiviranta, Jorma Toppari, Heqing Shen
    Abstract:

    Abstract The transplacental passage of thyroid hormones (THs) is of great significance since the maternal THs are vitally important in ensuring the normal fetal development. In this paper, we determined the concentrations of seven THs, viz. L-thyroxine (T4), 3,3′,5-triiodo- l -Thyronine (T3), 3,3′,5′-triiodo- l -Thyronine (rT3), 3,3′-diiodo- l -Thyronine (T2), 3,5-diiodo- l -Thyronine (rT2), 3-iodo- l -Thyronine (T1) and 3-iodothyronamine (T1AM), in placenta using isotope dilution liquid chromatography quadrupole time-of-flight mass spectrometry. We optimized the method using isotopically labeled quantification standards (13C6-T4, 13C6-T3, 13C6-rT3 and 13C6-T2) and recovery standard (13C12-T4) in combination with solid-liquid extraction, liquid–liquid extraction and solid phase extraction. The linearity was obtained in the range of 0.5–150 pg uL−1 with R2 values >0.99. The method detection limits (MDLs) ranged from 0.01 ng g−1 to 0.2 ng g−1, while the method quantification limits (MQLs) were between 0.04 ng g−1 and 0.7 ng g−1. The spike-recoveries for THs (except for T1 and T1AM) were in the range of 81.0%–112%, with a coefficient of variation (CV) of 0.5–6.2%. The intra-day CVs and inter-day CVs were 0.5%–10.3% and 1.19%–8.88%, respectively. Concentrations of the THs were 22.9–35.0 ng g−1 T4, 0.32–0.46 ng g−1 T3, 2.86–3.69 ng g−1 rT3, 0.16–0.26 ng g−1 T2, and

Riccardo Zucchi - One of the best experts on this subject based on the ideXlab platform.

  • quantification of thyroxine and 3 5 3 triiodo Thyronine in human and animal hearts by a novel liquid chromatography tandem mass spectrometry method
    Hormone and Metabolic Research, 2014
    Co-Authors: Alessandro Saba, Riccardo Donzelli, Daria Colligiani, A Raffaelli, Monica Nannipieri, Claudia Kusmic, C Dos G Remedios, Warner S Simonides, Giorgio Iervasi, Riccardo Zucchi
    Abstract:

    Assaying tissue T3 and T4 would provide important information in experimental and clinical investigations. A novel method to determine tissue T3 and T4 by HPLC coupled to mass spectrometry is described. The major difference vs. previously described methods lies in the addition of a derivatization step, that is, to convert T3 and T4 into the corresponding butyl esters. The yield of esterification was  100% for T3 and 80% for T4. The assay was linear (r>0.99) in the range of 0.2–50 ng/ml, accuracy was in the order of 70–75%, and the minimum tissue amount needed was in the order of 50 mg, that is, about one order of magnitude lower than observed with the same equipment (AB Sciex API 4000 triple quadrupole mass spectrometer) if derivatization was omitted. The method allowed detection of T3 and T4 in human left ventricle biopsies yielding concentrations of 1.51±0.16 and 5.94±0.63 pmol/g, respectively. In rats treated with different dosages of exogenous T3 or T4, good correlations (r>0.90) between plasma and myocardial T3 and T4 concentrations were observed, although in specific subsets different plasma T4 concentrations were not associated with different tissue content in T4. We conclude that this method could provide a novel insight into the relationship between plasma and tissue thyroid hormone levels.

Mary K Luidens - One of the best experts on this subject based on the ideXlab platform.

  • membrane receptor for thyroid hormone physiologic and pharmacologic implications
    Annual Review of Pharmacology and Toxicology, 2011
    Co-Authors: Paul J Davis, Faith B Davis, Shaaban A Mousa, Mary K Luidens
    Abstract:

    Plasma membrane integrin αvβ3 is a cell surface receptor for thyroid hormone at which nongenomic actions are initiated. L-thyroxine (T4) and 3,3′,5-triiodo-L-Thyronine (T3) promote angiogenesis and tumor cell proliferation via the receptor. Tetraiodothyroacetic acid (tetrac), a deaminated T4 derivative, blocks the nongenomic proliferative and proangiogenic actions of T4 and T3. Acting at the integrin independently of T4 and T3, tetrac and a novel nanoparticulate formulation of tetrac that acts exclusively at the cell surface have oncologically desirable antiproliferative actions on multiple tumor cell survival pathway genes. These agents also block the angiogenic activity of vascular growth factors. Volume and vascular support of xenografts of human pancreatic, kidney, lung, and breast cancers are downregulated by tetrac formulations. The integrin αvβ3 receptor site for thyroid hormone selectively regulates signal transduction pathways and distinguishes between unmodified tetrac and the nanoparticulate fo...

  • l thyroxine vs 3 5 3 triiodo l Thyronine and cell proliferation activation of mitogen activated protein kinase and phosphatidylinositol 3 kinase
    American Journal of Physiology-cell Physiology, 2009
    Co-Authors: Heng Yuan Tang, Mary K Luidens, Sandra Incerpi, Faith B Davis, George L Drusano, Shaker A Mousa, Paul J Davis
    Abstract:

    3,5,3′-Triiodo-l-Thyronine (T3), but not l-thyroxine (T4), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an αvβ3 integrin receptor on human glioblasto...

  • l thyroxine vs 3 5 3 triiodo l Thyronine and cell proliferation activation of mitogen activated protein kinase and phosphatidylinositol 3 kinase
    American Journal of Physiology-cell Physiology, 2009
    Co-Authors: Hung Yun Lin, Mary K Luidens, Sandra Incerpi, Faith B Davis, Heng Yuan Tang, George L Drusano, Shaker A Mousa, Mingzeng Sun, Cassie Lin, Paul J Davis
    Abstract:

    3,5,3'-Triiodo-l-Thyronine (T(3)), but not l-thyroxine (T(4)), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an alpha(v)beta(3) integrin receptor on human glioblastoma U-87 MG cells. Although both T(3) and T(4) stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T(3)-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T(3) and T(4). Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T(3)-treated U-87 MG cells. T(3) and T(4) both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T(3) on U-87 MG cells. PI3-kinase-dependent actions of T(3) in these cells included shuttling of nuclear thyroid hormone receptor-alpha (TRalpha) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1alpha mRNA; LY-294002 inhibited these actions. Results of studies involving alpha(v)beta(3) receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T(3) from the integrin by unlabeled T(3) and by unlabeled T(4), are consistent with the presence of two iodoThyronine receptor domains on the integrin. A model proposes that one site binds T(3) exclusively, activates PI3-kinase via Src kinase, and stimulates TRalpha trafficking and HIF-1alpha gene expression. Tetrac and RGD peptide both inhibit T(3) action at this site. The second site binds T(4) and T(3), and, via this receptor, the iodoThyronines stimulate ERK1/2-dependent tumor cell proliferation. T(3) action here is inhibited by tetrac alone, but the effect of T(4) is blocked by both tetrac and the RGD peptide.