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Bryan R. Haugen - One of the best experts on this subject based on the ideXlab platform.
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Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis.
Endocrinology, 2006Co-Authors: Vibha Sharma, William R. Hays, Umarani Pugazhenthi, Wojciech Krezel, William M Wood, Antonio C Bianco, Donald L. St. Germain, Pierre Chambon, Bryan R. HaugenAbstract:Retinoid X receptor (RXR)-selective Retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHbeta mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHbeta mRNA in TalphaT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TalphaT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHbeta promoter activity by 42% and the -200 to -149 region accounted for a majority of the LG 268-mediated suppression of promoter activity. The RXRgamma isotype is expressed in thyrotropes. In vitro transfection and in vivo transgenic studies indicate that any RXR isotype can mediate TSH suppression by rexinoids, but the RXRgamma isotype is most efficient at mediating this response. RXRgamma-deficient mice lacked pituitary D2 mRNA suppression by LG 268, but D2 activity remained intact. In summary, RXR-selective Retinoids (rexinoids) have multiple effects on the hypothalamic-pituitary-thyroid axis. Rexinoids directly suppress TSH secretion, TSHbeta mRNA levels and promoter activity, and D2 mRNA levels but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate type 1 iodothyronine deiodinase activity in the liver and pituitary.
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Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis.
Endocrinology, 2005Co-Authors: Vibha Sharma, William R. Hays, Umarani Pugazhenthi, Wojciech Krezel, William M Wood, Antonio C Bianco, Donald L. St. Germain, Pierre Chambon, Bryan R. HaugenAbstract:Retinoid X receptor (RXR)-selective Retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHβ mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHβ mRNA in TαT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TαT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHβ promoter activity by 42% and the −200 to −149 region accounted for a majority of the LG 268-mediated suppr...
Roshantha A S Chandraratna - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic applications for ligands of retinoid receptors.
Current pharmaceutical design, 2000Co-Authors: Scott M. Thacher, Jayasree Vasudevan, Roshantha A S ChandraratnaAbstract:Synthetic Retinoids, ligands for the RAR and RXR members of the steroid/thyroid superfamily of nuclear hormone receptors, are used for the treatment of psoriasis, acne, photoaging and cancer. Retinoid mechanisms of action for these conditions largely involve effects on epithelial differentiation and modulation of inflammation with some impact on the immune system. Retinoid medicinal chemistry in recent years has identified ligands highly specific for one of the three RAR subtypes (RAR-alpha) and for the RXR family of receptors, as well as antagonists for the RARs, RARa and the RXRs. Structure-activity relationships among the novel retinoid classes are reviewed along with potential therapeutic activities and side effects. RAR-alpha specific Retinoids inhibit cancer cell growth but lack other retinoid toxicities, including skin irritation now ascribed to RAR-gama . RXR-specific Retinoids lower blood glucose in animal models of type 2 diabetes albeit with a potential for mild hypothyroidism. Function-selective Retinoids, especially a class of RAR antagonists called inverse agonists, have unexpected gene regulatory activity. Given the diverse properties and tissue distributions of the retinoid receptors, synthesis of additional classes of receptor-specific and function-selective ligands has the potential to produce novel therapeutic applications.
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Novel Retinoids with receptor selectivity and functional selectivity.
The British journal of dermatology, 1999Co-Authors: A Johnson, Roshantha A S ChandraratnaAbstract:Retinoids mediate a number of physiological pathways through their effects on cellular growth and differentiation. Upon binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), Retinoids regulate cellular processes by directly modulating the expression of responsive genes. The wide-ranging effects of retinoid action are attributable to two main factors-the ubiquitous distribution of several subtypes and isoforms of RARs and RXRs, and the ability of these receptors to regulate numerous genes upon ligand activation. The broad range of effects mediated by Retinoids means not only that they have many potential therapeutic applications but also that non-selective Retinoids are associated with a high incidence of adverse effects. The design of Retinoids that are receptor-selective and function-selective is a strategy that is proving successful in developing novel Retinoids that offer not only good efficacy but also good tolerability. Tazarotene, a receptor-selective retinoid indicated for the topical treatment of psoriasis, is at the forefront of this new generation of Retinoids. In the near future, other receptor-selective Retinoids may prove useful for the treatment of other dermatological diseases, cancer, and diabetes.
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A new class of RAR subtype selective Retinoids: correlation of pharmacological effects with receptor activity.
Bioorganic & medicinal chemistry, 1999Co-Authors: Vidyasagar Vuligonda, Scott M. Thacher, Yuan Lin, Andrew M. Standeven, Devendra M. Kochar, Roshantha A S ChandraratnaAbstract:Abstract The synthesis and biological activity of a series of structurally related Retinoids with different RAR subtype selectivities are described. These Retinoids bind to all three RAR subtypes but in functional transactivation assays, they show RARβ or RARβ,γ selectivity with weak RARα activity. The subtype selectivity of these Retinoids was found to correlate with their efficacy (ODC inhibition) and toxicity (topical irritation and teratogenicity) profiles. The degree of RARγ transactivation activity correlates with their topical toxicity and teratogenicity as measured by the inhibition of chondrogenesis. Of the RARβ selective Retinoids reported here, retinoid 12 is the most promising, as it is completely devoid of two common retinoid related toxicities, namely topical irritation and teratogenesis.©
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Diminished teratogenicity of retinoid X receptor-selective synthetic Retinoids
Biochemical pharmacology, 1995Co-Authors: Heng Jiang, Roshantha A S Chandraratna, John D. Penner, Richard L. Beard, D. M. KochharAbstract:Abstract One feature that contraindicates the wide therapeutic use of Retinoids is their teratogenicity. Synthetic Retinoids are distinguishable from each other on the basis of their partial or exclusive preference in binding and activation of all- trans retinoic acid receptors (RARs) or retinoid X receptors (RXRs). Using mouse embryo limb bud cells in micromass cultures as a bioassay, we examined the inhibitory activities of a number of standard and novel Retinoids on chondrogenic cell differentiation. Transient cotransfection of HeLa cells was used to measure the ability of each retinoid to induce transcription of a reporter gene by activating RARor, RARβ, RARγ, or RXRα- chimeric constructs. All Retinoids in this study that activated RARs to any degree in the cotransfection assay also inhibited chondrogenesis in vitro , whereas Retinoids that were either specific for RXR or inactive in the cotransfection assay did not. The activity of RAR-selective agonists and the inactivity of RXR-specific agonists in the cotransfection assay correlated well with the relative teratogenicity of six of the representative Retinoids studied when orally administered at day 11 to pregnant ICR mice.
Pierre Chambon - One of the best experts on this subject based on the ideXlab platform.
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Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis.
Endocrinology, 2006Co-Authors: Vibha Sharma, William R. Hays, Umarani Pugazhenthi, Wojciech Krezel, William M Wood, Antonio C Bianco, Donald L. St. Germain, Pierre Chambon, Bryan R. HaugenAbstract:Retinoid X receptor (RXR)-selective Retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHbeta mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHbeta mRNA in TalphaT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TalphaT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHbeta promoter activity by 42% and the -200 to -149 region accounted for a majority of the LG 268-mediated suppression of promoter activity. The RXRgamma isotype is expressed in thyrotropes. In vitro transfection and in vivo transgenic studies indicate that any RXR isotype can mediate TSH suppression by rexinoids, but the RXRgamma isotype is most efficient at mediating this response. RXRgamma-deficient mice lacked pituitary D2 mRNA suppression by LG 268, but D2 activity remained intact. In summary, RXR-selective Retinoids (rexinoids) have multiple effects on the hypothalamic-pituitary-thyroid axis. Rexinoids directly suppress TSH secretion, TSHbeta mRNA levels and promoter activity, and D2 mRNA levels but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate type 1 iodothyronine deiodinase activity in the liver and pituitary.
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Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis.
Endocrinology, 2005Co-Authors: Vibha Sharma, William R. Hays, Umarani Pugazhenthi, Wojciech Krezel, William M Wood, Antonio C Bianco, Donald L. St. Germain, Pierre Chambon, Bryan R. HaugenAbstract:Retinoid X receptor (RXR)-selective Retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHβ mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHβ mRNA in TαT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TαT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHβ promoter activity by 42% and the −200 to −149 region accounted for a majority of the LG 268-mediated suppr...
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Retinoids regulate survival and antigen presentation by immature dendritic cells
Journal of Experimental Medicine, 2003Co-Authors: Frederic Geissmann, Patrick Revy, Nicole Brousse, Yves Lepelletier, Claudia Folli, Anne Durandy, Pierre ChambonAbstract:Maturation of dendritic cells (DCs) is a critical step for the induction of an immune response. We have examined the role of retinoid nuclear receptor pathways in this process. Retinoids induce DC apoptosis, in the absence of inflammatory signals, through retinoic acid receptor (RAR)α/retinoic X receptor (RXR) heterodimers. In contrast, via a cross talk with inflammatory cytokines, Retinoids increase DNA binding activity of nuclear factor κB in DCs, trigger membrane major histocompatibility complex class II and costimulatory molecule expression, induce the differentiation of immature DCs into mature DCs, and enhance antigen-specific T cell response. This maturation of DCs is mediated via a RXR-dependent/RAR-independent pathway and via an RARα/RXR pathway distinct from the one responsible for apoptosis. Apoptosis and activation, mediated through distinct nuclear retinoid receptor pathways, can be dissociated from each other with selective synthetic Retinoids. We identify a novel cellular function for Retinoids and suggest that selective Retinoids might be of interest for controlling antigen presentation.
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Retinoid receptors and binding proteins.
Journal of cell science. Supplement, 1992Co-Authors: David Lohnes, Andrée Dierich, Norbert B. Ghyselinck, Phillipe Kastner, Carmen Lampron, Marianne Lemeur, Thomas Lufkin, Cathy Mendelsohn, Harikrishna Nakshatri, Pierre ChambonAbstract:Retinoids, in particular all-trans retinoic acid (T-RA), are essential for normal development and homeostasis of vertebrates. Although many effects of Retinoids, particularly with regard to teratogenicity, have been described in the literature, the mechanisms by which these simple signalling molecules work has only recently begun to be elucidated. We now recognize at least two classes of retinoid-binding proteins and two families of retinoid receptors. The ultimate interpretation of the retinoid signal within a given cell is probably the result of a complex series of interactions between these proteins, yet little is understood concerning the role each member of this signalling pathway plays. It is therefore imperative to dissect the molecular mechanisms which transduce the effects of these ligands, both in vivo and in isolated systems. One approach we are employing is gene targeting of retinoic acid receptors (RARs) and cellular retinoid-binding proteins to generate mice in which one or more of these genes has been functionally inactivated.
Joseph L. Napoli - One of the best experts on this subject based on the ideXlab platform.
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Retinoid metabolism and functions mediated by retinoid binding-proteins
Methods in enzymology, 2020Co-Authors: Joseph L. Napoli, Hong Sik YooAbstract:Abstract Cellular retinoid-binding proteins (BP) chaperone retinol through esterification, conversion of retinol into retinal, reduction of retinal, conversion of retinal into all-trans-retinoic acid (ATRA), and ATRA to catabolism. They also deliver ATRA to nuclear receptors and mediate non-genomic ATRA actions. These retinoid-specific binding-proteins include: cellular retinol binding-protein, type 1 (Crbp1), cellular retinol binding-protein type 2 (Crbp2), cellular retinol binding-protein type 3 (Crbp3), cellular retinoic acid binding-protein type 1 (Crabp1); cellular retinoic acid binding-protein type 2 (Crabp2). Retinoid BP bind their ligands specifically and with high-affinity. These BP seemingly evolved to solubilize the lipophilic Retinoids in the aqueous cellular medium, and allow retinoid access only to enzymes that recognize both the BP and the retinoid. By chaperoning Retinoids through cells, retinoid BP provide specificity to Retinoids' metabolism and protect the scarce resource from dispersing into cell membranes and/or undergoing catabolism as xenobiotics. Other functions include non-genomic actions of Crabp1, delivery of ATRA to RAR by holo-Crabp2, and stabilization of HuR by apo-Crabp2. In addition to the retinoid-specific BP, Fabp5 also binds ATRA and delivers it to Pparδ. This article describes these BP and their functions, with a focus on experimental protocols to distinguish protein-protein interactions from diffusion-mediated transfer of ligand from BP to enzymes or receptors, and methods for quantifying Retinoids.
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Quantification of Endogenous Retinoids
Methods in molecular biology (Clifton N.J.), 2010Co-Authors: Maureen A. Kane, Joseph L. NapoliAbstract:Numerous physiological processes require Retinoids, including development, nervous system function, immune responsiveness, proliferation, differentiation, and all aspects of reproduction. Reliable retinoid quantification requires suitable handling and, in some cases, resolution of geometric isomers that have different biological activities. Here we describe procedures for reliable and accurate quantification of Retinoids, including detailed descriptions for handling Retinoids, preparing standard solutions, collecting samples and harvesting tissues, extracting samples, resolving isomers, and detecting with high sensitivity. Sample-specific strategies are provided for optimizing quantification. Approaches to evaluate assay performance also are provided. Retinoid assays described here for mice also are applicable to other organisms including zebrafish, rat, rabbit, and human and for cells in culture. Retinoid quantification, especially that of retinoic acid, should provide insight into many diseases, including Alzheimer's disease, type 2 diabetes, obesity, and cancer.
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Interactions of retinoid binding proteins and enzymes in retinoid metabolism.
Biochimica et Biophysica Acta, 1999Co-Authors: Joseph L. NapoliAbstract:Abstract Naturally occurring Retinoids (vitamin A or retinol and its active metabolites) are vital for vision, controlling the differentiation program of epithelial cells in the digestive tract and respiratory system, skin, bone, the nervous system, the immune system, and for hematopoiesis. Retinoids are essential for growth, reproduction (conception and embryonic development), and resistance to and recovery from infection. The functions of Retinoids in the embryo begin soon after conception and continue throughout the lifespan of all vertebrates. Both naturally occurring and synthetic Retinoids are used in the therapy of various skin diseases, especially acne, for augmenting the treatment of diabetes, and as cancer chemopreventive agents. Retinol metabolites serve as ligands that activate specific transcription factors in the superfamily of steroid/retinoid/thyroid/vitamin D/orphan receptors and thereby control gene expression. Additionally, Retinoids may also function through non-genomic actions. Various retinoid binding proteins serve as partners in retinoid function. These binding proteins show high specificity and affinity for specific Retinoids and seem to control retinoid metabolism in vivo qualitatively and quantitatively by reducing ‘free’ retinoid concentrations, protecting Retinoids from non-specific interactions, and chaperoning access of metabolic enzymes to Retinoids. Implementation of the physiological effects of Retinoids depends on the spatial-temporal expressions of binding proteins, receptors and metabolic enzymes. This review will discuss current understanding of the enzymes that catalyze retinol and retinoic acid metabolism and their unique and integral relationship to retinoid binding proteins.
Vibha Sharma - One of the best experts on this subject based on the ideXlab platform.
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Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis.
Endocrinology, 2006Co-Authors: Vibha Sharma, William R. Hays, Umarani Pugazhenthi, Wojciech Krezel, William M Wood, Antonio C Bianco, Donald L. St. Germain, Pierre Chambon, Bryan R. HaugenAbstract:Retinoid X receptor (RXR)-selective Retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHbeta mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHbeta mRNA in TalphaT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TalphaT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHbeta promoter activity by 42% and the -200 to -149 region accounted for a majority of the LG 268-mediated suppression of promoter activity. The RXRgamma isotype is expressed in thyrotropes. In vitro transfection and in vivo transgenic studies indicate that any RXR isotype can mediate TSH suppression by rexinoids, but the RXRgamma isotype is most efficient at mediating this response. RXRgamma-deficient mice lacked pituitary D2 mRNA suppression by LG 268, but D2 activity remained intact. In summary, RXR-selective Retinoids (rexinoids) have multiple effects on the hypothalamic-pituitary-thyroid axis. Rexinoids directly suppress TSH secretion, TSHbeta mRNA levels and promoter activity, and D2 mRNA levels but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate type 1 iodothyronine deiodinase activity in the liver and pituitary.
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Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis.
Endocrinology, 2005Co-Authors: Vibha Sharma, William R. Hays, Umarani Pugazhenthi, Wojciech Krezel, William M Wood, Antonio C Bianco, Donald L. St. Germain, Pierre Chambon, Bryan R. HaugenAbstract:Retinoid X receptor (RXR)-selective Retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHβ mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHβ mRNA in TαT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TαT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHβ promoter activity by 42% and the −200 to −149 region accounted for a majority of the LG 268-mediated suppr...
