Molecular Mechanisms of Actions of Formulations of the Thyroid Hormone Analogue, Tetrac, on the Inflammatory Response

Abstract Tetraiodothyroaetic acid (tetrac) is a derivative of L-thyroxine with anticancer properties. By multiple molecular mechanisms, tetrac and chemically-modified tetrac induce apoptosis in a variety of human cancer cells in vitro and in xenografts. The anticancer activities of tetrac are initiated at the thyroid hormone analogue receptor on the extracellular domain of plasma membrane integrin αvβ3 (PJ Davis et al., Physiol Rev 101:319-352, 2021). Induction of apoptosis in glioblastoma xenograft with chemically modified tetrac (P-bi-TAT) has yielded 90% in volume of grafts that continues after discontinuation of tetrac. In the present study, we show that human glioblastoma xenograft shrinkage in response to P-bi-TAT is associated with local appearance of phagocytic monocytes and clearance of apoptotic debris (efferocytosis). Primary culture xenograft of glioblastoma cells (GBM 052814, kindly provided by the University of Pittsburgh Medical Center, Department of Neurosurgery) and U87-luc (ATCC, Manassas, VA) xenografts were generated in 5-member groups of nude mice for each tumor cell type and for controls. Five days post-implantation, injection of animals was begun with PBS (control) or P-bi-TAT (10 mg/kg body weight). Injection was continued X21 days and animals were then maintained off-treatment for an additional 21 days. Tumors were harvested, formalin-fixed and slide-mounted, then analyzed by TUNEL assay for apoptosis and by anti-CD68 staining for monocytic macrophage content. Histologic analysis (H&E staining) was also carried out. TUNEL analysis and histopathology of both xenograft models revealed more than 90% apoptotic change with 21-days of P-bi-TAT treatment (P <0.001) and persistence of 40% apoptotic change 3 weeks post-discontinuation of drug (P<0.001 vs. end of treatment change). By H&E histology and CD68 analysis, monocytes accounted for more than 90% of the viable cells after 3 weeks’ drug treatment. Sixty percent of the end-of-treatment monocyte population persisted 3 weeks after discontinuation of P-bi-TAT (P <0.001). Histology revealed negligible cell debris after 3 weeks of drug treatment and at 3 weeks post-discontinuation of P-bi-TAT. Thus, the anticancer/pro-apoptotic action of tetrac-containing P-bi-TAT is associated with efferocytosis that contributes to the frank tumor shrinkage that results from P-bi-TAT treatment of human glioblastoma xenografts. This is the first documentation of efferocytosis regulated from the thyroid hormone analogue receptor on tumor cell integrin αvβ3.

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Molecular mechanisms of sex-dependent thyroid hormone action on target tissues

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0034-1372162 ◽

2014 ◽

Vol 122 (03) ◽

Author(s):

H Rakov ◽

K Engels ◽

D Zwanziger ◽

M Renders ◽

K Brix ◽

...

Keyword(s):

Thyroid Hormone ◽

Molecular Mechanisms ◽

Hormone Action ◽

Thyroid Hormone Action

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Faculty Opinions recommendation of Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2499964.4981064 ◽

2010 ◽

Author(s):

Sebastiano Filetti ◽

Cosimo Durante

Keyword(s):

Thyroid Hormone ◽

Hormone Analogue

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Relationship Between Gamma-glutamyl Transpeptidase Activity and Inflammatory Response in Lichen Planus

Revista de Chimie ◽

10.37358/rc.18.3.6189 ◽

2018 ◽

Vol 69 (3) ◽

pp. 739-743 ◽

Cited By ~ 3

Author(s):

Madalina Irina Mitran ◽

Ilinca Nicolae ◽

Corina Daniela Ene ◽

Cristina Iulia Mitran ◽

Clara Matei ◽

...

Keyword(s):

Inflammatory Response ◽

Lichen Planus ◽

Inflammatory Process ◽

Molecular Mechanisms ◽

Functional Adaptation ◽

Physical Factors ◽

Inflammatory Disorder ◽

Gamma Glutamyl Transpeptidase ◽

Gamma Glutamyl ◽

Glutamyl Transpeptidase

Chemicals used in the manufacture of synthetic fibers have been associated with undesirable side effects such as itching or skin lesions and it seems that they are involved in the induction of pathological processes such as oxidative stress and inflammation. Lichen planus (LP) can be regarded as an inflammatory disorder, chemical and physical factors playing an important role in the perpetuation of the inflammatory process. Gamma-glutamyl transpeptidase (GGT) plays an important role in the preservation of skin architecture and modulation of skin inflammation. In this study, we found that GGT activity is increased in LP patients with mild inflammation, whilst GGT is inactivated under conditions of severe inflammation. Therefore, GGT is involved in the inflammatory process, but there is no a positive correlation between its activity and the intensity of the inflammatory response. This functional adaptation of the enzyme may be due to down-regulation of its synthesis under free radical overload conditions. Understanding the molecular mechanisms involved in the modulation of intracellular redox homeostasis is an important step in the pharmacological management of patients with LP.

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A Thyroid Hormone Analogue, Triiodothyroacetic Acid, Corrects Corticosteroid-Downregulated Collagen Synthesis

Thyroid ◽

10.1089/105072504774193168 ◽

2004 ◽

Vol 14 (5) ◽

pp. 345-353 ◽

Cited By ~ 14

Author(s):

Parviz Yazdanparast ◽

Bo Carlsson ◽

Aarne Oikarinen ◽

Juha Risteli ◽

Jan Faergemann

Keyword(s):

Thyroid Hormone ◽

Collagen Synthesis ◽

Hormone Analogue

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Thyroid hormones regulate phosphate homoeostasis through transcriptional control of the renal type IIa sodium-dependent phosphate co-transporter (Npt2a) gene

Biochemical Journal ◽

10.1042/bj20090671 ◽

2010 ◽

Vol 427 (1) ◽

pp. 161-169 ◽

Cited By ~ 15

Author(s):

Mariko Ishiguro ◽

Hironori Yamamoto ◽

Masashi Masuda ◽

Mina Kozai ◽

Yuichiro Takei ◽

...

Keyword(s):

Thyroid Hormone ◽

Thyroid Hormones ◽

Molecular Mechanisms ◽

Hormone Receptors ◽

Critical Role ◽

Serum Phosphate ◽

Luciferase Assay ◽

Mobility Shift ◽

Intron 1 ◽

Sodium Dependent

The type IIa renal sodium-dependent phosphate (Na/Pi) co-transporter Npt2a is implicated in the control of serum phosphate levels. It has been demonstrated previously that renal Npt2a protein and its mRNA expression are both up-regulated by the thyroid hormone T3 (3,3′,5-tri-iodothyronine) in rats. However, it has never been established whether the induction was mediated by a direct effect of thyroid hormones on the Npt2a promoter. To address the role of Npt2a in T3-dependent regulation of phosphate homoeostasis and to identify the molecular mechanisms by which thyroid hormones modulate Npt2a gene expression, mice were rendered pharmacologically hypo- and hyper-thyroid. Hypothyroid mice showed low levels of serum phosphate and a marked decrease in renal Npt2a protein abundance. Importantly, we also showed that Npt2a-deficient mice had impaired serum phosphate responsiveness to T3 compared with wild-type mice. Promoter analysis with a luciferase assay revealed that the transcriptional activity of a reporter gene containing the Npt2a promoter and intron 1 was dependent upon TRs (thyroid hormone receptors) and specifically increased by T3 in renal cells. Deletion analysis and EMSAs (electrophoretic mobility-shift assays) determined that there were unique TREs (thyroid-hormone-responsive elements) within intron 1 of the Npt2a gene. These results suggest that Npt2a plays a critical role as a T3-target gene, to control phosphate homoeostasis, and that T3 transcriptionally activates the Npt2a gene via TRs in a renal cell-specific manner.

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Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

Acta Endocrinologica ◽

10.1530/eje.0.1450059 ◽

2001 ◽

pp. 59-64 ◽

Cited By ~ 18

Author(s):

F Bogazzi ◽

L Bartalena ◽

S Brogioni ◽

A Burelli ◽

F Raggi ◽

...

Keyword(s):

Thyroid Hormone ◽

Molecular Mechanisms ◽

Thyroid Hormone Receptor ◽

Molecular Level ◽

Inhibitory Effect ◽

Mobility Shift ◽

Down Regulation ◽

Nih3t3 Cells ◽

Peripheral Tissues

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

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Regulation of β myosin heavy chain, c-myc and c-fos proto-oncogenes in thyroid hormone-induced hypertrophy of the rat myocardium

Clinical Science ◽

10.1042/cs0840061 ◽

1993 ◽

Vol 84 (1) ◽

pp. 61-67 ◽

Cited By ~ 9

Author(s):

N. K. Green ◽

M. D. Gammage ◽

J. A. Franklyn ◽

A. M. Heagerty ◽

M. C. Sheppard

Keyword(s):

Thyroid Hormone ◽

Right Ventricular ◽

Myosin Heavy Chain ◽

Heavy Chain ◽

Molecular Mechanisms ◽

Left Ventricular ◽

Transcriptional Level ◽

Messenger Rnas ◽

Hypertrophic Response ◽

Left And Right

1. In order to investigate the molecular mechanisms determining the hypertrophic response of the ventricular myocardium to thyroid hormone administration, changes in left and right ventricular expression of the c-myc, c-fos and H-ras proto-oncogenes in response to treatment with 3,3′,5-tri-iodothyronine were defined. 2. Adult female Wistar rats were treated with daily subcutaneous injections of 3,3′,5-tri-iodothyronine (50 μg) for 1, 3, 7 or 14 days (n = 6 in each treatment group) and the results from 3,3′,5-tri-iodothyronine-treated animals were compared with those obtained from untreated controls (n = 6). Changes in the weight of the left and right ventricles in response to 3,3′,5-tri-iodothyronine treatment were measured; changes in expression of the c-myc, c-fos and H-ras proto-oncogenes were determined in parallel by measurement of specific messenger RNAs by Northern and dot hybridization, as well as changes in expression of β myosin heavy chain messenger RNA. 3. Treatment with 3,3′,5-tri-iodothyronine resulted in increases in both left and right ventricular weights after 3 days, an effect maintained up to 14 days. Despite an increase in left ventricular weight, levels of β myosin heavy chain, c-myc, c-fos and H-ras mRNAs in the left ventricle were unchanged; in contrast, an increase in right ventricular weight was associated with increased expression of β myosin heavy chain, c-myc and c-fos messenger RNAs. 4. These specific ventricular changes in gene expression, in the face of a hypertrophic response of both ventricles to 3,3′,5-tri-iodothyronine, suggest that the cardiac growth response to thyroid hormones reflects the well-documented secondary haemodynamic influences rather than direct gene regulatory actions of 3,3′,5-tri-iodothyronine at the transcriptional level on the genes studied. Changes in right ventricular proto-oncogene and β myosin heavy chain expression may in turn reflect an increase in right ventricular pressure load.

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DITPA, A Thyroid Hormone Analog, Reduces Infarct Size and Attenuates the Inflammatory Response Following Myocardial Ischemia

Journal of Surgical Research ◽

10.1016/j.jss.2011.04.009 ◽

2011 ◽

Vol 171 (2) ◽

pp. 379-385 ◽

Cited By ~ 7

Author(s):

Abdelrahman A. Abohashem-Aly ◽

Xianzhong Meng ◽

Jilin Li ◽

Miral R. Sadaria ◽

Lihua Ao ◽

...

Keyword(s):

Thyroid Hormone ◽

Myocardial Ischemia ◽

Inflammatory Response ◽

Infarct Size ◽

Hormone Analog

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Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v19i4.4130 ◽

2020 ◽

Author(s):

Zohreh Jadali

Keyword(s):

Inflammatory Response ◽

Chronic Inflammation ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Relevant Literature ◽

Regulatory Mechanisms ◽

Immune Mediated ◽

Key Factor ◽

Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

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