Evidence that diclofenac and celecoxib are thyroid hormone receptor beta antagonists

Zloh, Mire; Perez-Diaz, Noelia; Tang, Leslie; Patel, Pryank; Mackenzie, Louise

doi:10.1016/j.lfs.2016.01.013

Cited by 17 publications

(7 citation statements)

References 35 publications

(33 reference statements)

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“…In addition, the 1-h relaxation time in the myography chamber might reduce the available intracellular T3 and T4 concentrations, which would affect the hyperthyroid conditions more than the euthyroid conditions and could obscure subtle effects. Nevertheless, impaired relaxation has been observed previously in mice expressing a mutant TRβ (Owen et al 2007), and blocking TRβ in mesenteric arteries inhibited the T3-induced nongenomic vasodilation (Zloh et al 2016). Taken together, these findings suggest that activation of TRβ might be beneficial for aortic stiffness, a notion that is supported by reports that the TRβ-selective agonist GC-1 delays the onset of atherosclerosis in ApoE-deficient mice (Kannisto et al 2014).…”

Section: Role Of Th Receptor βsupporting

confidence: 77%

Aortic effects of thyroid hormone in male mice

Gachkar

Nock

Geißler

et al. 2019

Journal of Molecular Endocrinology

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It is well established that thyroid hormones are required for cardiovascular functions; however, the molecular mechanisms remain incompletely understood, especially the individual contributions of genomic and non-genomic signalling pathways. In this study, we dissected how thyroid hormones modulate aortic contractility. To test the immediate effects of thyroid hormones on vasocontractility, we used a wire myograph to record the contractile response of dissected mouse aortas to the adrenergic agonist phenylephrine in the presence of different doses of T3 (3,3′,5-triiodothyronine). Interestingly, we observed reduced vasoconstriction under low and high T3 concentrations, indicating an inversed U-shaped curve with maximal constrictive capacity at euthyroid conditions. We then tested for possible genomic actions of thyroid hormones on vasocontractility by treating mice for 4 days with 1 mg/L thyroxine in drinking water. The study revealed that in contrast to the non-genomic actions the aortas of these animals were hyperresponsive to the contractile stimulus, an effect not observed in endogenously hyperthyroid TRβ knockout mice. To identify targets of genomic thyroid hormone action, we analysed aortic gene expression by microarray, revealing several altered genes including the well-known thyroid hormone target gene hairless. Taken together, the findings demonstrate that thyroid hormones regulate aortic tone through genomic and non-genomic actions, although genomic actions seem to prevail in vivo. Moreover, we identified several novel thyroid hormone target genes that could provide a better understanding of the molecular changes occurring in the hyperthyroid aorta.

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Section: Role Of Th Receptor βsupporting

confidence: 77%

Aortic effects of thyroid hormone in male mice

Gachkar

Nock

Geißler

et al. 2019

Journal of Molecular Endocrinology

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“…Hwang et al 67 found a significant antagonistic effect of MLS on human THRB in gene reporter assays using the human kidney cell line HEK293 at concentrations of 10 and 20 μM MLS in the presence of 30 nM T3. Zloh et al 68 also reported a significant antagonistic effect of MLS on human THRB using 10 μM MLS in the presence of 100 nM T3, using a mammalian cell line, which was not further specified. The explanation for the absence of inhibition of wTHRB transcriptional activity by MLS remains unclear.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Environmental Pollutants Modulate Transcriptional Activity of Nuclear Receptors of Whales In Vitro

Lühmann

Lille-Langøy

Øygarden

et al. 2020

Environ. Sci. Technol.

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This study reports the transcriptional activity of fin (Balaenoptera physalus) and blue whale (Balaenoptera musculus) peroxisome proliferator-activated receptor γ (PPARG), glucocorticoid receptor (GR), and thyroid hormone receptor β (THRB), when exposed to 14 persistent organic pollutants (so-called “legacy” persistent organic pollutants (POPs)) and a synthetic mixture of POPs, using GAL4-UAS-based in vitro luciferase reporter gene assays. Polychlorinated biphenyls (PCBs) had both agonistic and antagonistic effects on PPARG and GR, and mainly antagonistic, except for PCB153, effects on THRB. 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and its metabolites had mainly antagonistic effects on all of the receptors, except for o,p′-DDT. Given that the ligand-binding domain (LBD) of PPARG is the same in killer whales, white whales, polar bears, and humans, and that GR–LBD is identical in killer whales and minke whales and that the LBD of THRB is the same in killer whales, white whales, and humans, it is likely that the results of this study are representative for these other species as well. It is important to note that several environmental pollutants modulated the transcriptional activity of tested nuclear receptors at environmentally relevant concentrations for whales.

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“…However, as it is the case with other classical NSAIDs, increased risk of gastrointestinal mucosa ulceration and bleeding is one of the most important side effects of diclofenac, which is due to the decreased production of locally protective COX-1-derived prostanoids, such as PGE 2 and prostacyclin (PGI 2 ) (11). In this way, selective COX-2 inhibitors are devoid of these deleterious effects (12). Of these, etoricoxib (available in some European countries, Latin-America and in the Asia-Pacific region) is used for pain relief and treatment of chronic inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Effects of Selective Versus Non-Selective COX-2 Inhibition on Experimental Periodontitis

Moro

Oliveira

et al. 2019

Braz. Dent. J.

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In the present study we compared the effects of the selective COX-2 inhibitor etoricoxib with those of the classical non-selective NSAID diclofenac on the inflammatory process and alveolar bone loss in an experimental model of periodontitis in rats. Ninety male Holtzman rats (250 g) were randomly sorted into four experimental groups: Sham+CMC and Ligature+CMC (control) groups which received 0.5% carboxymethylcellulose sodium (CMC) solution; Ligature+Diclofenac and Ligature+Etoricoxib groups which received Potassium Diclofenac and Etoricoxib, respectively, suspended in 0.5% CMC (10 mg/kg/day). At 7, 14 and 21 days after placing ligatures in the cervical region of both the lower right and left first molars, the animals were euthanized. At the end of each period, the mandibles were collected for radiographic examination of alveolar bone loss. In addition, alveolar bone and periodontal ligament tissue samples were collected for COX-2 expression analysis and gingival tissues were collected for measurement of PGE2 contents. Animals with ligature-induced periodontal disease showed significant increased COX-2 gene expression at days 7, 14 and 21 (p<0.05) on alveolar bone and periodontal ligament. However, both treatments resulted in significantly reduced alveolar bone loss when compared to the untreated Ligature group (p<0.05), with no statistical difference between Etoricoxib and Diclofenac Potassium groups. This study shows that both drugs were able to reduce alveolar bone loss after periodontal disease induction.

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Evidence that diclofenac and celecoxib are thyroid hormone receptor beta antagonists

Cited by 17 publications

References 35 publications

Aortic effects of thyroid hormone in male mice

Aortic effects of thyroid hormone in male mice

Environmental Pollutants Modulate Transcriptional Activity of Nuclear Receptors of Whales In Vitro

Effects of Selective Versus Non-Selective COX-2 Inhibition on Experimental Periodontitis

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