Reverse T3 interacts with αvβ3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms

Domingues, Juliana Tonietto; Cattani, Daiane; Cesconetto, Patrícia Acordi; Almeida, Bianka Alzira Nascimento de; Pierozan, Paula; Santos, Karin dos; Razzera, Guilherme; Silva, Fátima Regina Mena Barreto; Pessoa-Pureur, Regina; Zamoner, Ariane

doi:10.1016/j.mce.2017.11.013

Cited by 14 publications

(5 citation statements)

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“…While it is unclear from the data here if this is causative to the observed radial glia phenotype, others have shown that loss of neuroepithelial adherens junctions induce changes in radial glia structure and function, which can lead to cortical heterotopia 17,31,38,39 . With regards to thyroid signaling, differential expression of adherens junctions components like actin filaments and integrins have been reported in the brains of developing hypothyroid rodents 33,40–43 , and several other studies have shown that both T4 and reverse T3 (rT3) can directly modify cytoskeletal components via extranuclear signaling pathways 40,44–46 . Therefore dysregulation of TH signaling, even for a finite developmental period, may convergently affect cell junctions within the brain.…”

Section: Discussionmentioning

confidence: 99%

A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development

O’Shaughnessy

Thomas

Spring

et al. 2019

Sci Rep

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Cortical heterotopias are clusters of ectopic neurons in the brain and are associated with neurodevelopmental disorders like epilepsy and learning disabilities. We have previously characterized the robust penetrance of a heterotopia in a rat model, induced by thyroid hormone (TH) disruption during gestation. However, the specific mechanism by which maternal TH insufficiency results in this birth defect remains unknown. Here we first determined the developmental window susceptible to endocrine disruption and describe a cellular mechanism responsible for heterotopia formation. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil) during the perinatal period (GD19-PN2) induces a periventricular heterotopia in 100% of the offspring. Beginning in the early postnatal brain, neurons begin to aggregate near the ventricles of treated animals. In parallel, transcriptional and architectural changes of this region were observed including decreased Sonic hedgehog (Shh) expression, abnormal cell adhesion, and altered radial glia morphology. As the ventricular epithelium is juxtaposed to two sources of brain THs, the cerebrospinal fluid and vasculature, this progenitor niche may be especially susceptible to TH disruption. This work highlights the spatiotemporal vulnerabilities of the developing brain and demonstrates that a transient period of TH perturbation is sufficient to induce a congenital abnormality.

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Section: Discussionmentioning

confidence: 99%

A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development

O’Shaughnessy

Thomas

Spring

et al. 2019

Sci Rep

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“…In addition, TH modifications, including decarboxylation, deamination, ether-link cleavage, sulfation, and glucuronidation, affect their bioactivity and downstream metabolism (Figure 1). Most of them lead to deactivation and eventually degradation of THs (26), however some of the generated compounds, such as rT3 (44, 45), iodothyroacetic acids (tetrac and triac) and thyronamines (46–50), have been shown to convey biological effects in specific contexts. The conversions and main metabolites of THs are shown in Figure 1.…”

Section: Production and Metabolism Of Ths—maternal And Fetal Sourcesmentioning

confidence: 99%

Transport, Metabolism, and Function of Thyroid Hormones in the Developing Mammalian Brain

Stepien

Huttner

2019

Front. Endocrinol.

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Ever since the discovery of thyroid hormone deficiency as the primary cause of cretinism in the second half of the 19th century, the crucial role of thyroid hormone (TH) signaling in embryonic brain development has been established. However, the biological understanding of TH function in brain formation is far from complete, despite advances in treating thyroid function deficiency disorders. The pleiotropic nature of TH action makes it difficult to identify and study discrete roles of TH in various aspect of embryogenesis, including neurogenesis and brain maturation. These challenges notwithstanding, enormous progress has been achieved in understanding TH production and its regulation, their conversions and routes of entry into the developing mammalian brain. The endocrine environment has to adjust when an embryo ceases to rely solely on maternal source of hormones as its own thyroid gland develops and starts to produce endogenous TH. A number of mechanisms are in place to secure the proper delivery and action of TH with placenta, blood-brain interface, and choroid plexus as barriers of entry that need to selectively transport and modify these hormones thus controlling their active levels. Additionally, target cells also possess mechanisms to import, modify and bind TH to further fine-tune their action. A complex picture of a tightly regulated network of transport proteins, modifying enzymes, and receptors has emerged from the past studies. TH have been implicated in multiple processes related to brain formation in mammals—neuronal progenitor proliferation, neuronal migration, functional maturation, and survival—with their exact roles changing over developmental time. Given the plethora of effects thyroid hormones exert on various cell types at different developmental periods, the precise spatiotemporal regulation of their action is of crucial importance. In this review we summarize the current knowledge about TH delivery, conversions, and function in the developing mammalian brain. We also discuss their potential role in vertebrate brain evolution and offer future directions for research aimed at elucidating TH signaling in nervous system development.

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“…It is also speculated that rT3 has direct effects on mortality, but not yet completely clarified. In experimental animal studies, it was shown that rT3 might interact with the integrin avB3 reducing the oxidative stress induced by congenital hypothyroidism in the hippocampus of immature rats, 42 whereas rT3, through non-genomic mechanisms, can increase calcium uptake in Sertoli cells of immature rats 43 and participate in the regulation of actin polymerization of neurons of the central nervous system. 44 Besides, in addition to direct actions, rT3 may act as a competitive inhibitor disrupting T3 signaling that may correlate with unfavorable prognosis.…”

Section: Discussionmentioning

confidence: 99%

Thyroid Function, Reverse Triiodothyronine, and Mortality in Critically Ill Clinical Patients

Silveira¹,

Vasconcelos²,

Moura³

et al. 2022

Indian Journal of Critical Care Medicine

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A bstract Background To evaluate the association of thyroid hormones changes, including increased reverse triiodothyronine (rT3) level, with critically ill clinical patients´ mortality. Patients and methods This study analyzed the observational data prospectively collected over 8 months (2018) in an adult intensive care unit (ICU) in Brasilia, Brazil. All consecutive ICU-admitted clinical patients were included. Thyroxine (T4), free thyroxine (fT4), triiodothyronine (T3), free triiodothyronine (fT3), rT3, and thyroid-stimulating hormone (TSH) were collected within 48 hours of ICU admission. Patients with hypothyroidism or hyperthyroidism who were previously diagnosed were excluded. Results Of 353 included patients, age was 68.5 ± 19.0 years, sequential organ failure assessment (SOFA) score was 3.3 ± 2.9, and Acute Physiology and Chronic Health Evaluation II (APACHE II) was 17.1 ± 7.9. ICU mortality was 17.6% ( n = 62). Non-survivor patients had a higher incidence of increased rT3 (69.3 vs 59.2%, p = 0.042), lower incidence of low T4 (4.8 vs 9.7%, p = 0.045), and increased age (75.2 ± 16.3 years vs 67.1 ± 19.3 years, p = 0.001), SOFA (3.0 ± 0.4 vs 2.8 ± 2.6, p <0.001), and APACHE II (23.5 ± 7.5 vs 15.7 ± 7.2, p <0.001). Alterations in other thyroid hormones did not show association with mortality. Increased rT3 [odds ratio (OR): 2.436; 95% confidence interval (CI): 1.023–5.800; p = 0.020] and APACHE II (OR: 1.083, 95% CI: 1.012–1.158; p = 0.044) were associated with ICU mortality in the multivariate analysis. Conclusion Increased rT3 was independently associated with increased ICU mortality. In contrast, other thyroid hormone alterations did not show an association with mortality. Determining rT3 levels may be a helpful test to identify an increased risk for ICU mortality in clinical patients. How to cite this article da Silveira CDG, de Vasconcelos FPJ, Moura EB, da Silveira BTG, Amorim FFP, Shintaku LS, et al. Thyroid Function, Reverse Triiodothyronine, and Mortality in Critically Ill Clinical Patients. Indian J Crit Care Med 2021;25(10):1161–1166.

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Reverse T3 interacts with αvβ3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms

Cited by 14 publications

References 83 publications

A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development

A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development

Transport, Metabolism, and Function of Thyroid Hormones in the Developing Mammalian Brain

Thyroid Function, Reverse Triiodothyronine, and Mortality in Critically Ill Clinical Patients

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