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Thyroid Hormone Derivatives and Thyroid Hormone Receptors

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 7884

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Prof. Dr. Grazia Chiellini

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Department of Pathology, University of Pisa, 56100 Pisa, Italy
Interests: metabolic biochemistry; thyroid hormone analogs and metabolites; vitamin D analogs; drug design, synthesis and development
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Dr. Federica Saponaro

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Guest Editor

Department of Pathology, University of Pisa, Pisa, Italy
Interests: hypoparathyroidism; hyperparathyroidism; parathyroid tumors; thyroid hormone analogs and metabolites; vitamin D metabolism; serum vitamin D levels and heart failure; endocrinology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Thyroid hormone receptors (TRs) are potent regulators of the proliferation and differentiation of many cell types. This can explain the important role of the thyroid hormones (THs) and their receptors in key processes, such as growth, development, tissue homeostasis or cancer. Most THs effects are mediated by two different TR isoforms, namely TRα and TRβ, with the TRβ isoform known to be responsible for the main beneficial effects of TH on the liver. In the brain, despite the crucial role of TRα isoforms in neuronal development, TRβ was proposed to play a role in remyelination processes. Consequently, over the past two decades, considerable efforts have been made to develop TH analogues capable of differentiating between beneficial actions on the liver and central nervous system (CNS) and deleterious effects on the heart, muscle and bone. In addition to the classical genomic actions of THs, a relevant number of reports suggested that THs might act through alternative pathways that do not require direct interactions between TRs and DNA. Moreover, several TH metabolites, including 3,5-T2 or 3-T1AM, were associated with a broad range of actions, mostly attributable to short-term effects.

The aim of this Special Issue is to deepen our understanding of TH actions and the potential therapeutic applications of TH analogues.

Dr. Grazia Chiellini
Dr. Federica Saponaro
Guest Editors

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Keywords

thyroid hormone receptors
central nervous system diseases
neurodegenerative diseases
neurodegeneration
neuroinflammation
liver diseases
dyslipidemia
hyperlipidemia
obesity
T2DM (type 2 diabetes mellitus)
atherosclerosis
cancer
reduced sensitivity to TH
TH metabolites
TH mimetics
hypothyroidism
hyperthyroidism
deiodinases
regenerative medicine
biomarkers

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15 pages, 2886 KiB

Open AccessArticle

T1AM/TAAR1 System Reduces Inflammatory Response and β-Amyloid Toxicity in Human Microglial HMC3 Cell Line

by Beatrice Polini, Caterina Ricardi, Andrea Bertolini, Vittoria Carnicelli, Grazia Rutigliano, Federica Saponaro, Riccardo Zucchi and Grazia Chiellini

Int. J. Mol. Sci. 2023, 24(14), 11569; https://doi.org/10.3390/ijms241411569 - 17 Jul 2023

Cited by 8 | Viewed by 2811

Abstract

Microglial dysfunction is one of the hallmarks and leading causes of common neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD). All these pathologies are characterized by aberrant aggregation of disease-causing proteins in the brain, which can directly activate microglia, trigger microglia-mediated neuroinflammation, and increase oxidative stress. Inhibition of glial activation may represent a therapeutic target to alleviate neurodegeneration. Recently, 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormone (TH) able to interact directly with a specific GPCR known as trace amine-associated receptor 1 (TAAR1), gained interest for its ability to promote neuroprotection in several models. Nevertheless, T1AM’s effects on microglial disfunction remain still elusive. In the present work we investigated whether T1AM could inhibit the inflammatory response of human HMC3 microglial cells to LPS/TNFα or β-amyloid peptide 25–35 (Aβ25–35) stimuli. The results of ELISA and qPCR assays revealed that T1AM was able to reduce microglia-mediated inflammatory response by inhibiting the release of proinflammatory factors, including IL-6, TNFα, NF-kB, MCP1, and MIP1, while promoting the release of anti-inflammatory mediators, such as IL-10. Notably, T1AM anti-inflammatory action in HMC3 cells turned out to be a TAAR1-mediated response, further increasing the relevance of the T1AM/TAAR1 system in the management of NDDs. Full article

(This article belongs to the Special Issue Thyroid Hormone Derivatives and Thyroid Hormone Receptors)

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14 pages, 1449 KiB

Open AccessArticle

An Analysis of the Structural Relationship between Thyroid Hormone-Signaling Disruption and Polybrominated Diphenyl Ethers: Potential Implications for Male Infertility

by Ishfaq Ahmad Sheikh, Mohd Amin Beg, Taha Abo-Almagd Abdel-Meguid Hamoda, Hammam Mahmoud Siraj Mandourah and Erdogan Memili

Int. J. Mol. Sci. 2023, 24(4), 3296; https://doi.org/10.3390/ijms24043296 - 7 Feb 2023

Cited by 5 | Viewed by 2191

Abstract

Polybrominated diphenyl ethers (PBDEs) are a common class of anthropogenic organobromine chemicals with fire-retardant properties and are extensively used in consumer products, such as electrical and electronic equipment, furniture, textiles, and foams. Due to their extensive use, PBDEs have wide eco-chemical dissemination and tend to bioaccumulate in wildlife and humans with many potential adverse health effects in humans, such as neurodevelopmental deficits, cancer, thyroid hormone disruption, dysfunction of reproductive system, and infertility. Many PBDEs have been listed as chemicals of international concern under the Stockholm Convention on Persistent Organic Pollutants. In this study, the aim was to investigate the structural interactions of PBDEs against thyroid hormone receptor (TRα) with potential implications in reproductive function. Structural binding of four PBDEs, i.e., BDE-28, BDE-100, BDE-153 and BDE-154 was investigated against the ligand binding pocket of TRα using Schrodinger’s induced fit docking, followed by molecular interaction analysis and the binding energy estimation. The results indicated the stable and tight binding of all four PDBE ligands and similarity in the binding interaction pattern to that of TRα native ligand, triiodothyronine (T3). The estimated binding energy value for BDE-153 was the highest among four PBDEs and was more than that of T3. This was followed by BDE-154, which is approximately the same as that of TRα native ligand, T3. Furthermore, the value estimated for BDE-28 was the lowest; however, the binding energy value for BDE-100 was more than BDE-28 and close to that of TRα native ligand, T3. In conclusion, the results of our study suggested the thyroid signaling disruption potential of indicated ligands according to their binding energy order, which can possibly lead to disruption of reproductive function and infertility. Full article

(This article belongs to the Special Issue Thyroid Hormone Derivatives and Thyroid Hormone Receptors)

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19 pages, 6344 KiB

Open AccessArticle

Thyroid Hormone Receptor β Knockdown Reduces Suppression of Progestins by Activating the mTOR Pathway in Endometrial Cancer Cells

by Bingtao Ren, Jieyun Zhou, Yingyi Hu, Ruihua Zhong, Qiaoying Lv, Shuwu Xie, Guoting Li, Bingyi Yang, Xiaojun Chen and Yan Zhu

Int. J. Mol. Sci. 2022, 23(20), 12517; https://doi.org/10.3390/ijms232012517 - 19 Oct 2022

Cited by 2 | Viewed by 2333

Abstract

Progestin resistance is a major obstacle to conservative therapy in patients with endometrial cancer (EC) and endometrial atypical hyperplasia (EAH). However, the related inducing factor is yet unclear. In this study, thyroid hormone and its receptor α (TRα) and β (TRβ) of patients were assayed. THRB-silenced RL95-2 and KLE EC cells were cultured to investigate the response of progestins. Transcriptomics and Western blotting were performed to investigate the changes in signaling pathways. We found that THRB, rather than THRA, knockdown promoted the viability and motilities of RL95-2 cells but not KLE cells. The suppressive effect of progestins on cell growth and motility significantly decreased in THRB-silenced RL95-2 cells. Multiple proliferation-related signaling pathways were enriched, and the activities of mammalian targets of rapamycin (mTOR)/4e-binding protein 1 (4EBP1)/eukaryotic translation initiation factor 4G (eIF4G) rather than phosphorylated protein kinase B (Akt) were remarkably boosted. Progestin treatment enhanced the effects, and the augmentation was partially abated on supplementation with T3. In THRB-knockdown KLE cells, the progestins-activated partial signaling pathway expression (either mTOR or eIF4G), and supplementation with T3 did not induce noticeable alterations. The serum levels of triiodothyronine (T3) were significantly lower in patients with EC compared with healthy women. A strong expression of TRβ was observed in most patients with EC and EAH sensitive to progestin treatment. In contrast, TRα positive expression was detected in less than half of the patients sensitive to progestin therapy. In conclusion, THRB knockdown enhanced the viability and motility of type I EC cells and attenuated the suppressive effects of progestins by activating the mTOR-4EBP1/eIF4G pathway. Lower expression of THRB is likely correlated with progesterone resistance. Full article

(This article belongs to the Special Issue Thyroid Hormone Derivatives and Thyroid Hormone Receptors)

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