Effects Of Thyroid Hormones Research Articles

Cardiovascular Findings and Effects of Caffeine on Experimental Hypothyroidism.

Thyroid hormone deficiencies can disrupt organ functions, significantly impacting the cardiovascular system. Recently, the effects of thyroid hormones on the heart have garnered increased attention. However, most studies are conducted on humans using clinical data, while cellular-level and experimental studies remain limited. This study aimed to investigate the cardiovascular implications of hypothyroidism and evaluate the impact of caffeine on cardiac health in rats induced with hypothyroidism using propylthiouracil (PTU). The study involved 60 rats divided into six groups. Group 1 served as the untreated control. Group 2 received PTU for two months to induce hypothyroidism. Group 3 received PTU for one month, followed by caffeine for one month. Group 4 received caffeine for two months. Group 5 received both PTU and caffeine simultaneously for two months. Group 6 received PTU for one month, followed by one month under normal conditions. During necropsy, normal thyroid glands were observed in Groups 1, 4, and 6, enlarged thyroids in Group 2, and smaller thyroids in Groups 3 and 5. Microscopic examination revealed varying thyroid histologies: Group 2 showed significant epithelial cell proliferation and absent colloid, while Groups 3, 5, and 6 had altered yet colloid-containing acini. Macroscopic inspection of hearts appeared normal across all groups. However, histopathological examination revealed significant hyperemia and microhemorrhages in Group 2, contrasting with normal findings in other groups. Immunohistochemical analysis indicated reduced cardiac troponin expression in Group 2, while other groups maintained prominent expression. Additionally, Group 2 displayed increased serum TSH levels and decreased T3 and T4 levels. The findings suggest that administering caffeine alongside or after PTU treatment in rats with experimentally induced hypothyroidism may ameliorate thyroid and cardiac irregularities. This study indicates caffeine's potential in mitigating the adverse effects of hypothyroidism on thyroid and heart health.

Is Low-free Triiodothyronine (fT3) Associated with Increased Morbidity in Patients Admitted to Coronary Care Units?

The effects of thyroid hormone on patients hospitalized in coronary intensive care units are still controversial. We retrospectively examined thyroid hormone levels and their impact on cardiovascular morbidity in patients admitted to coronary intensive care units. A total of 208 (Female/Male; 47.1%/52.9%) patients without any history of thyroid disease were enrolled and screened. Patients with specific heart disease and existing thyroid hormone parameters were included in the study. Low triiodothyronine syndrome is characterized by reduced serum total or free T3 (fT3) concentrations in normal free T4 (fT4) and TSH levels. The common diagnosis of the patients in the coronary care unit is acute coronary syndrome (n=59, 28.2 %) and heart failure (n=46, 23.3%). Patients were divided into two groups according to left ventricular ejection fraction percentages (LVEF ≤39% vs LVEF ≥40%). Plasma fT3 levels were significantly correlated with low LVEF (≤39%) (p =0.002). fT3 (r=-0.183, p =0.013) and hospitalization etiology (r=-0.161, p =0.023) were also the most critical parameters affecting the length of hospitalization. Low fT3 was associated with reduced ejection fraction and prolonged hospitalization, which may lead to potential morbidities in HF patients, which may be useful in risk stratification and treatment strategies.

Generation of a Mouse Model for the Study of Thyroid Hormones Regulatory Effect on the Immune System.

The generation of hypothyroid and hyperthyroid mouse models is one of the approaches used to investigate the complex interplay between thyroid hormones and the immune system. We present a detailed protocol describing how to induce endotoxic shock by lipopolysaccharide (LPS) administration, and how to investigate the role of immune populations, specifically macrophages, responding to endotoxemia.This book chapter provides the use of different molecular techniques, such as Western Blotting, Immunohistochemistry, q-PCR, Luciferase assays, or ChIP assays, with which researchers can gain valuable insights into the immune system's interaction with hormonal signaling pathways, for instance, examining the effect of thyroid hormones on signaling of STAT3, NF-κB, and ERK in response to LPS, and inflammatory mediators, such as interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNFα) within these cells. The signaling pathways involved and the exploration of the relationship between thyroid hormones and the immune system can be analyzed using several molecular biology technologies in order to clarify their interplay in various disease states.

Thyroid hormone and the Liver.

It is known that thyroid hormone can regulate hepatic metabolic pathways including cholesterol, de novo lipogenesis, fatty acid oxidation, lipophagy, and carbohydrate metabolism. Thyroid hormone action is mediated by the thyroid hormone receptor (THR) isoforms and their coregulators, and THRβ is the main isoform expressed in the liver. Dysregulation of thyroid hormone levels, as seen in hypothyroidism, has been associated with dyslipidemia and metabolic dysfunction-associated fatty liver disease. Given the beneficial effects of thyroid hormone in liver metabolism and the advances illuminating the use of thyroid hormone analogs such as resmetirom as therapeutic agents in the treatment of metabolic dysfunction-associated fatty liver disease, this review aims to further explore the relationship between TH, the liver, and metabolic dysfunction-associated fatty liver disease. Herein, we summarize the current clinical therapies and highlight future areas of research.

Специфика влияния уровней тиреоидных гормонов на адаптационные возможности организма (обзор)

Thyroid hormones take an active part in the regulation of many body reactions, including adaptive responses. The purpose of this review was to analyse the role of thyroid hormones in the adaptive response of the body to stress factors. Materials and methods. The data presented in articles published in Russian and foreign scientific periodicals from 2019 to 2023 were studied. The following databases were searched: PubMed, Google Scholar, SpringerLink and eLIBRARY.RU. According to the results of this theoretical study, thyroid hormones are involved in almost all physiological processes, exerting a metabolic effect on a number of tissues and systems as well as influencing pro- and antioxidant mechanisms. In response to stress, the body consistently develops a number of adaptive reactions associated with the activity of thyroid hormones. Stressors of various nature affect the level of thyroid hormones in the body. A connection between the symptoms of thyroid dysfunction and a decrease in the body’s stress resistance has been noted, while the development of both hypo- and hyperthyroidism negatively affects the functioning of a number of organs and systems. The paper describes an interdependence between hypo-/hyperthyroidism and the body’s adaptive capabilities. The influence of thyroid hormones on the adaptive mechanisms realized at the metabolic level has been proven. There is data confirming the central role of thyroid hormones in the formation of exploratory behaviour and adaptive response. A more extensive investigation is required into the correlation between changes in the level of thyroid hormones and adaptive immune responses, as well as into the effect of thyroid hormones on the function of individual immune cells. Among the ongoing research, the article highlights studies aimed to determine patterns of changes in the level of thyroid hormones during adaptation to extreme stress, including climatic and geographical factors, as well as to find approaches to non-hormonal regulation of their concentrations in the body.

From Cutting-Edge Science to the Clinic: Possible Treatment with Thyroid Hormone Analogs and the Effects of Thyroid Hormone in the Brain

From Cutting-Edge Science to the Clinic: Possible Treatment with Thyroid Hormone Analogs and the Effects of Thyroid Hormone in the Brain

Exposure to multiple metals and leukocyte telomere length in children and adolescents: The mediating effect of thyroid hormones

Exposure to metals has been related to alterations in leukocyte telomere length (LTL), an aging marker. However, the evidence regarding this relationship in children and adolescents, as well as the underlying mechanisms, remains unclear. Therefore, we aimed to explore the individual and mixture effects of metals on LTL in children and adolescents and to assess the mediating role of thyroid hormones and the modifying effect of a healthy lifestyle. In a cross-sectional study performed in Liuzhou, China, we assessed 5 serum thyroid hormones, 18 urinary metals, and LTL among 1050 children and adolescents aged 6–18 years. We employed multivariate linear regression and weighted quantile sum (WQS) regression to assess the associations of urinary metals with LTL in children and adolescents. Mediation analyses were conducted to explore the effects of thyroid hormones on these relationships. Urinary cobalt (Co), nickel (Ni), strontium (Sr), mercury (Hg), cadmium (Cd), and thallium (Tl) were related to a shorter LTL in children and adolescents. The WQS regression showed a 6.31% (95% CI: −8.76%, −3.79%) decrease in LTL per quartile increase in the WQS index, and identified Ni (23.3%), Sr (21.7%), and Tl (18.0%) as the major contributors. Mediation analyses showed that triiodothyronine (T3) mediated 14.8% and 8.1% of the associations of urinary Sr and Hg with LTL, respectively, and suppressed 9.3% of the association with urinary Co. Furthermore, the inverse associations of Sr, Cd, and Tl with LTL were attenuated among participants who adopted a healthy lifestyle. Our findings suggested that exposure to Co, Ni, Sr, Cd, Hg, Tl, and their mixture were related to a shorter LTL in children and adolescents, potentially mediated by thyroid hormones. Additionally, adopting a healthy lifestyle may alleviate these adverse effects.

Structural insights into thyroid hormone receptors.

Thyroid hormone receptors (TRs) are essential components of the endocrine system, mediating the cellular effects of thyroid hormones. The two TR genes, THRA and THRB, encode four isoforms, with TRα1 and TRβ1 being the most prevalent. TRs are ligand-dependent transcription factors and members of the nuclear receptor superfamily, indispensable for human growth, development and metabolism. Dysfunctional TR signaling can lead to conditions like resistance to thyroid hormone (RTH) syndrome, thyroid cancer, and metabolic disorders. Structurally, TRs comprise several domains: a variable N-terminal domain, a conserved DNA-binding domain, and a ligand-binding domain that mediates interaction with hormones and transcriptional coregulators. TRs predominantly function as heterodimers with the retinoid X receptor (RXR), binding to thyroid hormone response elements (TREs) in target genes to regulate their transcription. This review examines the structural studies on TRs, primarily performed through X-ray crystallography, that have provided detailed insights into TR functions, including DNA recognition, ligand binding, and coregulator interactions. We also discuss how these findings have deepened our understanding of TR mechanisms and contributed to the interpretation of pathogenic mutations.

PKCα Activation via the Thyroid Hormone Membrane Receptor Is Key to Thyroid Cancer Growth.

Thyroid carcinoma (TC) is the most common endocrine neoplasia, with its incidence increasing in the last 40 years worldwide. The determination of genetic and/or protein markers for thyroid carcinoma could increase diagnostic precision. Accumulated evidence shows that Protein kinase C alpha (PKCα) contributes to tumorigenesis and therapy resistance in cancer. However, the role of PKCα in TC remains poorly studied. Our group and others have demonstrated that PKCs can mediate the proliferative effects of thyroid hormones (THs) through their membrane receptor, the integrin αvβ3, in several cancer types. We found that PKCα is overexpressed in TC cell lines, and it also appeared as the predominant expressed isoform in public databases of TC patients. PKCα-depleted cells significantly reduced THs-induced proliferation, mediated by the integrin αvβ3 receptor, through AKT and Erk activation. In databases of TC patients, higher PKCα expression was associated with lower overall survival. Further analyses showed a positive correlation between PKCα and genes from the MAPK and PI3K-Akt pathways. Finally, immunohistochemical analysis showed abnormal upregulation of PKCα in human thyroid tumors. Our findings establish a potential role for PKCα in the control of hormone-induced proliferation that can be explored as a therapeutic and/or diagnostic target for TC.

Effects of thyroid status on HbA1c

Introduction: Altered erythrocyte turnover may not adequately reflect the glycemic status in the glycated hemoglobin (HbA1c) levels. Hypothyroidism is one such condition that might cause reduced erythropoiesis and falsely high HbA1c values. The aim of the study is to evaluate the effect of thyroid hormone on HbA1c levels on non-diabetic hypothyroid individuals and also to evaluate HbA1c levels in hypothyroid individuals with diabetes and to compare them with normal healthy subjects. Methods: This prospective study was conducted on 210 individuals, of whom 70 were assigned to group I- hypothyroid individuals, 70 to group II- hypothyroid individuals with diabetes, and 70 to group III—Normal individuals. Following data regarding laboratory investigations were collected which included fasting blood sugar (FBS), postprandial blood sugar (PPBS), HbA1c, free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH). Data analysis was performed using SPSS version 16.0. Results: The median level of HbA1c was significantly higher in hypothyroid than in normal individuals (5.6 [5.5-5.7] % vs 5.2 [5-5.3] %, P≤0.001). The median level of TSH was significantly higher in hypothyroid than in normal individuals (11.13 [6.9-22.9] μIU/mL vs 2.15 (1.33-1.60) μIU/mL). The serum level of HbA1c was significantly positively correlated with TSH in hypothyroid individuals (r=0.281, P≤0.01). Conclusion: There is a positive correlation between HbA1c and TSH, and a negative correlation between HbA1c and fT4 levels. Serum HbA1c levels were significantly higher in hypothyroid individuals than the normal individuals. Therefore, our study suggests that we should proceed with caution while interpreting HbA1c levels in individuals with hypothyroidism.

Nanoscale organization of cardiac calcium channels is dependent on thyroid hormone status.

Thyroid hormone dysfunction is frequently observed in patients with chronic illnesses including heart failure, which increases the risk of adverse events. This study examined the effects of thyroid hormones (THs) on cardiac transverse-tubule (TT) integrity, Ca2+ sparks, and nanoscale organization of ion channels in excitation-contraction (EC) coupling, including L-type calcium channel (CaV1.2), ryanodine receptor type 2 (RyR2), and junctophilin-2 (Jph2). TH deficiency was established in adult female rats by propyl-thiouracil (PTU) ingestion for 8 wk; followed by randomization to continued PTU without or with oral triiodo-l-thyronine (T3; 10 µg/kg/day) for an additional 2 wk (PTU + T3). Confocal microscopy of isolated cardiomyocytes (CMs) showed significant misalignment of TTs and increased Ca2+ sparks in thyroid-deficient CMs. Density-based spatial clustering of applications with noise (DBSCAN) analysis of stochastic optical reconstruction microscopy (STORM) images showed decreased (P < 0.0001) RyR2 cluster number per cell area in PTU CMs compared with euthyroid (EU) control myocytes, and this was normalized by T3 treatment. CaV1.2 channels and Jph2 localized within a 210 nm radius of the RyR2 clusters were significantly reduced in PTU myocytes, and these values were increased with T3 treatment. A significant percentage of the RyR2 clusters in the PTU myocytes had neither CaV1.2 nor Jph2, suggesting fewer functional clusters in EC coupling. Nearest neighbor distances between RyR2 clusters were greater (P < 0.001) in PTU cells compared with EU- and T3-treated CMs that correspond to disarray of TTs at the sarcomere z-discs. These results support a regulatory role of T3 in the nanoscale organization of RyR2 clusters and colocalization of CaV1.2 and Jph2 in optimizing EC coupling.NEW & NOTEWORTHY Thyroid hormone (TH) dysfunction exacerbates preexisting heart conditions leading to an increased risk of premature morbidity/mortality. Triiodo-l-thyronine (T3) optimizes cardiac excitation-contraction (EC) coupling by maintaining myocardial T-tubule (TT) structures and organization of calcium ion channels. Single-molecule localization microscopy shows T3 effects on the clustering of ryanodine receptors (RyR2) with colocalization of L-type calcium channels (CaV1.2) and junctophilin-2 (Jph2) at TT-SR structures. Heart disease with subclinical hypothyroidism/low T3 syndrome may benefit from TH treatment.

The influence of triiodothyronine on the immune response and extracellular matrix remodeling during zebrafish heart regeneration

Damage to the human heart is an irreparable process that results in a permanent impairment in cardiac function. There are, however, a number of vertebrate species including zebrafish (Danio rerio) that can regenerate their hearts following significant injury. In contrast to these regenerative species, mammals are known to have high levels of thyroid hormones, which has been proposed to play a role in this difference in regenerative capacity. However, the mechanisms through which thyroid hormones effect heart regeneration are not fully understood. Here, zebrafish were exposed to exogenous triiodothyronine (T3) for two weeks and then their hearts were damaged through cryoinjury to investigate the effect of thyroid hormones on ECM remodeling and the components of the immune response during heart regeneration. Additionally, cardiac fibroblasts derived from trout, another species of fish known to display cardiac regenerative capacity, were exposed to T3in vitro to analyze any direct effects of T3 on collagen deposition. It was found that cryoinjury induction results in an increase in myocardial stiffness, but this response was muted in T3 exposed zebrafish. The measurement of relevant marker gene transcripts suggests that T3 exposure reduces the recruitment of macrophages to the damaged zebrafish heart immediately following injury but had no effect on the regulation of collagen deposition by cultured trout fibroblasts. These results suggest that T3 effects both the immune response and ECM remodeling in zebrafish following cardiac injury.

Associations between gestational exposure to perfluoroalkyl substances, fetal growth, and the mediation effect of thyroid hormones

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) may cause adverse birth outcomes. Thyroid hormones may play a key role in mediating the effects of PFAS. We enrolled 374 mother-infant pairs from the Ezhou birth cohort study between 2019 and 2020. Eight PFASs and six thyroid hormones were measured in maternal serum during the first trimester of pregnancy. Neonatal growth metrics, including birth weight, length, head circumference, and gestational age, were acquired. Multivariate linear regression was performed to determine the associations between maternal serum PFAS and thyroid hormone levels and birth outcomes and a mediation analysis was also conducted. Except for perfluoroheptanoic acid (41.2%), the other seven PFAS detection rates were more than 85%, and the highest median concentration was observed for PFOSA with levels of 5.21 ng/mL. After controlling for typical confounders, we observed a decrease in birth length (cm) with increasing serum concentrations of perfluorononanoic acid (PFNA) (β = -0.54; 95% CI = -1.0, -0.08) and perfluorohexane sulfonate (PFHxS) (β = -0.64; 95% CI = -0.86, -0.42). Additionally, a decrease in birth head circumference was observed with increasing concentrations of perfluorooctanote (PFOA) (β = -0.73, 95% CI = -1.19, -0.27) and PFHxS (β = -0.30; 95% CI = -0.53, -0.07). Maternal free triiodothyronine (FT3) mediated 36.7% of the negative association between PFNA and birth length, and free thyroxine (FT4) mediated 30.8% of the effect of PFOA on head circumference. When performing stratified analysis by infant sex, the associations might differ between boys and girls. Our study suggested prenatal exposure to some PFASs was negatively associated with birth length and circumference, and FT3 and FT4 may partly mediate the association.

Roles of thyroid and leptin hormones and their crosstalk in male reproductive functions: an updated review.

This review aims to provide updated information regarding the role of thyroid and leptin hormones and their crosstalk in affecting the male reproductive function in hypothyroid and obesity conditions. A wide literature search was made using online search engines on published articles using keywords including thyroid hormone, hypothyroidism, leptin hormone, hyperleptinemia, obesity, the relationship between thyroid and leptin hormones and male reproduction, and hypothyroidism, obesity, and male reproduction. All information pertaining thyroid and leptin hormone effects on male reproduction, hypothyroidism, hyperleptinemia, and obesity effect on male fertility as well as the related molecular mechanisms are obtained. Thyroid and leptin hormones individually play a significant role in male reproduction. Alterations of these hormones' levels could adversely affect the male reproductive functions. PI3K/AKT signaling was found to be the major signaling pathway involved in mediating the effect of both hormones on male reproduction. Impaired crosstalk between the two hormones may occur in hypothyroidism with obesity which would contribute towards male reproductive dysfunction.

Impact of thyroid hormones on predicting the occurrence of persistent inflammation, immunosuppression, and catabolism syndrome in patients with sepsis.

The prevalence of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has an upward trend in sepsis patients and can be associated with poor outcomes. Thyroid hormones are expected to be correlated with inflammation, immunity, and metabolism. Thus, the purpose of this study was to evaluate the effect of thyroid hormones on the occurrence of PICS and then further explore the optimal level of them in sepsis. This retrospective observational study used the online database Medical Information Mart for Intensive Care (MIMIC)-IV. Univariate and multivariate logistic regression analyses were employed to determine correlations between thyroid hormone levels and PICS. A combination of independent PICS development factors was established with accuracy assessed using the area under the receiver operating characteristic curve (AUC-ROC). Patients were divided into PICS (n=205) and non-PICS (n=671) groups. The third quartiles of triiodothyronine (T3) (60-80ng/dl) and thyroxine (T4) (5.5-6.8ug/dl) had the lowest PICS incidence and the adjusted odds ratio (OR) was 0.33 (T3, p=0.009) and 0.39 (T4, p=0.006), respectively, compared with the first quartiles of T3 and T4. For patients with a pre-existing T3 deficiency, severe deficiency (T3 <60ng/dl) and a high Sequential Organ Failure Assessment (SOFA) score were significantly related to PICS incidence. The AUC for these combined parameters in predicting PICS occurrence was 0.748 (all patients) and 0.861 (patients without thyroid disease). A mild T3 deficiency (60-80ng/dl) was significantly associated with the lowest risk-adjusted PICS occurrence in patients with sepsis. A severe T3 deficiency (<60ng/dl) and a high SOFA score were independent risk factors for PICS occurrence.

Effects of Thyroid Hormones on Cellular Development in Human Ovarian Granulosa Tumor Cells (KGN).

Ovarian cancer is a common malignant tumor in the female reproductive system, and Granulosa cell tumor (GCT) of the ovary is a rare type of ovarian cancer, which significantly threatens women's reproductive health. It has been reported that dysregulation of thyroid hormones (THs) may be closely related to the progression and prognosis of ovarian cancer. Moreover, THs regulate phosphorylation of signal transducer and activator of transcription (STAT3) and Octamer-binding transcription factor 4 (OCT4) expression. It has been reported that STAT3 and OCT4 play important roles in cellular development and tumorigenesis. However, the mechanisms by which THs affect the development of GCT are still remained unclear. To evaluate the effect of THs on human ovarian granulosa tumor cells (KGN), cells were treated with 3,5,3' -triiodothyronine (T3). Oct4 small interfering (Oct4 siRNA) or STAT3 inhibitor C188-9 was also co-cultured with cells in some experiments, respectively. The cell viability, proliferation, and proteins content were detected by CCK-8, EdU, and Western Blotting, respectively. The results showed that T3 enhanced cell viability and proliferation. Moreover, T3 also increased the expression of thyroid hormone receptor (TR), p-STAT3, and OCT4 proteins. The effects of T3 on both p-STAT3 and OCT4 expression were blocked by TR antagonist 1-850. Meanwhile, C188-9, an inhibitor of STAT3, decreased T3-induced cellular viability, proliferation, and OCT4 expression, highlighting that p-STAT3 can regulate the expression of OCT4 and affect cellular viability, and proliferation. Furthermore, T3-induced cellular growth was reduced by Oct4 siRNA, which indicates that T3 regulates cellular development through OCT4. These findings suggest that T3 increases cellular development via OCT4, which is mediated by phosphorylation of STAT3, and TR is also involved in these processes.

Magnitude of cardiac abnormality and its associated factors among hyperthyroidism patients on follow-up at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia

BackgroundThyroid hormones have an effect on every organ system, in particular, the heart responds to minimal changes in serum thyroid hormone level. Thyroid hormone causes a lot of changes in the cardiovascular system, such as increased heart rate, contractility, systolic hypertension, changes in peripheral vascular resistance, atrial fibrillation (AF), and hypercoagulability from the direct effect of thyroid hormone on cardiac myocyte and /or due to increased metabolic state. However, the magnitude of such heart abnormalities and its associated factors were not well studied in Ethiopia.ObjectiveTo determine the magnitude of cardiac abnormality and its associated factors among hyperthyroidism patients on follow-up at Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia, 2022.MethodsAn institution-based cross-sectional study was carried out among 318 hyperthyroid patients who were on follow-up at the endocrine clinic of TASH, Addis Ababa, Ethiopia from June to October 2022. The data were collected using a pretested structured interviewer administered questionnaire. The data were entered into the computer using EpiData version 3.1 and analyzed using SPSS version 25 software. Bivariable and multivariable logistic regression models were fitted to determine the association between the independent and dependent variables. Adjusted odds ratio with its 95% confidence interval and p-value < 0.05 were used to declare the presence and strength of statistically significant associations.ResultIn this study a total of 318 hyperthyroid patients were participated, most (90.9%) of them were females. The overall prevalence of heart failure among hyperthyroid patients was 17.0% (95% CI = 13.0, 21.6). More than half (52.7%) and one third (33.2%) of the participants showed abnormal electrocardiographic and echocardiographic findings respectively. Marital status (not married) [AOR = 2.37, 95% CI (1.03, 5.44)], pattern of hyperthyroidism [AOR = 13.09, 95% CI (4.70, 36.41)], being Asthmatic [AOR = 7.63, 95% CI (1.55, 37.52)], type of medication [AOR = 3.49, 95% CI (1.11, 11.02)] and duration of treatment [AOR = 4.95, 95% CI (2.05,11.99)] were significantly associated with cardiac abnormality.ConclusionA significant portion of hyperthyroid patients overburdened by cardiac abnormalities. Being unmarried, overt hyperthyroid, Asthmatic, long stay on treatment and type of treatment were significantly associated with cardiac abnormality. Hence, attention should be given for cardiac abnormalities while treating hyperthyroid patients.

TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

8398 Non-genomic Effects of Thyroid Hormones on the Breast Cancer Microenvironment

Abstract Disclosure: L. Drago: None. S. Shahrivari: None. N. Schwenk: None. P. Nelson: None. H. Hosseini: None. C. Spitzweg: None. Objective: Mesenchymal stem cells (MSCs) are central players in the genesis of the breast cancer tumor microenvironment and play a role in tumor initiation, progression, invasion, metastasis, angiogenesis as well as resistance to treatment. There is increasing evidence for an association between thyroid function and breast cancer risk. Thyroid hormone effects mediated through the αvβ3 integrin, a thyroid hormone receptor, are proposed as a pathophysiologic link to this observation. Methods: To evaluate the migratory behavior of MSCs in the presence or absence of thyroid hormone treatment in response to tumor-derived signals, a 3D migration assay was performed. MSCs pretreated with T3 (1nM) or T4 (1μM) with or without tetrac (100nM) (T4 analog, specific inhibitor of αvβ3 integrin-mediated thyroid hormone action) for 24 h were subjected to a gradient between serum-free medium and serum-free conditioned medium (CM) from five different breast cancer cell lines representative of different breast cancer subtypes including T47D as Luminal B, MCF7 as Luminal A, BT-474 and MDA-MB-453 as HER2, and MDA-MB-231 as Triple negative subtype. Results: MSCs subjected to a gradient between CM derived from each breast cancer cell line and serum-free medium showed directed chemotaxis towards tumor-CM with a significantly increased forward migration index (FMI) and center of mass (CoM). This migratory behavior was significantly enhanced upon treatment with T3 or T4. The cellular migration towards tumor-CM of MDA-MB-453, BT-474, and T47D was more effective upon MSC treatment with T3, but less so with T4. MSCs treated with T4 showed a better migratory performance towards the CM of MCF7 and MDA-MB-231. Except for T47D-CM, additional treatment with tetrac inhibited the enhanced effects of T3 and T4 on MSC migration demonstrating that this effect is mediated through αvβ3 integrin. Conclusion: Our preliminary in vitro data on the effects of thyroid hormones T3 and T4, and the thyroid hormone metabolite tetrac on MSC migration shows a distinct behaviour of MSCs in the presence of either T3 or T4 depending on the breast cancer cell subtype, suggesting a role of non-genomic, integrin αvβ3-mediated thyroid hormone action on MSC biology within the breast tumor microenvironment that warrants further investigation. Presentation: 6/3/2024

8398 Non-genomic Effects Of Thyroid Hormones On The Breast Cancer Microenvironment

Abstract Disclosure: L. Drago: None. S. Shahrivari: None. N. Schwenk: None. P. Nelson: None. H. Hosseini: None. C. Spitzweg: None. Objective: Mesenchymal stem cells (MSCs) are central players in the genesis of the breast cancer tumor microenvironment and play a role in tumor initiation, progression, invasion, metastasis, angiogenesis as well as resistance to treatment. There is increasing evidence for an association between thyroid function and breast cancer risk. Thyroid hormone effects mediated through the αvβ3 integrin, a thyroid hormone receptor, are proposed as a pathophysiologic link to this observation. Methods: To evaluate the migratory behavior of MSCs in the presence or absence of thyroid hormone treatment in response to tumor-derived signals, a 3D migration assay was performed. MSCs pretreated with T3 (1nM) or T4 (1μM) with or without tetrac (100nM) (T4 analog, specific inhibitor of αvβ3 integrin-mediated thyroid hormone action) for 24 h were subjected to a gradient between serum-free medium and serum-free conditioned medium (CM) from five different breast cancer cell lines representative of different breast cancer subtypes including T47D as Luminal B, MCF7 as Luminal A, BT-474 and MDA-MB-453 as HER2, and MDA-MB-231 as Triple negative subtype. Results: MSCs subjected to a gradient between CM derived from each breast cancer cell line and serum-free medium showed directed chemotaxis towards tumor-CM with a significantly increased forward migration index (FMI) and center of mass (CoM). This migratory behavior was significantly enhanced upon treatment with T3 or T4. The cellular migration towards tumor-CM of MDA-MB-453, BT-474, and T47D was more effective upon MSC treatment with T3, but less so with T4. MSCs treated with T4 showed a better migratory performance towards the CM of MCF7 and MDA-MB-231. Except for T47D-CM, additional treatment with tetrac inhibited the enhanced effects of T3 and T4 on MSC migration demonstrating that this effect is mediated through αvβ3 integrin. Conclusion: Our preliminary in vitro data on the effects of thyroid hormones T3 and T4, and the thyroid hormone metabolite tetrac on MSC migration shows a distinct behaviour of MSCs in the presence of either T3 or T4 depending on the breast cancer cell subtype, suggesting a role of non-genomic, integrin αvβ3-mediated thyroid hormone action on MSC biology within the breast tumor microenvironment that warrants further investigation. Presentation: 6/3/2024