Thyroid Hormone T3 Research Articles

7951 The Response of HPT Axis & BAT to Cold Exposure Is Delayed in Female Rats Compared to Males

Abstract Disclosure: A. Gutiérrez-Mata: None. L. Jaimes-Hoy: None. I. Sotelo-Rivera: None. F. Romero-Arteaga: None. R.M. Uribe: None. J.L. Charli: None. P. Joseph-Bravo: None. Cold exposure activates the sympathetic nervous system releasing NE in thermogenic brown adipose tissue (BAT) and in parallel, the Hypothalamus-Pituitary-Thyroid (HPT) axis, increasing synthesis and release of hypothalamic-TRH, pituitary-TSH, and thyroid hormones T4 and T3; T4 in concert with NE induce brown adipose tissue (BAT) thermogenesis through stimulation of deiodinase 2 (Dio2), and uncoupling protein 1 (Ucp1) expression. These changes are detected within the first hour in male rats [J Neuroendo 12:861, 2014] while in females, only in ovariectomized [J Neuroendocrinol 21:439, 2009]. Given the thermogenic effect of ovarian hormones, we hypothesized that females could respond to longer exposures. Female Wistar rats were exposed individually to 5°C for 1 to 5h and compared to male’s acute response (15 min to 4h); controls were moved individually to a nearby room at 22°C for similar times. Rats were euthanized by guillotine, rectal temperature was immediately measured, trunk blood collected, serum separated, and tissues kept at -70°C. Hormone concentrations were quantified in serum by RIA and ELISA, and gene expression in paraventricular nucleus (PVN), anterior pituitary (AP), and BAT by RT-PCR or qPCR. Body temperature of cold-exposed males was higher than isolated controls since the first 30min, Trh expression increased at 1h in the paraventricular nucleus (PVN), TSH release from 15 min up to 2 hours, T4 levels peaked until 4h, and T3 increased after 2h as in [Endocrinology 58:140, 1993]; Trhr1 in AP reached its lowest levels at 2h. In BAT, Dio2 expression peaked at 1h and subsequently decreased. Ucp1 increased from 30 min and remained elevated until 4h, Adrb3, and Ppargc1a expressions were highest at 4h. Cold exposure in females decreased body temperature after 4 hours when Trh PVN expression increased and that of TRH receptor 1 (Trhr1) in AP was lowest; TRH degrading enzyme (Trhde) expression peaked after 2h of cold and subsequently decreased at 4h. TSH in serum increased at 2h and then returned to control levels, T4 slightly increased at 3h, and T3 peaked at 5h. Progesterone serum concentration increased from 2h and peaked at 4h. No changes were found in estradiol serum concentration. In BAT, Dio2 expression increased from 2 to 4h, Ucp1 at 3 and 5h while that of β3 adrenergic receptor (Adrb3) decreased at 2h but rose reaching a peak at 4h. In contrast, expression of Pgc1α -the major transcriptional coactivator of Ucp1- rapidly increased (1h) decreasing afterward. The data suggest that when the ambient temperature decreases, the sympathetic system is activated including stimulation of progesterone, and supports a delayed response of female HPT axis to cold exposure, compared to male’s leading to the proposal that when female body temperature diminishes, the HPT axis and thyroid hormone-induced thermogenesis are activated.Funding: DGAPA IN217422, PAEP, CONAHCYT 790605. Presentation: 6/2/2024

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

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

B-114 Reference interval (RI) estimation for TSH in adults using an indirect method with unsupervised machine learning tool and R programming language

Abstract Background Thyroid-stimulating hormone (TSH) plays a fundamental role in regulating thyroid hormones T3 (triiodothyronine) and T4 (thyroxine). Understanding TSH test results is essential for effective management of thyroid disorders and depends, among other factors, on establishing specific reference intervals (RI) for the population being served. We aimed to estimate the reference intervals for TSH in the adult population served by a large diagnostic network in Brazil. Methods We employed data mining followed by estimation using an indirect method through the LabRI™ algorithm with parametric, non-parametric, and robust statistical treatments for outlier exclusion, a series of algorithms programmed in R Language. Included were TSH values from outpatients, aged 20 to 60 years, both sexes, from two analytical platforms. Used as a comparative RI recommended by the American Thyroid Association (ATA, 2014). Data were extracted from the Data Lake, from January to December 2022, from two laboratories in Brazil. Exclusion criteria: samples from hospital sources and referral laboratories; pregnant; some laboratory tests correlated with de TSH test; samples from patients using thyroid hormone and medications that may interfere with hormonal function and TSH laboratory analysis. Results After exclusion criteria, the sample totaled 26,909 adults of both sexes. After excluding 2.24% outliers, the estimated RI was 0.67-4.26 mIU/L, with the comparative RI chosen for this study being the one recommended by ATA of 0.40-4.00 mIU/L. The RI obtained in our study was similar to the Canadian RI harmonization study for TSH (0.60-4.48 mIU/L). Conclusions We estimated the RI, harmonized between Roche and Siemens platforms, to be 0.67-4.26 mIU/L. The RI obtained by the LabRI™ tool is equivalent to the Adeli study (2023) and is under discussion by the company's endocrinology committee for whether to use the estimated RI from our internal study or the one recommended by ATA (2014) in reports.

A Physiological Study of the Effect of Bee Pollen on Albino Rats Induced Hypothyroidism

The current study aimed to evaluate the therapeutic role of bee pollen (BP) in reducing the harmful effects resulting from hypothyroidism compared to the drug thyroxine on some physiological indicators and improving their levels, which included weight gain (gm), hormone level (T3, T4, TSH), level TPO, cholesterol levels, HDL, LDL, VLDL, and liver enzymes ALT, AST, Hypothyroidism was induced in (24) male rats using the drug carbimazole (CBZ) Which lasted for (15) days at 30 mg/kg of body weight. A random sample was chosen to confirm the occurrence of hypothyroidism, as the results of examining blood samples that were drawn from the animals showed a high concentration of the TSH hormone and Low concentrations of thyroid hormones in the serum compared to the negative control., and this indicates the occurrence of hypothyroidism. Then the animals in which hypothyroidism was induced were separated into 3 experimental collections in addition to the control group and a fifth group. Each group consists of (8) animals. The dosing period lasted thirty days orally. The negative control group, G1, was provided with a diet and water freely. G2 was continued to be dosed with the drug (CBZ) at a concentration of 30 mg/kg of body weight. G3 was continued to be dosed with the drug (CBZ) at a concentration of 30 mg/kg and solution (BP). At a concentration of 200 mg/kg body weight, G4 was dosed with levothyroxine at a concentration of 20 mg/kg body weight, while G5 was dosed with BP solution only at a concentration of 200 mg/kg body weight. At the end of the experiment, the animals were sacrificed and blood samples were obtained. The results were less than 0.05 in group G2 in body weight, the concentration of thyroid hormones T3 and T4, and the concentration of TPO and HDL, and a significant increase (P<0.05) in the concentration of TSH, Cholesterol, LDL, and VLDL, respectively, with an increase in the concentration of liver enzymes. AST and ALT compared to the control group. As for the G3 and G4 groups, the result appeared an original increase a total body weight and the concentration of the hormones T3, T4, and the TPO enzyme, a noticeable improvement in the lipid profile, and a low level of the ALT enzyme and the and thyroid-stimulating hormone compared to the G2 group. As for the group G5 has witnessed an increase in T4 concentration and a decrease in ALT concentration and body weight, and the concentrations of T3, TSH, and TPO are closer to control. We conclude from the current study that BP has a role in reducing the effects of hypothyroidism, increasing weight gain, and improving the lipid profile and the level of ALT liver enzymes. AST and Thyroid peroxidase (TPO) level.

Thyroïdites : pathologies les plus courantes

AbstractThyroiditis are common conditions, mostly benign and accompanied by a biological disruption in the thyroid function. In fact, their resolution can sometimes be spontaneous. The term ‘thyroiditis’ encompasses several diseases characterized by inflammation of the thyroid gland. Patients often describe a neck pain that may be associated with the presence of a goiter. The causes are multiple. The most common condition is Hashimoto’s thyroiditis, characterized by hypothyroidism. Conversely, Basedow’s thyroiditis is characterized by hyperthyroidism. These are two autoimmune diseases whose diagnosis, in addition to the measurement of thyrotropin and thyroid hormones T4 and T3, relies on the measurement of specific antibodies. There are also iatrogenic thyroiditis: amiodarone, an antiarrhythmic drug prescribed by cardiologists, can cause thyroid dysfunction and requires close monitoring. Postpartum thyroiditis is a transient, sometimes persistent thyroiditis that occurs within a year following a pregnancy or miscarriage. Finally, some thyroiditis have infectious origins, such as De Quervain’s subacute thyroiditis, which is of viral origin. The treatment implemented will be tailored to the aetiology of the thyroiditis and monitored by an endocrinologist.

Thyroid hormone T3 induces Fyn modification and modulates palmitoyltransferase gene expression through αvβ3 integrin receptor in PC12 cells during hypoxia.

Thyroid hormones (THs) are essential in neuronal and glial cell development and differentiation, synaptogenesis, and myelin sheath formation. In addition to nuclear receptors, TH acts through αvβ3-integrin on the plasma membrane, influencing transcriptional regulation of signaling proteins that, in turn, affect adhesion and survival of nerve cells in various neurologic disorders. TH exhibits protective properties during brain hypoxia; however, precise intracellular mechanisms responsible for the preventive effects of TH remain unclear. In this study, we investigated the impact of TH on integrin αvβ3-dependent downstream systems in normoxic and hypoxic conditions of pheochromocytoma PC12 cells. Our findings reveal that triiodothyronine (T3), acting through αvβ3-integrin, induces activation of the JAK2/STAT5 pathway and suppression of the SHP2 in hypoxic PC12 cells. This activation correlates with the downregulation of the expression palmitoyltransferase-ZDHHC2 and ZDHHC9 genes, leading to a subsequent decrease in palmitoylation and phosphorylation of Fyn tyrosine kinase. We propose that these changes may occur due to STAT5-dependent epigenetic silencing of the palmitoyltransferase gene, which in turn reduces palmitoylation/phosphorylation of Fyn with a subsequent increase in the survival of cells. In summary, our study provides the first evidence demonstrating the involvement of integrin-dependent JAK/STAT pathway, SHP2 suppression, and altered post-translational modification of Fyn in protective effects of T3 during hypoxia.

Effects of yeast culture on growth performance, immune function, antioxidant capacity and hormonal profile in Mongolian ram lambs.

As effective growth-promoters and immune-modulators, yeast fermented products have shown positive effects in ruminants. To explore the mechanisms of yeast culture promoting growth and regulating immunity, this study investigated the effects of yeast culture, and β-glucan as one of its main active ingredients, on the growth performance, immune function, antioxidant capacity and hormonal profile in Mongolian ram lambs. One hundred and five Mongolian ram lambs were randomly assigned to 3 groups, with 35 replicates in each group. The dietary treatments were: total mixed ration (TMR) as the control group, TMR supplemented with 50-70 g/kg yeast culture (YC) or 75 mg/kg β-glucan. The test period was 137 days. All the sheep were weighed and 6 serum samples were collected in each group on days 0, 30, 60, 90 and 130, respectively. The results showed that both YC and β-glucan could promote the growth performance with increased average daily gain and decreased feed to weight gain ratio. Moreover, these two feed additives facilitated the immune function by selectively increasing the serum levels of lysozyme, IgG, IgM, INF-γ, TNF-α and some interleukins (IL-1β, IL-2, IL-6 and IL-8); ameliorated the antioxidant capacity with higher total antioxidant capacity and enzyme activities of catalase and glutathione peroxidase; altered the metabolism-associated hormone levels with higher growth hormone and thyroid hormone T3 but lower cortisol and insulin. In conclusion, both YC and β-glucan could improve the growth performance, immune function and antioxidant capacity, and regulate the serum levels of metabolism-associated hormones, thus exerting effects of promoting growth and improving immune function. Therefore, YC could be considered as a suitable potential alternative strategy to antibiotics and be used as an animal feed additive. This article provides a theoretical basis for the clinical application of such yeast fermented preparations in mutton sheep husbandry.

Thyroid hormone T4 mitigates traumatic brain injury in mice by dynamically remodeling cell type specific genes, pathways, and networks in hippocampus and frontal cortex

The complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Thyroxine (T4) administration has been shown to prevent the cognitive impairments induced by mTBI in mice but the mechanism is poorly understood. To understand the underlying mechanism, we carried out a single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages in a mouse model of mTBI. We found that T4 treatment altered the proportions and transcriptomes of numerous cell types across tissues and timepoints, particularly oligodendrocytes, astrocytes, and microglia, which are crucial for injury repair. T4 also reversed the expression of mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, and Myo3a, as well as numerous pathways such as cell/energy/iron metabolism, immune response, nervous system, and cytoskeleton-related pathways. Cell-type specific network modeling revealed that T4 mitigated select mTBI-perturbed dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in oligodendrocytes. Cross cell-type ligand-receptor networks revealed the roles of App, Hmgb1, Fn1, and Tnf in mTBI, with the latter two ligands having been previously identified as TBI network hubs. mTBI and/or T4 signature genes were enriched for human genome-wide association study (GWAS) candidate genes for cognitive, psychiatric and neurodegenerative disorders related to mTBI. Our systems-level single cell analysis elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications as the mechanisms through which T4 mitigates cognitive dysfunction induced by mTBI.

Biochemical Study of Hypothyroidism Subjects and Relationship to Overweight

This article evaluates the relationship between thyroid hormone levels, including TSH, fT4, T4, T3, and lipid profiles, such as total cholesterol, LDL, and HDL, in obese individuals compared to healthy ones. The research included 80 individuals, of which 40 were categorized as obese (20 males and 20 females) and 40 were healthy controls (also 20 males and 20 females). All participants were between the ages of 25 and 45. To perform thyroid gland tests, blood samples of 10 ml were taken from both healthy and subjects participants without EDTA and put into test tubes. The plain tube containing blood was centrifuged to separate the serum for further thyroid function and chemical tests. The ELISA device was used following the manufacturer's instructions. The study found significant differences in the levels of TSH hormone between subjects and healthy participants based on the collected data. Furthermore, subjects had significantly lower levels of fT4 hormone in subjects (4.4±2.0) compared to healthy controls (8.1±2.1). The research findings indicated a significant reduction in T4 hormone levels (4.3±1.3) in subjects, which was consistent in both males and females and corresponded with the increase in TSH hormone levels (9.17±2.0) observed in subjects individuals compared to healthy subjects (2.98±2.1).However, there were no significant alterations in T3 hormone levels among subjects when compared to healthy individuals. Hence, the study concludes that there is a definitive correlation between hypothyroidism and obesity.

Thyroid status in patients with early stages of cancer of various localization

Purpose of the study. To determine the thyroid status of primary cancer patients in the early stages of uterine body cancer, kidney cancer, breast cancer, skin melanoma and lung cancer without a history of endocrine pathology.Patients and methods. The content levels of thyroid-stimulating hormone (TSH), thyroid hormones (THs) T4 and T3 of total and free forms were determined in the blood serum by RIA method in 132 patients with breast cancer, uterine body cancer, lung cancer, kidney cancer and skin melanoma (average age 55 years). The comparison group consisted of practically healthy donors.Results. Only in skin melanoma, serum TSH levels were reduced by 1.5 times (p < 0.05). The T4 content was reduced by 1.4–1.7 times (p < 0.05) in uterine body cancer and kidney cancer, increased in lung cancer patients and 16 % of breast cancer patients by 1.4–1.7 times though (p < 0.05). A 1.3–1.5‑fold low (p < 0.05) T3 level was found in breast cancer, kidney cancer, and skin melanoma, while an 1.6‑fold increase (p < 0.05) was found in uterine body cancer. The revealed changes in THs by the type of clinical hyperthyroidism are an increase of 1.8 times (p < 0.05) FT3 on the background of low TSH in the blood in patients with skin melanoma, and by the type of hyperthyroxinemia in patients with lung cancer and breast cancer, consisting in increased concentrations of T4 and FT3, and with free and total T3 levels in patients uterine body cancer, as well as FT4, without changes in TSH in the blood serum of patients, may be associated with the features of malignant pathology, since it is known that THs are proliferation stimulants and can build up in tumors.Conclusion. The development of a malignant tumor even in the early stages of the disease is perceived by the body as a threat for homeostasis and the response to the occurrence of neoplasm is the reaction of the hypothalamicpituitary-thyroid regulatory axis. As an outcome, patients develop euthyroid disorder syndrome.

Impact of Metformin on Blood Levels of Thyroid Function Tests, and Some Biochemical Parameters Levels in Polycystic Ovarian Women

Polycystic ovary syndrome (PCOS) is the most common form of chronic female disease associated with androgen excess; perhaps occurring in 5-10% of the reproductive age group in women. PCOS is viewed as a heterogeneous disorder of multifactorial etiology. It is also associated with increased metabolic and cardiovascular risk factors. Objectives: The purpose of this study is to evaluate the serum level of hormones TSH, T3 and T4 in women with PCOS and to investigate the effect of metformin on hormones TSH, T3, and T4 levels in subjects with PCOS. Patients and methods: The present study was conducted at Kirkuk General Hospital and Azadi General Hospital from March 2023 to January 2024.One hundred forty-one women with PCOS were selected as the PCOS group, while 120 healthy women matched for age with the PCOS patients were selected as the control group. The body mass index is determined before and after therapy. They take metformin 850 mg twice daily for three months and provide fasting blood samples on the second day of menstruation before and after treatment. The data collection done through a designed closed and open-ended questionnaire, by using direct interviewing, and Ultrasound examination, Data were analyzed using SPSS for Windows 7. Results: Treatment resulted in a significant decrease in in body mass index at p-values 0.05. This study reveals that the thyroid hormones TSH, T3 and T4 were highly significantly increased (P < 0.001) in the serum of PCOS patients compared to the control group. Serum levels of TSH in women with PCOS were high significantly elevated compared to healthy control group. However, the study found no significant difference (p > 0.05) in TSH level in treated group with metformin compared with pre-treatment. Conclusion: Metformin can induce changes of TSH levels in patients with polycystic ovary syndrome.

Impact of the thyroid hormone T3 and its nuclear receptor TRα1 on colon cancer stem cell phenotypes and response to chemotherapies

Colorectal cancers (CRCs) are highly heterogeneous and show a hierarchical organization, with cancer stem cells (CSCs) responsible for tumor development, maintenance, and drug resistance. Our previous studies showed the importance of thyroid hormone-dependent signaling on intestinal tumor development and progression through action on stem cells. These results have a translational value, given that the thyroid hormone nuclear receptor TRα1 is upregulated in human CRCs, including in the molecular subtypes associated with CSC features. We used an established spheroid model generated from the human colon adenocarcinoma cell line Caco2 to study the effects of T3 and TRα1 on spheroid formation, growth, and response to conventional chemotherapies. Our results show that T3 treatment and/or increased TRα1 expression in spheroids impaired the response to FOLFIRI and conferred a survival advantage. This was achieved by stimulating drug detoxification pathways and increasing ALDH1A1-expressing cells, including CSCs, within spheroids. These results suggest that clinical evaluation of the thyroid axis and assessing TRα1 levels in CRCs could help to select optimal therapeutic regimens for patients with CRC.Proposed mechanism of action of T3/TRα1 in colon cancer spheroids. In the control condition, TRα1 participates in maintaining homeostatic cell conditions. The presence of T3 in the culture medium activates TRα1 action on target genes, including the drug efflux pumps ABCG2 and ABCB1. In the case of chemotherapy FOLFIRI, the increased expression of ABC transcripts and proteins induced by T3 treatment is responsible for the augmented efflux of 5-FU and Irinotecan from the cancer cells. Taken together, these mechanisms contribute to the decreased efficacy of the chemotherapy and allow cells to escape the treatment. Created with BioRender.com.

Low TSH and low T3 hormone levels as a prognostic for mortality in COVID-19 intensive care patients.

Coronavirus diasease 2019 (COVID-19) can cause both pulmonary and systemic inflammation, potentially determining multi-organ dysfunction. The thyroid gland is a neuroendocrine organ that plays an important role in regulating immunity and metabolism. Low serum levels of thyroid hormones are common in critical disease situations. The association between low thyroid hormone levels and mortality in COVID-19 intensive care patients has yet to be studied. The aim of this study is to compare thyroid hormone levels between patients in the general intensive care unit (ICU) to patients in the COVID-19 ICU. This was a retrospective comparative study of 210 patients who were hospitalized at Ziv Medical Center in the general ICU and in the COVID-19 ICU. Clinical and demographic data were collected from patient's electronic medical records. Serum thyroid hormone levels of Thyroid Simulating Hormone (TSH), T4, and T3 were significantly lower in COVID-19 intensive care unit patients compared to the patients from the general intensive care unit (p < 0.05). The mortality rate in the COVID-19 ICU (44.4%) was higher compared to that in the general ICU (27.3%) (p < 0.05). No significant statistical difference was observed between the two groups in terms of gender and recorded comorbidities of diabetes mellitus, cerebral vascular accident, kidney disease, and cancer. Low serum thyroid hormone levels-T3, T4, and TSH-in COVID-19 ICU patients are associated with higher mortality and could possibly be used as a prognostic factor for mortality among COVID-19 ICU patients. Thyroid hormone levels should be a part in the routine evaluation of COVID-19 ICU patients.

Disruption of Thyroid Hormone Receptor Thrab Leads to Female Infertility in Zebrafish.

Thyroid hormones (THs) T4 and T3 are vital for development, growth, and metabolism. Thyroid dysfunction can also cause problems in fertility, suggesting involvement of THs in reproduction. In zebrafish, there exist 2 forms of TH receptor alpha gene (thraa and thrab). Disruption of these genes by CRISPR/Cas9 showed no reproductive irregularities in the thraa mutant; however, inactivation of the thrab gene resulted in female infertility. Although young female mutants (thrabm/m) showed normal ovarian development and folliculogenesis before sexual maturation, they failed to release eggs during oviposition after sexual maturation. This spawning failure was due to oviductal blockage at the genital papilla. The obstruction of the oviduct subsequently caused an accumulation of the eggs in the ovary, resulting in severe ovarian hypertrophy, abdominal distention, and disruption of folliculogenesis. Gene expression analysis showed expression of both TH receptors and estrogen receptors in the genital papilla, suggesting a direct TH action and potential interactions between thyroid and estrogen signaling pathways in controlling genital papilla development and function. In addition to their actions in the reproductive tracts, THs may also have direct effects in the ovary, as suggested by follicle atresia and cessation of folliculogenesis in the heterozygous mutant (thrab+/m), which was normal in all aspects of female reproduction in young and sexually mature fish but exhibited premature ovarian failure in aged females. In summary, this study provides substantial evidence for roles of THs in controlling the development and functions of both reproductive tract and ovary.

Association between thyroid disorders and extra-thyroidal cancers, a review.

Thyroid hormone has been shown to have both tumor-promoting and tumor-suppressing actions, which has led to significant debate over its involvement in the development of cancer. Proliferation, apoptosis, invasiveness, and angiogenesis are all aspects of cancer that are affected by the thyroid hormones T3 and T4, according to research conducted in animal models and in vitro experiments. The effects of thyroid hormones on cancer cells are mediated by many non-genomic mechanisms, one of which involves the activation of the plasma membrane receptor integrin αvβ3. Typically, abnormal amounts of thyroid hormones are linked to a higher occurrence of cancer. Both benign and malignant thyroid disorders were found to be associated with an increased risk of extra-thyroidal malignancies, specifically colon, breast, prostate, melanoma, and lung cancers. The purpose of this review was to shed light on this link to define which types of cancer are sensitive to thyroid hormones and, as a result, are anticipated to respond favorably to treatment of the thyroid hormone axis.

A case of nephrocalcinosis in a 7‐month‐old with congenital hypothyroidism: Insights from targeted exome sequencing

AbstractNephrocalcinosis is a complex disease with a multitude of triggering factors. An association with congenital hypothyroidism has been described in the literature, but the mechanisms leading to its development remain unclear. A 7‐month‐old infant presented with muscular hypotonia and signs of malnutrition was diagnosed with congenital hypothyroidism, nephrocalcinosis of unclear origin, and multiple kidney stones. Urine analysis revealed the presence of calcium oxalate crystals and slightly elevated oxaluria without hypercalciuria. Targeted exome sequencing found no variants in the four causative genes of primary oxaluria, namely AGXT, CBX5, GRHPR, and HOGA1. The clinical outcome was favorable with thyroid hormone and potassium citrate treatment. Ultrasound follow‐up showed progressive improvement of nephrocalcinosis. The low level of urinary oxalate and the prevalence of dihydrate calcium oxalate crystals spoke against primary or secondary oxaluria. Recent evidence from mitochondrial research shows that thyroid hormone T3 enhances mitochondrial calcium levels by stimulating calcium uptake by the mitochondrial calcium uniporter. A reduced calcium uptake and metabolism in mitochondria might represent an explanation for cytoplasmic calcium accumulation in tubular cells, subsequently precipitating nephrocalcinosis in the absence of thyroid hormone. Even if the pathophysiological mechanisms are not yet fully understood, recent evidence is supportive of a causal relationship between hypothyroidism and nephrocalcinosis, a sometimes overlooked association.

A Retrospective Study to Evaluate the Quality Assurance of Thyroid Profile In A Tertiary Care Clinical Biochemistry Laboratory

Background: The Six Sigma methodology has become a standard in quality assessment and management, widely adopted in various industries since the mid-1980s. This methodology is applicable wherever the outcome of a process needs measurement. One area where Sigma metrics find utility is in laboratory services, particularly in evaluating the quality assurance of biochemical parameters. Aims: This study aimed to measure and analyze the sigma metrics of thyroid hormones T3, T4, and TSH within the framework of NABL accreditation (National Accreditation Board for Testing and Calibration Laboratories). Materials &amp; Methods: The study was designed as a retrospective observational study, utilizing quality control data from the Clinical Biochemistry section spanning from January 2021 to December 2021 retrieved from laboratory records. The data considered included Bio-Rad Lyphochek Immunoassay Internal Quality Control (IQC) Control and Bio-Rad External Quality Assurance Scheme (EQAS) Immunoassay monthly program data. Calculations for Coefficient of variation (CV %), Bias %, and Total Error allowable (TEa) were made to derive the sigma metric. The formula used for sigma calculation was Sigma Σ(σ) = (TEa% - Bias%) / CV%, while the Quality Goal Index (QGI) ratio was determined using the formula QGI = Bias / 1.5CV. Results: The results categorized the assay performance based on sigma levels: &gt;6 denoted world-class performance, 5-6 indicated excellence, 4-5 represented good performance, 3-4 was deemed acceptable, and 2-3 signified poor performance. All analytes demonstrated sigma levels below 6 (2.61-5.85) varying from poor to excellent and the QGI was below 0.8, indicating a need to enhance the precision of assays. Conclusion: The Six Sigma metric analysis serves as a benchmark tool that can aid laboratories in enhancing assay performance, formulating protocols for Internal Quality Control (IQC), and evaluating existing laboratory procedures. Keywords Six sigma, Quality Goal Index, Internal Quality Control

Exploring the mechanism of interaction between TBG and halogenated thiophenols: Insights from fluorescence analysis and molecular simulation

Thyroxine-binding globulin (TBG) plays a vital role in regulating metabolism, growth, organ differentiation, and energy homeostasis, exerting significant effects in various key metabolic pathways. Halogenated thiophenols (HTPs) exhibit high toxicity and harmfulness to organisms, and numerous studies have demonstrated their thyroid-disrupting effects. To understand the mechanism of action of HTPs on TBG, a combination of competitive binding experiments, multiple fluorescence spectroscopy techniques, molecular docking, and molecular simulations was employed to investigate the binding mechanism and identify the binding site. The competition binding assay between HTPs and ANS confirmed the competition of HTPs with thyroid hormone T4 for the active site of TBG, resulting in changes in the TBG microenvironment upon the binding of HTPs to the active site. Key amino acid residues involved in the binding process of HTPs and TBG were further investigated through residue energy decomposition. The distribution of high-energy contributing residues was determined. Analysis of root-mean-square deviation (RMSD) demonstrated the stability of the HTPs-TBG complex. These findings confirm the toxic mechanism of HTPs in thyroid disruption, providing a fundamental reference for accurately assessing the ecological risk of pollutants and human health. Providing mechanistic insights into how HTPS causes thyroid diseases.

The role of selenium and zinc oxide nanoparticles on mitigating side effects of obesity in rats.

Twenty four adult male rats were divided into four groups, group1 control rats fed normal diet and the other three groups were fed high fat diet (HFD) for 10 weeks to induce obesity and injected intraperitoneally with saline, SeNPs (30μg/kg b.wt) and ZnONPs (5mg/kg b.wt) respectively on the last two weeks of feeding (9th and 10th). HFD increased body weight, oxidative stress as indicated by elevated lipid peroxidation and decreased glutathione and catalase levels, increased significantly serum lipid fractions, leptin, liver enzymes, creatinine and uric acid. While causing a substantial decrease in HDL-C and thyroid hormone T4 levels. The results confirmed that treatment with SeNPs and ZnONPs significantly reduced body weight, MDA and improved liver and kidney functions, ameliorated serum lipid fractions level and significantly increased glutathione, catalase, HDL-C and thyroid hormone. SeNPs and ZnONPs significantly mitigate hyperlipidemia and oxidative stress. So, they might be potential candidate for obesity amelioration.