Study of iodine transport and thyroid hormone levels in the human placenta under different iodine nutritional status.

Iodine and thyroid hormones (TH) transport in the placenta are essential for fetal growth and development, but there is little research focus on the human placenta. The research aimed to investigate iodine and TH transport mechanisms in the human placenta. The placenta was collected from sixty healthy pregnant women. Urinary iodine concentration (UIC), serum iodine concentration (SIC), placenta iodine storage (PIS) and the concentration of serum and placenta TH were examined. Five pregnant women were selected as insufficient intake (II), adequate intake (AI) and above requirements intake (ARI) groups. Localisation/expression of placental sodium/iodide symporter (NIS) and Pendrin were also studied. Results showed that PIS positively correlated with the UIC (R = 0·58, P < 0·001) and SIC (R = 0·55, P < 0·001), and PIS was higher in the ARI group than that in the AI group (P = 0·017). NIS in the ARI group was higher than that in the AI group on the maternal side of the placenta (P < 0·05). NIS in the II group was higher than that in the AI group on the fetal side (P < 0·05). In the II group, NIS on the fetal side was higher than on the maternal side (P < 0·05). Pendrin was higher in the II group than in the AI group on the maternal side (P < 0·05). Free triiodothyronine (r = 0·44, P = 0·0067) and thyroid-stimulating hormone (r = 0·75, P < 0·001) between maternal and fetal side is positively correlated. This study suggests that maternal iodine intake changes the expression of NIS and Pendrin, thereby affecting PIS. Serum TH levels were not correlated with placental TH levels.

Mechanism of multi-organ compensation under different iodine intake in pregnant rats: results from a repeated-measures study of iodine metabolism.

PURPOSE: This study aimed to explore the differences in iodine metabolism and expression of NIS and Pendrin in pregnant rats under different iodine nutritional status. METHODS: Female Wistar rats were divided into four groups: low iodine (LI), normal iodine (NI), ten fold high iodine (10HI), and fifty fold high iodine (50HI). The intervention began after one week of adaptive feeding. Iodine metabolism experiments were performed beginning on the 15th day of pregnancy. 24-h iodine intake and excretion were calculated. The concentrations of iodine in urine, fecal, thyroid, and placenta were measured by ICP-MS. PCR and Western Blot were used to detect the mRNA levels and cell membrane protein of sodium/iodide symporter (NIS) and Pendrin in the small intestine, thyroid, kidney, and placenta. RESULTS: Fecal iodine excretion (FIE) and urinary iodine excretion (UIE) in the 50HI group were significantly higher than those in the NI group (P < 0.05). The NIS protein and mRNA in the kidney and small intestine have an upward trend in iodine deficiency and a downward trend in iodine excess. Thyroid and placental iodine storage in the 50HI group were significantly higher than those in the NI group (P < 0.05). NIS, Pendrin protein, and mRNA in the thyroid and placenta tend to increase when iodine is deficient and decrease when there is excess. CONCLUSION: Iodine excretion and iodine stores in the placenta and thyroid gland are positively correlated with iodine intake. NIS and Pendrin are also regulated by iodine intake.

Morphological and functional changes in rat thyroid gland after a year following chronic exposure to low and intermediate doses of γ-radiation.

INTRODUCTION: Thyroid function depends on iodine uptake by the body as well as on exposure to various harmful environmental hazards (stress, ionizing radiation). AIM: The aim of the work was to assess the effect of exposure to low and intermediate doses of external γ-radiation on the thyroid structure and function in young female rats at remote periods after radiation. MATERIALS AND METHODS: Forty female rats were used to study remote effects of external γ-radiation exposure during 20 d (at daily doses of 0.1, 0.25 and 0.5 Gy) on the functional activity (levels of thyroid hormones, iodine metabolism) and the morphological structure of the rat thyroid) after 12 months following the radiation exposure. RESULTS: An increase in thyroid mass and a decrease in total thyroid protein concentration along with a reduction of blood T3 and T4 was shown only in rat groups exposed to 0.25 and 0.5 Gy. Both the concentration of total iodine and its protein-bound fraction (1.2-1.4 fold, p < .01) and the protein-bound to total iodine ratio were decreased in the thyroids of all irradiated animals. The 0.1-Gy group showed elevated thyroperoxidase (TPO) activity along with increased catalase activity, which may indicate the activation of iodine oxidation by thyrocytes. Only the 0.5-Gy group demonstrated reduced urinary excretion of iodine (2.1 fold, p < .01).The reduction of thyroid function at radiation doses of 0.25 and 0.5 Gy was characterized by a microfollicular structure and the development of atrophic changes in the parenchyma, desquamation of thyroid epithelium and an increase in epithelium proliferation. The diameter of the thyrocyte nuclei was increased in rats exposed to 0.25 and 0.5 Gy, which indicates functional tension of thyrocytes. CONCLUSION: Our research shows that after a year, the exposure to external γ-radiation of 0.1, 0.25 and 0.5-Gy caused changes in the structure and function of the rat thyroid which are manifested by the development of hypothyroiditis (0.5 Gy), 'subclinical' hypothyroiditis (0.25 Gy) and functional tension of thyrocytes. The mechanisms of thyroid dysfunction - impaired- uptake of iodine and its organification against the background of activation of free radical processes - suggest disturbances in the function of the sodium/iodide symporter (NIS), TPO and thyroglobulin synthesis. In contrast to the intermediate doses, the effects of the 0.1-Gy dose were mostly found at the remote periods compared to the earlier periods (180 days).

Fluorescein staining of chloroplast starch granules in living plants.

Chloroplast starch granules (cpSGs) store energy harvested through photosynthesis in plants, and cpSG dynamics have important roles in plant energy metabolism and stress responses. To date, cpSGs have been visualized using several methods, such as iodine staining; however, no method can be used to specifically visualize cpSGs in living cells from various plant species. Here, we report a simple method to visualize cpSGs in living plant cells in various species by staining with fluorescein, a commonly used fluorescent dye. We show that fluorescein is taken up into chloroplasts and interacts with cpSGs similarly to iodine. Fluorescein also interacts with refined starch in vitro. Using a fluorescein derivative for ultrabright cpSG imaging, we produced high-quality 3D reconstructions of cpSGs and evaluated their accumulation in multiple plant species. As fluorescein is well known and readily purchasable, our fluorescein-based staining method should contribute to all research regarding starch.

Curly Kale (Brassica oleracea var. Sabellica L.) Biofortified with 5,7-Diiodo-8-quinolinol: The Influence of Heat Treatment on Iodine Level, Macronutrient Composition and Antioxidant Content.

Many disorders are a result of an inadequate supply of macronutrients and micronutrients in the diet. One such element is iodine. This study used curly kale (Brassica oleracea var. Sabellica L.) biofortified with the 5,7-diiodo-8-quinolinol iodine compound. The effect of the heat treatment on the chemical composition of the curly kale was studied. In addition, iodine bioavailability was evaluated in in vivo studies. Our investigation showed that iodine loss depends on the type of heat treatment as well as on the variety of kale. Curly kale biofortified with iodoquinoline had significantly higher iodine levels after thermal processing (steaming, blanching, boiling) than the vegetable biofortified with KIO3. Generally, steaming was the best thermal processing method, as it contributed to the lowest iodine loss in curly kale. The red variety of kale, 'Redbor F1', showed a better iodine stability during the heat treatment than the green variety, 'Oldenbor F1'. The thermal treatment also significantly affected the dry matter content and the basic chemical composition of the tested varieties of the 5,7-diI-8-Q biofortified kale. The steaming process caused a significant increase in total carbohydrates, fiber, protein and crude fat content ('Oldenbor F1', 'Redbor F1'), and antioxidant activity ('Oldenbor F1'). On the other hand, boiling caused a significant decrease, while steaming caused a significant increase, in protein and dry matter content ('Oldenbor F1', 'Redbor F1'). The blanching process caused the smallest significant decrease in ash compared to the other thermal processes used ('Oldenbor F1'). A feeding experiment using Wistar rats showed that iodine from the 5,7-diI-8-Q biofortified kale has a higher bioavailability than that from the AIN-93G diet. A number of promising results have been obtained, which could form the basis for further research.

Long non-coding RNA EGOT is associated with 131iodine sensitivity and contributes to thyroid cancer progression by targeting miR-641/PTEN axis.

Thyroid cancer is a prevalent endocrine malignancy around the world. Radioactive 131iodine (131I) therapy is widely applied in TC patients, but the resistance affects its effectiveness in the clinics. Long non-coding RNA (lncRNA) EGOT has been reported to induce an inhibitory effect on cancer progression, but the specific function of EGOT in 131I resistance of TC cells remains unclear. Here, we successfully established 131I-resistant TC cells and evaluated the impact of EGOT on 131I resistance in the cells. Our data showed that EGOT and PTEN expression was reduced but the miR-641 expression was enhanced in 131I-resistant TC cells. EGOT inhibited viability, induced apoptosis and enhanced DNA damage in 131I-resistant TC cells. Mechanically, we identified that EGOT induced PTEN expression by targeting miR-641 in 131I-resistant TC cells. Moreover, the depletion of PTEN and miR-641 mimic reversed EGOT-relieved 131I resistance of TC cells in vitro. Thus, we conclude that lncRNA EGOT attenuated 131I resistance of TC cells by targeting miR-641/PTEN axis. The clinical functions of EGOT in TC therapy deserve to be validated in future exploration.

Alleviative Effect of Iodine Pretreatment on the Stress of Saccharina japonica (Phaeophyceae, Laminariales) Caused by Cadmium and Its Molecular Basis Revealed by Comparative Transcriptomic Analysis.

Iodide is accumulated by the brown alga Saccharina japonica at a high concentration and has been proven to be an inorganic antioxidant that plays an important role in oxidative metabolism. Vanadium-dependent bromoperoxidases (vBPOs) and iodoperoxidases (vIPOs), which catalyze the oxidation of iodide, are essential for iodine accumulation and metabolism. Heavy metal pollutant cadmium (Cd) from anthropogenic activities can cause damage to algae mainly by producing oxidative stress. Here, the effects of iodine pretreatment on the stress of S. japonica caused by cadmium were analyzed. The growth experiment showed that iodine pretreatment could reduce the damage of low concentration cadmium on S. japonica young thalli. At the transcriptomic level, gene ontology (GO) enrichment analysis confirmed that cadmium stress could cause a peroxidation reaction in S. japonica. However, the most significant GO term was "photosystem I" in the series with iodine pretreatment. Weighted gene co-expression network analysis (WGCNA) indicated that iodine pretreatment alleviated cadmium stress responses of S. japonica by affecting the photosynthesis process. Analysis of the differentially expressed genes (DEGs) showed that five enzymes from the vBPO family and 13 enzymes from the vIPO family might play crucial roles in this process.

Comparing tryptophan:lysine ratios in dried distillers grains with solubles-based diets with and without a dried distillers grains with solubles withdrawal strategy on growth, carcass characteristics, and carcass fat iodine value of growing-finishing pigs.

A total of 6,240 finishing pigs (DNA 600 × PIC 1050; initially 22.5 ±â€…1.00 kg), divided into two groups, were used in a 119 or 120 d study comparing increasing Trp:Lys ratio in diets containing dried distillers grains with solubles (DDGS) or a DDGS withdrawal strategy (removing all DDGS from the last phase before marketing) on growth performance and carcass fat iodine value (IV). Pigs were randomly allotted to one of seven dietary treatments with 30 to 36 pigs per pen and 26 replications per treatment. Diets were fed in four phases, approximately 23 to 44, 44 to 71, 71 to 100, and 100 kg to market. Diets included a control corn-soybean meal-based diet (no DDGS) formulated to a 19% standardized ileal digestibility (SID) Trp:Lys ratio, four diets with 30% DDGS fed in all four phases and formulated to provide SID Trp:Lys ratios of 16%, 19%, 22%, or 25%, and two DDGS withdrawal strategy diets: 19% SID Trp:Lys with 30% DDGS in phases 1 through 3 and then 0% DDGS in phase 4 with either a 19% or 25% Trp:Lys ratio. Overall, body weight (BW), average daily gain (ADG), average daily feed intake (ADFI), and gain:feed ratio (G:F) increased (linear, P < 0.05) as SID Trp:Lys ratio increased in diets with 30% DDGS fed in all phases. Simultaneously, hot carcass weight (quadratic, P = 0.014), carcass yield (quadratic, P = 0.012), and backfat depth (linear, P = 0.040) increased with increasing Trp:Lys ratio. Pigs fed the 19% SID Trp:Lys ratio withdrawal strategy diet had similar ADG and ADFI as those fed the control diet, the 25% Trp:Lys withdrawal diet, or the 30% DDGS diets with 25% Trp:Lys ratio throughout the study. Pigs fed the control diet had decreased (P < 0.05) carcass fat IV compared to pigs fed the DDGS diets throughout the study, with pigs fed the two DDGS withdrawal strategy diets intermediate. In summary, increasing the SID Trp:Lys ratio in diets with 30% DDGS resulted in a linear increase in ADG, ADFI, G:F, and BW but did not influence carcass fat IV, with most of the benefits observed as diets increased from 16% to 19% Trp:Lys. Removing DDGS from the diet in the last period reduced carcass fat IV and increased growth rate during the withdrawal period compared to pigs fed with 30% DDGS throughout, indicating value in a withdrawal strategy.

Feeding high levels of dried distillers grains with solubles (DDGS) up to marketing has been found to have negative impacts on growth performance and carcass characteristics of finishing pigs, specifically carcass yield. High inclusion of DDGS has also been shown to increase iodine value (IV), a measurement of fat quality, due to increased deposition of unsaturated fatty acids. However, recent data suggested that when feeding finishing pigs diets containing DDGS, increasing the standardized ileal digestible Trp:Lys ratio well above the NRC requirement estimates can prevent or lessen some of these negative effects. This study compared removing DDGS from the final dietary phase with two levels of Trp:Lys ratio, commonly referred to as a withdrawal strategy, to increasing levels of Trp:Lys in diets containing 30% DDGS. The results of this study indicate that increasing the Trp:Lys ratio in diets containing DDGS to a 25% Trp:Lys ratio resulted in growth performance similar to the control diet and the withdrawal strategy, with most of the benefits observed when Trp:Lys is increased from a deficient to adequate status. However, feeding diets with DDGS up to market resulted in increased IV.

Iodine-Biofortified Lettuce Can Promote Mitochondrial Dependent Pathway of Apoptosis in Human Gastrointestinal Cancer Cells.

Previously, our research provided evidence that exposure of gastric and colon cancer cells to extracts from iodine-biofortified lettuce leads to a reduction of cell viability and proliferation through cell cycle arrest and upregulation of pro-apoptotic genes. The aim of the present study was to determine the potential cellular mechanisms of induction of cell death in human gastrointestinal cancer cell lines after treatment with iodine-biofortified lettuce. We demonstrated that extracts from lettuce enriched with iodine induce apoptosis in gastric AGS and colon HT-29 cancer cells and the mechanism of programmed cell death may be triggered and executed through different signaling pathways, depending on the type of cells. Western blot analysis revealed that iodine-fortified lettuce leads to cell death through the release of cytochrome c to the cytosolic fraction and activation of the primary drivers of apoptosis: caspase-3, caspase-7, and caspase-9. Furthermore, we have reported that apoptotic effects of lettuce extracts may be mediated by poly (ADP-ribose) polymerase (PARP) and activation of pro-apoptotic Bcl-2 family proteins such as Bad, Bax, and BID. We also observed mitochondrial dysfunction with the dissipation of the mitochondrial membrane potential in cells exposed to lettuce extracts. Taken together, these results indicate that the organic form of iodine such as 5-ISA and 3,5-diISA is an important factor in the activation of intrinsic mitochondrial apoptotic pathway in AGS and HT-29 cancer cells in a p53-independent manner.

Iodine avidity in papillary and poorly differentiated thyroid cancer is predicted by immunohistochemical and molecular work-up.

Background: Successful radioiodine treatment of differentiated thyroid cancer requires iodine avidity: that is, the concentration and retention of iodine in cancer tissue. Several parameters have previously been linked with lower iodine avidity. However, a comprehensive analysis of which factors best predict iodine avidity status, and the magnitude of their impact, is lacking. Methods: Quantitative measurements of iodine avidity in surgical specimens (primary tumour and lymph node metastases) of 28 patients were compared to immunohistochemical expression of the thyroid-stimulating hormone receptor, thyroid peroxidase (TPO), pendrin, sodium-iodide symporter (NIS) and mutational status of BRAF and the TERT promoter. Regression analysis was used to identify independent predictors of poor iodine avidity. Results: Mutations in BRAF and the TERT promoter were significantly associated with lower iodine avidity for lymph node metastases (18-fold and 10-fold, respectively). Membranous NIS localisation was found only in two cases but was significantly associated with high iodine avidity. TPO expression was significantly correlated with iodine avidity (r = 0.44). The multivariable modelling showed that tumour tissue localisation (primary tumour or lymph node metastasis), histological subtype, TPO and NIS expression and TERT promoter mutation were each independent predictors of iodine avidity that could explain 68% of the observed variation of iodine avidity. Conclusions: A model based on histological subtype, TPO and NIS expression and TERT promoter mutation, all evaluated on initial surgical material, can predict iodine avidity in thyroid cancer tissue ahead of treatment. This could inform early adaptation with respect to expected treatment effect.

An Iodine Balance Study in Chinese School-age Children.

CONTEXT: Few iodine balance studies have been conducted in school-age children. OBJECTIVE: This study aimed to conduct an iodine balance study in school-age children. METHODS: We measured daily iodine intake, excretion, and retention for 3 consecutive days without any dietary interventions in school-age children. Linear mixed-effects models were used to fit the relationship between total iodine intake and iodine retention. RESULTS: 29 children aged 7-12 years (mean age 10.2 ± 1.4 years) with normal thyroid function and thyroid volume were recruited. The 0 balance value (iodine intake = iodine excretion, iodine retention = 0 µg/day) shifted with iodine intake in an iodine sufficient population. The 0 balance value for school-age children with an iodine intake of 235 (133, 401) µg/day is 164 µg/day. Children aged 7-12 years with iodine intake >400 µg/day were almost all in a positive iodine state. CONCLUSION: An iodine intake of 235 (133, 401) µg/day for children aged 7-10 years achieved a 0 balance value of 164 µg/day. Long-term iodine intake of >400 µg/day is not recommended.

Effects of different iodine levels on the DNA methylation of intrinsic apoptosis-associated genes and analysis of gene-environment interactions in patients with autoimmune thyroiditis.

Iodine is an essential nutrient that may change the occurrence of autoimmune thyroiditis (AIT). Apoptosis and DNA methylation participate in the pathogenesis and destructive mechanism of AIT. We detected the methylation and the expression of mRNA of intrinsic apoptosis-associated genes (YWHAG, ING4, BRSK2 and GJA1) to identify the potential interactions between the levels of methylation in these genes and different levels of iodine. 176 adult patients with AIT in Shandong Province, China, were included. The MethylTargetTM assay was used to verify the levels of methylation. We used PCR to detect the mRNA levels of the candidate genes. Interactions between methylation levels of the candidate genes and iodine levels were evaluated with multiplicative and addictive interaction models and GMDR. In the AIT group, YWHAG_1 and six CpG sites and BRSK2_1 and eight CpG sites were hypermethylated, whereas ING4_1 and one CpG site were hypomethylated. A negative correlation was found between methylation levels of YWHAG and mRNA expression. The combination of iodine fortification, YWHAG_1 hypermethylation and BRSK2_1 hypermethylation was significantly associated with elevated AIT risk. A four-locus model (YWHAG_1 × ING4_1 × BRSK2_1 × iodine level) was found to be the best model of the gene-environment interactions. We identified abnormal changes in the methylation status of YWHAG, ING4 and BRSK2 in patients with AIT in different iodine levels. Iodine fortification not only affected the methylation levels of YWHAG and BRSK2 but also interacted with the methylation levels of these genes and may ultimately increase the risk of AIT.

One-Minute Iodine Isotope Labeling Technology Enables Noninvasive Tracking and Quantification of Extracellular Vesicles in Tumor Lesions and Intact Animals.

Real-time monitoring of the biological behavior of extracellular vesicles (EVs) in vivo is limited, which hinders its application in biomedicine and clinical translation. A noninvasive imaging strategy could provide us with useful information on EVs' distribution, accumulation and homing in vivo, and pharmacokinetics. In this study, the long half-life radionuclide iodine-124 (124I) was used to directly label umbilical cord mesenchymal stem cell-derived EVs. The resulting probe, namely, 124I-MSC-EVs, was manufactured and ready to use within 1 min. 124I-labeled MSC-EVs had high radiochemical purity (RCP, >99.4%) and stable in 5% human serum album (HSA) with RCP > 95% for 96 h. We demonstrated efficient intracellular internalization of 124I-MSC-EVs in two prostate cancer cell lines (22RV1 and DU145 cell). The uptake rates of 124I-MSC-EVs in human prostate cancer cell lines 22RV1 and DU145 cells were 10.35 ± 0.78 and 2.56 ± 0.21 (AD%) at 4 h. The promising cellular data has prompted us to investigate the biodistribution and in vivo tracking capability of this isotope-based labeling technique in tumor bearing animals. Using positron emission tomography (PET) technology, we showed that the signal from intravenously injected 124I-MSC-EVs mainly accumulated in the heart, liver, spleen, lung, and kidney in healthy kun ming (KM) mice, and the biodistribution study was similar to the imaging results. In the 22RV1 xenograft model, 124I-MSC-EVs accumulated significantly in the tumor after administration, and with the optimal image acquired at 48 h postinjection, the maximum of standard uptake value (SUVmax) of the tumor was 3-fold higher than that of DU145. Taken together, the probe has a high application prospect in immuno-PET imaging of EVs. Our technique provides a powerful and convenient tool for understanding the biological behavior and pharmacokinetic characteristics of EVs in vivo and facilitates the acquirement of comprehensive and objective data for future clinical studies of EVs.

Drinking water disinfection byproduct iodoacetic acid affects thyroid hormone synthesis in Nthy-ori 3-1 cells.

Iodoacetic acid (IAA) is an emerging and the most genotoxic iodinated disinfection byproduct to date. IAA can disrupt the thyroid endocrine function in vivo and in vitro, but the underlying mechanisms remain unclear. In this work, transcriptome sequencing was used to investigate the effect of IAA on the cellular pathways of human thyroid follicular epithelial cell line Nthy-ori 3-1 and determine the mechanism of IAA on the synthesis and secretion of thyroid hormone (TH) in Nthy-ori 3-1 cells. Results of transcriptome sequencing indicated that IAA affected the TH synthesis pathway in Nthy-ori 3-1 cells. IAA reduced the mRNA expression of thyroid stimulating hormone receptor, sodium iodide symporter, thyroid peroxidase, thyroglobulin, paired box 8 and thyroid transcription factor-2, inhibited the cAMP/PKA pathway and Na+-K+-ATPase, and decreased the iodine intake. The results were confirmed by our previous findings in vivo. Additionally, IAA downregulated glutathione and the mRNA expression of glutathione peroxidase 1, leading to increased reactive oxygen species production. This study is the first to elucidate the mechanisms of IAA on TH synthesis in vitro. The mechanisms are associated with down-regulating the expression of genes related to TH synthesis, inhibiting iodine uptake, and inducing oxidative stress. These findings may improve future health risk assessment of IAA on thyroid in human.

Iodotyrosines Are Biomarkers for Preclinical Stages of Iodine-Deficient Hypothyroidism in Dehal1-Knockout Mice.

Background: Iodine is required for the synthesis of thyroid hormone (TH), but its natural availability is limited. Dehalogenase1 (Dehal1) recycles iodine from mono- and diiodotyrosines (MIT, DIT) to sustain TH synthesis when iodine supplies are scarce, but its role in the dynamics of storage and conservation of iodine is unknown. Methods: Dehal1-knockout (Dehal1KO) mice were generated by gene trapping. The timing of expression and distribution was investigated by X-Gal staining and immunofluorescence using recombinant Dehal1-beta-galactosidase protein produced in fetuses and adult mice. Adult Dehal1KO and wild-type (Wt) animals were fed normal and iodine-deficient diets for 1 month, and plasma, urine, and tissues were isolated for analyses. TH status was monitored, including thyroxine, triiodothyronine, MIT, DIT, and urinary iodine concentration (UIC) using a novel liquid chromatography with tandem mass spectrometry method and the Sandell-Kolthoff (S-K) technique throughout the experimental period. Results: Dehal1 is highly expressed in the thyroid and is also present in the kidneys, liver, and, unexpectedly, the choroid plexus. In vivo transcription of Dehal1 was induced by iodine deficiency only in the thyroid tissue. Under normal iodine intake, Dehal1KO mice were euthyroid, but they showed negative iodine balance due to a continuous loss of iodotyrosines in the urine. Counterintuitively, the UIC of Dehal1KO mice is twofold higher than that of Wt mice, indicating that S-K measures both inorganic and organic iodine. Under iodine restriction, Dehal1KO mice rapidly develop profound hypothyroidism, while Wt mice remain euthyroid, suggesting reduced retention of iodine in the thyroids of Dehal1KO mice. Urinary and plasma iodotyrosines were continually elevated throughout the life cycles of Dehal1KO mice, including the neonatal period, when pups were still euthyroid. Conclusions: Plasma and urine iodotyrosine elevation occurs in Dehal1-deficient mice throughout life. Therefore, measurement of iodotyrosines predicts an eventual iodine shortage and development of hypothyroidism in the preclinical phase. The prompt establishment of hypothyroidism upon the start of iodine restriction suggests that Dehal1KO mice have low iodine reserves in their thyroid glands, pointing to defective capacity for iodine storage.

Selenium, Iodine and Iron-Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism.

The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H2O2-dependent biosynthesis and the deiodinase-mediated (in-)activation of thyroid hormones, which is critical for their receptor-mediated mechanism of cellular action. Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus-pituitary-thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H2O2 as cofactor. The latter is generated by the dual oxidase system organized as 'thyroxisome' at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H2O2 and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures.

Molecular and Cellular Characterization of the TH Pathway in the Sea Urchin Strongylocentrotus purpuratus.

Thyroid Hormones (THs) are a class of signaling molecules produced by coupling iodine with tyrosine residues. In vertebrates, extensive data support their important role in a variety of processes such as metabolism, development and metamorphosis. On the other hand, in invertebrates, the synthesis and role of the THs have been, so far, poorly investigated, thus limiting our understanding of the function and evolution of this important animal signaling pathway. In sea urchins, for example, while several studies focused on the availability and function of external sources of iodotyrosines, preliminary evidence suggests that an endogenous TH pathway might be in place. Here, integrating available literature with an in silico analysis, various homologous genes of the vertebrate TH molecular toolkit have been identified in the sea urchin Strongylocentrotus purpuratus. They include genes involved in the synthesis (Sp-Pxdn), metabolism (Sp-Dios), transport (Sp-Ttrl, Sp-Mct7/8/10) and response (Sp-Thr, Sp-Rxr and Sp-Integrin αP) to thyroid hormones. To understand the cell type(s) involved in TH synthesis and/or response, we studied the spatial expression of the TH toolkit during urchin development. Exploiting single-cell transcriptomics data in conjunction with in situ hybridization and immunohistochemistry, we identified cell types that are potentially producing or responding to THs in the sea urchin. Finally, growing sea urchin embryos until the larva stage with and without a source of inorganic iodine, we provided evidence that iodine organification is important for larval skeleton growth.

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression.

Background: The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results: The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.

Bis-iodine-labeled Curcumin as a Potential CT Imaging Agent for ß-amyloid Plaques in the Brain.

BACKGROUND: Alzheimer's disease (AD) is one of the most common causes of dementia, affecting many old people. OBJECTIVES: By designing and synthesizing intracerebral imaging probes, we tried to provide a new solution for the early diagnosis of AD. METHODS: We designed and synthesized bis-iodine-labeled curcumin, and verified its performance through in vivo and in vitro experiments. RESULTS: In this study, bis-iodine-labeled curcumin (7, BICUR) was synthesized. In the in vitro mass spectrum binding assay, Kd values of BICUR with Aß1-40 and Aß1-42 aggregates were 46.29 nM and 64.29 nM, respectively. Aß plaques in AD brain adjacent sections were positively stained by BICUR, which was similar to some other curcumin derivatives. The Log P value of BICUR was 1.45. In the biodistribution experiment, BICUR showed the highest initial brain uptake (5.87% compared to the blood concentration) two minutes after the tail vein injection and rapid clearance from the mouse brain. In the acute toxicity experiment, BICUR showed low toxicity, and the LD50 was >100 mg/kg. Moreover, BICUR showed a high stability in vitro (86.68% unchanged BICUR after incubation for 120min in mouse brain homogenate). Besides, BICUR produced an enhanced CT imaging effect that could be sensitively detected in vitro, but it also showed an obvious differentiation from surrounding tissues after intracerebral injection. CONCLUSION: All results suggested that BICUR could probably act as a targeted CT imaging agent for Aß plaques in the brain.

Thyroid Hormone Metabolism: A Historical Perspective.

In this article, starting with the recognition that iodine is essential for normal thyroid function and is a component of thyroid hormone (TH) molecules, we discuss the many seminal observations and discoveries that have led to identification of various pathways of TH metabolism and their potential roles in TH economy and action. We then recount evidence that TH metabolism participates in maintaining the appropriate content of active hormone in a TH-responsive tissue or cell. Thus, metabolism of the TH is not merely a means by which it is degraded and eliminated from the body, but an essential component of an intricate system by which the thyroid exerts its multiple regulatory effects on almost all organs and tissues. The article ends with a summary of the current concepts and some outstanding questions that are awaiting answers.