NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells.

BACKGROUND: NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer. METHODS: The validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990-1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3). RESULTS: NKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H2O2 generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter. CONCLUSIONS: In summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis.

Regulation of thyroid sodium-iodide symporter in different stages of goiter: Possible involvement of reactive oxygen species.

Na+ /I- symporter (NIS) transports iodide into thyrocytes, a fundamental step for thyroid hormone biosynthesis. Our aim was to evaluate NIS regulation in different status of goitrogenesis and its underlying mechanisms. Wistar rats were treated with methimazole (MMI) for 5 and 21 days, to achieve different status of goiter. We then evaluated the effect of MMI removal for 1 day (R1d), after 5 (R1d-5d) or 21 (R1d-21d) days of MMI treatment. MMI increased thyroid weight, iodide uptake and in vitro TPO activity in a time-dependent way. Although MMI removal evoked a rapid normalization of TPO activity in R1d-5d, it was still high in R1d-21d. On the other hand, iodide uptake was rapidly down-regulated in R1d-21d, but not in R1d-5d, suggesting that the increased TPO activity in R1d-21d led to increased intraglandular organified iodine (I-X), which is known to inhibit iodide uptake. Since TGFß has been shown to mediate some effects of I-X, we evaluated TGFß and TGFß receptor mRNA levels, which were increased in R1d-21d. Moreover, it has been demonstrated that TGFß stimulates NOX4. Accordingly, our data revealed increased NOX4 expression and H2 O2 generation in R1d-21d. Finally, we evaluated the effect of H2 O2 on NIS function and mRNA levels in PCCL3 thyroid cell line, which were reduced. Thus, the present study suggests that there is a relationship between the size of the goiter and NIS regulation and that the mechanism might involve I-X, TGFß, NOX4 and increased ROS production.

Flavonoids, Thyroid Iodide Uptake and Thyroid Cancer-A Review.

Thyroid cancer is the most common malignant tumor of the endocrine system and the incidence has been increasing in recent years. In a great part of the differentiated carcinomas, thyrocytes are capable of uptaking iodide. In these cases, the main therapeutic approach includes thyroidectomy followed by ablative therapy with radioiodine. However, in part of the patients, the capacity to concentrate iodide is lost due to down-regulation of the sodium-iodide symporter (NIS), the protein responsible for transporting iodide into the thyrocytes. Thus, therapy with radioiodide becomes ineffective, limiting therapeutic options and reducing the life expectancy of the patient. Excessive ingestion of some flavonoids has been associated with thyroid dysfunction and goiter. Nevertheless, studies have shown that some flavonoids can be beneficial for thyroid cancer, by reducing cell proliferation and increasing cell death, besides increasing NIS mRNA levels and iodide uptake. Recent data show that the flavonoids apingenin and rutin are capable of increasing NIS function and expression in vivo. Herein we review literature data regarding the effect of flavonoids on thyroid cancer, besides the effect of these compounds on the expression and function of the sodium-iodide symporter. We will also discuss the possibility of using flavonoids as adjuvants for therapy of thyroid cancer.

Type 2 iodothyronine deiodinase is upregulated in rat slow- and fast-twitch skeletal muscle during cold exposure.

During cold acclimation, shivering is progressively replaced by nonshivering thermogenesis. Brown adipose tissue (BAT) and skeletal muscle are relevant for nonshivering thermogenesis, which depends largely on thyroid hormone. Since the skeletal muscle fibers progressively adapt to cold exposure through poorly defined mechanisms, our intent was to determine whether skeletal muscle type 2 deiodinase (D2) induction could be implicated in the long-term skeletal muscle cold acclimation. We demonstrate that in the red oxidative soleus muscle, D2 activity increased 2.3-fold after 3 days at 4°C together with the brown adipose tissue D2 activity, which increased 10-fold. Soleus muscle and BAT D2 activities returned to the control levels after 10 days of cold exposure, when an increase of 2.8-fold in D2 activity was detected in white glycolytic gastrocnemius but not in red oxidative gastrocnemius fibers. Propranolol did not prevent muscle D2 induction, but it impaired the decrease of D2 in BAT and soleus after 10 days at 4°C. Cold exposure is accompanied by increased oxygen consumption, UCP3, and PGC-1α genes expression in skeletal muscles, which were partialy prevented by propranolol in soleus and gastrocnemius. Serum total and free T3 is increased during cold exposure in rats, even after 10 days, when BAT D2 is already normalized, suggesting that skeletal muscle D2 activity contributes significantly to circulating T3 under this adaptive condition. In conclusion, cold exposure is accompanied by concerted changes in the metabolism of BAT and oxidative and glycolytic skeletal muscles that are paralleled by type 2 deiodinase activation.

Quercetin improves white adipose tissue redox homeostasis in ovariectomized rats.

Estrogen deficiency is a well-known hallmark of menopause and is associated with oxidative stress and metabolic dysfunction. Quercetin (Q), a flavonoid found in fruits and vegetables, has demonstrated anti-inflammatory effects in experimental models of metabolic disorders. In this study, we aimed to investigate the effects of quercetin on retroperitoneal white adipose tissue (rWAT) redox homeostasis and systemic metabolic parameters in ovariectomized (OVX) rats. Female Wistar rats at 3 months old were divided into the following experimental groups: sham-operated treated with vehicle (DMSO 10% + PBS - 1 mL/kg); OVX (vehicle treated) and OVX-Q (25 mg/kg) - via oral gavage, daily for 5 weeks. Q did not prevent weight gain but improved glucose tolerance and blood cholesterol profile, and attenuated uterine atrophy in OVX rats. Furthermore, Q had a protective effect on rWAT, once the OVX-Q group presented lower oxidative stress levels, and reduced levels of the pro-inflammatory cytokine tumor necrosis factor alpha, compared to the OVX group. Q improved antioxidant enzyme activities such as superoxide dismutase and catalase and decreased reactive oxygen species production, in OVX-Q rats. It was followed by increased levels of total thiol content and lower lipid peroxidation. Moreover, Q reduced senescent-related genes p16INK4a and p19ARF expression which were higher in the OVX group. In conclusion, quercetin supplementation improved redox homeostasis and reduced senescence-related markers, and inflammation in rWAT, which was reflected in preserved systemic metabolic health parameters in OVX rats. These findings suggest that quercetin may have therapeutic potential for the management of metabolic disorders associated with menopause-induced estrogen deficiency.

The Effect of Acute Aerobic Exercise on Redox Homeostasis and Mitochondrial Function of Rat White Adipose Tissue.

Physical exercise is characterized by an increase in physical and metabolic demand in face of physical stress. It is reported that a single exercise session induces physiological responses through redox signaling to increase cellular function and energy support in diverse organs. However, little is known about the effect of a single bout of exercise on the redox homeostasis and cytoprotective gene expression of white adipose tissue (WAT). Thus, we aimed at evaluating the effects of acute aerobic exercise on WAT redox homeostasis, mitochondrial metabolism, and cytoprotective genic response. Male Wistar rats were submitted to a single moderate-high running session (treadmill) and were divided into five groups: control (CTRL, without exercise), and euthanized immediately (0 h), 30 min, 1 hour, or 2 hours after the end of the exercise session. NADPH oxidase activity was higher in 0 h and 30 min groups when compared to CTRL group. Extramitochondrial ROS production was higher in 0 h group in comparison to CTRL and 2 h groups. Mitochondrial respiration in phosphorylative state increased in 0 h group when compared to CTRL, 30 min, 1, and 2 h groups. On the other hand, mitochondrial ATP production was lower in 0 h in comparison to 30 min group, increasing in 1 and 2 h groups when compared to CTRL and 0 h groups. CAT activity was lower in all exercised groups when compared to CTRL. Regarding oxidative stress biomarkers, we observed a decrease in reduced thiol content in 0 h group compared to CTRL and 2 h groups, and higher levels of protein carbonylation in 0 and 30 min groups in comparison to the other groups. The levels returned to basal condition in 2 h group. Furthermore, aerobic exercise increased NRF2, GPX2, HMOX1, SOD1, and CAT mRNA levels. Taken together, our results suggest that one session of aerobic exercise can induce a transient prooxidative state in WAT, followed by an increase in antioxidant and cytoprotective gene expression.

Bisphenol A increases hydrogen peroxide generation by thyrocytes both in vivo and in vitro.

Bisphenol A (BPA) is the most common monomer in polycarbonate plastics and an endocrine disruptor. Though some effects of BPA on thyroid hormone (TH) synthesis and action have been described, the impact of this compound on thyroid H2O2 generation remains elusive. H2O2 is a reactive oxygen species (ROS) which could have deleterious effect on thyrocytes if in excess. Therefore, herein we aimed at evaluating the effect of BPA exposition both in vivo and in vitro on H2O2 generation in thyrocytes, besides other essential steps for TH synthesis. Female Wistar rats were treated with vehicle (control) or BPA 40 mg/Kg BW for 15 days, by gavage. We then evaluated thyroid iodide uptake, mediated by sodium-iodide symporter (NIS), thyroperoxidase (TPO) and dual oxidase (DOUX) activities (H2O2 generation). Hydrogen peroxide generation was increased, while iodide uptake and TPO activity were reduced by BPA exposition. We have also incubated the rat thyroid cell line PCCL3 with 10-9 M BPA and evaluated Nis and Duox mRNA levels, besides H2O2 generation. Similar to that found in vivo, BPA treatment also led to increased H2O2 generation in PCCL3. Nis mRNA levels were reduced and Duox2 mRNA levels were increased in BPA-exposed cells. To evaluate the importance of oxidative stress on BPA-induced Nis reduction, PCCL3 was treated with BPA in association to n-acetylcysteine, an antioxidant, which reversed the effect of BPA on Nis. Our data suggest that BPA increases ROS production in thyrocytes, what could lead to oxidative damage thus possibly predisposing to thyroid disease.

The importance of sodium/iodide symporter (NIS) for thyroid cancer management.

The thyroid gland has the ability to uptake and concentrate iodide, which is a fundamental step in thyroid hormone biosynthesis. Radioiodine has been used as a diagnostic and therapeutic tool for several years. However, the studies related to the mechanisms of iodide transport were only possible after the cloning of the gene that encodes the sodium/iodide symporter (NIS). The studies about the regulation of NIS expression and the possibility of gene therapy with the aim of transferring NIS gene to cells that normally do not express the symporter have also become possible. In the majority of hypofunctioning thyroid nodules, both benign and malignant, NIS gene expression is maintained, but NIS protein is retained in the intracellular compartment. The expression of NIS in non-thyroid tumoral cells in vivo has been possible through the transfer of NIS gene under the control of tissue-specific promoters. Apart from its therapeutic use, NIS has also been used for the localization of metastases by scintigraphy or PET-scan with 124I. In conclusion, NIS gene cloning led to an important development in the field of thyroid pathophysiology, and has also been fundamental to extend the use of radioiodine for the management of non-thyroid tumors.

Effect of thimerosal on thyroid hormones metabolism in rats.

Mercury seems to exert an inhibitory effect on deiodinases, but there are few studies using Thimerosal (TM) as the mercury source. We aimed to elucidate the effect of TM on thyroid hormones peripheral metabolism. Adult Wistar female rats received 0.25 µg or 250 µg TM/100 g BW, IM, twice a week, for a month. We evaluated serum total T3 and T4, D1 activity using 125I-rT3 as tracer, and D2 activity using 125I-T4 NADPH oxidase activity was measured by Amplex-red/HRP method and mRNA levels by real time PCR. Serum T4 was increased and T3 decreased by the greatest dose of TM. Even though D1 activity in pituitary and kidney was reduced by the highest dose of TM, hepatic D1 activity and D1 mRNA levels remained unchanged. D2 activity was also significantly decreased by the highest dose of TM in all CNS samples tested, except cerebellum, but D2 mRNA was unaltered. mRNA levels of the tested NADPH oxidases were not affected by TM and NADPH oxidase activity was either unaltered or decreased. Our results indicate that TM might directly interact with deiodinases, inhibiting their activity probably by binding to their selenium catalytic site, without changes in enzyme expression.

Estrogen effects on thyroid iodide uptake and thyroperoxidase activity in normal and ovariectomized rats.

Sex steroids interfere with the pituitary-thyroid axis function, although the reports have been controversial and no conclusive data is available. Some previous reports indicate that estradiol might also regulate thyroid function through a direct action on the thyrocytes. In this report, we examined the effects of low and high doses of estradiol administered to control and ovariectomized adult female rats and to pre-pubertal females. We demonstrate that estradiol administration to both intact adult and pre-pubertal females causes a significant increase in the relative thyroid weight. Serum T3 is significantly decreased in ovariectomized rats, and is normalized by estrogen replacement. Neither doses of estrogen produced a significant change in serum TSH and total T4 in ovariectomized, adult intact and pre-pubertal rats. The highest, supraphysiological, estradiol dose produced a significant increase in thyroid iodide uptake in ovariectomized and in pre-pubertal rats, but not in control adult females. Thyroperoxidase activity was significantly higher in intact adult rats treated with both estradiol doses and in ovariectomized rats treated with the highest estradiol dose. Since serum TSH levels were not significantly changed, we suggest a direct action of estradiol on the thyroid gland, which depends on the age and on the previous gonad status of the animal.

Redox homeostasis of breast cancer lineages contributes to differential cell death response to exogenous hydrogen peroxide.

AIMS: Cancer cells produce higher amounts of reactive oxygen species (ROS) than their normal counterparts. It has been suggested that a further increase in ROS concentration in these cells would lead to oxidative damage-driven death. Thus, we aimed to understand how the intra- and extracellular redox homeostasis differences set cell death response to ROS in breast cancer cell lines. MAIN METHODS: Intra- and extracellular ROS generation was evaluated in tumoral (MCF-7 and MDA-MB-231) and non-tumoral (MCF10A) breast epithelial cells, as well as H2O2 concentration in the culture medium, glutathione peroxidase (GPx), total superoxide dismutase (SOD) and catalase activities, extracellular H2O2 scavenging capacity and total thiol content. Cell viability was determined after H2O2 exposure using the MTT assay. KEY FINDINGS: We have found an increased extracellular ROS production in tumor cells when compared to the non-tumoral lineage. MCF10A cells had higher H2O2 concentration in the extracellular medium. Moreover, extracellular H2O2-scavenging activity was higher in MDA-MB-231 when compared to MCF10A and MCF-7. Regarding intracellular antioxidant activity, a lower GPx activity in tumor cell lines and a higher catalase activity in MDA-MB-231 were observed. Thiol content was lower in MDA-MB-231. Additionally, tumor cell lines were more sensitive to H2O2 exposure than the non-tumoral cells. SIGNIFICANCE: The present report shows that the capability to generate and metabolize ROS differ greatly among the breast cancer cell lines, thus suggesting that redox balance is finely regulated during carcinogenesis. Therefore, our data suggest that therapeutic approaches targeting the redox status might be useful in the treatment of breast tumors.

Rapid regulation of thyroid sodium-iodide symporter activity by thyrotrophin and iodine.

Transport of iodide into thyrocytes, a fundamental step in thyroid hormone biosynthesis, depends on the presence of the sodium-iodide symporter (NIS). The importance of the NIS for diagnosis and treatment of diseases has raised several questions about its physiological control. The goal of this study was to evaluate the influence of thyroid iodine content on NIS regulation by thyrotrophin (TSH) in vivo. We showed that 15-min thyroid radioiodine uptake can be a reliable measurement of NIS activity in vivo. The effect of TSH on the NIS was evaluated in rats treated with 1-methyl-2-mercaptoimidazole (MMI; hypothyroid with high serum TSH concentrations) for 21 days, and after 1 (R1d), 2 (R2d), or 5 (R5d) days of withdrawal of MMI. NIS activity was significantly greater in both MMI and R1d rats. In R2d and R5d groups, thyroid iodide uptake returned to normal values, despite continuing high serum TSH, possibly as a result of the re-establishment of iodine organification after withdrawal of MMI. Excess iodine (0.05% NaI for 6 days) promoted a significant reduction in thyroid radioiodide uptake, an effect that was blocked by concomitant administration of MMI, confirming previous findings that iodine organification is essential for the iodide transport blockade seen during iodine overload. Therefore, our data show that modulation of the thyroid NIS by TSH depends primarily on thyroid iodine content and, further, that the regulation of NIS activity is rapid.

Sexual dimorphism and thyroid dysfunction: a matter of oxidative stress?

Thyroid diseases, such as autoimmune disease and benign and malignant nodules, are more prevalent in women than in men, but the mechanisms involved in this sex difference is still poorly defined. H2O2 is produced at high levels in the thyroid gland and regulates parameters such as cell proliferation, migration, survival, and death; an imbalance in the cellular oxidant-antioxidant system in the thyroid may contribute to the greater incidence of thyroid disease among women. Recently, we demonstrated the existence of a sexual dimorphism in the thyrocyte redox balance, characterized by higher H2O2 production, due to higher NOX4 and Poldip2 expression, and weakened enzymatic antioxidant defense in the thyroid of adult female rats compared with male rats. In addition, 17ß-estradiol administration increased NOX4 mRNA expression and H2O2 production in thyroid PCCL3 cells. In this review, we discuss the possible involvement of oxidative stress in estrogen-related thyroid pathophysiology. Our current hypothesis suggests that a redox imbalance elicited by estrogen could be involved in the sex differences found in the prevalence of thyroid dysfunctions.

Bone marrow mesenchymal stromal cells rescue cardiac function in streptozotocin-induced diabetic rats.

OBJECTIVES: In the present study, we investigated whether MSC-transplantation can revert cardiac dysfunction in streptozotocin-induced diabetic rats and the immunoregulatory effects of MSC were examined. BACKGROUND: Cardiac complications are one of the main causes of death in diabetes. Several studies have shown anti-diabetic effects of bone marrow mesenchymal stromal cells (MSC). METHODS/RESULTS: The rats were divided in three groups: Non-diabetic, Diabetic and Diabetic-Treated with 5 × 10(6) MSC 4 weeks after establishment of diabetes. Four weeks after MSC-therapy, systemic metabolic parameters, immunological profile and cardiac function were assessed. MSC-transplantation was able to revert the hyperglycemia and body weight loss of the animals. In addition, after MSC-transplantation a decrease in corticosterone and IFN-γ sera levels without restoration of insulin and leptin plasma levels was observed. Also, MSC-therapy improved electrical remodeling, shortening QT and QTc in the ECG and action potential duration of left ventricular myocytes. No arrhythmic events were observed after MSC-transplantation. MSC-therapy rescued the cardiac beta-adrenergic sensitivity by increasing beta-1 adrenergic receptor expression. Both alpha and beta cardiac AMPK and p-AMPK returned to baseline values after MSC-therapy. However, total ERK1 and p-ERK1/2 were not different among groups. CONCLUSION: The results indicate that MSC-therapy was able to rescue cardiac impairment induced by diabetes, normalize cardiac AMPK subunit expression and activity, decrease corticosterone and glycemia and exert systemic immunoregulation.

Diabetes mellitus increases reactive oxygen species production in the thyroid of male rats.

Diabetes mellitus (DM) disrupts the pituitary-thyroid axis and leads to a higher prevalence of thyroid disease. However, the role of reactive oxygen species in DM thyroid disease pathogenesis is unknown. Dual oxidases (DUOX) is responsible for H(2)O(2) production, which is a cosubstrate for thyroperoxidase, but the accumulation of H(2)O(2) also causes cellular deleterious effects. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is another member of the nicotinamide adenine dinucleotide phosphate oxidase family expressed in the thyroid. Therefore, we aimed to evaluate the thyroid DUOX activity and expression in DM rats in addition to NOX4 expression. In the thyroids of the DM rats, we found increased H(2)O(2) generation due to higher DUOX protein content and DUOX1, DUOX2, and NOX4 mRNA expressions. In rat thyroid PCCL3 cells, both TSH and insulin decreased DUOX activity and DUOX1 mRNA levels, an effect partially reversed by protein kinase A inhibition. Most antioxidant enzymes remained unchanged or decreased in the thyroid of DM rats, whereas only glutathione peroxidase 3 was increased. DUOX1 and NOX4 expression and H(2)O(2) production were significantly higher in cells cultivated with high glucose, which was reversed by protein kinase C inhibition. We conclude that thyroid reactive oxygen species is elevated in experimental rat DM, which is a consequence of low-serum TSH and insulin but is also related to hyperglycemia per se.

Retinoic acid effects on thyroid function of female rats.

AIMS: Retinoic acid is widely used in dermatological treatment and thyroid cancer management; however its possible side-effects on normal thyroid function remains unknown. We aimed to determine the effects of retinoic acid on thyroid function of adult female rats. MAIN METHODS: Female Wistar rats were treated with all-trans-retinoic acid and 13-cis retinoic acid for 14 and 28 days. Then, rats were killed and thyroid function was evaluated. KEY FINDINGS: Serum T4 and thyrotropin levels remained unchanged, while serum T3 increased in animals treated with all-trans-retinoic acid for 14 days. No changes were observed in hepatic or renal type 1 iodothyronine deiodinase (D1) activities, while thyroid D1 was higher in animals treated for 14 days with all-trans-retinoic acid, which could be related to the increased serum T3 levels. 13-cis retinoic acid increased thyroid iodide uptake after 28 days. These results show effects of retinoic acid treatment on these thyroid proteins: sodium/iodide symporter and deiodinase. SIGNIFICANCE: Retinoic acid is able to interfere with normal thyroid function, increasing thyroid type 1 deiodinase activity, serum T3 levels and sodium/iodide symporter function. However, the effects are time- and retinoic acid isomer-dependent. Since serum thyrotropin levels did not change in any group, the effects observed are probably mediated by a direct retinoic acid effect on the normal thyroid.

Negative correlation between thyroperoxidase and dual oxidase H2O2-generating activities in thyroid nodular lesions.

Iodine incorporation into thyroglobulin is dependent on the activities of both thyroperoxidase (TPO) and thyroid dual oxidase 2 (DuOx2). Although TPO expression is decreased in some thyroid nodular lesions, DuOx1 and 2 mRNA expressions are maintained, but DuOx H2O2-generating activity has never been evaluated in such tumors. Our goal was to determine DuOx activity in hypofunctioning lesions of the thyroid. We evaluated H2O2 generation by DuOx in 12 paranodular to cold nodule samples, 17 non-toxic multinodular goiters (MNG; 33 samples), 3 papillary carcinomas (PC; 4 samples), 3 follicular carcinomas (FC; 4 samples), and 10 follicular adenomas. DuOx activity was detected in all paranodular tissues (121+/-23 nmol H2O2/h per mg protein), but was undetectable (<1 nmol H2O2 generated) in all PC, two out of four FC samples and seven out of ten adenomas. In 11 MNG at least two different areas of the goiter have been evaluated, and in 5 of these goiters one of the samples had DuOx activity below the limit of detection. The coefficient of variation in MNG samples ranged from 11.3 to 57.2%. Interestingly, in all the adenomas studied, TPO activity (486+/-142 U/g protein, n=8) was well within the range found in paranodular tissues (414+/-116 U/g protein, n=3). We found a significant negative correlation between DuOx and TPO activities, suggesting that these enzymes are regulated in opposite directions, at least in thyroid tumors.

Inhibition of thyroid peroxidase by Myrcia uniflora flavonoids.

Thyroid peroxidase (TPO), the key enzyme in thyroid hormone biosynthesis, is inhibited by dietary flavonoids; thus, a high consumption of plants containing inhibitory flavonoids may affect thyroid function and lead to hypothyroidism. In this work, TPO inhibition by the aqueous partition of Myrcia uniflora and its isolated compounds has been evaluated. The aqueous partition of the methanolic extract of M. uniflora is able to inhibit TPO activity in vitro. Two known flavonoids were isolated and characterized by mass spectrometry and (1)H NMR from plant extracts: mearnsitrin and myricitrin. The degree of TPO inhibition produced by the aqueous solution of the flavonoids was very high, with a 50% inhibition of the original TPO activity (IC(50)) obtained at 1.97 microM mearnsitrin and at 2.88 microM myricitrin. These results suggest that the indiscriminated consumption of M. uniflora pharmaceutical products allied to the nutritional deficiency of iodine might contribute to the development of hypothyroidism and goiter.

The importance of sodium/iodide symporter (NIS) for thyroid cancer management

The thyroid gland has the ability to uptake and concentrate iodide, which is a fundamental step in thyroid hormone biosynthesis. Radioiodine has been used as a diagnostic and therapeutic tool for several years. However, the studies related to the mechanisms of iodide transport were only possible after the cloning of the gene that encodes the sodium/iodide symporter (NIS). The studies about the regulation of NIS expression and the possibility of gene therapy with the aim of transferring NIS gene to cells that normally do not express the symporter have also become possible. In the majority of hypofunctioning thyroid nodules, both benign and malignant, NIS gene expression is maintained, but NIS protein is retained in the intracellular compartment. The expression of NIS in non-thyroid tumoral cells in vivo has been possible through the transfer of NIS gene under the control of tissue-specific promoters. Apart from its therapeutic use, NIS has also been used for the localization of metastases by scintigraphy or PET-scan with 124I. In conclusion, NIS gene cloning led to an important development in the field of thyroid pathophysiology, and has also been fundamental to extend the use of radioiodine for the management of non-thyroid tumors.

A glândula tireóide tem capacidade de captar e concentrar iodeto, etapa fundamental na biossíntese dos hormônios tireóideos. O uso de iodo radioativo para fins de diagnóstico e terapia das doenças da tireóide vem sendo feito há muitos anos. Entretanto, somente após a clonagem do gene que codifica o co-transportador de sódio/iodeto (NIS) houve aumento significativo dos estudos relacionados ao mecanismo de transporte de iodeto. Os estudos sobre a regulação da expressão do NIS e a possibilidade de terapia gênica visando à transferência do gene NIS para células que normalmente não expressam esse transportador, foram também viabilizados. Na maior parte dos nódulos tireóideos hipofuncionantes, tanto benignos quanto malignos, a expressão do gene do NIS está presente, mas a proteína NIS fica retida no compartimento intracelular. A transferência do gene usando-se promotores tecido-específicos possibilitou a expressão do NIS em células tumorais não-tireóideas in vivo. Além do seu uso terapêutico, o NIS também vem sendo usado para a localização de metástases tumorais através da cintilografia ou do PET-scan usando-se 124I. Em conclusão, a clonagem do NIS possibilitou enorme avanço na área de fisiopatologia tireóidea e foi também fundamental para estender o uso do radioiodo para tumores não tireóideos.