Andrea Claudia Freitas Ferreira

Limnological features in Tapacurá reservoir (northeast Brazil) during a severe drought

The drastic interactions of weather as El Niño events with catchment and hydrological processes can cause unexpected changes in physical, chemical and biological properties of freshwater aquatic ecosystems. The severe drought during 1998–1999 in the northeastern region of Brazil induced ecological changes in numerous reservoirs as in Tapacurá reservoir, one of the biggest drinking-water suppliers in Pernambuco state. Investigations were based on monthly sampling over 2 years (May 1998–May 2000) conducted at 3 representative stations with 3 sampled depths through the water column (0.5 m, middle and 0.5 m above the bottom). Temporal changes in ecological processes, especially stratification, were driven by two major precipitation patterns, with an initial marked dry period (period 1) followed by a rainy season (period 2). Dissolved oxygen and pH variations, higher conductivity and alkalinity values, higher concentrations of particulate organic material (carbon, nitrogen and phosphorus) and higher levels of algal biomass (chlorophyll a) characterized the dry period (May 1998–May 1999). During this phase of low water level when the reservoir storage capacity reached a minimum of 3.9%, the concentrations of chlorophyll a gradually increased with a cyanobacterial bloom (Cylindrospermopsis raciborskii) noted in April 1999. The decline in chlorophyll a and particulate organic matter were observed as a result of the first rains in May–June 1999, with the drastic changes of quality of matter (higher particulate C/N ratio). After a phase characterized by the entire water column turning anoxic, a second phase in the stratification process could be identified from June 1999 with the pronounced rainfalls accompanied by an overturn event. Annual rainfall deficit and lack of reservoir water renewal in 1998–1999 linked to the 1997 El Niño consequences were important determinants of high eutrophication levels and drastic ecological modifications in Tapacurá reservoir.

Inhibition of thyroid type 1 deiodinase activity by flavonoids

Some dietary flavonoids inhibit thyroperoxidase and hepatic deiodinase activity, indicating that these compounds could be classified as anti-thyroid agents. In this study, we evaluated the in vitro effect of various flavonoids on thyroid type 1 iodothyronine deiodinase activity (D1). D1 activity was measured in murine thyroid microsome fractions by the release of 125I from 125I-reverse T3. D1 activity was significantly inhibited by all the flavonoids tested; however, the inhibitory potencies on thyroid D1 activity differed greatly among them. A 50% inhibition of D1 activity (IC(50)) was obtained at 11 microM baicalein, 13 microM quercetin, 17 microM catechin, 55 microM morin, 68 microM rutin, 70 microM fisetin, 72 microM kaempferol and 77 microM biochanin A. Our data reinforce the concept that dietary flavonoids might behave as antithyroid agents, and possibly their chronic consumption could alter thyroid function.

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.

MTOR downregulates iodide uptake in thyrocytes.

Phosphoinositide-3-kinase (PI3K) inhibition increases functional sodium iodide symporter (NIS) expression in both FRTL-5 rat thyroid cell line and papillary thyroid cancer lineages. In several cell types, the stimulation of PI3K results in downstream activation of the mechanistic target of rapamycin (MTOR), a serine-threonine protein kinase that is a critical regulator of cellular metabolism, growth, and proliferation. MTOR activation is involved in the regulation of thyrocyte proliferation by TSH. Here, we show that MTOR inhibition by rapamycin increases iodide uptake in TSH-stimulated PCCL3 thyroid cell line, although the effect of rapamycin was less pronounced than PI3K inhibition. Thus, NIS inhibitory pathways stimulated by PI3K might also involve the activation of proteins other than MTOR. Insulin downregulates iodide uptake and NIS protein expression even in the presence of TSH, and both effects are counterbalanced by MTOR inhibition. NIS protein expression levels were correlated with iodide uptake ability, except in cells treated with TSH in the absence of insulin, in which rapamycin significantly increased iodide uptake, while NIS protein levels remained unchanged. Rapamycin avoids the activation of both p70 S6 and AKT kinases by TSH, suggesting the involvement of MTORC1 and MTORC2 in TSH effect. A synthetic analog of rapamycin (everolimus), which is clinically used as an anticancer agent, was able to increase rat thyroid iodide uptake in vivo. In conclusion, we show that MTOR kinase participates in the control of thyroid iodide uptake, demonstrating that MTOR not only regulates cell survival, but also normal thyroid cell function both in vitro and in vivo.

Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid-sensitive tissues

In general, 3,5-diiodothyronine (3,5-T2) increases the resting metabolic rate and oxygen consumption, exerting short-term beneficial metabolic effects on rats subjected to a high-fat diet. Our aim was to evaluate the effects of chronic 3,5-T2 administration on the hypothalamus–pituitary–thyroid axis, body mass gain, adipose tissue mass, and body oxygen consumption in Wistar rats from 3 to 6 months of age. The rats were treated daily with 3,5-T2 (25, 50, or 75 μg/100 g body weight, s.c.) for 90 days between the ages of 3 and 6 months. The administration of 3,5-T2 suppressed thyroid function, reducing not only thyroid iodide uptake but also thyroperoxidase, NADPH oxidase 4 (NOX4), and thyroid type 1 iodothyronine deiodinase (D1 (DIO1)) activities and expression levels, whereas the expression of the TSH receptor and dual oxidase (DUOX) were increased. Serum TSH, 3,3′,5-triiodothyronine, and thyroxine were reduced in a 3,5-T2 dose-dependent manner, whereas oxygen consumption increased in these animals, indicating the direct action of 3,5-T2 on this physiological variable. Type 2 deiodinase activity increased in both the hypothalamus and the pituitary, and D1 activities in the liver and kidney were also increased in groups treated with 3,5-T2. Moreover, after 3 months of 3,5-T2 administration, body mass and retroperitoneal fat pad mass were significantly reduced, whereas the heart rate and mass were unchanged. Thus, 3,5-T2 acts as a direct stimulator of energy expenditure and reduces body mass gain; however, TSH suppression may develop secondary to 3,5-T2 administration.

Impact of flavonoids on thyroid function.

Flavonoids are polyphenolic compounds of natural occurrence produced by plants that are largely consumed both for therapeutic purposes and as food. Experimental data have shown that many flavonoids could inhibit thyroperoxidase activity, decreasing thyroid hormones levels thus increasing TSH and causing goiter. In humans, infants fed with soy formula have been shown to develop goiter. However, in post-menopausal women soy intake did not affect thyroid function. In thyroid tumor cell line, flavonoids were shown to inhibit cell growth, but they can also decrease radioiodine uptake, that could reduce the efficacy of radioiodine therapy. Flavonoids could also affect the availability of thyroid hormones to target tissues, by inhibiting deiodinase activity or displacing T4 from transthyretin. Thus, flavonoids have been shown to interfere with many aspects of the thyroid hormones synthesis and availability in in vivo and in vitro models. In the present article, we review and synthesize the literature on the effects of flavonoids on thyroid and discuss the possible relevance of these effects for humans.

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.

The anabolic androgenic steroid nandrolone decanoate disrupts redox homeostasis in liver, heart and kidney of male Wistar rats.

The abuse of anabolic androgenic steroids (AAS) may cause side effects in several tissues. Oxidative stress is linked to the pathophysiology of most of these alterations, being involved in fibrosis, cellular proliferation, tumorigenesis, amongst others. Thus, the aim of this study was to determine the impact of supraphysiological doses of nandrolone decanoate (DECA) on the redox balance of liver, heart and kidney. Wistar male rats were treated with intramuscular injections of vehicle or DECA (1 mg.100 g−1 body weight) once a week for 8 weeks. The activity and mRNA levels of NADPH Oxidase (NOX), and the activity of catalase, glutathione peroxidase (GPx) and total superoxide dismutase (SOD), as well as the reduced thiol and carbonyl residue proteins, were measured in liver, heart and kidney. DECA treatment increased NOX activity in heart and liver, but NOX2 mRNA levels were only increased in heart. Liver catalase and SOD activities were decreased in the DECA-treated group, but only catalase activity was decreased in the kidney. No differences were detected in GPx activity. Thiol residues were decreased in the liver and kidney of treated animals in comparison to the control group, while carbonyl residues were increased in the kidney after the treatment. Taken together, our results show that chronically administered DECA is able to disrupt the cellular redox balance, leading to an oxidative stress state.

Sexual Dimorphism of Thyroid Reactive Oxygen Species Production Due to Higher NADPH Oxidase 4 Expression in Female Thyroid Glands

BACKGROUND Dual oxidases (DUOX1 and DUOX2) are NADPH oxidases (NOX) involved in hydrogen peroxide production necessary for thyroid hormonogenesis, but recently, the NOX4 has also been described in the thyroid gland. The prevalence of thyroid disease is higher in women, and the basis for this difference might involve a higher oxidative stress level in the female thyroid gland. Hence, we aimed at evaluating whether the function and the expression of enzymes involved in the thyroid redox balance differ between females and males. METHODS DUOX1, DUOX2, NOX4, glutathione peroxidase (GPx), and catalase activities and expression levels were evaluated in the thyroids of prepubertal and adult male and female rats. The mRNA levels of DUOXA1 and DUOXA2, the DUOX maturation factors, and of p22phox and Poldip2 (subunits of NOX4) were also determined. RESULTS A higher calcium-independent H(2)O(2) production was detected in the adult female rat thyroid, being higher in the estrous phase of the cycle. Moreover, the expression of NOX4 and Poldip2 mRNA was higher in the thyroids of adult female rats, as well as in PCCL3 cells treated with 17β-estradiol. The GPx1 mRNA expression was higher in adult female thyroids, while GPx2 and GPx3 mRNA and total GPx activity were not significantly different. Catalase mRNA expression and activity, together with thyroid thiol levels were significantly lower in the adult female rat thyroid. CONCLUSIONS Taken together, our results show that the thyroid gland of female rats is exposed to higher oxidative stress levels due both to increased reactive oxygen species (ROS) production through NOX4, and decreased ROS degradation.

The mTOR protein as a target in thyroid cancer.

Introduction: The mammalian target of rapamycin (mTOR) protein is a downstream effector of the phosphatidilinositol-3 kinase (PI3K)/Akt pathway, which regulates not only cell proliferation and viability, but also iodide uptake in thyroid cells. Genetic alterations in the PI3K/Akt/mTOR pathway are common during thyroid cancer progression, and thus, these proteins are attractive targets for cancer therapy. So far, specific mTOR inhibitors, such as rapamycin analogs, have been developed and studied as anti-cancer agents. Areas covered: This review discusses evidence that justifies the potential use of mTOR signaling pathway inhibitors as therapeutic agents for thyroid cancer. Expert opinion: In the near future, mTOR-targeted drugs might represent a new approach for the therapy of thyroid cancer patients; rapamycin analogs have already been developed and are currently being clinically tested. Besides the antiproliferative action of mTOR inhibition, the stimulatory effect on thyroid iodide uptake can also be useful in the treatment of recurrent thyroid cancer. Therefore, if rapamycin analogs are able to increase iodide uptake in thyroid cancer, either alone or in combination with other agents, this will represent a new approach for the treatment of thyroid cancer, which may possibly improve the treatment of patients in which radioiodine therapy is not effective.