Andrea Ferreira | Universidade Federal do Rio de Janeiro (UFRJ) (original) (raw)

Papers by Andrea Ferreira

PLoS One., 2019

Inflammation and oxidative stress are linked to type 2 diabetes mellitus (T2DM). In this work, we... more Inflammation and oxidative stress are linked to type 2 diabetes mellitus (T2DM). In this work, we analyzed patients' blood markers of antioxidant capacity, oxidative stress and inflammation in individuals with T2DM, in pre-diabetes state (pre-DM) and controls without diabetes. Patients were divided into three groups, according to glycated hemoglobin A1c (HbA1c): <7%, 7-9%, and >9%. Superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities, total thiols, nitric oxide (•NO), tumor necrosis factor alpha (TNF-α) and intercellular adhesion molecule 1 (ICAM-1) levels of the individuals were measured. Plasma SOD activity was higher in T2DM subjects compared to the controls. While total thiols levels were lower in T2DM groups when compared to pre-DM, the values remained unchanged when compared to controls. ICAM-1 levels of T2DM groups were lower than in controls, while GPx activity, •NO, and TNF-α levels were similar among all groups. A positive correlation was found between SOD and HbA1c levels. Concluding, individuals with T2DM present altered SOD activity, total thiols, and ICAM-1 levels, which might contribute to further complications. There is a positive correlation between SOD activity and HbA1c levels. No apparent correlation exists between total thiols and ICAM-1 levels and with any other of the parameters evaluated in this study.

Horm Metab Res., 2019

Plastics are ubiquitously present in our daily life and some components of plastics are endocrine... more Plastics are ubiquitously present in our daily life and some components of plastics are endocrine-disrupting chemicals, such as bisphenol A and phthalates. Herein, we aimed to evaluate the effect of plastic endocrine disruptors on type 1 and type 2 deiodinase activities, enzymes responsible for the conversion of the pro-hormone T4 into the biologically active thyroid hormone T3, both in vitro and in vivo. Initially, we incubated rat liver type 1 deiodinase and brown adipose tissue type 2 deiodinase samples with 0.5 mM of the plasticizers, and the deiodinase activity was measured. Among them, only BPA was capable to inhibit both type 1 and type 2 deiodinases. Then, adult male Wistar rats were treated orally with bisphenol A (40 mg/kg b.w.) for 15 days and hepatic type 1 deiodinase and brown adipose tissue type 2 deiodinase activities and serum thyroid hormone concentrations were measured. In vivo bisphenol A treatment significantly reduced hepatic type 1 deiodinase activity but did not affect brown adipose tissue type 2 deiodinase activity. Serum T4 levels were higher in bisphenol A group, while T3 remained unchanged. T3/T4 ratio was decreased in rats treated with bisphenol A, reinforcing the idea that peripheral metabolism of thyroid hormone was affected by bisphenol A exposure. Therefore, our results suggest that bisphenol A can affect the metabolism of thyroid hormone thus disrupting thyroid signaling.

Thyroid., 2018

BACKGROUND: Thyroid iodide uptake, mediated by the sodium-iodide symporter (NIS), is essential fo... more BACKGROUND:
Thyroid iodide uptake, mediated by the sodium-iodide symporter (NIS), is essential for thyroid hormone synthesis and also for treatment of thyroid diseases, such as thyroid cancer, through radioiodine therapy. Therefore, compounds able to increase thyroid iodide uptake could be clinically useful, and it is of great importance to unravel the mechanisms underlying such an effect. It has been shown previously that the flavonoid rutin increases thyroid radioiodide uptake in vivo in rats. This study aimed to investigate the mechanisms involved in the stimulatory effect of rutin on iodide uptake.

METHODS:
This study evaluated iodide uptake, NIS expression and its subcellular distribution, iodide efflux, reactive oxygen species levels, and the intracellular pathways involved in NIS regulation in a rat thyroid PCCL3 cell line treated with rutin.

RESULTS:
Similar to previous results found in vivo, rutin increased radioiodide uptake in PCCL3 cells, which was accompanied by increased NIS expression (at both the mRNA and protein levels) and a reduction of radioiodide efflux. Moreover, the results suggest that rutin could regulate NIS subcellular distribution, leading to higher levels of NIS at the cell membrane. In addition, rutin decreased the levels of intracellular reactive oxygen species and phospho-5'-adenosine monophosphate-activated protein kinase.

CONCLUSIONS:
The flavonoid rutin seems to be an important stimulator of radioiodide uptake, acting at multiple levels, an effect that can be due to decreased oxidative stress, reduced 5'-adenosine monophosphate-activated protein kinase activation, or both. Since thyroid iodide uptake is crucial for effective radioiodine therapy, the results suggest that rutin could be useful as an adjuvant in radioiodine therapy.

Clin Exp Pharmacol Physiol., 2018

Na+ /I- symporter (NIS) transports iodide into thyrocytes, a fundamental step for thyroid hormone... more 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 TGFβ has been shown to mediate some effects of I-X, we evaluated TGFβ and TGFβ receptor mRNA levels, which were increased in R1d-21d. Moreover, it has been demonstrated that TGFβ stimulates NOX4. Accordingly, our data revealed increased NOX4 expression and H2O2 generation in R1d-21d. Finally, we evaluated the effect of H2O2 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, TGFβ, NOX4 and increased ROS production.

Horm Metab Res., 2018

Cell therapy with mesenchymal stem cells (MSC) has been proposed for the treatment of diabetes me... more Cell therapy with mesenchymal stem cells (MSC) has been proposed for the treatment of diabetes mellitus (DM). It is known that the prevalence of thyroid disease is higher among diabetic patients than in general population. Therefore, our aim was to investigate the effect of the treatment with MSC on thyroid function and ROS generation in an experimental model of type 1 DM. Adult male Wistar rats were divided into the following groups: control, DM (80 mg/kg BW streptozotocin, iv.) and DM+MSC. MSC treatment occurred 4 weeks after DM induction and the animals were euthanized 4 weeks after MSC administration. We also evaluated the effect of co-culture with MSC or extracellular vesicles (EV) obtained from these cells on the rat thyroid cell line PCCL3 exposed to high glucose. Thyroid H2O2 generation was increased in DM, which was reversed by MSC treatment. These changes paralled a significant DuOx1 mRNA increase. The incubation of PCCL3 with high glucose increased extracellular H2O2 generation, which was reversed by both the co-culture with MSC and EV. Even though MSC treatment normalized thyroid ROS generation, serum thyroid hormone (TH) concentration remained low, along with increased serum TSH concentrations. Thyroperoxidase (TPO) activity, was reduced in DM, and MSC treatment did not normalize TPO. Therefore, we conclude that the treatment with MSC was able to reverse the increased thyroid H2O2 generation in diabetic animals and in PCCL3 cells exposed to high glucose, an effect probably mediated by EV produced by these cells, acting in a paracrine fashion.

BMC Cancer., 2018

BACKGROUND: NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. ... more 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.

Environ Pollut., 2018

Tributyltin is a biocide used in nautical paints, aiming to reduce fouling of barnacles in ships.... more Tributyltin is a biocide used in nautical paints, aiming to reduce fouling of barnacles in ships. Despite the fact that many effects of TBT on marine species are known, studies in mammals have been limited, especially those evaluating its effect on the function of the hypothalamus-pituitary-thyroid (HPT) axis. The aim of this study was to investigate the effects of subchronic exposure to TBT on the HPT axis in female rats. Female Wistar rats received vehicle, TBT 200 ng kg-1 BW d-1 or 1000 ng kg-1 BW d-1 orally by gavage for 40 d. Hypothalamus, pituitary, thyroid, liver and blood samples were collected. TBT200 and TBT1000 thyroids showed vacuolated follicular cells, with follicular hypertrophy and hyperplasia. An increase in epithelial height and a decrease in the thyroid follicle and colloid area were observed in TBT1000 rats. Moreover, an increase in the epithelium/colloid area ratio was observed in both TBT groups. Lower TRH mRNA expression was observed in the hypothalami of TBT200 and TBT1000 rats. An increase in Dio1 mRNA levels was observed in the hypothalamus and thyroid in TBT1000 rats only. TSH serum levels were increased in TBT200 rats. In TBT1000 rats, there was a decrease in total T4 serum levels compared to control rats, whereas T3 serum levels did not show significant alterations. We conclude that TBT exposure can promote critical abnormalities in the HPT axis, including changes in TRH mRNA expression and serum TSH and T4 levels, in addition to affecting thyroid morphology. These findings demonstrate that TBT disrupts the HPT axis. Additionally, the changes found in thyroid hormones suggest that TBT may interfere with the peripheral metabolism of these hormones, an idea corroborated by the observed changes in Dio1 mRNA levels. Therefore, TBT exposition might interfere not only with the thyroid axis but also with thyroid hormone metabolism.

Environ Sci Pollut Res Int., 2018

Bisphenol A (BPA) is a well-known endocrine disruptor with several effects on reproduction, devel... more Bisphenol A (BPA) is a well-known endocrine disruptor with several effects on reproduction, development, and cancer incidence, and it is highly used in the plastic industry. Bisphenol S (BPS) was proposed as an alternative to BPA since it has a similar structure and can be used to manufacture the same products. Some reports show that BPA interferes with thyroid function, but little is known about the involvement of BPS in thyroid function or how these molecules could possibly modulate at the same time the principal genes involved in thyroid physiology. Thus, the aims of this work were to evaluate in silico the possible interactions of BPA and BPS with the thyroid transcription factors Pax 8 and TTF1 and to study the actions in vivo of these compounds in zebrafish thyroid gene expression. Adult zebrafish treated with BPA or BPS showed that sodium iodide symporter, thyroglobulin, and thyroperoxidase genes were negatively or positively regulated, depending on the dose of the exposure. Human Pax 8 alignment with zebrafish Pax 8 and Rattus norvegicus TTF1 alignment with zebrafish TTF1 displayed highly conserved regions in the DNA binding sites. Molecular docking revealed the in silico interactions between the protein targets Pax 8 and TTF1 with BPA and BPS. Importance of some amino acids residues is highlighted and ratified by literature. There were no differences between the mean energy values for BPA docking in Pax 8 or TTF1. However, BPS energy values were lower in TTF1 docking compared to Pax 8 values. The number of amino acids on the protein interface was important for Pax 8 but not for TTF1. The main BPA interactions with proteins occurred through Van der Waals forces and pi-alkyl and alkyl interactions, while BPS interactions mainly occurred through carbon hydrogen bonds and conventional hydrogen bonds in addition to Van der Waals forces and pi-alkyl interactions. These data point to a possible interaction of BPA and BPS with Pax 8 and TTF1.

Endocr Connect., 2018

Bisphenol A (BPA) is the most common monomer in polycarbonate plastics and an endocrine disruptor... more 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.

Appl Physiol Nutr Metab., 2019

The development of obesity-related metabolic disorders is more evident in male in comparison with... more The development of obesity-related metabolic disorders is more evident in male in comparison with female subjects, but the mechanisms are unknown. Several studies have shown that oxidative stress is involved in the pathophysiology of obesity, but the majority of these studies were performed with male animals. The aim of this study was to evaluate the sex-related differences in subcutaneous adipose tissue redox homeostasis and inflammation of rats chronically fed a high-fat diet. NADPH oxidase (NOX), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase activities were evaluated in the subcutaneous adipose tissue (SC) of adult male and female rats fed either a standard chow (SCD) or a high-fat diet (HFD) for 11 weeks. NOX2 and NOX4 messenger RNA (mRNA) levels, total reduced thiols, interleukin (IL)-1β, tumor necrosis factor α (TNF-α), and IL-6 were also determined. Higher antioxidant enzyme activities and total reduced thiol levels were detected in SC of control male compared with female rats. Chronic HFD administration increased NOX activity and NOX2 and NOX4 mRNA levels and decreased SOD and GPx activities only in male animals. IL-1β, TNF-α, and IL-6 levels, as well as Adgre1, CD11b, and CD68 mRNA levels, were also higher in SC of males after HFD feeding. In SC of females, catalase activity was higher after HFD feeding. Taken together, our results show that redox homeostasis and inflammation of SC is sexually dimorphic. Furthermore, males show higher oxidative stress in SC after 11 weeks of HFD feeding owing to both increased reactive oxygen species (ROS) production through NOX2 and NOX4 and decreased ROS detoxification.

J Steroid Biochem Mol Biol., 2017

Chronic administration of anabolic androgenic steroids (AAS) in adult rats results in cardiac hyp... more Chronic administration of anabolic androgenic steroids (AAS) in adult rats results in cardiac hypertrophy and increased susceptibility to myocardial ischemia/reperfusion (IR) injury. Molecular analyses demonstrated that hyperactivation of type 1 angiotensin II (AT1) receptor mediates cardiac hypertrophy induced by AAS and also induces down-regulation of myocardial ATP-sensitive potassium channel (KATP), resulting in loss of exercise-induced cardioprotection. Exposure to AAS during adolescence promoted long-term cardiovascular dysfunctions, such as dysautonomia. We tested the hypothesis that chronic AAS exposure in the pre/pubertal phase increases the susceptibility to myocardial ischemia/reperfusion (IR) injury in adult rats. Male Wistar rats (26day old) were treated with vehicle (Control, n=12) or testosterone propionate (TP) (AAS, 5mgkg-1 n=12) 5 times/week during 5 weeks. At the end of AAS exposure, rats underwent 23days of washout period and were submitted to euthanasia. Langendorff-perfused hearts were submitted to IR injury and evaluated for mechanical dysfunctions and infarct size. Molecular analysis was performed by mRNA levels of α-myosin heavy chain (MHC), βMHC and brain-derived natriuretic peptide (BNP), ryanodine receptor (RyR2) and sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) by quantitative RT-PCR (qRT-PCR). The expression of AT1 receptor and KATP channel subunits (Kir6.1 and SURa) was analyzed by qRT-PCR and Western Blot. NADPH oxidase (Nox)-related reactive oxygen species generation was assessed by spectrofluorimetry. The expression of antioxidant enzymes was measured by qRT-PCR in order to address a potential role of redox unbalance. AAS exposure promoted long-term cardiac hypertrophy characterized by increased expression of βMHC and βMHC/αMHC ratio. Baseline derivative of pressure (dP/dt) was impaired by AAS exposure. Postischemic recovery of mechanical properties was impaired (decreased left ventricle [LV] developed pressure and maximal dP/dt; increased LV end-diastolic pressure and minimal dP/dt) and infarct size was larger in the AAS group. Catalase mRNA expression was significantly decreased in the AAS group. In conclusion, chronic administration of AAS during adolescence promoted long-term pathological cardiac hypertrophy and persistent increase in the susceptibility to myocardial IR injury possible due to disturbances on catalase expression.

Int J Mol Sci., 2017

Thyroid cancer is the most common malignant tumor of the endocrine system and the incidence has b... more 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.

Mol Cell Endocrinol., 2018

Endocrine disruptors (EDs), chemical substances widely used in industry and ubiquitously distribu... more Endocrine disruptors (EDs), chemical substances widely used in industry and ubiquitously distributed in the environment, are able to interfere with the synthesis, release, transport, metabolism, receptor binding, action, or elimination of endogenous hormones. EDs affect homeostasis mainly by acting on nuclear and nonnuclear steroid receptors but also on serotonin, dopamine, norepinephrine and orphan receptors in addition to thyroid hormone receptors. Tributyltin (TBT), an ED widely used as a pesticide and biocide in antifouling paints, has well-documented actions that include inhibiting aromatase and affecting the nuclear receptors PPARγ and RXR. TBT exposure in humans and experimental models has been shown to mainly affect reproductive function and adipocyte differentiation. Since thyroid hormones play a fundamental role in regulating the basal metabolic rate and energy homeostasis, it is crucial to clarify the effects of TBT on the hypothalamus-pituitary-thyroid axis. Therefore, we review herein the main effects of TBT on important metabolic pathways, with emphasis on disruption of the thyroid axis that could contribute to the development of endocrine and metabolic disorders, such as insulin resistance and obesity.

Endocr Connect., 2017

Mercury seems to exert an inhibitory effect on deiodinases, but there are few studies using Thime... more 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.

Life Sci., 2018

Breast cancer cells may exhibit changes in iron homeostasis, which results in increased labile ir... more Breast cancer cells may exhibit changes in iron homeostasis, which results in increased labile iron pool (LIP) levels. Several studies highlight the crucial role of high LIP levels in the maintenance of tumor cell physiology. Iron chelators have been tested in anticancer therapy in combination with chemotherapeutic agents, to improve drug efficacy. Thus, the aim of this study was to evaluate the effect of 2,2'-dipyridyl (DIP), a Fe2+ chelator, in combination with doxorubicin (DOX) in breast tumor cells. The maximum concentration of DIP that did not significantly reduce the viability of MDA-MB-231 cells was 10μM and for MCF-7 cells was 50μM. We observed that MCF-7 had higher LIP levels than MDA-MB-231 cells. DIP alone increased ROS generation in MCF-7 cells, and DIP pretreatment reduced ROS generation induced by DOX treatment. In conclusion, the increase in MCF-7 cell viability induced by DIP pretreatment in DOX-treated cells seems to be related to an increase in the cellular antioxidant capacity and the iron chelator did not improve drug efficacy in the two breast tumor cell lines analyzed.

J Physiol., 2016

KEY POINTS: In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome prol... more KEY POINTS:
In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a) expression that is crucial to skeletal muscle mitochondrial function. The expression of type 2 deiodinase (D2), which activates thyroid hormone in skeletal muscle is upregulated by acute treadmill exercise through a β-adrenergic receptor-dependent mechanism. Pharmacological block of D2 or disruption of the Dio2 gene in skeletal muscle fibres impaired acute exercise-induced PGC-1a expression. Dio2 disruption also impaired muscle PGC-1a expression and mitochondrial citrate synthase activity in chronically exercised mice.

ABSTRACT:
Thyroid hormone promotes expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a), which mediates mitochondrial biogenesis and oxidative capacity in skeletal muscle (SKM). Skeletal myocytes express the type 2 deiodinase (D2), which generates 3,5,3'-triiodothyronine (T3 ), the active thyroid hormone. To test whether D2-generated T3 plays a role in exercise-induced PGC-1a expression, male rats and mice with SKM-specific Dio2 inactivation (SKM-D2KO or MYF5-D2KO) were studied. An acute treadmill exercise session (20 min at 70-75% of maximal aerobic capacity) increased D2 expression/activity (1.5- to 2.7-fold) as well as PGC-1a mRNA levels (1.5- to 5-fold) in rat soleus muscle and white gastrocnemius muscle and in mouse soleus muscle, which was prevented by pretreatment with 1 mg (100 g body weight)(-1) propranolol or 6 mg (100 g body weight)(-1) iopanoic acid (5.9- vs. 2.8-fold; P < 0.05), which blocks D2 activity . In the SKM-D2KO mice, acute treadmill exercise failed to induce PGC-1a fully in soleus muscle (1.9- vs. 2.8-fold; P < 0.05), and in primary SKM-D2KO myocytes there was only a limited PGC-1a response to 1 μm forskolin (2.2- vs. 1.3-fold; P < 0.05). Chronic exercise training (6 weeks) increased soleus muscle PGC-1a mRNA levels (∼25%) and the mitochondrial enzyme citrate synthase (∼20%). In contrast, PGC-1a expression did not change and citrate synthase decreased by ∼30% in SKM-D2KO mice. The soleus muscle PGC-1a response to chronic exercise was also blunted in MYF5-D2KO mice. In conclusion, acute treadmill exercise increases SKM D2 expression through a β-adrenergic receptor-dependent mechanism. The accelerated conversion of T4 to T3 within myocytes mediates part of the PGC-1a induction by treadmill exercise and its downstream effects on mitochondrial function.

Life Sci., 2016

AIMS: Cancer cells produce higher amounts of reactive oxygen species (ROS) than their normal coun... more 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.

Horm Metab Res., 2015

Wolff-Chaikoff effect is characterized by the blockade of thyroid hormone synthesis and secretion... more Wolff-Chaikoff effect is characterized by the blockade of thyroid hormone synthesis and secretion due to iodine overload. However, the regulation of monocarboxylate transporter 8 during Wolff-Chaikoff effect and its possible role in the rapid reduction of T4 secretion by the thyroid gland remains unclear. Patients with monocarboxylate transporter 8 gene loss-of-function mutations and monocarboxylate transporter 8 knockout mice were shown to have decreased serum T4 levels, indicating that monocarboxylate transporter 8 could be involved in the secretion of thyroid hormones from the thyroid gland. Herein, we aimed to evaluate the regulation of monocarboxylate transporter 8 during the Wolff-Chaikoff effect and the escape from iodine overload, besides the importance of iodine organification for this regulation. Monocarboxylate transporter 8 mRNA and protein levels significantly decreased after 1 day of NaI administration to rats, together with decreased serum T4; while no alteration was observed in LAT2 expression. Moreover, both monocarboxylate transporter 8 expression and serum T4 was restored after 6 days of NaI. The inhibition of thyroperoxidase activity by methimazole prevented the inhibitory effect of NaI on thyroid monocarboxylate transporter 8 expression, suggesting that an active thyroperoxidase is necessary for MCT8 downregulation by iodine overload, similarly to other thyroid markers, such as sodium iodide symporter. Therefore, we conclude that thyroid monocarboxylate transporter 8 expression is downregulated during iodine overload and that the normalization of its expression parallels the escape phenomenon. These data suggest a possible role for monocarboxylate transporter 8 in the changes of thyroid hormones secretion during the Wolff-Chaikoff effect and escape.

Journal of Environment and Health Science, 2015

Tributyltin is an environmental contaminant found in antifouling paints, widely used in ships and... more Tributyltin is an environmental contaminant found in antifouling paints, widely used in ships and other vessels. TBT causes endocrine-disrupting effects in mammals, due to its possible transfer through marine food chains, and the consequent consumption of contaminated seafood. Thus, we aimed to evaluate whether the treatment with TBT could induce histophysiological changes in the thyroid gland. TBT promoted disorganization of parenchyma, fibrosis and vascular congestion in the gland. Moreover, morphometric analysis showed statistically significant changes in the follicle of rats treated with TBT, with increased colloid and epithelial area, besides increased epithelial/colloid area relation, but no statistical differences were found in epithelial height. Nevertheless, collagen deposition was seen in the thyroids of treated groups. In thyroid physiological status, we did not observe intergroup significant changes in plasma levels of total T3 and T4 after treatment, even though we have found a time-dependent increase of T4 levels in TBT-treated groups. We also detected an increased H2O2 production in the thyroid of TBT-treated group, besides increased dual oxidase protein levels, the main enzyme involved in hydrogen peroxide production. Since H2O2 is a reactive oxygen specie, TBT could induce oxidative stress, what could be involved in the morphophysiological changes observed in the gland. These data provided the evidence that exposure to TBT induces morphophysiological changes in the thyroid gland, and may therefore correspond to a potential risk factor for thyroid disorders.

PLoS One, 2014

The abuse of anabolic androgenic steroids (AAS) may cause side effects in several tissues. Oxidat... more 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.