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1.
Life Sci ; 245: 117385, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32014425

RESUMO

AIM: The influence of thyroid hormones on exocrine pancreas function is poorly understood, and limited to the postnatal development period. Here, we evaluated the effects of hypo- and hyperthyroidism on the morphology and enzyme content of this tissue. MAIN METHODS: To induce hypothyroidism male Wistar rats were subjected to a thyroidectomy (Tx) or sham operated (SO). After 40 days, some of the Tx and SO rats were treated with T3 for 7 days. Following euthanization, the pancreas was removed and evaluated for morphology, as well as amylase, lipase and trypsin content, using histological and immunoreactive techniques analyses, respectively. Serum amylase levels were also evaluated. KEY FINDINGS: The pancreatic acinar cells of Tx rats were smaller, exhibited reduced Haematoxyllin stained areas, and contained lower amylase and lipase levels, indicative of low cell activity. Tx rats also presented higher collagen levels, and high trypsin content in pancreatic extracts. Interestingly, T3 administration reversed the observed acinar cell alterations and restored pancreatic enzyme content, by augmenting amylase and lipase and attenuating trypsin levels, but failed to change collagen content. Increased levels of lipase and decreased trypsin were also observed in T3-treated SO rats. SIGNIFICANCE: Thyroid hormones play an important role in acinar cell morphology and function. In the hypothyroid state there is a decrease in pancreatic enzyme levels that is restored with T3 treatment. In addition to participating in insulin sensitivity and glycemic control, THs also modulate enzyme expression and activity in the exocrine pancreas, consequently, delivering metabolic substrates to specific organs and tissues.


Assuntos
Pâncreas Exócrino/patologia , Hormônios Tireóideos/fisiologia , Amilases/sangue , Animais , Western Blotting , Hipertireoidismo/complicações , Hipertireoidismo/patologia , Hipotireoidismo/complicações , Hipotireoidismo/patologia , Masculino , Pâncreas Exócrino/efeitos dos fármacos , Pâncreas Exócrino/fisiopatologia , Ratos , Ratos Wistar , Tireoidectomia , Tireotropina/sangue , Tri-Iodotironina/farmacologia
2.
Ulus Travma Acil Cerrahi Derg ; 25(6): 545-554, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31701499

RESUMO

BACKGROUND: Sepsis can be defined as a life-threatening organ dysfunction due to a dysregulated host response to infection. In sepsis, the coagulation cascade is activated and the balance shifts to the procoagulant side. Recently, the use of protein C is proposed for the treatment of sepsis. Another therapeutic agent that has been intensively studied is tri-iodothyronine. METHODS: This study aimed to compare the effects of activated protein C and tri-iodothyronine, which are administered at a single dose to sepsis-induced rats at the late phase. Leukocyte, platelet, hemoglobin and antithrombin-III concentrations and histopathological changes in the small intestine, liver and lung were evaluated at 24 hours. RESULTS: Single-dose intraperitoneal recombinant human APC (activated protein C) has a partial curative effect on hematological parameters in the late phase, while it is possible to state that it has significant therapeutic effects on hepatic and intestinal tissues, but more remarkably on the lung tissue. Tri-iodothyronine is also considered to be used for the treatment and has a strong potential to be a therapeutic agent. CONCLUSION: We observed that the T3 hormone has significantly limited and reduced the sepsis-related damage to hepatic and intestinal tissues, but especially the lung tissue. Tri-iodothyronine can be a good alternative to APC, which is partially allowed due to high cost and complication of bleeding in the treatment of sepsis.


Assuntos
Proteína C , Sepse , Tri-Iodotironina , Animais , Modelos Animais de Doenças , Hemoglobinas/análise , Intestinos/efeitos dos fármacos , Intestinos/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Proteína C/farmacologia , Proteína C/uso terapêutico , Ratos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Tri-Iodotironina/farmacologia , Tri-Iodotironina/uso terapêutico
3.
Artigo em Inglês | MEDLINE | ID: mdl-31181291

RESUMO

Thyroid hormones (THs) play an important role in early stages development of fish species. Manual elevation of THs in the embryos improves viability and hatching success. However, the impacts of endocrine disrupting chemicals on THs-treated embryos are unclear. This study investigated the effect of triiodothyronine (T3) to mitigate toxic effects of diazinon in the endangered Persian sturgeon (Acipenser persicus) eggs and embryos. Fertilized eggs were exposed to nominal concentrations of 0, 2, 4, 6, and 8 mg/L diazinon and the 96 h LC50 value was calculated at 3.5 mg/L. Eggs were then treated with exogenous T3 (1 ng/mL: LT3, and 10 ng/mL: HT3) and exposed to 3.5 mg/L diazinon (DLT3 and DHT3). Total THs concentrations, levels of cortisol, and expression of the igf-II gene were measured during embryogenesis. All the measured endpoints were significantly different between treatments or stages of incubation. Generally, despite insignificance in some cases, higher levels of T3 and Thyroxin (T4) were observed in T3-treated embryos regardless of the presence of diazinon. Cortisol was high in unfertilized eggs which reduced after fertilization. The igf-II gene up-regulated quickly after fertilization; was higher in T3-treated embryos. Exposure of eggs to diazinon reduced the levels of T3, T4, and igf-II gene expression, which corresponded to the lowest hatching. We concluded that exogenous T3 improves embryos development in A. persicus, which is a promising application for conservation strategies. Our study suggests that treating embryos with 10 ng/L T3 is a suitable way to overcome problems of incubation in diazinon-polluted water sources.


Assuntos
Diazinon/antagonistas & inibidores , Diazinon/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Peixes/embriologia , Tri-Iodotironina/farmacologia , Zigoto/efeitos dos fármacos , Animais , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário , Disruptores Endócrinos/toxicidade , Poluentes Químicos da Água/toxicidade , Zigoto/crescimento & desenvolvimento
4.
Fish Physiol Biochem ; 45(4): 1233-1244, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31115741

RESUMO

Flatfish pigmentation is a complex process, affected by environmental factors including light, nutrients, and hormones. Of those, the thyroid hormone has been reported to increase the albinism rate of Japanese flounder (Paralichthys olivaceus). However, the underlying mechanism remains unclear. In the present study, triiodothyronine (T3), thyroxine, and thiourea were introduced into P. olivaceus larvae from 16 to 57 days after hatching (DAH). By comparison of albinism rate, T3 treatment and control larvae of 42 DAH were chosen for mRNA and miRNA high-throughput sequencing analyses. A total of 337 miRNAs were identified via miRNA-seq, and 12 miRNAs exhibited significantly differential expression patterns in D42_T3 versus D42_Con (TPM > 10, fold change ≥ 1.5 or ≤ 0.67 and q ≤ 0.05). These differentially expressed miRNAs targeted 3658 putative genes, which further enriched to 10 GO terms (q < 0.05). RNA-seq identified 146 differentially expressed genes (DEGs) in D42_T3 versus D42_Con (|log2 fold change| > 1 and q < 0.005), including pigmentation-related genes such as the receptor tyrosine-protein kinase erbB-3, pro-opiomelanocortin A, and melanotransferrin, and the growth-related gene somatotropin. These DEGs were significantly enriched to 15 GO terms and 8 KEGG pathways (q < 0.05), which included several sugar metabolic pathways (glycolysis/gluconeogenesis and the pentose phosphate pathway). Integrated analysis revealed that 26 overlapping genes between DEGs and mRNAs were targeted by miRNAs. Furthermore, seven mRNA-miRNA pairs exhibited reversed regulation patterns. This provides important clues to understand the role of thyroid hormones in flatfish pigmentation.


Assuntos
Linguado/genética , Larva/efeitos dos fármacos , Tioureia/farmacologia , Tiroxina/farmacologia , Tri-Iodotironina/farmacologia , Animais , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Larva/genética , MicroRNAs/genética , Pigmentação/efeitos dos fármacos , RNA Mensageiro/genética
5.
Endocrinology ; 160(10): 2243-2256, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095291

RESUMO

Traumatic brain injury (TBI) is associated with disruption of cerebral blood flow leading to localized brain hypoxia. Thyroid hormone (TH) treatment, administered shortly after injury, has been shown to promote neural protection in rodent TBI models. The mechanism of TH protection, however, is not established. We used mouse primary cortical neurons to investigate the effectiveness and possible pathways of T3-promoted cell survival after exposure to hypoxic injury. Cultured primary cortical neurons were exposed to hypoxia (0.2% oxygen) for 7 hours with or without T3 (5 nM). T3 treatment enhanced DNA 5-hydroxymethylcytosine levels and attenuated the hypoxia-induced increase in DNA 5-methylcytosine (5-mc). In the presence of T3, mRNA expression of Tet family genes was increased and DNA methyltransferase (Dnmt) 3a and Dnmt3b were downregulated, compared with conditions in the absence of T3. These T3-induced changes decreased hypoxia-induced DNA de novo methylation, which reduced hypoxia-induced neuronal damage and apoptosis. We used RNA sequencing to characterize T3-regulated genes in cortical neurons under hypoxic conditions and identified 22 genes that were upregulated and 15 genes that were downregulated. Krüppel-like factor 9 (KLF9), a multifunctional transcription factor that plays a key role in central nervous system development, was highly upregulated by T3 treatment in hypoxic conditions. Knockdown of the KLF9 gene resulted in early apoptosis and abolished the beneficial role of T3 in neuronal survival. KLF9 mediates, in part, the neuronal protective role of T3. T3 treatment reduces hypoxic damage, although pathways that reduce DNA methylation and apoptosis remain to be elucidated.


Assuntos
Córtex Cerebral/citologia , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Oxigênio/farmacologia , Tri-Iodotironina/farmacologia , 5-Metilcitosina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Metilação de DNA , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transcriptoma
6.
Theriogenology ; 133: 1-9, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31051388

RESUMO

The experiment was designed to study the effects of Thyroid hormone (T3) on the proliferation and differentiation of newborn calf Sertoli cells (SCs) to provide a theoretical and practical basis for increased testicular semen production. In this experiment, the cck8 method was used to detect the effects of different concentrations of T3 on the proliferation rate of newborn calf SCs. qPCR and Western Blot methods were used to explore the effects of T3 on the proliferation and differentiation of calves SCs and whether T3 through Wnt/ß-catenin and PI3K/Akt pathways can regulate the proliferation and differentiation of SCs. We found that dosage (T3) and time correlated with proliferation inhibition of SC. T3 inhibited the proliferation of SC by down-regulating cyclinD1, upregulating p21Cip, p27Kip1, and other cell-cycle factors. By up-regulating AR and down-regulating KRT-18, T3 promoted the maturated differentiation of SC. T3 could not affect the expression of ß-catenin in SC of newborn calf, indicating that T3 may not regulate SCs proliferation through the Wnt pathway. T3 also negatively regulated the gene expression and protein levels of some genes in the PI3K/Akt signaling pathway. We concluded that T3 inhibited newborn calf SCs proliferation through the PI3K/Akt signaling pathway and possibly promoted their differentiation.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células de Sertoli/metabolismo , Tri-Iodotironina/farmacologia , Animais , Animais Recém-Nascidos/metabolismo , Bovinos , Células Cultivadas , Masculino , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células de Sertoli/citologia , Transdução de Sinais/efeitos dos fármacos , Tri-Iodotironina/metabolismo , Tri-Iodotironina/fisiologia
7.
Cell Physiol Biochem ; 52(2): 354-367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30816679

RESUMO

BACKGROUND/AIMS: Although a cross-talk between immune and endocrine systems has been well established, the precise pathways by which these signals co-regulate pro- and antiinflammatory responses on antigen-presenting cells remain poorly understood. In this work we investigated the mechanisms by which triiodothyronine (T3) controls T cell activity via dendritic cell (DC) modulation. METHODS: DCs from wild-type (WT) and IL-6-deficient mice were pulsed with T3. Cytokine production and programmed death protein ligands (PD-L) 1 and 2 expression were assayed by flow cytometry and ELISA. Interferon-regulatory factor-4 (IRF4) expression was evaluated by RT-qPCR and flow cytometry. The ability of DCs to stimulate allogenic splenocytes was assessed in a mixed lymphocyte reaction and the different profile markers were analyzed by flow cytometry and ELISA. For in vivo experiments, DCs treated with ovalbumin and T3 were injected into OTII mice. Proliferation, cytokine production, frequency of FoxP3+ regulatory T (Treg) cells and PD-1+ cells were determined by MTT assay, ELISA and flow cytometry, respectively. RESULTS: T3 endows DCs with pro-inflammatory potential capable of generating IL-17-dominant responses and down-modulating expression of PD-L1 and 2. T3-stimulated WT-DCs increased the proportion of IL-17-producing splenocytes, an effect which was eliminated when splenocytes were incubated with T3-treated DCs derived from IL-6-deficient mice. Enhanced IL-17 expression was recorded in both, CD4- and CD4+ populations and involved the IRF-4 pathway. Particularly, γδ-T cells but not natural killer (NK), NKT, B lymphocytes nor CD8+ T cells were the major source of IL-17-production from CD4- cells. Moreover, T3-conditioned DCs promoted a decrease of the FoxP3+ Treg population. Furthermore, T3 down-modulated PD-1 expression on CD4- cells thereby limiting inhibitory signals driven by this co-inhibitory pathway. Thus, T3 acts at the DC level to drive proinflammatory responses in vitro. Accordingly, we found that T3 induces IL-17 and IFNγ-dominant antigen-specific responses in vivo. CONCLUSION: These results emphasize the relevance of T3 as an additional immune-endocrine checkpoint and a novel therapeutic target to modulate IL-17-mediated pro-inflammatory responses.


Assuntos
Células Dendríticas/imunologia , Interleucina-17/imunologia , Transdução de Sinais/efeitos dos fármacos , Tri-Iodotironina/farmacologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Dendríticas/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Interleucina-17/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Camundongos , Camundongos Knockout , Proteína 2 Ligante de Morte Celular Programada 1/genética , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Transdução de Sinais/imunologia
8.
Lipids ; 54(2-3): 133-140, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30891787

RESUMO

Adipose tissue (AT), an endocrine organ that modulates several physiological functions by synthesizing and releasing adipokines such as adiponectin, is a metabolic target of triiodothyronine (T3). T3 and adiponectin play important roles in controlling normal metabolic functions such as stimulation of fatty acid oxidation and increase in thermogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway is important for the differentiation of preadipocytes into adipocytes and can be activated by T3 for the transcription of specific genes, such as adiponectin. We examined the role of PI3K in adiponectin modulation by T3 action in murine adipocytes (3T3-L1). The 3T3-L1 adipocytes were treated with 1000 nM T3 for 1 h in the presence or absence of 50 µM LY294002 (LY), a PI3K inhibitor. Then, we assessed the expression of adiponectin and the phosphorylated serine/threonine kinase Akt (pAkt), a PI3K signaling protein, in the adipocytes. Adiponectin and pAKT levels were higher in the T3-adipocyte cells, whereas in the LY group adiponectin was elevated and pAKT was decreased compared to the control (C). PI3K pathway inhibition for 1 h and posterior treatment with T3, in LY + T3, reduced the adiponectin level and increased pAKT levels compared to those in LY. T3 stimulated adiponectin levels by PI3K pathway activation and T3 can compensate alteration in the PI3K pathway, because with inhibition of the pathway it is able to maintain the basal levels of adiponectin and pAKT.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adiponectina/farmacologia , Cromonas/farmacologia , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tri-Iodotironina/farmacologia , Células 3T3-L1 , Animais , Diferenciação Celular/efeitos dos fármacos , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Arch Endocrinol Metab ; 63(2): 142-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30916164

RESUMO

OBJECTIVE: To verify the physiological action of triiodothyronine T3 on the expression of transforming growth factor α (TGFA) mRNA in MCF7 cells by inhibition of RNA Polymerase II and the MAPK/ERK pathway. MATERIALS AND METHODS: The cell line was treated with T3 at a physiological dose (10-9M) for 10 minutes, 1 and 4 hour (h) in the presence or absence of the inhibitors, α-amanitin (RNA polymerase II inhibitor) and PD98059 (MAPK/ERK pathway inhibitor). TGFA mRNA expression was analyzed by RT-PCR. For data analysis, we used ANOVA, complemented with the Tukey test and Student t-test, with a minimum significance of 5%. RESULTS: T3 increases the expression of TGFA mRNA in MCF7 cells in 4 h of treatment. Inhibition of RNA polymerase II modulates the effect of T3 treatment on the expression of TGFA in MCF7 cells. Activation of the MAPK/ERK pathway is not required for T3 to affect the expression of TGFA mRNA. CONCLUSION: Treatment with a physiological concentration of T3 after RNA polymerase II inhibition altered the expression of TGFA. Inhibition of the MAPK/ERK pathway after T3 treatment does not interfere with the TGFA gene expression in a breast adenocarcinoma cell line.


Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/genética , Sistema de Sinalização das MAP Quinases/genética , Fator de Crescimento Transformador alfa/genética , Tri-Iodotironina/genética , Adenocarcinoma/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral/metabolismo , Feminino , Humanos , Células MCF-7/metabolismo , Proto-Oncogenes/genética , RNA Mensageiro/genética , Fator de Crescimento Transformador alfa/efeitos dos fármacos , Fator de Crescimento Transformador alfa/metabolismo , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia
10.
Endocr J ; 66(5): 409-422, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30814442

RESUMO

Graves' Disease is a representative autoimmune thyroid disease that presents with hyperthyroidism. Emerging evidence has shown the involvement of lysophosphatidic acid (LPA) and its producing enzyme, autotaxin (ATX), in the pathogenesis of various diseases; among them, the involvement of the ATX/LPA axis in some immunological disturbances has been proposed. In this study, we investigated the association between serum ATX levels and Graves' disease. We measured the levels of serum total ATX and ATX isoforms (classical ATX and novel ATX) in patients with untreated Graves' disease, Graves' disease treated with anti-thyroid drugs, patients with subacute thyroiditis, silent thyroiditis, Plummer's disease, or Hashimoto's thyroiditis, and patients who had undergone a total thyroidectomy, as well as normal subjects. The serum total ATX and ATX isoform levels were higher in the patients with Graves' disease, compared with the levels in the healthy subjects and the patients with subacute thyroiditis. Treatment with anti-thyroid drugs significantly decreased the serum ATX levels. The serum ATX levels and the changes in serum ATX levels during treatment were moderately or strongly correlated with the serum concentrations or the changes in thyroid hormones. However, the administration of T3 or T4 did not increase the expression or serum levels of ATX in 3T3L1 adipocytes or wild-type mice. In conclusion, the serum ATX levels were higher in subjects with Graves' disease, possibly because of a mechanism that does not involve hyperthyroidism. These results suggest the possible involvement of the ATX/LPA axis in the pathogenesis of Graves' disease.


Assuntos
Antitireóideos/uso terapêutico , Doença de Graves/sangue , Diester Fosfórico Hidrolases/sangue , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Doença de Graves/tratamento farmacológico , Humanos , Camundongos , Diester Fosfórico Hidrolases/metabolismo , Tireoidite/sangue , Tireoidite/tratamento farmacológico , Tiroxina/farmacologia , Tri-Iodotironina/farmacologia
11.
Horm Behav ; 110: 90-97, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30826308

RESUMO

Seasonal changes in day length enhance and suppress immune function in a trait-specific manner. In Siberian hamsters (Phodopus sungorus) winter-like short days (SDs) increase blood leukocyte concentrations and adaptive T cell dependent immune responses, but attenuate innate inflammatory responses to simulated infections. Thyroid hormone (TH) signaling also changes seasonally and has been implicated in modulation of the reproductive axis by day length. Immunologically, TH administration in long days (LD) enhances adaptive immune responses in male Siberian hamsters, mimicking effects of SDs. This experiment tested the hypothesis that T3 is also sufficient to mimic the effects of SD on innate immune responses. Adult male hamsters housed in LDs were pretreated with triiodothyronine (T3; 1 µg, s.c.) or saline (VEH) daily for 6 weeks; additional positive controls were housed in SD and received VEH, after which cytokine, behavioral, and physiological responses to simulated bacterial infection (lipopolysaccharide; LPS) were evaluated. SD pretreatment inhibited proinflammatory cytokine mRNA expression (i.e. interleukin 1ß, nuclear factor kappa-light-chain-enhancer of activated B cells). In addition, the magnitude and persistence of anorexic and cachectic responses to LPS were also lower in SD hamsters, and LPS-induced inhibition of nest building behavior was absent in SD. T3 treatments failed to affect behavioral (food intake, nest building) or somatic (body mass) responses to LPS in LD hamsters, but one CNS cytokine response to LPS (e.g., hypothalamic TNFα) was augmented by T3. Together these data implicate thyroid hormone signaling in select aspects of innate immune responses to seasonal changes in day length.


Assuntos
Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Phodopus , Síndrome de Resposta Inflamatória Sistêmica/patologia , Tri-Iodotironina/farmacologia , Animais , Anorexia/induzido quimicamente , Anorexia/metabolismo , Anorexia/patologia , Peso Corporal/fisiologia , Cricetinae , Modelos Animais de Doenças , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Comportamento de Doença/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , /metabolismo , Lipopolissacarídeos , Masculino , Phodopus/metabolismo , Fotoperíodo , Reprodução/efeitos dos fármacos , Estações do Ano , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia
12.
Ecotoxicol Environ Saf ; 174: 353-362, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30849655

RESUMO

The liver is one of the major targets of hormones, including thyroid hormones (THs), and many industrial chemicals, such as endocrine-disrupting chemicals. Those compounds may permeate the placenta barrier and pose a risk for embryonic development. Therefore, it is necessary to assess the toxic effects of those kind of industrial chemicals during liver development. In this study, to mimic liver specification in vitro, we differentiated human embryonic stem cells (ESCs) into functional hepatocyte-like cells. We performed this differentiation process in presence of two THs, triiodothyronine (T3) and thyroxine (T4), with the purpose of identifying biomarkers for toxicity screening. TH exposure (3, 30 and 300 nM) yielded to hepatocytes with impaired glycogen storage ability and abnormal lipid droplets' accumulation. Global gene expression analysis by RNA-seq identified a number of genes responsible for hepatic differentiation and function which were affected by 30 nM T3 and T4. Those differentially expressed genes were used to assess the potential developmental liver toxicity of two famous environmental pollutants, 2, 2, 4, 4-tetrabromodiphenyl ether (BDE-47) and decabromodiphenyl ether (BDE-209), at 10 nM to 1 µM treatments. Our findings demonstrate that BDE-47 and BDE-209, dysregulated pathways such as "chemical carcinogenesis", "steroid hormone biosynthesis" and "drug metabolism-cytochrome P450". Moreover, we were able to identify a set of 17 biomarkers, very useful to predict the potential developmental hepatotoxicity of industrial chemicals.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Hepatócitos/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Modelos Biológicos , Animais , Diferenciação Celular/genética , Doença Hepática Induzida por Substâncias e Drogas/embriologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Relação Dose-Resposta a Droga , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Feminino , Éteres Difenil Halogenados/toxicidade , Humanos , Gravidez , Tiroxina/farmacologia , Transcriptoma/efeitos dos fármacos , Tri-Iodotironina/farmacologia
13.
AAPS PharmSciTech ; 20(3): 110, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30756201

RESUMO

Angiogenesis is a vital component of the orchestrated wound healing cascade and tissue regeneration process, which has a therapeutic prominence in treatment of ischemic vascular diseases and certain cardiac conditions. Based on its eminence, several strategies using growth factors have been studied to initiate angiogenesis. However, growth factors are expensive and have short half-life. In this work, sustained release of triiodothyronine, which plays a crucial role in stimulating growth factors and other signaling pathways that are instrumental in initiating angiogenesis, has been attempted through electrospun polycaprolactone nanofibers. This delivery system enabled the slow and sustained delivery of triiodothyronine into the micro-environment, reducing seepage of excess into systemic circulation and eliminating the necessity of repeated dosage forms. It was observed that triiodothyronine-incorporated nanofibers exhibited favorable interaction with cells (phalloidin staining of actin filaments) and also enhanced the rate of endothelial proliferation, migration, and adhesion. The angiogenic potential of these nanofibers was further corroborated through chorioallantoic membrane and rat aortic ring assay (demonstrating cell sprouting area of 3.3 ± 0.71 mm2 compared to 1.2 ± 0.01 mm2 in control). The nanofiber matrix thus fabricated demonstrated a vibrant therapeutic potential to induce angiogenesis. Triiodothyronine also plays a significant role in wound healing independent of initiating angiogenesis. This further substantiates the positive impact of this delivery system as a dressing material for chronic wound therapeutics, ischemic vascular diseases, and certain cardiac conditions.


Assuntos
Portadores de Fármacos , Nanofibras , Neovascularização Fisiológica/efeitos dos fármacos , Tri-Iodotironina/administração & dosagem , Animais , Bandagens , Materiais Biocompatíveis/administração & dosagem , Células Endoteliais da Veia Umbilical Humana , Humanos , Poliésteres/administração & dosagem , Ratos , Tri-Iodotironina/farmacologia , Cicatrização/efeitos dos fármacos
14.
Biochim Biophys Acta Biomembr ; 1861(4): 748-759, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30639285

RESUMO

The functions of Sertoli cells, which structurally and functionally support ongoing spermatogenesis, are effectively modulated by thyroid hormones, amongst other molecules. We investigated the mechanism of action of rT3 on calcium (45Ca2+) uptake in Sertoli cells by means of in vitro acute incubation. In addition, we performed electrophysiological recordings of potassium efflux in order to understand the cell repolarization, coupled to the calcium uptake triggered by rT3. Our results indicate that rT3 induces nongenomic responses, as a rapid activation of whole-cell potassium currents in response to rT3 occurred in <5 min in Sertoli cells. In addition, the rT3 metabolite, T2, also exerted a rapid effect on calcium uptake in immature rat testis and in Sertoli cells. rT3 also modulated calcium uptake, which occurred within seconds via the action of selective ionic channels and the Na+/K+ ATPase pump. The rapid response of rT3 is essentially triggered by calcium uptake and cell repolarization, which appear to mediate the secretory functions of Sertoli cells.


Assuntos
Cálcio/metabolismo , Membrana Celular/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Tri-Iodotironina/farmacologia , Animais , Masculino , Ratos , Ratos Wistar , Células de Sertoli
15.
Cell Tissue Res ; 377(1): 107-113, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30627806

RESUMO

Major depressive disorder is a severe, disabling disorder that affects around 4.7% of the population worldwide. Based on the monoaminergic hypothesis of depression, monoamine reuptake inhibitors have been developed as antidepressants and nowadays, they are used widely in clinical practice. However, these drugs have a limited efficacy and a slow onset of therapeutic action. Several strategies have been implemented to overcome these limitations, including switching to other drugs or introducing combined or augmentation therapies. In clinical practice, the most often used augmenting drugs are lithium, triiodothyronine, atypical antipsychotics, buspirone, and pindolol, although some others are in the pipeline. Moreover, multitarget antidepressants have been developed to improve efficacy. Despite the enormous effort exerted to improve these monoaminergic drugs, they still fail to produce a rapid and sustained antidepressant response in a substantial proportion of depressed patients. Recently, new compounds that target other neurotransmission system, such as the glutamatergic system, have become the focus of research into fast-acting antidepressant agents. These promising alternatives could represent a new pharmacological trend in the management of depression.


Assuntos
Antidepressivos/farmacologia , Monoaminas Biogênicas/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Fármacos atuantes sobre Aminoácidos Excitatórios/farmacologia , Antipsicóticos/farmacologia , Buspirona/farmacologia , Sinergismo Farmacológico , Humanos , Lítio/farmacologia , Pindolol/farmacologia , Tri-Iodotironina/farmacologia
16.
J Endocrinol Invest ; 42(3): 271-282, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29934772

RESUMO

PURPOSE: Thyroid disorders are clinically associated with impaired fertility in women, and these abnormalities can be improved by restoring the euthyroid state. The exact mechanisms of thyroid effect on female fertility are not well known; however, it is conceivable that thyroid hormones (THs) might act on ovarian physiology via receptors in granulosa cells. This work is aimed at evaluating the effects of THs on non-tumoral granulosa cells and follicles. METHODS: Freshly isolated rat ovarian follicles and granulosa cells were exposed to T3 or T4 (THs). Cell growth and viability were evaluated by cell counting and the MTT assay, respectively, follicle growth was evaluated by volume measurements. Apoptosis was evaluated by the TUNEL assay and active Caspase 3 staining. rGROV cells were exposed to T3, and apoptosis was induced by serum deprivation. Bcl2, Bcl-2-associated X protein (BAX), Akt and pAkt expression were evaluated by western blot. RESULTS: T3 induced a 40% increase in follicle volume (after 7 days). This increase was presumably due to the observed decrease (33%) in the apoptotic rate of the granulosa cell population. Both T3 and T4 caused a dose-dependent increase in rat granulosa cell number and viability. In addition, THs decreased the cell apoptotic rate in a dose-dependent manner. In both conditions, T3 appeared to be more efficient. In rGROV cells, 100 nM T3 induced cell growth and, in the absence of growth factors, reduced cell apoptosis by 40%, downregulating Caspase 3 and BAX. This effect was associated with an increase in pAkt levels. The involvement of the PI3 K pathway was confirmed by the ability of the PI3 K specific inhibitor (LY-294,002) to abolish T3 pro-survival action. CONCLUSIONS: THs influence cell survival of ovarian granulosa cells. This effect likely contributes to the TH-induced follicle volume increase.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células da Granulosa/citologia , Mitógenos/farmacologia , Folículo Ovariano/citologia , Tiroxina/farmacologia , Tri-Iodotironina/farmacologia , Animais , Apoptose , Células Cultivadas , Feminino , Células da Granulosa/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Ratos , Ratos Wistar
17.
FASEB J ; 33(1): 738-749, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020829

RESUMO

Secretory phospholipase A2 group IIA (PLA2G2A) is a phospholipase which has a role in inflammation, atherogenesis, and host defense. Previously, we found that PLA2G2A protects mice on high-fat diets from weight gain and insulin resistance. Here, we examined the regulation of PLA2G2A and the metabolic changes that occur in response to variations in thyroid status. In particular, the impact of PLA2G2A on the brown adipose tissue (BAT) thermogenic gene expression was explored. We induced hypothyroidism in C57BL/6 and PLA2G2A-overexpressing (IIA+) mice over a 10 wk period or treated them with thyroid hormone (T3) for 5 wk. There were no significant changes in PLA2G2A abundance in response to thyroid status. The energy expenditure of hypothyroid IIA+ mice did not increase; however, the energy expenditure, substrate utilization, insulin sensitivity, and glucose tolerance were all elevated in the IIA+ mice given T3. Moreover, white adipocytes from IIA+ mice were much more prone to "beiging," including increased expression of brown adipose thermogenic markers such as uncoupling protein 1 (UCP1), PR domain containing 16, and early B cell factor 2. Finally, the BAT of IIA+ mice had increased UCP1 and other proteins indicative of mitochondrial uncoupling and nonshivering adaptive thermogenesis. These data reveal a novel role for PLA2G2A on adipose tissue thermogenesis depending on thyroid status.-Kuefner, M. S., Deng, X., Stephenson, E. J., Pham, K., Park, E. A. Secretory phospholipase A2 group IIA enhances the metabolic rate and increases glucose utilization in response to thyroid hormone.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Fosfolipases A2 do Grupo II/metabolismo , Hipotireoidismo/tratamento farmacológico , Tri-Iodotironina/farmacologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Fosfolipases A2 do Grupo II/genética , Hipotireoidismo/metabolismo , Hipotireoidismo/patologia , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Termogênese
18.
Gen Comp Endocrinol ; 271: 91-96, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472386

RESUMO

Amphibian metamorphosis has long been used as model to study postembryonic development in vertebrates, a period around birth in mammals when many organs/tissues mature into their adult forms and is characterized by peak levels of plasma thyroid hormone (T3). Of particular interest is the remodeling of the intestine during metamorphosis. In the highly-related anurans Xenopus laevis and Xenopus tropicalis, this remodeling process involves larval epithelial cell death and de novo formation of adult stem cells via dedifferentiation of some larval cells under the induction of T3, making it a valuable system to investigate how adult organ-specific stem cells are formed during vertebrate development. Here, we will review some studies by us and others on how T3 regulates the formation of the intestinal stem cells during metamorphosis. We will highlight the involvement of nucleosome removal and a positive feedback mechanism involving the histone methyltransferases in gene regulation by T3 receptor (TR) during this process.


Assuntos
Células-Tronco Adultas/metabolismo , Epigênese Genética/efeitos dos fármacos , Intestinos/citologia , Metamorfose Biológica/genética , Tri-Iodotironina/farmacologia , Xenopus laevis/crescimento & desenvolvimento , Xenopus laevis/genética , Células-Tronco Adultas/citologia , Células-Tronco Adultas/efeitos dos fármacos , Animais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Retroalimentação Fisiológica/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Larva/metabolismo , Metamorfose Biológica/efeitos dos fármacos , Modelos Biológicos , Receptores dos Hormônios Tireóideos/metabolismo , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismo
19.
Mol Cell Endocrinol ; 482: 28-36, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30543877

RESUMO

Cystatin C (CysC) is a marker for estimation of glomerular filtration rate (GFR). CysC levels may depend not only on clearance/GFR but possibly also on changes in production. Our studies on tissue distribution of CysC protein in mice showed that adipose tissue expresses significant amounts of CysC, suggesting that adipocytes could contribute to circulating CysC levels in vivo. As growth hormone (GH) and triiodothyronine (T3) increase both GFR and CysC (increased in acromegaly and hyperthyroidism) in vivo, we studied whether they could increase CysC production in 3T3-L1 adipocytes in vitro. CysC accumulated in culture media of 3T3-L1 adipocytes in a time-dependent fashion. GH and T3 both (10 nmol/l) increased accumulation of CysC, to 373 ±â€¯14 and 422 ±â€¯20, respectively, vs 298 ±â€¯10 ng per well over 4 days in controls. Thus, GH and T3 enhance the production of CysC by adipocytes in vitro.


Assuntos
Tecido Adiposo/metabolismo , Cistatina C/metabolismo , Hormônio do Crescimento/farmacologia , Tri-Iodotironina/farmacologia , Células 3T3-L1 , Tecido Adiposo/efeitos dos fármacos , Animais , Cistatina C/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Camundongos , Fatores de Tempo
20.
Pathol Oncol Res ; 25(2): 653-658, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30406874

RESUMO

Breast cancer (BC) severely threatens women's life, and Triiodothyronine (T3) shows a positive role on BC cell proliferation, while the potential mechanism underlying it is still unclear. T3 was used to stimulate BC cell lines MCF-7 and T47-D. Real-time PCR was performed to determine the expression of miRNAs, while western blot was used to measure protein expression of Amphiregulin (AREG), AKT and p-AKT. The interaction between miR-204 and AREG was determined using luciferase reporter assay. MTT was performed to detect cell viability. The expression of miR-204 was decreased, while AREG and p-AKT was increased in T3 stimulated BC cell lines. T3 stimulation promoted cell viability. miR-204 targets AREG to regulate its expression. T3 promoted expression of AREG and p-AKT, while miR-204 overexpression reversed the effect of T3, however, pcDNA-AREG transfection abolished the effect of miR-204 mimic. T3 promoted cell viability of BC cells via modulating the AKT signaling pathway. The detailed mechanism was that the down-regulated miR-204 that induced by T3 stimulation promoted the expression of AREG, the up-regulated AREG activated AKT signaling pathway, while the activated AKT signaling promoted cell proliferation.


Assuntos
Anfirregulina/biossíntese , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/biossíntese , Tri-Iodotironina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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